Research Article: 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

Date Published: May 25, 2010

Publisher: Public Library of Science

Author(s): Fiona M. Blows, Kristy E. Driver, Marjanka K. Schmidt, Annegien Broeks, Flora E. van Leeuwen, Jelle Wesseling, Maggie C. Cheang, Karen Gelmon, Torsten O. Nielsen, Carl Blomqvist, Päivi Heikkilä, Tuomas Heikkinen, Heli Nevanlinna, Lars A. Akslen, Louis R. Bégin, William D. Foulkes, Fergus J. Couch, Xianshu Wang, Vicky Cafourek, Janet E. Olson, Laura Baglietto, Graham G. Giles, Gianluca Severi, Catriona A. McLean, Melissa C. Southey, Emad Rakha, Andrew R. Green, Ian O. Ellis, Mark E. Sherman, Jolanta Lissowska, William F. Anderson, Angela Cox, Simon S. Cross, Malcolm W. R. Reed, Elena Provenzano, Sarah-Jane Dawson, Alison M. Dunning, Manjeet Humphreys, Douglas F. Easton, Montserrat García-Closas, Carlos Caldas, Paul D. Pharoah, David Huntsman, Francesco M. Marincola

Abstract: Paul Pharoah and colleagues evaluate the prognostic significance of immunohistochemical subtype classification in more than 10,000 breast cancer cases with early disease, and examine the influence of a patient’s survival time on the prediction of future survival.

Partial Text: Breast cancer is a heterogeneous disease that can be classified using a variety of clinical and pathological features. Classification may help in prognostication and targeting of treatment to those most likely to benefit. Currently, estrogen receptor (ER) status and human epidermal growth factor receptor-2 (HER2) status are routinely used as predictive markers to select specific adjuvant therapies. Prognostic markers may also be used to target adjuvant chemotherapy to those at highest risk of poor outcome—for example, the risk prediction tool Adjuvant!Online ( uses prognostic markers to predict the likely absolute benefit of postoperative hormonal and/or chemotherapy and is widely used by oncologists to identify patients most likely to benefit from adjuvant treatment.

Eight studies provided data on ER, PR, HER2, CK5/6, and EGFR with a further four studies providing data on ER, PR, HER2, and CK5/6, but not EGFR. Based on these data, there were 10,159 subjects that could be classified into one of the five major breast subtypes. There were 3,181 deaths in 85,799 person-years of follow-up, with 1,975 deaths from breast cancer. The multivariate, period-specific hazard ratios for age (in four categories), tumour grade, tumour size, node status, and the IHC markers are given in Table 2. These data show that the hazard ratios for all variables except age at diagnosis attenuate over time, and that for ER, PR, HER2, CK5/6, EGFR, and grade the effect changes direction with time. The time-dependent changes were most pronounced for ER and PR status. There was little difference in the hazard ratios for all-cause mortality and breast cancer-specific mortality, except for in the youngest and oldest age groups (Figures S1 and S2). Breast cancer-specific hazard ratios tended to be higher for women diagnosed under the age of 40 y (reference age at diagnosis 50–59 y). In contrast, for age at diagnosis ≥60 y, all-cause mortality hazard ratios were greater, as might be expected because of the impact of mortality from other causes.

We evaluated the prognostic significance of five previously described major subtypes of breast cancer that were classified using five IHC markers. To our knowledge, this study represents one of the largest datasets analysed for prognosis research in breast cancer using IHC markers. Our data confirm the observations of others that the pattern of survival in ER-positive tumours is qualitatively different to that in ER-negative tumours. In ER-positive tumours, the mortality rate is approximately constant over time since diagnosis, whereas the mortality rate associated with ER-negative disease is initially high and then progressively declines over time. However, the pattern of mortality rates associated with the HER2-positive subgroup of ER-positive tumours (luminal 2) is similar to those of the nonluminal subtypes (Figure 3A).



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