Treatment Patterns And Clinical Outcomes Among Patients With Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer (mBC) Receiving Palbociclib in Combination With Fulvestrant (PB+FUL) In The US Community Oncology Setting
Conditions: Breast Cancer
Sponsor: Pfizer

Palbociclib (IBRANCE)
Study Number A5481128 NON-INTERVENTIONAL STUDY PROTOCOL
Protocol Version 2, August 30, 2021
PFIZER CONFIDENTIAL  
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Study information
Title
Treatment Patterns And Clinical Outcomes Among Patients With 
Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 
2-Negative Metastatic Breast Cancer (mBC) Receiving Palbociclib in 
Combination with Fulvestrant (PB+FUL) In The US Community 
Oncology Setting
Protocol 
number
A5481128
Protocol 
version 
identifier
Version 2
Date
August 30, 2021
Active 
substance
Palbociclib (IBRANCE®; PD 0332991)
Medicinal 
product
Palbociclib 
Research 
question and 
objectives
The following primary and secondary objectives will be assessed among 
all study-eligible patients who initiated first-line PB+FUL in the 
metastatic setting:  
Primary Objectives
1. Describe baseline patient demographic and clinical characteristics, 
as well as provider- and clinic-level characteristics 
2. Describe treatment patterns including number of complete cycles, 
post-discontinuation treatment regimens and treatment initiation 
by quarter 
Secondary Objectives
3. Evaluate, from initiation of index treatment: 
o
Time to chemotherapy
o
Reasons for treatment discontinuation   
o
Real-world duration of therapy (rwDOT)
o
Time to next treatment (TTNT)
o
Provider-documented progression
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o Real-world time to progression (rwTTP) 
o Real-world progression-free survival (rwPFS)  
o Overall survival (OS) 
 
 
 
 
  
 
 
 
 
 
 
 
Author 
 
, MPH 
 
 
 
 
Phone: 
 
Email: 
 
 
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 
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TABLE OF CONTENTS 
1. LIST OF ABBREVIATIONS ............................................................................................ 5 
2. RESPONSIBLE PARTIES ................................................................................................ 8 
3. ABSTRACT ...................................................................................................................... 9 
4. AMENDMENTS AND UPDATES ................................................................................. 12 
5. MILESTONES ................................................................................................................ 14 
6. RATIONALE AND BACKGROUND ............................................................................ 15 
7. RESEARCH QUESTION AND OBJECTIVES ............................................................... 18 
7.1. Primary objectives ............................................................................................... 18 
7.2. Secondary objectives ........................................................................................... 18 
 
8. RESEARCH METHODS ................................................................................................ 19 
8.1. Study design ........................................................................................................ 19 
8.2. Setting ................................................................................................................. 21 
8.2.1. Inclusion criteria ..................................................................................... 21 
8.2.2. Exclusion criteria .................................................................................... 22 
8.2.3. Cohort definitions and stratifications ....................................................... 23 
8.2.4. Chart review selection ............................................................................. 23 
8.3. Variables ............................................................................................................. 24 
8.4. Data sources ........................................................................................................ 38 
8.5. Study size ............................................................................................................ 40 
8.6. Data management ................................................................................................ 44 
8.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic 
data record ................................................................................................... 44 
8.8. Record retention ......................................................................................... 45 
8.7. Data analysis ....................................................................................................... 46 
8.7.1. Analysis sets ........................................................................................... 46 
8.7.2. Derived and transformed data .................................................................. 46 
8.7.3. Statistical methods .................................................................................. 46 
8.7.4. Sequence of analyses ............................................................................... 48 
8.8. Quality control .................................................................................................... 48 
8.9. Limitations of the research methods .................................................................... 49 
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8.9.1. Internal validity of study design .............................................................. 49 
8.9.2. External validity of study design (generalizability) .................................. 50 
8.9.3. Analysis limitations ................................................................................. 50 
8.9.4. Limitations due to missing data and/or incomplete data ........................... 50 
8.10. Other aspects ..................................................................................................... 50 
9. PROTECTION OF HUMAN SUBJECTS ....................................................................... 50 
9.1. Patient information .............................................................................................. 51 
9.2. Patient consent .................................................................................................... 51 
9.3. Patient withdrawal ............................................................................................... 51 
9.4. Institutional review board (IRB)/Independent ethics committee (IEC) ................. 52 
9.5. Ethical conduct of the study ................................................................................. 52 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS REQUIREMENTS ................................................................................... 52 
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ....... 54 
13. REFERENCES .............................................................................................................. 55 
14. LIST OF TABLES ........................................................................................................ 59 
15. LIST OF FIGURES ....................................................................................................... 59 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS ....................................................... 60 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ....................................... 60 
ANNEX 3. ADDITIONAL INFORMATION ...................................................................... 61 
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1. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse events 
AEM 
Adverse event monitoring 
BC 
Breast cancer 
BMI 
Body mass index 
BOR 
Best overall response 
BRCA 
Breast cancer gene 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical 
Sciences 
CDK 
Cyclin-dependent kinase 
CRF 
Case report form 
DCT 
Data collection tool 
eCRF 
Electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
EHR 
Electronic healthcare record 
EMA 
European Medicines Agency 
ENCePP 
European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance 
ESR1 
Estrogen receptor 1 gene 
FDA 
Food and Drug Administration 
FUL 
Fulvestrant 
 
 
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GEP 
Good Epidemiological Practice 
GPP 
Good Pharmacoepidemiology Practices 
HEOR 
Health Economics Outcomes Research 
HER2- 
Human epidermal growth factor receptor 2 negative 
HIPAA 
Health Insurance Portability and Accountability Act 
HITECH 
Health Information Technology for Economic and 
Clinical Health 
HR 
Hazard ratio 
HR+ 
Hormone-receptor positive 
ICD 
International Classification of Diseases 
ICMJE 
International Committee of Medical Journal Editors 
IEA 
International Epidemiological Association 
IEC  
Independent Ethics Committee  
IPTW 
Inverse probability of treatment weighting  
IRB 
Institutional review board 
iKM 
iKnowMed 
LADMF 
Limited Access Death Master File 
LHRH 
Luteinizing hormone-releasing hormone 
LOT 
Line of therapy 
mBC 
Metastatic breast cancer 
MRN 
Medical record number 
NCCN 
National Comprehensive Cancer Network 
NDI 
National Death Index 
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NGS 
Next generation sequencing 
NIS 
Non-interventional study 
OS 
Overall survival 
PASS 
Post-Authorization Safety Study 
PB+FUL 
Palbociclib combination therapy with fulvestrant cohort 
PFS 
Progression-free survival 
QC 
Quality control 
RECIST 
Response Evaluation Criteria In Solid Tumors 
rwDOT 
Real-world duration of therapy 
rwPFS 
Real-world progression-free survival 
rwTTP 
Real-world time to progression  
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SD 
Standard deviation  
SEER 
Surveillance Epidemiology and End Results 
TNM 
Tumor, Node, Metastasis  
TTNT 
Time to next treatment 
US 
United States 
USON 
US Oncology Network 
 
 
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2. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
 
 
 
Name, degree(s) 
Job Title 
Affiliation 
Address 
, MD 
Medical Director 
 
 
 
,
 
 
, MPH 
Sr. Research 
Manager 
 
 
 
, 
 
 
, DrPH 
Sr. Director,
 
Pfizer, Inc. 
 
, 
 
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3. ABSTRACT 
Title: Treatment Patterns And Clinical Outcomes Among Patients With Hormone Receptor-
Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer 
(mBC) Receiving Palbociclib in Combination with Fulvestrant (PB+FUL) In the US 
Community Oncology Setting 
 
Protocol date/version:  August 30, 2021/ Version 2 
 
Primary protocol authors: 
, MPH, 
 
 
Rationale and background: Palbociclib is approved in the United States (US) for the 
treatment of adult patients with hormone receptor-positive (HR+), human epidermal growth 
factor receptor 2 negative (HER2-) advanced or metastatic breast cancer (mBC) in 
combination with an aromatase inhibitor as initial endocrine-based therapy in 
postmenopausal women or in men; or fulvestrant in patients with disease progression on 
prior endocrine therapy. While recent real-world studies have evaluated palbociclib in 
combination with aromatase inhibitors, limited evidence currently exists to describe the real-
world treatment patterns and outcomes of PB+FUL. By leveraging a community-based, 
cancer-specific electronic healthcare record for this study, we aim to provide new insights 
into the patients with mBC who received PB+FUL within the context of a large community 
oncology network and outside of an academic or clinical trial setting in the US.  
 
Research question and objectives:  
The following primary and secondary objectives will be assessed among all study-eligible 
patients who initiated first-line PB+FUL in the metastatic setting:  
Primary Objectives 
1. Describe baseline patient demographic and clinical characteristics, as well as 
provider- and clinic-level characteristics  
2. Describe treatment patterns including number of complete cycles, post-
discontinuation treatment regimens and treatment initiation by quarter  
Secondary Objectives 
3. Evaluate, from initiation of index treatment: 
o Time to chemotherapy  
o Reasons for treatment discontinuation   
o Real-world duration of therapy (rwDOT) 
o Time to next treatment (TTNT) 
o Provider-documented progression 
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o Real-world time to progression (rwTTP) 
o Real-world progression-free survival (rwPFS)  
o Overall survival (OS) 
 
 
 
 
  
 
 
 
 
 
 
 
Study design: The is a retrospective observational cohort study to examine patient and 
practice-level characteristics, treatment patterns and clinical outcomes among HR+/ HER2- 
mBC patients treated in the US Oncology Network (USON). Patients who initiated a 
qualifying treatment between 01 February 2016 and 31 December 2019 will be eligible for 
inclusion in the study. To allow of a potential minimum follow-up period of 6 months, study-
eligible patients will be followed longitudinally until 30 June 2020 last patient record or date 
of death, whichever occurs first.  
 
Population: The study population will consist of patients with a diagnosis of hormone 
receptor-positive/human epidermal growth factor receptor 2-negative mBC who initiated 
PB+FUL 
 
  
 
Variables: A complete list of study variables and their associated operational definition are 
presented in Table 2. 
 
Data sources: Structured data fields within the iKnowMed (iKM) electronic healthcare 
record (EHR) database will provide information needed to address most research questions. 
These data will be supplemented by additional unstructured data collected through chart 
review for a subset of the study population.  
 
Study size: A feasibility assessment from iKM identified 783 patients who met study 
eligibility criteria and initiated PB+FUL and 
 
. The 1035 patients who initiated PB+FUL and 
 in the first- through third-
line setting were selected for chart review (633 PB+FUL and 
). 
During chart review, these patients’ eligibility was confirmed and some patients were 
disqualified. The final sample size for analysis will consist of the confirmed eligible patients 
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who initiated first-line PB+FUL and,
 
.  
 
Data analysis: Descriptive analyses will be conducted to evaluate demographic, clinical and 
treatment characteristics of the study population, stratified by pre-specified cohorts. Time-to-
event outcomes will be assessed using the Kaplan-Meier method with 95% confidence 
intervals (CIs) and summary tables for patients who initiated first-line PB+FUL.
 
 
  
 
Milestones: Chart review was completed December 2020. Updated descriptive analyses for 
the primary, secondary and 
 are expected September 2021. Primary 
 outcomes analyses are expected January 2022. The final study report is 
expected February 2022.  
 
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4. AMENDMENTS AND UPDATES 
Amendment 
number 
Date 
Protocol 
section(s) 
changed 
Summary of amendment(s) 
Reason 
1 
21 
Septemb
er 2020 
Sections 1, 2, 3, 
4, 5, 6, 7, 8, 9 
and 11. 
- 
Changed eligibility criteria to 
solely focus on patients who 
received 
 or 
PB+FUL (removed the cohorts 
focused on aromatase 
inhibitors alone or with 
palbociclib).  
- 
Revised study objectives to 
reflect removal of cohorts 
focused on aromatase 
inhibitors alone or with 
palbociclib. 
- 
Revised throughout to indicate 
that a structured feasibility 
assessment was completed, 
including the description of the 
study phases and milestones.  
- 
Updated the sample size 
estimates based on the 
structured feasibility results.  
- 
Updated references in 
background section. 
- 
Extended the study 
identification and observation 
periods. 
- 
Updated the eligibility criteria 
and variables list to reflect 
changes made during 
development of the eCRF. 
- 
Updated chart review selection 
criteria to reflect focus on 
patients who received 
 
 or PB+FUL in the first- 
through third-line setting.  
- 
Updated the description of the 
sources of death.  
- 
Updated the eCRF and record 
retention sections to reflect the 
Pfizer protocol template.  
The strategic aim of the study has 
shifted to focus on patients who 
received 
 or PB+FUL. 
Additionally, the protocol was updated 
to reflect recent changes by the study 
team.  
2 
August 
30, 2021 
All 
- 
Revised objectives to focus on 
patients who received first-line 
PB+FUL,
 
 
- 
Revised the study identification 
to start on 01 February 2016 
and updated the attrition table 
accordingly.  
- 
Updated the milestone timeline 
to reflect completion dates of 
activities that have concluded 
and the anticipated completion 
dates of those that remain.  
The strategic aim of the study has 
shifted to focus on the subset of patients 
who received first-line PB+FUL after 
01 February 2016.  
Some project activities have been 
completed and other dates have shifted.  
Newly available publications were cited 
to strengthen the Background section.  
The original Pfizer study leads have 
transitioned off the project.  
 
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- 
Updated Background section 
with newly published 
literature.  
- 
Changed the Pfizer study leads. 
- 
Removed  the provider   -
documented response to 
treatment (real-world response 
rate) endpoint. 
Removed the provider   -documented 
response to treatment (real-world 
response rate) endpoint given the 
number of patients with non-evaluated 
tumor assessments.  
 
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5. MILESTONES 
The table below reflects actual and planned completion dates of study milestones. Note, 
some milestones were completed under prior versions of this protocol.  
Table 1. Study milestones 
Milestone 
Planned/completed date 
Finalization of study protocol (version 1) and 
submission to the Institutional Review Board (IRB) 
October 2019 (complete) 
Initial structured data collection 
November 2019 (complete) 
Updated structured data collection 
July 2020 (complete) 
Start of chart review 
August 2020 (complete) 
End of chart review 
December 2020 (complete) 
Primary and secondary descriptive analyses 
September 2021  
 
 
Unadjusted outcomes analyses 
December 2021 
Adjusted outcomes analyses 
January 2022  
Final study report 
February 2022  
 
 
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6. RATIONALE AND BACKGROUND 
Breast cancer is the most common noncutaneous cancer in the United States (US), with 
279,100 new cases expected in 2020.1 Breast cancer predominantly occurs among women, 
with men accounting for approximately 1% of new cases.2 Among women diagnosed with 
localized or regional disease, the 5-year overall survival (OS) ranges from 85%-99%.3 In 
contrast, the 5-year survival rate is 27% among women diagnosed with distant disease. 
Annually, over 42,000 deaths associated with breast cancer are expected in the US.1 
For patients diagnosed with recurrent or metastatic breast cancer (mBC), treatment 
recommendations are guided by the presence or absence of bone metastases (visceral versus 
non-visceral disease), as well as patients’ hormone receptor and human epidermal growth 
factor receptor-2 status.4 In particular, patients who are hormone receptor-positive (estrogen 
receptor- and/or progesterone receptor-positive) are eligible for endocrine therapies, which 
have more favorable toxicity profiles than cytotoxic regimens.5 The National Comprehensive 
Cancer Network (NCCN) currently provides recommendations for the following endocrine 
therapies among postmenopausal, human epidermal growth factor receptor 2-negative 
patients: aromatase inhibitors (anastrozole, letrozole and exemestane), fulvestrant (a selective 
estrogen receptor down-regulator) and estrogen receptor down-regulators (tamoxifen and 
toremifene). 
Up to 50% of mBC patients treated with endocrine therapy are either initially refractory or 
eventually become resistant to the treatment.6-9 To prolong the clinical benefit of these 
treatments, endocrine therapies can be administered in combination with cyclin-dependent 
kinases 4/6 (CDK 4/6) inhibitors.4,6 CDK 4/6 inhibitors disrupt the G1 and S phases of the 
cell cycle and reduce cellular proliferation. The NCCN currently provides category 1 
recommendations for abemaciclib, palbociclib, and ribociclib to be administered in 
combination with either an aromatase inhibitor or fulvestrant.4 
Palbociclib (Ibrance®) was initially granted accelerated approval in 2015 from the US Food 
and Drug Administration (FDA) to be administered in combination with letrozole among 
treatment-naïve patients with estrogen receptor-positive, human epidermal growth factor 
receptor 2-negative advanced breast cancer.10 This approval was based on results from the 
PALOMA-1 Phase 2 study, which demonstrated improved progression-free survival (PFS) 
among patients who received palbociclib plus letrozole compared to those who received 
letrozole alone (median PFS 20.2 versus 10.2 months; hazard ratio 0.488, 95% CI 0.319-
0.748; p=0.0004).11 The PALOMA-2 trial subsequently affirmed this advantage of 
palbociclib plus letrozole.12  
In 2016, the FDA approved PB+FUL for women with hormone receptor-positive/human 
epidermal growth factor receptor 2-negative advanced or mBC following progression on an 
endocrine therapy.13 This approval was based on the PALOMA-3 double-blind, randomized 
Phase 3 trial of hormone receptor-positive/human epidermal growth factor receptor 2-
negative mBC who had progressed on prior endocrine therapy (n=521).14 Median PFS was 
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significantly longer among patients who received PB+FUL compared to those who received 
FUL mono (9.5 versus 4.6 months; hazard ratio 0.46, 95% CI 0.36-0.59, p<0.0001).  
Further analyses of the PALOMA-3 trial evaluated the influence baseline characteristics on 
OS among the patient population.15 As reported by Rugo et al. (2021), these multivariable 
analyses of the PALOMA-3 trial suggested that endocrine sensitivity, non-visceral disease, 
lack of prior chemotherapy and ECOG performance status score of 0 influenced OS among 
patients with advanced breast cancer who received PB+FUL. In particular, among patients 
who did not receive prior chemotherapy, median OS was 3.9 months (versus 29.5 months 
among those who received prior chemotherapy; hazard ratio [HR] 0.91 [95% confidence 
interval (CI) 0.63, 1.32]).  
While median PFS across the overall population was 11.2 and 4.6 months among patients 
who received palbociclib and placebo, respectively, Rugo et al. (2021) reported among select 
patient subgroups.15,16 In all subgroups analyzed, median PFS was longer among those who 
received fulvestrant with palbociclib compared to those who received fulvestrant with the 
placebo.15 Specifically, among patients without prior chemotherapy, median PFS was 12.9 
months (95% CI 11.0, 15.0) who received palbociclib and fulvestrant, compared to 5.5 
months (95% CI 3.6, 7.6) among those who received fulvestrant and the placebo (HR 0.49; 
95% CI 0.37, 0.65). Likewise, among patients with prior chemotherapy, median PFS was 9.5 
months (95% CI 7.3, 11.3) among those who received palbociclib and fulvestrant and 3.5 
months (95% 1.9, 5.4) among those who receive fulvestrant with the placebo (HR 0.53, 95% 
CI 0.37, 0.77). Among those who were endocrine sensitive, median PFS was 12.0 and 4.2 
months among patients who received palbociclib with fulvestrant and those who received 
fulvestrant with the placebo, respectively (HR 0.46; 95% CI 0.36, 0.59).  
There were two studies which examined the efficacy of palbociclib + fulvestrant combination 
within the endocrine sensitive population. In the first study, PARSIFAL, Llombart-Cussac et 
al. (2020) randomly assigned treatment-naive estrogen receptor positive/HER- mBC patients 
who were all endocrine sensitive to receive palbociclib with fulvestrant or palbociclib with 
letrozole.17 Among the 486 patients included in the study, 243 received PB+FUL and 243 
received palbociclib-letrozole and baseline characteristics between the groups were similar. 
The median PFS durations were 27.9 months and 32.8 among the PB+FUL and palbociclib-
letrozole cohorts, respectively. The difference between the groups did not demonstrate 
statistical advantage for PB+FUL compared to palbociclib-letrozole. The three-year OS rate 
was 79.4% and 77.1% among the PB+FUL and palbociclib-letrozole cohorts, respectively.  
In a double-blind phase II study, FLIPPER, Albanell et al. (2020) randomly assigned 
postmenopausal HR+/HER2- patients with all with endocrine sensitive advanced breast 
cancer to first-line PB+FUL or fulvestrant-placebo.18 Among the 189 patients included in the 
study, 94 received PB+FUL and 95 received fulvestrant-placebo. Patients who received 
PB+FUL had a longer median PFS than those who received fulvestrant-placebo (31.8 versus 
22.0 months, respectively; HR 0.52; 95% CI 0.39, 0.68; p=0.002). Likewise, the overall 
response rates were 68.3% and 42.2% among the PB+FUL and fulvestrant-placebo cohorts, 
respectively.  
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While recent real-world studies have evaluated palbociclib in combination with aromatase 
inhibitors, limited evidence currently exists to describe the real-world treatment patterns and 
outcomes of PB+FUL or FUL mono.  
The objective of this retrospective, observational cohort database study is to describe the 
real-world demographic, clinical and treatment characteristics, as well as clinical outcomes 
of hormone receptor-positive/human epidermal growth factor receptor 2-negative mBC 
patients treated with PB+FUL. By leveraging a community-based, cancer-specific electronic 
healthcare record (EHR) for this study, we aim to provide new insights into the patients with 
mBC who received PB+FUL within the context of a large community oncology network and 
outside of an academic or clinical trial setting in the US.  
This non-interventional study is not designated as a Post-Authorization Safety Study (PASS) 
and is conducted voluntarily by Pfizer. 
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7. RESEARCH QUESTION AND OBJECTIVES 
The overall objective of this study is to understand the demographic, clinical, and treatment 
characteristics, as well as clinical outcomes of hormone receptor-positive/human epidermal 
growth factor receptor 2-negative mBC patients in the US community oncology setting.  
Complete study eligibility criteria and cohort definitions are presented in Section 8.2. If 
supported by the final sample size, all study results will be stratified by the subgroups 
defined in Section 8.2.4. 
The following primary and secondary objectives will be assessed among all study-eligible 
patients who initiated first-line PB+FUL in the metastatic setting.  
7.1. Primary objectives 
1. Describe baseline patient demographic and clinical characteristics, as well as 
provider- and clinic-level characteristics  
2. Describe treatment patterns including number of complete cycles, post-
discontinuation treatment regimens and treatment initiation by quarter  
 
7.2. Secondary objectives 
3. Evaluate, from initiation of index treatment: 
o Time to chemotherapy  
o Reasons for treatment discontinuation  
o Real-world duration of therapy (rwDOT) 
o Time to next treatment (TTNT) 
o Provider-documented progression 
o Real-world time to progression (rwTTP) 
o Real-world progression-free survival (rwPFS)  
o Overall survival (OS) 
 
 
 
 
  
 
 
 
 
 
 
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8. RESEARCH METHODS 
8.1. Study design  
The is a retrospective observational cohort study to examine patient and practice-level 
characteristics, treatment patterns and clinical outcomes among hormone receptor-
positive/human epidermal growth factor receptor 2-negative mBC patients treated in the US 
Oncology Network (USON). Patients who initiated a qualifying treatment between 01 
February 2016 and 31 December 2019 will be eligible for inclusion in the study. Complete 
study eligibility criteria and cohort definitions are presented in Section 8.2. To allow of a 
potential minimum follow-up period of 6 months, study-eligible patients will be followed 
longitudinally until 30 June 2020, last patient record or date of death, whichever occurs first.*
An overview of the study design is presented in Figure 1. 
Figure 1. Overview of study design
* Data can be updated at a later time to extend the follow-up period through an amendment to refresh the 
data and revisit charts of patients who were alive at the end of the original study period. The health information 
available for research purposes may vary in accordance with the data rights under agreements with physician 
practices. Therefore, data from some practices that are part of the USON may not be available for research 
purposes. 
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A phased approach to project execution is being undertaken for this study. First, a feasibility 
assessment has been performed based solely on structured data to describe demographic, 
clinical and treatment characteristics of all patients who meet the eligibility criteria defined in 
Section 8.2. Next, chart review was performed to verify patients’ eligibility and capture 
additional details about eligible patients. The chart review sampling method is described in 
Section 8.2.4.  
Study objectives are described in Section 7. The primary and secondary objectives will be 
assessed among patients who initiated first-line PB+FUL, 
 
 
 
 
 
  
 
A complete list of study variables and their associated operational definition are presented in 
Table 2. The clinical endpoints to be evaluated for this study include:  
x Time to chemotherapy  
x Reasons for treatment discontinuation 
x rwDOT 
x TTNT 
x Provider-documented progression 
x rwTTP 
x rwPFS  
x OS 
 
The complete analysis plan is presented in Section 8.7. Descriptive analyses will be 
conducted to evaluate demographic, clinical and treatment characteristics of the study 
population, stratified by pre-specified cohorts. Time-to-event outcomes will be assessed 
using the Kaplan-Meier method with 95% CIs and summary tables among those who 
initiated first-line PB+FUL. 
 
 
 
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8.2. Setting 
The study population will consist of patients with a diagnosis of hormone receptor-
positive/human epidermal growth factor receptor 2-negative mBC who initiated a who 
initiated PB+FUL and 
 
 The USON includes 1,200 affiliated physicians operating in over 470 sites of 
care across states and treats approximately 1 million US cancer patients annually.20 
 
 
Figure 1 presents a graphical depiction of the study time periods, which are as follows:  
 
Study observation period: 01 February 2016 – 30 June 2020.*  
 
Study identification period: 01 February 2016 – 31 December 2019.  
 
Index date: The date of initiation with PB+FUL or 
 during the study 
identification period. For PB+FUL, the date of the first administration of either 
drug will be used. 
 
Baseline: Assessment will be done for the data collected at the closest date prior 
to index within 30 days of index (in absolute value). Variables to be assessed at 
baseline are specified in Table 2. 
 
Prior medical history: Patients’ available history in the iKnowMed (iKM) EHR 
will vary based on the length of disease and the time within the USON. The prior 
medical history period will end the day prior to the index date. Variables to be 
assessed with prior medical history are specified in Table 2. 
 
Follow-up: Patients will be followed through the end of the study observation 
period, date of last visit or date of death, whichever occurs first. For analysis, 
patients will have a potential of at least 6 months of follow-up duration; however, 
patients will have variable follow-up time periods, depending on their index dates 
and last contact dates. 
8.2.1. Inclusion criteria 
Patients must meet all the following inclusion criteria to be eligible for inclusion in the study: 
 
* Data can be updated at a later time to extend the follow-up period through an amendment to refresh the 
data and revisit charts of patients who were alive at the end of the original study period.  
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1) Patients with a documented diagnosis of hormone receptor-positive (estrogen receptor-
positive or progesterone receptor-positive), human epidermal growth factor receptor 2-
negative mBC* 
2) Aged 18 years at initial recorded diagnosis of mBC 
3) Initiated one of the following qualifying regimens within the USON during the study 
identification period:  
a) PB+FUL as first-line (for primary and secondary objectives) or 
 
  
 
4) Received care at a USON site(s) utilizing the full EHR capacities of iKM at the time of 
treatment. 
5) EHR data available from the USON site(s) where the patient received treatment are 
accessible for research purposes. 
6) During the study observation period, patients observed with at least 2 visits† after the 
index date.  
8.2.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
1) Enrollment in an interventional clinical trial during the study observation period since 
clinical trial participants may have clinical scenarios that deviate from the population of 
interest.  
2) Evidence of prior treatment with CDK 4/6 inhibitors (ribociclib or abemaciclib) in the 
metastatic setting.  
3) Receipt of treatment indicated for another primary cancer during the study observation 
period or history of another primary cancer within the USON iKM EHR database.  
 
* Diagnosis of hormone receptor-positive/human epidermal growth factor receptor 2-negative breast 
cancer (BC) will be determined through a review of iKM’s discrete diagnosis fields, which are populated during 
the routine course of care (International Classification of Diseases [ICD] codes will not be used). To identify 
patients with metastatic disease status, patients must have at least one of the following indicators: 1) receipt of a 
numbered LOT, 2) Stage IV disease, 3) Tumor, Node, Metastasis (TNM) staging with M value of 1, 4) record 
of location of metastatic disease or 5) current or prior disease status containing reference to metastatic disease. 
† Visits are defined as physical encounters with the practice, detected by vital sign records. The second and third 
visits must be observed after the index date to demonstrate continuity of care. There is no required time span 
between the additional visits and the index date. 
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4) Initiated first treatment more than 120 days after metastatic date.  
8.2.3. Cohort definitions and stratifications 
Patients who meet the eligibility criteria described in Sections 8.2.1-8.2.2 will be classified 
into the following cohorts described in Section 8.1.  
As supported by the final sample size, each of the results tables and figures will be stratified 
to present the data for the following stratifications:  
x Menopausal status (pre-, peri-, and post-menopausal) – post-menopausal only 
x Metastases (visceral vs. non-visceral, bone only vs. non-bone only) 
x Metastatic status (de novo versus relapsed/recurrent) 
x Stage at diagnosis (I/II, III, IV or not documented) 
x Number of metastatic sites (1, 2 and 3) 
x Prior adjuvant endocrine therapy (both prior to and after metastases) 
x Prior adjuvant chemotherapy (both prior to and after metastases) 
x Age stratifications (e.g., 18-50, 51-69, 70) also <65 years and 65 years 
x Race (White, Black, other, not documented) 
x Palbociclib starting dose (75 mg, 100 mg, and 125 mg starting dose) 
x Eastern Cooperative Oncology Group (ECOG) performance status score (0/1, and 2+) 
90 days prior to index  
x Disease-free interval from end of adjuvant treatment (< 12 months, 12 months) 
8.2.4. Chart review selection 
For an initial feasibility assessment, all patients who meet the eligibility criteria described in 
Sections 8.2.1-8.2.2 were included in the interim analysis. A subset of patients (n=1035) who 
initiated PB+FUL and 
 in the first- through third-line setting were selected for 
chart review.  
 
During the course of abstraction, patients’ eligibility for the study was verified and some of 
these patients were found to be ineligible. Reasons for disqualification are presented.  
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8.3. Variables 
Table 2 presents the list of variables that will be considered for this study. Most data will 
originate from 1 of 2 sources: the iKM EHR database (structured data) or chart review 
(unstructured data), although some variables may be derived from these raw data sources 
(e.g., age from date of birth). Derived and transformed data needed for the analysis are 
described and presented along with the operational definitions in the table below.  
For variables that are listed as being sourced from both structured and unstructured fields, 
chart review is recommended and, in some cases, may be required. Specifically, many of 
these are variables that are available in structured fields but have been found to be more 
reliably and comprehensively captured through chart review of unstructured fields. Other 
variables require information that can only be sourced through chart review (e.g., response 
and progression). Data elements listed as being “not reported” will be used to determine 
eligibility or in calculations of derived variables.  
Variables described as being captured at “baseline” will be captured at the date closest to the 
index date initiation within 30 days (90 days for performance status). Variables described as 
being captured with “prior medical history” will be sourced from patients’ entire medical 
history within the USON prior to index treatment initiation. Other variable assessment 
periods are indicated below. If multiple values are available during the time period of 
measurement, the one closest (in absolute value) to treatment initiation will be used. 
Some data elements will be captured from both iKM and chart review. Since the chart review 
data are expected to provide a richer source of information, if data are available from both 
sources for a single patient, then chart review data will supersede what is available in the 
structured iKM data for the final analysis. 
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Table 2. Study variables and operational definitions 
Variable 
Source(s) 
Role(s) in 
study 
Period of 
measurement 
Operational definition 
Demographic and patient characteristics 
Patient identification 
number 
iKM 
structured 
data 
Data linkage 
Study 
observation 
period 
Unique patient identifier that will be used to 
link clinical records. This information will 
not be disclosed to the study sponsor. 
Medical record 
number (MRN) 
iKM 
structured 
data 
Data linkage 
Study 
observation 
period 
Unique patient identifier that will be used to 
link clinical records. This information will 
not be disclosed to the study sponsor. 
Clinical trial 
participation 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria 
Follow-up 
Patients will be confirmed as not being 
enrolled in interventional clinical trials 
(patients in only observational studies will be 
retained, if applicable) in the USON during 
the study observation period. If participation 
(on any trial other than observational only, if 
applicable) is detected, the patient will be 
excluded. 
Other cancer 
diagnosis 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria 
Prior medical 
history + study 
observation 
period 
Patients will be confirmed as having no 
additional primary or secondary malignancies 
prior to and after the index date. Patients with 
a secondary diagnosis or receipt of treatment 
indicated for another primary cancer will be 
excluded. 
Hormone receptor 
status 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria; 
Baseline 
characteristic 
Prior medical 
history 
Patients who have a documented hormone 
receptor-positive status, either estrogen 
and/or progesterone, will be included in the 
study. 
The proportions of patients who are estrogen 
or progesterone receptor-positive will be 
reported. 
Human epidermal 
growth factor 
receptor 2-negative 
status 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria 
Prior medical 
history 
Patients who have a documented human 
epidermal growth factor receptor 2-negative 
status will be included in the study. 
Prior treatment 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria 
Prior medical 
history 
Patients will be excluded if they have 
evidence of prior treatment with other CDK 
4/6 inhibitors in the advanced or metastatic 
setting.  
Additional visits 
iKM 
structured 
data 
Eligibility 
criteria 
Follow-up 
To capture a sample of patients with 
longitudinal records, patients will be required 
to have 2 records of either additional visits 
following the index date visit and/or a record 
of death prior to the end of the study follow-
up period. Visits are defined as physical 
encounters with the practice, detected by vital 
sign records There will be no distinction 
made, for purposes of inclusion, between 
patients that have an additional USON visit 
and those with a record of death. There is no 
minimum or maximum requirement on time 
from index date to these qualifying events. 
Sex 
iKM 
structured 
data + 
Baseline 
characteristic 
Prior medical 
history 
Patients will be categorized as: 
Male 
Female 
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chart 
review 
Date of birth 
iKM 
structured 
data 
Eligibility; 
Data linkage; 
Baseline 
characteristic 
Prior medical 
history 
Patient’s date of birth as recorded in iKM. 
This information will not be disclosed to the 
study sponsor. 
Age 
iKM 
structured 
data 
(derived) 
Eligibility; 
Baseline 
characteristic 
Baseline 
Patient’s age (in years) at the date of 
diagnosis, which will be calculated as the 
integer of [(diagnosis date – date of birth + 1) 
/ 365.25]. 
Patients aged less than 18 years at the initial 
recorded diagnosis of mBC will be excluded 
from the study. 
Age groups 
iKM 
structured 
data 
(derived) 
Baseline 
characteristic 
Baseline 
Multiple age categories will be created based 
on the continuous age data: 
Age (<18 years, 18-50 years, 51-70 years, 
 years) 
No information 
Race 
iKM 
structured 
data 
Baseline 
characteristic 
Prior medical 
history 
Categorized as: 
White or Caucasian 
Black or African American 
Asian 
Native American 
Other 
No information 
The specific categories outside of 
White/Caucasian and Black/African 
American will be confirmed after reviewing 
sample sizes and the added value to the study 
with McKesson’s Privacy and Compliance 
team. 
Height 
iKM 
structured 
data 
Baseline 
characteristic 
Baseline 
Patient’s height in meters. 
Weight 
iKM 
structured 
data 
Baseline 
characteristic 
Baseline 
Patient’s weight in kilograms. 
Body mass index 
(BMI) at index date 
iKM 
structured 
data 
(derived) 
Baseline 
characteristic 
Baseline 
BMI = Weight (in kilograms)/(Height (in 
meters))2 
Based on the resulting BMI values, patients 
will then be categorized as underweight (BMI 
< 18.5), normal (BMI 18.5 – 24.9), 
overweight (BMI 25 – 29.9), obese (BMI Ŏ 
30) or no information (missing height or 
weight data). 
Smoking history 
iKM 
structured 
data 
Baseline 
characteristic 
Baseline 
Categorized as: 
Never smoked 
Current smoker 
Former smoker 
No information 
Family history of 
cancer 
Chart 
review 
Baseline 
characteristic 
Prior medical 
history 
Categorized as: 
Yes 
No 
Menopausal status 
iKM 
structured 
data + 
chart 
review 
Baseline 
characteristic 
Baseline 
Categorized as documented by physicians: 
Pre-menopausal 
Peri-menopausal 
Post-menopausal 
No information 
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Menopausal type 
Chart 
review 
Baseline 
characteristic 
Prior medical 
history 
If patients were menopausal, whether it was 
natural or induced and, if induced, the method 
(luteinizing hormone-releasing hormone 
[LHRH] suppression, surgical, other).  
Healthcare setting and provider characteristics 
Practice location 
iKM 
structured 
data 
(derived) 
Baseline 
characteristic 
Baseline 
The US census region of the USON clinic 
where the patient received care at the index 
visit: 
Midwest: Illinois, Indiana, Michigan, 
Ohio, Wisconsin, Iowa, Kansas, 
Minnesota, Missouri, Nebraska, North 
Dakota and South Dakota 
Northeast: Connecticut, Maine, 
Massachusetts, New Hampshire, Rhode 
Island, Vermont, Pennsylvania, New 
Jersey and New York 
South: Delaware, Florida, Georgia, 
Maryland, North Carolina, South 
Carolina, Virginia, Washington D.C., 
West Virginia, Alabama, Kentucky, 
Mississippi, Tennessee, Arkansas, 
Louisiana, Oklahoma and Texas 
West: Arizona, Colorado, Idaho, 
Montana, Nevada, New Mexico, Utah, 
Wyoming, California, Oregon and 
Washington State 
Missing clinic values will be captured in a 
“no information” category. 
Some of the regions may need to be collapsed 
if there are small sample sizes (e.g., South 
versus non-South). This determination will be 
confirmed after reviewing sample sizes and 
the added value to the study with McKesson’s 
Privacy and Compliance team. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Practice size 
iKM 
structured 
data 
(derived) 
Baseline 
characteristic 
1/1/2018 – 
12/31/2018 
The number of patients seen at the USON 
clinic where the patient receive care for 
his/her index visit in the year 2018: 
<50 patients/ year 
50-99 patients/year 
100-149 patients/year 
Ŏ150 patients/year 
Physician BC patient 
volume 
iKM 
structured 
data 
(derived) 
Baseline 
characteristic 
1/1/2018 – 
12/31/2018 
The number of BC patients seen by the 
physician who provided care for the patient’s 
index visit in the year 2018: 
<10 patients/ year 
11-49 patients/year 
> 50 patients/year 
Physician specialty 
iKM 
structured 
data 
Baseline 
characteristic 
Baseline 
Specialty of the physician who provided care 
for the patient’s index visit: 
Hematology & medical oncology 
Internal medicine 
Other 
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Not documented 
iKM use at practice 
location 
iKM 
structured 
data 
Eligibility 
criteria 
Baseline 
Patients who are treated at USON sites that 
utilize the full EHR capacities of iKM for 
their index visit will be eligible for 
participation in the study; otherwise, patients 
will be excluded. 
Data accessibility 
iKM 
structured 
data 
Eligibility 
criteria 
Baseline 
Patients whose data are accessible for 
research purposes will be eligible for 
participation in the study; otherwise, patients 
will be excluded. 
Disease characteristics 
Date of initial BC 
diagnosis 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria, 
Baseline 
characteristic 
Medical history 
prior to index 
To assess BC diagnoses that occurred prior to 
index, patients’ available medical history in 
iKM will searched. The completeness of this 
history will vary based on the length of 
disease and the time within the USON. 
Records may also be incomplete for patients 
with an initial BC diagnosis that occurred 
outside of the USON. 
Diagnosis of BC will be determined through a 
review of iKM’s discrete diagnosis and 
histology fields, which are populated during 
the routine course of care (International 
Classification of Diseases [ICD] codes will 
not be used). 
If no initial diagnosis date is documented, the 
first recorded diagnosis date in iKM will be 
used. This date will be used in calculations, 
not reported separately. 
Patients without a recorded diagnosis of BC 
will be excluded from the study. 
Date of mBC disease 
diagnosis 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria, 
Baseline 
characteristic 
Medical history 
prior to index 
Date of first recorded diagnosis of metastatic 
disease within the EHR. Patients will be 
qualified initially based on the date identified 
in the structured data; this will be confirmed 
during chart review among patients selected 
for chart review. Ultimately, the primary 
source will be the chart if available. 
Patients without recorded evidence of 
metastatic disease will be excluded from the 
study. 
Structured data will confirm the patient as 
metastatic and as available, indicate the 
earliest associated date of any of these 
criteria: 
1) Stage IV disease 
2) Tumor, Node, Metastasis (TNM) stage 
with M value of 1 
3) Record of location of metastatic 
disease 
4) Current or prior disease status 
containing reference to metastatic disease 
Time since initial BC 
diagnosis 
iKM 
structured 
data + 
chart 
review 
(derived) 
Baseline 
characteristic 
Medical history 
prior to index 
The duration of time, in weeks, between the 
date of BC diagnosis and presentation of 
metastatic disease will be calculated for each 
patient and summarized as the mean (± SD) 
and median (range) of values. The number of 
patients with available data will be reported. 
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Date of BC diagnosis and presentation of 
metastatic disease will be determined as 
defined above. 
Time since mBC 
diagnosis 
iKM 
structured 
data + 
chart 
review 
(derived) 
Baseline 
characteristic 
Medical history 
prior to index 
The duration of time, in weeks, between the 
index date and presentation of metastatic 
disease will be calculated for each patient and 
summarized as the mean (± SD) and median 
(range) of values. The number of patients 
with available data will be reported. 
Presentation of metastatic disease will be 
determined as defined above. 
Distant metastatic 
site(s) 
iKM 
structured 
data + 
chart 
review 
Baseline 
characteristic 
Medical history 
prior to index 
Baseline metastatic location(s) will be 
identified and categorized as: 
Bone (single) 
Bone (multiple) 
Brain 
Liver (single) 
Liver (multiple) 
Lung (single) 
Lung (bilateral) 
Lung (pleural effusion) 
Lymph nodes (regional) 
Lymph nodes (distant) 
Ovary 
Other 
No information 
Note, “no information” can indicates that 
metastases were not documented in the chart, 
not necessarily that patients did not have 
metastases. 
Endocrine sensitivity 
at 12 months 
iKM 
structured 
data 
Baseline 
characteristic  
Baseline  
Patients who experienced relapse more than 
12 months of completing adjuvant endocrine 
therapy will be considered to be endocrine 
sensitive; those who relapse in less than 12 
months, endocrine resistant.  
Endocrine sensitivity 
at 24 months 
iKM 
structured 
data 
Baseline 
characteristic  
Baseline  
Patients who experienced relapse more than 
24 months of completing adjuvant endocrine 
therapy will be considered to be endocrine 
sensitive; those who relapse in less than 24 
months, endocrine resistant.  
Visceral/non-visceral 
status 
iKM 
structured 
data + 
chart 
review 
(derived) 
Baseline 
characteristic 
Medical history 
prior to index 
Categorized as: 
Visceral (asymptomatic or symptomatic*) 
Adrenal gland 
Bronchus 
Cervix 
Esophagus 
Gastrointestinal tract 
Genital organ 
Intestinal tract 
Kidney 
Large intestine 
Liver 
Lung 
Mediastinum 
Omentum 
Other respiratory organ 
Other urinary organ 
Ovary 
Pancreas 
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Pericardium 
Peritoneum 
Pleura 
Rectum 
Retroperitoneum 
Small intestine 
Spleen 
Non-visceral  
Brain 
Breast 
Cervical nodes 
Chest wall 
Eye 
Ipsilateral supraclavicular lymph node 
Leptomeninges 
Other parts of nervous system 
Skin 
Spinal cord 
Bone only 
Bone 
Bone marrow 
Skull 
Other 
No information  
 
The above list will be confirmed or updated 
after chart review is complete 
 
*Asymptomatic visceral disease will be 
captured by chart review for patients who 
have explicit documentation of symptoms in 
the EHR records. All others will be assumed 
to be asymptomatic.  
 
 
Count of metastatic 
site(s) 
iKM 
structured 
data + 
chart 
review 
(derived) 
Baseline 
characteristic 
Medical history 
prior to index 
The total count of metastatic site(s) at index: 
No documentation 
1 
2 
3 
4+ 
Note, “no documentation” can indicates that 
metastases were not documented in the chart, 
not necessarily that patients did not have 
metastases. 
Stage at diagnosis 
iKM 
structured 
data 
Baseline 
characteristic 
Medical history 
prior to index 
Categorized as: 
Stage 0 
Stage IA 
Stage IB 
Stage IIA 
Stage IIB 
Stage IIIA 
Stage IIIB 
Stage IIIC 
Stage IV 
No information 
Eastern Cooperative 
Oncology Group 
iKM 
structured 
data 
Baseline 
characteristic 
Up to 90 days 
prior to index 
The ECOG performance status score is a 
rating of a patient’s disease status, daily 
living activities and quality of life, with low 
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(ECOG) performance 
status 
scores indicating greater functioning than 
high scores: 
0 
1 
2 
Ŏ3 
No information 
Karnofsky performance status is a similar 
measure and will be converted to ECOG 
using the methodology outlined below. 
Karnofsky 
Performance 
Status 
ECOG 
Performance 
Status 
ECOG 
Performance 
Status 
Description 
100 
0 
Fully active 
80, 90 
1 
Restricted in 
physically 
strenuous 
activity 
60, 70 
2 
Ambulatory 
and capable 
of self-care 
but unable to 
work 
40, 50 
3 
Capable only 
of limited 
self-care 
10, 20, 30 
4 
Completely 
disabled 
0 
5 
Dead 
 
Comorbidities 
Chart 
review 
Baseline 
characteristic 
6 months prior 
to index 
Comorbidities documented within 6 months 
prior to or on the index date will be captured 
and summarized as: 
Atrial fibrillation 
Bradyarrhythmia 
Cerebrovascular disease 
Congestive heart failure 
Chronic pulmonary disease 
Connective tissue disease 
Dementia 
Diabetes with end organ damage 
Diabetes without end organ damage 
Depression 
Electrolyte abnormalities 
Hemiplegia 
HIV/AIDS 
Hyperlipidemia 
Hypertension 
Infection 
Leukemia 
Long QT syndrome (congenital) 
Long QT syndrome (drug induced) 
Lymphoma 
Metastatic solid tumor (other than breast 
cancer) 
Mild liver disease 
Moderate to severe renal disease 
Myelosuppression 
Myocardial infarction 
Peptic ulcer disease 
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Peripheral vascular disease 
Tachycardia 
Stroke 
Unstable angina 
Venous thromboembolism (pulmonary 
embolism or deep vein thrombosis) 
Disease histology 
iKM 
structured 
data 
Baseline 
characteristic 
Baseline 
Categorized as: 
Ductal 
Lobular 
Mixed 
Metaplastic 
Tubular 
Mucinous 
Other 
No information 
Breast cancer gene 
(BRCA) 1/2 status 
Chart 
review 
Baseline 
characteristic 
Medical history 
prior to index 
Categorized as: 
Positive 
Negative 
No information 
Estrogen receptor 1 
gene (ESR1) status 
Chart 
review 
Baseline 
characteristic 
Medical history 
prior to index 
Categorized as: 
Positive 
Negative 
No information 
Next generation 
sequencing (NGS) 
status 
Chart 
review 
Baseline 
characteristic 
Medical history 
prior to index 
Categorized as: 
Positive 
Negative 
No information 
Treatment 
characteristics 
 
 
 
 
Prior adjuvant 
hormonal treatment 
iKM 
structured 
data + 
chart 
review 
Treatment 
characteristics 
Medical history 
prior to index 
The proportion of patients with prior adjuvant 
hormonal treatment for breast cancer prior to 
the index treatment. 
Prior neo-
adjuvant/adjuvant 
chemotherapy 
iKM 
structured 
data + 
chart 
review 
Treatment 
characteristics 
Medical history 
prior to index 
The proportion of patients with prior neo-
adjuvant/adjuvant chemotherapy for breast 
cancer prior to the index treatment. 
Prior metastatic 
hormonal treatment 
iKM 
structured 
data + 
chart 
review 
Treatment 
characteristics 
Medical history 
prior to index 
The proportion of patients with prior 
metastatic hormonal treatment for breast 
cancer prior to the index treatment. 
Adjuvant treatment 
end dates 
iKM 
structured 
data + 
chart 
review 
Treatment 
characteristics 
Medical history 
prior to index 
Date of adjuvant treatment discontinuation. 
Disease-free interval 
iKM 
structured 
data + 
chart 
review 
(derived) 
Treatment 
characteristics 
Medical history 
prior to index 
The duration (in weeks) between 
discontinuation of adjuvant therapy and the 
start of treatment for metastatic disease. The 
number of patients with available data will be 
reported. 
 
Findings will be summarized as the mean (± 
SD) and median (range) of values, along with 
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the proportion of patients with a duration less 
than or greater than/equal to 12 months.  
 
Surgery 
Chart 
review 
Treatment 
characteristics 
Medical history 
prior to index 
The proportion of patients who had surgery 
prior to the index treatment. 
Radiotherapy 
Chart 
review 
Treatment 
characteristics 
Medical history 
prior to index 
The proportion of patients who received 
radiation prior to the index treatment. 
Index treatment 
regimen 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria, 
Treatment 
characteristics 
Study 
observation 
period 
Patients’ index treatment will be categorized 
based on the cohort descriptions in Section 
8.1: 
PB+FUL 
 
Date of treatment 
initiation during the 
patient identification 
period (i.e., index 
date) 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria, 
Treatment 
characteristics 
Study 
observation 
period 
The date of initiation with a PB+FUL or 
 
 during the study identification period. 
If the combination regimen consists of more 
than one drug with drugs given on different 
dates, the date of the first administration of 
any drug will be used. 
Patients who did not initiate a qualifying 
regimen during the patient identification 
period will be excluded from the study. 
Treatment initiation 
by quarter 
iKM 
structured 
data + 
chart 
review 
(derived) 
Treatment 
characteristics 
Study 
observation 
period 
The proportion of patients who initiate 
treatment by quarter. 
Index treatment end 
date(s) 
iKM 
structured 
data + 
chart 
review 
Treatment 
characteristics 
Study 
observation 
period 
Date of final treatment for each drug or 
regimen. It is possible that the patient’s 
treatment stop date is not documented if the 
patient dies, is lost-to follow-up or is still on-
therapy. The final treatment date, death date 
or end of study date will be used, whichever 
is earliest. 
Index line of therapy 
(LOT) 
iKM 
structured 
data + 
chart 
review 
(derived) 
Treatment 
characteristics 
Study 
observation 
period 
LOT will be assigned based on the absolute 
chronologic order of regimens, based 
treatment start and stop dates. Specifically, 
first-line treatment designation will be 
assigned to the first treatment received after 
metastatic diagnosis. Line of therapy will 
advance with each subsequent regimen.  
Mean and median 
duration of index 
therapy 
iKM 
structured 
data 
Treatment 
characteristics 
Study 
observation 
period 
The duration (in weeks) between the start and 
stop of the index treatment regimen. Findings 
will be summarized as the mean (± SD) and 
median (range) of values. 
Number of cycles 
(index treatment) 
iKM 
structured 
data 
Treatment 
characteristics 
Study 
observation 
period 
The number of provider-documented therapy 
cycles received for the index treatment. 
Findings will be summarized as the mean (± 
SD) and median (range) of values. The 
number of patients with available data will be 
reported. 
Index treatment 
schedule (cycle 
length and frequency) 
iKM 
structured 
data + 
chart 
review 
Treatment 
characteristics 
Study 
observation 
period 
The planned frequency cycle length of the 
index treatment. 
Findings will be summarized as the mean (± 
SD) and median (range) of values. The 
number of patients with available data will be 
reported. 
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Index treatment 
schedule changes 
Chart 
review 
Treatment 
characteristics 
Study 
observation 
period 
Index treatment schedule changes will be 
captured and reported as the proportion of 
patients with changes. 
Index palbociclib 
treatment starting 
dose 
iKM 
structured 
data + 
chart 
review 
Treatment 
characteristics 
Study 
observation 
period 
The actual index treatment starting 
palbociclib dosage received. If needed, the 
dose is automatically calculated with the 
EHR based on patient’s body surface area or 
weight and dosage.  
 
Findings will be summarized as the mean (± 
SD) and median (range) for all patients within 
the specified cohort. The number of patients 
with available data will be reported. 
Reasons for 
palbociclib initiation 
of less than 125 
mg/day  
Chart 
review 
Treatment 
characteristics 
Study 
observation 
period 
For patients who initiated palbociclib at a 
dose lower than 125 mg/day, reasons will be 
captured and reported:  
Age 
Concomitant medications 
Diagnosis 
Due to line of therapy received 
ECOG performance status score 
Patient request 
Presentence of comorbidities 
To avoid toxicity 
Other 
Index palbociclib 
treatment 
dose/schedule 
changes 
Chart 
review 
(derived) 
Treatment 
characteristics 
Study 
observation 
period 
Index dose/schedule changes will be captured 
and reported as the proportion of patients 
with dose changes. 
Reason for 
palbociclib dose 
changes 
Chart 
review 
Treatment 
characteristics 
Study 
observation 
period 
Data for palbociclib dose change reason will 
exclusively come from chart review. 
Reviewers will be asked to select reason(s) as 
explicitly documented in patients’ charts. 
If available, reason patients discontinued 
treatment will be abstracted: 
Lack of response 
Patient preference 
Toxicity 
Other 
No information 
Reviewers will specify other reasons; these 
will be reported if any represent >5% of 
patients. 
Reason for treatment 
discontinuation 
Chart 
review 
Treatment 
characteristics 
Study 
observation 
period 
Data for discontinuation reason will 
exclusively come from chart review. 
Reviewers will be asked to select reason(s) as 
explicitly documented in patients’ charts. 
If available, reason patients discontinued 
treatment will be abstracted: 
Progression 
Toxicity 
Decline in performance status 
Financial/insurance 
Completed planned treatment 
Death 
Hospice 
Patient preference (if other categories do 
not apply) 
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Physician preference (if other categories 
do not apply) 
Other  
 
Proportion of patients 
who advance/do not 
advance 
iKM 
structured 
data + 
chart 
review 
(derived) 
Treatment 
characteristics 
Study 
observation 
period 
The proportion of patients who advance and 
do not advance from the index treatment will 
be summarized as the count and percentage of 
the following: 
Patients with ongoing index treatment 
Patients who died following index 
treatment 
Patients who advanced to a subsequent 
treatment 
Patients who did not advance to a 
subsequent treatment for unknown 
reasons 
Post-index treatment 
regimen 
iKM 
structured 
data + 
chart 
review 
Treatment 
characteristics 
Study 
observation 
period 
The regimen received by patients following 
discontinuation from the index treatment. 
Time to 
chemotherapy 
iKM 
structured 
data 
+chart 
review 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
Time to chemotherapy will be defined as the 
interval (in weeks) between index treatment 
and start of chemotherapy as documented in 
the iKM EHR database. Patients with 
ongoing treatment at the study observation 
period will be censored on the study end date 
or the last visit date available in the dataset, 
whichever occurred first. rwDOT will be 
analyzed using the Kaplan-Meier method 
with 95% CIs, and summary tables of the 
number of events and censored patients at 6, 
12, 18, 24, 30, and 36 months. 
Real-world duration 
of treatment 
(rwDOT) 
iKM 
structured 
data + 
chart 
review 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
rwDOT will be defined as the interval (in 
weeks) between the start and stop index as 
documented in the iKM EHR database. 
Patients with ongoing treatment at the study 
observation period will be censored on the 
study end date or the last visit date available 
in the dataset, whichever occurred first. 
rwDOT will be analyzed using the Kaplan-
Meier method with 95% CIs, and summary 
tables of the number of events and censored 
patients at 6, 12, 18, 24, 30, and 36 months. 
Time to next 
treatment (TTNT) 
iKM 
structured 
data 
+chart 
review 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
TTNT will be defined as the interval (in 
weeks) between the start of the index 
treatment and the date of the next-line 
treatment as documented in the iKM EHR 
database. Patients who did not advance to the 
next treatment within the study observation 
period will be censored on the study end date 
or the last visit date available in the dataset, 
whichever occurred first. TTNT will be 
analyzed using the Kaplan-Meier method 
with 95% CIs, and summary tables of the 
number of events and censored patients at 6, 
12, 18, 24, 30, and 36 months. 
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Provider-
documented tumor 
assessments 
 
 
 
 
Provider-documented 
tumor assessment 
Chart 
review 
Clinical 
outcomes 
Study 
observation 
period 
In prospective clinical trials, response is 
generally assessed according to Response 
Evaluation Criteria In Solid Tumors 
(RECIST) criteria. However, the parameters 
underlying these criteria are less reliably 
available in retrospective, observational 
studies.20 Instead, for this study, we will rely 
on provider documented assessments of 
response. No attempts will be made to mimic 
the RECIST guidelines. 
Response assessments documented for the 
index treatment (depending on cohort). It is 
possible that patients have multiple response 
assessments in their charts during this period. 
All documented responses described in scan 
reports and progress notes (along with the 
associated note date) will be captured. 
Response assessments will be classified as: 
Complete response: Documented as “a 
complete response” to therapy; indication 
patient is in “remission”; “all lesions” 
have disappeared or “no evidence of 
disease”). 
Response not otherwise specified (partial 
response or response not otherwise): any 
documentation of improved disease or 
responding disease not definitively 
classified as a complete response. 
Stable disease: Documented as disease is 
stable (not progressed or not improved; 
e.g. Stable appearance of lobe nodules). 
Mixed response: Combination of 
improved and worsened disease. 
Progressive disease: Documented as 
disease has “progressed”; or worsening of 
disease. 
Not evaluated: No documentation of 
status of disease. 
Best overall response 
(BOR) 
Chart 
review 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
Each patient will be assigned one BOR based 
on all recorded response assessments 
captured during chart review. 
The responses will be ranked in the following 
order (from best to worst): 
Complete response 
Improved disease 
Stable disease 
Mixed response 
Progressive disease 
Not evaluated 
The proportion of patients with each BOR 
category will be reported. 
Date of provider-
documented 
progression or 
recurrent disease 
Chart 
review 
Clinical 
outcomes 
Study 
observation 
period 
The date of provider-documented progression 
or recurrent disease as explicitly noted by a 
clinician in a scan report or progress note. 
Frequently, this will be the date the provider 
recorded evidence of progression, not 
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necessarily the date the radiologic assessment 
was made. 
Real-world complete, 
improved or stable 
disease rate (clinical 
benefit rate) 
Chart 
review 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
In real-world research, the parameters 
underlying response as defined by RECIST 
criteria are often unavailable. As such, this 
study will assess response to treatment as 
documented by providers and capture real-
world assessments of response, including 
complete response, improved disease and 
stable disease. This measure will be similar to 
clinical benefit rate as defined by RECIST 
criteria. 
Clinical outcomes 
 
 
 
 
Last USON visit date 
iKM 
structured 
data + 
chart 
review 
Clinical 
outcomes 
Study 
observation 
period 
Each patient’s most recent visit date, prior to 
or on close of study observation period will 
be recorded. A visit is defined as a physician 
encounter with the practice where either 
treatment is given or vital signs are recorded. 
For patients with a death date, this last visit 
date should occur prior to the death date. 
This will not be reported separately; it will be 
used in calculating the patient’s available 
follow-up time as a descriptive measure. 
available follow-up time = Integer (latest of 
last visit date or death date – index date +1) 
Death date 
iKM 
structured 
data, 
chart 
review + 
external 
sources 
Clinical 
outcomes 
Study 
observation 
period 
Date of death will be captured from the iKM 
EHR, limited access death master file 
(LADMF), national death index (NDI) and, 
possibly, other commercial sources of death 
information (the study team is confirming the 
utility of these sources). If dates conflict 
among the sources, the NDI, followed by the 
LADMF date will be prioritized. If severe 
data discordance is observed (i.e., death is 
reported to occur prior to the index date), then 
the iKM death date will be used. Further 
information on the sources of death 
information is presented in Section 8.4. 
Follow-up duration 
iKM 
structured 
data, 
chart 
review + 
external 
sources 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
The duration between index and last follow-
up date. Findings will be summarized as the 
mean (± SD) and median (range) for all 
patients within the specified cohort. The 
number of patients with available data will be 
reported. 
Vital status 
iKM 
structured 
data, 
chart 
review + 
external 
sources 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
Patients without a date of death recorded in 
iKM, LADMF, NDI or other commercial 
sources of death information used for the 
study will be assumed to be alive at the end 
of the study. Those with a date of death in 
available records will be flagged as deceased. 
Further information on the sources of death 
information is presented in Section 8.4. 
Overall survival (OS) 
iKM 
structured 
data, 
chart 
Clinical 
outcomes 
Study 
observation 
period 
OS will be defined as the interval (in weeks) 
between index treatment and the date of death 
(any cause) as documented in the iKM EHR 
database, LADMF, NDI and other 
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review + 
external 
sources 
(derived) 
commercial sources of death records that may 
be used for this study. Patients who did not 
die within the study observation period will 
be censored on the study end date or the last 
visit date available in the dataset, whichever 
occurred first. OS will be analyzed using the 
Kaplan-Meier method with 95% CIs, and 
summary tables of the number of events and 
censored patients 6, 12, 18, 24, 30, and 36 
months. 
Survival rate 
iKM 
structured 
data, 
chart 
review + 
external 
sources 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
Survival rates will be provided along with the 
Kaplan-Meier OS analyses described above 
as survival rates at 6, 12, 18, 24, 30, and 36 
months. 
Real-world 
progression-free 
survival (rwPFS) 
iKM 
structured 
data, 
chart 
review + 
external 
sources 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
The rwPFS will be measured from the 
initiation of the index treatment to the date of 
progression or date of death due to any cause, 
censoring patients who are still alive at the 
end of the study observation period and did 
not progress at the last visit date. The rwPFS 
will be estimated in weeks using the Kaplan-
Meier method with 95% CIs, and summary 
tables of the number of events and censored 
patients at 6, 12, 18, 24, 30, and 36 months. 
rwPFS rate 
iKM 
structured 
data, 
chart 
review + 
external 
sources 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
PFS rates will be provided along with the 
Kaplan-Meier PFS analyses described above 
as PFS rates at 6, 12, 18, 24, 30, and 36 
months. 
Real-world time to 
tumor progression 
(rwTTP) 
iKM 
structured 
data, 
chart 
review + 
external 
sources 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
The rwTTP will be measured from the 
initiation the index treatment to the date of 
provider-documented progression, censoring 
patients without evidence of provider-
documented progression at the last visit date. 
The rwTTP will be estimated in weeks using 
the Kaplan-Meier method with 95% CIs, and 
summary tables of the number of events and 
censored patients at 6, 12, 18, 24, 30, and 36 
months. 
 
8.4. Data sources  
Table 2 presents the data elements that will be evaluated through this study and their 
associated source. Most study data will originate from the EHR system of the USON, iKM. 
iKM captures outpatient practice encounter histories for patients under community-based 
care, including, but not limited to patient demographics such as age and gender; clinical 
information such as disease diagnosis, diagnosis stages, performance status information and 
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laboratory testing results; and treatment information, such as dosages and treatment 
administration within the USON.  
Structured data fields within the iKM EHR database will provide information needed to 
address most research questions. These data will be supplemented by additional unstructured 
data collected through chart review for a subset of the study population (selection 
methodology described in Section 8.2.4). Electronic chart review data was collected by 
means of a secure, web-based electronic case report form (eCRF) by healthcare professionals 
with oncology experience.  
The study will only use data from USON practices utilizing full EHR capacities of iKM. 
Data management and administrative processing is supported by McKesson’s quality 
assurance procedures. Additionally, iKM has previously been used to evaluate patient 
profiles, treatment patterns and outcomes among mBC patients and the results have been 
consistent with other published studies.21-33 Thus the study team does not plan to conduct any 
additional studies to validate the accuracy of demographic, clinical, treatment and outcome 
information in the iKM EHR database. 
The primary source of death information will be structured and unstructured records of death 
in the iKM EHR database. McKesson has certification to access the LADMF of the Social 
Security Administration and, as such, this will be a supplementary source of vital (death) 
records in addition to the NDI of the Centers for Disease Control. The study team is also 
evaluating the potential for other commercial sources of death information to be used for this 
study, including ObituaryData.com, Legacy.com, Datavant and others. If it is confirmed that 
these sources can be used, they will be an additional source of death information.  
Death information is updated weekly in the LADMF and is as current as it is reported to the 
Social Security Administration.34 However, death dates recorded in the LADMF are not 
complete due to limitations on access of records for research purposes.35,36 Levin et al. (2019) 
compared LADMF and hospital death records after access restrictions imposed in 2011.35 
After 2011, LADMF sensitivity for in-hospital deaths was 14.8% (compared with 88.9% 
before 2011) and 28.9% for out-of-hospital deaths (compared with 71.4% before 2011). The 
LADMF specificity, however, was greater than 99% both prior to and after 2011. Peters et al. 
(2017) compared capture of death dates in the LADMF with a multiphase approach that 
assessed online databases (including LADMF), EHR records and provider follow-up.36 The 
authors reported that 42.7% of death records were identified by the LADMF, with the 
remainder from another online database (32.6%), EHR records (22.2%) and provider follow-
up (3.5%). Overall, the sensitivity was 58.5%, with 100% specificity.  
In a study of the iKM EHR database and LADMF, it was observed that 93.3% of all death 
records were captured in structured fields and 6.7% of death records were solely identified by 
the LADMF.37 Among deaths recorded by both structured data and the LADMF, 
concordance was 88.0%. When both structured and unstructured data are available, 99.4% of 
death records are captured from these sources, with 0.6% death records solely identified by 
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the LADMF. Between 2015 and 2019, the proportion of death records captured by structured 
data trended upward (slope = 4.04).  
Death records in the NDI index are updated quarterly with a lag time of approximately 1 
year. Curtis et al. (2018) compared several sources of death, including EHR data, Social 
Security Death Index and commercial death data, with the NDI, for a cohort of patients with 
non-small cell lung cancer.38 The sensitivity between the NDI and structured data was 66% 
and the specificity was 97%. With combined EHR and commercial death dataset, sensitivity 
increased to 84%. Inclusion of the Social Security Death Index increased sensitivity to 89% 
and, last, with supplementation of missing death information through chart abstraction 
(unstructured data), sensitivity increased to 91%. No studies to date have compared the 
capture of death information with the iKM EHR to the NDI.  
Some data elements will be available from multiple sources, structured data (i.e. from iKM), 
unstructured data (i.e. chart review), the LADMF, NDI and, possibly, commercial sources of 
death records. During chart review, abstractors reviewed patients’ entire medical record, 
including information that is also captured in structured fields. Discrepancies in the medical 
record will be reviewed by McKesson’s Data Quality Manager, Medical Director/Physician 
Investigator to determine the most appropriate value to be abstracted based on clinical 
judgement and operational guidelines.  
If there is a discrepancy in dates of death among the sources, the LADMF date, followed by 
the NDI date will be prioritized as it reflects the official date of death reported to government 
agencies unless: 1) EHR activity indicates that a patient visit occurred after date of death as 
documented in the LADMF or NDI; 2) date of deaths between the two sources vary by more 
than 6 months. In these cases, the date of death recorded in the iKM EHR as part of patient 
follow-up by USON physicians and staff may be sourced from non-official records, 
including telephone conversations with the patient’s family. 
Data from all sources and any derived variables will be merged into one master dataset for 
analysis. Data will be handled in compliance with the Health Insurance Portability and 
Accountability Act (HIPAA) and Health Information Technology for Economic and Clinical 
Health (HITECH). 
8.5. Study size 
A feasibility assessment from iKM identified 783 patients who met study eligibility criteria 
and initiated PB+FUL and 
 (Table 3). 
The 1035 patients who initiated PB+FUL and 
 in the first- through third-line 
setting were selected for chart review (633 PB+FUL and 
). During 
chart review, these patients’ eligibility was confirmed and some patients were disqualified. 
The final sample size for analysis will consist of the confirmed eligible patients who initiated 
first-line PB+FUL 
 
 
 
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Table 3. Initial feasibility assessment 
Eligibility criteria 
Patient count - Excluded 
Patient count - remained 
Documented diagnosis of hormone receptor-
positive (estrogen receptor-positive or 
progesterone receptor-positive), human 
epidermal growth factor receptor 2-negative 
metastatic breast cancer (mBC) who received a 
qualifying treatment (i.e., palbociclib, letrozole, 
exemestane, anastrozole or fulvestrant) within the 
USON during the study identification period [1] 
- 
19,720 
Aged 18 years at initial recorded diagnosis of 
mBC 
1 
19,719 
Exclusion of patients enrolled in an 
interventional clinical trial during the study 
observation period 
1216 
18,503 
Did not receive a treatment indicated for another 
primary cancer during the study observation 
period 
1572 
16,931 
Received care at a USON site(s) utilizing the full 
EHR capacities of iKM at the time of treatment. 
0 
16,931 
EHR data available from the USON site(s) where 
the patient received treatment are accessible for 
research purposes 
0 
16,931 
Exclusion of patients with qualifying treatments 
(i.e., palbociclib, letrozole, exemestane, 
anastrozole or fulvestrant) received only prior to 
metastases date and not after metastatic diagnosis  
2558 
14,373 
Exclusion of patients with start of first regimen 
more than 120 days after metastases date 
1455 
12,918 
Exclusion of patients whose data are inaccessible 
for research purposes 
5594 
7,324 
Initial cohort counts (patients who initiated the cohort-specific regimen in an appropriate LOT) 
PB+FUL: Palbociclib combination therapy with 
fulvestrant following as first-line or beyond 
therapy in the metastatic setting. Patients with 
evidence of prior treatment with CDK 4/6 
inhibitors (ribociclib or abemaciclib) in the 
metastatic setting were excluded. Study 
identification period: 01 February 2015 - 31 
December 2019. 
- 
840 
 
 
 
 
 
 
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Exclusion of patients who initiated qualifying regimens prior to the start of the study period (by 
cohort) 
PB+FUL 
47 
793 
First-line = 39 
  
 
  
Third-line = 2 
  
Fourth-line = 1 
  
Fifth-line or beyond = 3 
  
 
 
 
Exclusion of patients with fewer than 2 visits after index (by cohort)  
PB+FUL 
10 
783 
  
First-line = 488 
  
 
  
Third-line = 53 
  
Fourth-line = 45 
  
Fifth-line or beyond = 105 
 
 
 
  
 
  
 
  
  
  
 
Patients selected for chart review (PB+FUL and 
 who initiated 1L-3L treatment; n= 1035) 
Exclusion of patients whose data were 
inaccessible for chart review 
29 
1006 
Exclusion of patients who were not 
diagnosed with HR+ mBC 
45 
961 
Exclusion of patients who were not 
diagnosed with HER2- disease 
10 
951 
Exclusion of patients who did not receive a 
qualifying treatment 
124 
828 
Exclusion of patients who participated in 
clinical trials 
21 
807 
Exclusion of patients with other primary 
cancers 
40 
767 
Exclusion of patients who do not receive 1L-
3L qualifying treatment (sequencing 
activities performed during analysis) 
52 
715 
Exclusion of patients with an index date prior to 01 Feb 2016 (by cohort)  
PB+FUL 
- 
428 
 
 
 
Final cohort counts  
1L PB+FUL 
- 
317 
2L PB+FUL 
- 
78 
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1L 
 
 
 
 
 
 
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8.6. Data management  
A description of the data sources to be used for this study is provided in Section 8.4. 
Operational definitions, periods of assessment and data sources of all data elements to be 
used for this study, along with descriptions of how raw data elements will be transformed 
into derived variables, is presented in Table 2.  
The McKesson study team will collaborate with McKesson’s Commercial Intelligence group 
to collect the structured iKM data that will be used for analysis. The Commercial Intelligence 
team will be provided with a Data Collections Variable List, which will detail the specific 
data elements that will need to be included in the study dataset. A Data Analyst will begin by 
generating high-level study sample counts that demonstrate attrition rates of the 
inclusion/exclusion criteria.  
The study team will review the attrition count and the Data Analyst will proceed with 
collecting the remaining data elements on the Data Collections Variable List. The Data 
Analyst will perform an initial quality control check of the study dataset before providing the 
file to the study team’s Biostatistician on a secure server. Once received by the 
Biostatistician, data validation will continue and will consist of, but is not limited to, quality 
control checks for appropriate values, logical sequences and quantity of missing values.  
A list of patients eligible for chart review was generated by the Data Analyst and the 
Biostatistician applied the agreed upon sampling technique to identify the specific patients 
that underwent chart review. This list of patients was then securely transmitted to the Chart 
Review Team Manager. The chart review team consists of experienced oncology healthcare 
providers.  
The McKesson study team led a training session with chart abstractors to discuss study 
specific considerations. Reference materials were provided to abstractors at this time. If chart 
abstractors have questions during the abstraction process, these were first raised to the Chart 
Review Team Manager. As needed, questions were escalated to the Outcomes Researcher 
and Principal Investigator.  
Chart review was accomplished by use of a secure, web-based eCRF. The main purpose of 
the eCRF is to obtain data required by this non-interventional study protocol in a complete, 
accurate, legible and in a timely manner.  
Analyses will be conducted using statistical analysis software (SAS®; SAS Institute Inc., 
Cary, NC, US) and/or R: A Language and Environment for Statistical Computing (R 
Foundation for Statistical Computing, Vienna, Austria) as appropriate. 
8.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
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A CRF is required and should be completed for each included patient. The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. McKesson shall ensure that the CRFs are 
securely stored at the study site in encrypted electronic and/or paper form and will be 
password protected or secured in a locked room to prevent access by unauthorized third 
parties. 
McKesson has ultimate responsibility for the collection and reporting of all clinical, safety, 
and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
The source documents are the hospital or the physician's chart. In these cases, data collected 
on the CRFs must match those charts.  
8.8. Record retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, 
McKesson agrees to keep all study-related records, including the identity of all participating 
patients (sufficient information to link records, e.g., CRFs and hospital records), copies of all 
CRFs, safety reporting forms, source documents, detailed records of treatment disposition, 
and adequate documentation of relevant correspondence (e.g., letters, meeting minutes, and 
telephone call reports). The records should be retained by McKesson according to local 
regulations or as specified in the research agreement, whichever is longer. McKesson must 
ensure that the records continue to be stored securely for so long as they are retained. 
If McKesson becomes unable for any reason to continue to retain study records for the 
required period, Pfizer should be prospectively notified. The study records must be 
transferred to a designee acceptable to Pfizer, such as another investigator, another 
institution, or to an independent third party arranged by Pfizer. 
 
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless McKesson and Pfizer have expressly agreed to a different period of 
retention via a separate written agreement. Record must be retained for longer than 15 years 
if required by applicable local regulations. 
 
McKesson must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met. 
 
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8.7. Data analysis  
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be dated, filed and maintained 
by Pfizer. The SAP may modify the plans outlined in the protocol; any major modifications 
of primary endpoint definitions or their analyses would be reflected in a protocol 
amendment.* 
8.7.1. Analysis sets 
Separate analysis sets will be created to address the study objectives based on the cohorts of 
patients to be included (an overview of these analyses is presented in Table 2). For the 
primary and secondary objectives, the analyses will consist of patients who initiated first-line 
PB+FUL, 
 
 
 
8.7.2. Derived and transformed data 
Some of the data elements needed for the study objectives will be derived from available data 
during the analysis phase of the study. Details about these calculations are provided along 
with the operational definition in Table 2. Prior to constructing these variables, the 
McKesson biostatistician will perform data validation activities. Data validation will 
continue and will consist of, but is not limited to, quality control checks for appropriate 
values, logical sequences and quantity of missing values.  
Missing data will be identified and reported in the results tables as percentages for all 
variables. If there is a large amount of missing or illogical data, a decision to include, exclude 
or impute that variable will be subsequently made based on the study sponsor’s decision. 
8.7.3. Statistical methods 
Description of study enrollment 
To be included in the study patients must meet each of the inclusion criteria and none of the 
exclusion criteria listed in Sections 8.2.1-8.2.2. Counts of patients excluded for each criterion 
will be summarized.  
Description of patient demographic, clinical and treatment characteristics 
Descriptive analyses will be conducted to evaluate the demographic, clinical and treatment 
characteristics overall, as well as for the cohorts and stratifications defined above. Results 
will be reported in aggregate. Categorical variables (e.g., ECOG performance status) will be 
reported as frequency and percentage. Continuous variables such as age will be reported as 
mean, standard deviation, median and range (minimum-maximum). In the case of missing 
observations, the number and percentage of missing values will be reported.  
 
* If the SAP is modified, the study protocol will be updated accordingly and re-submitted to the IRB.  
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All descriptive tables will be presented overall and for each of the Cohorts defined above 
and, as supported by the final sample size, stratified to present the results for the subgroups 
defined in Section 8.2.4. 
Clinical outcomes 
Time-to-event outcomes, time to chemotherapy, rwDOT, TTNT, OS, rwTTP and rwPFS, 
will be assessed using the Kaplan-Meier method with 95% CIs, and summary tables of the 
number of events and censored patients at 6, 12, 18, 24, 30, and 36 months among those who 
initiated first-line PB+FUL. Further details about these calculations are presented in Table 2.  
 
 
To reduce the effect of selection bias, the study team will first consider baseline 
variables/covariates compared among propensity score matched cohorts. The propensity 
score, defined as the probability of being initiated on PB+FUL treatment, will be estimated 
using a multivariate logistic regression model conditional on the baseline covariates (e.g., 
age, gender, ethnicity, body mass index (BMI), menopausal status, comorbidities, ECOG, 
stage of diagnosis, count of metastatic sites and site of metastases). Each individual will have 
a propensity score that represents the probability of being treated with PB+FUL. Pairs of 
treated and untreated subjects will be matched on the logit of the propensity score using a 
caliper of width equal to 0.2 of the standard deviation of the logit of the propensity score, as 
this caliper has been shown to be optimal in a range of settings.  
 
Alternatively, if propensity score matching is not supported by the sample size, standardized 
or normalized inverse probability of treatment weighting (IPTW) using propensity score may 
be applied to balance baseline demographic and clinical characteristics between the 2 
comparison cohorts. For standardized IPTW, the propensity score weight will be calculated 
as the inverse of the propensity score (1/propensity score), then create a weight reflect the 
sample size for each of the treatment groups, i.e., (1/propensity score)*(number of obs. in 
treatment A)/(number of obs. in entire study group). For normalized IPTW, the weights will 
be calculated as the inverse of patients’ estimated probability of being in treatment. Finally, 
the normalized weights will be calculated by dividing each weight by the overall mean 
weight. After weighting, the sum of weights attributed to each patient in a given cohort may 
not be equal to the sample size of this cohort, consequently, the effective sample size after 
weighting may be different than the original sample size (i.e., before weighting), although the 
total size of whole study population will not be changed. 
 
Last, during analysis, multivariable Cox regression models will be used to further reduce bias 
associated with underlying characteristics of the patient populations that may affect treatment 
selection. Specifically, all variables will be fitted into a multivariable Cox proportional 
hazard regression model to assess independent associations between clinical outcomes and 
probability of an event (hazard ratio) adjusting for the influence of other variables within the 
model.  
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Additional analyses 
An intent-to-treat approach will be taken for the analyses. 
 
Based on the resulting sample sizes, a decision to proceed with sensitivity analyses or 
additional stratifications will be made. In particular, the team may opt to pursue an analysis 
to assess the impact of follow-up duration on outcomes, endocrine sensitivity time periods 
(12 vs. 24 months) or compare the patient population with clinical trials. These additional 
analyses will require a study amendment. 
8.7.4. Sequence of analyses 
An initial feasibility assessment has been performed based solely on structured data. 
Following chart review, analyses will be undertaken to meet the primary and secondary 
objectives for the final study population using both structured an unstructured data. 
 
 
8.8. Quality control 
For structured data, McKesson’s Commercial Intelligence and Real World Evidence teams 
conduct quality assurance checks on all analytics projects. The process includes both 
technical and clinical quality checks. Technical review of the dataset consists of identifying 
inappropriate values (e.g., out of range, illogical), logical sequences and quantity of missing 
values. Illogical and missing data will be reported to the study team, which may opt to 
exclude or impute these values. Clinical review of the data subsequently occurs to ensure 
aggregate data are aligned with expectations and prior publications.  
 
The quality assurance process includes the following areas: 
 
Project scope and study rules 
 
Protocol/statistical analysis plan (SAP) development 
 
Data extraction and integrity 
 
Populated tables and Study Report development 
As results of quality assurance and quality control, we confirm: 
 
The source of the data and/or results will be documented and that results/data will 
be verified against the source 
 
The internal consistency of the medical research data presented 
 
The conclusions are objective, balanced and consistent with the study results 
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 
The format and content of the document are aligned with the agreed upon 
template and standards 
Quality control and validation of chart review (unstructured) data occurred in multiple 
phases. Prior to full chart review, a pilot was conducted with at least 5% of the patient 
population, up to 25 patients. Charts were reviewed by each reviewer on the team to ensure 
inter-rater reliability. Data Collection Manager/Team Lead reviewed pilot data for accuracy 
and consistency, including implausible dates (i.e., date of death prior to last date of 
treatment), non-standard treatments, results which are inconsistent with known clinical 
parameters or other clinical data which is inconsistent with known standards and outcomes. 
Chart review team met following pilot and before launch of full chart review to clarify 
ambiguous or conflicting data and address potential problems and questions. Pilot data were 
presented to the research team for review and approval. As necessary, revisions to the tool 
and/or additional training were implemented.  
Once the pilot chart review was complete, the remaining chart reviews proceeded. During 
this phase of chart review, Data Collection Manager/Team Lead performed random and 
detailed checks of the data by verifying original source data. The Data Collection Manager 
also initiated queries, quality control of randomly selected charts and review of final data set 
before submission to researcher. Finally, the researcher and study’s statistical lead provided a 
final examination of the final dataset by looking for missing or illogical data before preparing 
it for analyses. This analysis included a descriptive analysis of the provider characteristics, 
demographics, baseline clinical and disease characteristics, and characteristics of treatment 
patterns. Data points flagged as outliers were reviewed by the Chart Review Team Lead.  
Based on extensive experience with chart abstraction of real-world oncology data, the 
McKesson Life Sciences team has created chart abstraction guidelines to reflect best 
practices in data collection across a number of disease areas.39 The intent of this document is 
to ensure accurate, objective and consistent data capture.  
8.9. Limitations of the research methods 
8.9.1. Internal validity of study design  
Measurement error(s)/misclassification(s) 
This observational and retrospective study uses iKM EHR data. The iKM database is not 
collected for research purposes but for clinical practice reasons. This may impede the 
standardization of the data collection methods and instruments and the reporting practices of 
the physician. As with all administrative databases, iKM data are subject to coding errors of 
omission and commission. Problems with inadequate or inaccurate codes in the databases 
may introduce some level of misclassification bias of certain diagnoses, events, or procedures 
of interest. Likewise, some variables of interest may not be as complete across the entire 
population. The iKM EHR contains information on patients only when they are seen by 
USON physicians. Services and procedures provided outside of the USON are not captured 
by the database, as well as drugs received by patients from pharmacies not affiliated with 
USON practices.  
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A patient’s treatment history prior to his/her first encounter at a USON practice may be only 
available in physician progress notes and is not well captured in the iKM EHR. We cannot 
rule out the possibility that some patients coded as receiving being treatment naïve for 
metastatic disease in iKM EHR actually had previous chemotherapy for metastatic disease in 
healthcare facilities outside the USON. 
Information bias 
 
Due to the nature of the study design, there is potential for bias to be introduced into the 
calculations of clinical outcomes. Specifically, patients who initiated treatment during the 
patient identification period may be meaningfully different from other patients who initiated 
therapy prior or after the study identification period.  
Confounding 
The iKM system is used for clinical practice reasons, not solely for research purposes. As 
such, associations but not causality can be detected, thus bias may be introduced by 
confounding factors. For example, data may be collected with an intent-to-treat approach, 
meaning based on when treatment is assigned rather than received. In particular, it will not be 
possible to determine if oral therapies were dispensed or taken; therefore, we’ll use an intent-
to-treat approach for analysis, with the assumption that all prescribed oral therapies were 
taken. Likewise, patients who do and do not receive the treatment at one point in time may be 
fundamentally different than those who received treatment during the observation period. 
These confounding factors are most likely to affect the outcomes being considered for this 
estimation study. 
8.9.2. External validity of study design (generalizability) 
Not all community oncology practices are included in the iKM dataset. Furthermore, not all 
of the USON utilize the full capabilities of the iKM EHR. The USON encourages use of 
evidence-based treatment guidelines. Therefore, practices that participate in the USON may 
be different from other community oncology practices in the patient population that is seen or 
the prescribing practices of the physicians. 
8.9.3. Analysis limitations 
As a retrospective observational study, data entry errors at the point of care cannot be 
detected or corrected during analysis. 
8.9.4. Limitations due to missing data and/or incomplete data 
Although data quality checks are conducted, it is possible that some variables of interest may 
not be as complete across the entire population. 
8.10. Other aspects 
Not applicable.  
9. PROTECTION OF HUMAN SUBJECTS 
This study will include both a structured data analysis and human-level review of 
unstructured (chart review). As such, separate patient protections and reporting requirements 
are described below for each phase.  
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9.1. Patient information  
Structured data analysis 
This study involves data that exist in anonymized structured format and contain no patient 
personal information.  
 
Human Review of Unstructured Data 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data. Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws.  
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, any patient names will be removed and will be replaced by a single, specific, 
numerical code. All other identifiable data transferred to Pfizer or other authorized parties 
will be identified by this single, patient-specific code. In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with the McKesson contract and applicable privacy laws. 
IRB approval will be received prior to any patient level data transfer that occurs between 
McKesson and Pfizer. All other data will be reported to the Sponsor only in aggregate form 
and with attention to results that represent small counts of patients. 
Study data will be reported in aggregate; no identifiable data will be transferred to Pfizer. 
 
9.2. Patient consent 
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required.  
The McKesson study team will submit a request for exemption, waiver of informed consent 
and authorization to the Intuitional Review Board (IRB). This project involves the study of 
existing data and records; study information will be analyzed by the McKesson study team in 
such a manner that research participants will not be directly identified. Once exemption 
status and a waiver of informed consent are met, a waiver of authorization can be approved, 
allowing the retrospective study to occur. 
9.3. Patient withdrawal 
Not applicable, as this project does not require informed consent. 
 
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9.4. Institutional review board (IRB)/Independent ethics committee (IEC) 
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents (e.g., informed consent forms if applicable) from the relevant IRBs/IECs. 
All correspondence with the IRB/IEC must be retained. Copies of IRB/IEC approvals must 
be forwarded to Pfizer.  
All study data will be reported to the Sponsor only in aggregate form and with attention to 
results that represent small counts of patients. 
9.5. Ethical conduct of the study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology, Good Epidemiological Practice (GEP) 
guidelines issued by the International Epidemiological Association (IEA), Good Practices for 
Outcomes Research issued by the International Society for Pharmacoeconomics and 
Outcomes Research, International Ethical Guidelines for Epidemiological Research issued by 
the Council for International Organizations of Medical Sciences (CIOMS), European 
Medicines Agency (EMA) European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance (ENCePP) Guide on Methodological Standards in 
Pharmacoepidemiology, and FDA Guidance for Industry: Good Pharmacovigilance and 
Pharmacoepidemiologic Assessment, FDA Guidance for Industry and FDA Staff: Best 
Practices for Conducting and Reporting of Pharmacoepidemiologic Safety Studies Using 
Electronic Healthcare Data Sets, Guidance for Industry: Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims and/or 
equivalent. 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS REQUIREMENTS 
Structured Data Analysis 
This study involves EHR data that exist as structured data by the time of study start or a 
combination of existing structured data and unstructured data, which will be converted to 
structured form during the implementation of the protocol solely by a computer using 
automated/algorithmic methods, such as natural language processing. 
In these data sources, individual patient data are not retrieved or validated, and it is not 
possible to link (i.e., identify a potential association between) a particular product and 
medical event for any individual. Thus, the minimum criteria for reporting an adverse event 
(AE) (i.e., identifiable patient, identifiable reporter, a suspect product, and event) cannot be 
met. 
Human Review of Unstructured Data 
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This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database. The reviewer is obligated to report adverse events 
(AEs) with explicit attribution to any Pfizer drug that appear in the reviewed information 
(defined per the patient population and study period specified in the protocol). Explicit 
attribution is not inferred by a temporal relationship between drug administration and an AE, 
but must be based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE. 
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows: 
x All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the eCRF and reported, 
within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report Form. 
x Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy, and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form. 
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the unstructured data reviewed is captured in the Event 
Narrative section of the report form, and constitutes all clinical information known regarding 
these AEs. No follow-up on related AEs will be conducted. 
All the demographic fields on the NIS AEM Report Form may not necessarily be completed, 
as the form designates, since not all elements will be available due to privacy concerns with 
the use of secondary data sources. While not all demographic fields will be completed, at the 
very least, at least one patient identifier (e.g., gender, age as captured in the narrative field of 
the form) will be reported on the NIS AEM Report Form, thus allowing the report to be 
considered a valid one in accordance with pharmacovigilance legislation. All identifiers will 
be limited to generalities, such as the statement “A 35-year-old female...” or “An elderly 
male...” Other identifiers will have been removed.  
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug 
Name” may be documented in month/year (mmm/yyyy) format rather than identifying the 
actual date of occurrence within the month /year of occurrence in the day/month/year 
(DD/MMM/YYYY ) format. 
 
All research staff members must complete the following Pfizer training requirements:  
x “YRR Training for Vendors Working on Pfizer Studies (excluding interventional 
clinical studies and non-interventional primary data collection studies with 
sites/investigators)”.  
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These trainings must be completed by research staff members prior to the start of data 
collection. All trainings include a “Confirmation of Training Certificate” (for signature by 
the trainee) as a record of completion of the training, which must be kept in a retrievable 
format. Copies of all signed training certificates must be provided to Pfizer.  
Re-training must be completed on an annual basis using the most current Your Reporting 
Responsibilities training materials.  
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.  
Study reporting 
The completed study will be summarized in a final report that accurately and completely 
presents the study objectives, methods, results, limitations of the study and interpretation of 
the findings. 
Publication 
It is anticipated that the results of this analysis will be disseminated in the following 
publications: 
 
At least one conference abstract 
 
At least one manuscript 
The McKesson study team will collaborate with the Sponsor to determine the appropriate 
conference(s) and journal(s) for submission, following assessment of the study findings. 
Authorship will follow the guidelines proposed by the International Committee of Medical 
Journal Editors. All authors should meet the criteria for authorship, and all people who meet 
the criteria should be authors. Any potential conflicts of interest will be disclosed. Authors 
will adhere to the International Committee of Medical Journal Editors (ICMJE) guidelines, 
specifically, all authors will have (1) made substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) participated in drafting 
the article or revising it critically for important intellectual content; (3) approved the version 
to be published, and (4) agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. Acquisition of funding, collection of data, or general supervision 
of the research group does not justify authorship. Each author should have participated 
sufficiently in the work to take public responsibility for appropriate portions of the content. 
 
 
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13. REFERENCES 
 
1. 
Siegel RL, Miller KD, Jemal A: Cancer statistics, 2020. CA Cancer J Clin 70:7-30, 
2020 
2. 
Breast Cancer Treatment (PDQ(R)): Health Professional Version: PDQ Cancer 
Information Summaries. Bethesda (MD), 2002 
3. 
National Cancer Institute Surveillance Epidemiology and End Results (Seer) 
Program: Cancer Stat Facts: Female Breast Cancer,  
4. 
Nccn Guidelines for Breast Cancer V.5.2020: Clinical practice guidelines in 
oncology: breast cancer 2020 
5. 
Wilcken N, Hornbuckle J, Ghersi D: Chemotherapy alone versus endocrine therapy 
alone for metastatic breast cancer. Cochrane Database Syst Rev:CD002747, 2003 
6. 
Preusser M, De Mattos-Arruda L, Thill M, Criscitiello C, Bartsch R, Ruhstaller T, De 
Azambuja E, Zielinski CC: CDK4/6 inhibitors in the treatment of patients with breast 
cancer: summary of a multidisciplinary round-table discussion. ESMO Open 
3:e000368, 2018 
7. 
Ma CX, Sanchez CG, Ellis MJ: Predicting endocrine therapy responsiveness in breast 
cancer. Oncology (Williston Park) 23:133-42, 2009 
8. 
Horibata S, Rice EJ, Mukai C, Marks BA, Sams K, Zheng H, Anguish LJ, Coonrod 
SA, Danko CG: ER-positive breast cancer cells are poised for RET-mediated 
endocrine resistance. PLoS One 13:e0194023, 2018 
9. 
Szostakowska M, Trebinska-Stryjewska A, Grzybowska EA, Fabisiewicz A: 
Resistance to endocrine therapy in breast cancer: molecular mechanisms and future 
goals. Breast Cancer Res Treat, 2018 
10. 
Beaver JA, Amiri-Kordestani L, Charlab R, Chen W, Palmby T, Tilley A, Zirkelbach 
JF, Yu J, Liu Q, Zhao L, Crich J, Chen XH, Hughes M, Bloomquist E, Tang S, 
Sridhara R, Kluetz PG, Kim G, Ibrahim A, Pazdur R, Cortazar P: FDA Approval: 
Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-
Positive, HER2-Negative Metastatic Breast Cancer. Clin Cancer Res 21:4760-6, 2015 
11. 
Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, 
Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, 
Kim ST, Randolph S, Slamon DJ: The cyclin-dependent kinase 4/6 inhibitor 
palbociclib in combination with letrozole versus letrozole alone as first-line treatment 
of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-
1/TRIO-18): a randomised phase 2 study. Lancet Oncol 16:25-35, 2015 
12. 
Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, 
Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Dieras V, Slamon DJ: 
Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 375:1925-1936, 
2016 
13. 
Walker AJ, Wedam S, Amiri-Kordestani L, Bloomquist E, Tang S, Sridhara R, Chen 
W, Palmby TR, Fourie Zirkelbach J, Fu W, Liu Q, Tilley A, Kim G, Kluetz PG, 
Mckee AE, Pazdur R: FDA Approval of Palbociclib in Combination with Fulvestrant 
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for the Treatment of Hormone Receptor-Positive, HER2-Negative Metastatic Breast 
Cancer. Clin Cancer Res 22:4968-4972, 2016 
14. 
Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, 
Demichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, 
Bartlett CH, Koehler M, Slamon D: 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 multicentre, double-blind, phase 3 randomised controlled trial. Lancet 
Oncol 17:425-439, 2016 
15. 
Rugo HS, Cristofanilli M, Loibl S, Harbeck N, Demichele A, Iwata H, Park YH, 
Brufsky A, Theall KP, Huang X, Mcroy L, Bananis E, Turner NC: Prognostic Factors 
for Overall Survival in Patients with Hormone Receptor-Positive Advanced Breast 
Cancer: Analyses From PALOMA-3. Oncologist, 2021 
16. 
Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, et al. Overall survival 
with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 2018; 
379:1926-36. 
17. 
Llombart-Cussac A, Pérez-García JM, Bellet M, Dalenc F, Gil MJG, Borrego MR, 
Gavilá J, Sampayo-Cordero M, Aguirre E, Schmid P, Marmé F, Cosimo SD, 
Gligorov J, Schneeweiss A, Albanell J, Zamora P, Wheatley D, Dueñas EM-D, 
Amillano K, Cortes J: PARSIFAL: A randomized, multicenter, open-label, phase II 
trial to evaluate palbociclib in combination with fulvestrant or letrozole in endocrine-
sensitive patients with estrogen receptor (ER)[+]/HER2[-] metastatic breast cancer. 
Journal of Clinical Oncology 38:1007-1007, 2020 
18. 
Albanell J, Martinez MTM, Ramos M, Connor MO, De La Cruz-Merino L: First 
analysis from a randomized phase II trial of fulvestrant (F)/palbociclib (P) versus (vs) 
F/placebo (PL) as first-line therapy in postmenopausal women with HR (hormone 
receptor)+/HER2– endocrine sensitive advanced breast cancer (ABC). Annals of 
Oncology 31:S1151, 2020 
19. 
The US Oncology Network, 2020 
20. 
Espirito J, Aguilar K, Boyd M, Frytak J, Robert N: Retrospective real-world 
assessment of response outcome in oncology. Presented at the ISPOR, New Orleans, 
LA, May 21, 2019 
21. 
Patt D, Mitra D, Harrell R, Espirito JL, Perkins JJ, Mcroy L, Arondekar B: Early 
treatment utilization of palbociclib for metastatic breast cancer (MBC) in a U.S. 
community oncology network. Presented at the ASCO, Chicago, IL, Jun 3-7, 2016 
22. 
Gruschkus S, Shankleton JA, Brammer M, Forsyth M, Lalla D: Trastuzumab use and 
community-based outpatient healthcare utilization among metastatic breast cancer 
patients. Presented at the Miami Breast Cancer Conference, Miami, FL, Jun 17-19, 
2009 
23. 
Jones SE, Tseng WY, Saravanan S, Santos E, Dhanda R, Rembert D, Yap M, Lalla 
D, Brammer M: Retrospective analysis of long-term survivors with HER2+ 
metastatic breast cancer (MBC) treated with trastuzumab in a community setting. 
Presented at the San Antonio Breast Cancer Symposium, San Antonio, TX, Dec 10-
14, 2013 
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24. 
Gruschkus SK, Shankleton JA, Brammer M, Forsyth M, Lalla D: Patterns of care and 
outcomes among HER2-positive metastatic breast cancer patients receiving 
trastuzumab in the community setting. Presented at the Breast Cancer Symposium, 
San Francisco, CA, Oct 8-10, 2009 
25. 
Patt D, Richardson P, Rembert D, Corzo D, Chen C: Treatment of patients (pts) with 
HER2- metastatic breast cancer (MBC) with nab-paclitaxel (nab-P) in the clinical 
practice setting—Results of a US Oncology survey. Presented at the ASCO Annual 
Meeting, Chicago, IL, May 30 - June 3, 2014 
26. 
Sharma PP, Sail K, Delea TE, Forsyth M, Halm M, Nagarwala M, Lopez W, Patt D: 
Patterns of care and patient characteristics in postmenopausal women with HER2+ 
and hormone receptor-positive (HR+) metastatic breast cancer (MBC). Presented at 
the ASCO Annual Meeting, Chicago, IL, Jun 3-7, 2011 
27. 
Patt D, Liang C, Li L, Ko A, Duval Fraser C, Corzo D, Enger C: Real-world safety 
and efficacy of nab-paclitaxel in patients with metastatic breast cancer (mBC) treated 
in the united states: results from a health insurance database. Presented at the ISPOR 
Annual International Meeting, Montreal, QC, Canada, May 31 - Jun 4, 2014 
28. 
Robert N, Goertz HP, Chopra P, Jiao X, Yoo B, Patt D, Antao V: Clinical 
characteristics, treatment patterns, and outcomes for patients with HER2-positive 
metastatic breast cancer treated with pertuzumab in the first-line in a real-world 
setting. Presented at the European Cancer Congress, Vienna, Austria, Sept 25-29, 
2015 
29. 
Robert N, Goertz HP, Jiao X, Yoo B, Patt D, Antao V: Pertuzumab (P) use in first-
line HER2-positive metastatic breast cancer (mBC) in US community oncology 
practices: Treatment patterns and outcomes. Presented at the San Antonio Breast 
Cancer Symposium, San Antonio, TX, Dec 8-12, 2015 
30. 
Gruschkus SK, Shankleton JA, Brammer M, Forsyth M, Lalla D: First-line 
trastuzumab utilization: Patterns of care and progression in the community setting. 
Presented at the ASCO Annual Meeting, Orlando, FL, May 29-Jun 2, 2009 
31. 
Patt D, Rembert D, Corzo D: Treatment of metastatic breast cancer with -paclitaxel in 
the community practice setting: a US Oncology survey. J Community Support Oncol 
13:173-80, 2015 
32. 
Patt D, Jiao X, Fonseca E, Clark J, Fox P, Horblyuk R, Mcroy L, Mardekian J, 
Arondekar B: Real-world use of first-line chemotherapy in post-menopausal patients 
with HR-positive HER2-negative metastatic breast cancer (mBC) in a US community 
oncology network Presented at the ASCO Annual Meeting, Chicago, IL, Jun 3-7, 
2016 
33. 
Patt D, Fonseca E, Yoo B, Wilson T, Goertz HP, Lai C: Real world treatment patterns 
and outcomes in HER2 positive MBC patients with brain metastasis in the US 
community oncology setting. Presented at the ASCO Quality Care Symposium, 
Phoenix, AZ, Feb 26-27, 2016 
34. 
National Technical Information Services: Limited Access Death Master File 
Download,  
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35. 
Levin MA, Lin HM, Prabhakar G, Mccormick PJ, Egorova NN: Alive or dead: 
Validity of the Social Security Administration Death Master File after 2011. Health 
Serv Res 54:24-33, 2019 
36. 
Peterss S, Charilaou P, Ziganshin BA, Elefteriades JA: Assessment of survival in 
retrospective studies: The Social Security Death Index is not adequate for estimation. 
J Thorac Cardiovasc Surg 153:899-901, 2017 
37. 
Boyd M, Fulcher N, Annavarapu S: Concordance of death date assessments between 
the Social Security Death Master File and electronic health records in a US 
community oncology setting. Presented at the ISPOR, Orlando, FL, USA, May 16-20, 
2020, 2020 
38. 
Curtis MD, Griffith SD, Tucker M, Taylor MD, Capra WB, Carrigan G, Holzman B, 
Torres AZ, You P, Arnieri B, Abernethy AP: Development and Validation of a High-
Quality Composite Real-World Mortality Endpoint. Health Serv Res 53:4460-4476, 
2018 
39. 
Robert N, Espirito J, Haydon W, Jenson K, Montelongo N, Spark S: Development of 
Playbook for Chart Review in Real-World Data. Presented at the ISPOR, New 
Orleans, LA, May 21, 2019 
 
 
 
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14. LIST OF TABLES  
Table 1. Study milestones .................................................................................................... 14 
Table 2. Study variables and operational definitions ............................................................ 25 
Table 3. Initial feasibility assessment................................................................................... 41 
15. LIST OF FIGURES 
Figure 1. Overview of study design ..................................................................................... 19 
 
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ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None. 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Not applicable.  
 
 
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ANNEX 3. ADDITIONAL INFORMATION 
Study Sponsor Sign-Off page 
This Protocol/Statistical Analysis Plan has been reviewed and agreed upon by the study 
sponsor and McKesson project team. Sign-off is required prior to submission to McKesson’s 
Privacy and Compliance Review. 
 
Study Sponsor Lead 
 
Signature:         
 
 
Name: 
  
 
Title: 
, 
 
 Pfizer, Inc 
 
Date:         
 
 
 
 
, Principal Clinical Investigator 
 
Signature:         
 
 
Name: 
  
 
Title: 
, 
 
    
 
Date:         
 
 
 
, Outcomes Researcher 
Signature:         
 
Name: 
 
Title: 
, 
  
Date:         
 
 
 
 
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