A Retrospective Non-interventional Study of Breast Cancer Patients Diagnosed With HR+/HER2- Locally Advanced or Metastatic Breast Cancer Treated With Palbociclib in Denmark
Conditions: Breast Cancer
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
Study information 
Title 
A Retrospective Non-interventional Study of Breast Cancer Patients 
Diagnosed With HR+/HER2- Locally Advanced or Metastatic Breast 
Cancer Treated With Palbociclib in Denmark
Protocol number 
A5481176 
Protocol version identifier 
Final Protocol Version 1.0 
Date 
09 December 2021 
Active substance 
L01XE33 - palbociclib 
Medicinal product 
Ibrance (palbociclib) 
Research question and 
objectives 
The objective is to retrospectively describe and assess clinical and 
demographical characteristics, treatment patterns in a real-world (RW) 
setting of patients with HR+/HER2- (hormone receptor positive/human 
epidermal growth factor receptor 2 negative) locally advanced or 
metastatic breast cancer receiving palbociclib in combination treatment. 
Primary objectives:                                                                         
Progression free survival (PFS) and Time on Treatment (ToT) of patients 
receiving palbociclib in combination with aromatase inhibitor (AI)  
Secondary objectives:  
 
Demographic charactersitics of the patients 
 
Disease specific characteristics 
 
PFS and ToT of palbociclib in combination with fulvestrant  
 
Overall survival (OS) of patients receiving palbociclib in 
combination with AI (with censoring by 01 May 2022 and also 
reported after 6, 12 and 24 months of palbociclib treatment 
(landmark)) 
 
OS of patients receiving palbociclib in combination with fulvestrant 
(with censoring by 01 May  2022 and also reported after 6, 12 and 
24 months (landmark)) 
 
First subsequent post-palbociclib treatment upon progression
Author  
 
 MD, MSc, and 
 
 MSc, PhD, 
 
 MD, PhD and 
 
 MD, 
 and 
  
 
 MSc, and 
 
 
 MSc, 
 
 
 
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1. TABLE OF CONTENTS 
 
1. TABLE OF CONTENTS .......................................................................................................2 
2. LIST OF ABBREVIATIONS ................................................................................................4 
3. RESPONSIBLE PARTIES ....................................................................................................5 
4. ABSTRACT ...........................................................................................................................6 
5. AMENDMENTS AND UPDATES .......................................................................................9 
6. MILESTONES .....................................................................................................................10 
7. RATIONALE AND BACKGROUND ................................................................................11 
8. RESEARCH QUESTION AND OBJECTIVES .................................................................14 
8.1. Definitions ...............................................................................................................15 
9. RESEARCH METHODS ....................................................................................................15 
9.1. Study design ............................................................................................................15 
9.2. Setting ......................................................................................................................16 
9.2.1. Inclusion criteria .........................................................................................16 
9.2.2. Exclusion criteria ........................................................................................16 
9.3. Variables ..................................................................................................................16 
9.4. Data sources ............................................................................................................18 
9.5. Study size ................................................................................................................18 
9.5.1. Sub-groups ..................................................................................................18 
9.6. Data management ....................................................................................................18 
9.7. Data analysis ...........................................................................................................18 
9.8. Quality control .........................................................................................................19 
9.9. Strengths and limitations of the research methods ..................................................19 
9.10. Other aspects .........................................................................................................20 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................20 
10.1. Patient information ................................................................................................20 
10.2. Patient consent .......................................................................................................20 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) ................20 
10.4. Ethical conduct of the study ..................................................................................20 

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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................21 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........21 
13. REFERENCES ..................................................................................................................22 
14. LIST OF TABLES .............................................................................................................24 
15. LIST OF FIGURES ...........................................................................................................24 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................24 
ANNEX 2. ADDITIONAL INFORMATION .........................................................................24 
 

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2. LIST OF ABBREVIATIONS 
Abbreviation
Definition
AI
Aromatase inhibitor
a/MBC
Advanced metastatic breast cancer
CDK
Cyclin-dependent kinase
CDK4
Cyclin Dependent Kinase 4
CDK6
Cyclin Dependent Kinase 6
CI
Confidence interval
CPR 
Centrale Personregister – CPR is the registry that holds the personal ID 
numbers that every Danish citizen has
DBCG
Danish Breast Cancer Group
DC50
ICD-10 code for patients with breast cancer
E2F 
A group of genes that encodes a family of transcription factors in higher 
eukaryotes
EC
European Commission
EMA
European Medicines Agency
ER+
Estrogen Receptor-positive
FDA
Food and Drug Administration
FSFV
First subject first visit
G1 phase
Growth 1 phase
GDPR
General Data Protection Regulation
HR
Hormone receptor; hazard ratio
HR+
Hormone receptor positive
HER2
Human epidermal growth factor receptor 2
HER2-
HER2 negative
ICD-10 
International Statistical Classification of Diseases and Related Health 
Problems, 10th Revision
ICMJE
International Committee of Medical Journal Editors
IEC
Institutional Ethics Committee
IRB
Institutional Review Board
LSLV
Last subject last visit
MBC
Metastatic breast cancer
NIS
Non-Interventional Study
OS 
Overall survival
PFS
Progression free survival
Rb
Retinoblastoma protein
RCT
randomized controlled trials
RW
Real-World
RWE
Real-World Evidence
S phase
Synthesis phase
SAP
Statistical Analysis Plan
ToT
Time on Treatment
USA
United States of America
 

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3. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
Name, degree(s) 
Job Title 
Affiliation 
Address 
 
MD, MSc
 
 
 
 
 
 
, 
MSc, PhD
 
 
 
 
 
 
 
, MD, PhD 
 
 
 
 
 
 
 
 
 MD 
 
 
 
 
 
 
 
 
, MSc 
 
 
 
  
 
 
 MSc 
 
 
  
 
 
 
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4. ABSTRACT 
Title 
A Retrospective Non-interventional Study of Breast Cancer Patients Diagnosed With 
HR+/HER2- Locally Advanced or Metastatic Breast Cancer Treated With Palbociclib in 
Denmark. 
Authors  
 MD, and 
 MD, PhD, 
 
 
 
 
 MD, MSc, and 
, PhD, 
 
, 
 MSc, and 
 
 
 MSc, 
  
Rationale and background 
There is a need for additional and updated real-world evidence (RWE) about the cyclin-
dependent kinase 4/6(CDK4/CDK6) inhibitors in a real-world setting. In Denmark, access to 
the DBCG clinical registry is unique and feasible. Thus collecting clinical and pathological 
data from patients from all regions of Denmark will add on to the existing clinical evidence. 
The project aims at collecting restrospective clinical effectiveness data and treatment pattern 
data on palbociclib. 
Research question and objectives 
The objective is to retrospectively describe and assess clinical and demographical 
characteristics, treatment patterns in a real-world (RW) setting of patients with HR+/HER2- 
locally advanced or metastatic breast cancer receiving palbociclib in combination treatment. 
Primary objectives: 
 PFS of patients receiving palbociclib in combination with AI 
 ToT of patients receiving palbociclib in combination with AI  
 
Secondary objectives:  
 Demographic charactersitics of the patients who have received palbociclib 
o Split into different age groups (below 50, 50 -70, and above 70 years of age) 
 Disease specific characteristics of the patients who have received palbociclib 
o Type, number and location of metastases (visceral vs non-visceral) 
o Surgery 
o Type and number of adjuvant treatment 
o De novo (primary metastatic breast cancer [MBC]) 
o Recurrent MBC 
o Median time from initial breast cancer diagnosis (incidence date) to relapse 
 PFS of patients receiving palbociclib in combination with fulvestrant 
 ToT with palbociclib in combination with fulvestrant 
 OS in patients receiving palbociclib in combination with AI (with censoring by 01 May  
2022 and also reported after 6, 12 and 24 months of palbociclib treatment (landmark)) 
PPD
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PPD
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 OS in patients receiving palbociclib in combination with fulvestrant (with censoring by 
01 May 2022 and also reported after 6, 12 and 24 months of palbociclib treatment 
(landmark)) 
 First subsequent post-palbociclib treatment upon progression 
 
Study design 
The study is designed as a secondary data collection Non-Interventional Study (NIS) based 
on retrospective data from an existing registry. The study is a single-arm study only focusing 
on patients treated with palbociclib in Denmark. 
 
Population   
Patients with HR+/HER2- locally advanced or metastatic breast cancer treated with 
palbociclib (1st or 2nd line) (01 January 2017- 31 December 2020).  
Inclusion criteria 
Patients must meet the following inclusion criteria to be eligible for inclusion in the study : 
 
1. Patients with breast cancer (International Statistical Classification of Diseases and 
Related Health Problems, 10th Revision [ICD-10]: ICD-10 code for patients with breast 
cancer [DC50]) 
2. A diagnosis of HR+/HER2- locally advanced or metastatic breast cancer 
3. Initiated treatment with palbociclib as either 1st or 2nd line treatment between 01 January  
2017 and 31 December  2020 
4. Inclusion date: Date of relapse/stage IV disease/progression leading to initiation of 
palbociclib+AI/progression leading to initiation of palbociclib+fulvestrant 
 
Variables and outcomes (a detailed overview of the variables is listed in section 9.3)  
 Diagnosis (ICD-10 code: DC50) (exposure/inclusion) 
 Treatment with palbociclib (exposure/inclusion) 
 Date of birth 
 Date of breast cancer diagnosis 
 Occurrence of metastases 
 Type of metastases (visceral vs. non-viseral) 
 Number of metastases sites 
 Location of metastases 
 Surgery 
 De Novo (primary MBC) 
 Breast cancer disease duration – median time from initial breast cancer diagnosis 
(incidence date) to relapse 
 Date of relapse 
 Date for treatment initiation with palbociclib 
 Date for treatment stop with palbociclib 
 ToT (palbociclib) (outcome) 

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 Reasons to discontinuation with palbociclib  
 PFS (outcome) 
 Date of death 
 OS (outcome) 
 Post-palbociclib treatment (first subsequent treatment post-palbociclib) 
 
Data sources 
This study will be based on the DBCG registry. No other Danish healthcare registries will be 
included. 
Study size 
It is estimated that the total population of palbociclib-treated breast cancer patients with 
HR+/HER2- locally advanced or metastatic breast cancer included in the DBCG registry 
constitutes of 1,500 patients in Denmark. 
Data analysis 
Descriptive statistics, including stratification on sub-groups. In the PFS and OS analyses, 
Kaplan-Meier survival distribution functions will be estimated. Besides an OS analysis with 
censoring at 01 May 2022, supplementary OS analyses will be made after 6, 12 and 24 
months of palbociclib treatment (landmark cut-off time points). A separate Statistical 
Analysis Plan (SAP), including shell tables, will be developed prior to data analysis. 
Milestones 
Final Protocol: 17 December 2021 
Final Statistical Analysis Plan: 31 January 2022 
Start of data collection (first subject first visit [FSFV] – database study, historic data): 01 
February 2022 
Data setup: 01 February 2022 
Data analyses: 01 February-01 August 2022 
End of data collection (last subject last visit [LSLV] – database study, historic data): 01 
August 2022 
DBCG Final study report: 30 September 2022 
Manuscript ready for submission: 15 December 2022 
 
 

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5. AMENDMENTS AND UPDATES 
None. 

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6. MILESTONES 
 
Milestone 
Planned date 
Final Protocol 
17 December 2021 
Final Statistical Analysis Plan 
31 January 2022 
Start of data collection (FSFV – database study, 
historic data) 
01 February 2022 
Data setup 
01 February 2022 
Data analyses  
01 February – 01 August 2022  
End of data collection (LSLV – database study, 
historic data) 
01 August 2022 
DBCG Final study report   
30 September 2022 
Manuscript ready for submission   
15 December 2022 
 
 
 

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7. RATIONALE AND BACKGROUND  
The discovery and development of CDK4/CDK6 inhibitors have revolutionized the paradigm 
of therapeutic management of HR+ MBC worldwide. The most common cancer globally is 
breast cancer (1). In Denmark, breast cancer is the most frequent cancer in women, with 
approximately 4,700 new cases per year; and the 5 year OS is estimated to be 86%. To date 
roughly 64,000 women are living with the breast cancer diagnosis. It is estimated that 
roughly 20% of the patients initially diagnosed with breast cancer will at some stage in their 
life experience a relapse of the disease (loco-regional or distant metastasis). The median OS 
of metastatic breast cancer is between 2-3 years however 25% of the patients can attain an 
OS of 5 years. The incidence of loco-regional or metastatic estrogen receptor-positive 
(ER+)/HER2- breast cancer in Denmark is therefore estimated to be roughly 650 patients 
yearly (2). 
 
Cyclin-dependent kinases (CDKs) ( are essential regulatory players in the controlled cell 
cycle trajectory, a process needed for the division of cells in the body. This cell cycle is a 
series of events which are tightly controlled and regulated. This cell cycle machinery 
however can be deregulated if the CDKs responsible for driving the cell cycle become 
hyperactive resulting in an uncontrolled proliferation of cells. This hyperactivity of CDKs 
resulting in uncontrolled cell proliferation is a well-recognized hallmark of malignancy (3). 
Targeting and inhibition of the cell cycle machinery ie, the CDK’s has therefore been of great 
interest in the past decade and led finally to the therapeutic development of the 
pharmacologic inhibitors known as CDK4/CDK6 inhibitors. These inhibitors hinder the 
transition from growth 1 (G1) phase to synthesis (S) phase by inhibiting the phosphorylation 
of retinoblastoma protein (Rb) and a group of genes that encodes a family of transcription 
factors in higher eukaryotes (E2F) release. This results therefore in the arrest at G1 phase 
resulting in inhibition of tumor cell growth (4-7). 
 
The first cell cycle inhibitor was palbociclib which was approved by Food and Drug 
Administration (FDA) on the basis of the Phase 2 study PALOMA-1 (8). This study showed 
doubling of the PFS from 10.2 to 20.2 months when a combination of palbociclib and 
letrozole was given to the HR+/HER2- advanced breast cancer patients. These significant 
results were later confirmed in a Phase 3 study PALOMA-2 as well (9). This approval was 
followed by the other two CDK4/CDK6 inhibitors, ribociclib and abemaciclib. In Denmark 
these targeted therapeutic agents were incorporated in the clinical practice since 2016 (10).  
 
The introduction of CDK4/CDK6 inhibitors has permanently transformed the therapeutic 
management of HR+ MBC worldwide. The three CDK4/CDK6 inhibitors palbociclib, 
ribociclib, and abemaciclib are approved with a combination of AI or with fulvestrant. 
Abemaciclib also has the indication of monotherapy therapy of pre-treated patients. 
To date, several Phase 2 and 3 randomized controlled trials (RCTs) have evaluated 
CDK4/CDK6 inhibitors in the treatment of HR+/HER2- advanced metastatic breast cancer 
(a/MBC). Palbociclib was evaluated in three registrational trials with different patient 
populations: PALOMA-1 (11), PALOMA-2 (3) and PALOMA-3 (12,13). For palbociclib, 

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the Phase 3 trial PALOMA-2 demonstrated a median PFS of 24.8 vs. 14.5 months, 
respectively, for patients treated with palbociclib or placebo in addition to letrozole (hazard 
ratio [HR] 0.58; p < 0.001). After a median follow-up of approximately 38 months, median 
PFS was 27.6 months for palbociclib-letrozole and 14.5 months for letrozole (HR 0.563; P < 
0.0001) (14).   
PALOMA-3 (fulvestrant with/without palbociclib) included both pre-menopausal (goserelin 
added for premenopausal women) and post-menopausal women with HR+/HER2- MBC who 
had relapsed or progressed during prior endocrine treatment, and there was no limit on no of 
prior endocrine therapies (2nd line and plus setting). Overall, the addition of palbociclib 
resulted in an improvement in PFS from 4.6 months to 9.5 months (HR 0.46; p < 0.001) 
(12,13). 
Ribociclib was evaluated in the three trials, Phase 3 MONALEESA-2 (15) , MONALEESA-
3 (16) and MONALEESA-7 (17). Abemaciclib was evaluated in MONARCH 1 (18), 
MONARCH 2 (19) and MONARCH 3 (20).  
Randomization and blinding are considered to be the gold standard for determining the effect 
of a treatment in randomized controlled clinical trials. However due to strict protocol-
specified definition of inclusion criteria, populations in the randomized trials does not always 
represent patients treated in clinical practice. For example patients with wider ranges of 
disease severity and age, taking a broader range of concomitant medications, and with more 
and varying comorbidities are not always fully represented in clinical trials (21). Less than 
5% of adult patients with cancer participate in clinical trials (22) hence there is a need to 
expand our knowledge by collecting more RWE data from the clinical practice. 
Therefore, real-world data are increasingly being used to understand the safety and 
effectiveness of new drug regimens in actual clinical practice where patients populations are 
heterogenous (21,23). Although the definition of RWE is evolving, most associate RWE with 
data derived from medical practice among heterogeneous sets of patients in real-life settings, 
such as insurance claims data and clinical data from electronic health records (24). RW data 
can also be defined as data relating to patient health status or the delivery of health care 
routinely collected from a variety of sources, such as the electronic health records and 
administrative data (21) 
The first comprehensive systematic literature review of RWE studies on CDK4/CDK6 
inhibitors in the treatment of HR+/HER2- a/MBC was carried out by Harbeck et al. (25). 
Their work identified 114 studies between 2015–2019, 85 of which were only presented at 
conferences. The results on efficacy and safety of CDK4/CDK6 inhibitors complemented the 
results seen in randomized clinical trials. However most of the published studies were 
conducted in United States of America (USA). Hence there is a need to look at RWE data for 
CDK4/CDK6 inhibitors in the treatment of HR+/HER2- a/MBC from a local perspective 
(25). 

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A comprehensive retrospective observational analysis of electronic health records within the 
Flatiron Health Analytic Database was carried out with palbociclib (26). A total of 1430 
patients with ≥ 3 months of follow-up received palbociclib plus letrozole or letrozole alone in 
the first-line setting between 03 February 2015, and 28 February 2019. Real-world PFS and 
OS were analyzed. The results showed that plus letrozole was associated with longer PFS 
than letrozole alone in a heterogeneous population and among various patient subgroups. In 
the adjusted analysis to balance patient characteristics between arms, palbociclib 
combination treatment was associated with significantly longer median PFS compared to 
letrozole alone (20.0 vs 11.9 months; HR, 0.58; 95% confidence interval [CI], 0.49–0.69; P < 
0.0001).These results complement the results from the randomized Phase 3 study PALOMA-
2 where the hazard ratio was = 0.58 (95% CI: 0.46–0.72; two-sided P < 0.001) (26).  
Compared to existing RWE studies the present study will with access to the national DBCG 
clinical registry allow us to analyse patient data for a total country population with no 
selection bias as all patients are included. Thus collecting clinical and pathological RW data 
from patients from all regions of Denmark via the DBCG registry will add on to the existing 
pool of RWE.  
 
 

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8. RESEARCH QUESTION AND OBJECTIVES 
In general, the overall objective is using data from the Danish DBCG registry to 
retrospectively describe and assess clinical and demographical characteristics, treatment 
patterns in a RW setting of patients with HR+/HER2- locally advanced or metastatic breast 
cancer receiving palbociclib in combination treatment. The project will look at both 1st and 
2nd line patients. 
The results of the study will provide valuable insights to supplement the results from the 
randomized clinical trials as well as the existing RWE published. 
Primary objectives: 
 PFS of patients receiving palbociclib in combination with AI 
 ToT of patients receiving palbociclib in combination with AI  
 
Secondary objectives:  
 Demographic characteristics of the patients who have received palbociclib 
o Split into different age groups (below 50 years, 50-70, and above 70 years of age) 
 Disease specific characteristics of the patients who have received palbociclib 
o Type, number and location of metastases (visceral vs. non-visceral) 
o Surgery 
o Type and number of adjuvant treatment 
o De novo (primary MBC) 
o Recurrent MBC 
o Median time from initial breast cancer diagnosis (incidence date) to relapse 
 PFS of patients receiving palbociclib with palbociclib in combination with fulvestrant 
 ToT with palbociclib in combination with fulvestrant  
 OS in patients receiving palbociclib in combination with AI (with censoring by 01 May 
2022 and also reported after 6, 12 and 24 months of palbociclib treatment (landmark) 
 OS in patients receiving palbociclib in combination with fulvestrant (with censoring by 
01 May 2022 and also reported after 6, 12 and 24 months of palbociclib treatment 
(landmark) 
 First subsequent post-palbociclib treatment upon progression 
 
Following the inclusion criteria (see section 9.2.1 below) the analyses will be performed on 
the overall population of palbociclib-treated patients with HR+/HER2- locally advanced or 
metastatic breast cancer.  
In addition, some of the research questions above will be addressed on specific sub-groups in 
terms of age (grouped into below 50, 50-70, and above 70 years of age) as well as patients 
with visceral disease (defined as metastases in the organs, eg, lung, liver). See section 9.5.1 
for further details. 
As stated, the research questions will be addressed and analysed using the DBCG registry 
(see section 9.1 for a description of the registry).  

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8.1. Definitions 
PFS is defined as the date of relapse or stage IV disease (index date) to progression or death, 
whichever occurs first.  
 Patients will be censored for PFS by 31 December 2020  
 Progression of disease is based on scans and blood testing results 
 
ToT is defined as date of palbociclib treatment start to date of treatment stop with 
palbociclib.  
 
OS is defined as the date of relapse or stage IV disease (index date) until death of any cause  
 Patients will be censored for OS by 01 May 2022  
 Overall survival will also be reported after 6, 12 and 24 months (landmark cut-off time 
points) 
 
9. RESEARCH METHODS  
9.1. Study design  
The study is designed as a secondary data collection NIS based on retrospective data from an 
existing registry focusing on HR+/HER2- locally advanced or metastatic breast cancer 
treated with palbociclib. The study is a single-arm study only focusing on patients treated 
with palbociclib in Denmark. 
The study is purely descriptive and explorative. No formal hypotheses will be tested in the 
study. 
Since the establishment in 1976, the DBCG has maintained a clinical registry for early breast 
cancer patients in Denmark in which surgeons, pathologists, medical geneticists and 
oncologists report data regarding diagnosis, treatment and follow-up of breast cancer. This is 
a unique clinical registry. This well-established breast cancer registry (1976) managed by 
DBCG was expanded in 2017 to include retrospective and prospective clinical and 
pathological data on breast cancer patients with a relapse. This includes both the primary 
MBC (De Novo) and recurrent MBC. 
The DBCG registry focusing on relapses which the study will be based is one of several 
DBCG registries. It is estimated that end of 2021 the DBCG registry will include all Danish 
patients with locally advanced or metastatic breast cancer. The data and records in the 
registry are based on systematic review following a standard case report form of all 
electronic patient records of patients diagnosed with locally advanced or metastatic breast 
cancer. 
The data collection and the ongoing populating of the DBCG registry are performed by 
healthcare professionals in the DBCG secretariat and are conducted independently of this 
study. Compared to other exhaustive national Danish patient registries, the DBCG registry 
contains detailed clinical and pathological data about the treatment patterns of patients with 

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HR+/HER2- locally advanced or metastatic breast cancer. Thus, the registry is an important 
and well-suited source to address the research questions (See section 8). 
The present NI-Study will only use and rely on the existing data in the DBCG registry and no 
additional data will be collected as part of the study, as well as no review of medical records 
will be made. Therefore, the present NI-Study is defined as a retrospective secondary data 
collection study, where all data needed for the analysis exist as structured data by the time of 
study start. This also means that there are no human review of unstructured data conducted as 
part of the protocol.    
9.2. Setting 
In the DBCG registry, patients with HR+/HER2- locally advanced or metastatic breast cancer 
treated with palbociclib will be identified. Palbociclib was approved by the European 
Commission (EC) and European Medicines Agency (EMA) in November 2016. Hence, the 
study period will be 2017-2020. A follow-up on patients until 01 May 2022 in terms of the 
estimation of OS will be made. 
The CDK4/CDK6 inhibitors ribociclib and abemaciclib were approved later (2018 and 2020, 
respectively) and data regarding these treatments are currently not included in the registry. 
The study will only include patients treated with palbociclib. 
9.2.1. Inclusion criteria 
Patients must meet the following inclusion criteria to be eligible for inclusion in the study : 
 
1. Patients with breast cancer (ICD-10: DC50) 
2. A diagnosis of HR+/HER2- locally advanced or metastatic breast cancer 
3. Initiated treatment with palbociclib as either 1st or 2nd line treatment between 01 January 
2017 and 31 December 2020 
4. Inclusion date: Date of relapse/stage IV disease/progression leading to initiation of 
palbociclib+AI/progression leading to initiation of palbociclib+fulvestrant 
9.2.2. Exclusion criteria 
There are no exclusion criteria for this study. 
9.3. Variables 
The main variables included in the study are the following: 
 
 

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Table 1. List of variables 
Variable 
Role 
Data source(s) 
DBCG variable(s) 
Diagnosis (ICD-10 code: DC50) 
Exposure/Inclusion 
DBCG registry  
Not applicable 
Treatment with palbociclib 
Exposure/Inclusion 
DBCG registry  
RE201, RE201A 
Date of birth 
Baseline characteristic 
DBCG registry  
Based on M1 
Date of breast cancer diagnosis 
Baseline characteristic 
DBCG registry  
Not applicable 
Occurrence of metastases 
Baseline characteristic 
DBCG registry  
RE220-RE227 
Type of metastases (visceral vs non-
visceral) 
Baseline characteristic 
DBCG registry  
RE220-RE227 
Number of metastases sites 
Baseline characteristic 
DBCG registry  
RE220-RE227 
Location of metastases 
Baseline characteristic 
DBCG registry  
RE10-18 + 80-81, 
117-119, 219-222 
Surgery 
Baseline characteristic 
DBCG registry  
RE19 
De Novo (primary MBC) 
Baseline characteristic 
DBCG registry  
Calculated 
Breast cancer disease duration – 
median time from initial breast cancer 
diagnosis (incidence date) to relapse 
Baseline characteristic 
Estimated via 
DBCG registry 
registrations
Based on variables 
listed in this table 
Date of relapse 
Baseline characteristic 
DBCG registry  
RE1-RE3 
Date for treatment initiation with 
palbociclib
Baseline characteristic 
DBCG registry  
RE203-RE205 
Date for treatment stop with 
palbociclib
Baseline characteristic 
DBCG registry  
RE206-RE208 
Post-palbociclib treatment (first 
subsequent treatment post-palbociclib) 
Baseline characteristic 
DBCG registry  
RE24, RE24A, RE33, 
RE33A, RE42, 
RE42A, RE69, RE69A 
Reasons to discontinuation with 
palbociclib
Baseline characteristic 
DBCG registry 
RE209, RE209A 
Death date 
Baseline characteristic 
DBCG registry 
Not applicable 
PFS (see section 8.1 for definition) 
Outcome 
Estimated via 
DBCG registry
Based on variables 
listed in this table 
ToT with palbociclib (see section 8.1 
for definition) 
Outcome 
Estimated via 
DBCG registry 
registrations
Based on variables 
listed in this table 
OS (see section 8.1 for definition) 
Outcome 
Estimated via 
DBCG registry 
registrations 
Based on variables 
listed in this table 
(overall and after 6, 12 
and 24 months of 
palbociclib treatment 
(landmark times))

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9.4. Data sources  
This study will be based solely on the DBCG registry. No other Danish healthcare registries 
will be included. The DBCG registry also includes information on death. 
9.5. Study size 
It is estimated that the total population of palbociclib-treated patients with HR+/HER2- 
locally advanced or metastatic breast cancer included in the DBCG registry constitutes of 
1,500 patients since the introduction of palbociclib in Denmark (from 01 January 2017 to 31 
December 2020). 
9.5.1. Sub-groups 
In addition, the primary objective (PFS, ToT) as well as some of the secondary objectives 
(OS and first subsequent post-palbociclib treatment) will be addressed for the following sub-
groups such as those below provided sample size is sufficient: 
 Specific age groups (below 50 years, 50 -70, and above 70 years of age) 
 Patients with visceral disease (defined as metastases in the organs, eg, lung, liver) 
9.6. Data management  
The Danish Breast Cancer Group hosts the DBCG registry and all analyses will be performed 
by DBCG’s biostatistical researchers following this protocol and a pre-specified SAP. Pfizer 
will not have access to data at the individual level – only summary data in tables produced by 
DBCG as part of the discussion of results and reporting.  
The individual-level patient data in the registry are well-structured, of high quality, and in a 
ready-to-analyse format. Data will be analysed using SAS software. 
9.7. Data analysis  
In general, some research questions will be addressed via descriptive statistics, including 
stratification on sub-groups. In the PFS and OS analyses, Kaplan-Meier survival distribution 
functions will be estimated, implying that statistics on median survival expectedly will be 
available. Overall survival will be estimated for all patients with a censoring of data by 01 
May 2022, ie, why the maximum follow-up period for the first treated palbociclib patient 01 
January 2017 will be close to 5.5 years. In Kaplan-Meier landmark analyses OS will 
furthermore be analysed and reported after 6, 12 and 24 months from treatment initiation. 
A separate SAP, including shell tables, will be developed prior to data analysis. The SAP will 
be dated, filed, and maintained by the sponsor. The SAP will also include precise definitions 
of the sub-groups. 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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9.8. Quality control 
DBCG’s biostatistical researchers will compile the full data set and perform the analyses. 
The researchers will follow generally accepted methods as well as DBCG’s internal 
guidelines for data analysis. 
The study involves analyses of individual data. DBCG’s biostatistical researchers will, 
however, only have access to data in de-personalized form (by encrypted personal 
identification codes). Pfizer will not have access to any individual data in the project, only 
the summary data produced by DBCG’s biostatistical researchers. 
Furthermore, the study design, literature, decisions on data analysis, interpretation of the 
results of the study, as well as reporting (manuscript) will be only discussed in the project 
group (see list of responsible parties in section 3).  
The study though will as a Non-Interventional Study with Pfizer as sponsor, collaborator and 
part of the project group have to use certain templates, incl. the present protocol template and 
a template for the SAP, etc. Furthermore, the study has to follow certain review stages by the 
sponsor such as a technical protocol review and a review of the final scientific manuscript 
prior to submission to a scientific journal. 
9.9. Strengths and limitations of the research methods 
Naturally, this study has both strengths and limitations. 
DBCG has provided  a long history of compiling and maintaining registry data since the past 
40 years. The data from DBCG has been part of both national and international studies. In 
addition the data collected by DBCG have been published in more than 430 peer-reviewed 
papers (27). 
And has been part of several meta-analyses conducted by Early Breast Cancer Triallists’ 
Collaborative Group (28-29). The extension of this registry to include relapsed patients 
nationwide is therefore a very unique feature of this registry. To collect relapse data about 
MBC patients has been a challenge in many countries.  
The DBCG registry holds the most detailed and comprehensive information about patients 
diagnosed with HR+/HER2- locally advanced or metastatic breast cancer, implying that, 
compared to other Danish healthcare registries, new and more detailed results can be 
presented. Furthermore, the study is a study carried out at the population level, which makes 
the study and its results as complete and generalizable as possible and minimizes the risk of 
selection bias. 

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At the same time, since this study only involves data from the DBCG registry, the 
completion and validity of the analyses rely 100% on the quality and validity of the data in 
the registry.  
The study does furthermore only include the data available in the DBCG registry and only 
data of a quantitative nature. More qualitative data and outcomes following the treatment of 
the breast cancer patients will though not be included. 
9.10. Other aspects 
Not applicable. 
10. PROTECTION OF HUMAN SUBJECTS 
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, or publications, or in any other disclosures except where 
required by law. As described, DBCG’s biostatistical researchers will have access only to 
data in de-personalized form (encrypted personal identification codes (CPR)). Pfizer will not 
have access to any individual data in connection with the project but only the summary data 
produced by DBCG’s biostatistical researchers. 
10.1. Patient information  
This study involves data that exist in anonymized structured format and contain no patient 
personal information. 
10.2. Patient consent 
As this study involves anonymized structured 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. Institutional review board (IRB)/Independent ethics committee (IEC) 
Approval from the Danish Data Protection Agency is not necessary for this type of study. 
However, in accordance with General Data Protection Regulation (GDPR) the study will be 
reported via Pactius to the Capital Region of Denmark’s research list.  
Approval from an ethics committee is not required by Danish law since a retrospective 
database study does not involve collection of or research on biological material. 
No other approvals from IRBs or IECs are necessary under Danish law. 
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 will follow generally accepted research 
practices described Good practices for real-world data studies of treatment and/or 

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comparative effectiveness: Recommendations from the joint ISPOR-ISPE Special Task 
Force on real-world evidence in health care decision making (30). 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
This study involves data that exist as structured data by the time of study start or a 
combination of existing structured data and unstructured data, which will be converted to 
structured form during the implementation of the protocol solely by a computer using 
automated/algorithmic methods, such as natural language processing. 
In these data sources, individual patient data are not retrieved or validated, and it is not 
possible to link (ie, identify a potential association between) a particular product and medical 
event for any individual. Thus, the minimum criteria for reporting an adverse event (AE) (ie, 
identifiable patient, identifiable reporter, a suspect product, and event) cannot be met. 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
Besides a study report presenting the results, a manuscript for a scientific article will be 
written and submitted to an international peer-reviewed journal. Authorship of the article 
manuscripts will follow the requirements set by the International Committee of Medical 
Journal Editors (ICMJE) (http://www.icmje.org/recommendations/browse/roles-and-
responsibilities/defining-the-role-of-authors-and-contributors.html). All members of the 
project group as described in section 3 of this protocol, including external members and 
Pfizer employees, fulfilling these requirements with respect to the article manuscripts are 
offered co-authorship of the scientific article.  
The study and its results will also be disclosed at the ClinicalTrials.gov website. 
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 party responsible for collecting 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 
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fremskreden-eller-metastatisk-erplus-her2-brystkraeft-vers-1-1_adlegacy.pdf 
3. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J 
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9. 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. The Lancet Oncology 2015;16:25-35. 
10. Danish Medicines Council. The Danish Medicines Council drug recommendation and treatment 
guidelines for cdk4/cdk6 inhibitors for ER + / HER2- locally advanced or metastatic breast 
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11. 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 II 
study. Lancet Oncol 2015;16(1):25-35.  
12. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant 
plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer 
that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, 
double-blind, Phase III randomised controlled trial. Lancet Oncol 2016;17(4):425-39.  
13. Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced 
breast cancer. N Engl J Med 2018;379(20):1926-36. 
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receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with 
extended follow-up. Breast Cancer Res Treat 2019;174(3):719-29.   
15. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, 
advanced breast cancer. N Engl J Med 2016;375(18):1738-48.  
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randomised Phase III trial. Lancet Oncol 2018;19(7):904-15. 
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18. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a Phase II study of abemaciclib, a 
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fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while 
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drug safety and effectiveness. JAMA 2018;320(9):867-8. 
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progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 
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doi.org/10.1200/PO.17.00132. [Epub].  
24. Makady A, Ham RT, de Boer A, et al. Policies for use of real-world data in health technology 
assessment (HTA): A comparative study of six HTA agencies. Value Health 2017;20(4):520-32.  
25. Harbeck N, Bartlett M, Spurden D, et al. CDK4/6 inhibitors in HR+/HER2- advanced/metastatic 
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26. DeMichele A, Cristofanilli M, Brufsky A, et al. Comparative effectiveness of first-line 
palbociclib plus letrozole versus letrozole alone for HR+/HER2- metastatic breast cancer in US 
real-world clinical practice. Breast Cancer Res 2021;23(1):37. doi: 10.1186/s13058-021-01409-8. 
27. Danish Breast Cancer Cooperative Group [homepage on the Internet]. Copenhagen: Statutter 
[updated 2013 May 23; cited 2016 Jan 30]. Avail¬able from http://www.dbcg.dk/.  
28. EBCTCG (Early Breast Cancer Triallists` Collaborative Group). Effects of radiotherapy and of 
differences in the extent of surgery for early breast cancer on local recurrence and on 15-year 
survival. An overview of randomized trials. Lancet 2005;366(9503):2087–106. 
29. EBCTCG (Early Breast Cancer Triallists´ Collaborative Group). Effects of chemotherapy and 
hormonal therapy on local recurrences and on 15-year survival. An overview of randomized 
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30. Berger ML, Sox H, Willke RJ, Brixner DL, Eichler HG, Goettsch W, Madigan D, Makady A, 
Schneeweiss S, Tarricone R, Wang SV, Watkins J, Mullins CD. Good practices for real‐world 
data studies of treatment and/or comparative effectiveness: Recommendations from the joint 
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Pharmacoepidemiol Drug Saf 2017;26(9):1033–9.  
 
 
 
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14. LIST OF TABLES  
Table 1. List of variables (see section 9.3). 
15. LIST OF FIGURES 
Not applicable. 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
Not applicable. 
ANNEX 2. ADDITIONAL INFORMATION 
Not applicable.  
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