Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies.
BACKGROUND
Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype.


RESULTS
We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy.


CONCLUSIONS
The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required.
Department of Oncology, University of Cambridge, United Kingdom.
Fiona M
FM
Blows
Kristy E
KE
Driver
Marjanka K
MK
Schmidt
Annegien
A
Broeks
Flora E
FE
van Leeuwen
Jelle
J
Wesseling
Maggie C
MC
Cheang
Karen
K
Gelmon
Torsten O
TO
Nielsen
Carl
C
Blomqvist
Päivi
P
Heikkilä
Tuomas
T
Heikkinen
Heli
H
Nevanlinna
Lars A
LA
Akslen
Louis R
LR
Bégin
William D
WD
Foulkes
Fergus J
FJ
Couch
Xianshu
X
Wang
Vicky
V
Cafourek
Janet E
JE
Olson
Laura
L
Baglietto
Graham G
GG
Giles
Gianluca
G
Severi
Catriona A
CA
McLean
Melissa C
MC
Southey
Emad
E
Rakha
Andrew R
AR
Green
Ian O
IO
Ellis
Mark E
ME
Sherman
Jolanta
J
Lissowska
William F
WF
Anderson
Angela
A
Cox
Simon S
SS
Cross
Malcolm W R
MW
Reed
Elena
E
Provenzano
Sarah-Jane
SJ
Dawson
Alison M
AM
Dunning
Manjeet
M
Humphreys
Douglas F
DF
Easton
Montserrat
M
García-Closas
Carlos
C
Caldas
Paul D
PD
Pharoah
David
D
Huntsman
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D066246:ErbB Receptors / Q000032:analysis*; D005260:Female; D006728:Hormones / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055815:Young Adult
D014408:Biomarkers, Tumor; D006728:Hormones; D011956:Receptors, Cell Surface; D007633:Keratins; D066246:ErbB Receptors