Abstract
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.
Highlights
Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among womenCombined quantitative measures of ER, PR, HER2, and KI67 provide more prognostic information than. . .human epidermal growth factor receptor 2 (HER2/neu) gene [5, 9]. most women with luminal-like disease do well on endocrine therapy alone, some of them develop fatal recurrence thereby necessitating the need for additional cytotoxic therapy
We have previously demonstrated the independent prognostic value of automated scores for ER, PR, HER2, and KI67 separately, but it remains unclear whether combining these in the IHC4-score algorithm will provide additional prognostic information to immunohistochemistry-based subtypes or other clinical prognostic factors
We investigated the prognostic value of the IHC4-score in relation to other clinical prognostic factors, combined in the clinical treatment score (C-score) and PREDICT-score
Summary
Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among womenCombined quantitative measures of ER, PR, HER2, and KI67 provide more prognostic information than. . .human epidermal growth factor receptor 2 (HER2/neu) gene [5, 9]. most women with luminal-like disease do well on endocrine therapy alone, some of them develop fatal recurrence thereby necessitating the need for additional cytotoxic therapy. Several prognostic tools have been developed to address this, including those that rely on standard clinical prognostic factors [11,12,13] and others, such as the IHC4-score, that are based on immunohistochemical measures on ER, PR, HER2, and KI67 [13]. Because standard immunohistochemistry-based luminal A-like/ B-like subtype definition is based on dichotomous categories of the individual immunohistochemical markers, this may lead to the loss of prognostically relevant information. It remains unclear whether quantitative measures of ER, PR, HER2, and KI67 provide more prognostic information than categorial combinations in breast cancer subtypes
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