Phase II Open-label, Multicentre, Randomized Trial of Neoadjuvant Palbociclib in Combination With Hormonal Therapy and HER2 Blockade Versus Paclitaxel in Combination With HER2 Blockade for Postmenopausal Patients With Hormone Receptor Positive/HER2 Positive Early Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer, Estrogen Receptor Positive Tumor, HER2-positive Breast Cancer
Sponsor: ETOP IBCSG Partners Foundation

IBCSG 55-17 TOUCH 
 
1-47 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Phase II open-label, multicenter, randomized trial of neoadjuvant 
palbociclib in combination with hormonal therapy and HER2 
blockade versus paclitaxel in combination with HER2 blockade for 
postmenopausal patients with hormone receptor positive/HER2 
positive early breast cancer 
To reduce the use of Chemotherapy in postmenopausal patients with 
ER-positive and HER2-positive breast cancer: the TOUCH trial 
EudraCT number: 
2017-005067-40 
Pfizer number: 
WI223904 
Roche number: 
MO40405 
Sponsor: 
International Breast Cancer Study Group 
(IBCSG) 
IBCSG Coordinating Center, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 511 94 00 
Fax: +41 31 511 94 01 
Amendment 2 
Protocol Version 2.1, 12 June 2020 
 
 
 
INTERNATIONAL BREAST CANCER 
STUDY GROUP 
IBCSG 55-17 
TOUCH 
 
 
 
 
 
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IBCSG 55-17 TOUCH 
 
2 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Trial Specific Contacts 
Trial Co-Chairs 
Laura Biganzoli, MD 
USL Toscana Centro, Hospital of 
Prato, Italy 
Email: laura.biganzoli@uslcentro.toscana.it 
Tel: +39 (0574) 802523 
Fax: +39 (0574) 802903 
Etienne Brain, MD, PhD  
Institut Curie, Paris, France 
Email: etienne.brain@curie.fr 
Tel: +33 1 47 11 18 75 
Fax: +33 1 47 11 16 64 
Trial Chair for translational 
research 
Luca Malorni, MD, PhD 
USL Toscana Centro, Hospital of 
Prato, Italy 
Email: lmalorni@uslcentro.toscana.it 
Tel: +39 (0574) 802520 
Trial Statisticians 
Meredith Regan, ScD 
Svitlana Tyekucheva, PhD 
IBCSG Statistical Center 
Email: mregan@jimmy.harvard.edu 
Email: svitlana@jimmy.harvard.edu 
Tel: +1 617-632-3012 
Fax: +1 617-632-5444 
Trial Data Manager Trial 
Coordinator 
Susan Fischer 
Meredith Kissel 
IBCSG Data Management Center 
Email: ibcsg55_touch@frontierscience.org 
Tel: +1 716-834-0900 (general) 
Fax: +1 716-833-3990 
Trial Monitoring 
 
TOUCH-Monitoring@ibcsg.org 
Translational Research Coordinator Rosita Kammler 
 
Email: rosita.kammler@ibcsg.org 
 
IBCSG Contacts 
Coordinating Center 
Anita Hiltbrunner 
Barbara Ruepp, PharmD 
Manuela Rabaglio, MD 
Heidi Roschitzki, PhD 
Linda Fritzsche 
IBCSG Coordinating Center 
Effingerstrasse 40 
CH-3008 Bern, Switzerland 
Email: anita.hiltbrunner@ibcsg.org  
Email: barbara.ruepp@ibcsg.org 
Email: manuela.rabaglio@ibcsg.org 
Email: heidi.roschitzki@ibcsg.org 
Email: drugsupply@ibcsg.org 
Tel: +41 31 511 94 00 
Fax: +41 31 511 94 01 
Data Management Center 
Lynette Blacher 
Karolyn Scott 
Holly Shaw 
Frontier Science 4033 Maple Rd. 
Amherst, NY 14226 USA 
Email: blacher@frontierscience.org 
Email: scott@frontierscience.org 
Email: hshaw@frontierscience.org 
Tel: +1 716 834-0900 
Fax: +1 716 833-3990 
Data Quality Control Office 
IBCSG Data Management Center 
Email: ib.dqc@frontierscience.org 
Center Training Office 
IBCSG Data Management Center 
Email: ibcsg.training@frontierscience.org 
Statistical Center 
Meredith M. Regan, ScD 
Div. of Biostatistics, CLSB 11007 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 USA 
Email: mregan@jimmy.harvard.edu 
Tel: +1 617-632-3012 
Fax: +1 617-632-5444 
Scientific Committee Co-Chairs 
Dr. Marco Colleoni  
European Institute of Oncology 
Milan, Italy 
Email: marco.colleoni@ieo.it 
 
Dr. Angelo Di Leo 
USL Toscana Centro, Hospital of 
Prato, Italy 
 
Email: angelo.dileo@uslcentro.toscana.it 
In collaboration with Pfizer Italy (supply of palbociclib and trial support) and Roche (supply 
of trastuzumab and pertuzumab). 
 
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IBCSG 55-17 TOUCH 
 
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Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Protocol Signature Page Amendment 2 
 
IBCSG 55-17 TOUCH 
Approved by: 
Group Statistician, International Breast Cancer Study Group 
Dr. M.M. Regan 
 
______________________________________________________________________________________________________________________ 
 
_______________________________________________ 
 
Date 
 
 
Approved by: 
Director, International Breast Cancer Study Group 
Anita Hiltbrunner 
 
______________________________________________________________________________________________________________________ 
 
_______________________________________________ 
 
Date 
 
 
Approved by: 
Trial Co-Chair;  
Dr. Laura Biganzoli, "Sandro Pitigliani" Medical Oncology Department, Hospital of Prato, Prato, 
Italy 
 
 
______________________________________________________________________________________________________________________ 
 
_______________________________________________ 
 
Date 
 
 
Approved by: 
Trial Co-Chair;  
Dr. Etienne Brain, Institut Curie, Paris, France 
 
______________________________________________________________________________________________________________________ 
 
_______________________________________________ 
 
Date 
 
 
Approved by: 
Trial Chair Translational Research;  
Dr. Luca Malorni, "Sandro Pitigliani" Medical Oncology Department, Hospital of Prato, Prato, Italy 
 
 
______________________________________________________________________________________________________________________ 
 
_______________________________________________ 
 
Date 
DocuSign Envelope ID: 19E1CCAE-970A-4D1B-87A3-481172E12D24
16.06.2020
18.06.2020
16.06.2020
16.06.2020
16.06.2020

IBCSG 55-17 TOUCH 
 
4 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Principal Investigator Protocol Signature Page Amendment 2 
 
IBCSG 55-17 
 
TOUCH 
 
I have read the protocol and agree that it contains all necessary details for conducting this trial. I will 
conduct the trial as outlined in the following protocol and in compliance with GCP, and will apply 
due diligence to avoid protocol deviations. I will provide copies of the protocol and all drug 
information relating to preclinical and prior clinical experience furnished to me by IBCSG, to all 
physicians responsible to me who participate in this trial. I will discuss this material with them 
to assure that they are fully informed regarding the drugs and the conduct of the trial. I agree to 
keep records on all patient information (Case Report Forms and patient's Informed Consent 
statement), drug-shipment and return forms, and all other information collected during the trial for a 
minimum period of 15 years. 
Name of Principal Investigator: ___________________________________________ 
___________________________________________________ 
______________ 
Signature 
Date 
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Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
TABLE OF CONTENTS  
Section 
Page 
1. 
Protocol Summary ................................................................................................. 8 
2. 
Trial schedule ...................................................................................................... 16 
2.1. 
Arm A (paclitaxel, trastuzumab, pertuzumab) .................................................... 16 
2.2. 
Arm B (palbociclib, letrozole, trastuzumab, pertuzumab) .................................. 18 
3. 
List of abbreviations ............................................................................................ 20 
4. 
Background and scientific rationale .................................................................... 22 
4.1. 
Introduction .......................................................................................................... 22 
4.2. 
Neoadjuvant treatment in HR+ and HER2+ BC ................................................. 22 
4.3. 
Endocrine treatment ............................................................................................. 23 
4.4. 
Chemotherapy ...................................................................................................... 24 
4.5. 
Anti-HER2 treatment ........................................................................................... 25 
4.6. 
CDK inhibition .................................................................................................... 27 
4.7. 
Palbociclib ........................................................................................................... 28 
4.8. 
Elderly patients .................................................................................................... 31 
4.9. 
Biomarkers for CDK4/6 inhibitor activity ........................................................... 32 
4.10. 
Trial hypothesis ................................................................................................... 34 
4.11. 
Overall risk-benefit assessment ........................................................................... 34 
4.12. 
Rationale for the trial design ................................................................................ 34 
5. 
Trial objectives and endpoints ............................................................................ 36 
5.1. 
Primary objective ................................................................................................. 36 
5.2. 
Primary endpoint ................................................................................................. 36 
5.3. 
Secondary objectives ........................................................................................... 37 
5.4. 
Correlative objectives .......................................................................................... 37 
6. 
Trial design, duration and termination ................................................................ 37 
6.1. 
Trial design .......................................................................................................... 37 
6.2. 
Trial schema ......................................................................................................... 38 
6.3. 
Treatment ............................................................................................................. 38 
6.4. 
Clinical evaluations ............................................................................................. 38 
6.5. 
Biological evaluations ......................................................................................... 39 
6.6. 
Sample size and trial duration .............................................................................. 39 
7. 
Patient selection .................................................................................................. 39 
7.1. 
Inclusion criteria .................................................................................................. 39 
7.2. 
Exclusion criteria ................................................................................................. 40 
8. 
Randomization and stratification ........................................................................ 42 
8.1. 
Randomization ..................................................................................................... 42 
8.2. 
Randomization Help Desk ................................................................................... 43 
8.3. 
Stratification ........................................................................................................ 43 
9. 
Trial drugs formulation and handling ................................................................. 43 
9.1. 
Palbociclib ........................................................................................................... 44 
9.2. 
Trastuzumab ........................................................................................................ 44 
9.3. 
Pertuzumab .......................................................................................................... 44 
9.4. 
Paclitaxel .............................................................................................................. 45 
9.5. 
Letrozole .............................................................................................................. 45 
10. 
Treatment ............................................................................................................ 45 
10.1. 
Trial treatments .................................................................................................... 45 
10.2. 
Treatment Administration .................................................................................... 45 
10.3. 
Dose delays and modifications for palbociclib .................................................... 46 
10.4. 
Dose modifications and delays for trastuzumab and pertuzumab ....................... 51 
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10.5. 
Dose modifications and delays for paclitaxel ...................................................... 52 
10.6. 
Dose modifications and delays for letrozole ....................................................... 53 
10.7. 
Concomitant therapy ............................................................................................ 54 
10.8. 
Stop of trial treatment .......................................................................................... 55 
10.9. 
Removal from the trial ......................................................................................... 55 
11. 
Safety ................................................................................................................... 56 
11.1. 
Adverse reactions to palbociclib .......................................................................... 56 
11.2. 
Adverse reactions to trastuzumab ........................................................................ 58 
11.3. 
Adverse reactions to pertuzumab ......................................................................... 59 
11.4. 
Adverse reactions to paclitaxel ............................................................................ 61 
11.5. 
Adverse reactions to letrozole ............................................................................. 63 
11.6. 
Potential drug induced liver injury ...................................................................... 64 
11.7. 
Drug-drug interactions ......................................................................................... 65 
12. 
Adverse event and serious adverse event reporting ............................................ 65 
12.1. 
Adverse event reporting ....................................................................................... 65 
12.2. 
Targeted adverse events ....................................................................................... 66 
12.3. 
Adverse events of special interest (AESIs) ......................................................... 67 
12.4. 
Otherwise reportable events ................................................................................ 67 
12.5. 
Serious adverse event (SAE) ............................................................................... 67 
12.6. 
Reporting SAEs ................................................................................................... 69 
12.7. 
Occupational exposure ......................................................................................... 70 
13. 
Disease assessment, response and progression ................................................... 70 
13.1. 
Tumor measurements ........................................................................................... 70 
13.2. 
Response criteria .................................................................................................. 70 
13.3. 
Best overall response ........................................................................................... 71 
13.4. 
Treatment in case of progression ......................................................................... 71 
13.5. 
Pathological complete response ........................................................................... 71 
14. 
Clinical and laboratory evaluations and follow-up ............................................. 71 
14.1. 
Screening ............................................................................................................. 71 
14.2. 
During treatment .................................................................................................. 73 
14.3. 
Tumor assessments .............................................................................................. 73 
14.4. 
Before surgery ..................................................................................................... 74 
14.5. 
After surgery ........................................................................................................ 74 
15. 
Biological evaluations ......................................................................................... 75 
15.1. 
Tumor tissue ........................................................................................................ 75 
15.2. 
Submitting pathology material to IBCSG............................................................ 75 
15.3. 
Translational research .......................................................................................... 75 
16. 
Data submission .................................................................................................. 76 
16.1. 
Case report forms schedule .................................................................................. 77 
16.2. 
Signing and submitting forms .............................................................................. 78 
16.3. 
Data management ................................................................................................ 78 
16.4. 
Investigator Site File ............................................................................................ 79 
16.5. 
Authorization log ................................................................................................. 80 
16.6. 
Patient identification log ...................................................................................... 80 
17. 
Statistical considerations ..................................................................................... 81 
17.1. 
Design .................................................................................................................. 81 
17.2. 
Sample size determination ................................................................................... 81 
17.3. 
Definitions of Trial Populations .......................................................................... 82 
17.4. 
Primary Objective ................................................................................................ 82 
17.5. 
Secondary Objectives .......................................................................................... 83 
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17.6. 
Interim Analyses .................................................................................................. 83 
17.7. 
Accrual ................................................................................................................. 83 
17.8. 
Data and Safety Monitoring ................................................................................. 84 
17.9. 
Correlative Objectives ......................................................................................... 84 
18. 
Criteria for termination of the trial ...................................................................... 84 
18.1. 
General criteria for termination of the trial .......................................................... 84 
18.2. 
Patient-specific criteria for termination and withdrawal ..................................... 84 
19. 
Ethical aspects, regulatory approval, and patient informed consent ................... 85 
19.1. 
Ethical Review Board/Ethics Committee ............................................................ 85 
19.2. 
Regulatory approval procedures .......................................................................... 85 
19.3. 
Protection of human patients ............................................................................... 86 
19.4. 
Informed Consent ................................................................................................ 86 
20. 
Governance and Administrative Considerations ................................................. 87 
20.1. 
Final report ........................................................................................................... 87 
20.2. 
Clinical trial insurance ......................................................................................... 87 
20.3. 
Steering Committee ............................................................................................. 87 
20.4. 
Data and Safety Monitoring Committee (DSMC) ............................................... 87 
20.5. 
Publication of trial results .................................................................................... 87 
20.6. 
Premature discontinuation of the trial.................................................................. 87 
20.7. 
Quality Assurance ................................................................................................ 88 
20.8. 
Protocol adherence ............................................................................................... 88 
20.9. 
Data protection ..................................................................................................... 88 
20.10. Record Retention ................................................................................................. 89 
21. 
Confidentiality..................................................................................................... 89 
22. 
References ........................................................................................................... 89 
Appendices  
1. 
Patient Information Sheet and Informed Consent Form 
Index of Tables 
Table 1. 
ECOG Performance Status .................................................................................. 41 
Table 2. 
NYHA functional classification .......................................................................... 42 
Table 3. 
Available dose levels for palbociclib .................................................................. 49 
Table 4. 
Palbociclib dose modification and management ................................................. 49 
Table 5. 
Actions to be taken in case of trastuzumab and/or pertuzumab (anti-HER2 therapy) 
related adverse events ......................................................................................... 51 
Table 6. 
Actions to be taken in case of paclitaxel related adverse events ......................... 53 
Table 7. 
Adverse reactions to palbociclib based on pooled dataset from 3 randomized studies 
(N=872) ............................................................................................................... 56 
Table 8. 
Undesirable effects reported with intravenous trastuzumab monotherapy or in 
combination with chemotherapy in pivotal clinical trials (N = 8386) and in post-
marketing ............................................................................................................. 58 
Table 9. 
Summary of ADRs in patients treated with pertuzumab in the metastatic and 
neoadjuvant setting .............................................................................................. 60 
Table 10. Summary of ADRs in patients treated with paclitaxel in the metastatic and post 
marketing surveillance setting ............................................................................. 61 
Table 11. Adverse reactions to letrozole by system organ class and frequency ................. 63 
Table 12. Hypothesized pCR rates in subgroups defined by treatment and RBsig status for sample 
size determination. .............................................................................................. 82 
Table 13. Statistical power for test of treatment-by-RBsig interaction in exact logistic regression 
model (two-sided α=0.05) on the basis of simulations. ...................................... 82 
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1. 
Protocol Summary  
 
Title 
Phase II open-label, multicenter, randomized trial of neoadjuvant palbociclib in combination 
with hormonal therapy and HER2 blockade versus paclitaxel in combination with HER2 
blockade for postmenopausal patients with hormone receptor positive/HER2 positive early 
breast cancer 
Sponsor  
International Breast Cancer Study Group IBCSG 
Pharma 
Partner 
Pfizer and Roche 
Clinical Phase 
Randomized Phase II 
Patient 
population 
Postmenopausal patients with histologically confirmed estrogen receptor positive, HER2 
positive primary breast cancer 
Treatment 
Patients will be randomized in a 1:1 fashion to: 
 Arm A  
Paclitaxel 80 mg/m2 i.v. on day 1, 8, 15 every 28 days for 4 cycles 
Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 
3 weeks for a total of 5 doses 
 Arm B  
Palbociclib 125 mg/day orally for 21 days followed by 7 days’ rest, for 
four 28-day cycles 
Letrozole 2.5 mg/day orally for 16 weeks 
Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 
3 weeks for a total of 5 doses 
Patients will then proceed to surgery 
Background 
and rationale 
Human epidermal growth factor receptor-2 (HER2) is overexpressed and/or amplified in about 
10-20% of breast tumors. HER2+ breast cancer (BC) is usually treated with regimens containing 
anti-HER2 agents and chemotherapy. Clinically approved anti-HER2 agents include 
monoclonal antibodies (trastuzumab and pertuzumab), tyrosine kinase inhibitors (lapatinib) or 
antibody–drug conjugates (T-DM1).  
Early BC, 
ER+, HER2+,
postmenopausal,
Neo-adj. 
treatment 
planned
R
A:
paclitaxel
trastuzumab
pertuzumab
B:
palbociclib
letrozole
trastuzumab
pertuzumab
surgery
surgery
Week   
1     2     3     4     5     6     7     8     9    10    11   12   13   14   15   16  
+
+
staging
FFPE sample
FFPE sample
Pertuzumab: 
loading dose
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Amendment 2, Protocol V2.1 - 12 June 2020 
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Around 50% of HER2+ tumors co-express estrogen receptors (ERs), dividing HER2+ patients 
into hormone receptor (HR) negative and positive subgroups (HRneg/HER2+ and 
HR+/HER2+). Clinical data have increasingly demonstrated that these two subgroups of HER2+ 
patients show different prognosis when treated with anti-HER2 targeted agents and 
chemotherapy [Prat et al., 2014]. However, patients with HR+/HER2+ BC receive 
chemotherapy in combination with anti-HER2 agents as first choice treatment and only secondly 
endocrine treatment (ET). 
Extensive preclinical evidence indicates that ER and HER2 pathways are strictly interdependent 
and that targeting both pathways in ER- and HER2- co-expressing tumors might be an effective 
therapeutic strategy [Osborne et al., 2011]. Few trials investigated the addition of ET to anti-
HER2 in patients with HR+/HER2+ advanced disease indicating that a proportion of patients 
with HR+/HER2+ advanced BC benefit from the combination of hormonal and anti-HER2 
therapy with manageable side effects [Johnston et al., 2009; Kaufman et al., 2009]. However, 
whether the combination of anti-HER2 and ET would be superior to the approved combination 
of anti-HER2 and chemotherapy in patients with advanced HR+/HER2+ BC remains an open 
question since there is no direct comparison between these two strategies. Additionally, a recent 
phase II pre-operative trial of trastuzumab + lapatinib + the endocrine agent letrozole showed 
that the combination yielded a pCR rate of only 21% in a cohort of 39 ER+/HER2+ patients 
[Rimawi et al, 2013]. These considerations highlight that the current paradigm for the treatment 
of HER2+ patients (chemotherapy + anti-HER2 agents) does not necessarily fit the subgroup of 
patients co-expressing ER, and that current endocrine treatments alone might not be a sufficient 
partner for anti-HER2 agents in HR+/HER2+ disease.  
Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are bringing great improvements in the 
management of patients with HR+/HER2neg advanced BC. Three different CDK4/6 inhibitors 
(palbociclib, abemaciclib and ribociclib) are in clinical development in this patient subgroup, 
mostly in combination with endocrine therapy. Palbociclib has been granted FDA approval in 
the U.S. for the treatment of HR+/HER2neg advanced BC in combination with the hormonal 
treatments letrozole and fulvestrant given the unprecedented results in terms of efficacy of two 
pivotal clinical trials (PALOMA-2 and PALOMA-3) [Finn et al. 2016; Cristofanilli et al., 2016]. 
Palbociclib and other CDK4/6 inhibitors have also shown a good toxicity profile and therefore 
are ideal candidates for combination with hormonal therapy.  
CDK4 and 6 control the transition from the G1 to the S phase in the cell cycle by binding to D-
type cyclins. A primary target of CDK action is the retinoblastoma susceptibility gene product 
(RB), which mediates G1 arrest through sequestration of transcriptional factors of the E2F 
family. Phosphorylation of RR (pRB) by active cyclin-CDK complexes leads to release of E2F 
transcription factors and the transcription of genes required for S-phase entry. CDK4/6 
inhibitors, by inhibiting RB phosphorylation, induce a cell cycle arrest in RB proficient cancer 
cells. CyclinD1-CDK4/6-Rb pathway is critical for the development and maintenance not only 
of ER+ but also of HER2+ tumors [Migliaccio et al., 2014] and molecular alterations involving 
the RB pathway frequently occur both in ER+ and in HER2+ BC [Cancer Genome Atlas, 2012]. 
Indeed, preclinical studies demonstrated that ER+ or HER2+ cell lines are the most sensitive to 
inhibition by CDK4/6 inhibitors and that combination of CDK4/6 inhibitors and ET or CDK4/6 
inhibitors and anti-HER2 agents are synergistic in ER+ or HER2+ BC models, respectively [Finn 
et al., 2009]. CDK4/6 pathway activation is a well-known mechanism of resistance to endocrine 
therapy [Migliaccio et al., 2014], indeed CDK4/6 inhibitors have shown activity in cellular 
models of acquired resistance to endocrine therapies [Wardell et al., 2015]. Also, palbociclib 
showed activity in cellular models of acquired resistance to lapatinib indicating that activation 
of the pathway might be implicated in resistance to such agents [Witkiewicz et al., 2014].  
These data collectively indicate that CDK4/6 are therapeutic targets that function downstream 
of both ER and HER2 pathways. Therefore tumors co-expressing ER and HER2 might be the 
most sensitive to CDK4/6 inhibition.  
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Genetic loss of RB1 is a marker of primary resistance to CDK4/6 inhibitors but it is uncommon 
in HR+ or HER2+ subtypes. Recent studies have shown that functional loss of the 
CyclinD1/CDK4-6/RB pathway can be measured by gene-expression studies. Several gene-
signatures of RB-loss have been developed which have shown to be prognostic in breast cancer 
subtypes as well as predictive of response to neoadjuvant chemotherapy [Witkiewicz et al., 
2012; Herschkowitz et al., 2008]. 
A recently developed gene-signature of functional loss of RB (RBsig) that is prognostic in 
luminal breast cancer subtypes can predict response to the CDK4/6 inhibitor palbociclib in cell 
line models of breast cancer [Malorni et al., 2016]. In particular, cell lines with increased levels 
of RBsig (RBsig HIGH) are among the most resistant to palbociclib treatment. 
Additionally, preliminary data suggest that the RBsig might be also predictive of response to 
chemotherapy + trastuzumab in ER+/HER2+ breast cancer patients. Indeed, we performed a 
retrospective in-silico study using publicly available datasets of gene-expression data (10 
studies) obtained from a total of 514 HER2+ BC patients treated with neoadjuvant chemotherapy 
+/- anti-HER2 therapy. For these patients, we computed the RBsig and correlated the RBsig 
expression with clinical outcome. The pCR rate to neoadjuvant CT + anti-HER2 for patients 
with RBsig LOW expression was significantly lower than the pCR rate for patients with RBsig 
HIGH expression. Results were similar for patients receiving neoadjuvant CT alone. Of note, 
the relationship between RBsig and pCR was observed only in HER2+/ER+, and not in 
HER2+/ER-negative tumors, suggesting that, as expected, RBsig seems to be relevant only in 
tumors with a luminal phenotype. These data suggest that RBsig identifies a subset of 
HR+/HER2+ patients (RBsig LOW) who derive little benefit from chemotherapy. 
Taken together, our data suggest that, among patients with ER+/HER2+ BC, those with RBsig 
HIGH derive benefit from chemotherapy and might be resistant to CDK4/6 inhibitors. 
Conversely, patients with RBsig LOW BC who derive little benefit from chemotherapy may 
benefit from CDK4/6 inhibitors.  
Based on this rationale, we hypothesize that the CDK4/6 inhibitor palbociclib in combination 
with the anti-HER2 trastuzumab + pertuzumab and the endocrine therapy letrozole may be 
effective neoadjuvant therapy in patients with ER+/HER2+ BC, especially in the subset of RBsig 
LOW patients. 
We also hypothesize that patients with RBsig HIGH ER+/HER2+ BC might be particularly 
sensitive to neoadjuvant chemotherapy with paclitaxel and trastuzumab + pertuzumab. 
In 2019, it is estimated that of 260,600 newly diagnosed cases of invasive breast cancer in the 
United States, 82% occurred in women aged 50 or over. Furthermore, of the 41,760 breast 
cancer-related deaths in the same year, 90% occurred in this predominantly post-menopausal 
age group [American Cancer Society, 2019]. Around 40% of breast cancers occur in women 
aged 65 and older. Of these, 10-15% have tumors that overexpress HER2 [Musgrove et al., 2011; 
Turner et al., 2015]. Jenkins et al. recently showed that among patients with HR+/HER2+ 
tumors, BC subtypes vary with age with luminal B tumors ranging from 20% in patients aged 
<60 years to 50% in patients over 60 [Jenkins et al., 2014]. Elderly patients are generally 
underrepresented in clinical trials; subgroup analyses have shown that they benefit from anti-
HER2 agents as much as the younger population [Biganzoli et al., 2012; Miles et al., 2013; Syed 
et al., 2014]. Overall a higher incidence of adverse events has been observed in the elderly, 
mainly related to the chemotherapy backbone of the treatment [Miles et al., 2013]. For this trial, 
we have therefore chosen 4 cycles of weekly paclitaxel with a 3 out of 4 weeks schedule 
[Biganzoli et al., 2016]. Palbociclib can be safely and effectively administered to older patients 
without requiring dose adjustment based solely on age [Rugo et al., 2017]. De-escalation of 
chemotherapy is of particular appeal in the older population. Recruitment of older women and 
prospective use of geriatric assessment instruments in those aged 65 will produce valuable 
safety and efficacy data within this under-represented subgroup. 
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IBCSG 55-17 TOUCH 
 
11 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Primary 
Objective and 
Endpoint 
 
The primary objective is to explore the interaction between the RBsig status (HIGH or LOW) 
and treatment activity, assessed by pathological complete response (pCR), of palbociclib + 
letrozole versus paclitaxel when given with trastuzumab + pertuzumab) for ER+/HER2+ 
primary BC. 
 
The study hypothesis is that,  
- 
in patients with RBsig LOW, trastuzumab + pertuzumab + palbociclib + letrozole will 
be more active than trastuzumab + pertuzumab + paclitaxel,  
- 
while in patients with RBsig HIGH, trastuzumab + pertuzumab + paclitaxel will be more 
active than trastuzumab + pertuzumab + palbociclib + letrozole. 
Primary endpoint:  
Pathological complete response pCR, defined as absence of invasive tumor cells in the breast 
and in the axillary lymph nodes at the time of surgery (ypT0/ypTis ypN0). 
Secondary 
Endpoints 
 
pCR in breast only 
 
Objective response prior to surgery, defined as partial or complete response assessed 
clinically and by ultrasound and/or mammography 
 
Tolerability, as defined by adverse events according to CTCAE version 5  
 
Rate of breast-conserving surgery 
Number of 
patients 
Randomization of 144 patients during approximately 24 months, after a start-up period of 6 
months as the trial is being activated by participating Centers. Patients will be followed and 
documented until End of Treatment visit to be done within 30 days after surgery. 
Trial duration 
With a start-up period of 6 months during which the sites will be activated, 24 months of 
recruitment, approximately 5 months after the inclusion of the last patient until End of Treatment 
visit, and 6 months for completion of the documentation and writing the trial report, the total 
duration of the trial is estimated to be 41 months after the randomization of the first patient. 
Inclusion 
criteria 
 
Histologically confirmed invasive breast cancer, with the following characteristics: 
- 
Early breast cancer with tumor size >1 cm (as measured by at least one of the 
required examination methods of clinical examination, mammography and 
ultrasonography) 
- 
No clinical evidence of regional lymph node metastasis (via physical and/or 
radiological exam) (cN0), OR clinical evidence of cN1 status, defined by nodal 
involvement limited to clinically detectable metastasis to movable ipsilateral level 
I, II axillary lymph node(s) ) 
- 
No evidence of metastasis (M0) 
 
Postmenopausal, defined as women with: 
- 
Prior bilateral surgical oophorectomy; OR 
- 
Amenorrhea and age 60 years; OR 
- 
Age <60 years and amenorrhea for 12 or more consecutive months in the absence 
of alternative pathological or physiological cause (including chemotherapy, 
tamoxifen, toremifene, ovarian suppression, or hormonally-based contraception) 
plus FSH and serum estradiol levels within the laboratory’s reference ranges for 
post-menopausal women 
 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
 
Primary tumor must have positive estrogen receptor (ER) ≥10% 
 
Primary tumor must be HER2-positive (by IHC and/or ISH) 
 
Baseline LVEF ≥55% measured by Echocardiography (preferred) or MUGA scan 
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IBCSG 55-17 TOUCH 
 
12 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
Normal hematologic status,  
- 
Absolute neutrophil count ≥1500/mm3 (1.5 × 109/L) 
- 
Platelets ≥100 × 109/L 
- 
Hemoglobin ≥9 g/dL (≥90 g/L) 
 
Normal renal function: serum creatinine ≤1.5 ULN 
 
Normal liver function:  
- 
Serum total bilirubin ≤1.5 × upper limit of normal (ULN). In the case of known 
Gilbert’s syndrome, a higher serum total bilirubin (<2 × ULN) is allowed 
- 
AST or ALT ≤2.5 × ULN 
- 
Alkaline phosphatase ≤2.5 × ULN 
 
Written Informed Consent (IC) must be signed and dated by the patient and the Investigator 
prior to randomization. 
 
The patient has been informed of and agrees to data transfer and handling, in accordance 
with national data protection guidelines. 
 
The patient agrees in writing to make tumor (mandatory diagnostic core biopsy and surgical 
specimen) available for submission for central pathology review and to conduct translational 
studies as part of this protocol. 
NOTE: Central Pathology Review on the primary tumor is mandatory for this trial, but 
patients will be evaluated for eligibility according to tumor characteristics as determined by 
the local pathologist. Both the diagnostic breast core biopsy specimen and the final breast 
surgical specimen (unless no residual invasive tumor is found at surgery) must be submitted 
for Central Pathology Review which will be done by the IBCSG Central Pathology Office 
in Milan, Italy. 
Exclusion 
criteria 
 
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or 
skin nodules) (T4 according to AJCC 8th edition cancer staging TNM) 
 
Inflammatory breast cancer 
 
Bilateral invasive breast cancer 
 
Received any prior treatment for primary invasive breast cancer 
 
Any active tumor of non-breast-cancer histology 
 
Any of the following in the previous 6 months: myocardial infarction, severe/unstable 
angina pectoris, ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2, atrial fibrillation 
of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure 
(NYHA functional classification ≥II), cerebrovascular accident including transient ischemic 
attack, or symptomatic pulmonary embolism 
 
Concurrent disease or condition that would make the subject inappropriate for study 
participation or any serious medical disorder that would interfere with the subject’s safety 
 
Contraindications or known hypersensitivity to any of the trial medications or excipients 
 
Treatment with any investigational agents within 30 days prior to expected start of trial 
treatment 
 
Any GI disorder that may affect absorption of oral medications, such as malabsorption 
syndrome or status post major bowel resection 
 
Evidence via physical and/or radiological exam of cN2 or cN3 nodal involvement defined 
by: metastasis to ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted, 
OR involvement of ipsilateral infraclavicular, internal mammary and/or supraclavicular 
lymph node(s) 
 
History of extensive disseminated/bilateral or known presence of interstitial fibrosis or 
interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, 
interstitial pneumonia, obliterative bronchiolitis, and pulmonary fibrosis. History of prior 
radiation pneumonitis is not an exclusion criterion. 
Assessments 
Efficacy: 
 
Breast disease assessment with clinical examination by caliper and bilateral breast 
ultrasound and mammography will be performed at baseline and before surgery. 
 
A physical tumor examination by caliper should be done after 2 treatment cycles 
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IBCSG 55-17 TOUCH 
 
13 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
Evaluation of tumor response will be the task of the Investigator. Scans will not be centrally 
reviewed. 
Safety:  
 
Complete blood count will be performed as required by treatment schedule 
 
Blood chemistry will be checked every 4 weeks, prior to the next treatment cycle 
 
Adverse events will be graded according to CTCAE version 5; worst grade of adverse events 
will be recorded at beginning of next cycle 
 
All Serious Adverse Events must be notified to IBCSG within 24h 
 
End of treatment visit within 30 days after surgery 
For patients aged 65 years: geriatric assessment at baseline: 
 
G8  
 
Instrumental Activity of Daily Living (IADL)  
 
Charlson Comorbidity Index  
Documentation Electronic Case Report Forms (eCRFs) must be completed in DFexplore 
Integral 
translational 
research 
Pre-treatment biopsy will be analyzed by gene-expression profiling to assess RBsig status. 
Translational 
research  
Pre-treatment biopsy gene-expression profiling may also be utilized to explore potential 
biomarkers in the randomized arms. Surgical tumor tissue samples may be analyzed by gene-
expression profiling to assess changes in RBsig status between baseline and surgery and explore 
potential biomarkers of resistance to treatment. 
Additionally, studies on proteins and genes involved in the ER and RB1 pathway may be 
conducted using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) 
on both pre-treatment and surgical samples. 
The use of the biological material for future research not outlined in this protocol will be under 
the guardianship of the Steering Committee. As part of the trial Informed Consent process, 
patients are asked to indicate whether they agree to donate their sample for not yet specified 
future research. The patient’s decision is recorded on the trial Consent Form. 
Translational research proposals not outlined in this protocol will be assessed by IBCSG’s 
Biological Protocol Working Party (BPWG) for merit and feasibility.  
Biomarkers that are published in the future and considered to be of relevance may be assessed 
in the context of this trial. 
Randomization 
and 
Stratification 
Stratification will be performed according to: 
 
Age and G8 score (<65 years vs. ≥65y and G8 score >14 vs ≥65y and G8 score ≤14) 
 
No clinical evidence of regional lymph nodes metastasis (cN0) vs nodal involvement limited 
to clinically detectable metastasis to movable ipsilateral level I, II axillary lymph node(s) 
(cN1)  
Randomization will be in a 1:1 ratio to: 
Arm A: paclitaxel + trastuzumab + pertuzumab  
Arm B: palbociclib + letrozole + trastuzumab + pertuzumab 
Statistical 
considerations 
For the primary objective, pCR rates are assumed to be: 
 
 
A: Paclitaxel + trastuzumab 
+ pertuzumab 
B: Palbociclib + letrozole + 
trastuzumab + pertuzumab 
Odds Ratio 
(B:A) 
RBsig LOW 
15% 
30% 
2.429 
RBsig HIGH 
50% 
10% 
0.111 
 
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IBCSG 55-17 TOUCH 
 
14 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Statistical power for RBsig-by-treatment interaction is summarized below for varied sample 
sizes and for two-sided alpha error of 0.05, under two assumptions of RBsig prevalence: 
Prevalence 
N=100 
N=110 
N=120 
RBsig 
low / high 
α=0.05 
α=0.05 
α=0.05 
50% / 50% 
75% 
80% 
86% 
Freq. questionable fit* 
(9%) 
(7%) 
(5%) 
25% / 75% 
52% 
60% 
68% 
Freq. questionable fit* 
(17%) 
(13%) 
(11%) 
* Frequency that simulation resulted in a 0% pCR rate in one subgroup and a questionable 
model 
Power was estimated on the basis of simulations of exact logistic regression test for RBsig-by-
treatment interaction, as with the two low expected pCR rates, the appropriateness of an 
asymptotic method such as that of Demidenko et al., 2008 was uncertain. On the basis of 
simulations, taking into consideration the frequency with which 0 pCRs occurred in one of the 
subgroups, we propose an analyzable sample size of 120 patients with successful RBsig results. 
The enrolled sample size is inflated by 20% to 144 to account for non-assessable RBsig status 
(which is determined after randomization).  
The primary analysis will use exact logistic regression to test RBsig-by-treatment interaction 
and estimate the odds ratios for Arm B vs. A according to RBsig (rate ratios and rate differences 
will also be estimated; all with alpha-level confidence intervals).  
References 
American Cancer Society. Breast Cancer Facts & Figures 2019-2020. Atlanta: American Cancer 
Society, Inc. 2019 
Biganzoli L, Wildiers H, Oakman C, et al. Management of elderly patients with breast cancer: updated 
recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of 
Breast Cancer Specialists (EUSOMA). Lancet Oncol. 2012 Apr;13(4):e148-60. 
Biganzoli L, Aapro M, Loibl S, et al. Taxanes in the treatment of breast cancer: Have we better defined 
their role in older patients? A position paper from a SIOG Task Force. Cancer Treatment Reviews 2016; 
43: 19–26 
Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490: 
61-70.2012 
Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus 
placebo for treatment of hormone-receptor positive, HER2-negative metastatic breast cancer that 
progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicenter, double-blind, 
phase 3 randomised controlled trial.Lancet Oncol 2016 Apr 17(4): 425-39. 
Demidenko E. Sample size and optimal design for logistic regression with binary interaction. Stat Med 
2008; 27: 36-46. 
Finn RS, Dering J, Conklin D et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially 
inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast 
Cancer Res 2009; 11: R77. 
Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 
2016;375:1925-36. 
Herschkowitz JI, He X, Fan C, et al. The functional loss of the retinoblastoma tumour suppressor is a 
common event in basal-like and luminal breast carcinomas. Breast Cancer Res 2008; 10:R75. 
Jenkins EO, Deal AM, Anders CK, et al. Age-specific changes in intrinsic breast cancer subtypes: A focus 
on older women. Oncologist 2014;19 :1076-1083  
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Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Johnston S, Pippen J, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as 
first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 
2009; 27:5538-5546. 
Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for 
the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, 
hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM 
study. J Clin Oncol 2009; 27:5529-5537. 
Malorni L, Piazza S, Ciani Y et al. A gene expression signature of Retinoblastoma loss-of-function is a 
predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients 
with ER positive early breast cancer. Oncotarget 2016. 
Migliaccio I, Di Leo A, Malorni L. Cyclin-dependent kinase 476 inhibitors in breast cancer therapy. Curr 
Opin Oncol 2014; 26: 568-575 
Miles D, Baselga J, Amadori D et al. Treatment of older patients with HER2-positive metastatic breast 
cancer with pertuzumab, trastuzumab, and docetaxel: subgroup analyses from a randomized, double-blind, 
placebo-controlled phase III trial (CLEOPATRA). Br Cancer Res Treat 2013; 142: 89-99. 
Musgrove EA, CaldonCE, Barraclough J, et al. Cyclin D as a therapeutic target in cancer. Net Rev Cancer 
2011; 11:558-572. 
Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 2011; 
62:233-247. 
Prat A, Carey LA, Adamo B, et al. Molecular features and survival outcomes of the intrinsic subtypes 
within HER2-positive breast cancer. J Natl Cancer Inst 2014; 106. 
Rimawi MF, Mayer IA, Forero A et al. Multicenter phase II study of neoadjuvant lapatinib and 
trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth 
factor receptor 2-overexpression breast cancer: TBCRC 006. J Clin Oncol 2013; 31:1726-1731. 
Rugo HS, Turner NC, Finn RS, et al. Palbociclib in combination with endocrine therapy in treatment-
naive and previously treated elderly women with HR+, HER2– advanced breast cancer: a pooled analysis 
from randomized phase 2 and 3 studies [abstract]. In: Proceedings of the Thirty-Ninth Annual CTRC-
AACR San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): 
AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-03 
Syed BM, Green AR, Ellis IO, Cheung KL. Human epidermal growth receptor-2 overexpressing early 
operable primary breast cancers in older (≥70 years) women: biology and clinical outcome in comparison 
with younger (<70 years) patients. Ann Oncol 2014; 25: 837-842 
Turner NC, Ro J, Andre F, et al. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N 
Engl J Med 2015; 373:209-219. 
Wardell SE, Ellis MJ, Alley HM, et al. Efficacy of SERD/SERM Hybrid-CDK476 Inhibitor Combinations 
in Models of Endocrine Therapy-Resistant Breast Cancer. Clin Cancer Res 2015;21:5121-5130 
Witkiewicz AK, Ertel A, McFalls J, et al. RB-pathway disruption is associated with improved response 
to neoadjuvant chemotherapy in breast cancer. Clin Cancer Res 2012; 18: 5110-5122 
Witkiewicz AK, Cox D, Knudsen ES. CDK4/6 inhibition provides a potent adjunct to Her2-targeted 
therapies in preclinical breast cancer models. Genes Cancer 2014; 5:261-272. 
 
 
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IBCSG 55-17 TOUCH 
 
 
 
 
 
 
16 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
2. 
Trial schedule 
2.1. 
Arm A (paclitaxel, trastuzumab, pertuzumab) 
 
≤4 weeks 
prior to 
rando 
week 
Up to 4 
weeks 
prior to 
surgery 
30 days 
after 
surgery 
week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, ECOG 
PS 
x 
Day 1 of every paclitaxel cycle 
x 
x 
Baseline comorbidities 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
At the end of every cycle: all grades for targeted events, all grade 3/4 non-targeted events;  
record grade 2 non-targeted events only if they require relevant medical intervention 
SAEs 
only 
Geriatric assessment (for 
patients aged 65 years) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neoadjuvant Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Paclitaxel 80 mg/m2 1 
 
x  
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
 
Trastuzumab 600 mg 
2 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
Pertuzumab 420 mg 
3 
 
x  
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
Laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology
4 
x 
Prior to every dose of paclitaxel 
x 
 
Blood chemistry
5 
x 
Prior to every paclitaxel cycle 
x 
 
Tumor Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Caliper/ruler 
x 
 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
x 
 
Mammography6 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Breast Ultrasound6
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Chest x-ray or CT7 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal US or CT 8 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone scan9 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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IBCSG 55-17 TOUCH 
 
 
 
 
 
 
17 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
≤4 weeks 
prior to 
rando 
week 
Up to 4 
weeks 
prior to 
surgery 
30 days 
after 
surgery 
week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
Other tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Echocardiography (preferred) 
or MUGA scan 
x 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
 
x 
 
Pathology eval. (local) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
FFPE sample10 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x = mandatory 
√ = if medically indicated 
* = ±1 week 
# only SAEs 
Legend for trial schedule: 
Neoadjuvant treatment: 4 cycles of 28 days each 
1. Paclitaxel 80 mg/m2 i.v. on day 1,8,15 for four cycles of 28 days 
2. Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
3. Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 3 weeks for a total of 5 doses. 
Laboratory tests 
4. Hematology (Hemoglobin, platelet count, white blood cell count including differential (absolute neutrophil count) must be done within 14 days prior to 
randomization, on day 1 or within 3 days prior to every paclitaxel dose, and at the visit prior to surgery.  
5. Blood chemistry (creatinine, alkaline phosphatase, AST or ALT, total bilirubin) must be done within 14 days prior to randomization, on day 1 or within 3 days 
prior to every 28 day paclitaxel cycle, and at the visit prior to surgery. 
Tumor evaluation 
6. Bilateral mammography, and tumor assessments by breast/axilla palpation and ultrasound (caliper/ruler measurement) must be done prior to randomization, and 
prior to surgery. A tumor assessment (breast/axilla palpation and caliper measurement) should be done after 2 paclitaxel cycles. 
7. Chest X-ray or CT scan, if medically indicated; not required in patients who have undergone a PET scan.  
8. Abdominal ultrasound or CT scan, if medically indicated not required in patients who have undergone a PET scan. 
9. Bone scan if medically indicated. Requiredif the patient has unexplained bone pain; not required in patients who have undergone a PET scan. 
Biological material 
10. A formalin-fixed, paraffin-embedded (FFPE) tumor block from core biopsy at diagnosis and from surgery (if not pCR) must be submitted for central pathology 
review and for gene-expression profiling to assess RBsig status and future translational research studies.  
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IBCSG 55-17 TOUCH 
 
 
 
 
 
 
18 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
2.2. 
Arm B (palbociclib, letrozole, trastuzumab, pertuzumab) 
 
≤4 weeks 
prior to 
rando 
week 
Up to 4 
weeks 
prior to 
surgery 
30 days 
after 
surgery 
week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, ECOG PS 
x 
Day 1 of every palbociclib cycle 
x 
x 
Baseline comorbidities 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
At the end of every cycle: all grades for targeted events, all grade 3 and 4 non-targeted events;  
record grade 2 non-targeted events only if they require relevant medical intervention 
SAEs 
only 
Geriatric assessment (for patients 
aged 65 years) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neoadjuvant Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Palbociclib 125 mg/day 
1 
 
........daily ♯..... 
 
........daily ♯..... 
 
........daily ♯..... 
 
........daily ♯..... 
 
 
 
Letrozole 2.5 mg/day 
2 
 
 ......................................................…….daily.........................................................……….. 
 
 
Trastuzumab 600 mg 
3 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
Pertuzumab 420 mg 
4 
 
x  
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
Laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology
5 
x 
Day 1 and 14 during the first two palbociclib cycles, then on day 1 of cycles 3 and 4 
x 
 
Blood chemistry
6 
x 
Prior to every palbociclib cycle 
x 
 
Tumor Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Caliper/ruler 
x 
 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
x 
 
Mammography7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Breast Ultrasound7
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Chest x-ray or CT8 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal US or CT9 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone scan10 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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IBCSG 55-17 TOUCH 
 
 
 
 
 
 
19 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
≤4 weeks 
prior to 
rando 
week 
Up to 4 
weeks 
prior to 
surgery 
30 days 
after 
surgery 
week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
Electrocardiogram (ECG)  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Echocardiography (preferred) or 
MUGA scan 
x 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
 
x 
 
Pathology eval. (local) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
FFPE sample11 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x = mandatory 
√ = if medically indicated 
* = ±1 week 
♯ = check patient diary; hand out new patient diary for next cycle 
Legend for trial schedule: 
Neoadjuvant treatment: 4 cycles of 28 days each 
1. Palbociclib 125 mg/day orally for 21 days followed by 7 days rest, for 4 cycles.  
2. Letrozole 2.5 mg/day orally, continuously for 16 weeks 
3. Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
4. Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 3 weeks for a total of 5 doses 
Laboratory tests 
5. Hematology (Hemoglobin, platelet count, white blood cell count including differential (absolute neutrophil count)) must be done within 14 days prior to 
randomization, on day 1 (or within 3 days prior) and day 14 during the first two palbociclib cycles, then on day 1 (or within 3 days prior) of cycles 3 and 4, and at 
the visit prior to surgery.  
6. Blood chemistry (creatinine, alkaline phosphatase, AST or ALT, total bilirubin) must be done within 14 days prior to randomization, prior to every palbociclib 
cycle, and at the visit prior to surgery. 
Tumor evaluation 
7. Bilateral mammography, and tumor assessments by breast/axilla palpation and ultrasound (caliper/ruler measurement) must be done prior to randomization and 
prior to surgery. A tumor assessment (breast/axilla palpation and caliper measurement) should be done after 2 palbociclib cycles. 
8. Chest X-ray or CT scan, if medically indicated; not required in patients who have undergone a PET scan.  
9. Abdominal ultrasound or CT scan, if medically indicated; not required in patients who have undergone a PET scan. 
10. Bone scan if medically indicated. Required if the patient has unexplained bone pain; not required in patients who have undergone a PET scan. 
Biological material 
11. A formalin-fixed, paraffin-embedded (FFPE) tumor block from core biopsy at diagnosis and from surgery (if not pCR) must be submitted for central pathology 
review and for gene-expression profiling to assess RBsig status and future translational research studies.  
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IBCSG 55-17 TOUCH 
 
20 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
3. 
List of abbreviations 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AI 
Aromatase Inhibitor 
AJCC 
American Joint Committee on Cancer 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute Neutrophil Count 
AST  
Aspartate transaminase 
BC 
Breast Cancer 
BIG 
Breast International Group  
BSC 
Breast-Conserving Surgery 
CBR 
Clinical Benefit Rate 
CDK 
Cyclin Dependent Kinase 
CHF 
Congestive Heart Failure 
CI 
Confidence interval 
CNS 
Central Nervous System 
CPO 
Central Pathology Office 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed tomography 
CTCAE 
Common toxicity criteria for adverse events 
CYP3A 
Cytochrom P450 3A4 
DC 
Disease control  
DMC 
Data Management Center 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EEA 
European Economic Area 
ET 
Endocrine Treatment 
EoT 
End of Treatment 
ER 
Estrogen receptor 
ERB 
Ethical Review Board 
FDG 
Fluoro-D-Glucose 
FFPE 
Formalin-fixed paraffin-embedded 
FISH 
Fluorescence in situ hybridization 
FLT 
Fluorothymidine 
FSTRF 
Frontier Science and Technology Research Foundation 
GCP 
Good clinical practice 
GGT  
Gamma-Glutamyl Transferase 
HER2 
Human Epidermal Growth Factor Receptor 2 
HIV 
Human Immunodeficiency Virus 
HR 
Hormone Receptors 
IADL 
Instrumental Activities of Daily Living 
IB 
Investigator’s Brochure 
IBCSG 
International Breast Cancer Study Group 
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IC 
Informed consent 
IC50 
Half Maximal Inhibitory Concentration 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ISH 
In Situ Hybridization 
LHRH 
Luteinizing Hormone-Releasing Hormone 
LPD 
Largest Perpendicular Diameter 
MBC 
Metastatic breast cancer 
MD 
Maximal Diameter 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTOR 
Mechanistic Target of Rapamycin 
NAT 
Neoadjuvant Treatment 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NIMP 
Non-Investigational Medicinal Product 
NYHA 
New York Heart Association 
OHRP 
Office for Human Research Protection 
ORR 
Overall response rate 
pCR 
Pathological Complete Response 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression free survival 
PgR 
Progesterone receptor 
PI 
Principal Investigator 
PIS/IC 
Patient information sheet / informed consent 
PR 
Partial response 
pRb 
Phosphorylated Retinoblastoma 
 
PS 
Performance status 
PT 
Prothrombin Time 
QD 
Once daily (Quaque Die) 
QTc 
Corrected QT Interval 
Rb 
Retinoblastoma 
RR 
Response Rate 
SAE 
Serious adverse event 
SD 
Stable disease 
SPC 
Summary of Product Characteristics 
SPIM 
Standard Procedures Imaging Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEV 
Tumor Evaluation Form 
TNM 
Tumor-Node-Metastasis 
ULN 
Upper limit of normal 
 
 
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4. 
Background and scientific rationale 
4.1. 
Introduction 
About 70% of all invasive breast cancers (BC) express hormone receptors (HR) (Estrogen 
Receptor – ER and Progesterone Receptor – PgR) and are therefore treated with endocrine 
therapy (ET). The human epidermal growth factor receptor-2 (HER2) is overexpressed and/or 
amplified in about 10-20% of BC. Until recently, HER2 positive (HER2+) BC has been 
considered as a single entity, yet studies are increasingly demonstrating that HER2+ BCs are 
clinically and biologically heterogeneous. Around 50% of the HER2+ tumors co-express ER, 
dividing HER2+ patients in two main subgroups (HR-neg/HER2+ and HR+/HER2+).  
Patients with HR+/HER2+ BC represent a unique group of patients with an unmet clinical need. 
This population is the focus of this trial. 
4.2. 
Neoadjuvant treatment in HR+ and HER2+ BC 
Neoadjuvant therapy (NAT) (also called preoperative or primary systemic therapy) is delivered 
before surgical treatment and has historically been used mainly for locally advanced or 
inflammatory BC, because of its ability to downstage the disease and to favor operability in 
primary inoperable breast tumors. 
More recently, NAT use has become increasingly common also for patients with operable disease 
for a number of reasons including: a) tumor downsizing with a subsequent increased chance to 
achieve breast conserving surgery b) early treatment of distant micro-metastases c) selection of 
individualized therapy by early detection of treatment failures. NAT also offers a unique platform 
in clinical research to rapidly evaluate new drugs or treatment modalities to be further studied in 
other clinical settings. 
One of the main therapeutic goals of NAT is pathological complete response (pCR). The 
frequency of pCR following NAT varies among, and also within, BC subtypes.  
Triple negative and HER2+ BCs have the highest pCR rates after NAT, while HR+ tumors 
achieve lower pCR rates. Within HR+ tumors, pCR rates are particularly low for patients with 
low-grade tumors, while they are more than doubled for patients with high-grade tumors. Within 
HER2+ tumors, HR status also affects the pCR rates after neoadjuvant chemotherapy, pCR being 
less common for HR+ compared to HR negative BCs [1].  
Several studies revealed an association between pCR and improved survival. However, pCR rate 
has a clear prognostic value only in particular BC subgroups. A recent meta-analysis from von 
Minckwitz and colleagues [2] including more than 6000 patients showed that, among HER2+ 
patients, pCR after NAT is prognostic for survival in HR negative BC but not in HR+ BC, 
irrespective of trastuzumab treatment.  
Bhargava and colleagues divided HER2+ BC into three subgroups based on the levels of 
expression of ER and PgR [3]. These authors reported that the pCR rate and the level of ER 
expression are inversely correlated.  
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Recently, clinical trials of NAT in HER2+ disease (NeoALTTO, NeoSphere, CALGB40601, see 
below) also showed different response rates to anti-HER2 agents in HR+ vs HR- tumors. 
Available current data in the NAT setting suggest that HR+/HER2+ BC behaves differently from 
HR negative/HER2+ BC, achieving lower pCR rates after neoadjuvant chemotherapy with or 
without anti-HER2 agents; pCR may not be predictive of outcome in this subtype of BC. 
4.3. 
Endocrine treatment 
Endocrine treatment (ET) with aromatase inhibitors (AI), tamoxifen or fulvestrant represents the 
mainstay of HR+ BC treatment given its efficacy and very limited toxicity. HER2 is a major and 
well-recognized factor of primary resistance to ET and therefore HR+/HER2+ BC patients are 
seldom treated with ET alone. 
Extensive preclinical and clinical data have shown a complex bi-directional cross talk between 
ER and HER2 signaling pathways that may have important implication in resistance of 
HR+/HER2+ tumors to endocrine therapy and anti-HER2 agents [4]. HER2 overexpression or 
amplification affects endocrine therapy responsiveness; indeed, HR+/HER2+ BC patients treated 
with letrozole or tamoxifen, showed less Ki67 suppression when compared to HR+/HER2 
negative patients, despite similar short-term clinical efficacy [5].  
Combining targeted treatments that simultaneously block both signaling pathways is a promising 
approach to prevent or overcome either endocrine or anti-HER2 therapy resistance in some 
HR+/HER2+ tumors. 
Indeed, several clinical trials have explored this concept both in the metastatic and in the NAT 
setting. A small phase II trial of trastuzumab and letrozole enrolled 31 evaluable post-menopausal 
patients with HR+/HER2+ metastatic BC. More than 80% of included patients had received prior 
tamoxifen [6]. This trial showed an objective response rate of 26% and a clinical benefit rate 
(CBR) of 52%. The median time to progression was 5.8 months and the median duration of 
response was 20.6 months, suggesting that durable responses can be seen with combined ET and 
anti-HER2 therapy. 
In the randomized phase II TAnDEM trial, 207 patients with ER+/HER2+ metastatic breast 
cancer (MBC) were treated with either anastrozole alone or in combination with trastuzumab as 
first-line therapy. This trial demonstrated that the 2-year progression-free survival (PFS) rate was 
about 15% with anastrozole plus trastuzumab and only 5% with anastrozole alone. No difference 
in overall survival was seen. Clinical Benefit Rate (CBR) was about 43% with trastuzumab plus 
anastrozole compared to about 28% with anastrozole alone. Combination treatment was well 
tolerated with mostly mild to moderate side effects including fatigue (21%), diarrhea (20%), 
vomiting (21%), and pyrexia (17.5%) [7]. 
The eLEcTRA trial, compared letrozole alone or with trastuzumab as first line therapy and 
showed a non-significant trend toward longer PFS with combination therapy. CBR was 65% in 
the combination arm and 39% in the letrozole alone arm. Also in this trial, the more commonly 
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reported symptoms included fatigue (27%), diarrhea (19%), vomiting (19%) and peripheral 
edema (19%) [8]. 
The dual HER1/2 (EGFR/HER2) kinase inhibitor lapatinib has also been investigated in 
combination with hormonal therapy. The EGF30008 trial randomized 1286 patients with ER+ 
MBC to receive letrozole in combination with lapatinib or placebo as first line therapy. Of these, 
219 patients had HER2+ tumors. In the ER+/HER2+ population, there was a large and 
statistically significant improvement in PFS and the CBR was significantly improved from 29 to 
48% with the combination [9].  
All these trials in the MBC setting have confirmed that ET and anti-HER2 therapy can be safely 
and effectively combined. 
Only two published trials in early disease setting tested the combination of ET and anti-HER2 
agents in HR+/HER2+ BC. In the phase II TBCRC006 study [10], 64 patients with stages I–III 
HER2+ BC, received lapatinib plus trastuzumab for 12 weeks in the NAT setting. The 39 women 
with HR+ disease also received letrozole (plus luteinizing hormone-releasing hormone (LHRH) 
agonist if premenopausal). HR+/HER2+ patients achieved a pCR rate of 21% which was 
remarkable, given the absence of chemotherapy in the study regimen. 
The TBCRC023 trial compared lapatinib plus trastuzumab, adding letrozole (along with ovarian 
suppression if premenopausal) in HR+ patients, for 12 weeks vs 24 weeks. Longer treatment 
duration of endocrine therapy and anti-HER2 therapy (without chemotherapy) led to a 
meaningful increase in pCR rate in HR+/HER2+ BC (33% with 24 weeks vs 9% with 12 weeks 
of therapy) while pCR rates were quite similar for the ER negative patients, independently from 
treatment duration [11]. 
Regarding the choice of ET agent in ER+/HER2+ BC, data suggest a superiority of AI over 
tamoxifen. The advantage of the AI letrozole over tamoxifen in HR+/HER2+ BC, was shown in 
a phase III study including 330 postmenopausal women; the difference in response rate (RR) 
between the two treatment arms, was more evident in HER2+ patients (RR= 88% vs 21%), than 
in HER2- patients (RR=54% vs 42%) [12]. 
These results were confirmed in the IMPACT trial, comparing the AI anastrozole vs tamoxifen 
vs the combination of the two agents; patients with HER2 overexpressing tumors presented a 
higher response rate with the AI when compared with tamoxifen although the difference was not 
statistically significant (58% vs 22% vs 31% with anastrozole, tamoxifen, and combination 
therapy, respectively) [13]. 
4.4. 
Chemotherapy 
Chemotherapy in combination with anti-HER2 agents remains the most frequently used treatment 
for HR+/HER2+ BC patients. 
pCR rates and outcomes of patients treated with chemotherapy and anti-HER2 agents vary 
between trials according to the type of chemotherapy and the anti-HER2 agent under study. 
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The addition of trastuzumab to primary chemotherapy has significantly improved the pCR rate 
in HER2+ BC. The first randomized trial was reported by Buzdar and colleagues in 2005 [14]. 
Patients were randomized to receive taxane and anthracycline-based chemotherapy with or 
without weekly trastuzumab for a total of 24 weeks. The results were strongly in favor of 
trastuzumab combination therapy in both the whole population (pCR rate=65.2% versus 26%), 
and in patients selected by HR status. The updated safety and efficacy data from this trial [15] 
confirmed the initial findings and showed an improved disease-free survival among trastuzumab-
treated patients without clinical cardiac dysfunctions or other relevant toxicities.  
In the NOAH trial, neoadjuvant chemotherapy with doxorubicin, paclitaxel, cyclophosphamide, 
methotrexate and fluorouracil, was administered alone or in combination with trastuzumab. The 
study included 235 patients with HER2+ BC, 151 of whom had HR+ status. In the overall 
population, the pCR rate was higher in patients receiving trastuzumab, but the difference between 
the two treatment arms was more evident in HR negative tumors compared to HR+ tumors 
(Hazard ratios= 0,46 vs 0,87 in HR- and HR+ respectively). Equally, in terms of event free 
survival, HR negative patients had a more pronounced benefit from trastuzumab than HR+ 
patients [16, 17]. 
The GeparQuattro study [18] evaluated the incorporation of capecitabine into an 
anthracycline/taxane-based regimen and the concurrent use of trastuzumab in HER2+ patients. 
Also in this case, HR status was the only factor independently associated with pCR in a univariate 
and multivariate analysis (pCR rate= 43.5% in HR negative vs 23.4% in HR+). 
The phase III ACOSOG Z1041 trial [19] randomized patients to paclitaxel and trastuzumab 
followed by concurrent 5-fluorouracil + epirubicin + cyclophosphamide (FEC) and trastuzumab 
compared with FEC alone followed by concurrent paclitaxel and trastuzumab. No difference in 
pCR rate was found between the two arms, irrespective of hormone receptor status, and pCR rates 
were lower in those patients with HR+ status (pCR rate=70.4% and 77.6% in HR negative vs. 
47.6% and 38.1% in HR+).  
Collectively, these data show that, among patients with HER2 + disease, those with HR+ BC 
derive less benefit from combination of chemotherapy and anti-HER2 agents, compared to 
patients with HR negative disease. 
4.5. 
Anti-HER2 treatment 
Clinically approved anti-HER2 agents include monoclonal antibodies (trastuzumab and 
pertuzumab), tyrosine kinase inhibitors (lapatinib) or antibody–drug conjugates (T-DM1).  
Trastuzumab was the first anti-HER2 agent used as chemotherapy partner in HR+/HER2+ 
tumors. However, preclinical data have suggested that a more complete inhibition of the HER2 
pathway by means of dual blockade with trastuzumab and lapatinib could be a more efficacious 
treatment strategy. 
The dual combination of the anti-HER2 agents lapatinib and trastuzumab with chemotherapy was 
used in the in the NSABP B-41 [20], NeoALTTO trial [21], CALGB 40601 trial [22], and CHER-
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LOB trial [23], and was associated with higher pCR rates compared with single-agent anti-HER2 
treatments independent of the receptor status.  
Regarding toxicity, all the trials including a lapatinib + trastuzumab arm showed consistently that 
the addition of lapatinib increases the incidence of class-specific side effects such as diarrhea, 
rash and liver toxicity.  
The positive results in the NAT setting in terms of activity of the dual blockade with trastuzumab 
and lapatinib were not replicated in the post-operative adjuvant setting. In the phase III ALTTO 
trial, a total of 8,331 patients with operable HER2+ BC were randomized to receive either 
lapatinib concurrently with trastuzumab, trastuzumab followed by lapatinib, lapatinib alone, or 
trastuzumab alone. The lapatinib-alone arm was closed early due to demonstrated superiority of 
trastuzumab over lapatinib alone. No significant difference between the lapatinib plus 
trastuzumab and the trastuzumab alone arms was observed in terms of the primary endpoint 
disease free survival (DFS) [24]. 
Given these unexpected results, along with the tolerability data from the NAT studies, the dual 
blockade with trastuzumab and lapatinib is not clinically indicated in the NAT setting. 
Trastuzumab has also been evaluated in combination with pertuzumab in the NAT setting. 
In the phase II NeoSphere trial 417 patients with HER2+ BC were randomized to one of the four 
following treatment arms: 1) trastuzumab + docetaxel; 2) pertuzumab + docetaxel; 
3) trastuzumab and pertuzumab + docetaxel; or 4) trastuzumab and pertuzumab without 
chemotherapy prior to breast surgery. After surgery, all groups received additional chemotherapy 
+ trastuzumab. This study showed that patients who were given the dual blockade of pertuzumab 
and trastuzumab plus docetaxel had a significantly improved pCR (45.8%) compared with those 
given trastuzumab with docetaxel (29%) or pertuzumab with docetaxel (24%). In this study, pCR 
rates in the docetaxel-trastuzumab-pertuzumab arm were higher in patients with HR negative 
(63.2%) compared to HR+ (26%) tumors. This was also observed in the chemo-free dual HER2 
blockade arm (27.3% vs 5.9%) [25]. 
In the phase II TRYPHAENA study, pertuzumab and trastuzumab were combined with different 
chemotherapy regimens. Patients randomized to arms A and B received three cycles of FEC 
followed by three cycles of docetaxel and were randomized to start the combination of 
pertuzumab and trastuzumab with cycle 1 of FEC (Arm A) or with cycle 1 of docetaxel (Arm B). 
Patients randomized in Arm C received six cycles of concurrent docetaxel, carboplatin and 
pertuzumab plus trastuzumab [26]. 
All three treatment regimens were highly active; indeed a pCR was seen in 50.7% (Arm A), 
45.3% (Arm B) and 51.9% (Arm C). Higher pCR rates were observed in patients with HR 
negative disease (79.4%, 65% and 83.8% for arms A, B and C, respectively) than in patients with 
HR+ disease (46.1 %, 48.6% and 50% for Arm A,B and C, respectively). TRYPHAENA was not 
intended to evaluate superiority of any arm, with all three arms being experimental. However this 
study showed that pertuzumab does not increase the rate of cardiac dysfunction observed with 
the combination of trastuzumab plus standard chemotherapy. 
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The results from the NeoSphere trial drove the FDA approval of pertuzumab for neoadjuvant 
treatment of HER2+ BC.  
The combination of trastuzumab and pertuzumab was also tested in the APHINITY trial, a 
randomized, double-blind, placebo controlled study, evaluating adjuvant pertuzumab plus 
trastuzumab plus chemotherapy vs trastuzumab plus placebo plus chemotherapy [27]. The study 
met the primary objective, indeed the addition of pertuzumab to trastuzumab was shown to lower 
the chance of developing recurrent invasive BC by 19% compared to trastuzumab alone. 
However the absolute benefit from adding pertuzumab was lower than 1% against increased 
toxicity and costs. A bigger benefit was observed only in high risk patients with node positive or 
ER-negative disease. 
Since August 2013, a subcutaneous formulation of trastuzumab has been available for patients 
with HER2-positive early and MBC. The subcutaneous formulation is administered as a fixed 
dose of 600 mg over a period of up to 5 minutes. The efficacy of subcutaneous versus intravenous 
trastuzumab as neoadjuvant/adjuvant therapy in patients with HER2-positive BC was evaluated 
in the HannaH study [28, 29]. This phase III, open-label, multinational study compared 
subcutaneous with intravenous administration and found comparable pharmacokinetics, efficacy 
and tolerability for both administration forms of trastuzumab. Furthermore, in the randomized, 
open-label, multinational, crossover study PrefHer, neoadjuvant/adjuvant or adjuvant 
subcutaneous administration of trastuzumab was preferred over intravenous administration by 
patients, mainly because it was time saving and induced less pain and discomfort [30, 31]. 
In the recent Phase III KATHERINE study, 1486 patients with HER2-positive early breast cancer 
who were found to have residual disease in the breast or axilla at surgery after neoadjuvant 
taxane-containing chemotherapy were randomized to receive adjuvant trastuzumab emtansine 
(T-DM1) or trastuzumab for 14 cycles. T-DM1 reduced the risk of recurrence of invasive breast 
cancer or death by 50% compared to adjuvant trastuzumab alone (95% CI, 0.39-0.64, p<0.001), 
with a 3-year invasive disease-free survival rate of 88.3% in the T-DM1 group, versus 77% in 
the trastuzumab group [32]. 
4.6. 
CDK inhibition 
Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are bringing great improvements in the 
management of patients with HR+/HER2neg advanced BC. Three different CDK4/6 inhibitors 
(palbociclib, abemaciclib and ribociclib) are in clinical development in this patient subgroup, 
mostly in combination with endocrine therapy.  
CDK4 and 6 control transition from the G1 to the S phase of the cell cycle by binding to D-type 
cyclins. A primary target of CDK action is the retinoblastoma susceptibility gene product (Rb), 
which mediates G1 arrest through sequestration of transcriptional factors of the E2F family. 
Phosphorylation of Rb (pRb) by active cyclin-CDK complexes leads to release of E2F 
transcription factors and transcription of requisite genes for S-phase entry. CDK4/6 inhibitors, by 
inhibiting Rb phosphorylation, induce a cell cycle arrest in Rb proficient cancer cells [33]. 
CyclinD1-CDK4/6-Rb pathway is critical for the development and maintenance not only of ER+ 
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but also of HER2+ tumors [34] and molecular alterations involving the Rb pathway frequently 
occur both in ER+ and in HER2+ BC [35]. Indeed, preclinical studies demonstrated that ER+ or 
HER2+ cell lines are the most sensitive to inhibition by CDK4/6 inhibitors and that combination 
of CDK4/6 inhibitors and ET or CDK4/6 inhibitors and anti-HER2 agents are synergistic in ER+ 
or HER2+ BC models, respectively [36]. CDK4/6 pathway activation is a well-known 
mechanism of resistance to endocrine therapy [37], indeed CDK4/6 inhibitors have shown 
activity in cellular models of acquired resistance to endocrine therapies [38]. Little is known 
about the role of CDK4/6 pathways in anti-HER2-targeted therapies resistance. However 
palbociclib showed activity in cellular models of acquired resistance to lapatinib indicating that 
activation of the pathway might be implicated in resistance to such agents [39]. These data 
collectively indicate that CDK4/6 is a therapeutic target that functions downstream of both ER 
and HER2 pathways. Therefore tumors co-expressing ER and HER2 might be more sensitive to 
CDK4/6 inhibition.  
Notwithstanding this rationale, to date there is a lack of data on the effect of the addition of 
CDK4/6 inhibitors to the combination of endocrine and HER2-targeted therapies in tumors co-
expressing ER and HER2 and there are only very few clinical trials assessing the combination in 
patients with ER+/HER2+ BC. 
4.7. 
Palbociclib 
Palbociclib has been granted approval both in the U.S. and more recently in Europe for the 
treatment of HR+/HER2neg advanced BC in combination with the hormonal treatments letrozole 
and fulvestrant given the unprecedented results in terms of efficacy of two pivotal clinical trials 
(PALOMA-2 and PALOMA-3) [40, 41]. Palbociclib and other CDK4/6 inhibitors, have also 
shown a good toxicity profile.  
Palbociclib is a selective ATP-competitive, orally-administered inhibitor of CDK4 and CDK6 
and was the first compound of this class to be developed and tested in clinical trials. Palbociclib 
is highly specific for CDK4 (IC50, 0.011 mol/L) and CDK6 (IC50, 0.016 mol/L). It exerts G1 
arrest with consequent anti-proliferative activity in vitro and prevents tumor growth in vivo in an 
array of Rb-positive tumor cells [42, 43]. Palbociclib was first studied in two phase I dose 
escalation trials in patients with advanced solid tumor or non-Hodgkin’s lymphoma with 
histologically proven Rb tumor expression [44, 45]. These studies revealed that hematological 
toxicity in general is common with this agent. Grade 3 or 4 hematological adverse events 
consisted of lymphopenia (36%), neutropenia (24%), leucopenia (21%), thrombocytopenia (9%) 
and anemia seen in a single patient (3%). The most common non-hematological adverse events 
were fatigue, nausea and diarrhea. However, treatment was generally well tolerated and no patient 
discontinued treatment permanently because of treatment-related adverse events [44]. Tumor 
responses were observed in non-seminomatous germ cell testicular tumor, liposarcomas, thyroid 
tumor, melanoma, cholangiosarcoma and angiomyxoma. The recommended phase II dose of 
palbociclib was 125 mg once daily. Palbociclib subsequently moved into Phase II and III clinical 
trials in different tumor types, including BC. 
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Clinical data from several trials confirmed the activity of CDK4/6 inhibitors in patients with HR 
positive BC. Although palbociclib showed modest activity (CBR of 21%) when used as a single-
agent in a phase II trial (NCT01037790) in heavily pre-treated advanced BC patients, partial 
responses and stable disease were observed in patients with ER positive tumors [46].  
Additional clinical data for palbociclib in combination with endocrine therapy in the metastatic 
setting come from the seminal randomized phase II PALOMA-1/TRIO-18 trial where the 
combination of palbociclib plus letrozole was compared to single-agent letrozole in the first line 
treatment setting for post-menopausal patients with ER-positive/HER2 negative MBC. The study 
was composed of two parts: Part 1 enrolled patients with ER+/HER2 negative disease with no 
further biomarker assessment, while Part 2 enrolled patients with tumor harboring Cyclin D1 
gene amplification and/or loss of p16. The primary endpoint was Investigator-assessed PFS. A 
total of 165 patients were randomized in this study (66 patients in Part 1 and 99 patients in Part 
2).  
The final analysis of primary endpoint showed a statistically significant improvement in PFS for 
the combination arm (20.2 months) compared to the letrozole (10.2 months) with hazard ratio 
0.488 (95% CI: 0.319 to 0.748, 1-sided p=0.0004). Significant improvements in PFS were also 
seen in both Part 1 and Part 2 when analyzed separately (hazard ratio=0.299 [95% CI: 0.156, 
0.572]; 1-sided p=0.0001 for Part 1 and hazard ratio =0.508 [95% CI: 0.303, 0.853]; 1-sided 
p=0.0046 for Part 2) [47].  
These results were further confirmed in a larger phase III, double-blind, registration trial with the 
same design, namely the PALOMA-2 trial. In this trial, 666 postmenopausal women with ER-
positive, HER2-negative BC, who had not received prior treatment for advanced disease, were 
randomized in a 2:1 fashion to receive palbociclib plus letrozole or placebo plus letrozole. The 
primary end point was PFS, as assessed by the Investigators. Results showed that the median PFS 
was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) in the palbociclib–
letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo–letrozole 
group (hazard ratio, 0.58; 95% CI, 0.46 to 0.72; P<0.001). Subgroup analysis did not reveal any 
subset of patients who received benefit from the combination [41].  
In the setting of endocrine pre-treated MBC, results from the phase III PALOMA-3 trial have 
recently been published [48]. This trial involved patients with ER-positive/HER2-negative MBC 
that had relapsed or progressed during prior ET. Patients were randomized in a 2:1 ratio favoring 
the combination arm, to receive palbociclib and fulvestrant or placebo and fulvestrant. 
Premenopausal or perimenopausal women were eligible and also received the LHRH agonist 
goserelin. Patients who had received one line of prior chemotherapy for the treatment of 
metastatic disease were eligible for this trial. A total of 521 patients were randomized in this 
study, 347 in the palbociclib and fulvestrant arm and 174 in the palbociclib and placebo arm. The 
majority of the patients were post-menopausal (79.3% in both arms) and had received one or 
more prior lines of therapy for metastatic disease (patients who had received no prior treatment 
for metastatic disease represented 24.2% and 25.9% of the trial population in the palbociclib + 
fulvestrant and the placebo + fulvestrant arms, respectively). The study met its primary objective, 
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showing improved median PFS of 9.2 months with palbociclib and fulvestrant and 3.8 months 
with placebo and fulvestrant, corresponding to a hazard ratio 0.42 (95% CI, 0.32 to 0.56, p<0.001) 
[48].  
Overall survival analysis of the phase II PALOMA 1 ([49] Finn R.S. ASCO 2017) showed a 
numerical but not statistically significant superiority of the combination treatment versus the 
single agent arm. However, it must be noted that this study was not powered to detect a significant 
difference in overall survival. PALOMA-3 demonstrated a statistically insignificant 
improvement in median overall survival of 34.9 months for palbociclib plus fulvestrant, versus 
28.0 months for fulvestrant plus placebo (hazard ratio for death, 0.81; 95% CI 0.64-1.03; p=0.09) 
[50]. Overall survival data from the first-line PALOMA-2 study are not yet mature. 
The toxicity profile of palbociclib appears very favorable. In the above-mentioned single agent 
trial [46], side effects were mainly hematological, in line with data from the phase 1 trials. Grade 
3 and 4 toxicities were limited to transient neutropenia (50%) and thrombocytopenia (21%), and 
all other toxicities were grade 1/2. Similarly, in the PALOMA-1 study, the most common adverse 
events in the combination arm were neutropenia, leucopenia, fatigue and anemia [47]. In 
particular, grade 3-4 neutropenia was reported in 54% of the patients in the combination arm 
versus 1% of the patients in the letrozole arm. Of note, no cases of febrile neutropenia or 
neutropenia-related infections were reported and discontinuation rates due to adverse events were 
13% in the combination arm versus 2% in the letrozole arm. This was further confirmed in the 
larger PALOMA -2 trial where the most common grade 3 or 4 adverse events were neutropenia 
(occurring in 66.4% of the patients in the palbociclib– letrozole group vs. 1.4% in the placebo–
letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 
0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib–letrozole group 
and in none of the patients in the placebo–letrozole group. Permanent discontinuation of any trial 
treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib–letrozole 
group and in 13 patients (5.9%) in the placebo–letrozole group [41]. Also in PALOMA-3, similar 
figures were observed in terms of adverse events with toxicities being in line with previous data. 
The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with 
placebo. Hematological toxicities, especially neutropenia, are the most frequently reported 
adverse events for palbociclib [48]. A recent work investigated the mechanism of palbociclib-
induced bone marrow suppression and compared it to that induced by cytotoxic chemotherapeutic 
agents [51]. The authors demonstrated that, in contrast to chemotherapeutic agents which caused 
DNA damage and apoptotic cell death in human bone marrow mononuclear cells (hBMNCs), 
palbociclib did not induce senescence, with hBMNCs resuming proliferation following 
palbociclib withdrawal. These data, along with clinical data, confirm that the hematological 
toxicity induced by palbociclib is intrinsically different from the one observed with chemotherapy 
and is more clinically manageable, inducing less morbidity and complications. 
Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in 
patients treated with palbociclib when taken in combination with endocrine therapy. Across 
clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.4% of palbociclib-treated patients had 
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ILD/pneumonitis of any grade, 0.1% had Grade 3, and no Grade 4 or fatal cases were reported. 
Additional cases of ILD/pneumonitis have been observed in the post- marketing setting, with 
fatalities reported. 
4.8. 
Elderly patients 
Around 40% of BCs occur in women aged 65 and older and 20% in women over 75. Older 
patients have tumors with more favorable biological characteristics when compared with younger 
postmenopausal patients, i.e., a higher degree of ER and PgR expression, less peritumoral 
vascular invasion, less HER2 expression, lower proliferative rates, diploidy, and normal p53 [52]. 
However, some studies suggest that BC in the elderly is not more indolent. In a single-institution 
analysis by Sigh et al. in a subgroup of elderly patients (>70 years of age) with lymph node-
negative disease, BC appeared to be more aggressive, with a greater risk of developing distant 
metastases compared with younger patients [53]. Similarly, in another single-institution analysis 
smaller tumors seemed to be associated with increased axillary lymph node involvement [54]. 
The hypothesis made by the authors was that small BCs in older patients have different behavior 
because of decreased immune defense mechanisms related to aging. Overexpression of HER2 is 
reported in 10-15% of older BC patients [33, 40]. Jenkins et al. recently showed that among 
patients with HR+/HER2+ tumors, BC subtypes vary with age with luminal B tumors ranging 
from 20% in patients aged <60 years to 50% in patients over 60 [55]. 
HER2 directed therapy in combination with chemotherapy is the standard of care for HER2 
overexpressing BC. Elderly patients are generally underrepresented in clinical trials; only 16% 
of patients in the key studies of adjuvant trastuzumab were 60 and above [56, 57]. Subgroup 
analyses have shown that they benefit from anti-HER2 agents as much as the younger population 
[58-60]. However, in elderly populations, there is a concern for increasing toxicity, especially 
cardiotoxicity, when these patients also receive anthracycline-based chemotherapy regimens. In 
a large and recent meta-analysis of randomized and cohort studies including 29,000 women, 
cardiotoxicity increased from 2.3% in individuals <50 years to 3.5% and 4.9% in those 50-59 
years and >60 years of age [61]. In a single-arm study, patients with HER2+ node-negative BC 
received weekly paclitaxel × 12 and trastuzumab. This regimen has not been evaluated in older 
cancer patients specifically but, given its safety profile, is an attractive option [62]. Elderly 
patients are almost unrepresented in neoadjuvant trials. In Geparquinto, for example, only five of 
307 patients in the trastuzumab arm were older than 70 [63]. Due to the limited participation of 
older patients in neoadjuvant trials subgroup analyses by age are not performed. 
Limited data are available on the safety and efficacy of pertuzumab in patients ≥65 years of age. 
NeoSPHERE randomized patients up to the age of 80; no subgroup analysis by age was 
performed in this study in which patients’ median age was 50 [25]. In the Cleopatra trial no 
significant differences in efficacy of pertuzumab were observed between elderly patients aged 65 
to 75 years and adult patients aged <65 years. Diarrhea, fatigue, asthenia, decreased appetite, 
vomiting, and dysgeusia were reported more frequently in patients 65 years of age or older 
compared with younger patients. The safety profile of a Cleopatra-like regimen can be improved 
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by substituting docetaxel with paclitaxel. No febrile neutropenia or symptomatic left ventricular 
systolic dysfunction were reported in a phase II study that evaluated paclitaxel in combination 
with trastuzumab and pertuzumab as first-line treatment for advanced BC (patients median age 
53, range 26-84) [64]. No dose adjustment is necessary when pertuzumab is used in the elderly 
population ≥65 years of age [59].  
Subgroup analyses looking at the efficacy and the safety profile of the combination of CDK 4/6 
inhibitors with ET have been conducted and recently published [65, 66]. Focusing on palbociclib, 
Rugo and colleagues have conducted a pooled analysis of data from elderly patients enrolled in 
randomized phase 2 and 3 trials of palbociclib (PALOMA studies). Overall, among 872 patients 
treated with palbociclib plus ET, 221 patients (25%) were aged ≥65-74 years while 83 (10%) 
were aged ≥75 years. Amongst patients aged ≥65 years, 218 (of whom 56 were 75 years old or 
older) were treated with palbociclib plus letrozole (PL) as first-line therapy, while 86 (of whom 
27 were aged ≥75 years) were treated with palbociclib plus fulvestrant. In patients treated with 
PL, median PFS was significantly improved with the addition of palbociclib to the AI in all age 
groups. No new safety concerns were identified for palbociclib in elderly patients. Hematologic 
toxicities were the most frequently registered AEs during palbociclib treatment across all age 
groups. Most events were of grade 1 or 2 severity, with the exception of neutropenia and 
leukopenia: neutropenia was reported in 81% of patients treated with palbociclib vs 5% of 
patients in control group, with similar incidence among patients aged 65-74 years (77% vs 1%) 
and higher incidence in the ≥75 years-old subgroup (90% vs 3%). Febrile neutropenia was 
reported in 11 patients receiving palbociclib, including 2 (1%) aged 65-74 years and 2 (1%) aged 
≥75 years. Treatment discontinuation due to AE occurred in 77 (9%) in the palbociclib group vs 
22 (5%) in the control group. Among patients aged ≥65-74 years, 28 (13%) in the palbociclib 
group and 8 (6%) in the control group discontinued because of AEs, compared with 16 patients 
(19%) and 4 (13%) aged ≥75 years. The most common AE leading to permanent discontinuation 
across all age groups was neutropenia. The authors presented also pharmacokinetics data 
indicating that no dose adjustment of palbociclib based solely on age is required in elderly 
patients.  
Elderly patients are under-represented in clinical trials and as such, inclusion of older women and 
the prospective utilization of geriatric assessment instruments in those 65 years will produce 
valuable safety and efficacy data within this subpopulation. 
4.9. 
Biomarkers for CDK4/6 inhibitor activity 
Currently, there is a lack of biomarkers to identify patients more likely to achieve a response to 
CDK4/6 inhibitors. Efforts have been made towards the identification of single biomarkers in the 
CyclinD1/CDK4-6/RB1 pathway itself or in other co-activating pathways such as the PI3K 
pathway, but have proven unsuccessful so far. This suggests that single biomarkers may not 
capture the complex biology of resistance to CDK4/6 inhibitors and that a more thorough 
evaluation of the pathway activity may be necessary. 
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Genetic loss of RB1 is a marker of primary resistance to CDK4/6 inhibitors but it is uncommon 
in HR+ or HER2+ subtypes. Recent studies have shown that functional loss of the 
CyclinD1/CDK4-6/Rb pathway can be measured by gene-expression studies [67]. Several gene-
signatures of RB-loss have been developed which have shown to be prognostic in BC subtypes 
as well as predictive of response to neoadjuvant chemotherapy [68, 69]. 
A recently developed gene signature of functional loss of Rb (RBsig) that is prognostic in luminal 
BC subtypes can predict response to the CDK4/6 inhibitor palbociclib in cell line models of BC 
[70]. In particular, cell lines with increased levels of RBsig (RBsig HIGH) are among the most 
resistant to palbociclib treatment. 
Additionally, preliminary data suggest that the RBsig might be also predictive of response to 
chemotherapy + trastuzumab in ER+/HER2+ BC patients. Indeed, we performed a retrospective 
in-silico study using publicly available datasets of gene-expression data (10 studies) obtained 
from a total of 514 HER2+ BC patients treated with neo-adjuvant chemotherapy +/- anti-HER2 
therapy. For these patients, we computed the RBsig and correlated the RBsig expression with 
clinical outcome. The pCR rate to neoadjuvant CT + anti-HER2 for patients with RBsig LOW 
expression was significantly lower than the pCR rate for patients with RBsig HIGH expression. 
Results were similar for patients receiving neoadjuvant CT alone. Of note, the relationship 
between RBsig and pCR was observed only in HER2+/ER+, and not in HER2+/ER− tumors, 
suggesting that, as expected, RBsig seems to be relevant only in tumors with a luminal phenotype. 
These data suggest that RBsig identifies a subset of HR+/HER2+ patients (RBsig LOW) who 
derive little benefit from chemotherapy. 
Further validation of RBsig has been shown within the phase III NeoALTTO study, a neoadjuvant 
trial involving women with HER2+ primary breast cancer, which originally showed that 
pathological complete response (pCR) rates were significantly improved in patients receiving 
paclitaxel plus dual HER2 blockade in the form of trastuzumab and lapatinib compared with 
paclitaxel given with either of the two anti-HER2 agents alone[21]. RNA sequencing data from 
pre-treatment biopsies derived from NeoALTTO were collected, with RBsig status subsequently 
correlated with pCR. Overall, the pCR rate was significantly higher in patients with RBsig HIGH 
tumours than those with RBsig LOW (35% versus 18% respectively; p=0.01). In the subset of 
patients with HR+/HER2+ disease, a remarkably low pCR rate was observed in those with RBsig 
LOW status (11%), versus those with RBsig HIGH status (28%) [71]. 
Taken together, our data suggest that, among patients with ER+/HER2+ BC, those with RBsig 
HIGH derive benefit from chemotherapy and might be resistant to CDK4/6 inhibitors. On the 
other end, patients with RBsig LOW who derive little benefit from chemotherapy may benefit 
from CDK4/6 inhibitors. 
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4.10. Trial hypothesis 
Based on this rationale, we hypothesize that the CDK4/6 inhibitor palbociclib in combination 
with the anti-HER2 trastuzumab and the ET letrozole may be active as neoadjuvant therapy in 
patients with ER+/HER2+ BC, especially in the subset of RBsig LOW patients. 
We also hypothesize that patients with RBsig HIGH ER+/HER2+ BC might be particularly 
sensitive to neoadjuvant chemotherapy with paclitaxel and trastuzumab. 
4.11. Overall risk-benefit assessment 
Patients with operable HR+/HER2+ BC represent a population for whom standard treatment 
options include either surgery, most of the time followed by adjuvant chemotherapy + anti-HER2 
agents, or NAT. In patients considered fit for chemotherapy, the latter would consist of 
chemotherapy plus anti-HER2 agents in most cases, as per current recommendations. 
We hypothesize that chemotherapy could be safely avoided in this population by using a 
combination of ET, trastuzumab plus pertuzumab and palbociclib. This regimen would be 
substantially less toxic compared to standard chemotherapy. 
The setting of the NAT is particularly suitable to test our hypothesis because it supports easy 
monitoring of the effects of therapy therefore minimizing the risk of offering a sub-optimal 
treatment in the experimental arm. Also, tissue biopsies for the evaluation of the RBsig from each 
patient may be acquired as part of routine clinical practice, therefore limiting the need for invasive 
procedures to obtain tissue samples. 
The available data provide scientific rationale for the combination of palbociclib, letrozole and 
trastuzumab plus pertuzumab in this patient population. 
4.12. Rationale for the trial design 
This is an open label, international, phase II neoadjuvant trial with the primary objective to 
explore the interaction between the RBsig status (HIGH or LOW, as determined centrally on the 
mandatory pre-treatment biopsy collected as FFPE specimen) and treatment activity, assessed by 
pathological complete response (pCR), of palbociclib + letrozole versus paclitaxel when 
administered in combination with trastuzumab plus pertuzumab for ER+/HER2+ primary BC. 
The neo-adjuvant setting was chosen to evaluate these therapy combinations in a short time-frame 
and to provide access to biomaterial both at baseline and after the end of the treatment, at surgery. 
Palbociclib is a potent, highly selective, reversible, orally active, inhibitor of CDK 4/6. This 
compound prevents progression of the cell cycle from G1 into the S phase, therefore inhibiting 
cell growth. CDK4/6 is a key downstream effector of both the ER and HER2 pathways, 
representing a major driver of the proliferation and growth of HR+/HER2+ BC cells. In 
preclinical experiments, palbociclib synergizes with anti-estrogens and also with trastuzumab to 
cause tumor regression in ER + and HER2+ BC cell lines.  
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Clinical data from the HR+/HER2 negative setting show that combinations of palbociclib and 
letrozole are safe and effective. These combinations have not yet been tested in the HR+/HER2+ 
population that we include in this trial. However, combinations of trastuzumab and ET, including 
letrozole have shown to be safe and to have some additional activity compared to ET alone in the 
HR+/HER2+ population. Therefore, the role of palbociclib in addition to letrozole and 
trastuzumab plus pertuzumab needs to be further studied. Of note the combination of 
trastuzumab, pertuzumab, palbociclib and fulvestrant has been recently evaluated in the context 
of a neoadjuvant trial. The four drug regimen was well tolerated and led to a 30% pCR in breast 
and 27% in breast and axilla and to a 97% clinical response rate. The authors concluded that 
overall the data support further evaluation of the approach of multi-signaling block including 
CDK4/6 inhibition in HER2+ and ER+ BC [72]. 
Current standard of care for treatment of HER2+ BC incorporates chemotherapy and anti-HER2 
agents, with chemotherapy regimens of sequential anthracyclines and taxanes, used as single 
agents or in combination with other chemotherapy drugs. Trastuzumab is often administered 
concurrently with a single agent taxane to avoid the possible additive cardiac toxicity of 
combinations of anthracycline containing regimens and trastuzumab. Additional chemotherapy, 
depending on the schedule used pre-operatively, can be administered following surgery. 
Combinations of chemotherapy and anti-HER2 therapy may result in excessive toxicity in 
patients with ER+ and HER2+ disease, and a non-chemotherapy-based treatment may provide a 
less toxic treatment without compromising efficacy. However, endocrine therapy alone may not 
be a sufficient partner for anti-HER2 agents. 
A regimen of weekly paclitaxel and trastuzumab plus pertuzumab was chosen as the comparator 
arm in this trial. This was based on a twofold rationale: i) the particular features of patients 
included (patients with ER+ and HER2+ BC of limited stage), representing a population where 
more aggressive chemotherapy may not be justified, and ii) considering that patients participating 
in the trial may receive additional treatment after surgery, at the discretion of the Investigator. As 
outlined in the background section, previous trials in this setting have used different schedules of 
paclitaxel and trastuzumab, and there is no currently defined standard schedule. Duration of the 
preoperative trastuzumab + paclitaxel treatment varies among clinical trials, ranging from 12 
(neoALTTO) to 16 weeks (CALGB40601) of continuous treatment.  
Preclinical and clinical rationale exists to support the proposal that palbociclib may represent a 
valuable option for increasing the activity of ET and anti-HER2 agents, such that a triple 
combination with these agents could prove superior to a standard treatment with chemotherapy 
and anti-HER2 agents. 
Additionally, further data suggest that the substantial heterogeneity in response observed within 
the HR+/HER2+ population may be in part resolved by classifying these tumors by means of the 
RBsig status. This marker may represent a tool to identify the patients who are more likely to 
benefit from a chemotherapy-free regimen in this population 
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The optimal duration of endocrine + anti-HER2 therapy in the pre-operative setting has not been 
finally determined, with studies suggesting that extending the duration of the combination 
treatment from 12 to 24 weeks led to improved outcomes (TBCR-023). We hypothesize that the 
combination of palbociclib, letrozole and trastuzumab plus pertuzumab proposed in this trial will 
be more efficacious compared to the combinations of anti-HER2 agents and ET reported in other 
trials. Therefore, we set the duration of treatment in the experimental arm to 16 weeks, consisting 
of 4 cycles of palbociclib. 
The choice of administering paclitaxel in 12 weekly doses over a 16 week period (day 1,8,15 
every 28 days) was chosen to match the minimum number of weekly paclitaxel administrations 
with the total duration of 16 weeks of treatment in the experimental arm. It also matches the 
paclitaxel + trastuzumab schedule used in the NSABP B-41 trial. 
Around 40% of BCs occur in women aged 65 and older. Of these, 10-15% have tumors that 
overexpress HER2 [33, 40]. Jenkins et al. recently showed that among patients with HR+/HER2+ 
tumors, BC subtypes vary with age with luminal B tumors ranging from 20% in patients aged 
<60 years to 50% in patients over 60 [55]. Elderly patients are generally underrepresented in 
clinical trials; subgroup analyses have shown that they benefit from anti-HER2 agents as much 
as the younger population [58, 59, 73]. Overall a higher incidence of adverse events has been 
observed in the elderly mainly related to the chemotherapy backbone of the treatment [59]. For 
this trial, we have therefore chosen 4 cycles of weekly paclitaxel with a 3 out of 4 weeks schedule 
[74]. Palbociclib can be safely and effectively administered to older patients without need for 
dose adjustment based solely on age [66]. Treatment de-escalation, namely harnessing and taking 
maximum advantage of targeted therapies vs conventional treatment (chemotherapy) in order to 
limit side effects, is particularly appealing in the older population. Active enrollment of older 
women and prospective utilization of geriatric assessment instruments in all participating women 
aged 65 will provide much-needed safety and efficacy data in this under-represented population. 
5. 
Trial objectives and endpoints 
5.1. 
Primary objective 
The primary objective is to explore the interaction between the RBsig status (HIGH or LOW, as 
determined centrally on the mandatory pre-treatment biopsy collected as an FFPE specimen) and 
treatment activity, assessed by pathological complete response (pCR), of palbociclib + letrozole 
versus paclitaxel when given with trastuzumab plus pertuzumab for ER+/HER2+ primary BC. 
The pre-treatment biopsy will be analyzed at the end of the trial by gene-expression profiling to 
assess RBsig status. 
5.2. 
Primary endpoint 
Pathological complete response pCR, defined as absence of invasive tumor cells in the breast and 
in the axillary lymph nodes at the time of surgery (ypT0/ypTis ypN0). 
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5.3. 
Secondary objectives 
To evaluate: 
 pCR in breast only (ypT0/ypTis) 
 Objective response prior to surgery, defined as partial or complete response assessed 
physically and by ultrasound and mammography 
 Tolerability, as defined by adverse events according to CTCAE version 5 
 Rate of breast-conserving surgery 
5.4. 
Correlative objectives 
Evaluations may be done to identify: 
 molecular characteristics of responding tumors by immunohistochemistry (IHC), 
fluorescence in situ hybridization (FISH), gene expression 
 factors at baseline and prior to surgery predictive of response to randomized treatments 
 Ki67 proliferation marker changes between baseline and residual invasive tumor at 
surgery 
 For subgroup of women aged 65 years, features in geriatric assessments which correlate 
with (lack of) tolerability of trial treatment 
6. 
Trial design, duration and termination 
6.1. 
Trial design 
This is an international, multi-center, randomized phase II trial that will randomize 
postmenopausal women with histologically confirmed ER+, HER2+ primary breast cancer to 
receive the combination of palbociclib plus letrozole plus trastuzumab plus pertuzumab or 
paclitaxel plus trastuzumab plus pertuzumab during a treatment period of 16 weeks prior to 
surgery. Patients will be randomized in a ratio of 1:1. 
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6.2. 
Trial schema 
 
6.3. 
Treatment 
Patients will be randomized in a 1:1 fashion to: 
Arm A: Paclitaxel 80 mg/m2 i.v. on day 1, 8, 15 every 28 days for 4 cycles 
Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 3 weeks for a total 
of 5 doses 
 
Arm B: Palbociclib 125 mg/day orally for 21 days followed by 7 days’ rest, for four 28-day 
cycles 
 
Letrozole 2.5 mg/day orally for 16 weeks 
Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 3 weeks for a total 
of 5 doses 
Definitive surgery should be performed not later than 4 weeks after the final dose of any of the 
drugs in the combinations described above. 
6.4. 
Clinical evaluations 
Tumor assessments will be performed by ultrasound and mammography at screening (prior to 
start of protocol therapy), and before surgery. Tumor measurements by caliper will be assessed 
at the same time points and after 2 cycles (8 weeks) of therapy. All patients who are discontinued 
from the protocol therapy for any reason will be documented within 30 days after surgery. If a 
patient does not undergo surgery, the end of treatment visit should take place within 30 days after 
her last dose of trial treatment.  
Early BC, 
ER+, HER2+,
postmenopausal,
Neo-adj. 
treatment 
planned
R
A:
paclitaxel
trastuzumab
pertuzumab
B:
palbociclib
letrozole
trastuzumab
pertuzumab
surgery
surgery
Week   
1     2     3     4     5     6     7     8     9    10    11   12   13   14   15   16  
+
+
staging
FFPE sample
FFPE sample
Pertuzumab: 
loading dose
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6.5. 
Biological evaluations 
An FFPE tumor specimen of the pre-treatment biopsy must be submitted for all patients. At 
surgery, one FFPE tumor specimen for central review and translational research has to be 
retained, unless no residual invasive tumor is found at surgery. Both specimens will be submitted 
to the IBCSG Central Pathology Office in Milan, Italy, and will be analyzed by gene-expression 
profiling to assess RBsig status. The laboratory analyzing RBsig will be defined and carefully 
selected closer to the time of the analysis, based on their scientific track record. 
Gene-expression profiling will also be utilized to explore potential biomarkers of response or 
resistance to treatment.  
Additionally, studies on proteins and genes involved in the ER and RB1 pathway will be 
conducted using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) on 
both pre-treatment and surgical samples. 
6.6. 
Sample size and trial duration 
A total of 144 patients will be randomized by approximately 30 sites in Belgium, Italy, France 
and Switzerland. 
The enrollment is expected to occur over a period of 24 months after a start-up period of 6 months 
as the trial is being activated by participating Centers. Individual patient’s trial participation ends 
with the End of Treatment visit to be done within 30 days after surgery. The final trial analysis is 
expected 41 months after the randomization of the first patient. 
7. 
Patient selection 
7.1. 
Inclusion criteria  
7.1.1. 
Histologically confirmed invasive breast cancer, with the following characteristics: 
- Early breast cancer with tumor size >1 cm (as measured by at least one of the required 
examination methods of clinical examination, mammography and ultrasonography) 
- No clinical evidence of regional lymph node metastasis (via physical and/or 
radiological exam) (cN0) OR  
- Clinical evidence of cN1 status, defined by nodal involvement limited to clinically or 
radiologically detectable metastasis to movable ipsilateral level I, II axillary lymph 
node(s) 
- No evidence of metastasis (M0) 
7.1.2. 
Postmenopausal, defined by women with: 
- Prior bilateral surgical oophorectomy; OR 
- Amenorrhea and age 60 years; OR 
- Age <60 years and amenorrhea for 12 or more consecutive months in the absence of 
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alternative pathological or physiological cause (including chemotherapy, tamoxifen, 
toremifene, ovarian suppression, or hormonally-based contraception) plus FSH and 
serum estradiol levels within the laboratory’s reference ranges for postmenopausal 
women 
7.1.3. 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (see Table 1) 
7.1.4. 
Primary tumor must have positive estrogen receptor (ER) ≥10%  
7.1.5. 
Primary tumor must be HER2-positive (by IHC and/or ISH) 
7.1.6. 
Baseline LVEF ≥55% measured by Echocardiography (preferred) or MUGA scan 
7.1.7. 
Normal hematologic status: 
- Absolute neutrophil count ≥1500/mm3 (1.5 × 109/L) 
- Platelets ≥100 × 109/L 
- Hemoglobin ≥9 g/dL (≥90 g/L). 
7.1.8. 
Normal renal function: serum creatinine ≤1.5 upper limit of normal (ULN). 
7.1.9. 
Normal liver function: 
- Serum total bilirubin ≤1.5 × ULN. In the case of known Gilbert’s syndrome, a higher 
serum total bilirubin (<2 × ULN) is allowed 
- AST or ALT ≤2.5 × ULN 
- Alkaline phosphatase ≤2.5 × ULN 
7.1.10. Written Informed Consent (IC) must be signed and dated by the patient and the 
Investigator prior to randomization. 
7.1.11. The patient has been informed of and agrees to data transfer and handling, in accordance 
with national data protection guidelines. 
7.1.12. The patient agrees in writing to make tumor samples (mandatory diagnostic core biopsy 
and surgical specimen) available for submission for central pathology review and to 
conduct translational studies as part of this protocol. 
NOTE: Central Pathology Review on the primary tumor is mandatory for this trial, but 
patients will be evaluated for eligibility according to tumor characteristics as determined 
by the local pathologist. Both the diagnostic breast core biopsy specimen and the 
final breast surgical specimen (unless no residual invasive tumor is found at surgery) 
must be submitted for Central Pathology Review which will be done by the IBCSG 
Central Pathology Office in Milan, Italy. 
7.2. 
Exclusion criteria 
7.2.1. 
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration 
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or skin nodules) (T4 according to AJCC 8th edition cancer staging TNM) 
7.2.2. 
Inflammatory breast cancer 
7.2.3. 
Bilateral invasive breast cancer 
7.2.4. 
Received any prior treatment for primary invasive breast cancer 
7.2.5. 
Any active tumor of non-breast-cancer histology 
7.2.6. 
Any of the following in the previous 6 months: myocardial infarction, severe/unstable 
angina pectoris, ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2, atrial 
fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure (NYHA functional classification ≥II, see Table 2 below), 
cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary 
embolism. 
7.2.7. 
Concurrent disease or condition that would make the subject inappropriate for study 
participation or any serious medical disorder that would interfere with the subject’s 
safety. 
7.2.8. 
Contraindications or known hypersensitivity to any of the trial medications or 
excipients. 
7.2.9. 
Treatment with any investigational agents within 30 days prior to expected start of trial 
treatment. 
7.2.10. Any GI disorder that may affect absorption of oral medications, such as malabsorption 
syndrome or status post major bowel resection. 
7.2.11. Evidence via physical and/or radiological exam of cN2 or cN3 nodal involvement 
defined by: metastasis to ipsilateral level I, II axillary lymph nodes that are clinically 
fixed or matted, OR involvement of ipsilateral infraclavicular, internal mammary and/or 
supraclavicular lymph node(s) 
7.2.12. History of extensive disseminated/bilateral or known presence of interstitial fibrosis or 
interstitial lung disease, including a history of pneumonitis, hypersensitivity 
pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and pulmonary fibrosis. 
A history of prior radiation pneumonitis is not considered an exclusion criterion. 
 
 
Table 1. 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction. 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light housework, office work. 
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PS 2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
 
Table 2. 
NYHA functional classification 
Class 
Functional Capacity: How a patient with cardiac disease feels during physical 
activity. 
I 
Patients with cardiac disease but resulting in no limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort 
increases. 
8. 
Randomization and stratification 
This trial will use a web-based randomization system. Specific details for randomization are in 
the “IBCSG Registration/Randomization Procedures Manual” which is available on the IBCSG 
website (www.ibcsg.org). 
8.1. 
Randomization  
8.1.1. 
Patient needs to give informed consent to trial participation, screening procedures and 
biomaterial submission. 
8.1.2. 
Verify eligibility (see Section 7). Screening procedures need to be done within 28 days 
(hematology within 14 days) before randomization. 
8.1.3. 
For subgroup of women aged 65 years: Complete the Geriatric Assessment G8 
questionnaire (Form 55-G8) and calculate the total score needed for the stratification. 
8.1.4. 
Access the IBCSG Registration/Randomization System (Registration: Step 1) and 
provide the requested information as indicated on the Confirmation of Randomization 
(55-A) Form. The date the Informed Consent Form was signed by the patient and the 
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date signed by the Investigator are both required to complete randomization. 
The IBCSG Registration/Randomization System will provide the Patient ID 
(randomization number) and treatment assignment via email. 
8.1.5. 
Submit the Confirmation of Randomization (55-A) electronic case report form (eCRF) 
via DFexplore. 
8.2. 
Randomization Help Desk 
The IBCSG Data Management Center (located at Frontier Science and Technology Research 
Foundation (FSTRF)) is responsible for developing and maintaining the IBCSG 
Registration/Randomization System. The Help Desk includes technical personnel and 
administrators of the registration programs at the Data Management Center in Amherst, NY, 
USA. 
The Help Desk is available round the clock 7 days per week, except for New Year's Eve, 
Memorial Day, Independence Day, Thanksgiving Day, Christmas Day. 
FSTRF Randomization Help Desk 
Frontier Science & Technology Research Foundation (FSTRF) 
4033 Maple Rd, Amherst, NY 14226 USA 
Phone: +1 716 834 0900 Extension 7301 
Fax: +1 716 832-8437 
Email: bc.helpdesk@frontierscience.org  
8.3. 
Stratification 
For randomization, patients will be stratified by 
 Age and G8 score (<65 years vs ≥65y and G8 score >14 vs ≥65y and G8 score ≤14), 
see 14.1.14 
 No 
clinical 
evidence 
of 
regional 
lymph 
nodes 
metastasis 
(cN0) 
vs  
nodal involvement limited to clinically detectable metastasis to movable ipsilateral 
level I, II axillary lymph node(s) (cN1) 
Dynamic institution balancing will be used in order to balance randomized assignments within 
institutions. 
9. 
Trial drugs formulation and handling 
Palbociclib is the Investigational Medicinal Product (IMP) used in this trial; IMP will be supplied. 
Trastuzumab and pertuzumab are Non-Investigational Medicinal Products (NIMPs) and used as 
background treatment in both arms. Both will be supplied. 
Letrozole and paclitaxel are part of standard neoadjuvant treatment and will be sourced locally. 
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Complete details of the trial drug logistics, distribution, packaging, labeling, storage and handling 
as well as accountability are described in a separate Drug Supply Manual. This document is 
available for reference by the pharmacist and trial personnel. 
9.1. 
Palbociclib 
9.1.1. 
Formulation 
Refer to the current version of the palbociclib SPC (Summary of Product Characteristics) for 
pharmaceutical formulation information. 
9.1.2. 
Packaging and labeling 
IMP will be affixed with a clinical label in accordance with regulatory requirements. 
9.1.3. 
Storage and handling 
Supplies must be stored at 15°C to 30°C in a secure, limited-access location under the storage 
conditions specified on the label. The Investigator shall take responsibility for and shall take all 
steps to maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations.  
9.2. 
Trastuzumab  
Trastuzumab is used in accordance with the currently approved SPC (Summary of Product 
Characteristics), and with the applicable EU legislation and current guidelines.  
9.2.1. 
Packaging and labeling 
Supplies will be packaged and labeled in accordance with regulatory requirements. 
9.2.2. 
Storage and handling 
Supplies must be stored at 2°C to 8°C in a secure, limited-access location under the storage 
conditions specified on the label. 
9.3. 
Pertuzumab 
Pertuzumab is used in accordance with the currently approved SPC (Summary of Product 
Characteristics), and with the applicable EU legislation and current guidelines. Supplies will be 
packaged and labelled in accordance with regulatory requirements. 
9.3.1. 
Packaging and labeling 
Supplies will be packaged and labelled in accordance with regulatory requirements. 
9.3.2. 
Storage and handling 
Supplies must be stored at 2°C to 8°C in a secure, limited-access location under the storage 
conditions specified on the label. 
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9.4. 
Paclitaxel 
Paclitaxel is used in accordance with the currently approved SPC (Summary of Product 
Characteristics), and with the applicable EU legislation and current guidelines. 
9.5. 
Letrozole 
Letrozole is used in accordance with the currently approved SPC (Summary of Product 
Characteristics), and with the applicable EU legislation. 
10. 
Treatment 
10.1. Trial treatments 
Trial treatment should start within one week after randomization. Trial treatments will be 
administered in four 28-day cycles, or until protocol treatment is discontinued (see Section 10.8).  
Treatment administration should comply with the protocol; compliance will be monitored by the 
Monitoring Team and Data Management Center. Complete details of dispensation and dosing are 
recorded on the eCRF.  
10.2. Treatment Administration 
10.2.1. Palbociclib administration 
Palbociclib will be administered orally at a dose of 125 mg per day continuously dosed for 
21 days followed by 7 days rest; repeated at each subsequent cycle. The duration of a cycle of 
treatment is 28 days. A deviation of 1-3 days from this schedule is permitted. On treatment day 
1, patients will be provided with trial treatment for self-administration at home. Sufficient 
capsules should be provided to cover administration until next scheduled visit. The patients will 
be instructed to take the trial treatment exactly as prescribed, promoting compliance. 
Palbociclib intake should be documented by the patient on the patient diary which will be 
dispensed for each cycle. 
Patients should be instructed to take the palbociclib with food. Concomitant intake of proton 
pump inhibitors does not significantly affect the overall exposure to palbociclib when taken with 
food. Patients should be instructed to swallow palbociclib capsules whole and not to chew them 
prior to swallowing. No capsule should be ingested if it is broken, cracked, or otherwise not intact. 
Patients should be encouraged to take their dose at approximately the same time each day. 
Patients should be instructed to record daily administration of the trial drug in the patient diary, 
and to bring the diary to the clinic at each visit. The Investigator should keep a copy in the patient 
file. 
10.2.2. Trastuzumab administration 
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Trastuzumab will be administered at a dose of 600 mg, irrespectively of the patient body weight 
for a total of 5 doses. Trastuzumab will be administered by s.c. injection according to local 
guidelines.  
10.2.3. Pertuzumab administration 
Pertuzumab will be administered at a loading dose of 840 mg on day 1 of cycle 1, and then every 
3 weeks at a dose of 420 mg for a total of 5 doses. Pertuzumab will be administered over 30-60 
minutes (60 minutes for 840 mg/kg loading dose) by i.v. infusion according to local guidelines.  
10.2.4. Paclitaxel administration 
Paclitaxel will be administered at a dose of 80 mg/m2 on days 1, 8, and 15 of every cycle. The 
administration is by i.v. infusion according to local guidelines.  
10.2.5. Letrozole administration 
Letrozole will be taken as one tablet of 2.5 mg/day orally continuously during four cycles of 28 
days each for a total of 16 weeks. On day 1 of each cycle, one bottle of letrozole tablets will be 
dispensed to the patient. 
Letrozole intake should be documented by the patient on the patient diary which will be dispensed 
for each cycle. 
10.3. Dose delays and modifications for palbociclib 
In the event of significant treatment-related toxicity, palbociclib dosing may be interrupted or 
delayed and/or reduced as described below. In the event of multiple toxicities, dose modification 
should be based on the worst toxicity observed. Patients are to be instructed to notify Investigators 
at the first occurrence of any adverse sign or symptom. 
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, 
dyspnea). In patients who have new or worsening respiratory symptoms and are suspected to have 
developed ILD/pneumonitis, interrupt palbociclib immediately and evaluate the patient. 
Permanently discontinue palbociclib in patients with severe ILD or pneumonitis. 
10.3.1. Dose delays 
Patients experiencing the following adverse events should have their treatment of palbociclib 
interrupted/delayed until criteria for retreatment (see below) are met:  
 Grade 3 or 4 neutropenia (ANC<1000/mm3) associated with a documented infection 
or fever 38.5C; 
 Grade 3 or 4 thrombocytopenia (Platelet count <50,000/mm3); 
 Non-hematologic toxicity persisting despite optimal medical treatment if either grade 
2 lasting more than 3 weeks, or grade 3 (including nausea, vomiting, diarrhea, and 
hypertension). Patients should not hold or discontinue palbociclib for non-
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hematological side effects potentially or likely related to concomitant antihormonal 
therapy (e.g., grade 3 or long lasting grade 2 joint pain) as per the Investigator’s 
judgment; 
 In case of concurrent >3×ULN ALT and 2×ULN total bilirubin, the dose needs to be 
held while the cause is being investigated. 
Appropriate follow up assessments should be done until adequate recovery occurs as assessed by 
the Investigator. Criteria required before treatment can resume are described in the Retreatment 
Criteria Section (see below). 
Doses may be held as needed until toxicity resolution. Depending on when the adverse event 
resolved, a treatment interruption may lead to the patient missing all subsequent planned doses 
within that same cycle or delayed initiation of the subsequent cycle.  
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
resuming treatment in that cycle is allowed. Doses omitted for toxicity are not replaced within 
the same cycle. The need for a dose reduction at the time of treatment resumption should be based 
on the criteria defined in the Section 10.3.2, unless expressly agreed otherwise following 
discussion 
between 
the 
Investigator 
and 
IBCSG 
(please 
contact 
ibcsg55_touch@frontierscience.org). If a dose reduction is applied in the same cycle, the patient 
will need to return to the clinic to receive new drug supply. 
In the event of a treatment interruption due to toxicity and for reasons other than treatment-related 
toxicity (e.g., non-cancer related surgery) lasting >3 weeks, treatment resumption will be decided 
in consultation with IBCSG (please contact ibcsg55_touch@frontierscience.org). 
In the event of palbociclib related adverse effects, doses should be reduced rather than delayed; 
the total cumulative delay across all 4 cycles should not exceed 4 weeks. If the total delay is >4 
weeks, palbociclib should be stopped and treatment should continue with the other drugs. 
Retreatment Criteria 
Retreatment with palbociclib following treatment interruption for treatment related toxicity or at 
the start of any new cycle may not occur until all of the following parameters have been met: 
 Platelet count 50’000/mm3;  
 ANC 1000/mm3 and no fever; 
 Grade 3 or higher treatment-related non-hematologic AEs considered related to 
palbociclib (including, nausea, vomiting, diarrhea, and hypertension only if persisting 
despite optimal medical treatment), have recovered to grade ≤1 or baseline. 
If a treatment delay results from decline in hematologic parameters, the frequency of blood count 
assessments should be adjusted as clinically indicated. 
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