Patient Characteristics, Treatment Patterns, and Clinical Outcomes in Patients Diagnosed With HR+/HER2- Advanced/Metastatic Breast Cancer Receiving Palbociclib + Aromatase Inhibitor (AI) Combination Therapy as First-Line Treatment
Conditions: Breast Cancer
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study Information
Title
Patient Characteristics, Treatment Patterns, and Clinical 
Outcomes in Patients Diagnosed with 
HR+/HER2- Advanced/Metastatic Breast Cancer 
Receiving Palbociclib + Aromatase Inhibitor (AI) 
Combination Therapy as First-Line Treatment
Protocol number
A5481155
Protocol version identifier
1.0
Date
21 April 2020
Active substance
Palbociclib (L01XE33)
Medicinal product
Palbociclib
Research question and 
objectives
Primary Objectives:
Objective 1 - Among patients with 
HR+/HER2- advanced/metastatic breast cancer (A/MBC) 
receiving palbociclib +AI combination therapy as 
first-line therapy: 
a.
Describe demographic and clinical characteristics.
b. Describe treatment patterns (eg, dose changes, 
discontinuations).
Objective 2 - Among patients receiving palbociclib + AI 
as first-line therapy, examine clinical effectiveness 
outcomes including real-world progression-free survival 
(rwPFS) and real-world overall survival (rwOS). 
Author
 Ph.D.
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 Pharm.D.
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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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................3
2. LIST OF ABBREVIATIONS................................................................................................5
3. RESPONSIBLE PARTIES....................................................................................................7
4. ABSTRACT...........................................................................................................................8
5. AMENDMENTS AND UPDATES.....................................................................................10
6. MILESTONES.....................................................................................................................11
7. RATIONALE AND BACKGROUND................................................................................11
8. RESEARCH QUESTION AND OBJECTIVES .................................................................12
9. RESEARCH METHODS ....................................................................................................14
9.1. Study Design ...........................................................................................................14
9.2. Setting......................................................................................................................14
9.2.1. Inclusion Criteria ........................................................................................14
9.2.2. Exclusion Criteria.......................................................................................15
9.3. Variables..................................................................................................................15
9.3.1. Regimens and Lines....................................................................................15
9.3.2. Curated Data ...............................................................................................15
9.3.3. Derived Variables .......................................................................................21
9.4. Data Sources............................................................................................................23
9.5. Study Size................................................................................................................23
9.6. Data Management ...................................................................................................25
9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic 
Data Records....................................................................................................25
9.6.2. Record Retention ........................................................................................26
9.7. Data Analysis ..........................................................................................................26
9.8. Quality Control........................................................................................................27
9.8.1. Data Integration and Quality ......................................................................27
9.8.2. Review and Verification of Data Quality...................................................28
9.9. Limitations of the Research Methods......................................................................29
9.10. Other Aspects ........................................................................................................29
10. PROTECTION OF HUMAN SUBJECTS ........................................................................30
10.1. Patient Information................................................................................................30
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10.2. Patient Consent......................................................................................................30
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............30
10.4. Ethical Conduct of the Study ................................................................................31
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................31
11.1. Human Review of Unstructured Data ...................................................................31
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........32
13. REFERENCES ..................................................................................................................33
14. LIST OF TABLES.............................................................................................................35
15. LIST OF FIGURES ...........................................................................................................35
16. ANNEX 1. LIST OF STAND ALONE DOCUMENTS ...................................................35
17. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ...................................35
18. ANNEX 3. ADDITIONAL INFORMATION...................................................................35
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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
A/MBC
advanced/metastatic breast cancer
ACS
American College of Surgeons
AE
adverse event
AEM
adverse event monitoring
AI
aromatase inhibitor
ASCO
American Society of Clinical Oncology
BC
breast cancer
BRCA
BReast CAncer susceptibility gene
CCI
Charlson Comorbidity Index
CDK4/6i
cyclin-dependent kinase 4/6 inhibitor
CI
confidence interval
CoC
Commission on Cancer
CPOE
computerized physician order entry
CR
complete response
CTR
Certified Tumor Registrar
DCT
data collection tools
DFI
Disease Free Interval
ECOG
Eastern Cooperative Oncology Group
EDW
electronic data warehouse
EHR
electronic health record
EMR
electronic medical record
ER
estrogen receptor
FDA
Food and Drug Administration
FHIR
fast healthcare interoperability resource
FORDS
Facility Oncology Registry Data Standards
H&P
history and physical
HEOR
Health Economics and Outcomes Research
HER2
human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HL7
health level seven international
HR
Hormone receptor; hazard ratio
ICD
International Classification of Diseases
ID
identification
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IRB
Institutional Review Board
IRIS
Ibrance Real-World Insights Study
ISH
In situ hybridization
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Abbreviation
Definition
ISPOR
International Society for Pharmacoeconomics and 
Outcomes Research
JSON
JavaScript object notation
KPS
Karnofsky Performance Score
LHRH
luteinizing hormone releasing hormone
LIS
laboratory information system
MA
manual abstraction
MBC
metastatic breast cancer
NAACCR
North American Association of Central Cancer 
Registries
NDI
National Death Index
NE
not evaluable
NGS
next generation sequencing
NI
non-interventional
NIS
non-interventional study
NOS
not otherwise specified
OS
overall survival
PACS
picture archiving and communication system
palbo
palbociclib
PCR
polymerase chain reaction
PD
progressive disease
PFS
progression-free survival 
PHI
protected health information
PR
Progesterone receptor; partial response
QC
quality control
RCT
randomized control trial
RWD
real world data
rwOS
Real-world overall survival
rwPFS
Real-world progression-free survival
rwTTD
Real-world time to treatment discontinuation
rwTTNT
Real-world time to next treatment
SABCS
San Antonio Breast Cancer Symposium
SAP
Statistical Analysis Plan
SD
stable disease 
SEER
Surveillance, Epidemiology, and End Results
SSDI
Social Security Death Index
STORE
STandards for Oncology Registry Entry
UD
undocumented
US
United States
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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Job Title
Affiliation
Address
 
Ph.D.
Syapse
 
 
 MPH
Syapse
 
 
 MD
 
Pfizer Oncology
 
 
MA
 
 
Pfizer
 
 
Ph.D.
Pfizer
 
 
Pharm.D.
 
Pfizer
 
 Ph.D.
 
Pfizer
 
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4. ABSTRACT
Title: Patient Characteristics, Treatment Patterns, and Clinical Outcomes in Patients 
Diagnosed with HR+/HER2- Advanced/Metastatic Breast Cancer Receiving Palbociclib + AI 
Combination Therapy as First-Line Treatment
Rationale and Background: The treatment landscape for HR+/HER2- advanced and 
metastatic breast cancer (A/MBC) has changed with the advent of  approval of CDK4/6i in 
combination with aromatase inhibitor (AI) approval for use in the first-line with palbociclib 
being the first to market in the US in February 2015. Treatment patterns and early clinical 
outcomes have been reported in real world use with limited follow up and cohort size. The 
present single-arm study is designed to describe patient characteristics, treatment patterns,
and clinical effectiveness outcomes in patients diagnosed with HR+/HER2- A/MBC who 
received palbociclib combination therapy with AI as first-line treatment in the US
community oncology setting.
Research Question and Objectives: The objective of this single-arm study is to describe the 
patient characteristics, treatment patterns, and clinical effectiveness outcomes for patients 
with a diagnosis of HR+/HER2- A/MBC who received palbociclib combination therapy with 
AI as the first-line therapy in the A/MBC setting. 
Primary Objectives:
Objective 1 – Among patients with HR+/HER2- advanced/metastatic breast cancer (A/MBC) 
receiving palbociclib combination therapy with AI as first-line therapy: 
a.
Describe demographic and clinical characteristics. 
b. Describe treatment patterns (eg, dose changes, discontinuations). 
Objective 2 – Among patients receiving palbociclib + AI as first-line therapy, examine 
clinical effectiveness outcomes including real-world progression-free survival (rwPFS) and 
real-world overall survival (rwOS). 
Study Design: This is a retrospective, observational database study that will document the 
treatment patterns and clinical outcomes of patients diagnosed with HR+/HER2- A/MBC 
who received palbociclib combination therapy with AI as the first-line therapy in the A/MBC 
setting in US community health systems participating in the Syapse Learning Health 
Network.
Population: The study will include adult patients 18 years or older, diagnosed with 
HR+/HER2- A/MBC who initiated palbociclib combination therapy with AI as the first-line
therapy on or after 03 February 2015 up to and including 31 July 2019. Patients for this 
study will be identified from the Syapse Learning Health Network database. 
Variables: Patient demographics, clinical characteristics, treatment patterns, and clinical 
effectiveness outcomes will be collected and analyzed.
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Data Source: 
The Syapse Learning Health Network consists of large community health systems based in 
the United States. These US providers manage care delivery networks that span the 
continuum of care in multiple regions. Syapse’s point of care software platform ingests 
comprehensive real-world data on a daily basis and includes structured inpatient and 
outpatient, clinical and molecular data integrated from both health systems and molecular 
labs. Syapse Certified Tumor Registrars (CTRs) provide additional curation. This resultant 
database provides the basis for this study.
Study Size: 
Study sample will include all eligible cases in the Syapse Learning Health Network database. 
Preliminary analysis identified up to 1,074 patients with evidence of key primary inclusion 
criteria: breast cancer diagnosis and palbociclib treatment. This population will be further 
examined and limited to those matching all inclusion criteria: patients with 
HR+/HER2- A/MBC with first-line palbociclib + AI treatment, on or after 03 February 2015
through 31 July 2019. Three to four hundred patients are expected to fulfill complete study 
inclusion criteria. Given the inclusion criterion requiring a qualifying treatment 
identification period between 03 February 2015 through 31 July 2019, and assuming a data 
cutoff date of 01 February 2020, the minimum follow-up available is therefore 6 months.  
Data Analysis: Descriptive analysis will be conducted to describe patient demographics, 
clinical characteristics, treatment patterns (eg dose changes, discontinuations), and clinical 
effectiveness outcomes (rwPFS, rwOS).
Milestones:
Data analysis will be conducted once data/related variables are available, and the final study 
report will be completed September 2020.
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5. AMENDMENTS AND UPDATES
None.
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6. MILESTONES
Milestone
Planned date
IRB approval of study protocol 
April 2020
Start of data collection
April 2020
Interim statistical analysis
June 2020
End of data collection
August 2020
Final statistical analysis
August 2020
Final study report
September 2020
7. RATIONALE AND BACKGROUND
It is estimated that 42,260 people (41,760 female and 500 male) in the United States (US) 
will die of breast cancer in 2019. Breast cancer is the second leading cause of cancer death 
for women after lung cancer (Siegel et al, 2019). Currently, the average risk of a woman in 
the United States developing breast cancer sometime in their life is about 13% with 
276,480 new cases of invasive breast cancer and 42,170 deaths from breast cancer expected 
this year in the United States.  At this time there are more than 3.5 million women living with 
a history of breast cancer (BC) in the US including women who are still being treated (Miller 
et al, 2016) and in the US, women under the age of 50 comprise 20% of all breast cancers 
diagnoses. Metastatic breast cancer remains an incurable disease with 5-year survival rates 
of 27% (American Cancer Society Facts & Figures, 2020). About 71% of all breast cancers 
are HR+ and HER2- (American Cancer Society Breast Cancer Facts and Figures, 2018) 
HR+/HER2- A/MBC presents a challenge because patients with exposure to prior hormonal 
therapy, including aromatase inhibitor (AI) treatment, ultimately develop resistant disease
(Ma et al, 2015). The treatment landscape for patients with HR+/HER2- A/MBC has 
changed with the approval of palbociclib in February 2015 as the first in class 
cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) indicated in combination with letrozole for 
the first endocrine therapy for patients with HR+/HER2- A/MBC and subsequently expanded 
to all AIs as well as for the treatment of male breast cancer. Palbociclib was approved in the 
US based on improved median PFS demonstrated in 3 pivotal clinical trials: PALOMA-1 and 
PALOMA 2 (initial endocrine-based therapy in combination with letrozole for advanced 
disease) and PALOMA-3 (in combination with fulvestrant after progression on or after prior 
endocrine therapy). Approval was granted based on findings from the Phase 2 PALOMA-1 
trial (Finn et al, 2015) in February 2015. The OS results from that study demonstrated a HR 
of 0.897; 95% CI (0.623, 1.294); 1-sided p= 0.281 in a sample of 165 patients total (Finn et 
al, 2015).  Palbociclib in combination with fulvestrant was approved 1 year later 
(February 2016) in pre or postmenopausal women with disease progression following 
endocrine therapy based on results from the PALOMA-3 trial (Turner et al, 2015; 
Cristofanilli et al, 2016). Final OS data from that study has been reported (Turner et al, 
2018) demonstrating median of 34.9 months versus 28 months in the palbociclib + 
fulvestrant group versus fulvestrant alone (HR 0.81; 95% CI; 0.64, 1.03; 1-sided p=0.0249) 
which was not statistically significant. The safety profile from the PALOMA-2 and -3 trials 
were consistent, with no new safety signals identified across the Phase 3 studies. Long-term 
pooled safety analyses of the 3 randomized Phase 2 and 3 studies demonstrated no evidence 
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of specific cumulative or delayed toxicities with palbociclib plus endocrine therapy (Diéras et 
al, 2019). The primary toxicity of palbociclib is neutropenia, which can be managed with 
dosing interruption and/or dose reduction. Additional CDK4/6i therapies, ribociclib and 
abemaciclib, were approved in 2017 and 2018, respectively, for use in first-line therapy as 
well. All of the CDK4/6i therapies also received FDA approval for use in combination with 
fulvestrant for patients who progressed after prior endocrine therapy (Eggersmann et al, 
2019).
Understanding the effectiveness of new treatments in a diverse clinical practice as a 
complement to RCT data is important as this provides evidence of the clinical benefit of 
these treatments in a more heterogeneous population with comorbid conditions and variations 
in care delivery seen in routine clinical practice.  Real-world outcomes for patients with 
A/MBC who were treated with palbociclib in combination with AI or fulvestrant have been 
reported in several publications and at medical congresses. A comparative effectiveness 
analysis of palbociclib + letrozole versus letrozole alone was presented at the SABCS 2019 
congress. Using the Flatiron Health Analytics Database, a total of 1,430 female patients with 
HR+/HER2-MBC in the first-line setting were included in the analysis demonstrating in an 
unadjusted  HR for PFS of 0.59 (95% CI: 0.51, 0.67; p<0.0001) and an HR for OS of 
0.63 (95% CI: 0.53, 0.76; p<0.0001) (DeMichele et al, 2019).  Another study reported on the 
Ibrance® Real World Insights Study (IRIS) involving medical chart review of 652 US
patients with A/MBC treated with palbociclib in combination with either AI (n=360) or 
fulvestrant (n=292) (Taylor-Stokes et al, 2019). The 12-month progression-free rate was 
84.1% for patients treated with palbociclib + AI and 79.8% for those treated with palbociclib 
+ fulvestrant. The 12-month survival rates were 95.1% for palbociclib + AI and 87.9% for 
palbociclib + fulvestrant (Taylor-Stokes et al, 2019).
This present study is designed to examine further real-world use of palbociclib and aromatase 
inhibitor combination therapy in both male and female patients with A/MBC as first-line
treatment.  All patients initiating palbociclib + an AI from the Syapse Learning Health 
Network dataset who meet the inclusion and exclusion criteria and initiated palbocicilb 
combination therapy between February 2015 and July 2019 will be evaluated. This study is 
designed to describe patient characteristics, treatment patterns, and clinical effectiveness 
outcomes in a cohort of patients diagnosed with HR+/HER2- A/MBC who were treated with 
palbociclib combination with AI in the US community oncology setting. 
8. RESEARCH QUESTION AND OBJECTIVES
The objective of this study is to describe the patient characteristics, treatment patterns, and 
clinical effectiveness outcomes for patients with a diagnosis of HR+/HER2- A/MBC who 
initiated palbociclib combination therapy with AI as the first-line therapy in the A/MBC 
setting between 03 February 2015 and 31 July 2019.
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Primary Objectives:
1.
Among patients with HR+/HER2- A/MBC receiving palbociclib combination 
therapy with AI as first-line therapy:
a.
Describe demographic and clinical characteristics:
•
Demographic characteristics will include age, sex, race, insurance status, 
menopausal status, and region of residence at A/MBC diagnosis;
•
Clinical characteristics will include variables such as, stage of initial 
diagnosis, histology, Eastern Cooperative Oncology Group (ECOG) 
performance status (where ECOG score unavailable, Karnofsky performance 
status will be converted to corresponding ECOG score) and comorbid disease 
burden, HER2 and estrogen receptor (ER)/progesterone receptor (PR) status, 
number and sites of distant metastasis at A/MBC diagnosis; modalities of 
treatment received prior to A/MBC diagnosis (chemotherapy, hormone 
therapy, surgery, radiation therapy) and disease free interval (time between 
completion of adjuvant therapy and diagnosis of A/MBC). 
b. Describe treatment patterns:
•
Distribution of regimens from the diagnosis of A/MBC through the end of the 
record;
•
Sequence of regimens across lines, through the end of the record of systemic 
therapy;
•
Description of the dosing will include the starting dose, end dose, dose 
adjustment (dose increase and dose reduction), type of dose adjustment (dose 
modification, schedule changes, dose delay, hold, or discontinuation), 
discontinuation, reason, and time to dose adjustment (discontinuation).
2. Among patients receiving palbociclib + AI as first-line therapy, examine clinical 
effectiveness outcomes including:
a.
Real-world progression-free survival (rwPFS) will be assessed for the first-line
therapy.
b. Real-world overall survival (rwOS) will be assessed from the start of the first-line
therapy.
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9. RESEARCH METHODS 
9.1. Study Design 
This is an observational, retrospective cohort study. Eligible patients will be identified from 
the Syapse Learning Health Network database and medical chart review will be conducted by 
Syapse Certified Tumor Registrars (CTRs). All study data are secondary data and will have 
been collected retrospectively from existing clinical data originally collected as part of 
routine care. This single-arm descriptive analysis will describe the patient characteristics, 
clinical attributes and treatment patterns of A/MBC patients with HR+/HER2- disease, who 
were treated with palbociclib + AI as first-line therapy.  Additionally, clinical effectiveness 
outcomes for these patients will be evaluated between Feb 2015 and July 2019.
9.2. Setting
This study uses eligible patients identified from the Syapse Learning Health Network 
database.
9.2.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. Female or male sex.
2. Diagnosis (confirmed by clinical review) of A/MBC, defined as breast cancer at stage 
IIIB, stage IIIC, stage IV or identified as having distant metastasis.
3. Age ≥18 years at A/MBC diagnosis.
4. Initiated palbociclib in combination with an AI as first-line therapy after A/MBC 
diagnosis on or after 03 February 2015 through 31 July 2019. Note that the date of 
the start of the inclusion period reflects the month of palbociclib US FDA approval.
5. Evidence of ER or PR positive disease, or absence of any indication of ER and PR 
negative disease closest to A/MBC diagnosis (ie, patients are eligible without 
affirmative indication of ER/PR+ status as long as ER/PR- indication is not present).
6. Evidence of HER2 negative disease, or absence of any indication of HER2 positive 
disease closest to A/MBC diagnosis (ie, patients are eligible without affirmative 
indication of HER2- status as long as HER2+ indication is not present).
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9.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study:
1. Enrollment in an interventional clinical trial for A/MBC during the study observation 
period.
2. Evidence of prior treatment with any CDK4/6 inhibitor in the adjuvant setting.
3. Evidence of another primary cancer within 3 years prior to the initial line containing 
palbociclib.
9.3. Variables
9.3.1. Regimens and Lines
Firstline regimen is defined as the first antineoplastic drug/s a patient receives after diagnosis 
of an advanced/metastatic breast cancer, including all drugs received within a 60 day window 
of the first antineoplastic agent received. For example, if an additional drug is added to the 
regimen within 60 days, it is considered part of the line of therapy. The end of the firstline 
regimen is defined as discontinuation of all antineoplastic drugs in regimen AND a gap of 
≥90 days for each drug before evidence of next treatment; OR addition of a 
non-interchangeable new antineoplastic after the first 60 days of firstline regimen (if added 
before 60 day cut-off it does not trigger a new line of therapy). Switching between 
aromatase inhibitors does not trigger a new line. The end date of the firstline regimen is the 
date of last antineoplastic treatment in the regimen. Two parameters in the algorithm are: 
regimen window (currently 60 days) and treatment gap window (currently 90 days).
9.3.2. Curated Data
Patients will be identified and data will come from the Syapse Learning Health Network 
database which includes both inpatient and outpatient clinical and molecular data captured 
through manual abstraction and interoperative data feeds from a number of health system 
source systems, including:  
•
Electronic medical record (EMR), including inpatient, outpatient oncology, 
ambulatory, surgical, etc. 
•
Electronic data warehouse (EDW).
•
Laboratory information system (LIS).
•
Picture archiving and communication system (PACS).
•
Hospital based cancer registries.
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•
Computerized physician order entry (CPOE):
•
Additionally, Syapse augments health system data with the Surveillance, 
Epidemiology, and End Results (SEER) national cancer registry, other regional 
registries, the Social Security Death Index (SSDI), digitized obituary data. In 
order to capture complete and accurate vital status and dates of death, Syapse 
brings together data from multiple sources to create a composite view of patients’ 
mortality (including EHR, hospital registry, manual abstraction, digital obituaries 
(such as tributes.com and legacy.com), Social Security Death Index, and SEER). 
Syapse is in the process of validating the completeness and accuracy of the 
Syapse mortality composite score versus the National Death Index (NDI), a 
centralized database of death records. Initial analysis shows that the combined 
Syapse Data Sources are very accurate. More detailed information forthcoming in 
the data management document.
The following data elements will be extracted from feeds and/or curated by Certified Tumor 
Registrars (CTRs) for this study:   
Data Elements
Description
Demographic characteristics
Date of birth
Year, month, day (Availability of the exact date will depend on the Expert 
de-ID approach).
Date of initial BC 
diagnosis
Date of initial breast cancer (BC) diagnosis.
Date of A/MBC 
diagnosis
Date of advanced/metastatic breast cancer (A/MBC) diagnosis.
Patient sex
Male, Female, Transsexual, Other, Not Provided.
Primary race
American Indian/Alaska Native; Asian; Black/African American/Native 
Hawaiian/Pacific Islander; White; Not Provided; Other (Exact list will 
depend on the expert de-ID approach).
Secondary race
(if provided) (Exact list will depend on the expert de-ID approach).
Ethnicity
Non-Hispanic/Non-Latino; Hispanic/Latino; Unknown (Exact list will 
depend on the expert de-ID approach).
Region of 
residence
Northeast, Midwest, South, West.
Captured at A/MBC diagnosis (Exact list will depend on the expert de-ID 
approach).
Insurance type
Medicare/Medicaid; Commercial; Commercial and Medicare/Medicaid; 
None; Not Provided.
Captured at 1) date of A/MBC diagnosis; and 2) at initiation of palbo.
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Data Elements
Description
Menopause status Premenopausal; Postmenopausal; Perimenopausal; Unknown; Not 
applicable. Captured on date closest to but before: 1) A/MBC diagnosis; 
and 2) initiation of palbo.
Menopausal status: captured if explicitly stated in clinician notes. 
Otherwise captured based on following definition of menopause from 
NCCN Guideline v.3.2019:
•
Prior bilateral oophorectomy (date of surgery);
•
Age >=60 years old;
•
Age <60 years old and amenorrheic for 12 months+ in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression.
Additionally, type, name, and start/end date of ovarian suppression agent 
is captured.
Date of death
If patient vital status = deceased, date of death from the medical record 
(capturing from EMR, registries, third party integrations) (Availability of 
the exact date will depend on the Expert de-ID approach).
Last contact date
If patient is alive (not deceased), date of the last contact by a healthcare 
provider from the medical record (Availability of the exact date will 
depend on the Expert de-ID approach).
Clinical characteristics
Breast cancer 
histology
List captured at initial breast cancer diagnosis including: Adenoid cystic; 
Cribriform; Ductal; Inflammatory; Intraductal; Lobular; Medullary with 
lymphoid stroma; Medullary, NOS; Mucinous; Paget’s disease and 
infiltrating; Paget’s disease and intraductal; Papillary; Secretory; 
Squamous cell; Tubular, and more.
ECOG/KPS 
performance 
score
Score captured on date closest to (with a ±60 day cutoff around) 
1) A/MBC diagnosis; and 2) initiation of palbo.
Stage at initial BC 
diagnosis
0, I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IIIC, IV, Unable to stage, Not 
found, Not applicable.
Presence of 
distant metastasis
Yes; No.
Note: this variable would be “yes” if patient is diagnosed with de novo 
metastatic breast cancer or if patient developed metastasis after initial
breast cancer diagnosis.
Date of first 
distant metastasis
Same as initial BC diagnosis if de novo metastatic BC, otherwise captured 
as date that the patient developed distant metastatic disease.
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Data Elements
Description
Site(s) of distant 
metastasis at 
MBC diagnosis
Bone; Chest Wall; Contralateral Breast; Distant Lymph node(s); Liver; 
Lung; Peritoneum; Pleural nodules; Malignant pleural effusion; Skin; 
Brain; Ovary; Undocumented; Other, Specify; 
Visceral sites; 
Bone only.
Comorbidities
List of comorbidities at time of A/MBC diagnosis (sourced from problem 
list encompassing entire patient journey and confirmed from clinician 
notes), including: anemia, heart arrhythmia, hypertension, myocardial 
infarction, congestive heart failure, peripheral vascular disease, 
cerebrovascular accident, hemiplegia, chronic obstructive pulmonary 
disease, ulcer disease, diabetes with chronic complications, diabetes 
without chronic complications, renal disease, connective tissue disease 
such as rheumatoid arthritis or lupus, Alzheimer’s or other dementia, 
cirrhosis or other serious liver disease, non-breast cancer malignancy 
(excluding sites of breast cancer metastasis and malignant neoplasm 
of skin), metastatic solid tumor (other than breast cancer), 
HIV/AIDS, and other comorbidities of interest.
Note: comorbidities in bold are in CCI; CCI listed in derived variables 
section.
Biomarkers
ER, PR, HER2 
status
Positive; Negative; Equivocal; Unknown.
ER, PR, HER2 
test type
ISH, IHC, NGS, PCR, Other, Unknown.
ER, PR, HER2
sample collection 
date
Year, month, day.
ER, PR, HER2 
report date
Year, month, day.
BRCA status
BRCA1 Mutation; BRCA2 Mutation; BRCA NOS Mutation.
BRCA sample 
collection date
Year, month, day.
BRCA report date Year, month, day.
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Data Elements
Description
Treatment modalities prior to A/MBC diagnosis
Breast surgery
Yes; No.
Surgery type
Partial mastectomy; Lumpectomy/excisional biopsy; Segmental 
mastectomy; Subcutaneous mastectomy; Total mastectomy; Modified 
radical mastectomy; Radical mastectomy; Extended radical mastectomy;
Mastectomy, NOS; Surgery, NOS.
Note: if multiple, all will be listed (longitudinal data).
Surgery date
Year, month, day.
Breast radiation 
therapy
Yes; No.
Radiation therapy 
site
Whole breast; Partial breast; Chest wall; Regional lymph nodes; 
Unknown.
Note: limited to primary breast cancer site. If multiple, all will be listed 
(longitudinal data).
Radiation 
start/end dates
Year, month, day.
Recurrence
Patient had 
recurrence
Yes; No.
Recurrence date
Year, month, day (Captures first time locally, first time regionally, and 
first time distant; if multiple sites, hierarchy prioritizes most advanced 
site).
Recurrence site
Local; Regional; Distant; Unknown.
Recurrence test 
source
Biopsy; Imaging; Imaging confirmed by biopsy; Unknown.
Clinician 
confirmation of 
recurrence
Sources including: Medical oncology consult/note; Radiation oncology 
note; Discharge summary; Other.
Recurrence linked 
to therapy
Yes; No.
Progression
Patient had 
progression
Yes; No.
Progression date
Year, month, day.
Progression test 
source
Biopsy; Imaging; Imaging confirmed by biopsy; Unknown.
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Data Elements
Description
Clinician 
confirmation of 
progression
Sources including: Medical oncology consult/note; Radiation oncology 
note; Discharge summary; Other.
Clinician 
confirmation date
Year, month, day.
Progression 
linked to therapy
Yes; No.
Complete systemic therapy history
Therapy name
Therapy name.
Administration 
route
Categories including: Oral; Infusion; Injection; Other; Unknown.
Therapy start date Year, month, day.
Therapy end date Year, month, day.
Start reason
Recurrence; Progression; Other reason not related to worsening disease.
Start reason 
source date
Year, month, day (can be linked to clinician confirmation date of 
recurrence/progression if start reason is recurrence/progression).
Stop reason
Categories including: Progression; Toxicity; End of planned therapy; 
Insurance changes; Treatment ongoing; Other.
Stop reason 
source date
Year, month, day (can be linked to clinician confirmation date of 
recurrence/progression if stop reason is recurrence/progression).
Treatment part of 
clinical trial
Yes; No.
Palbociclib-specific variables (captured in addition to above variables)
Combination AI 
partner
Letrozole, Anastrozole, Exemestane.
Concomitant 
LHRH Agonists
Goserelin (Zoladex), Histrelin (Vantas), Leuprolide (Eligard, Lupron), 
Triptorelin (Trelstar).
Dose 1 (start 
dose)
125mg, 100mg, 75mg.
Dose 1 start date
Year, month, day.
Dose n (where 
n>=2)
125mg, 100mg, 75mg.
Dose n start date
Year, month, day.
Dose n 
adjustment type 
or reason
Categories include schedule change; dose delay; hold; cost; patient 
refusal; toxicity.
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9.3.3. Derived Variables 
Variables that will be derived from curated data will include the following:
Data Elements
Description
Age at A/MBC 
diagnosis
Age in years; age categories: <50, 50-64, 65 –74, ≥75 years (Exact list 
will depend on the expert de-ID approach).
Age at start of 
palbociclib
treatment
Age in years; age categories: <50, 50-64, 65 –74, ≥75 years.
Date of death
If patient vital status = deceased, date of death from the medical record 
(capturing from EMR, registries, third party integrations) (Availability of 
the exact date will depend on the Expert de-ID approach).
Palbo dose change 
ever
Yes; No.
Disease Free 
Interval (DFI)
Months from the end of adjuvant/neo-adjuvant therapy to the date of 
disease recurrence.
•
≤12 months, 13-24 months, 25-36 months;
•
>36 months;
•
Unknown.
Endocrine 
sensitivity
≥12 months without recurrence/progression after completion of 
endocrine therapy in the adjuvant setting.
Primary endocrine 
resistance
Relapse during first 2 years of adjuvant endocrine therapy or progressive 
disease within first 6 months of first-line endocrine therapy for metastatic 
breast cancer.
Secondary 
endocrine 
resistance
Relapse while on adjuvant endocrine therapy but after first 2 years of 
treatment, relapse within 12 months of completing adjuvant endocrine 
therapy, or progressive disease 6 or more months after starting endocrine 
therapy for metastatic breast cancer.
Charlson 
Comorbidity Index 
(CCI)
Calculated based on the presence of 17 Charlson comorbidities at 
A/MBC.
Line of therapy
Line number (1; 2; 3; etc.) in the A/MBC setting assigned based on 
Syapse line of therapy algorithm.
Regimen 
medication(s)
Systemic therapies included in line regimen defined by Syapse line of 
therapy algorithm.
Line start date
Year, month, day.
Line end date
Year, month, day.
Time to first dose 
change
Days from palbo dose 1 start date to palbo dose 2 start date, if applicable.
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Data Elements
Description
Number of dose 
changes
Number of dose reduction(s) and number of dose increases over the 
calendar time (quarter since February 2015) and over treatment cycle 
since palbo dose 1 start date.
Bone only distant 
metastasis at MBC 
diagnosis
From sites of distant metastasis: bone only.
Visceral distant 
metastasis at MBC 
diagnosis
From sites of distant metastasis: visceral sites.
Visceral sites defined as: Liver; Lung; Peritoneum; Pleural nodules; 
Malignant pleural effusion.
Disease burden at 
MBC diagnosis
Lesions in liver, bone, or lung metastatic sites: Single, Multiple, 
Unknown.
Effectiveness 
Outcomes
Real-world 
Overall Survival 
(rwOS)
Length of time from the start of palbociclib + AI treatment to the earliest 
of the following: date of death, date of last contact, or the end of study 
period.
Real-world 
progression free 
survival (rwPFS)
Length of time from the start of palbociclib + AI treatment to the earliest 
of the following: clinician-assessed progression event, date of death, date 
of last contact, or end of study period.
Progression identified from tissue/pathology or imaging/radiology and
confirmed by clinician (in 2 separate data points), from MA guidance:
1. Medical Oncology Consult/Note (can also include medical oncologist 
history and physical (H&P).
2. Radiation Oncology note/consult/(can also include radiation 
oncology H&P).
3. Progress Note (can also include /H&P/Consult - use this option for 
physician of other discipline in the absence of numbers1and 2).
4. Discharge Summary.
5. Nursing Note.
6. Care Everywhere/Scanned Documents/External lab reports (for 
information diagnosed outside of facility for which patient is being 
abstracted).
7. Other.
Real world time to 
treatment 
discontinuation 
(rwTTD)
Length of time from the start of palbociclib + AI treatment to the earliest 
of the following: date the patient discontinues first-line treatment, date of 
death, last known usage of first-line treatment, or end of study period.
Real world time to 
next treatment 
(rwTTNT)
Length of time from the start of palbociclib + AI treatment to the earliest 
of the following: subsequent line of therapy initiation, date of death, date 
of last contact, or end of the study period.
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9.4. Data Sources 
The Syapse Learning Health Network includes patient-level data from large community 
health systems based primarily in the United States. These US providers manage care 
delivery networks that span the continuum of care in multiple regions across 25 states 
including California, Nevada, Oregon, Washington, Arizona, Nebraska, Minnesota, 
Michigan, Illinois, Indiana, Wisconsin, Kansas, Missouri, Oklahoma, Arkansas, Louisiana, 
Texas, Kentucky, Tennessee, Mississippi, Alabama, Georgia, Florida, Maryland, and New 
York. Identification of cancer cases at each health system varies but in general includes a 
combination of billing codes and provider specialties.
At each participating health system where Syapse is deployed, structured clinical data is 
ingested into the Syapse database for any patient meeting any one of the following criteria: 
1) was seen by the health system’s oncology department(s), 2) was seen by an oncology 
specialist, or 3) has documented evidence of cancer based on a neoplasm ICD code. Syapse 
leverages the health system’s existing source system feeds wherever possible to utilize active 
feeds that are relied on for clinical care purposes. Additionally, Syapse Certified Tumor 
Registrars (CTRs) capture additional information and context directly from health system 
EMRs.  
For cancer cases identified at each health system, Syapse obtains structured somatic 
molecular results through its direct integration with commercially available molecular 
somatic testing laboratories.
In addition, Syapse augments vital status and date of death for patients captured in 
(1) Surveillance, Epidemiology, and End Results (SEER) national cancer registry, as well as 
regional and institutional registries, (2) the Social Security Death Index (SSDI) from a third 
party vendor, (3) online obituary data from a third party vendor, (4) manually abstracted data 
from online obituaries and physician notes, (5) health system’s electronic medical record 
(EMR), including hospital-based cancer registries for date of death and vital status.
The detailed data from Syapse Learning Health Network database enables insight into cancer 
care in routine clinical settings (real-world), for example, by permitting hypothesis 
generation and retrospective research. The database is fit for purpose for this objective due 
to the health systems distribution broadly across 
 the US
 
, the type and extent of patient-level data, the minimal lag time for data 
availability and the data QC and verification processes in place including 7 year record 
retention and direct access to source EMR. See Section 9.8 for more details on quality 
control processes.
9.5. Study Size
Study sample will include all eligible cases in the Syapse database. Preliminary analysis 
identified up to 1,074 patients with evidence of key primary inclusion criteria: breast cancer 
diagnosis and palbociclib treatment. This population will be further examined and limited to 
those matching all inclusion criteria: Patients diagnosed with HR+/HER2- A/MBC with 
first-line palbociclib + AI treatment, on or after 03 February 2015 through 31 July 2019.
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Three to four hundred patients are expected to fulfill complete study inclusion criteria.
Given the inclusion criterion requiring a qualifying treatment identification period between 
03 February 2015 through 31 July 2019, and assuming a data cutoff date of 
01 February 2020, the minimum follow-up available is therefore 6 months.  
Structured diagnosis code for breast cancer 
(ICD9 174.x or 175.x or ICD10 C50.x).
Structured medication orders or administrations 
for evidence of treatment with palbociclib 
(generic/trade name: palbociclib/Ibrance, 
RXNorm: 1601374, 1601381).
Certified tumor registrars apply a protocol 
screening procedure during initial patient chart 
review involving the following inclusion 
criteria:
1. Patient has A/MBC.
2. Patient is HR+/HER2- (Patients are 
included in the absence of any 
indication of HR- or HER2+).
3. Patient is treated with palbociclib on or 
after 03 February 2015 through 
31 July 2019.
4. Patient is treated with palbociclib in 
combination with an aromatase 
inhibitor.
Excluded:
1. Patient does not have 
A/MBC.
2. Patient has indicated HR- or 
HER2+ status.
3. No treatment with 
palbociclib, or treatment is 
not on or after 
03 February 2015.
4. Palbociclib treatment is not 
in combination (ie, within 
60 days) with an aromatase 
inhibitor.
Patient received palbociclib + AI in the 
first-line setting.
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9.6. Data Management 
Data curation procedure, logic, definitions, and normalization are developed in collaboration 
between qualified clinical informaticists, epidemiologists, clinical oncologists, and certified 
tumor registrars (CTRs) before data collection and reviewed for quality during and after 
collection. Collection practices are standardized across the team through rigorous training, a 
qualification process for each CTR, as well as having all collected records undergo a quality 
control (QC) review to ensure accuracy and uniformity of collection practices. Syapse CTRs 
utilize an Electronic Data Capture system to document the patient's medical history 
according to protocol. To enable consistent and effective analysis and interpretation of 
Real-World Data, Syapse manages a data dictionary of data elements and their definitions. 
Records are retained and secured according to HIPAA regulations, and as governed by 
specific provisions in customer contracts.
Data collection will begin following development of curation guidance, CTR training, and 
Institutional Review Board (IRB) approval of a study protocol. Data will be maintained in a 
secure database for analysis. The collected data will be de-identified based on expert 
recommendation for this specific dataset upon which a final data format and data types for 
the dataset will be determined. 
Syapse will engage a third party for the purpose of obtaining a formal determination by 
a qualified expert to de-identify a dataset of breast cancer patients in accordance with the 
Expert Determination Method described in section 164.514(b)(1) of the HIPAA Privacy 
Rule. In order to deliver the Pfizer Regulatory Breast Cancer Real-World Dataset while 
fulfilling our responsibilities as a Business Associate to our Health System customers, this 
dataset must be de-identified while preserving a level of detail, especially around dates, that 
meets the research objectives. A general workflow for expert determination can take a few 
weeks or months and starts once the data dictionary is finalized in the protocol. The 
approach includes various steps. First, the expert will evaluate the extent to which the health 
information can (or cannot) be identified by the anticipated recipients. Second, the expert 
often will provide guidance on which statistical or scientific methods can be applied to the 
health information to mitigate the anticipated risk of re-identification. The expert will then 
execute such methods using some percentage of the actual data set. Finally, the expert will 
evaluate the identifiability of the resulting health information to confirm that the risk is no 
more than very small when disclosed to the anticipated recipients. This process may require 
several iterations until the expert and the recipients agree upon an acceptable solution.
9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic Data 
Records
As used in this protocol, the term CRF/DCT 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.
A CRF/DCT is required and should be completed for each included patient.  The completed 
original CRFs/DCTs 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 
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authorities, without written permission from Pfizer.  Syapse shall ensure that the CRFs/DCTs 
are securely stored at Syapse in encrypted electronic form and will be password protected to 
prevent access by unauthorized third parties.
Syapse has ultimate responsibility for the collection and reporting of all clinical, safety, and 
laboratory data entered on the CRFs/DCTs 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/DCTs must be signed by Syapse to attest that the data contained on the CRFs/DCTs 
are true. Any corrections to entries made in the CRFs/DCTs 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/DCTs must match those charts.
9.6.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, Syapse 
agrees to keep all study-related records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs/DCTs and hospital records), copies of all 
CRFs/DCTs, safety reporting forms, source documents, detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (eg, letters, meeting 
minutes, and telephone call reports).  The records should be retained by Syapse according to 
local regulations or as specified in the vendor agreement, whichever is longer.  Syapse must 
ensure that the records continue to be stored securely for so long as they are retained.
If Syapse 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.
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless Syapse 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. 
Syapse must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met.
9.7. 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 the sponsor. 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.
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The primary and secondary objectives of the study are to describe patient characteristics, 
real-world treatment patterns and clinical effectiveness of palbociclib + AI as first-line
treatment for A/MBC patients. 
Descriptive analyses: For categorical variables (eg region, race, and stage at initial 
diagnosis), data will include the frequency (number of cases) and percentage (%) of total 
patients observed in each category; for continuous variables (eg, age and time from initial 
breast cancer diagnosis to metastatic diagnosis), variables will be presented as the mean, 
standard deviation (SD), median, 25th and 75th percentiles and ranges (minimum and 
maximum) in some cases. The calculation of percentages will always include the missing 
category in the case of missing values.  Continuous variables may be categorized into 
intervals, with the distribution of patients (N, %) provided. 
Kaplan-Meier curves and landmark analyses will be performed to estimate rwPFS, rwOS, 
rwTTD, and rwTTNT. Specifically, landmark time points are; 3, 6, 12, 18, 24, 30, and 
36 months for rwPFS and 6, 12, 18, 24, 30, and 36 months for rwOS. For rwTTD and 
rwTTNT, landmark time points are; 3, 6, 12, 18, 24, 30, and 36 months. Ninety-five percent 
confidence intervals on the median rwPFS, rwOS, rwTTD, and rwTTNT will be reported.
Censoring for each event will be defined in the SAP.
Cox proportional hazard models will be fit using age categories, ECOG performance, 
menopausal status, metastatic status (De novo, versus number of metastatic sites), number of 
disease sites (1, 2, ≥3), menopausal status, prior endocrine therapy, prior chemotherapy, prior 
surgery, prior radiation therapy as appropriate based on availabilities of the data and sample 
sizes. Potential interactions will be examined using survival trees for time to events. 
9.8. Quality Control
9.8.1. Data Integration and Quality
Syapse acquires clinical structured data from a number of health system source systems 
including, but not limited to, electronic data warehouse (EDW)/North American Association 
of Central Cancer Registries (NAACCR) flat files, health level seven international (HL7) 
messages including HL7 version 2 and HL7 fast healthcare interoperability resource 
specification (HL7 FHIR), and JavaScript object notation (JSON) files. Syapse leverages the 
health system’s existing source system feeds wherever possible to utilize active feeds that are 
relied on for clinical care purposes. Quality control measures include collaboration with 
clinical data analysts, informaticists, and EMR analysts employed by the health systems, who 
are familiar with the specific context of the source system, to validate the output of the 
structured data represented in the Syapse database appropriately matches the respective 
source system.
For cancer cases identified at each health system, Syapse obtains structured somatic 
molecular results through its direct integration with commercially available molecular 
somatic testing laboratories (eg Foundation Medicine, Tempus, Neogenomics, Caris 
CellNetix, Paradigm, among others). Molecular laboratories structure the molecular results 
according to Syapse’s data schema standard for interoperability. Syapse ingests structured 
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molecular results as reported by each laboratory without any modification. Quality control 
measures include retention of the original and any addendum PDF reports for each patient. 
Syapse structured data was a part of an abstract describing normalization of structured 
outcomes presented at 2018 ASCO (Tittel, et al, 2018)
Additionally, demographic, clinical characteristics, testing, treatment, and outcomes data is 
abstracted from the participating health system’s EHR by certified tumor registrars (CTRs) 
for cancer cases identified via Syapse’s interop data feeds. Guidance for abstraction is based 
on the Facility Oncology Registry Data Standards, better known as FORDS, which was 
developed in 2003 by the Commission on Cancer (CoC) of the American College of 
Surgeons (ACS) for its CoC accredited programs. FORDS is considered a set of entities that 
have been well established and proven through years of collection and validation. The 
traditional way in which a CTR codes a core set of data has been redefined within the scope 
of Syapse. A separate guidance has been created to capture both Syapse core data elements 
and all other data elements needed specifically to support the protocols used. The Syapse 
redefining of data standards supersedes FORDS/STORE manual when appropriate to 
understand RWD in the context of insights and outcomes to meet research and regulatory 
purposes. During abstraction, the data is manually entered into defined fields controlled for 
source documentation and vocabulary. Quality controls include CTR training and testing, 
QC of 100% of cases, and use of inter-rater agreement applied at appropriate intervals during 
the abstraction process to pre-agreed data points.
9.8.2. Review and Verification of Data Quality
All cases will be re-reviewed at least once either from the CTR that completed the case or a 
review from another CTR ensuring high quality and accuracy from an Inter-Rater QC 
process. The abstraction tool itself also has various quality checks built in that would detect 
potential data entry errors at the time of abstraction, rather than allowing errors to perpetuate. 
After the dataset is curated by the CTRs, the data will be analyzed by a Syapse 
epidemiologist and the CTRs consulted to re-review sections of the data for overall data 
consistency and high quality. 
All data abstracted from the Syapse Learning Health Network undergo an independent 
quality control review, with evaluation for consistency, completeness, and outlier values. 
This review is conducted by the Syapse Epidemiology and Syapse Clinical Analytics teams. 
Data queries generated as part of quality review are documented and resolved, with 
documentation of queries and resolution maintained in a complete query log.
Data housed in the electronic data capture tool will then be exported for data cleaning and 
preparation, creation of derived values, and preparation of analysis datasets using R statistical 
software. Data will then undergo initial statistical review, including examination of all fields 
for outlier values, and evaluation for internal consistency of study data. Values that are 
flagged as potentially anomalous during statistical review will be queried and resolved before 
analysis datasets are finalized. All study data also undergoes scientific review of study 
results prior to data lock.
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9.9. Limitations of the Research Methods
Limitations of the Analysis
This study is subject to limitations of accuracy and completeness of the Syapse data. The 
data is derived from routinely collected clinical data; therefore data is subject to missing 
information for variables and errors in the source EMR data. Due to potential missing data in 
the EMR, certain variables may not be obtainable for the entire Syapse population, which 
will limit stratification and subgroup analyses. In addition, biomarker testing and result 
availability is variable across participating Syapse health systems.
Selection Bias
Since the database is limited to participating sites of care, if the populations that are treated at 
these centers are disproportionately represented relative to the total population in the United 
States, the results from the descriptive analyses may be biased. If, for example, more severe 
patients are referred to the larger specialty hospitals/academic centers, their treatment 
regimens, survival, and the distribution of tumor types may be different.
Measurement Error(s)/Misclassification(s)
Although it is expected that the quality of the data should be generally high, depending on 
missing variables and potential errors in abstraction of unstructured data, there is a possibility 
of challenges to the internal validity of the data. Syapse abstracted database will be used to 
support this study. We expect minimal measurement error and/or misclassification due to 
Syapse data collection process as Syapse has direct access to longitudinal patient records in 
the EMR detailing the full cancer progression. Furthermore, these data are collected by
trained, experienced CTRs. Misclassification may result if the source EMR data has missing 
data where not all events or treatments are recorded.
External Validity of Study Design
The generalizability of this study will depend on the representativeness of the Syapse 
participating health systems compared to the US population. Syapse is deployed in urban 
hospitals in 25 states. Eligible cases are identified and slated for abstractions from those 
geographic regions.
9.10. Other Aspects
Not applicable.
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10. PROTECTION OF HUMAN SUBJECTS
10.1. Patient Information 
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.
Patient personal data will be stored at Syapse in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access. Syapse will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster. In the event of a potential personal data breach, 
Syapse shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
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 Syapse research agreement and applicable privacy laws.
Syapse is a third-party business associate to each health system utilizing the platform and 
operates under HIPAA quality improvement exception. Syapse platform is utilized by health 
systems partners for population-based activities relating to improving health, reducing health 
care costs, protocol development, case management, and care coordination. Syapse hosts 
health system data in compliance with HIPAA Privacy Rule as well as contractual 
obligations related to protecting the privacy and security of the PHI. Syapse has all policies 
and necessary protections in place for the protection of human subjects, as outlined in Data 
Use/Sharing Agreements between Syapse and its health system partners
10.2. 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.
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
No identifying information is released about any individual unless required by law. Under 
no other circumstances would any identifying information be made available to outside 
parties or be used for other purposes by the study team. To conduct this study, Syapse will 
submit this protocol for exemption to a commercial Institutional Review Board (IRB) prior to 
study start.
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10.4. 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 Good Practices for Outcomes Research issued by the International Society for 
Pharmacoeconomics and Outcomes Research (ISPOR).
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
11.1. Human Review of Unstructured Data
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 appears 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:
•
All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the data collection tool and 
reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report 
Form.
•
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 (eg, 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.
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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:
•
“YRR Training for Vendors Working on Pfizer Studies (excluding interventional 
clinical studies and non-interventional primary data collection studies with 
sites/investigators)”. 
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.
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
The final study report will be completed by Pfizer and is estimated to be September 2020.
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
competent authority in any area of the world, or if Syapse 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.
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13. REFERENCES
1.
American Cancer Society. Breast Cancer Facts and Figures 2017-2018. 2018; 
http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/docu 
ment/acspc-030975.pdf. Accessed August 15, 2018.
2.
American Cancer Society. Cancer Facts & Figures 2020. Atlanta: American Cancer 
Society; 2020.  
3.
Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus 
Fulvestrantplus 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 2016;17(4):425-39.
4.
DeMichele A, Cristofanilli M, Brufsky A, et al.  Overall survival for first-line 
palbociclib plus letrozole versus letrozole alone for HR+/HER2- metastatic breast 
cancer patients in US real-world clinical practice.  Poster Presented at: 2019 San 
Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX.
5.
Diéras V, Rugo HS, Schnell P, et al. Long-term pooled safety analysis of palbociclib in 
combination with endocrine therapy for HR+/HER2- advanced breast cancer. J Natl 
Cancer Inst 2019;111(4):419-30.
6.
Eggersmann, TK, Degenhardt T, Gluz O, et al.  CDK4/6 inhibitors expand the 
therapeutic options in breast cancer: palbociclib, ribociclib and abemaciclib BioDrugs 
2019;33:125–35.
7.
Finn RS, Crown JP, Lang I, et al. 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 2015;16(1):25-35.
8.
Finn RS, Crown J, Lang I, et al. Overall survival results from the randomized phase II 
study of palbociclib (P) in combination with letrozole (L) versus letrozole alone for 
frontline treatment of ER+/HER2– advanced breast cancer (PALOMA-1; TRIO-18). 
Oral presentation presented at: 2017 American Society of Clinical Oncology Annual 
Meeting; June 2-6; Chicago, IL. 
9.
Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor 
resistance. Nat Rev Cancer 2015;15(5):261-75.
10.
Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. 
CA Cancer J Clin. 2016;66(4):271-89.
11.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 
2019;69(1):7-34.
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12.
Taylor-Stokes G, Mitra D, Waller J, Gibson K, Milligan G, Iyer S. Treatment patterns 
and clinical outcomes among patients receiving palbociclib in combination with an 
aromatase inhibitor or fulvestrant for HR+/HER2-negative advanced/metastatic breast 
cancer in real-world settings in the US: Results from the IRIS study. Breast 2019;43:22-
7.
13.
Tittel J, Zaman A, Shma JE, et al. Successful automated normalization of cancer 
outcomes for half a million patients across four disparate health systems. J Clin Oncol 
36;15_suppl Published online June 01, 2018. DOI: 
10.1200/JCO.2018.36.15_suppl.e18763.
14.
Turner NC, Ro J, Andre F, et al. Palbociclib in Hormone-Receptor-Positive Advanced 
Breast Cancer. N Engl J Med 2015;373(3):209-19.
15.
Turner NC, Slamon DJ, Ro J, et al. Overall Survival with Palbociclib and Fulvestrant in 
Advanced Breast Cancer. N Engl J Med 2018;379:1926-36.
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14. LIST OF TABLES 
None.
15. LIST OF FIGURES
None.
16. ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
17. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.
18. ANNEX 3. ADDITIONAL INFORMATION
Not applicable.
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