DESCARTES: De-ESCAlation of RadioTherapy in Patients With Pathologic Complete rESponse to Neoadjuvant Systemic Therapy
Phase: NA
Conditions: Breast Cancer
Sponsor: The Netherlands Cancer Institute

DESCARTES study
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DESCARTES study: De-ESCAlating RadioTherapy in patients with 
pathologic complete response to neoadjuvant systemic therapy 
(September 2024) 

DESCARTES study
 
 
 
PROTOCOL TITLE “DESCARTES study: De-ESCAlating RadioTherapy in patients with 
pathologic complete response to neoadjuvant systemic therapy’’ 
 
 
Protocol ID 
Short title 
DESCARTES study 
Version 
9.0 
Date 
 September 2nd 2024 
Coordinating investigator/project F.H. van Duijnhoven, M.D, Ph.D., surgical 
leader 
oncologist 
NKI-AVL 
Plesmanlaan 121, 1066 CX Amsterdam 
T: +31(0)20 5126170 
f.v.duijnhoven@nki.nl 
Principal investigator(s) (in 
L.J.  Boersma, MD, PhD, radiation oncologist 
Dutch: hoofdonderzoeker/ 
Maastro 
uitvoerder) 
Dr. Tanslaan 12, 6229 ET Maastricht 
Liesbeth.boersma@maastro.nl 
T: +31(0)88 4455600 
J. H. Maduro. MD, PhD, radiation oncologist 
UMCG 
Hanzeplein 1, 9713 GZ Groningen 
j.h.maduro@umcg.nl 
T: +31 (0)50 3613665 
N. Russell, MD, PhD, radiation oncologist 
NKI-AVL 
Plesmanlaan 121, 1066 CX Amsterdam 
n. russell@nki.nl 
T: +31(0)20 5122134 

DESCARTES study
 
 
 
E.J.Th. Rutgers, MD, PhD, surgical oncologist 
NKI-AVL 
Plesmanlaan 121, 1066 CX Amsterdam 
e.rutgers@nki.nl 
T: +31(0)20 5122561 
J. Tol, MD, PhD, medical oncologist 
Jeroen Bosch Ziekenhuis 
Henri Dunantstraat 1, 5223 GZ 's-Hertogenbosch 
J.Tol@jbz.nl 
T: +31 (0)73 553 200 
M. Vrancken Peeters, MD, PhD, surgical 
oncologist 
NKI-AVL 
Plesmanlaan 121, 1066 CX Amsterdam 
m.vrancken@nki.nl 
T: +31 (0)512 2978 
Sponsor (in Dutch: 
Antoni van Leeuwenhoek 
verrichter/opdrachtgever) 
Plesmanlaan 121, 1066 CX Amsterdam 
Subsidising party 
Not applicable 
Independent expert 
W. van Houdt, MD, PhD 
NKI-AVL 
 w.v.houdt@nki.nl 
T +31 (0)20-5126978 

DESCARTES study
 
 
 
PROTOCOL SIGNATURE SHEET 
 
 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
Prof.dr. M.W.J.M. Wouters  
(Head of Division Surgical Oncology)  
 
 
Coordinating Investigator/Project 
leader/Principal Investigator 
F.H. van Duijnhoven, M.D, Ph.D., surgical 
oncologist 
 
Local Principal Investigator  
 

DESCARTES study
 
 
 
TABLE OF CONTENTS 
 
 
 
1. INTRODUCTION AND RATIONALE .............................................................................9 
2. OBJECTIVES ................................................................................................................12 
3. STUDY DESIGN ...........................................................................................................13 
4. STUDY POPULATION ..................................................................................................15 
4.1 
Population (base) ...................................................................................................15 
4.2 
Inclusion criteria .....................................................................................................15 
4.3 
Exclusion criteria ....................................................................................................15 
4.4 
Sample size calculation ..........................................................................................17 
5. TREATMENT OF SUBJECTS .......................................................................................18 
5.1 
Investigational product/treatment............................................................................18 
5.2 
Use of co-intervention (if applicable) ......................................................................18 
5.3 
Escape medication (if applicable) ...........................................................................18 
6. METHODS ....................................................................................................................19 
6.1 
Study parameters/endpoints...................................................................................19 
6.1.1 
Main study parameter/endpoint .......................................................................19 
6.1.2 
Secondary study parameters/endpoints (if applicable) ....................................19 
6.2 
Randomisation, blinding and treatment allocation ..................................................19 
6.3 
Study procedures ...................................................................................................19 
6.4 
Withdrawal of individual subjects ............................................................................20 
6.4.1 
Specific criteria for withdrawal (if applicable) ...................................................20 
6.5 
Replacement of individual subjects after withdrawal ...............................................20 
6.6 
Follow-up of subjects withdrawn from treatment .....................................................20 
6.7 
Premature termination of the study.........................................................................20 
7. SAFETY REPORTING ..................................................................................................21 
7.2 
AEs, SAEs and SUSARs........................................................................................21 
7.2.2 
Serious adverse events (SAEs).......................................................................21 
7.5 
Safety Committee...................................................................................................22 
8. STATISTICAL ANALYSIS .............................................................................................23 
8.1 
Primary study parameter(s) ....................................................................................23 
8.2 
Secondary study parameter(s) ...............................................................................23 
8.3 
Other study parameters..........................................................................................23 
8.4 
Interim analysis (if applicable) ................................................................................23 
9. ETHICAL CONSIDERATIONS ......................................................................................24 
9.1 
Regulation statement .............................................................................................24 
9.2 
Recruitment and consent........................................................................................24 
9.3 
Objection by minors or incapacitated subjects........................................................24 

DESCARTES study
 
 
 
9.4 
Benefits and risks assessment, group relatedness .................................................24 
9.5 
Compensation for injury .........................................................................................24 
9.6 
Incentives ...............................................................................................................25 
10. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................26 
10.1 Handling and storage of data and documents ........................................................26 
10.2 Monitoring and Quality Assurance..........................................................................26 
10.3 Amendments ..........................................................................................................26 
10.4 Annual progress report ...........................................................................................28 
10.5 Temporary halt and (prematurely) end of study report ............................................28 
10.6 Public disclosure and publication policy..................................................................28 
11. 
STRUCTURED RISK ANALYSIS...............................................................................28 
12. 
REFERENCES ..........................................................................................................29 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
 
 
 
AE 
Adverse Event 
 
ALND 
Axillary Lymph Node Dissection 
BCS 
  Breast Conserving Surgery 
BCT 
 Breast Conserving Therapy 
AR 
Adverse Reaction 
 
CA 
Competent Authority 
 
CV 
Curriculum Vitae 
 
DSMB 
Data Safety Monitoring 
 
DFS 
Disease free survival 
 
IC 
Informed Consent 
 
METC 
Medical research ethics committee (MREC); in Dutch: 
 
medische ethische toetsing commissie (METC) 
NAC 
Neoadjuvant chemotherapy 
NCI 
Netherlands Cancer Institute  
NST 
Neoadjuvant systemic therapy 
pCR 
Pathologic complete response 
rCR 
Radiologic complete response 
(S)AE 
(Serious) adverse event 
Sponsor 
The sponsor is the party that commissions the organization 
of performance of the research, for example a 
pharmaceutical company, academic hospital, scientific 
organization or investigator. A party that provides funding 
for a study but does not commission it is not regarded as 
the sponsor, but referred to as a subsidising party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
WMA 
World Medical Association 
 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: 
Wet Medisch-wetenschappelijk Onderzoek met Mensen) 
 
 

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SUMMARY 
Rationale: 
Over 60% of the women who are diagnosed with breast cancer in the Netherlands are 
treated with systemic treatment, which may be administered before (neoadjuvant systemic 
therapy, NST) or after (adjuvant) locoregional treatment. Depending on the subtype, 
10-75% of patients will have a pathologic complete response (pCR) after NST. In this patient 
group, risk of local recurrence is extremely low. The administration of adjuvant radiotherapy 
in these patients is not expected to contribute significantly to overall survival, but may cause 
considerable morbidity. 
Objective: 
 
Primary aim: to assess whether local recurrence is acceptable when radiotherapy is omitted 
after breast conserving surgery in patients treated with NST who achieve a pathologic 
complete response. 
Secondary aim: to assess quality of life and cancer worry after omitting radiotherapy. 
 
Study design: 
 
DESCARTES is a national, multicentre, non-randomized, single-arm prospective cohort 
study. 
Study population: 
 
Patients >18 years with cT1-2, N0 HR+HER2-, HER2+(HR+/-) or TN breast cancer who are 
treated with breast conserving surgery and achieve pathologic complete response. 
Intervention: 
 
Omitting radiotherapy following breast-conserving surgery. 
 
Main study parameters/endpoints: 
 
The primary endpoint is the local recurrence rate (LRR) at 5 years. Secondary determinants 
are local non-salvageable recurrence free survival, quality of life, regional recurrence rate, 
distant recurrence free survival, disease-specific survival and overall survival. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: 
The immediate impact for participants is to be spared intensive radiotherapy and subsequent 
risk of side effects (such as pain, fatigue, possible lung damage). An expected 4% will 
develop a local recurrence within 5 years, about half of which would not have happened with 
standard radiotherapy. The majority of these local recurrences can however effectively be 
treated with salvage breast-conserving or ablative surgery and previous studies indicated 
that patient survival will not be affected.

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1.  INTRODUCTION AND RATIONALE 
 
NST is increasingly used in breast cancer treatment(1), resulting in tumour downsizing 
and increase in breast conserving surgery(BCS) rates without compromising local 
recurrence or overall survival.(2-6) The extent of tumour downsizing is largely dependent 
on breast cancer molecular subtypes with highest pCR rates in triple negative(TN) and 
HER2+ subtypes (40-88%) and pCR rates of 10-15% in HR+/HER2- breast cancer.(7-14) 
De-escalating locoregional treatment following NST cannot be achieved by omitting 
surgery, since biopsies or MRI do not accurately assess pCR. (15-17). Adjuvant whole 
breast irradiation however may be de-escalated in pCR patients who do not have an 
indication for regional irradiation.(18) 
In this patient group, risk of distant and local failure is low. Mamounas first reported 
retrospectively on cT1-3N0-2 patients treated with NST in two major clinical trials 
conducted from 1988 to 1993 and from 1995 to 2000. Only 10-year results on local 
recurrence were reported. In 225 clinically node-negative patients with pCR, local 
recurrence was 5.2 and 6.9% for patients >50 and <50 years respectively.(19) Notably, 
pCR definition included patients with residual in situ disease and axillary lymph node 
status was defined by palpation only. As the large majority of local recurrences occur 
within 5 years from treatment, especially in Her2 positive and triple-negative breast 
cancer, the reported 10-year recurrences will have included new primary cancers.(20) 
However, this overview confirmed that the absence of pCR was the most important 
predictor for locoregional recurrence with a hazard ratio of 2.77.(19) 
 
 
Recent studies including up-to-date systemic treatments and pre-NST staging with MRI 
and axillary ultrasound report considerably lower 5 year recurrence rates, as shown in 
Table 1. All studies include patients with stage I-III disease and include residual DCIS in 
pCR definition. Samples sizes for pCR patients vary between 157 and 426, with local 
recurrence rates between 1.0-3.5%, with isolated tumour cells considered pCR in the 
highest reported recurrence.  Locoregional recurrence rates in pCR patients range from 
0.0%-3.2%.(21-23) Swisher et al report recurrence rates per molecular subtype, with 
lowest rates in hormone receptor positive breast cancer.(22) Notably, 61% of patients in 
this cohort presented with node-positive disease, but LRR was not specified for cN0 
versus cN+ patients.(22)  
 
Even more recent studies investigating risk factors for DFS and OS in patients achieving 
a pCR, have reported poorer outcomes for patients with ypTis compared to ypT0, cN+ 
compared to cN0 and cT3/4 compared to cT1/2. (24-25) Although ypTis is considered a 
risk factor for poorer outcomes, it is expected that not all patients with DCIS in pre-NST 
biopsy have the same prognosis. A study by Groen et al. demonstrated that DCIS can 

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respond well to NST and reported several risk factors associated with response of DCIS 
to NST; calcifications on mammography prior to NST, treatment with dual HER2+ 
blockade and absence of calcifications or Ki67>20% in pre-NST biopsy. (26) 
 
 
 
Table 1. Local and locoregional recurrence rates following NST; *patients with non- 
inflammatory breast cancer excluded and ** no LVI, pCR or solitary residual invasive 
tumour of <2 cm 
 
 
A recent study reports on locoregional recurrence following NST when radiotherapy is 
omitted. In this series, 197 cT1-4N0-3 patients with pCR following NST and treated with 
BCS were included, 110 of which did not receive adjuvant radiotherapy.(27) Notably, 
57% of patients included in the study presented with node-positive disease and patients 
with residual in situ disease were considered as pCR. Five year local recurrence rates 
without radiotherapy are 0% for luminal and HER2 subtype, 3.1% for TNBC and 3.2% 
for luminal HER2+ breast cancer (Table 2.(27) (results obtained via personal 
communication with author) 

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Table 2. Local recurrence rates for pCR patients treated with NST and breast conserving 
surgery. For pCR definition, ypTis was included. 
 
 
The effect of omitting radiotherapy on survival was investigated by Mandish et al. in 5383 
patients with cT0-4, N0-3 breast cancer treated with NST and breast conserving surgery 
who showed pCR of both breast and lymph nodes. Of these patients, 364 did not receive 
adjuvant radiotherapy. This did not compromise survival, as 5-year OS rates did not 
significantly differ (93.6% with RT and 93% without RT, adjusted hazard ratio 1.33, 95% 
CI 0.76-2.31, p=0.3181).(28) 
 
 
Radiotherapy of the breast is associated with both short-term and long-term morbidity in 
up to 50% of patients(29-32. Radiotherapy negatively influences quality of life by long- 
term morbidity consisting of secondary lung cancer, cardiac mortality, painful fibrosis of 
the breast and impaired cosmetics.(29-34) De-escalating local therapy by partial breast 
and hypofractionated radiotherapy was shown to positively impact quality of life by 
reducing fibrosis and breast deformation.(35-37) Omitting radiotherapy altogether in 
patients with extremely low risk of local recurrence is already implemented for a group of 
older patients with low risk of recurrence following primary surgical treatment 
(NCT03375801)(TOP-1). This results in increased local recurrence rates without 
compromising survival.(28,38, 39) 
 
 
As the relation between radiotherapy and long-term side effects of breast conserving 
treatment is thus well established, omitting radiotherapy altogether can be assumed to 
further improve breast-specific quality of life. We therefore propose a single-arm study in 
which radiotherapy is omitted in eligible patients. 

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2.  OBJECTIVES 
 
 
 
Primary Objective: 
 
To show that omitting radiotherapy in patients with a pathologic complete response to NST 
 
results in a 5-year local control rate of >94%. 
 
 
 
Secondary Objective: 
 
To show that omitting radiotherapy in patients with a pathologic complete response to NST 
 
results in good quality of life without compromising cancer worry levels. 
 
To assess the 5- and 10-year local control rate, distant- and regional metastasis free survival 
and local non salvageable recurrence free survival. 

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3.  STUDY DESIGN 
 
The DESCARTES trial is a prospective single arm study investigating the effects on local control 
and quality of life of omitting radiotherapy after NST in cT1-2N0 patients who achieve breast 
and axillary pCR after NST. Eligibility of patients will be assessed at multi-disciplinary meetings. 
 
 
Women with any type of invasive breast cancer are eligible for inclusion. Patients with a history 
of breast cancer, DCIS or LCIS are excluded. Concurrent DCIS in pre-NST biopsy is allowed if 
there is no suspicion of an extensive component; patients are excluded if they have the 
combination of concurrent DCIS in pre-NST biopsy and calcifications on pre-NST 
mammography and/or non-mass enhancement on pre-NST MRI, contrast-enhanced 
mammography or breast-specific gamma imaging. Concurrent LCIS of any type in pre-NST 
biopsy is not allowed. A  marker  should  be  placed  in  the  center  of  the  tumour  before  start  
of  NST.  Contrast- enhanced breast MRI, a contrast-enhanced mammography or breast-
specific gamma imaging is conducted pre-NST for reliable  assessment of unifocal disease. 
Axillary status is  evaluated  by  ultrasound.  In  case  of  suspicious  axillary  lymph  node(s),  
fine  needle aspiration is performed for cytology analysis to confirm node-negative disease. 
Following NST, breast conserving surgery is performed. A post-NST sentinel node biopsy 
procedure (if not performed pre-NST) is performed using single or dual-tracer technique. The 
surgical specimen will be assessed by a specialized breast pathologist according to national 
guidelines. A pathologic complete response is defined as ypT0N0 (i.e. absence of invasive 
carcinoma and in-situ carcinoma in breast and axilla). In case One-Step Nucleid Acid 
Amplification (OSNA) is used to determine status of sentinel node, only negative OSNA results 
will be accepted as N0. 
 
 
 
If pCR of breast and lymph nodes is present (ypT0N0), patients may be entered into the 
single-arm study, in which radiotherapy of the breast is omitted. Adjuvant systemic therapy is 
administered according to national breast cancer guidelines. 
 
 
Patients will be followed yearly for a period of 5 years and at 10 years to assess local-
regional recurrence. Quality of life (QOL) is measured using the Patient Reported Outcome 
Measures (PROMs), which are integrated in standard care in the Antoni van Leeuwenhoek 
and other centers, and additional questionnaires containing measure not included in the 
standard PROMS set. The PROMs include the EORTC-QLQ-C30 and EORTC-QLQ-BR23. 
The 8-item Cancer Worry Scale will be used to measure if worry related to omission of 
radiotherapy may affect QOL. Two demographic variables (education level and tolerance for 
uncertainty) will be measured at baseline as these patient characteristics could be 
associated with quality of life and level 

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Baseline 
EORTC-QLQ-C30, EORTC- 
QLQ-BR23 
Education level, 12-item 
Intolerance of uncertainty 
scale, Cancer Worry Scale 
1 year after surgery 
4 years after surgery 
of experienced cancer worry and need to be considered in the analyses. The additional QOL 
questionnaires are provided simultaneously with the PROMs: the first are provided for 
baseline measurement, and the following are provided at 1 year and 4 years after surgery. 
See table 3 for an overview of the QOL measurements. 
 
All recurrences should be confirmed with pathology analysis. All lesions suspect for disease 
recurrence  are  discussed  at  multidisciplinary  meetings,  according  to  clinical  practice 
guidelines. 
 
Figure 1. Descartes trial study design 
 
 
 
 
 
PROMs 
Additional QOL 
questionnaires 
 
 
 
 
 
EORTC-QLQ-C30, EORTC- 
Cancer Worry Scale 
QLQ-BR23 
EORTC QLQ-C30 
Cancer Worry Scale, 
EORTC-QLQ-BR23 
Table 3. Overview of quality of life questionnaires

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4.  STUDY POPULATION 
 
4.1   Population (base) 
 
Eligible  patients  are  women  with  cT1-2,  N0  HR+HER2-,  HER2+(HR+/-)  or TN  breast 
cancer who achieve pathologic complete response after NST. Concurrent DCIS in pre-NST 
biopsy is allowed if there is no suspicion of an extensive component; patients are excluded if 
they have the combination of concurrent DCIS in pre-NST biopsy and calcifications on pre-
NST mammography and/or non-mass enhancement on pre-NST MRI, contrast-enhanced 
mammography or breast-specific gamma imaging. Concurrent LCIS of any type in pre-NST 
biopsy is not allowed. Patients are clinically node negative in the absence of suspect nodes 
on ultrasound and/or FDG-PET/CT, or the absence  of  tumour  cells  at  cyto-/histopathology  
in  patients  with  suspect  nodes  on ultrasound and/or FDG-PET/CT pre-NST. A marker 
should be placed in the tumour before start of NST and adequate position should be 
confirmed by mammography or ultrasound. In  case  of  suspicious  axillary  lymph  node(s),  
fine  needle  aspiration  is  performed  for cytology analysis. 
 
 
 
4.2   Inclusion criteria 
 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
Women, aged  ≥ 18 years 
 
Invasive HR positive/Her2 negative, Her2+ (ER/PR +/-) or TN breast cancer 
 
Concurrent DCIS in pre-NST biopsy is allowed if there is no suspicion of extensive 
component i.e. absence of non-mass enhancement on pre-NST MRI, contrast-
enhanced mammography or breast-specific gamma imaging and/or absence of 
calcifications on pre-NST mammography 
 
Primary tumour (T) clinical stage cT1-2 
 
Unifocal disease; confirmed by pre-NST MRI, contrast-enhanced 
mammography or breast-specific gamma imaging 
 
Clinical nodal stage 0; absence of lymph node metastases should be 
confirmed by ultrasound or FDG-PET/CT 
 
Neoadjuvant systemic treatment (NST) 
 
Marker placed in breast tumour prior to NST 
 
Breast conserving surgery performed, i.e. no mastectomy 
 
Sentinel node biopsy performed before or after NST 
 
Pathologic complete response in breast and lymph nodes, i.e. no residual 
tumour cells, DCIS or LCIS detected 
 
Written informed consent within 16 weeks following the date of surgery 
 
 

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4.3   Exclusion criteria 
 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
 
Primary tumour (T) clinical stage cT3-4 
 
Pre- or post-NST diagnosis of nodal disease including isolated tumour cells 
 
Concurrent LCIS of any type in either pre-NST biopsy or surgical specimen 
 
Patients without axillary ultrasound or FDG-PET/CT pre-NST 
 
History of breast cancer, DCIS or LCIS 
 
Synchronous contralateral breast cancer, DCIS or LCIS 
 
Synchronous M1 disease 
 
Carrier of gene mutation associated with increased risk of breast cancer, i.e. 
BRCA1, BRCA2, CHEK2, TP53 or PALB-2 

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              4.4   Sample size calculation 
 
Reported 5 year local and locoregional recurrence rates for patients with stage 2 and 3 
disease (cT1-4N0-3) treated with NST, breast conserving surgery and radiotherapy who 
achieve pCR range from 0 to 3.5%, in which patients with DCIS (all reports) and even 
isolated tumour cells (one report, with highest reported LR of 3.5%(23)) were included in 
the pCR group. 
As radiotherapy in primary breast cancer reduces recurrence with at least a factor 2.5, 
local recurrence at 5 year without radiotherapy could be in the range of 0-8.75% for pCR 
patients.(28) 
Recently, 5-year local recurrence rates in NST patients treated with breast conserving 
surgery without radiotherapy were reported in a relatively large group of 110 pCR 
patients, with a very low recurrence rate of 1.8%. Notably, this concerned a group of cT1- 
4N0-3 patients, with >60% of patients being node-positive. Also, residual DCIS was 
included in the pCR group.(27) 
As we will include only node negative patients with tumours <5 cm AND will exclude 
patients with residual DCIS, we may expect the recurrence rate to be on the lower side of 
the hypothesized range of 0-8.75%. For our statistical analysis, we have therefore used 
an expected rate of local recurrence of 4%. 
A 5 year local recurrence rate of less than 6% is deemed acceptable, as studies have 
shown that the effect of RT on local recurrence is mainly achieved in the first 5 years 
following treatment(40), especially in TN and Her2 positive subtypes which will constitute 
the majority of our population. 
Simulations were performed to calculate the sample size of a two stage single arm trial 
(including an interim analysis of futility), using the one sample log rank test. Assuming a 5 
year follow up and a 5 year uniform accrual, assuming as well an exponential distribution 
for survival, we calculated that the expected number of events when 325 patients are 
included should be at most 6, under the null hypothesis. If less or equal events are 
observed at that time, the trial continues and 595 patients in total are needed to achieve 
a power of >80% (an one-side alpha of 0.05). The expected number of events during 
the study are 35 to exclude a local recurrence risk at 5 years of 6% or more, if the actual 
local recurrence rate is 4%. 

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5.  TREATMENT OF SUBJECTS 
 
5.1   Investigational product/treatment 
 
Not applicable 
 
5.2   Use of co-intervention (if applicable) 
 
Not applicable 
 
5.3   Escape medication (if applicable) 
 
Not applicable 

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6.  METHODS 
 
6.1   Study parameters/endpoints 
 
 
6.1.1 Main study parameter/endpoint 
 
The primary endpoint of the DESCARTES study is the local recurrence rate after 5 
years. 
 
6.1.2 Secondary study parameters/endpoints 
 
 
- 
Local non-salvageable recurrence free survival (i.e. an in-breast 
recurrence that cannot be adequately cured with breast conserving 
surgery with RTx) after 5 years 
- 
Quality of life at baseline and after 1 and 4 years after surgery 
 
- 
Cancer worry at baseline and after 1 and 4 years after surgery 
 
- 
Regional recurrence after 5 years 
 
- 
Distant RFS after 5 and 10 years 
 
- 
Disease-specific survival after 5 and 10 years 
 
- 
OS after 5 and 10 years 
 
 
 
6.2   Randomisation, blinding and treatment allocation 
 
This is a prospective non-randomized clinical trial. 
 
 
 
6.3   Study procedures 
 
-   Neoadjuvant systemic therapy 
 
 
 
Patients included in the DESCARTES trial will receive neoadjuvant chemotherapy +/- 
antiHER2 therapy  according to national and local breast cancer guidelines. 
 
 
-   Surgery of breast and axilla 
 
 
 
Breast conserving surgery should be performed. If studies show post-NST biopsies to be equally  
reliable   in   assessing   pCR,   these  may  substitute   surgery  following   protocol amendment. 
Axillary surgery will consist of SLNB. 
 
 
- 
Pathology examination 

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Breast and lymph node tissue will be assessed according to standard clinical practice. Pathologic 
complete response is defined by the absence of any residual tumour or DCIS cells, including 
isolated tumour cells. In case One-Step Nucleid Acid Amplification (OSNA) is used to determine 
status of sentinel node, only negative OSNA results will be accepted as N0. 
 
 
 
- 
Inclusion and follow-up 
 
 
Patients are not randomized. Patients will be followed for 10 years and assessed for local 
disease recurrence with yearly mammography and physical examination in the first 5 years. 
After five years the patient may be referred back to the breast cancer screening program. At 10 
years, data on recurrence will be retrieved for all patients. If deemed necessary by the medical 
specialist assessing the patient, additional imaging and/or histopathology analysis may be 
performed. Axillary recurrences should be confirmed with pathology analysis. All lesions suspect 
for disease recurrence are discussed at multidisciplinary meetings, according to clinical practice 
guidelines. QoL will be evaluated  with  the  PROMs  including  the  EORTC  QLQ-C30  and  
BR23.  Additionally  the Cancer Worry Scale, education level and 12-item Intolerance of 
uncertainty scale will be used to measure if anxiety is related to omission of radiotherapy may 
affect QoL. 
 
 
 
6.4   Withdrawal of individual subjects 
 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. 
 
6.4.1 Specific criteria for withdrawal (if applicable) 
 
Not applicable. 
 
 
 
6.5   Replacement of individual subjects after withdrawal 
 
Not applicable. 
 
 
 
6.6   Follow-up of subjects withdrawn from treatment 
 
Not applicable. 
 
 
 
6.7   Premature termination of the study 
 
If the interim analysis for futility shows a higher than acceptable local recurrence rate, the 
study will be terminated. See statistics for detailed information. 

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7.  SAFETY REPORTING 
 
7.1   Temporary halt for reasons of subject safety 
 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety. The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed. 
 
 
 
7.2   AEs, SAEs and SUSARs 
 
 
 
 
 
7.2.2 Serious adverse events (SAEs) 
 
A serious adverse event is any untoward medical occurrence or effect that 
 
- 
results in death; 
 
- 
is life threatening (at the time of the event); 
 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
 
- 
results in persistent or significant disability or incapacity; or 
 
 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
 
 
All serious adverse events that occur within 90 days of omission of 
radiotherapyconsidered by the investigator to be related to study treatment , must be 
medically well documented and reported to the NKI Data Center within 24 hours or, 
at the latest, on the following working day. 
 
The report must be sent by email (drugsafety@nki.nl) to the Antoni van 
Leeuwenhoek Data Centre. The Data Centre can also be contacted by telephone 
(+316205129047) between 09.00 and 17.00 hours (GM+1) Monday to Friday. 
 
 

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The sponsor will not report the SAEs through the web portal ToetsingOnline. All SAEs 
will be reported to the accredited METC that approved the protocol, within 7 days of 
first knowledge for SAEs that result in death or are life threatening followed by a period 
of maximum of 8 days to complete the initial preliminary report. All other SAEs will be 
reported within a period of maximum 15 days after the sponsor has first knowledge of 
the serious adverse events. 
 
 
 
 
 
 
 
 
 
 
7.5   Safety Committee 
 
A data safety committee will be established to monitor the number and nature of 
any recurrences that may occur. The data safety committee will consist of a 
surgical oncologist, radiation oncologist, pathologist and statistician. 
 
 
 
 

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8. 
STATISTICAL ANALYSIS 
 
 
 
8.1   Primary study parameter(s) 
 
The primary endpoint of the study is the local recurrence rate, defined as recurrence in 
the ipsilateral breast. Any LR is considered as an event and is included in the analysis. 
Time to LR will be estimated by the Kaplan-Meier method and compared to the acceptable 
rate of 6% at 5 years by the one sample log rank test. Additionally an estimation of cumulative 
incidence of LR using death as a competing risk will be computed. 
 
 
 
8.2   Secondary study parameter(s) 
 
Rates of distant metastasis free survival, overall survival and disease specific free 
survival and local non-salvageable recurrence free survival after 5 and 10 years are 
calculated by the method of Kaplan-Meier and comparisons are made by log-rank test. 
 
 
 
8.3   Other study parameters 
 
Characteristics of the cohort will be described in detail using mean and standard deviation 
for continuous variables, and count and percentage for categorical variables. To compare 
distribution of clinical factors among subgroups (molecular subtypes), the Chi square test 
are used for categorical factors and Kruskal-Wallis test for continuous factors. 
 
 
 
8.4   Interim analysis 
 
An analysis of futility will be performed after inclusion of 325 patients and a minimum 
median follow up time of 16.2 months. Assuming a 5 year follow up and a 5 year uniform 
accrual, assuming as well an exponential distribution for survival, we calculated that the 
expected number of events when 325 patients are included should be at most 6, under 
the null hypothesis. If less or equal events are observed at that time, the trial continues 
and 595 patients in total needed to achieve power of >80%  (an one-side alpha of 0.5). 
The expected number of events during the study are 35 to exclude a local recurrence risk 
at 5 years of 6% or more.  

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9.  ETHICAL CONSIDERATIONS 
 
9.1   Regulation statement 
 
The study will be conducted according to the principles of the Declaration of Helsinki 
(version 2013) and in accordance with the Medical Research Involving Human Subjects 
Act (W MO) and other guidelines, regulations and Acts. 
 
 
 
9.2   Recruitment and consent 
 
Patients eligible for the study will be contacted during the pre-operative outpatient clinical 
appointment by a specialist. Patients will receive oral information and a patient information 
letter as well as the informed consent form (see attachment). Patients will be given 
enough time to consider the provided information and ask questions about it. Every 
patient will receive a copy of the signed informed consent form. The informed 
consent form must be signed within 16 weeks following the date of surgery.  
 
 
 
9.3   Objection by minors or incapacitated subjects 
 
Not applicable. 
 
 
 
9.4   Benefits and risks assessment, group relatedness 
 
Patients participating in this study will be spared side-effects associated with 
radiotherapy. Patients in which radiotherapy is omitted may have a higher risk of 
developing a local recurrence. The majority of local recurrences can be treated with 
breast conserving therapy and radiotherapy. Extra burden during the study are additional 
questionnaires according quality of life which will be provided simultaneously with the 
PROMs, which are integrated in standard care in the Antoni van Leeuwenhoek and other 
centers. 
 
 
 
9.5   Compensation for injury 
 
 
 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the W MO. 
The sponsor (also) has an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 W MO). This insurance provides cover for damage to 
research subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 

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9.6 
Incentives 
 
Not applicable. 

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10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
10.1 Handling and storage of data and documents 
The central data management will be performed by the Netherlands Cancer Institute- 
Antoni van Leeuwenhoek. Registration will be done after the written informed consent is 
obtained and after verification of eligibility. After the written informed consent is obtained, 
patients will be assigned to a registration number. 
Registration will be performed using ALEA® registration package run by the NKI Data 
Center.  
 
All data that are relevant for the study will be collected on eCRFs developed by the NKI 
data Center. The system can be accessed via internet to include data directly in the Data 
Centre Servers. The AVL Datacenter will supply accounts to the local data manager to 
enter data into the system. Checks will be incorporated into the eCRF system to prompt 
queries at the moment that data is entered facilitating the work of the local data manager 
who could quickly correct errors. Additional checks will be programmed using statistical 
programs with the goal of obtaining a clean file. 
The time between the patient’s visit and completion of eCRF pages should be kept to a 
reasonable minimum allowing answering the questions posed by the study. In all cases it 
remains the responsibility of the investigator to check and validate the data after verifying 
that they are completed and filled out correctly. If information is not known, this must be 
clearly indicated.  
The investigator will retain all pertinent information for a period of at least 15 years from 
study completion. 
 
 
 
10.2 Monitoring and Quality Assurance 
 
The study will be monitored according to ICH GCP, either on site or remote. This study 
will be considered as a low risk study. 
A monitoring plan specific to the study and describing the nature and frequency of the 
monitoring will be written by the appointed monitor and approved by the Principal 
Investigator and the Head of the Data Centre. 
Data from all patients will also be centrally checked at the Data Centre. Through central 
monitoring of the data collected, the Data Centre will be able to detect outliers or 
apparently spurious data. When persistent irregularities or protocol violations are 
detected, the Data Centre will inform the local investigator (and Principal Investigators) 
and queries will be sent to the local Data Manager 
 
 
10.3 Amendments 
 
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 

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a favourable opinion. 
 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor. 

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10.4 Annual progress report 
 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments. 
 
 
 
10.5 Temporary halt and (prematurely) end of study report 
 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit. 
 
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. 
 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC 
 
within 15 days, including the reasons for the premature termination. 
 
 
 
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC. 
 
 
 
10.6 Public disclosure and publication policy 
 
The data will be published by the project leader and investigators mentioned in this 
protocol. 
 
 
 
 
11. STRUCTURED RISK ANALYSIS 
Not applicable. 

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