Real-world Treatment Patterns and Effectiveness of Palbociclib in Combination With an Aromatase Inhibitor as Initial Endocrine Based Therapy in Metastatic/Advanced Breast Cancer
Conditions: Metastatic Breast Cancer
Sponsor: Pfizer

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Study Information
Title
Real-world treatment patterns and effectiveness of 
Palbociclib in combination with an aromatase 
inhibitor as initial endocrine based therapy in 
metastatic/advanced breast cancer 
Protocol number
A5481122
Protocol version identifier
Amendment 1
Date of last version of protocol
22 January 2019
Active substance
L01XE33 
Palbociclib (IBRANCE;PD-0332991)
Medicinal product
Palbociclib (IBRANCE;PD-0332991)
Research Question & Objectives
Primary objectives

To describe demographic and clinical 
characteristics of metastatic/advanced (MBC)
patients who were treated with Palbociclib
+ an aromatase inhibitor (AI) as initial 
endocrine based therapy.

To describe treatment patterns of Palbociclib
+ AI as initial endocrine based therapy for
MBC.

To examine effectiveness of Palbociclib + AI 
as initial endocrine based therapy for MBC, 
including real world progression free survival 
(rwPFS), overall survival (OS), and real 
world tumor response (rwTR).
Secondary objectives

To examine effectiveness of Palbociclib + AI 
as initial endocrine based therapy for MBC 
by subgroups such as age, ECOG 
performance, metastatic status, menopausal 
status, and prior therapy.

To examine the time from Palbociclib + AI

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initiation to the next line of anti-cancer 
treatment and time to first use of 
chemotherapy.
Authors
MD, PhD
Senior Director, US Medical Affairs
Pfizer Oncology
PhD
Executive Director, Statistics
Pfizer Oncology
PhD
Senior Director, RWE
Pfizer Oncology
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
LIST OF TABLES.....................................................................................................................4
2. LIST OF ABBREVIATIONS................................................................................................5
3. RESPONSIBLE PARTIES....................................................................................................6
4. ABSTRACT...........................................................................................................................6
5. AMENDMENTS AND UPDATES.....................................................................................10
6. MILESTONES.....................................................................................................................11
7. RATIONALE AND BACKGROUND................................................................................11
8. RESEARCH QUESTION AND OBJECTIVES .................................................................12
9. RESEARCH METHODS ....................................................................................................13
9.1. Study Design ...........................................................................................................13
9.2. Setting......................................................................................................................14
9.2.1. Inclusion Criteria ........................................................................................14
9.2.2. Exclusion Criteria.......................................................................................14
9.2.3. Study Cohorts .............................................................................................15
9.3. Variables..................................................................................................................15
9.4. Data Source .............................................................................................................21
9.5. Study Size................................................................................................................22
9.6. Data Management ...................................................................................................22
9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic 
Data Record .....................................................................................................22
9.6.2. Record Retention ........................................................................................22
9.7. Data Analysis ..........................................................................................................23
9.8. Quality Control........................................................................................................24
9.9. Limitations of the Research Methods......................................................................25
9.10. Other Aspects ........................................................................................................25
10. PROTECTION OF HUMAN SUBJECTS ........................................................................25
10.1. Patient Information................................................................................................25
10.2. Patient Consent......................................................................................................26
10.3. Patient Withdrawal................................................................................................26
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10.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............26
10.5. Ethical Conduct of the Study ................................................................................26
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................27
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........28
13. REFERENCES ..................................................................................................................29
14. LIST OF TABLES.............................................................................................................31
15. LIST OF FIGURES ...........................................................................................................31
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................31
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................31
ANNEX 3. ADDITIONAL INFORMATION.........................................................................31
LIST OF TABLES
Table 1.
List of Variables .......................................................................................16
Table 2.
List of Medications for the Treatment of HR+/HER2- Metastatic 
Breast Cancer............................................................................................18

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse event
AI
Aromatase inhibitor
ASCO
American Society of Clinical Oncology
BC
Breast cancer
BRCA
BReast CAncer susceptibility gene
CDK
Cyclin-dependent kinase
CI
Confidence interval
ECOG
Eastern Cooperative Oncology Group
ER
Estrogen receptor
ET
Endocrine therapy
EHR
Electronic health record
FDA
US Food and Drug Administration
GPO
Group Purchasing Organization
GPP
Good Pharmacoepidemiology Practices
HR+
Hormone receptor-positive 
HCP
Health Care Professional
HER
Human Epidermal Growth Factor Receptor
HIPPA
Health Insurance Portability and Accountability Act
HR
Hormone receptor
ICD
International Classification of Diseases
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IPTW
Inverse probability treatment weighting 
LHRH
Luteinizing hormone releasing hormone
LOT
Line of therapy
MBC
Metastatic breast cancer
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NI
Non-interventional
OS
Overall survival
PR
Progesterone receptor
PS
Propensity score 
QC
Quality Control
rwDOT
Real-world duration of treatment 
rwPFS
Real-world progression-free survival
rwTR
Real-world tumor response
SAP 
Statistical analysis plan 
SD
Standard deviation
SEER
Surveillance, Epidemiology, and End Results
SQL
Structured Query Language
US
United States

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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, Degree(s)
Title
Affiliation
Address
 MD, PhD
Senior Director
US Medical Affairs
Pfizer Oncology
235 E 42nd Street
New York, NY, 10017
 MD
VP
Global Breast Medical 
Lead
Pfizer Oncology
235 E 42nd Street
New York, NY, 10017
PhD
Executive Director
Statistics
Pfizer Oncology
235 E 42nd Street
New York, NY, 10017
 PhD
Senior Director 
Global RWE Lead
Pfizer Oncology
235 East 42nd Street 
New York, NY, 10017
MPH
Director
HEOR
Pfizer Oncology
235 E 42nd Street
New York, NY, 10017
 PharmD
Senior Director
Global Medical Affairs
Pfizer Oncology
235 E 42nd Street
New York, NY, 10017
4. ABSTRACT
Title: Real-world treatment patterns and effectiveness of Palbociclib in combination with an 
aromatase inhibitor as initial endocrine based therapy in metastatic/advanced breast cancer
Date of Abstract: 10 November 2019
Amendment 1
Name and affiliation of the main author: 
MD, PhD
Pfizer Inc.
Senior Medical Director, US MA
Rationale and Background: 
Palbociclib, the first oral cyclin-dependent kinase (CDK) 4/6 inhibitor, is approved for
HR+/HER2–metastatic/advanced breast cancer (MBC) in combination with an aromatase 
inhibitor or fulvestrant. Improved median PFS was observed with Palbociclib plus Letrozole
as first-line therapy (PALOMA-2) and with Fulvestrant in patients who have failed prior 
endocrine therapy (PALOMA-3). Since its approval in February 2015, Palbociclib has been 
prescribed for more than 100,000patients. Recent real-world studies support the 
effectiveness of Palbociclib-based therapy in HR+/HER2– MBC patients. It is important to 
better understand a treatment’s benefits and risks in a real world setting as published 
real-world studies to date have limitations including small cohorts, short duration of 
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follow-up, inconsistent definitions of outcomes, and lack of a comparator. Electronic health 
record (EHR) data are collected as part of routine clinical practice and enable quick access to 
richer health information (as compared to claims database) in a timely manner (as compared 
to primary data collection) in a relatively large population. Utilizing Flatiron Health’s 
longitudinal, demographically and geographically diverse database derived from electronic 
health record (EHR)data from over 265 cancer clinics (~800 sites of care), the current study 
is designed to describe patient characteristics, treatment patterns and effectiveness of 
Palbociclib in combination with an aromatase inhibitor (AI) as initial endocrine based 
therapy in HR+/HER2- MBC. 
Research question and objectives: 
This study aims to describe patient characteristics, treatment patterns and effectiveness in 
HR+/HER2- MBC patients initiating Palbociclib + AI as initial endocrine based therapy 
during the period of February/3/2015 through August/31/2018 (or 3 months prior to study 
cut-off date) in the United States (US) real-world clinical practice setting.
Primary Objectives
•
To describe demographic and clinical characteristics of metastatic/advanced (MBC) 
patients who were treated with Palbociclib + AI as initial endocrine based therapy.
•
To describe treatment patterns of Palbociclib + AI as initial endocrine based therapy 
for MBC.
•
To examine effectiveness of Palbociclib + AI as initial endocrine based therapy for 
MBC, including real world progression free survival (rwPFS), overall survival (OS), 
and real world tumor response (rwTR).
Secondary objectives
•
To examine effectiveness of Palbociclib + AI as initial endocrine based therapy for 
MBC by subgroups such as age, ECOG performance, metastatic status, menopausal 
status, and prior therapy.
•
To examine the time from Palbociclib + AI initiation to the next line of anti-cancer 
treatment and time to first use of chemotherapy.  
Study design: This is a retrospective cohort study utilizing data derived from the Flatiron 
Health Analytic Database to describe patient characteristics, treatment patterns and 
effectiveness of Palbociclib + AI as initial endocrine based therapy in HR+/HER2- MBC 
during the period of February/3/2015 through August/31/2018 (or 3 months prior to study 
cut-off date) in the US real-world clinical practice setting. The date of the first Palbociclib
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+ AI line of therapy after February 3, 2015 is defined as the index date. Patients will be 
evaluated retrospectively from index date to November 30, 2018 (or study cut-off date), or
death, whichever came first.
 
 
 
Population Setting: This study uses secondary de-identified Flatiron Healthcare Analytic 
data that involve patients who have been diagnosed with MBC in the United States.
Study Population: Female patients will be eligible for analysis if they were aged 18 or 
above at MBC diagnosis, HR+/HER2- as confirmed by a test before or up to 60 days after the 
date of MBC diagnosis, and were treated with Pablociclib + AI or Letrozole alone for MBC 
during the period from February 2015 through August 2018 (or 3 months prior to study 
cut-off date). Eligible patients will be identified from the Flatiron Health Analytic Database.
Variables: Variables will be obtained from both structured and unstructured data using 
Flatiron’s technology-enabled data processing. The following variables will be included for 
the analyses: demographics (eg, age, race, ethnicity, region), baseline clinical characteristics 
(eg, date of diagnosis of MBC, HR+/HER2- status, ECOG performance status, disease stage 
at initial diagnosis, site of metastasis, and number of disease sites), treatment patterns (eg, AI
therapy partner, starting dose, dose adjustment, duration of treatment, discontinuation, and 
reasons for dose adjustment and discontinuation), and effectiveness (real-world 
progression-free survival, overall survival, real-world tumor response, time to next line of 
anti-cancer treatment, and time to chemotherapy).  
Data source
Flatiron Health’s longitudinal, demographically and geographically diverse database derived 
from electronic health record (EHR) data from over 265 cancer clinics (~800 sites of care) 
including more than 2 million active US cancer patients.
Study Size: Based on an initial feasibility assessment using Flatiron Health Analytic 
Database between February 2015 – November 2018, there are 1,367 HR+/HER2- MBC 
patients who received Palbociclib + AI (including 1,221 Pablociclib + Letrozole, 
70 Palbociclib + Anastrozole, and 76 Palbociclib + Exemestane) and 627 patients who 
received Letrozole monotherapy in the database. All patients satisfying inclusion and 
exclusion criteria will be included in the statistical analyses. 
Data Analysis: Descriptive analyses will be performed to describe baseline demographics
and clinical characteristics, treatment patterns, and effectiveness outcomes for patients 
receiving Palbociclib + AI as initial endocrine based therapy for MBC. Kaplan-Meier curves 
and landmark analyses will be performed to estimate real-world progression-free survival, 
overall survival, real-world tumor response, and time to chemotherapy from Palbociclib + AI
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initiation. Subgroup analyses will be conducted according to age, ECOG performance, 
metastatic status, menopausal status, and prior therapy.
 
Milestones: Data analysis will be conducted once data/related variables are available, and 
the final study report will be completed on Oct 27, 2021.
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5. AMENDMENTS AND UPDATES
Amendment 
number
Date
Protocol 
section(s) 
changed
Summary of 
amendment(s)
Reason
1
10 
November 
2019
Section 8-9
Index period was changed 
from ’31 August 2018 (or 
3 months prior to study
cut-off date)’ and study 
end date was changed 
from November 30 to 
study cut-off date. 
To be consistent with 
Flatiron’s data cut-off 
date.
Section 9.2.1 
Inclusion criterion #5.
1. “letrozole alone” was 
added.
2. “first line therapy” was 
added.
1. To include 
letrozole cohort.
2. To specify “initial 
endocrine based 
therapy” in the study 
to be consistent with 
PALOMA 2.
Section 9.2.2
Exclusion criteria were 
updated
Follow Flatiron’s 
protocol.
Section 9.3
Follow-up period, rwPFS, 
and OS were clarified
Follow Flatiron’s 
protocol.  
Section 9.3
Change Palbociclib +AI 
to index treatment
To be applicable to 
letrozole cohort.
Section 6
Final report changed to 
10/27/2021
Further analyses need 
to be done and to be 
consistent with 
complete date in
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6. MILESTONES
Milestone
Planned date (mm/dd/yyyy)
Completion of feasibility assessment using Flatiron Health 
Analytic Databases
22 January 2019
Analyses for primary objectives
25 January 2019
Final study report
27 October 2027
7. RATIONALE AND BACKGROUND
Breast cancer is the most common cancer in women and the second most common cancer 
overall. In 2016, there were approximately 3.5 million women living with a history of breast 
cancer (BC) in the US.1 It is estimated that 154,794 American women living with metastatic 
BC in the US in 2017 and that 3 in 4 initially diagnosed with early stage BC will progress to 
MBC.2 Hormone receptor-positive (HR+) breast cancer is the most commonly diagnosed 
subtype (~70-80%), and it is potentially sensitive to endocrine therapy.3
Palbociclib, the first oral CDK4/6 inhibitor, is approved for HR+/HER2– advanced and 
metastatic breast cancer in combination with an aromatase inhibitor or Fulvestrant.
Palbociclib is approved in the US based on improved median PFS demonstrated in 3 pivotal 
clinical trials: PALOMA-1 and PALOMA 2 (initial endocrine based therapy) and 
PALOMA-3 (after progression following endocrine therapy). Approval was first granted 
based on findings from the phase II PALOMA-1 trial4 in February 2015. Palbociclib in 
combination with Fulvestrant was approved one year later (February 2016) in pre- or 
post-menopausal women with disease progression following endocrine therapy based on 
results from the PALOMA-3 trial.5,6  The phase III PALOMA-2 confirmed the findings in 
PALOMA-1, demonstrating a median progression-free survival (PFS) in the Palbociclib plus 
Letrozole arm of 24.8 months compared to 14.5 months in the placebo plus Letrozole arm 
(hazard ratio [HR] = 0.58; P = <0.001).7  Subgroup analyses of PFS according to 
stratification factors and demographic or prognostic factors revealed consistent results in 
PALOMA-27 [6] and PALOMA-3 trial.5,6  The primary toxicity of Palbociclib is neutropenia,
which can be managed with dose interruption/reduction, resulting in a favorable safety 
profile and delayed deterioration of global QoL.8,9 The safety results from all three trials 
were consistent, with no new safety signals identified in the phase III studies. Subsequently,
Palbociclib has been granted regular approval in combination with an aromatase inhibitor 
(AI) for initial endocrine based treatment.10
Since its approval in February 2015, Palbociclib has rapidly become the standard of care in 
the treatment of HR+/HER2- MBC in women, commercially available multi-nationally. 
Palbociclib has been prescribed for more than 100,000 patients. Long-term pooled safety 
analyses of three randomized phase II and III studies demonstrated no evidence of specific 
cumulative or delayed toxicities with Palbociclib plus endocrine therapy.11  Recent 
real-world data have demonstrated that Palbociclib is effective in HR+/HER2– MBC patients 
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in the routine clinical practice setting.12-15 It is important to better understand a treatment’s 
benefits and risks in a real world setting as published real-world studies to date have 
limitations including small cohorts, short duration of follow-up, inconsistent definitions of 
outcomes, and lack of a comparator. 
Electronic health record (EHR) data is collected as part of the routine clinical practice and 
enables quick access to richer health information (as compared to medical or pharmacy 
claims data) in a timely manner (as compared to primary data collection) in a relatively large 
population. The Flatiron Health database (https://flatiron.com/real-world-evidence/) is a 
longitudinal, demographically and geographically diverse database derived from electronic 
health record (EHR) data. The database includes data from over 265 cancer clinics 
(~800 sites of care) representing more than 2 million active U.S. cancer patients available for 
analysis. In the current study, a novel non-interventional (NI) study approach will be taken 
to utilize Flatiron Health database to understand patient characteristics, treatment patterns 
and effectiveness of Palbociclib + AI at initial endocrine based therapy in MBC patients. 
The current protocol is not designed as a PASS per CT34 Post-Authorization Safety Studies 
(PASS) and the study is not a commitment or requirement to any regulatory authority.
8. RESEARCH QUESTION AND OBJECTIVES
This study aims to assess treatment patterns and real-world effectiveness in 
HR+/HER2- MBC patients initiating Palbociclib + AI as initial endocrine based therapy 
during the period February/3/2015 through August/31/2018 (or 3 months prior to study 
cut-off date) in the US real-world clinical practice setting.
Primary objectives

To describe demographic and clinical characteristics of metastatic/advanced (MBC) 
patients who were treated with Palbociclib + an aromatase inhibitor (AI) as initial 
endocrine based therapy.

To describe treatment patterns of Palbociclib + AI as initial endocrine based therapy 
for MBC.

To examine effectiveness of Palbociclib + AI as initial endocrine based therapy for 
MBC, including real world progression free survival (rwPFS), overall survival (OS), 
and real-world tumor response (rwTR).

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Secondary objectives
•
To examine effectiveness of Palbociclib + AI as initial endocrine based therapy for 
MBC by subgroups such as age, ECOG performance, metastatic status, menopausal 
status, and prior therapy.
•
To examine the time from Palbociclib + AI initiation to the next line of anti-cancer 
treatment and time to first use of chemotherapy.  
9. RESEARCH METHODS 
9.1. Study Design
A retrospective cohort study of treatment patterns and effectiveness of Palbociclib + AI as 
initial endocrine based therapy during the period February/3/2015 through August/31/2018 
(or 3 months prior to study cut-off date) for MBC will be conducted utilizing secondary 
de-identified Flatiron Healthcare Analytic data in the United States. This study design is 
selected to meet the study objectives with consideration of feasibility and availability and 
validity of exiting database.
•
Index date: the date of first prescription for + AI between February 3, 2015 and 
August 31, 2018 (or 3 months prior to study cut-off date).
•
Observation period: February 3, 2015 – study cut-off date.
•
Follow-up: Patients will be followed from the index date to the end of the study 
(study cut-off date) or death, whichever came first. 
•
Primary endpoints
•
RwPFS.
•
Secondary endpoints
•
OS.
•
RwTR.
•
Response rate.
•
Real-world duration of treatment (rwDOT).
•
Time from index date to next line of anti-cancer therapy and time to first use 
of chemotherapy.
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9.2. Setting
This study uses secondary de-identified Flatiron Healthcare Analytic data that involve 
patients who have been diagnosed with MBC in the United States.
9.2.1. Inclusion Criteria
Patients must meet all the following inclusion criteria to be eligible for inclusion in the study:
1. Female sex.
2. At least 18 years old at MBC diagnosis.
3. Diagnosis of MBC at any point in patient history.
a.
ICD-9 (174.x, 175.x) or ICD-10 (C50.xx) diagnosis of BC.
b. Confirmation of metastatic disease.
c.
At least 2 document clinical visits.
d. Evidence of stage IV or recurrent MBC with a metastatic diagnosis date on or 
after 2011, as confirmed by unstructured clinical documents.
4. HR+/HER2-.
a.
HR+: ER+ or PR+ test before or up to 60 days after MBC diagnosis.
b. HER2-: any HER2 negative test and the absence of a positive test (IHC positive 
3+, FISH positive/amplified, Positive NOS) before or up to 60 days after MBC 
diagnosis.
5. Palbociclib + AI or letrozole alone as initial endocrine based therapy (ie, first line 
therapy) for MBC during the period from February/2015 through August/31/2018 (or 
3 months prior to study cut-off date) to allow for a possible minimum follow-up time 
of 90 days until the study cut-off date. AI was administered within (±) 28 days of 
Palbociclib index date.
9.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study:
1. Evidence of prior treatment with other CDK4/6I (Ribociclib or Abemaciclib), AI 
(Letrozole, Exemestane, and Anastrazole), Tamoxifen, Raloxifene, Toremifene, or 
Fulvestrant for MBC.
2. First structured activity greater than 90 days after MBC diagnostic date.
3. Treatment with a CDK4/6 inhibitor as part of a clinical trial.

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9.2.3. Study Cohorts
Eligible MBC patients will be assigned into the following cohorts:
Cohort 1: Patients who were treated with Palbociclib + AI as the initial endocrine based 
therapy to be analyzed for the primary and secondary objectives.
Cohort 2: Patients who were treated with Palbociclib + Letrozole to be analyzed for the 
primary and secondary objectives 
 
.
 
 
 
9.3. Variables
All variables are assessed or defined by Flatiron using business rules before and after 
Palbociclib + AI initiation.
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Table 1.
List of Variables
Variable
Operational definition
Demographic characteristics
Age
Age at MBC diagnosis, years
Age category
<50, 50-64, 65 –74, ≥75 years
Gender
Female
Race
White, Black, Asian, other, unknown
Region of residence
Based on state where the patient resides: Northeast, Midwest, 
South, West
Practice type
Academic, community
Insurance type
Commercial, Medicare, Medicaid
Menopause status
Pre-/peri-menopausal, postmenopausal, Unknown based on 
patients age at diagnosis and/or treatment
Duration of follow-up
Months from index date to the end of the study or death, 
whichever came first
Clinical characteristics
Type of MBC
De novo MBC (newly diagnosed): Stage 4 at initial BC
diagnosis
Recurrent MBC: Stages 0-3 at initial BC diagnosis
ECOG performance score
ECOG performance at index date, 0, 1,2,3,4
Stage at initial BC diagnosis
Stage I, II, III, IV, unknown/ undocumented
Time from initial BC diagnosis 
to first MBC diagnosis
Months from the date of initial BC diagnosis to the date of 
metastatic diagnosis
ER status
Positive, negative or unknown
PR status
Positive, negative or unknown
HER2 status
Positive, negative or unknown
BRAC status
BRAC 1 and BRAC 2: positive, negative, unknown/unassessed
Organ-level metastatic sites
Number of sites; Sites of metastases (bone, lung, liver, brain, 
distant lymph nodes, other)
Visceral vs. non-visceral, bone only
De novo metastatic
Yes or 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
Prior neo/adjuvant therapies 
Chemotherapy
Hormonal therapy
Unknown
See Table 2 for detail
Prior chemotherapy at MBC 
setting
Chemotherapy (See Table 2 for detail)
Unknown
Modified Charlson comorbidity
index (CCI)
Include Myocardial infarction, Congestive heart failure,
Peripheral vascular disease, Cerebrovascular disease, Dementia, 
Chronic pulmonary disease, Rheumatologic disease, Peptic ulcer 
disease, liver disease, diabetes, Hemiplegia or paraplegia, renal 
diseases/impairment, and AIDS/HIV

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Longitudinal treatment patterns
Lines of therapy
Lines of therapy in the metastatic setting are assigned by 
Flatiron to evaluate systemic treatment on or after the MBC date
Initial prescribed dose
Palbociclib: 125mg, 100mg, 75mg using  
Dose adjustment
Dose strength other than initial/previous prescription
Type of the first dose change
Dose reduction
    125mg to 100mg, 125mg to 75mg, 100mg to 75mg
Dose increase
   75mg to 100mg, 100mg to 125mg, 75 mg to 125 mg
Time to the first dose change
Days from index date to first dose change
Number of dose adjustment
Number of dose reduction and number of dose increase over the
calendar time (quarter since February 2015) and over treatment 
cycle since index date
Reasons for dose adjustment
As categorized by Flatiron
Reasons for discontinuation
Disease progress, toxicity, financial, patient request, other
Duration of treatment
Days from index prescription order date to end of treatment
Combination endocrine partner
Letrozole, Anastrozole, Exemestane
Concomitant LHRH Agonists
Goserelin (Zoladex), Histrelin (Vantas), Leuprolide (Eligard, 
Lupron), Triptorelin (Trelstar)
Other concomitant anti-cancer 
therapies
Chemotherapy (See Table 2 for detail)
Effectiveness outcomes
Real-world PFS (rwPFS)
Months from index date to death or disease progression (growth 
or worsening in the disease concluded by the treating clinician 
based on radiology, laboratory evidence, pathology, or clinical 
assessment) whichever came first. If patients did not die or have 
disease progression, they were censored at the date of initiation
of next line of therapy for patients with two or more lines of
therapy or their last visit date during the study period for 
patients with only one line of therapy
Overall survival (OS)
Months from index date to the date of death.  Patients who did
not die period are censored at the time of data cut-off
Real-world tumor responses
(rwTR)
Real-world tumor responses are assessed based on treating 
clinician’s assessment of radiological evidence for change in 
burden of disease over the course of treatment:

Complete response: complete resolution of all visible 
disease. 

Partial response: partial reduction in size of visible disease 
in some or all areas without any areas of increase in visible 
disease. 

Stable disease: no change in overall size of visible disease; 
also included cases where some lesions increased in size and
some lesions decreased in size.

Progressive disease: an increase in visible disease and/or 
presence of any new lesions; included cases where the 
clinician indicated progressive disease.
Response rate  
Complete response or partial response divided by the number of 
patients with at least one tumor assessment while on the index
treatment  

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Real-world duration of 
treatment (rwDOT)
Months from index treatment initiation to end of the treatment
Time to next line of anti-cancer 
therapy
Months from index treatment initiation to next line of 
anti-cancer therapy or death from any cause, whichever occurred 
first
Time to chemotherapy
Months from index treatment initiation to first use of 
chemotherapy or death from any cause, whichever occurred first
Table 2.
List of Medications for the Treatment of HR+/HER2- Metastatic Breast 
Cancer
Drug Name
Brand Name
Type of therapy
Code
Anastrozole
Arimidex
Endocrine
S0170
Exemestane 
Aromasin
Endocrine
S0156
Fulvesterant
Faslodex
Endocrine
J9395
Letrozole
Femara
Endocrine
N/A
Megestrol acetate
Megace
Endocrine
S0179
Raloxifene
Evista
Endocrine
N/A
Tamoxifen
Nolvadex
Endocrine
G8376, G8380, G8381, S0187
Toremifene 
Fareston
Endocrine
N/A
Everolimus
Afinitor
Target therapy
J7527, J8561
Palbociclib
Ibrance
Target therapy
N/A
Ribociclib
Kisqali
Target therapy
N/A
Abemaciclib
Verzenio
Target therapy
N/A
Capecitabine
Xeloda
Chemotherapy
J8520, J8521
Cyclophosphamide
Cytoxan
Chemotherapy

C9420 -
cyclophosphamide (2)
(HCPCS Procedure 
Drug).

C9421 -
cyclophosphamide (2)
(HCPCS Procedure 
Drug).

J8530 -
Cyclophosphamide oral 25 
mg (2) (HCPCS 
Procedure Drug).

J9070 -
Cyclophosphamide 
100 mg inj (2) (HCPCS 
Procedure Drug).

J9080 -
Cyclophosphamide 

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Drug Name
Brand Name
Type of therapy
Code
200 mg inj (2) (HCPCS 
Procedure Drug).

J9090 -
Cyclophosphamide 
500 mg inj (2) (HCPCS 
Procedure Drug).

J9091 -
Cyclophosphamide 
1.0 grm inj (2) (HCPCS 
Procedure Drug).

J9092 -
Cyclophosphamide 
2.0 grm inj (2) (HCPCS 
Procedure Drug).

J9093 -
Cyclophosphamide 
lyophilized (2) (HCPCS 
Procedure Drug).

J9094 -
Cyclophosphamide 
lyophilized (2) (HCPCS 
Procedure Drug).

J9095 -
Cyclophosphamide 
lyophilized (2) (HCPCS 
Procedure Drug).

J9096 -
Cyclophosphamide 
lyophilized (2) (HCPCS 
Procedure Drug).

J9097 -
Cyclophosphamide 
lyophilized (2) (HCPCS 
Procedure Drug).
Nab-paclitaxel
Abraxane
Chemotherapy
No code specific to Abraxane
Paclitaxel
Taxol
Chemotherapy

C9127 - paclitaxel (2)
(HCPCS Procedure 
Drug).

C9431 - paclitaxel (2)
(HCPCS Procedure 
Drug).

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Drug Name
Brand Name
Type of therapy
Code

I - PACLITAXEL NO 
STRENGTH (Uncoded 
Product Identifier).

J9264 - Paclitaxel protein 
bound (2) (HCPCS 
Procedure Drug).

J9265 - Paclitaxel 
injection (2) (HCPCS 
Procedure Drug).

J9267 - Paclitaxel 
injection (2) (HCPCS 
Procedure Drug).
Doxorubicin
Taxotere
Chemotherapy

C9415 - doxorubicin (2)
(HCPCS Procedure 
Drug).

J9000 - Doxorubicin hcl 
injection (2) (HCPCS 
Procedure Drug).

J9001 - Doxorubicin hcl 
liposome inj (2) (HCPCS 
Procedure Drug).

Q2050 - Doxorubicin inj 
10mg (2) (HCPCS 
Procedure Drug).
Carboplatin
Paraplatin
Chemotherapy

C9418 - cisplatin (2)
(HCPCS Procedure 
Drug).

J9060 - Cisplatin 10 mg 
injection (2) (HCPCS 
Procedure Drug).

J9062 - Cisplatin 50 mg 
injection (2) (HCPCS 
Procedure Drug).
Eribulin
Halaven
Chemotherapy

C9280 - Injection, eribulin 
mesylate (2) (HCPCS 
Procedure Drug).

J9179 - Eribulin mesylate 
injection (2) (HCPCS 
Procedure Drug).
Gemcitabine
Gemzar
Chemotherapy
J9201
Ixabepilone
Ixempra
Chemotherapy
J9207

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Drug Name
Brand Name
Type of therapy
Code
5-fluorouracil
Adrucil
Chemotherapy
J9190
Epirubicin
Pharmorubicin
Chemotherapy
J9178
Vinorelabine
Navlabine
Chemotherapy
J9390
Methotrexate
Chemotherapy
J8610, J9250, J9260, 
Mitomycin
Chemotherapy
J9280
Mitoxantrone
Novantrone
Chemotherapy
J9293
9.4. Data Source
Flatiron Health Database (https://flatiron.com/real-world-evidence/).
This retrospective observational study utilized Flatiron Health’s longitudinal, 
demographically and geographically diverse database derived from electronic health record 
(EHR) data from over 265 cancer clinics (~800 sites of care) including more than 2 million 
active US cancer patients available for analysis. Across the clinics in the Flatiron Health 
Network, data become available in near real time after each clinical encounter and contribute 
to Flatiron’s continuously aggregating centralized data set.  The patient-level data in the 
EHRs includes structured data (ie, data points that are organized in a predefined manner, 
such as dropdown fields that reside in an EHR to capture a patient’s gender or date of birth or 
laboratory data), unstructured data collected via expert human chart abstraction of 
physician’s notes and other free text fields couple with quality controlled natural language 
processing and business rules technology, and other unstructured documents (ie, information 
from a portable document format [PDF] laboratory reports or narratives from synoptic 
reports). Flatiron integrates the structured EHR data with quality controlled curated data 
from unstructured EHR data into a single data model, where all data are certified 
HIPAA-compliant with all de-identified patients being assigned a longitudinally stable 
identifier. Details of de-identification procedure and data management are outline in the 
Flatiron’s parent database protocol (NEIRB#15 159, “The Flatiron Health Analytic 
Database”). 
The data used in this analysis already exist within this 
model, stored in an electronic database.  
All data, code to create the MBC dataset, and other technical artifacts are version-controlled 
and managed within a Flatiron repository. These artifacts are stored and backed up on 
Flatiron’s servers for at least 7 years. All data within the dataset can be traced back to the 
original source data or documents within the EHR, and appropriate change management and 
provenance best practices are maintained by Flatiron in the event of a regulatory audit. 
Institutional Review Board approval of the study protocol was obtained prior to study 
conduct, and included a waiver of informed consent. Data provided to third parties were 
de-identified and provisions were in place to prevent re-identification in order to protect 
patients’ confidentiality.
The data cut-off for this study is November 30, 2018 (or latest Flatiron data cut-off date).
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9.5. Study Size
Based on an initial feasibility assessment using Flatiron Health Analytic Database between 
February 2015 – November 2018, there are 1,367 HR+/HER2- MBC patients who received 
Palbociclib + AI (including 1,221 Pablociclib + Letrozole, 70 Palbociclib + Anastrozole, and
76 Palbociclib + Exemestane) and 627 patients who received Letrozole monotherapy in 
the database. All eligible patients will be included for descriptive analyses. 
9.6. Data Management
Flatiron Health Database (https://flatiron.com/real-world-evidence/) collects data through a 
HIPAA-compliant process that results in de-identified patient data as described above. 
De-identified data are prepared by Flatiron and transferred securely to Pfizer in a standard 
flat file format. Once on Pfizer servers, Pfizer staff perform quality assurance on the data, 
checking that the metadata align with the data dictionary from Flatiron Health, that the 
number of records equals that expected from the vendor and that the data types and 
controlled vocabularies are correct in a semi-automated process. The data are then loaded 
into a secure Pfizer server. Pfizer servers are backed up nightly, and have failover and 
off-site redundancy. Access to data is limited only to Pfizer colleagues and is monitored with 
all end user activity is logged. Pfizer maintains copies of all EHR or other real world data in 
accordance with the FDA's July 2018 Industry Guidance on Use of Electronic Health Record 
Data in Clinical Investigations 
(https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM501068.pdf), though Pfizer maintains its data in excess of the guidance – for a 
minimum of 7 years.  
9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic Data Record
As described above, Flatiron Health Database collects data through a HIPAA-compliant 
process that results in de-identified patient data.
9.6.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, Flatiron 
Health has agreed to keep all study-related records, including electronic health records, data 
curated by Flatiron from unstructured fields within those records, rationale for a curated data 
point, query code and the dataset provided under this protocol from their larger MBC 
registry.  The records should be retained by Flatiron according to local regulations or as 
specified in the statement of work, whichever is longer. Flatiron must ensure that the records 
continue to be stored securely for so long as they are retained.
If Flatiron 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 7 years after completion or discontinuation of 
the study, as expressly agreed to within the statement of work by Flatiron and Pfizer. Pfizer 
will retain all analysis datasets, code and other artefacts generated over the course of 

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executing this protocol for at least 15 years or longer if required by applicable local 
regulations.  
Flatiron must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met.
9.7. Data Analysis
The primary and secondary objectives of the study are to describe patient characteristics, 
real-word treatment patterns and effectiveness of Palbociclib + AI as initial endocrine based 
therapy for metastatic breast cancer. 
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 real-world 
progression-free survival, overall survival, and time on treatment, time to next line of 
anti-cancer therapy, and time to first use of chemotherapy. Specifically, landmark time 
points are 3, 6, 12, 18, 24, 30, and 36 months for rwPFS and rwTR, 0.5, 1, 1.5, 2, 2.5, and 
3 years for overall survival, and 3, 6, 12, 18, 24, 30, and 36 months for Time on Treatment 
with Palbociclib + AI and time to next ant-cancer therapy and to first use of chemotherapy. 
Ninety-five percent (95%) confidence intervals on the median rwPFS, overall survival, and 
treatment time will be reported.
The maximum real-world tumor response will be computed for each patient with at least one
on-Palbociclib + AI treatment tumor assessment.  If a patient has a maximum tumor response 
of a CR or PR, then the patient will be considered to be a responder. Response rate will be 
computed using the number of patients with a CR or PR as the numerator and the number of 
patients with at least 1 on-treatment tumor assessment as the denominator.
Subgroup analyses will be conducted according to age, ECOG performance (0, 1, ≥2), de 
novo metastatic, visceral, non-visceral, bone only, 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. 
The following sensitivity analyses will be performed as appropriate: 
1. A subset of patients receiving Palbociclib+AI in the first-line metastatic setting with 
at least three prescriptions for Palbociclib will be included.
2. Patients were followed for at least 6 months.

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Detailed methodology for summary and statistical analyses of data collected in this study for 
the primary and secondary objectives is documented herein, following the requirements of 
the Statistical Analysis Plan (SAP) template; therefore a separate SAP document will not be 
necessary for these analyses.  
 
 
 
 
 
 
9.8. Quality Control
This is a retrospective study, so issues of quality control at study sites, eg, data clarification 
queries, do not apply. Analyses are programmed according the specifications in the 
protocol's SAP and all code and other technical artifacts are documented and stored 
following established programming practices on Pfizer servers and in Pfizer’s Global
Document Management System.  Quality control (QC) will follow the Flatiron’s standard 
procedure for quality control and assurance as described in Flatiron Health Analytic Database 
Parent Protocol.  QC for structured and unstructured data is conducted prior to delivery of 
each dataset.  For each data model, Flatiron generates and continually maintains a set of 
quality standards and versioned business rules. These QC standards cover themes such as 
demographics, biomarkers, treatment, therapy shares, treatment length/dosage, lines of 
therapy, real world recurrence, and real world progression free survival. They have a team of 
900 expert nurse and physician abstractors that co-create and version rules, and also to create 
QC that includes both medical considerations (eg, what are expected based on the literature 
and clinical practice) and data considerations (eg, stability from prior months). Missingness 
of death data is a major confounding factor for many real-world oncology analyses. For 
survival data, Flatiron Health utilizes four resources, including the National Death Index, US 
Social Security Death Index, obituaries and commercial death data published from a vendor 
to identify when patients have died 
(https://onlinelibrary.wiley.com/doi/full/10.1111/1475-6773.12872). In a study of advanced 
non-small cell lung cancer patients, sensitivity increased from 66% from Flatiron's 
HER-based registry alone to over 91% from the composite of the four sources.
QC will be performed for the results of the study, including reviewing and double checking 
for correct data, consistency, spelling, grammar and structure. It is also reviewed to ensure 
that it conforms to Flatiron's data dictionary, has internal consistency (eg, that date of 
diagnosis occurs after date of birth) and meets the study objectives. The final review of the 
findings and content will be conducted in a summary presentation.
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9.9. Limitations of the Research Methods
The proposed study may have the following limitations.
One of the main challenges of EHR data is the potential for missing, inaccurate or incomplete 
data.  For example, EHR contains only that a physician prescribed a drug but not whether it 
was filled/refilled. The quality of information extracted from the EHR depends on the 
quality of information entered the EHR by the clinician.  Feeds of EHR data may be updated 
only every 3-6 months, with some vendors providing more rapid updates. Data quality, 
missingness and other challenges are mitigated with Flatiron's semi-automated enhanced 
curation and quality control, though these challenges are not fully obviated by these expert 
biocurators, rules and processes.
The patient populations in the Flatiron database may not be reflective of the general 
population nationally.  Some skewing in the data is possible if differences exist between 
patients in this study cohort and general patient population. Thus, the results of this study 
will be unprojected (ie, analyses will be based on the sample collected and not projected to 
the national level).  
Due to the nature of the data employed in this study, it is not feasible to make an assessment 
of causality between medical events recorded and the medicinal products at an individual 
case level. As a result of the way this study is designed, no causal inference can be 
ascertained, as this is an observational study using retrospective data. Secondary data does 
not report the causality.
In addition, sample size may limit subgroup analyses and generalizability of the findings.  
9.10. Other Aspects
Not applicable.
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 Flatiron in encrypted electronic form and will be 
password protected to ensure that only authorized study staff has access.  Flatiron 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, 
Flatiron shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.

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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 statement of work with Flatiron and applicable privacy laws.
10.2. Patient Consent
As this study involves de-identified data, which according to applicable legal requirements 
do not contain data subject to privacy laws, obtaining informed consent from patients by 
Pfizer is not required.
10.3. Patient Withdrawal
Not applicable.
10.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
The IRB approval of this observational study with secondary data use from an existing EHR 
database is covered by IRB approval on Flatiron parent protocol.  Data provided by Flatiron 
to third parties were de-identified and provisions were in place to prevent re-identification in 
order to protect patients’ confidentiality. This study is exempt from institutional review 
board approval because it is retrospective, non-interventional, and will use anonymized data 
provide by Flatiron.
10.5. 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 Guidelines for Good 
Pharmacoepidemiology Practices (GPP) issued by the International Society for 
Pharmacoepidemiology (ISPE) research practices 
(https://www.pharmacoepi.org/resources/guidelines_08027.cfm), Good Practices for 
Outcomes Research issued by the International Society for Pharmacoeconomics and 
Outcomes Research (ISPOR) (http://www.ispor.org/workpaper/practices_index.asp) and 
Good practices for real-world data studies of treatment and/or comparative effectiveness: 
Recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in 
health care decision making (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639372/) and 
similar standards.

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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study uses existing health care databases, in which it is generally not possible to link (ie,
identify a potential association between) a particular product and medical event for any 
individual.
In addition, 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 reviewers are obligated to 
report adverse events (AE) 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:

All serious and non-serious AEs with explicit attribution to any Pfizer drug that
appear in the reviewed information must be recorded on the chart abstraction form 
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 NIS AEM Report 
Form.
For these safety events with an explicit attribution to or associated with use of, respectively, a 
Pfizer product, the data captured in the medical record will constitute all clinical information 
known regarding these AEs. No follow-up on related AEs will be conducted.
All research staff members will complete the Pfizer requirements regarding training on the 
following: “Your Reporting Responsibilities: Monitoring the Safety, Performance and 
Quality of Pfizer Products (Multiple Languages)” and any relevant Your Reporting 
Responsibilities supplemental training. This training 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. 

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12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
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 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. 

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13. REFERENCES
1.
Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. 
CA Cancer J Clin. 2016;66(4):271-289.
2.
Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation of the Number 
of Women Living with Metastatic Breast Cancer in the United States. Cancer Epidemiol 
Biomarkers Prev. 2017;26(6):809-815.
3.
Kumler I, Knoop AS, Jessing CA, Ejlertsen B, Nielsen DL. Review of hormone-based 
treatments in postmenopausal patients with advanced breast cancer focusing on 
aromatase inhibitors and Fulvestrant. ESMO Open. 2016;1(4):e000062.
4.
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.
5.
Turner NC, Ro J, Andre F, et al. Palbociclib in Hormone-Receptor-Positive Advanced 
Breast Cancer. N Engl J Med. 2015;373(3):209-219.
6.
Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrantplus 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):425-439.
7.
Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast 
Cancer. N Engl J Med. 2016;375(20):1925-1936.
8.
Degenhardt T, Wuerstlein R, Eggersmann T, Harbeck N. The safety of palbociclib for 
the treatment of advanced breast cancer. Expert Opin Drug Saf. 2018;17(3):325-330.
9.
Rugo HS, Dieras V, Gelmon KA, et al. Impact of palbociclib plus Letrozole on patient-
reported health-related quality of life: results from the PALOMA-2 trial. Ann Oncol. 
2018;29(4):888-894.
10.
Inc. P. IBRANCE® (palbociclib) Capsules Package Insert 2018.
11.
Dieras 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. 2018.
12.
McRoy L MJ, Trocio J. Real-world Clinical Outcomes in Patients Treated With First 
Line Palbociclib in Combination Endocrine Partner at Two Years Post-Approval. Miami 
Breast Cancer Conference (MBCC). 2018.

Palbociclib (IBRANCE)
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13.
Mitra D T-SG, Waller J, Gibson K, Milligan G, Iyer S. . Real world clinical outcomes 
associated with palbociclib combination therapy in the United States: Results from the 
IRIS Study. Miami Breast Cancer Conference (MBCC) 2018.
14.
Pizzuti L, Giordano A, Michelotti A, et al. Palbociclib plus endocrine therapy in HER2 
negative, hormonal receptor-positive, advanced breast cancer: A real-world experience. 
J Cell Physiol. 2018.
15.
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 Fulvestrantfor HR+/HER2-negative advanced/metastatic breast 
cancer in real-world settings in the US: Results from the IRIS study. Breast. 
2018;43:22-27.
16.
Austin PC, Stuart EA. Moving towards best practice when using inverse probability of 
treatment weighting (IPTW) using the propensity score to estimate causal treatment 
effects in observational studies. Stat Med. 2015;34(28):3661-3679.

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14. LIST OF TABLES
Table 1.
List of Variables .......................................................................................16
Table 2.
List of Medications for the Treatment of HR+/HER2- Metastatic
Breast Cancer............................................................................................18
15. LIST OF FIGURES
None.
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.
ANNEX 3. ADDITIONAL INFORMATION
Not applicable.