Triple negative PAM50 non-basal breast cancer subtype predicts benefit from extended adjuvant capecitabine

Clin Cancer Res. 2022 Nov 8;CCR-22-2191. doi: 10.1158/1078-0432.CCR-22-2191. Online ahead of print.

Abstract

Purpose: Predictive biomarkers for capecitabine benefit in triple negative breast cancer (TNBC) have been recently proposed using samples from phase III clinical trials, including non-basal phenotype and biomarkers related to angiogenesis, stroma and capecitabine activation genes. We aimed to validate these findings on the larger phase III GEICAM/CIBOMA clinical trial.

Experimental design: Tumor tissues from TNBC patients randomized to standard (neo)adjuvant chemotherapy followed by capecitabine vs. observation were analyzed using a 164-gene NanoString custom nCounter codeset measuring mRNA expression. A prespecified statistical plan sought to verify the predictive capacity of PAM50 non-basal molecular subtype and tested the hypotheses that breast tumors with increased expression of (meta)genes for cytotoxic cells, mast cells, endothelial cells, PDL2 and 38 individual genes benefit from adjuvant capecitabine for distant recurrence free survival (DRFS, primary endpoint) and overall survival.

Results: Of the 876 women enrolled in the GEICAM/CIBOMA trial, 658 (75%) were evaluable for analysis (337 with capecitabine and 321 without). 553 (84%) cases were profiled as PAM50 basal-like while 105 (16%) were PAM50 non-basal. Non-basal subtype was the most significant predictor for capecitabine benefit (HRcapecitabine=0.19; 95%CI, 0.07-0.54; P<0.001) when compared to PAM50 basal-like (HRcapecitabine=0.9; 95%CI, 0.63-1.28; P=0.55) (P-interaction<0.001, adjusted P-value=0.01). Analysis of biological processes related to PAM50 non-basal subtype revealed its enrichment for mast cells, extracellular matrix, angiogenesis, and features of mesenchymal stem-like TNBC subtype.

Conclusions: In this prespecified correlative analysis of the GEICAM/CIBOMA trial, PAM50 non-basal status identified early-stage TNBC patients most likely to benefit from capecitabine.