TY - JOUR
T1 - Combined quantitative measures of ER, PR, HER2, and KI67 provide more prognostic information than categorical combinations in luminal breast cancer
AU - Abubakar, Mustapha
AU - Figueroa, Jonine
AU - Ali, H. Raza
AU - Blows, Fiona
AU - Lissowska, Jolanta
AU - Caldas, Carlos
AU - Easton, Douglas F.
AU - Sherman, Mark E.
AU - Garcia-Closas, Montserrat
AU - Dowsett, Mitch
AU - Pharoah, Paul D.
N1 - Funding Information:
Acknowledgements MD acknowledges support from the Royal Marsden NIHR Biomedical Research Center. MA acknowledges funding support from CRUK and the Institute of Cancer Research (ICR), London at the time part of this work was conducted at the ICR.
Funding Information:
Funding The Polish Breast Cancer Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The Study of Epidemiology and Risk Factors in Cancer Heredity is funded by a program grant from Cancer Research UK (CRUK) (C490/A10124. C490/A16561) and supported by the UK National Institute for Health Research (NIHR) Biomedical Research Center at the University of Cambridge. Part of this work was supported by the European Community’s Seventh Framework Program under grant agreement number 223175 (grant number HEALTH-F2–2009223175) (COGS).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Although most women with luminal breast cancer do well on endocrine therapy alone, some will develop fatal recurrence thereby necessitating the need to prospectively determine those for whom additional cytotoxic therapy will be beneficial. Categorical combinations of immunohistochemical measures of ER, PR, HER2, and KI67 are traditionally used to classify patients into luminal A-like and B-like subtypes for chemotherapeutic reasons, but this may lead to the loss of prognostically relevant information. Here, we compared the prognostic value of quantitative measures of these markers, combined in the IHC4-score, to categorical combinations in subtypes. Using image analysis-based scores for all four markers, we computed the IHC4-score for 2498 patients with luminal breast cancer from two European study populations. We defined subtypes (A-like (ER + and PR + : and HER2- and low KI67) and B-like (ER + and/or PR + : and HER2 + or high KI67)) by combining binary categories of these markers. Hazard ratios and 95% confidence intervals for associations with 10-year breast cancer-specific survival were estimated in Cox proportional-hazard models. We accounted for clinical prognostic factors, including grade, tumor size, lymph-nodal involvement, and age, by using the PREDICT-score. Overall, Subtypes [hazard ratio (95% confidence interval) B-like vs. A-like = 1.64 (1.25–2.14); P-value < 0.001] and IHC4-score [hazard ratio (95% confidence interval)/1 standard deviation = 1.32 (1.20–1.44); P-value < 0.001] were prognostic in univariable models. However, IHC4-score [hazard ratio (95% confidence interval)/1 standard deviation = 1.24 (1.11–1.37); P-value < 0.001; likelihood ratio chi-square (LRχ2) = 12.5] provided more prognostic information than Subtype [hazard ratio (95% confidence interval) B-like vs. A-like = 1.38 (1.02–1.88); P-value = 0.04; LRχ2= 4.3] in multivariable models. Further, higher values of the IHC4-score were associated with worse prognosis, regardless of subtype (P-heterogeneity = 0.97). These findings enhance the value of the IHC4-score as an adjunct to clinical prognostication tools for aiding chemotherapy decision-making in luminal breast cancer patients, irrespective of subtype.
AB - Although most women with luminal breast cancer do well on endocrine therapy alone, some will develop fatal recurrence thereby necessitating the need to prospectively determine those for whom additional cytotoxic therapy will be beneficial. Categorical combinations of immunohistochemical measures of ER, PR, HER2, and KI67 are traditionally used to classify patients into luminal A-like and B-like subtypes for chemotherapeutic reasons, but this may lead to the loss of prognostically relevant information. Here, we compared the prognostic value of quantitative measures of these markers, combined in the IHC4-score, to categorical combinations in subtypes. Using image analysis-based scores for all four markers, we computed the IHC4-score for 2498 patients with luminal breast cancer from two European study populations. We defined subtypes (A-like (ER + and PR + : and HER2- and low KI67) and B-like (ER + and/or PR + : and HER2 + or high KI67)) by combining binary categories of these markers. Hazard ratios and 95% confidence intervals for associations with 10-year breast cancer-specific survival were estimated in Cox proportional-hazard models. We accounted for clinical prognostic factors, including grade, tumor size, lymph-nodal involvement, and age, by using the PREDICT-score. Overall, Subtypes [hazard ratio (95% confidence interval) B-like vs. A-like = 1.64 (1.25–2.14); P-value < 0.001] and IHC4-score [hazard ratio (95% confidence interval)/1 standard deviation = 1.32 (1.20–1.44); P-value < 0.001] were prognostic in univariable models. However, IHC4-score [hazard ratio (95% confidence interval)/1 standard deviation = 1.24 (1.11–1.37); P-value < 0.001; likelihood ratio chi-square (LRχ2) = 12.5] provided more prognostic information than Subtype [hazard ratio (95% confidence interval) B-like vs. A-like = 1.38 (1.02–1.88); P-value = 0.04; LRχ2= 4.3] in multivariable models. Further, higher values of the IHC4-score were associated with worse prognosis, regardless of subtype (P-heterogeneity = 0.97). These findings enhance the value of the IHC4-score as an adjunct to clinical prognostication tools for aiding chemotherapy decision-making in luminal breast cancer patients, irrespective of subtype.
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U2 - 10.1038/s41379-019-0270-4
DO - 10.1038/s41379-019-0270-4
M3 - Article
C2 - 30976105
AN - SCOPUS:85064271551
VL - 32
SP - 1244
EP - 1256
JO - Modern Pathology
JF - Modern Pathology
SN - 0893-3952
IS - 9
ER -