Impact of Age and Comorbidities on Treatment Outcomes of First-line Treatment With Palbociclib in Combination With an Aromatase Inhibitor (AI) in Patients Diagnosed With HR+/HER2 - Metastatic Breast Cancer - Danish Non-Interventional Study
Conditions: Breast Cancer
Sponsor: Pfizer

Pal b ocicli b  
A 5 4 8 1 1 8 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br u ar y 2 0 2 5   
 
 
P FI Z E R G E N E R A L B U SI N E S S  
Staff m ust al wa ys refer t o a n d f oll o w t he c urre nt official electr o nic d oc u me nt re p osit or y versi o n.  
 T his d oc u me nt was create d base d o n  
Q M S 0 4 -G S O P -S D -G L 0 6 9. 0 C M C D F or ms Te m pl ate W O R D  0 1 -N o v -2 0 2 1  
Pa ge 1  of 2 7  
 
 
N O N -I N T E R V E N TI O N A L ( NI) S T U D Y P R O T O C O L 
St u d y  i nf or m ati o n 
Title  
Im pact of a g e a n d c o m or bi dities o n treat me nt o utc o mes of first -li ne treat me nt wit h 
pal b ocicli b i n c o m bi nati o n wit h a n ar o matase i n hi bit or ( AI) i n patie nts dia g n ose d 
wit h H R +/ H E R 2  - metastatic breast ca ncer –  Da nis h N o n -I nter ve nti o nal St u d y 
Pr ot oc ol n u m ber  
A 5 4 8 1 1 8 8  
Pr ot oc ol versi o n i de ntifier  
Versi o n  3 . 0 
D ate  
1 7  Fe br uar y  2 0 2 5  
Acti ve s u bst a nce  
L 0 1 X E 3 3 –  Pal b ocicli b  
Me dici n al pr o d uct  
I bra n ce ( pal b ocicli b) 
Rese arc h q uesti o n a n d 
o bjecti ves  
T he o bjecti ve is t o i n vesti gate t he o utc o mes ( p r o gressi o n free s ur vi val (P F S ) a n d 
o verall s ur vi val ( O S )) of first-li ne treat me nt wit h pal b ocicli b i n c o m bi nati o n wit h 
a n ar o matase i n hi bit or ( AI) i n h or m o ne rece pt or p ositi ve  ( H R +) or hu ma n 
e pi der mal gr o wt h fact or rece pt or  (H E R 2 ) metastatic breast ca ncer  (m B C ) patie nts 
i n De n mar k. T hese patie nts c o nsist of e n d ocri ne se nsiti ve , e n d ocri ne resista nt  as 
well as  de n o v o  patie nts.  
Pri mar y o bjecti ves:  
- P F S of all m B C patie nts recei vi n g pal b ocicli b  +  AI  as first-li ne treat me nt 
- O S of all m B C patie nts recei vi n g pal b ocicli b  +  AI as first-li ne treat me nt 
Sec o n dar y o bjecti ves:  
A ge s u b gr o u p a nal yses:  
- A ge distri b uti o n i n f ull data set  of m B C patie nts recei vi n g pal b oci cli b  +  AI  as 
first-li ne treat me nt 
- P F S / O S of all  m B C patie nts bel o w 6 5 years of a ge, 6 5 -7 4 years of a ge a n d 7 5 + 
years of a ge , res pecti vel y, recei vi n g pal b ocicli b + AI  as first-li ne treat me nt 
C o m or bi dit y s u b gr o u p a nal yses ( C harls o n C o m or bi dit y I n de x ( C CI)) is use d as a 
data s o urce f or c o m or bi dit y a n d c o m or bi dit y b ur de n):  
- P F S /O S i n t he f ull data set of m B C patie nts recei vi n g pal b ocicli b + AI  as first-
li ne treat me nt s plit i nt o C CI p oi nt sc ores of 0, 1, 2, a n d 3 or hi g her ( 3 +)  
- P F S /O S i n t he f ull data set of m B C  patie nts recei vi n g pal b ocicli b + AI  as first-
li ne treat me nt s plit i nt o n u m ber of c o m or bi dities ( n one , o ne, a n d t w o or m ore)  
- P F S /O S i n t he f ull data set of m B C patie nts recei vi n g pal b ocicli b + AI as first li ne 
treat me nt s plit i nt o t y pe of c o m or bi dit y –  wit h f oc us o n fi ve mai n gr o u ps: Car diac  
disease , Vasc ular disease, Met a b olic disease, Ps yc hiatric disease, Bl o o d a n d 
l y m p hatic s yste m. 
A ut h or  
, M D, M Sc; 
 
 M Sc ; 
 
, M Sc, P h D; 
, 
M Sc, Pfizer De n mar k  
, M D, P h D; a n d 
 
, M D, Da nis h Breast Ca ncer Gr o u p a n d Ri gs h os pitalet 
 
P P D
P P D
P P D
P P D
P P D
P P D

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 2  of 2 7  
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n bel o n gi n g t o Pfizer.  E xce pt as ot her wise a gree d t o i n writi n g, 
b y acce pti n g or re vie wi n g t his d oc u me nt, y o u a gree t o h ol d t his i nf or mati o n i n c o nfi de nce a n d n ot c o p y or 
discl ose it t o ot hers (e xce pt w here re q uire d b y a p plica ble la w) or use it f or u na ut h orize d p ur p oses.  I n t he e v e nt 
of a n y act ual or s us pecte d breac h of t his o bli gati o n, Pfizer m ust be pr o m ptl y n otifie d.  
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 3  of 2 7  
1.  T A B L E O F C O N T E N T S  
 
1.  T A B L E O F C O N T E N T S  .......................................................................................................3  
2.  LI S T O F A B B R E VI A TI O N S  ................................................................................................5  
3.  R E S P O N SI B L E P A R TI E S  ....................................................................................................6  
4.  A B S T R A C T  ...........................................................................................................................7  
5.  A M E N D M E N T S A N D U P D A T E S  .....................................................................................1 0  
6.  MI L E S T O N E S  .....................................................................................................................1 1  
7.  R A TI O N A L E A N D B A C K G R O U N D  ................................................................................1 2  
8.  R E S E A R C H Q U E S TI O N A N D O BJ E C TI V E S  .................................................................1 4  
8. 1.  Defi niti o ns  ...............................................................................................................1 5  
9.  R E S E A R C H M E T H O D S  ....................................................................................................1 5  
9. 1.  St u d y Desi g n  ...........................................................................................................1 5  
9. 2.  Setti n g  ......................................................................................................................1 6  
9. 2. 1.  I n cl usi o n Criteria ........................................................................................1 6  
9. 2. 2.  E xcl usi o n Criteria  .......................................................................................1 6  
9. 3.  Varia bles  ..................................................................................................................1 6  
9. 4.  C harls o n C o m or bi dit y I n d e x ( C CI) a n d c o m or bi dities  ...........................................1 8  
9. 5.  Data S o urces  ............................................................................................................2 0  
9. 6.  St u d y Size  ................................................................................................................2 0  
9. 7.  Data Ma n a ge me nt  ...................................................................................................2 1  
9. 8.  Data A nal ysis  ..........................................................................................................2 1  
9. 9.  Q ualit y C o ntr ol  ........................................................................................................2 1  
9. 1 0.  Li mitati o ns of t he Researc h M et h o ds  ....................................................................2 2  
9. 1 1.  Ot her As pects  ........................................................................................................2 2  
1 0.  P R O T E C TI O N O F H U M A N P A R TI CI P A N T S  ...............................................................2 2  
1 0. 1.  Patie nt I nf or mati o n  ................................................................................................2 2  
1 0. 2.  Patie nt C o nse nt  ......................................................................................................2 3  
1 0. 3.  I nstit uti o nal Re vie w B oar d (I R B)/ Et hics C o m mittee ( E C) ..................................2 3  
1 0. 4.  Et hical C o n d uct of t he St u d y  ................................................................................2 3  
1 1.  M A N A G E M E N T A N D R E P O R TI N G O F A D V E R S E E V E N T S/ A D V E R S E 
R E A C TI O N S  ......................................................................................................................2 3  
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 4  of 2 7  
1 2.  P L A N S F O R DI S S E MI N A TI N G A N D C O M M U NI C A TI N G S T U D Y R E S U L T S ........2 3  
1 3.  R E F E R E N C E S  ..................................................................................................................2 4  
1 4.  LI S T O F T A B L E S  .............................................................................................................2 7  
1 5.  LI S T O F FI G U R E S  ...........................................................................................................2 7  
A N N E X 1. LI S T O F S T A N D A L O N E D O C U M E N T S  ..........................................................2 7  
A N N E X 2. A D DI TI O N A L I N F O R M A TI O N  .........................................................................2 7  
 
0
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 5  of 2 7  
2.  LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Defi niti o n  
A B C  
A d va nce d Breast Ca ncer  
A E  
A d verse e ve nt  
AI  
Ar o matase In hi bit or  
a/ M B C 
A d va nce d metastatic breast ca ncer  
B C  
Breast Ca ncer  
C 5 0  
I C D-1 0 c o de f or patie nts wit h breast ca ncer  
C CI  
C harls o n C o m or bi dit y I n de x  
C D K  
C ycli n -de pe n de nt ki nase  
C D K 4  
C ycli n De pe n de nt Ki nase 4  
C D K 6  
C ycli n De pe n de nt Ki nase 6  
C N S  
C e ntral N er v o us S yste m  
C P R  
Ce ntrale Pers o n Re gister –  re gistr y t hat h ol ds t he pers o nal I D n u m bers t hat e ver y 
Da nis h citize n has  
C V  
Car di o vasc ular  
D B C G  
Da nis h Breast Ca ncer Gr o u p  
E C  
Et hical C o m mittee  
E M A  
E ur o pea n Me dici nes A ge nc y  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S F V  
First s u bject first visit  
G D P R  
Ge neral Data Pr otecti o n Re g ulati o n  
HI V/ AI D S  
H u ma n Im m u n o deficie nc y V ir us / A c q uire d Im m u n o D eficie nc y S y n dr o me  
H R  
Hazar d rati o  
H R +  
H or m o ne rece pt or p ositi ve , i ncl u di n g estr o ge n rece pt or p ositi ve ( E R +) 
H E R 2  
H u ma n e pi der mal gr o wt h fact or rece pt or 2  
H E R 2 - 
H E R 2 ne gati ve  
I C D-1 0  
I nter nati o nal Classificati o n of Diseases a n d Relate d Healt h Pr o ble ms, 1 0 t h Re visi o n  
I C MJ E 
I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors 
I E C 
I nstit uti o nal Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 
L O T  
Li ne of Treat me nt  
L P R  
Nati o nal Patie nt Re gistr y ( La n ds patie ntre gistret)  
L S L V  
Last s u bject last visit  
M B C  
M etastatic breast ca ncer  
NI -St u d y  
N o n -I nter ve nti o nal St u d y 
O S  
O verall s ur vi val  
P F S  
Pr o gressi o n free s ur vi val  
R C T  
ra n d o mize d c o ntr olle d trials 
R W  
Real -W orl d  
R W E  
Real -W orl d E vi de nce  
S A P  
Statistical A nal ysis Pla n  
U S  
U nite d States of A merica  
0
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 6  of 2 7  
3.  R E S P O N SI B L E P A R TI E S  
Pri nci p al I n vesti g at or (s) of t he Pr ot oc ol  
N a me, de gree(s)  
J o b Title  
Affili ati o n  
A d dress  
H u m ma K ha n, 
M D, M Sc  
Sr. Me dical  
Affairs Scie ntist   
Pfizer De n m ar k, 
O nc ol o g y  
La utr u p va n g 8, 2 7 5 0 
Baller u p, De n mar k  
Ha n ne K a pel , 
M Sc  
Sr. Me dical  
Affairs Scie ntist  
Pfizer De n m ar k, 
O nc ol o g y  
La utr u p va n g 8, 2 7 5 0 
Baller u p, De n mar k  
Peter B o P o ulse n, 
M Sc, P h D  
Sr. Healt h 
Ec o n o mics a n d 
O utc o mes 
Researc h  
Ma na ger  
Pfizer De n m ar k, 
Healt h & Val ue  
La utr u p va n g 8, 2 7 5 0 
Baller u p, De n mar k  
Da niel Sl ot h 
Ha u ber g, M Sc  
Sr. Mar ket 
Access M a na ger  
Pfizer FI N D, 
Access & Val ue  
La utr u p va n g 8, 2 7 5 0 
Baller u p, De n mar k  
A n n S øe gaar d 
K n o o p, M D, P h D  
C hief P h ysicia n  
D B C G a n d 
Ri gs h os pitalet  
De part me nt of O nc ol o g y  
Secti o n 5 0 7 3 , Ri gs h os pitalet 
Ble g da ms vej 9  
2 1 0 0 C o pe n ha ge n Ø  
De n mar k  
T o bias Ber g, M D  
Researc h 
Assista nt  
D B C G a n d 
Ri gs h os pitalet  
De part me nt of O nc ol o g y  
Secti o n 5 0 7 3 , Ri gs h os pitalet 
Ble g da ms vej 9  
2 1 0 0 C o pe n ha ge n Ø  
De n mar k  
Ala n Celi k, 
B Sc. Me d  
Researc h 
Assista nt  
D B C G a n d 
Ri gs h os pitalet  
De part me nt of O nc ol o g y  
Secti o n 5 0 7 3 , Ri gs h os pitalet 
Ble g da ms vej 9  
2 1 0 0 C o pe n ha ge n Ø  
De n mar k  
 
 
 
0
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 7  of 2 7  
4.  A B S T R A C T  
Title  
I m pa ct of a g e a n d c o m or bi dities o n treat me nt o utc o mes of first -li ne treat me nt wit h palb ocicli b i n 
c o m bi nati o n wit h a n ar o matase i n hi bit or ( AI)  i n p atie nts dia g n ose d wit h H R +/ H E R 2 –  metastatic 
breast c a ncer –  Da nis h N o n -I nter ve nti o nal Stu d y . Pr ot oc ol versi o n 3 . 0, Fe br uar y 1 7 t h, 2 0 2 5 . 
 
A ut h ors  
, M D, M Sc; 
, 
M Sc ; 
, M Sc, P h D; 
 
, M Sc , Pfizer De n m ar k; 
 
, M D, P h D; a n d 
, M D, Da nis h Breast Ca ncer Gr o u p a n d 
Ri gs h os pitalet.   
R ati o n ale a n d b ack gr o u n d  
R a n d o mize d c o ntr olle d trials ( R C T) ma y ha ve li mitati o ns  wit h patie nts i n dail y practice b ei n g  m ore 
heter o ge n e o us t ha n i n t he R C Ts. M etastatic breast ca ncer ( m B C)  patie nt p o p ulati o ns i ncl u de, li ke 
t he rest of t he p o p ulati o n, m ore el derl y p atie nts as well as patie nts wit h c o m or bi dities besi des t heir 
ca ncer diseas e. H o we v er el derl y a n d patie nts wit h c o m or bi dities ha ve bee n u n derre prese nt e d i n 
R C Ts d ue t o strict i n - a n d e xcl usi o n criteria, a n d t heref ore t he o utc o m e of treat me nt wit h 
C D K 4/ C D K 6, i ncl. pal b ocicli b , is u nclear fr o m t hese R C Ts. St u dies usi n g real -w orl d ( R W) data of 
t he patie nts i n act ual dail y cli nical practice ca n a d dress t he q uesti o n of effecti ve ness a n d safet y i n 
t hese m ore het er o ge n o us patie nt p o p ulati o ns.  A n u m ber of R W -e vi de nce ( R W E) st u dies –  ma n y 
fr o m t he U S –  f o u n d si g nifica nt i m pr o ve me nts i n O S a n d P F S f or H R +/ H E R 2 - m B C patie nts  treate d 
wit h pal b ocicli b + AI  c o m pare d t o AI al o ne. I n a Da nis h setti n g t h o u g h, li mite d e vi de nce o n t he 
effecti veness of p al b ocicli b in ol der m B C  patie nts wit h c o m or bi dities is a vailab le. As a n u p date a n d 
e xte nsi o n of t he Garl y et al. st u d y, t he prese nt st u d y t heref ore ai ms t o i n vesti gate t he use a n d 
effecti ve ness of p al b ocicli b + AI as first -li ne tr eat m e nt i n s u b gr o u ps of el derl y patie nts as well as 
patie nts wit h c o m or bi dities ha vi n g  H R +/ H E R 2 - m B C.   
All first -li ne m B C patie nts c o nsist of e n d ocri ne resista nt, e n d ocri ne se nsiti ve a n d de n o v o p atie nts. 
As i n Garl y et al. e n d o cri ne resista nt patie nts are d efi ne d as rec urre nt patie nts wit h a d va nce d dise ase 
wit hi n 1 2 m o nt hs of c o m pleti n g a dj u va nt e n d ocri n e t hera p y or d uri n g a dj u v a nt e n d ocri ne t h era p y. 
E n d ocri ne se nsiti ve patie nts are defi n e d as rec urre nt patie nts wit h a d va nce d disease aft er 1 2 m o nt hs 
of c o m pleti n g a dj u va nt e n d ocri ne t hera p y, rec urre nt patie nts w h o recei ve d n o a dj u va nt e n d ocri n e 
t hera p y or p atie nts wit h de n o v o, a d va n ce d breast ca ncer. De n o v o p atie nts are defi ne d as n e wl y 
metastatic patie nts.  
Rese arc h q uesti o n a n d o bjectives  
T he o bjecti ve is t o retr os pecti vel y i n vesti gate t he o utc o mes ( o verall P F S a n d O S) of first -li ne 
treat me nt with pal b ocicli b i n c o m bi nati o n wit h a n AI i n ke y s u b gr o u ps of m B C  patie nts i n De n mar k  
f oc usi n g o n a ge a n d c o m or bi dit y b ur de n . 
•  Pri mar y o bjecti ves:  
o  P F S of all m B C patie nts recei vi n g pal b o cicli b + AI  as first-li ne treat me nt 
o  O S of all m B C patie nts recei vi n g pal b ocicli b + AI  as first-li ne treat me nt  
 
P P D
P P D
P P D
P P D
P P D
P P D

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 8  of 2 7  
 
Sec o n dar y o bje cti ves:  
o  A ge s u b gr o u p a n al yses:  
▪ A ge distri b uti o n i n t he f ull data set of m B C patie nts recei vi n g pal b oci cli b + AI  as 
first-li ne treat me nt 
▪ P F S a n d O S i n m B C pa tie nts bel o w 6 5 years of a g e , 6 5 -7 4  years of a g e a n d 7 5 + 
years of a ge, res pecti vel y , recei vi n g pal b o cicli b + AI as first-li ne treat me nt. 
 
o  C o m or bi dit y s u b gr o u p a nal yses ( C CI) is use d as a data s o urce f or c o m or bi dit y a n d 
e x pressi o n of c o m or bi dit y b ur de n):  
▪ P F S a n d O S i n t he f ull data set of m B C patie nts recei vi n g pal b ocicli b + AI  as 
first-li ne treat me nt s plit i nt o C CI p oi nt sc ores of 0, 1, 2, a n d 3 or hi g her ( 3 +)  
▪ P F S a n d O S i n t he f ull data set of m B C patie nts recei vi n g pal b ocicli b + AI  as 
first-li ne treat me nt s plit i nt o n u m ber of c o m or bi dities ( n o c o m or bi dit y, o ne 
c o m or bi dit y, a n d t w o or m ore c o m or bi dities)  
▪ P F S a n d O S i n t he f ull dataset of m B C patie nts recei vi n g pal b ocicli b + AI  as first-
li ne treat me nt s plit i nt o t y pe of c o m or bi dit y –  f oc us o n fi ve mai n gr o u ps: Car diac  
disease , Vas c ular dise ase, Meta b olic disease, Ps yc hiatric disease, Bl o o d a n d 
l y m p hatic s yste m. 
 
St u dy desi g n  
T he st u d y is desi g ne d as a sec o n dar y data c ollecti o n N o n -I nter v e nti o nal St u d y ( NI S) base d o n 
retr os pecti ve d ata fr o m a n e xisti n g re gistr y. T he st u d y is a si n gle-ar m st u d y o nl y f oc usi n g o n 
H R +/ H E R 2 - m B C patie nts treate d wit h pal b ocicli b i n c o m bi nati o n wit h a n AI as first-li ne tr eat me nt 
i n De n mar k. 
 
P o p ul ati o n   
T he f ull dataset c o nsists  of e n d ocri n e se nsiti ve , e n d ocri ne resista nt a n d de n o v o H R +/ H E R 2 - m B C 
patie nts treate d wit h pal b ocicli b as first-li ne treat me nt ( 0 1 Ja n uar y 2 0 1 7- 3 1 Dece m b er 2 0 2 1 ). 
Patie nts will be ce ns ore d f or O S a n d P F S b y 1 st Fe br uar y  2 0 2 4 . 
 
I ncl usi o n criteri a 
Patie nts m ust meet t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or i ncl usi o n i n t he st u d y:  
1.  Patie nts wit h breast ca ncer (I C D -1 0: C 5 0)  
2.  A dia g n osis of H R +/ H E R 2 - l ocall y a d va nce d or metastatic breast ca ncer 
3.  E n d ocri ne se nsiti ve e n d o cri ne resista nt  or de n ov o  m B C patie nt  
4.  I nitiate d tr eat me nt wit h p al b ocicli b as first-li ne treat me nt ( pal b ocicli b + AI) bet wee n 1 Ja n uar y 
2 0 1 7 a n d 3 1 Dece m ber 2 0 2 1  
5.  I n cl usi o n date: Dat e of rela pse/sta ge I V disease/ pr o gressi o n lea di n g t o i nitiati o n of pal b ocicli b + 
AI  
 
V ari a bles (see secti o n 9. 3 f or a d diti o n al det ails)  
•  Dia g n osis (I C D -1 0 c o d e: C 5 0)  (ex p os ure/i ncl usi o n) 
•  Treat me nt wit h pal b ocicli b  
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 9  of 2 7  
•  Date of birt h  
•  Date of breast c a ncer dia g n osis  
•  Occ urre nce of metast ases  
•  Visceral stat us ( visceral a n d n o n -visceral)  
•  B o ne o nl y  
•  Metastatic sites (li ver, l u n g, ce ntral ner v o us s yste m (C N S ), l y m p h n o des)  
•  De N ov o  ( pri mar y m B C) 
•  Date of rela pse  
•  Date f or treat me nt i nitiati o n wit h pal b ocicli b  
•  Date f or treat me nt st o p wit h pal b ocicli b  
•  C harls o n C o m or bi dit y I n de x ( C CI) (p oi nt sc ores of 0, 1, 2 , a n d 3 or hi g her ( 3 +) ) at start of 
pal b ocicli b treat me nt  
•  N u m ber of c o m or bi dities  at start of pal b ocicli b treat me nt  
•  T y pes of c o m or bi dities  at start of pal b ocicli b treat me nt  (Car diac  dise ase , Vasc ular dise ase, 
Meta b olic disease, Ps yc hiatric disease, Bl o o d a n d l y m p hatic s yste m ) 
•  Deat h date  
•  P F S ( o utc o me ) 
•  O S ( o utc o me ) 
 
D at a s o urces  
T his st u d y will be base d o n t he Da nis h Breast Ca n cer Gr o u p ( D B C G ) re gistr y a n d t he Nati o nal 
Patie nt Re gistr y ( L P R) wit h res pect t o t he c o m or bi dities.  
 
St u dy size  
It is esti mate d t hat t he t ot al p o p ulati o n of first-li ne pal b ocicli b -treat e d breast ca ncer patie nts wit h 
H R +/ H E R 2 - m B C  i ncl u de d i n t he D B C G re gistr y fr o m t he peri o d 2 0 1 7-2 0 2 1 c o nstit utes of 5 8 0  
patie nts i n De n mar k.  
 
D at a a n alysis  
Descri pti ve statistics, i ncl u di n g stratificati o n o n s u b -gr o u ps. I n t he P F S a n d O S a nal yses, Ka pla n -
Meier s ur vi val distri b uti o n f u ncti o ns will be esti mate d. Ce ns ori n g f or O S a n d P F S a nal yses will be 
1 st Fe br uar y  2 0 2 4 . A se p arate Statistical A nal ysis Pla n ( S A P), i ncl u di n g s hell ta bles, will be 
de vel o pe d pri or t o d ata a nal ysis.  
 
Milest o nes  
•  Fi nal Pr ot oc ol  
 
 
 
 
 
2 9  Fe br uar y 2 0 2 4  
•  Fi nal Statistical A nal ysis Pla n  
 
 
 
5 Marc h  2 0 2 4  
•  Start of data c ollecti o n ( F S F V –  data bas e st u d y)   
6  Marc h  2 0 2 4  
•  Data set u p   
 
 
 
 
 
6  Marc h  2 0 2 4  
•  E n d of data c ollecti o n ( L S L V –  data base st u d y)   
1 9 A pril  2 0 2 4  
•  Data a n al yses  
 
 
 
 
 
2 2  A pril  –  J ul y 2 0 2 4  
•  D B C G Fi nal st u d y re p ort   
 
 
 
0 1 A u g ust 2 0 2 4  
•  Ma n uscri pt rea d y f or s u b missi o n  
 
 
3 1 A u g ust 2 0 2 4  
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 1 0  of 2 7  
5.  A M E N D M E N T S A N D U P D A T E S  
 
Versi o n 
I de ntifier 
D ate  
A me n d me nt 
T y pe    
(s u bst a nti al or 
a d mi nistr ati ve)  
 Pr ot oc ol 
Secti o n(s)    
C h a n ge d  
S u m m ar y 
of 
A me n d me n
t(s) 
Re as o n  
3. 0  
 
1 7 Fe br uar y 
2 0 2 5  
S u bsta ntial  
 
3. Res p o nsi ble 
Parties  
4. A bstracts  
A d de d 
Da niel 
Sl ot h 
Ha u ber g as 
a Pri nci pal 
I n v esti gat or 
of t he 
Pr ot oc ol  
Si nce 
 has 
left Pfizer,  
 has 
ta ke n o ver t he 
res p o nsi bilit y as NI 
st u d y lea d 
res p o nsi ble f or 
pr ot oc ol a me n d me nts  
1 7 Fe br uar y 
2 0 2 5  
4. A bstracts  
U p date of 
A bstract 
title 
U p date d title wit h 
c orrect pr ot oc ol 
versi o n n u m ber a n d 
date  
1 7 Fe br uar y 
2 0 2 5  
4. A bstracts  
8. 1 Defi niti o ns  
9. 2 Setti n g  
9. 8 Data 
A nal ysis  
U p date of 
O S a n d P F S 
ce ns ori n g 
date  
D ue t o a d diti o nal 
f oll o w-u p data 
a vaila ble, t he 
ce ns ori n g date h as 
bee n c h a n ge d fr o m 
3 1 st Dece m ber 2 0 2 3 
t o 1st Fe br uar y 2 0 2 4  
 
 
 
P P D
P P D

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 1 1  of 2 7  
6.  MI L E S T O N E S   
 
Milest o ne  
Pl a n ne d d ate  
Fi nal Pr ot oc ol  
2 9 Fe br uar y 2 0 2 4  
Fi nal Statistical A nal ysis Pla n  ( S A P) 
5 Marc h  2 0 2 4  
S tart of data c ollecti o n ( F S F V –  data bas e st u d y, 
hist oric data)  
6  Marc h  2 0 2 4  
Data set u p  
6  Marc h  2 0 2 4  
E n d of data c ollecti o n ( L S L V –  data base st u d y, 
hist oric data)  
1 9  A pril  2 0 2 4  
Data a n al yses   
2 2 A pril  – J ul y 2 0 2 4  
D B C G F i nal st u d y re p ort   
0 1 A u g ust  2 0 2 4  
Ma n uscri pt rea d y f or s u b missi o n   
3 1 A u g ust  2 0 2 4  
 
 
 
 
0
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 1 2  of 2 7  
7.  R A TI O N A L E A N D B A C K G R O U N D  
T he first cell c y cle i n hi bit or was pal b ocicli b w hic h was a p pr o ve d b y F o o d a n d Dr u g A d mi nistrati o n 
( F D A) base d o n  t h e P hase 2 st u d y P A L O M A-1 ( 1 ). T his st u d y s h o we d d o u bli n g of P F S fr o m 1 0. 2 t o 
2 0. 2 m o nt hs w he n a c o m bi nati o n of pal b ocicli b a n d letr oz ole was gi v e n t o H R +/ H E R 2 - a d va n ce d 
breast c a ncer patie nts. T h ese si g nifica nt r es ults were later c o nfir me d i n t he P A L O M A -2 P hase 3 
st u d y (2 ). T his a p pr o val was f oll o we d b y t he ot her t w o C D K 4/ C D K 6 i n hi bit ors; ri b ocicli b a n d 
a be maci cli b. I n De n mar k t hese tar get e d t h era p e utic a ge nts ha v e bee n  i n c or p orate d i nt o cli nical 
practice si n ce 2 0 1 6 ( 3 ).  
T he i ntr o d ucti o n of C D K 4/ C D K 6 i n hi bit ors has  re v ol uti o nize d t he para di g m of t hera pe utic 
ma na ge me nt of H R + m B C w orl d wi de. T he m ost c o m m o n ca ncer gl o b all y is breast ca n cer ( 4 ). I n 
De n mar k, breast c a ncer is t he m ost fre q ue nt ca ncer i n w o me n, wit h a p pr o xi matel y 4, 7 0 0 ne w cases 
per year; a n d t he 5 -y ear  O S is esti mate d t o be 8 6 %. T o date r o u g hl y 6 4, 0 0 0 w o me n  i n De n mar k are 
li vi n g wit h a breast ca n cer dia g n osis wit h 2 0 % of t he m e x perie n ci n g a rela pse of t he diseas e at s o me 
sta ge i n t heir life.  
T he t hree C D K 4/ C D K 6 i n hi bit ors pal b ocicli b, ri b ocicli b, a n d a be m acicli b are a p pr o ve d i n 
c o m bi nati o n wit h  A I or wit h f ul vestra nt. T o date, se veral P hase 2 a n d 3 R C Ts ha ve e val uat e d 
C D K 4/ C D K 6 i n hi bit ors i n t he treat me nt of H R +/ H E R 2 - a d va n ce d metastatic breast c a ncer (a/ m B C). 
Pal b ocicli b was e val uat e d i n t hree re gistrati o nal trials wit h differe nt patie nt p o p ulati o ns: P A L O M A -
1 ( 5 ), P A L O M A-2 ( 2 ) a n d P A L O M A-3 ( 6, 7 ). Ri b ocicli b was e val u ate d i n t hree trials, P hase 3 
M O N A L E E S A -2 ( 8 ), M O N A L E E S A-3 ( 9 ) a n d M O N A L E E S A-7  (1 0 ). A be macicli b was e val uate d 
i n M O N A R C H 1 (1 1 ), M O N A R C H 2 (1 2 ) a n d M O N A R C H 3 (1 3 ).  
S pecificall y,  f or p al b ocicli b, t he P hase 3 trial P A L O M A -2 de m o nstrate d a me dia n P F S of 2 4. 8 vs. 
1 4. 5 m o nt hs, res pecti vel y, f or patie nts treate d wit h pal b ocicli b or place b o i n a d diti o n t o letr oz ole 
( hazar d rati o [ H R] 0. 5 8; p < 0. 0 0 1). After a me dia n f oll o w-u p of a p pr o xi m atel y 3 8 m o nt hs, me dia n 
P F S was 2 7. 6 m o nt hs f or pal b ocicli b -letr oz ole a n d 1 4. 5 m o nt hs f or letr oz ol e ( H R 0. 5 6 3; P < 0. 0 0 0 1) 
(1 4 ). P atie nts  recei vi n g pal b ocicli b a n d letr oz ol e  h a d n u mericall y l o n ger O S c o m pare d t o place b o 
a n d letr oz ole ( me dia n O S was 5 3. 9 m o nt hs vers us  5 1. 2 m o nt hs ), b ut t he res ults were n ot statisticall y 
si g nifica nt ( H R = 0. 9 5 6 ; P = 0. 3 3 7 8 ) (1 5 ).  
R C T s re mai n t he g ol d sta n dar d i n t he scie ntific e vi de nce hierarc h y t o s h o w efficac y of dr u gs. 
H o we ver, it is als o well esta blis he d t hat des pite bei n g ra n d o mize d s uc h st u dies ma y  ha ve li mitati o ns 
s uc h as h o m o ge n o us pati e nt p o p ulati o n s w hic h ofte n d o  n ot reflect t he cli nical pict ure e nc o u ntere d 
i n t he heter o ge n e o us real-w orl d. B ot h patie nt -relat e d a n d diseas e-relate d varia bles ca n i m pact t he 
pr o g n osis of metastatic breast c a ncer patie nts. S o me varia bles are sites of metastatic i n v ol ve me nt, 
t u m or s u bt y pes, b ur de n of disease, a n d patie nt c om or bi dities ( 1 6 ). I n a d diti o n, ma n y patie nts ha ve 
c o-e xisti n g c o m or bi dities , w he n t he y are dia g n ose d wit h ca ncer, es peciall y t he el derl y patie nts ( 1 7 ). 
T he n u m ber of el derl y c a ncer patie nts h a s i ncrease d d ue t o t he a gi n g p o p ulati o n t hr o u g h t he past 
ma n y years ( 1 8 ). I nter nati o nal st u dies s h o w t hat 2 0-3 5 % of breast c a ncer ( B C ) patie nts ha ve o ne or 
m ore c o m or bi dities at t he ti me of t he ir B C dia g n osis ( 1 9 ). I n Da nis h w o me n dia g n ose d wit h earl y 
breast c a ncer, t he  s hare of patie nts wit h c o m or bi dities has bee n s h o w n t o be a r o u n d 1 6 -2 0 % ( 2 0 -2 3 ).   
St u dies usi n g R W data of t he patie nts i n act ual dail y cli nical practice ca n a d dress t he q uesti o n of 
effecti ve ness a n d s afet y i n m ore heter o g e n o us pati e nt p o p ulati o ns c o m pare d t o t he st u d y p o p ulati o n s 
i n R C Ts (2 4 -2 5 ).  
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 1 3  of 2 7  
Acc or di n g t o t he s yste matic literat ure re vie w b y Har bec k et al. a n u m ber of  R W -e vi de nce ( R W E) 
st u dies o n C D K 4/ C D K 6 i n hi bit ors i n t he treat me nt of H R +/ H E R 2 - m B C has  bee n carrie d o ut ( 26 ). 
T he m aj orit y of t hese st u dies c o nfir me d t he efficac y a n d safet y of C D K 4/ C D K 6 i n hi bit ors  as f o u n d 
i n R C Ts (2 6 ). A  retr os pecti ve o bser vati o nal a nal ysis of electr o nic h ealt h rec or ds wit hi n t he U S 
Flatir o n Healt h A nal ytic Data base of patie nts treat e d wit h pal b ocicli b pl us letr oz ole b y De Mic hele et 
al ., c onfir me d  t he res ults of t he P A L O M A-2 R C T st u d y ( 2 7 ). Si milarl y, R u g o et al. utilizi n g Flatir o n 
data o n 2 8 8 8 patie nts wit h H R +/ H E R 2 − m B C treate d wit h first -li ne pal b oci cli b+ AI vers us AI al o n e 
f o u n d a me dia n O S of  4 9. 1 m o nt hs i n t he pal b ocicli b gr o u p  a n d 4 3. 2 m o nt hs i n t he AI gr o u p ( H R = 
0. 7 6; P  <   0. 0 0 0 1) a n d me dia n P F S of  1 9. 3 m o nt hs a n d 1 3. 9, res pecti vel y ( H R = 0. 7 0; P  <   0. 0 0 0 1) 
(2 8 ). R W E  o n Da nis h p atie nts treate d wit h pal b oci cli b  utiliz i n g data fr o m t he D B C G nati o nal 
cli nical re gistr y  ha v e rece ntl y bee n p u blis he d s h o wi n g a me dia n O S of 5 6. 9 m o nt hs  a n d P F S of 3 1. 3 
m o nt hs in t he first-li ne, e n d ocri ne se n siti ve, AI gr o u p  (2 9 ).  
Des pite t he hi g h i nci de nce of breast ca n cer i n t he el derl y p o p ulati o n, el derl y  patie nts ha ve bee n  less 
fre q ue ntl y i ncl u de d i n t h e R C Ts, res ulti n g i n an e vi de nce  ga p wit h res pect t o t he treat me nt o utc o me 
f or t his patie nt gr o u p. T h e Allia nce f or Cli nical Trials i n O nc ol o g y f o u n d i n an a nal ysis of t he breast 
ca ncer trials c o n d u cte d t hat < 2 0 % of t he tri al partici pa nts were ≥ 6 5 years of a ge a n d < 1 0 % were ≥ 
7 0 years of a ge  ( 30 ). Als o , i n t he t hree P A L O M A trials t he maj o rit y of t he i ncl u de d patie nts were  
y o u n ger t ha n 6 5 years of a ge, a n d o nl y 9. 5 % were ≥7 5 years of a ge  ( 31 ).  
S o me st u dies ha ve trie d t o a d dress t his u n met nee d a n d lac k of e vi de nce i n R C Ts re gar di n g t he 
el derl y p o p ulati o n b y utilizi n g data fr o m t he U S Flatir o n data bas e. Br ufs k y et al. f o u n d si g nifica nt 
i m pr o ve me nts i n O S ( 4 3. 0 vs 3 2. 4 m o nt hs, H R = 0. 6 6, p = 0. 0 0 0 7) a n d P F S  ( 2 0. 0 vs 1 5. 0 m o nt hs, 
H R = 0. 7 2, p = 0. 0 0 2 1)  f or H R +/ H E R 2 - m B C patie nts a ge d ≥ 7 5 years  treat e d wit h p al b ocicli b +  AI 
c o m pare d wit h AI al o ne  ( 32 ). I n a not h er st u d y R u g o et al. f o u n d si g nifica nt i m pr o ve me nts i n P F S  
( 2 2. 2 vs 1 5. 8 m o nt hs; H R = 0. 5 9, p < 0. 0 0 0 1)  f or p atie nts wit h m B C a ge d ≥6 5 years  treate d wit h 
pal b ocicli b +  letr oz ol e vers us letr oz ole al o n e ( 33 ). 
Strict i ncl usi o n a n d e xcl usi o n criteria i n cli nical tri als als o restricts i ncl usi o n of patie nts wit h certai n 
c o m or bi dities . H o we ver, a  st u d y o n U S patie nts re veale d t hat m ore t h a n half ( 6 2 %) of t he patie nts 
wit h ne wl y dia g n ose d H R +/ H E R 2 - m B C ha d at least o ne pree xisti n g  car di o vasc ular ( C V ) 
c o m or bi dit y at t he ti me of B C dia g n osis, a n d a m o n g t h ose a ge d 6 5 years or ol der it was 8 7 %, a n d of 
t h ose wit h pree xisti n g C V c o m or bi dit y, 5 3 % were prescri be d me dicati o n wit h a ris k of Q Tc 
pr ol o n gati o n ( 3 4 ). A gai n , t here is a n u n met nee d a n d lac k of e vi de nce fr o m t he R C Ts o n  t he 
effecti ve ness of  C D K 4/ C D K 6 i n hi bit ors i n t he treat me nt of H R +/ H E R 2 - a/ m B C  in c o m or bi d patie nt 
p o p ula ti o ns. T he  i m pact of c o m or bi dities o n pal b ocicli b effecti ve ness h as rece ntl y bee n st u die d i n a 
n u m ber of  real-w orl d o bser vati o nal st u dies  fr o m t he U S. T he P O L A RI S st u d y, w hic h i ncl u de d 1 ,2 5 0 
patie nts recei vi n g pal b ocicli b i n r o uti ne cli nical practice i n U S a n d Ca n a da, s h o we d t hat  p atie nts  ha d 
a me dia n of 2 c o m or bi dities  at baseli ne (ra n ge 0-9) ( 3 5 ). T he st u d y f o u n d t hat p atie nts i n real-life 
recei vi n g pal b o cicli b i n first li ne of t hera p y ( 1 L O T) or ≥ 2 L O T wit h  C CI sc ore of 2 or l o wer  t e n de d 
t o ha ve l o n ger P F S  a n d O S t ha n t h ose wit h C CI s c ore of 3  or hi g her . Si milarl y, p atie nts  wit h car di ac 
dis or ders i n t he 1 L O T a s well as bl o o d a n d l y m p hatic dis or ders i n t he ≥ 2 L O T ha d s h orter P F S . F or 
t he ot her c o m or bi dit y s u b gr o u ps i n t he st u d y c o m para ble cli nical o utc o mes  were f o u n d ( 3 5). 
A n ot her ne w real-w orl d  effecti ve ness st u d y c o nfir me d t h at patie nts wit h H R +/ H E R 2 - m B C , w h o 
ha d car di o v asc ular dis eas e  as c o m or bi dit y , w he n recei vi n g pal b ocicli b + AI as first-li ne t hera p y 
o btai ne d  si g nifica nt pr ol o n ge d O S ( 4 0. 7 vs 2 6. 5 m o nt hs, H R = 0. 7 3 2,  p = 0. 0 4 7 6 ) an d  si g nifica nt 
0
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 1 4  of 2 7  
i m pr o ve d P F S ( 2 0. 0 vs 1 2. 5 m o nt hs, H R = 0. 6 7 9,  p = 0. 0 0 7 0 ) c o m pare d t o si milar patie nts o nl y 
recei vi n g AI al o ne ( 3 6). 
I n a Da nis h setti n g, li mite d e vi de nce is a vaila ble o n ol der metastatic breast ca ncer patie nts wit h 
c o m or bi dities a n d t he effecti ve ness of treat me nt wit h pal b ocicli b i n t hese s u b gr o u ps of t he Da nis h  
m B C patie nts . A s a n u p date a n d e xt e nsi o n of t he Garl y et al. st u d y (2 9 ), th e prese nt st u d y t heref ore 
ai ms t o i n vesti gate t he use a n d effecti ve ness of p al b ocicli b + AI as first-li ne treat me nt i n all 
H R +/ H E R 2 - m B C patie nts i n De n mar k, as w ell as i n s u b gr o u ps of el derl y patie nts an d t h ose wit h 
c o m or bi di ties.  
All first -li ne m B C patie nts c o nsist of e n d ocri ne resista nt, e n d ocri ne se nsiti ve a n d de n o v o p atie nts. 
As i n Garl y et al. ( 2 9) e n d ocri ne resista nt patie nts are defi ne d as rec urre nt p atie nts wit h a d va nce d 
disease wit hi n 1 2 m o nt hs of c o m pleti n g a dj u va nt e n d ocri ne t hera p y or d uri n g a dj u va nt e n d ocri n e 
t hera p y. E n d ocri ne se nsiti ve patie nts are d efi ne d as rec urre nt patie nts wit h a d va nced disease after 1 2 
m o nt hs of c o m pleti n g a dj u va nt e n d ocri ne t hera p y, rec urre nt patie nts w h o recei ve d n o a dj u v a nt 
e n d ocri ne t hera p y or patie nts wit h de n o v o, a d va n ce d breast ca n cer. De n o v o patie nts are d efi ne d as 
ne wl y metastatic patie nts.  T h e st u d y data will be base d o n t he D B C G c li nical data base as t he 
pre vi o us st u d y b y Garl y et al. (2 9 ). 
T he st u d y will , as a R W E st u d y , f oll o w a n d c o m pl y wit h t he rece nt s pecific G R O W g ui da nce f or 
re p orti n g o nc ol o g y R W E st u dies i n peer-re vie we d j o ur nals prese nte d at E S M O 2 0 2 3  ( 37 ). 
 
8.  R E S E A R C H Q U E S TI O N A N D O B J E C TI V E S  
T he o verall o bjecti ve is t o retr os pecti vel y i n vesti g ate t he o utc o mes ( o verall P F S a n d O S) of first-li n e 
treat me nt wit h pal b ocicli b i n c o m bi nati o n wit h a n AI i n ke y s u b gr o u ps of m B C patie nts i n De n mar k  
f oc usi n g o n a ge a n d c o m or bi dit y b ur de n . 
 
Pri mar y o bjecti ves:  
•  P F S of all m B C p atie nts recei vi n g pal b o cicli b i n c o m bi nati o n wit h AI  as first -li ne treat me nt 
•  O S  of all m B C patie nts recei vi n g pal b ocicli b i n c o m bi nati o n wit h AI as first -li ne treat me nt 
 
Sec o n dar y o bje cti ves:  
•  A ge s u b gr o u p a n alyses:  
•  A ge distri b uti o n i n t he f ull data set of m B C patie nts recei vi n g pal b oci cli b + AI as first -li ne 
treat me nt  
•  P F S a n d O S i n m B C patie nts bel o w 6 5 years of a g e, 6 5 -7 4 years of a g e a n d 7 5 + years of a g e, 
res pecti vel y, recei vi n g pal b ocicli b + AI as first-li ne treat me nt  
 
•  C o m or bi dity s u b gr o u p a n alyses ( C harls o n C o m or bi dit y I n de x ( C CI) (3 8 ) is use d as a dat a s o urce 
f or c o m or bi dit y a n d c o m or bi dit y  b ur de n  –  c o m or bi dities at start of pal b ocicli b treat me nt ): 
•  P F S a n d O S i n t he f ull dataset of m B C  patie nts recei vi n g pal b ocicli b + AI as first -li ne 
treat me nt split i n t o C CI p oi nt sc ores of  0, 1, 2 , a n d 3 or hi g her ( 3 +)  
0
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 1 5  of 2 7  
•  P F S a n d O S i n t he f ull dataset of m B C patie nts recei vi n g pal b ocicli b + AI as first -li ne 
treat me nt split i n t o n u m ber of c o m or bi dities ( n o  c o m or bi dit y , o ne  c o m or bi dit y, a n d t w o or 
m ore  c o m or bi dities ) 
•  P F S a n d O S i n t he f ull dataset of m B C patie nts recei vi n g pal b ocicli b + AI as first -li ne 
treat me nt split i n t o t y pe of c o m or bi dit y –  f oc us o n fi ve mai n gr o u ps: Car diac  disease , 
Vasc ular dise ase, M eta b olic disease, Ps yc hiatric disease, Bl o o d a n d l y m p hatic s yste m .  
 
F oll o wi n g t he i ncl usi o n criteria (see sec ti o n 9. 2. 1 bel o w) t he a n al yses will be perf or me d o n t he f ull 
data set of patie nts wit h H R +/ H E R 2 - l ocall y a d va nce d or metast atic breast ca ncer treate d wit h 
pal b ocicli b + AI as first -li ne treat me nt.  
As state d, t he res earc h q uesti o ns will be a d dresse d a n d a nal yse d usi n g t he D B C G re gistr y (see 
secti o n 9. 1 f or a d escri pti o n of t he re gistr y).  
8. 1.  Defi niti o ns  
P F S is defi ne d as t he dat e of rel a pse or sta g e I V disease (i n de x d ate) t o pr o gressi o n or deat h, 
w hi c he ver occ urs first.  
•  Patie nts will be ce ns ore d f or P F S b y 1 st Fe br uar y  2 0 2 4   
•  Pr o gressi o n of disease is base d o n sca ns a n d bl o o d testi n g res ults  
 
O S is defi ne d as t he date of rela pse or sta ge I V dis ease (i n d e x date) u ntil deat h of a n y ca use .  
•  Patie nts will be ce ns ore d f or O S b y 1 st Fe br uar y  2 0 2 4   
 
9.  R E S E A R C H M E T H O D S  
9. 1.  St u d y D esi g n   
T he st u d y is desi g ne d as a sec o n dar y data c ollecti o n NI -S t u d y. Retr os pecti ve data will be c ollecte d 
fr o m a n e xisti n g re gistr y - t he D B C G re gistr y. T he f oc us of t his st u d y will be o n H R +/ H E R 2- l ocall y 
a d va nce d or metastatic breast c a ncer treate d wit h pal b ocicli b. T he st u d y is a si n gle -ar m st u d y 
f oc usi n g o n patie nts treat e d wit h pal b ocicli b i n De n mar k. 
 
T he st u d y is p urel y descri pti ve a n d e x pl orati ve. N o f or mal h y p ot heses will be teste d i n t he st u d y.  
 
Si nce t he esta blis h me nt i n 1 9 7 6, t he D B C G has mai ntai ne d a cli nical re gistr y f or earl y breast ca n cer 
patie nts i n De n mar k i n w hic h s ur ge o ns, pat h ol o gists, me dical ge neticists a n d o nc ol o gists re p ort data 
re gar di n g dia g n osis, treat me nt a n d f oll o w-u p of breast  ca n cer (3 9 ,4 0 ). T his is a u ni q ue cli nical 
re gistr y. T his well-esta blis he d breast c a ncer re gistr y ( 1 9 7 6) ma na ge d b y D B C G was e x pa n de d i n 
2 0 1 7 t o i ncl u de retr os pecti ve a n d pr os pecti ve cli nical a n d pat h ol o gical data o n breast c a ncer patie nts 
wit h a rela pse. T his i ncl u des b ot h t he pri mar y m B C ( De N o v o) a n d rec urre nt m B C . 
T he D B C G re gistr y f o c usi n g o n rela pses o n w hic h t he st u d y will be base d is o ne of se veral D B C G 
re gistries. A ll Da nis h patie nts wit h l ocall y a d va nce d or metastatic breast c a ncer are i ncl u d e d i n t he 
D B C G re gistr y . T he data a n d rec or ds i n t he re gistr y are bas e d o n s yste matic re vie w f oll o wi n g a 
sta n dar d case re p ort f or m of all electr o nic p atie nt r ec or ds of p atie nts dia g n ose d wit h l ocall y 
a d va nce d or metastatic breast c a ncer.  
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 1 6  of 2 7  
 
T he data c ollecti o n a n d t he o n g oi n g p o p ulati n g of t he D B C G re gistr y are p erf or me d b y h ealt hcare 
pr ofessi o nals i n t he D B C G secretariat a n d are c o n d ucte d i n de pe n d e ntl y of t his st u d y. C o m pare d t o 
ot her e x ha usti ve n ati o nal Da nis h patie nt re gistries, t he D B C G r e gistr y c o ntai ns detaile d cli nical a n d 
pat h ol o gical data a b o ut t he treat me nt patter ns of p atie nts wit h H R +/ H E R 2 - l ocall y a d va nce d or 
metastatic breast ca ncer. T h us, t he re gistr y is a n i m p orta nt a n d well -s uite d s o urce t o a d dress t he 
researc h q uesti o ns of t h e prese nt st u d y a n d has pre vi o usl y bee n use d t o a nal yze treat me nt o utc o mes 
f or all first- a n d s ec o n d -li ne pal b ocicli b patie nts i n De n mar k (2 9 ). 
 
T he prese nt NI -St u d y will t heref ore rel y o n d ata i n t he D B C G re gistr y, as w ell as data fr o m t he 
Nati o nal Patie nt Re gistr y (c o m or bi dit y data) . No a d diti o nal data will be c ollecte d as p art of t he 
st u d y, f urt her m ore n o re vie w of me dical rec or ds will be ma de. T heref ore, t he prese nt NI -St u d y is 
defi ne d as a retr os p ecti ve sec o n dar y data c ollecti o n st u d y, w here all dat a nee de d f or t h e a nal ysis 
e xist as str uct ure d dat a b y t he ti me of st u d y start. T his als o mea ns t hat t her e is n o h u ma n re vie w of 
u nstr uct ure d data c o n d ucte d as part of t he pr ot oc ol.  
 
9. 2.  Setti n g  
I n t he D B C G re gistr y, all H R +/ H E R 2 - l ocall y a d v a nce d or m B C patie nts treate d wit h pal b oci cli b i n 
c o m bi nati o n wit h AI as first -li ne treat me nt will be i de ntifie d. Pal b ocicli b was a p pr o ve d b y t h e 
E ur o pea n C o m missi o n a n d E ur o pea n M e dici nes A ge nc y ( E M A) i n N o ve m ber 2 0 1 6. He n ce, t he 
st u d y peri o d will be fr o m 1 Ja n uar y 2 0 1 7 a n d t o 3 1 Dece m b er 2 0 2 1 . A f oll o w-u p o n patie nts u ntil 1 st 
Fe br uar y  2 0 2 4  i n ter ms of t he esti mati o n of P F S a n d O S will be ma de.  
 
T he st u d y will o nl y i ncl u de patie nts treate d wit h pal b ocicli b.   
9. 2. 1.  I ncl usi o n C riteri a  
Patie nts m ust meet t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or i ncl usi o n i n t he st u d y:  
 
1.  
Patie nts wit h breast ca ncer (I C D -1 0: C 5 0)  
2.  
A dia g n osis of H R +/ H E R 2 - l ocall y a d va nce d or metastatic breast ca ncer 
3.  
E n d ocri ne se nsiti ve, e n d ocri ne resista nt , or de n o v o m B C patie nt  
4.  
I nitiate d tr eat me nt wit h p al b ocicli b as first-li ne treat me nt ( pal b ocicli b + AI) bet wee n 1 
Ja n uar y 2 0 1 7 a n d 3 1 Dece m ber 2 0 2 1  
5.  
I n cl usi o n date: Date of rela pse/sta ge I V disease/ pr o gressi o n lea di n g t o i nitiati o n of 
pal b ocicli b + AI  
9. 2. 2.  E xcl usi o n C riteri a  
T here are n o e xcl usi o n criteria f or t his st u d y.  
9. 3.  V ari a bles  
T he mai n varia bles i n cl u de d i n t he st u d y are s h o w n i n Ta ble 1.  
T a ble  1. V ari a bles i n t he st u d y 
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 1 7  of 2 7  
V ari a ble  
R ole  
D at a s o urce(s)  
D B C G 
v ari a ble(s)  
Dia g n osis (I C D -1 0 c o de: C 5 0)  
E x p os ure/I ncl usi o n  D B C G re gistr y   
N ot a p plica ble  
Treat me nt wit h Pal b ocicli b  
E x p os ure/I ncl usi o n  D B C G re gistr y   
R E 2 0 1, R E 2 0 1 A  
Date of birt h  
Baseli ne  
D B C G re gistr y   
Base d o n M 1  
Date of breast ca ncer dia g n osis  
Baseli ne  
D B C G re gistr y   
N ot a p plica ble  
Occ urre n ce of metastases  
Baseli ne  
D B C G re gistr y   
R E 2 2 0 -R E 2 2 7  
Visceral stat us ( visceral a n d n o n -visceral –  
visceral defi ne d as metastases i n t he or ga ns, 
e. g., l u n g, li ver))  
Baseli ne  
D B C G re gistr y   
R E 2 2 0 -R E 2 2 7  
B o ne o nl y  
Baseli ne  
D B C G re gistr y   
R E 1 4  
Metastatic sites (li ver, l u n g, C N S, l y m p h n o des)  Baseli ne  
D B C G re gistr y   
R E 1 0 -1 8 + 8 0 -8 1, 
1 1 7 -1 1 9, 2 1 9 -2 2 2  
De N o v o ( pri mar y m B C)  
Baseli ne  
D B C G re gistr y  
Calc ulate d  
Date of rela pse 
Baseli ne  
D B C G re gistr y   
R E 1 -R E 3  
Date f or treat me nt i nitiati o n wit h pal b ocicli b  
Baseli ne  
D B C G re gistr y   
R E 2 0 3 -R E 2 0 5  
Date f or treat me nt st o p wit h pal b ocicli b  
Baseli ne  
D B C G re gistr y   
R E 2 0 6 -R E 2 0 8  
C harls o n C o m or bi dit y I n de x ( C CI) –  p oi nt 
sc ores of 0, 1, 2 , a n d 3 or hi g her ( 3 +)  
(calc ulate d at start of pal b ocicli b treat me nt ) 
Baseli ne  
Nati o nal Patie nt Re gistr y 
( L P R) data use d t o defi ne 
C CI i n D B C G re gistr y  
N ot a p plica ble  
N u m ber of c o m or bi dities  (calc ulate d at start of 
pal b ocicli b treat me nt)  
Baseli ne  
Nati o nal Patie nt Re gistr y 
( L P R) data use d t o defi ne 
C CI i n D B C G re gistr y  
N ot a p plica ble  
T y pes of c o m or bi dities ( Car diac  disease , 
Vasc ular disease, Meta b olic disease, Ps yc hiatric 
disease, Bl o o d a n d l y m p hatic s yste m ) 
(calc ulate d at start of pal b ocicli b treat me nt) 
Baseli ne  
Nati o nal Patie nt Re gistr y 
( L P R) data use d t o defi ne 
C CI i n D B C G re gistr y  
N ot a p plica ble  
Deat h date  
Baseli ne 
c haracteristic  
D B C G re gistr y  
N ot a p plica ble 
P F S (see secti o n 8. 1 f or defi niti o n) 
O utc o me  
Esti mate d via D B C G 
re gistr y 
Base d o n 
varia bles liste d i n 
t his ta ble  
O S  (see secti o n 8. 1 f or defi niti o n) 
O utc o me  
Esti mate d via D B C G 
re gistr y re gistrati o ns 
Base d o n 
varia bles liste d i n 
t his ta ble  
 
 
 
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 1 8  of 2 7  
9. 4.  C h arls o n C o m or bi dit y I n de x ( C CI) a n d c o m or bi dities  
T he C harls o n C o m or bi dit y I n de x ( C CI) is use d as t he data s o urce f or c o m or bi dit y i n t he st u d y.  
T he data i n t he D B C G data base f or t h e C CI are ori gi nall y dra w n fr o m t he L P R. T he Nati o nal Patie nt 
Re gistr y has disease dat a o n all patie nts re q uiri n g a h os pital c o ntact, i.e. o ut patie nt a n d i n patie nt , 
w hic h mea ns t hat I C D -c o des (t o da y I C D -1 0 classificati o n) of patie nts diseases are rec or de d. I n C CI 
all c o m or bi dities, e xcl u di n g t he s pecific ca ncer t y p e u n der i n vesti gati o n, are i ncl u de d as 
c o m or bi dities, a n d i ncl u de d i n t he o verall C CI sc ore. I n t he prese nt st u d y t his mea ns t hat breast 
ca ncer i n itself (I C D -1 0: C 5 0 x) is n ot i ncl u de d, b ut ot her ca ncer -t y p es a n d t u m ors are. Data o n 
c o m or bi dities i n patie nts are rec or de d a n d calc ulat e d at start of t heir p al b ocicli b treat me nt, i.e. h o w 
ma n y a n d w hic h c o m or bi dities are pres e nt at t he ti me t he m B C patie nt gets pal b ocicli b , a n d w hat is 
t he ass ociate d C CI sc ore at t his ti me? 
Wit h t h e C harls o n C o m or bi dit y I n de x an o verall  C CI -sc ore ca n be calc ulate d f or eac h patie nt. F or 
eac h c o m or bi dit y re c or de d f or t he patie nt a s c ore b et wee n 0 a n d 6 is assi g ne d  de pe n di n g o n t he 
c o m or bi dit y a n d w het her it is  part of t he C CI . All sc ores are t he n s u m me d u p at t he e n d f or eac h 
patie nt. T he hi g her t he C CI sc ore t he m or e se vere t he c o m or bi dit y stat us.  
T he C CI i nstr u me nt use d i n t he st u d y is s h o w n bel o w i n Ta ble 2. 
 
 
 
0
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 1 9  of 2 7  
T a ble 2. C h arls o n C o m or bi dit y I n de x ( C CI) i n D B C G Re gistr y  ( S o urce: 3 8 ).
 
0
 
C O P Y RI G H T E D M A T E RI A L

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 2 0  of 2 7  
In  t he prese nt st u d y t he C CI sc ore is gr o u pe d i nt o f o ur g r o u ps as d efi ne d bel o w: 
•  P atie nts wit h a C CI sc ore of 0  defi n e s patie n ts wit h n o c o m or bi dit y  besi des t he breast c a ncer 
disease.  
•  P atie nts wit h a C CI sc ore of 1  defi n es patie nt s wit h o ne c o m or bi dit y  of t he t y pe wit h a sc ore of 
1 , e. g., m y ocar dial i nfarcti o n or dia betes mellit us . 
•  P atie nts wit h a C CI sc ore of 2  defi n es  patie nt s wit h  t w o c o m or bi dities eac h ha vi n g a sc ore of 1 
or o ne c o m or bi dit y al o ne wit h a C CI sc ore of 2, e. g., dia betes mellit us wit h o r ga n da ma ge or a 
s oli d t u m or besi des breast ca ncer disease.  
•  P atie nts wit h a C CI sc ore of 3  or hi g her ( 3 + ) defi n es patie nt s wit h se vere c o mor bi dit y /ies 
ha vi n g o n e c o m or bi dit y wit h a C CI sc ore of 6 , e. g., H u ma n I m m u n o defici e nc y Vir us/ Ac q uire d 
I m m u n o D eficie n c y S y n dr o me (HI V/ AI D S ), or t w o or m ore c o m or bi dities eac h wit h C CI  sc ores 
of 1 -2 . T hese c o m or bi dities are als o besi des t he patie nts'  breast ca n cer disease.  
 
A gai n, t he hi g her t he C CI s c ore t he m ore se v ere t he c o m or bi dit y stat us f or t he patie nt, lea vi n g t h ose 
wit h a C CI sc ore of 3 or hi g her ( C CI 3 +) as patie nts  bei n g m ost i m pacte d b y t heir c o m or bi d ities. 
 
Besi des usi n g t he C CI sc ore f or s u b gr o u p a nal yses of t he treat me nt o utc o m es ( P F S a n d O S), t he 
n u m ber of c o m or bi dities is als o use d f or s u b gr o u p a nal yses a n d calc ulate d fr o m t he C CI . P atie nts are 
s plit i nt o t hree c o m or bi dit y gr o u ps –  n o c o m or bi dit y, o ne c o m or bi dit y  a n d t w o or m ore 
c o m or bi dit ies. S plitti n g t he s u b gr o u p a nal ysis acc or di n g t o n u m ber of c o m or bi dities per patie nt p uts 
e q ual wei g ht o n all c o m or bi dities.  
 
I n the t hir d s u b gr o u p a nal ys es of t he treat me nt o ut c o mes ( P F S a n d O S) c o m or bi dities are 
categ orize d  i nt o fi ve mai n disease gr o u ps : Car diac  disease , Vasc ular disease, Meta b olic diseas e, 
Ps yc hiatric disease, Bl o o d a n d l y m p hatic s yste m . Rec or di n g of t hese will als o c o me fr o m t he C CI. 
 
9. 5.  D at a S o urces   
T his st u d y will be base d o n t he D B C G re gistr y  a n d t he Nati o nal Patie nt Re gistr y ( L P R)  wit h res pect 
t o t he c o m or bi dities. N o ot her Da nis h healt hcare re gistries will be i ncl u de d.  
 
9. 6.  St u d y S ize 
T he st u d y f oc usses o n all H R +/ H E R 2 - l ocall y a d v a nce d m B C patie nts (e n d ocri ne se nsiti ve , 
e n d ocri ne resista nt or de n o v o) t hat have  recei ve d pal b ocicli b i n c o m bi nati o n wit h AI as first -li ne 
treat me nt i n t he i ncl usi o n peri o d 1 Ja n uar y 2 0 1 7 t o 3 1 Dece m b er 2 0 2 1 .  
 
It is esti mate d t hat t he t ot al p o p ulati o n of pal b ocicli b-treate d patie nts f oll o wi n g t hese i ncl usi o n 
criteria i n t he D B C G re gistr y c o nstit utes 5 8 0  patie nts  o verall . 
 
S u b gr o u p a nal ys es of t his patie nt p o p ulati o n will be ma de bas e d o n a ge a n d c o m or bi dit y stat us as 
descri be d i n secti o n 8 a b o ve.  
0
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 2 1  of 2 7  
9. 7.  D at a M a n a ge me nt  
T he Da nis h Breast Ca ncer Gr o u p h osts t he D B C G re gistr y , a n d all a n al yses will be perf or me d b y 
D B C G’s bi ostatistical researc h ers f oll o wi n g t his pr ot oc ol a n d a pre -s pecifie d S A P. Pfizer will n ot 
ha ve access t o dat a at t he i n di vi d ual le vel –  o nl y s u m mar y data i n ta bles pr o d uce d b y D B C G as part 
of t he disc ussi o n o f res ults a n d re p orti n g.  
 
T he i n di vi d ual -le vel pati e nt data i n t he re gistr y are well-str uct ur e d, of hi g h q ualit y, a n d i n a rea d y-
t o-a nal yze f or mat. D ata will be a nal y ze d usi n g S A S s oft ware.  
 
9. 8.  D at a A n al ysis  
I n g e neral, t he res earc h q uesti o ns will be a d dresse d via descri pti ve statistics, i ncl u di n g stratificati o n 
o n s u b gr o u ps. I n t h e P F S a n d O S a nal yses, Ka pla n -Meier s ur vi v al distri b uti o n f u ncti o ns will be 
esti mate d, i m pl yi n g t hat statistics o n me dia n s ur vi val e x pect a nc y will be a v aila ble. O verall s ur vi val 
will be esti mate d f or all patie nts wit h a ce ns ori n g of data b y 1 st Fe br uar y 2 0 2 4 , ie, w h y t he ma xi m u m 
f oll o w-u p peri o d f or t he first treate d pal b oci cli b patie nt 1 Ja n uar y 2 0 1 7 will be 7  years  a n d o ne 
m o nt h .  
 
A se parate S A P, i ncl u di n g s hell ta bles, will be de v el o pe d pri or t o data a nal ysis. T he S A P will be 
date d, file d, a n d mai ntai n e d b y t he s p o ns or. T he S A P will als o i ncl u de precise defi niti o ns of t he 
s u b gr o u ps. T he S A P ma y m o dif y t he pla ns o utli ne d i n t he pr ot oc ol; a n y maj or m o dificati o ns of 
pri mar y e n d p oi n t defi niti o ns or t heir a nal yses w o ul d be reflecte d i n a pr ot o c ol a me n d me nt. 
 
9. 9.  Q u alit y C o ntr ol  
D B C G’s bi ostatistical researc h ers will c o m pile t he f ull data set a n d perf or m t he a nal yses. T he 
researc hers will f oll o w ge nerall y acce pte d met h o ds as well as D B C G’s i nter nal g ui deli nes f or d ata 
a nal ysis.  
 
T he st u d y i n v ol ves a nal yses of i n di vi d ual data. D B C G’s bi ostatistical researc hers will, h o we ver, 
o nl y ha ve access t o data i n de -pers o n alize d f or m ( b y e ncr y pte d p ers o nal i d e ntificati o n c o des). Pfi zer 
will n ot ha ve access t o a n y i n di vi d ual data i n t he pr oject, o nl y t he s u m mar y data pr o d uce d b y 
D B C G’s bi ostatistical researc h ers.  
 
F urt her m ore, t he st u d y d esi g n, literat ure, decisi o ns o n data a nal ysis, i nter pretati o n of t he res ults of 
t he st u d y, as well as re p orti n g ( ma n uscri pt) will be o nl y disc usse d i n t he pr oject gr o u p (see list of 
res p o nsi ble parties i n secti o n 3).  
 
T h is NI -St u d y wit h Pfizer as s p o ns or, c olla b orat or,  a n d part of t he pr oject gr o u p , will ha ve t o use 
certai n te m plates, i ncl. t h e prese nt pr ot o c ol te m plate a n d a te m plate f or t he S A P, etc. F urt her m ore, 
t he st u d y m ust  f oll o w certai n re vie w sta g es b y t he s p o ns or s uc h as a tec h nical pr ot oc ol re vie w a n d a 
re vie w of t h e fi nal scie ntific ma n uscri pt pri or t o s u b missi o n t o a scie ntific j o ur nal.  
 
 
 
0
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 2 2  of 2 7  
9. 1 0.  Li mit ati o ns  of t he R ese arc h M et h o ds  
T his st u d y has b ot h stre n gt hs a n d li mitati o ns.  
 
 
D B C G has a l o n g hist or y of c o m pili n g a n d mai ntai ni n g re gistr y data f or t he past 4 0 years. T he data 
fr o m D B C G has bee n p art of b ot h nati o nal a n d i nter nati o nal st u dies. I n a d diti o n, t he data c ollecte d 
b y D B C G ha ve bee n p u blis he d i n m ore t ha n 6 3 2  peer -re vie we d pa p ers (2 9 , 41 ). 
 
A n d ha ve  bee n part of se veral meta -a nal yses c o n d ucte d b y Earl y Br east Ca ncer Tri allists’ 
C olla b orati ve Gr o u p ( 4 2 , 43 ). T he e xte nsi o n of t his re gistr y t o i ncl u de rela pse d patie nts nati o n wi de is 
t heref ore a u ni q ue  feat ur e of t his re gistr y a n d was pre vi o usl y utilize d i n t he st u d y b y Garl y et al. 
(3 0 ). C ollect i n g rela pse d ata a b o ut M B C patie nts has bee n a c halle n g e i n ma n y c o u ntries.  
 
T he D B C G re gistr y h ol ds t he m ost detaile d a n d c o m pre he nsi ve i nf or m ati o n a b o ut patie nts dia g n ose d 
wit h H R +/ H E R 2 - l ocall y a d va nce d or metastatic breast c a ncer, i m pl yi n g t hat, c o m pare d t o ot her 
Da nis h healt hcare re gistries, ne w a n d m or e detaile d res ults ca n b e prese nte d. F urt her m ore, t he st u d y 
is carrie d o ut at t he p o p ul ati o n le vel, w hic h ma kes t he st u d y a n d its res ults as c o m plete a n d 
ge neraliza ble as p ossi ble a n d mi ni mizes t he ris k of selecti o n bias.  
 
At t he sa me ti me, si nce t his st u d y o nl y i n v ol ves data fr o m t he D B C G re gistr y, t he c o m pleti o n a n d 
vali dit y of t he a nal yses rel y 1 0 0 % o n t he q ualit y a n d vali dit y of t he data i n t he re gistr y.  
T he st u d y d oes f urt her m ore o nl y i ncl u de t he dat a a vaila ble i n t he D B C G re gistr y a n d o nl y data of a 
q ua ntitati ve nat ure. M or e q ualitati ve data a n d o utc o mes f oll o wi n g t he treat me nt of t he breast ca ncer 
patie nts will t h u s n ot be i ncl u de d.  
 
9. 1 1.  Ot her A s pects 
N ot a p plica ble.  
 
1 0.  P R O T E C TI O N O F H U M A N P A R TI CI P A N T S  
All parties will e ns ure pr otecti o n of patie nt pers o n al data a n d will n ot i ncl u de patie nt na mes o n a n y 
s p o ns or f or ms, re p orts, or p u blicati o ns, or i n a n y ot her discl os ures e x ce pt w here re q uire d b y la w. As 
descri be d, D B C G’s bi ost atistical researc hers will ha ve access o nl y t o data i n de -pers o nalize d f or m 
(e ncr y pt e d pers o n al i de ntificati o n c o des ( C P R)). Pfizer will n ot ha ve access t o a n y i n di vi d ual data i n 
c o n necti o n wit h t he pr oject b ut o nl y t he s u m mar y data pr o d uce d b y D B C G’s  bi ostatistical 
researc hers. 
1 0. 1.  P atie nt Inf or m ati o n  
T his st u d y i n v ol ves data t hat e xist i n a dei de ntifie d/ a n o n y mize d str uct ure d f or mat  a n d c o nt ai n n o 
patie nt pers o nal i nf or m ati o n .   
 
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 2 3  of 2 7  
1 0. 2.  P atie nt C o nse nt  
As t his st u d y i n v ol ves dei de ntifie d /a n o n y mize d  str uct ure d d ata, w hic h acc or di n g t o a p plica ble le gal 
re q uire me nts d o n ot c o nt ai n data s u bject t o pri vac y la ws, o btai ni n g i nf or me d c o nse nt fr o m p atie nts 
b y Pfizer is n ot re q uire d.    
1 0. 3.  I nstit uti o n al R e vie w B o ar d (I R B)/ E t hics C o m mittee ( E C)  
A p pr o val fr o m t he Da nis h Data Pr otecti o n A ge n c y is n ot necessar y f or t his t y pe of st u d y. H o we ver, 
i n acc or da nce wit h Ge neral Data Pr otecti o n Re g ulati o n ( G D P R) t he st u d y will be re p orte d via 
Pacti us t o t he Ca pital Re gi o n of De n mar k’s researc h list.  
 
A p pr o val fr o m a n et hics c o m mittee is n ot re q uire d b y Da nis h la w si nce a retr os pecti ve d ata base 
st u d y d oes n ot i n v ol ve c ollecti o n of or res earc h o n bi ol o gical material.  
 
N o ot her a p pr o vals fr o m I R Bs or I E Cs are necessar y u n der Da nis h la w.   
1 0. 4.  Et hic al C o n d uct of t he S t u d y 
T he st u d y will be c o n d ucte d i n acc or da nce wit h le gal a n d re g ulat or y re q uir e me nts, as well as wit h 
scie ntific p ur p ose, v al ue, a n d ri g or a n d f oll o w ge n erall y acce pte d researc h practices d escri b e d i n  
G o o d pr actices f or re al -w orl d d at a st u dies of tre at me nt a n d/ or c o m p ar ative effective ness: 
Rec o m me n d ati o ns fr o m t he j oi nt I S P O R -I S P E S p eci al T ask F orce o n re al-w orl d evi de nce i n he alt h 
c are decisi o n m a ki n g  (4 4 ).  
F urt her m ore, t he st u d y will c o m pl y wit h t he rece nt E S M O G R O W  g ui d a n ce f or re p orti n g o nc ol o g y 
real-w orl d e vi de nce ( 3 7 ). 
 
1 1.  M A N A G E M E N T A N D R E P O R TI N G O F A D V E R S E E V E N T S/ A D V E R S E R E A C TI O N S  
T his st u d y i n v ol ves data t hat e xist as str uct ure d data b y t he ti me of st u d y start . I n t hese d ata s o urces, 
i n di vi d ual patie nt data are n ot retrie v e d or vali dat e d, a n d it is n ot p ossi ble t o li n k (i.e., i de ntif y a 
p ote ntial ass ociati o n bet wee n) a partic ul ar pr o d u ct a n d me dical e ve nt f or a n y i n di vi d ual. T h us, t he 
mi ni m u m criteria f or re p orti n g a n a d verse e ve nt ( A E) (i.e., i de ntifia bl e patie nt, i de ntifia ble re p ort er, 
a s us pect pr o d u ct, a n d e v e nt) ca n n ot be m et.  
 
1 2.  P L A N S F O R DI S S E MI N A TI N G A N D C O M M U NI C A TI N G S T U D Y R E S U L T S  
Besi des a st u d y re p ort prese nti n g t he res ults, a ma n uscri pt f or a s cie ntific article will be writte n a n d 
s u b mitte d t o a n i nter nati o nal peer-re vie we d j o ur n al. T he c h ose n t ar get ma n uscri pt f or s u b missi o n of 
t he ma n uscri pt is deci de d i n c o nse ns us b y t he pr oj ect gr o u p (see gr o u p i n s ecti o n 3). 
A ut h ors hi p criteria of t h e article ma n uscri pts will f oll o w t he re q uire me nts s et b y t he I nter n ati o nal 
C o m mittee of Me dical J o ur nal E dit ors (I C MJ E) 
( htt p:// w w w.ic mje. or g/rec o m me n dati o ns/ br o wse/r oles-a n d-res p o nsi bilities/ defi ni n g-t he-r ol e-of -
a ut h ors -a n d-c o ntri b ut ors. ht ml). All m e m bers of t he pr oject gr o u p as descri be d i n secti o n 3 of t his 
pr ot oc ol, i ncl u di n g e xter nal me m bers a n d Pfizer e m pl o yees, as well as ot hers i n v ol ve d fr o m D B C G 
i n t he prese nt st u d y, all f ulfilli n g t hese re q uire me nts wit h res pect t o t he man uscri pts s h o ul d be 
0
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 2 4  of 2 7  
offere d c o -a ut h ors hi p of t he scie ntific articl e. First drafts of t he ma n us cri pt s h o ul d be ma de a vaila bl e 
t o all c o-a ut h ors f or t h eir o bli gati o n t o c o m me nt o n t he ma n uscri pt as c o -a ut h or. All c o -a ut h ors 
s h o ul d a p pr o ve t he fi nal ma n uscri pt pri or t o s u b missi on t o t he a gree d j o ur n al.  
T he st u d y a n d its res ults will als o be discl ose d at t he Cli nical Trials. g o v we bsite.  
I n t he e ve nt of a n y pr o hi biti o n or restricti o n i m p ose d (e g, cli nical h ol d) b y a n a p plica ble c o m pete nt 
a ut h orit y i n a n y area of t he w orl d, or if t he p art y res p o nsi ble f or c ollecti n g is a ware of a n y ne w 
i nf or mati o n w hic h mi g ht i nfl ue nce t he e val uati o n of t he be nefits a n d ris ks of a Pfizer pr o d uct, Pfizer 
s h o ul d be i nf or me d i m me diatel y.   
 
1 3.  R E F E R E N C E S   
1. Bea ver J A, A miri -K or desta ni L, C harla b R, et al. F D A a p pr o val: pal b ocicli b f or t he treat me nt of p ost me n o pa usal 
patie nts wit h estr o ge n rece pt or -p ositi ve, H E R 2 -ne gati ve metastatic breast ca ncer. Cli n Ca ncer Res 2 0 1 5; 2 1: 4 7 6 0 -6.  
 
2. Fi n n R S, Cr o w n J P, La n g I, et al. T he c y cli n -de pe n de nt ki nase 4/ 6 i n hi bit or pal b ocicli b i n c o m bi nati o n wit h letr oz ole 
vers us letr oz ole al o ne as first -li ne treat me nt of oestr o ge n rece pt or-p ositi ve, H E R 2 -ne gati ve, a d va nce d breast ca n cer 
( P A L O M A-1/ T RI O -1 8): a ra n d o mise d p hase 2 st u d y. T he La n cet O nc ol o g y 2 0 1 5; 1 6: 2 5 -3 5.  
 
3. Da nis h Me dici nes C o u ncil. T he Da nis h Me dici nes C o u ncil dr u g rec o m me n dati o n a n d treat me nt g ui deli nes f or 
c d k 4/c d k 6 i n hi bit ors f or E R + / H E R 2 - l ocall y a d va nce d or metastatic breast ca ncer. Versi o n 2. 1. A u g ust 9 2 0 2 3 . 
A vaila ble fr o m: w w w. me dici nraa det. d k . 
 
4 . Bra y F, Ferla y J, S oerj o matara m I, et al. Gl o bal ca ncer statistics 2 0 1 8: G L O B O C A N esti mates of i nci de nce a n d 
m ortalit y w orl d wi de f or 3 6 ca ncers i n 1 8 5 c o u ntries. C A Ca ncer J Cli n 2 0 1 8; 6 8( 6): 3 9 4 -4 2 4.  
 
5 . Fi n n R S, Cr o w n J P, La n g I, et al. T he c y cli n -de pe n de nt ki nase 4/ 6 i n hi bit or pal b ocicli b i n c o m bi nati o n wit h letr oz ole 
vers us letr oz ole al o ne as first -li ne treat me nt of oestr o ge n rece pt or-p ositi ve, H E R 2 -ne gati ve, a d va nce d breast ca n cer 
( P A L O M A-1/ T RI O -1 8): a ra n d o mise d P hase II st u d y. La ncet O nc ol 2 0 1 5; 1 6( 1): 2 5 -3 5.  
 
6 . Crist ofa nilli M, T ur ner N C, B o n dare n k o I, et al. F ul vestra nt pl us pal b ocicli b vers us f ul vestra nt pl us place b o f or 
treat me nt of h or m o ne-rece pt or-p ositi ve, H E R 2 -ne gati ve metastatic breast ca ncer t hat pr o gresse d o n pre vi o us e n d ocri ne 
t hera p y ( P A L O M A-3): fi nal a nal ysis of t he m ultice ntre, d o u ble -bli n d, P hase  III ra n d o mise d c o ntr olle d trial. La ncet 
O nc ol 2 0 1 6; 1 7( 4): 4 2 5 -3 9.  
 
7 . T ur ner N C, Sla m o n DJ, R o J, et al. O verall s ur vi val wit h pal b ocicli b a n d f ul vestra nt i n a d va nce d breast ca ncer. N E n gl 
J Me d 2 0 1 8; 3 7 9( 2 0): 1 9 2 6-3 6.  
 
8 . H ort o ba g yi G N, Ste m mer S M, B urris H A, et al. Ri b ocicli b as first -li ne t hera p y f or H R-p ositi ve, a d va nce d breast 
ca ncer. N E n gl J Me d 2 0 1 6; 3 7 5( 1 8): 1 7 3 8 -4 8.  
 
9 . Sla m o n DJ, Ne v e n P, C hia S, et al. P hase III ra n d o mize d st u d y of ri b ocicli b a n d f ul vestra nt  i n h or m o ne rece pt or-
p ositi ve, h u ma n e pi der mal gr o wt h fact or rece pt or 2 -ne gati ve a d va nce d breast ca ncer: M O N A L E E S A -3. J Cli n O nc ol 
2 0 1 8; 3 6( 2 4): 2 4 6 5 -7 2.  
 
1 0 . Tri pat h y D, I m S A, C olle o ni M, et al. Ri b ocicli b pl us e n d ocri ne t hera p y f or pre me n o pa usal w o me n wit h h or m o ne -
rece pt or-p ositi ve, a d va nce d breast ca n cer ( M O N A L E E S A -7): a ra n d o mise d P hase III trial. La ncet O nc ol 
2 0 1 8; 1 9( 7): 9 0 4 -1 5.  
 
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 2 5  of 2 7  
1 1 . Dic kler M N, T ola ne y S M, R u g o H S, et al. M O N A R C H 1, a P hase II st u d y of a be macicli b, a C D K 4 a n d C D K 6 
i n hi bit or, as a si n gle a ge nt, i n patie nts wit h refract or y H R( +)/ H E R 2(-) metastatic breast ca ncer. Cli n. Ca ncer Res 
2 0 1 7; 2 3( 1 7): 5 2 1 8 -2 4.  
 
1 2 . Sle d ge G W Jr, T oi M, Ne ve n P, et al. M O N A R C H 2: a be macicli b i n c o m bi nati o n wit h f ul vestra nt  i n w o me n wit h 
H R +/ H E R 2 - a d va n ce d breast ca ncer w h o ha d pr o gresse d w hile recei vi n g e n d ocri ne t hera p y. J Cli n O nc ol 
2 0 1 7; 3 5( 2 5): 2 8 7 5 -8 4.  
 
1 3 . G oetz M P, T oi M, Ca m p o ne M, et al. M O N A R C H 3: a be macicli b as i nitial t hera p y f or a d va nce d breast ca ncer. J 
Cli n O nc ol 2 0 1 7; 3 5( 3 2): 3 6 3 8 -4 6.  
 
1 4. R u g o H S, Fi n n R S, Diéras  V, et al. Pal b ocicli b pl us letr oz ole as first -li ne t hera p y i n estr o ge n rece pt or-
p ositi ve/ h u ma n e pi der mal gr o wt h fact or rece pt or 2 -ne gati ve a d va n ce d breast ca ncer wit h e xte n de d f oll o w -u p. Breast 
Ca n cer Res Treat 2 0 1 9; 1 7 4( 3): 7 1 9 -2 9.   
 
1 5. Fi n n R S, R u g o H S, Dieras V C, Har bec k N, I m S -A, Gel m o n K A, Wals he J M, Marti n M, Gre g or M C M, Ba na nis E, 
Ga ut hier E R, L u D R, Ki m S, Sla m o n DJ; O verall s ur vi val ( O S) wit h first -li ne pal b ocicli b pl us letr oz ole ( P A L + L E T) 
vers us place b o pl us letr oz ole ( P B O + L E T) i n w o me n wit h estr o ge n rece pt or – p ositi ve/ h u ma n e pi der mal gr o wt h fact or 
rece pt or 2– ne gati ve a d va nce d breast ca n cer ( E R +/ H E R 2 − A B C): A nal yses fr o m P A L O M A -2. J C O 2 0 2 2 v ol 4 0 Iss ue 1 7 
S u p pl. htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 2 0 2 2. 4 0. 1 7 _s u p pl. L B A 1 0 0 3 . 
 
1 6 . Car d os o F, Har bec k N, Fall o wfiel d L et al. L ocall y rec urre nt or metastatic breast ca ncer: E S M O Cli nical Practice 
G ui deli nes f or dia g n osis, treat me nt a n d f oll o w -u p. A n n O nc ol 2 0 1 2; 2 3 (s u p pl 7): vii 1 1 – vii 1 9.  
 
1 7 . J ør ge nse n T L, Hallas J, Friis S, Herrste dt J. C o m or bi dit y i n el derl y ca ncer patie nts i n relati o n t o o verall a n d ca ncer-
s pecific m ortalit y. Br J Ca n cer. 2 0 1 2 Mar 2 7; 1 0 6( 7): 1 3 5 3 -6 0. d oi: 1 0. 1 0 3 8/ bjc. 2 0 1 2. 4 6. E p u b 2 0 1 2 Fe b 2 1. P MI D: 
2 2 3 5 3 8 0 5; P M CI D: P M C 3 3 1 4 7 8 2.  
 
1 8 . E n g h ol m G, Ferla y J, C hriste nse n N, Gjerst orff M L, J o ha n nese n T B, Kli nt A˚, K øtl u m J E, O´lafs d o´ttir E, P u k kala 
E, St or m H H ( 2 0 1 1) N O R D C A N: Ca n cer I nci de nce, M ortalit y, Pre vale n ce a n d S ur vi val i n t he N or dic C o u ntries, 
Versi o n 4. 0. Ass ociati o n of t he N or d ic Ca n cer Re gistries. Da nis h Ca ncer S ociet y (htt p:// w w w.a ncr. n u ). 
 
1 9 . S ø gaar d M, T h o mse n R W, B osse n K S, S øre nse n H T, N ør gaar d M. T he i m pact of c o m or bi dit y o n ca ncer s ur vi val: a 
re vie w. Cli n E pi de mi ol. 2 0 1 3 N o v 1; 5( S u p pl 1): 3-2 9. D oi: 1 0. 2 1 4 7/ C L E P. S 4 7 1 5 0. P MI D: 2 4 2 2 7 9 2 0; P M CI D: 
P M C 3 8 2 0 4 8 3.  
 
2 0 . State ns Ser u m I nstit ut. Sa m me n h æ n g melle m k o m or bi ditet o g be ha n dli n g i n de n f or sta n dar df orl ø bsti der ne i 
pa k kef orl ø b f or kr æft. K ø be n ha v n: State ns Ser u m I nstit ut & Nati o nal S u n d he ds d o k u me ntati o n o g -I T; 2 0 1 5. 
 
2 1 . La n d L H, Dalt o n S O, Je nse n M B, E wertz M. I m pact of c o m or bi dit y o n m ortalit y: a c o h ort st u d y of 6 2, 5 9 1 Da nis h 
w o me n dia g n ose d wit h earl y breast ca n cer, 1 9 9 0 -2 0 0 8. Breast Ca ncer Res Treat. 2 0 1 2; 1 3 1( 3): 1 0 1 3 – 2 0. 
htt ps:// d oi. or g/ 1 0. 1 0 0 7/s 1 0 5 4 9 -0 1 1 -1 8 1 9 -1 . 
 
2 2 . Ja k o bse n M, K ol o dziejcz y k C, Je nse n M S, P o ulse n P B, K ha n H, K ü mler T, A n derss o n M. Car di o vasc ular disease i n 
w o me n wit h breast ca n cer –  a nati o n wi de c o h ort st u d y. B M C Ca ncer 2 0 2 1; 2 1: 1 0 4 0 htt ps:// d oi. or g/ 1 0. 1 1 8 6/s 1 2 8 8 5 -0 2 1 -
0 8 7 1 6 -5 .  
 
2 3 . K ol o dziejcz y k C, Ja k o bse n M, Je nse n M S, P o ulse n P B, K ha n H, K ü mler T, A n derss o n M. M ortalit y fr o m 
car di o vasc ular disease i n w o me n wit h breast ca ncer - a nati o n wi de re gistr y st u d y. Acta O nc ol 2 0 2 1; 1 -7. 
htt ps:// d oi: 1 0. 1 0 8 0/ 0 2 8 4 1 8 6 X. 2 0 2 1. 1 9 5 9 0 5 4 . 
 
2 4 . C orri ga n -C ura y J, Sac ks L, W o o dc o c k J. Real -w orl d e vi de nce a n d real -w orl d data f or e val uati n g dr u g safet y a n d 
effecti ve n ess. J A M A 2 0 1 8; 3 2 0( 9): 8 6 7-8.  
 
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 2 6  of 2 7  
2 5 . G ya wali B, Parsa d S, Fei n ber g B A, et al. Precis O nc ol. 2 0 1 7. htt ps:// d oi. or g/ 1 0. 1 2 0 0/ P O. 1 7. 0 0 1 3 2. [ E p u b].  
 
2 6 . Har bec k N, Bartlett M, S p ur de n D, et al. C D K 4/ 6 i n hi bit ors i n H R +/ H E R 2 - a d va nce d/ metastatic breast ca ncer: a 
s yste matic literat ure re vie w of real-w orl d e vi de n ce st u dies. F ut ure O nc ol 2 0 2 1; 1 7( 1 6): 2 1 0 7 -2 2.  
 
2 7 . De Mic hele A, Crist ofa nilli M, Br ufs k y A, et al. C o m parati ve effecti ve ness of first -li ne pal b ocicli b pl us letr oz ole 
vers us letr oz ole al o ne f or H R +/ H E R 2 - metastatic breast ca ncer i n U S real -w orl d cli nical practice. Breast Ca ncer Res 
2 0 2 1; 2 3( 1): 3 7. htt ps:// d oi. or g/ 1 0. 1 1 8 6/s 1 3 0 5 8 -0 2 1 -0 1 4 0 9 -8 . 
 
2 8 . R u g o H S, Br ufs k y A, Li u X, Li B, Mc R o y L, C he n C, La y ma n R M, Crist ofa nilli M, T orres M A, C uri glia n o G, Fi n n 
R S & A n gela De Mic hele A; Real -w orl d st u d y of o verall s ur vi val wit h pal b ocicli b pl us ar o matase i n hi bit or i n 
H R +/ H E R 2 − metastatic breast ca ncer. n pj Breast Ca ncer 2 0 2 2. htt ps:// d oi. or g/ 1 0. 1 0 3 8/s 4 1 5 2 3 -0 2 2 -0 0 4 7 9 -x .  
 
2 9 . Garl y R, Ber g T, Je nse n M B, K n o o p A, V ol mer L, Gla vicic V, K ha n H, P o ulse n P B, Olse n J, K ü mler I. A 
Retr os pecti ve, N o n -I nter ve nti o nal St u d y of Breast Ca ncer Patie nts Dia g n ose d Wit h E R +/ H E R 2 Ne g ati ve, L ocall y 
A d va n ce d or Metastatic Breast Ca ncer Treate d wit h Pal b ocicli b i n De n mar k. Acta O nc ol o gica 2 0 2 3; 1 -8. 
htt ps:// d oi: 1 0. 1 0 8 0/ 0 2 8 4 1 8 6 X. 2 0 2 3. 2 1 9 4 0 3 0 . 
 
3 0 . Free d ma n R A, F oster J C, Seisler D K, Laf k y J M, M uss H B, C o he n HJ, Ma n del blatt J, Wi ner E P, H u dis C A, 
Partri d ge A H, Care y L A, Cirri nci o ne C, M ore n o -As pitia A, Ki m mic k G, Jat oi A, H urria A. Accr ual of Ol der Patie nts 
Wit h Breast Ca n cer t o Allia nce S yste mic T hera p y Trials O ver Ti me. Cli n O nc ol ( 2 0 1 7) 3 5( 4): 4 2 1 -2 1. 
htt ps:// d oi. or g/ 1 0. 1 2 0 0/jc o. 2 0 1 6. 6 9. 4 1 8 2 .  
 
3 1 . R u g o H S, T ur ner N C, Fi n n R S, J o y A A, Ver ma S, Har bec k N, Mas u da N, I m S-A, H ua n g X, Ki m S, S u n W, I yer S, 
Sc h nell P, Bartlett C H, J o h nst o n S.  Pal b ocicli b pl us e n d ocri ne t hera p y i n ol der w o me n wit h H R +/ H E R 2 –  a d va nce d 
breast ca n cer: a p o ole d a nal ysis of ra n d o mise d P A L O M A cli nical st u dies. EJ C 1 0 1 ( 2 0 1 8) 1 2 3 -1 3 3. 
htt ps:// d oi. or g/ 1 0. 1 0 1 6/j.ejca. 2 0 1 8. 0 5. 0 1 7 . 
  
3 2 . Br ufs k y A, Li u X, Li B, Mc R o y L, C he n C, La y ma n R M, R u g o H S. Real -w orl d treat me nt patter ns a n d effecti ve n ess 
of pal b ocicli b pl us a n ar o matase i n hi bit or i n patie nts wit h metastatic breast ca ncer a ge d 7 5 years or ol der. Fr o ntiers i n 
O nc ol o g y, V ol 1 3 2 0 2 3 htt ps:// d oi. or g/ 1 0. 3 3 8 9/f o nc. 2 0 2 3. 1 2 3 7 7 5 1 .  
  
3 3 . R u g o H S, Li u X, Li B, Mc R o y L, La y ma n R M, Br ufs k y A; Real-w orl d c o m parati ve effecti ve ness of pal b ocicli b pl us 
letr oz ole vers us letr oz ole i n ol der patie nts wit h metastatic breast ca ncer. T he Breast 6 9 ( 2 0 2 3) 3 7 5-3 8 1. 
htt ps:// d oi. or g/ 1 0. 1 0 1 6/j. breast. 2 0 2 3. 0 3. 0 1 5 .  
 
3 4. De nt S, G u ha A, M o ore H, Mc Cale b R, Arias I, Ster gi o p o ul os S, Li B, Ma kari D, Fra dle y M. C A R DI A C -S T A R: 
Pre vale n ce of Car di o vasc ular C o m or bi dities i n H or m o ne Rece pt or P ositi ve H u ma n E pi der mal Gr o wt h Fact or Ne g ati ve 
meta Static breas T c A n ce R. P oster P O 1 -0 4 -1 3. S A B C S 2 0 2 3. 
htt ps://at g pr o d ucti o ns. net/at gclie nts/sa b cs/ 2 0 2 3 _ S A B C S _ A bstract _ Re p ort -1 2 -3 -2 3. p df  
 
3 5. Tri pat h y D, Bl u m J L, Kar ut uri M S, Mc C u ne S, K uria n S, M o ezi M M, A n ders o n D M, Wa n g Y, M o ntel o n g o M Z, 
Z ha n g Z, Ga ut hier E, R oc q ue E; I m pact of c o m or bi dities o n real -w orl d patie nt -re p orte d o utc o mes of patie nts wit h 
h or m o ne rece pt or p ositi ve h u ma n e pi der ma l gr o wt h fact or 2 ne gati ve ( H R +/ H E R 2– ) a d va nce d breast ca ncer e nr olle d i n 
t he P O L A RI S trial. E S M O 2 0 2 3 3 7 3 P. htt ps:// o nc ol o g y pr o.es m o. or g/ meeti n g -res o urces/es m o-c o n gress/i m pact -of -
c o m or bi dities -o n -real-w orl d -r w-cli nical -o utc o mes -of -patie nts -pts -wit h -h or m o ne -rece pt or-p ositi ve -h u ma n -e pi der mal -
gr o wt h -fact or-2 -ne g at . 
 
3 6. Br ufs k y A, Li u X, Li B, Mc R o y L, C he n C, Ma kari D, La y ma n R, R u g o H; Real -w orl d effecti ve ness of pal b ocicli b 
pl us ar o matase i n hi bit ors ( AI) i n metastatic breast ca ncer patie nts wit h car di o vasc ular diseases. S A B C S 2 0 2 3 P O 1 -1 7 -
0 5. 2 0 2 3 S A B C S A bstract Re p ort -1 2 -1 -2 3 (at g pr o d ucti o ns. net ). 
 
 
 
 

Pal b ocicli b  
A 5 4 8 1 1 8 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 3 . 0, 1 7  Fe br uar y 2 0 2 5   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -A u g -
2 0 2 3    
Pa ge 2 7  of 2 7  
3 7 . Castel o-Bra n c o L, Pellat  A, Marti ns -Bra n c o D, Valac his A, Der kse n J W G,  
S uij ker b uij k K P M, Daf ni U, Della p orta T, V o gel A, Prelaj A, Gr oe n w ol d R H H, Marti ns H, Sta hel R, Bliss J, Kat h er J, 
Ri belles N, Perr o ne F, Hall P S, Die nst ma n n R, B o ot h C M, Pe nt her o u da kis G, Delal o ge S, K o o p ma n M. E S M O 
G ui da n ce f or Re p orti n g O nc ol o g y real -W o rl d e vi de nce ( G R O W). E S M O Real W orl d Data a n d Di gital O nc ol o g y ( 2 0 2 3), 
d oi: htt ps:// d oi. or g/ 1 0. 1 0 1 6/j.es m or w. 2 0 2 3. 1 0. 0 0 1 . 
 
3 8 . D M C G. d k Be n c h mar ki n g C o ns orti u m. Ra p p ort o m ca ncer o verle velse i Da n mar k 1 9 9 5-2 0 1 2. 
htt ps:// w w w. d mc g. d k/siteassets/ars beret ni n ger -o g -u d gi velser/ be nc h mar ki n g -
c o ns orti u m/a _f orsi der _ _ _ met o der _ 1 0 _ 1 1 _ 2 0 1 4. p df .  
 
3 9 . C olli n LJ, Cr o ni n-Fe nt o n D P, A her n T P, C hristia nse n P M, Da m kier P, Ejlertse n B, Ha milt o n -D ut oit S, Kj ærs gaar d 
A, Silli ma n R A, S øre nse n H T, Las h T L. T he Pre dict ors of Breast Ca ncer Rec urre nce ( Pr o Be Ca R E) Pre me n o pa usal 
Breast Ca ncer C o h ort St u d y i n De n mar k. B MJ O pe n 2 0 1 8; 8( 7):e 0 2 1 8 0 5. htt ps:// d oi. or g/ 1 0. 1 1 3 6/ b mj o pe n -2 0 1 8 -0 2 1 8 0 5 .  
 
4 0 . Je nse n M B, Lae n k h ol m V K, Offerse n B V, C hristia nse n P, Kr o ma n N, M o uri dse n HJ, Ejlertse n B. T he cli nical 
data b ase a n d i m ple me ntati o n of treat me nt g ui deli nes b y t he Da nis h Breast Ca ncer C o o perati ve Gr o u p i n 2 0 0 7 – 2 0 1 6. 
Acta O nc ol o gica 2 0 1 8; 5 7( 1): 1 3 -1 8.  
4 1 . Da nis h Breast Ca ncer C o o perati ve Gr o u p [ h o me pa ge o n t he I nter net]. C o pe n ha ge n. A vaila ble fr o m 
htt p:// w w w. d bc g. d k/  (accesse d Dece m ber 1 7t h 2 0 2 3). 
 
4 2 . E B C T C G ( Earl y Breast C a n cer Triallists` C olla b orati ve Gr o u p). Effects of ra di ot hera p y a n d of differe nces i n t he 
e xte nt of s ur ger y f or earl y breast ca ncer o n l ocal rec urre nce a n d o n 1 5 -year s ur vi val. A n o ver vie w of ra n d o mize d trials. 
La n cet 2 0 0 5; 3 6 6( 9 5 0 3): 2 0 8 7 – 1 0 6.  
 
4 3 . E B C T C G ( Earl y Breast C a n cer Triallists´ C olla b orati ve Gr o u p). Effects of c he m ot hera p y a n d h or m o nal t hera p y o n 
l ocal rec urre nces a n d o n 1 5-year s ur vi val. A n o ver vie w of ra n d o mize d trials. La ncet 2 0 0 5; 3 6 5( 9 4 7 2): 1 6 8 7 – 7 1 7.  
 
4 4. Ber ger M L, S o x H, Will ke RJ, Bri x ner D L, Eic hler H G, G oettsc h W, Ma di ga n D, Ma ka d y A, Sc h nee weiss S, 
Tarric o ne R, Wa n g S V, Wat ki ns J, M ulli ns C D. G o o d practices f or real‐ w orl d data st u dies of treat me nt a n d/ or 
c o m parati ve effecti ve n ess: Rec o m me n dati o ns fr o m  t he j oi nt I S P O R‐I S P E S pecial Tas k F orce o n real‐ w orl d e vi de n ce i n 
healt h care decisi o n ma ki n g. P har mac oe pi de mi ol Dr u g Saf 2 0 1 7; 2 6( 9): 1 0 3 3 – 9.  
 
1 4.  LI S T O F T A B L E S  
Ta ble 1. Varia bles i n t he st u d y  
Ta ble 2. C harls o n C o m or bi dit y I n de x ( C CI)  
 
1 5.  LI S T O F FI G U R E S  
N ot a p plica ble.  
A N N E X 1. LI S T O F S T A N D A L O N E D O C U M E N T S  
N o ne.  
A N N E X 2 . A D DI TI O N A L I N F O R M A TI O N 
N ot a p plica ble.