Predictive Significance of an Optimized Panel for Basal-like Breast Cancer: Results from the Canadian Cancer Trials Group MA.5 and MA.12 Phase III Clinical Trials

Purpose: Accurate IHC biomarkers incorporating nestin positivity or inositol polyphosphate-4-phosphate (INPP4B) loss have recently been optimized to identify the basal-like intrinsic breast cancer subtype regardless of estrogen, progesterone, or Her2 status. We examined the predictive capacity of these basal biomarkers in the CCTG MA.5 chemotherapy and MA.12 endocrine therapy trials. Experimental Design: Formalin-fixed paraffin embedded blocks of primary tumors from patients randomized in the two trials were used to build tissue microarrays. IHC staining for nestin and INPP4B followed published methods and REMARK criteria. A prespecified statistical plan tested the hypothesis that patients with basal breast cancer (nestin(+) or INPP4B(-)) would not benefit from anthracycline substitution in MA.5 or from tamoxifen in MA.12. Results: Nestin positivity or INPP4B loss was observed in 110/453 (24%) interpretable samples from MA.5 and 47/366 (13%) from MA.12, and was associated with high grade, younger age, estrogen receptor negativity, triple-negative, core basal, and PAM50 basal-like subtypes. In the MA.5 trial, patients assigned as basal experienced lower benefit from anthracycline versus nonanthracycline adjuvant chemotherapy [HR, 1.49; 95% confidence interval (CI), 0.72-3.10] when compared with non-basal (nestin(-) and INPP4B(+)) cases where there was a higher benefit from anthracyclines (HR, 0.75; 95% CI, 0.54-1.04; P-interaction = 0.01). In the MA.12 trial, patients assigned as basal did not demonstrate a benefit from adjuvant tamoxifen versus placebo (HR, 0.48; 95% CI, 0.12-1.86; P = 0.29), whereas nonbasal cases displayed significant benefit (HR, 0.66; 95% CI, 0.45-0.98; P = 0.04), although the interaction test was not significant. Conclusions: The nestin/INPP4B IHC panel identifies women with basal breast cancers who benefit from nonanthracycline chemotherapy but not endocrine adjuvant treatments.