Differential Response to Neoadjuvant Chemotherapy Among 7 Triple-Negative Breast Cancer Molecular Subtypes

Abstract

Purpose The clinical relevancy of the 7-subtype classification of triple-negative breast cancer (TNBC) reported by Lehmann and Bauer et al is unknown. We investigated the clinical relevancy of TNBC heterogeneity by determining pathological complete response (pCR) rates after neoadjuvant chemotherapy, based on TNBC subtypes. Experimental Design We revalidated the Lehmann and Bauer et al. experiments using Affymetrix CEL files from public datasets. We applied these methods to 146 TNBC patients with gene expression microarrays obtained from June 2000 to March 2010 at our institution. Of those, 130 had received standard neoadjuvant chemotherapy and had evaluable pathological response data. We classified the TNBC samples by subtype, then correlated subtype and pCR status using Fisher’s exact test and a logistic regression model. We also assessed survival and compared the subtypes to PAM50 intrinsic subtypes and residual cancer burden (RCB) index. Results TNBC subtype and pCR status were significantly associated (P=0.04379). The basal-like 1 (BL1) subtype had the highest pCR rate (52%); basal-like 2 (BL2) and luminal androgen receptor (LAR) had the lowest (0% and 10%, respectively). TNBC subtype was an independent predictor of pCR status (P=0.022) by a likelihood ratio test. The subtypes better predicted pCR status than did the PAM50 intrinsic subtypes (basal-like vs non basal-like). Conclusions Classifying TNBC by 7 subtypes predicts high vs. low pCR rate. We confirm the clinical relevancy of the 7 subtypes of TNBC. We need to prospectively validate whether the pCR rate differences translate into long-term outcome differences. The 7-subtype classification may spur innovative personalized medicine strategies for TNBC patients.

Clinicopathological Characteristics of Triple Negative Breast Cancer at a Tertiary Care Hospital in India

“…More recently, the subtyping of three large clinical trials (MA.5 [Levine et al, 2005], GEICAM/9906 [Martín et al, 2008] and MA.12 [Bramwell et al, 2010]) using the PAM50 qRT-PCR based assay showed that approximately 30% of TNBC identified by central pathology review do not fall under the BL subtype category (Cheang et al, 2012). Lately, Lehmann et al (2012) and Masuda et al (2013) have reported that TNBC can be classified into 7 subtypes (6 defined subtypes and an unstable group) by gene expression microarray. The subtypes were characterized as BL 1, BL 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor and unstable.…”

Immunohistochemical Surrogates for Molecular Classification of Breast Carcinoma: A 2015 Update

“…12 Responses to neoadjuvant chemotherapy are also different, with basallike 1 having the highest complete pathologic response rate (52%) and basal-like 2 and luminal androgen receptor tumors having the lowest complete pathologic response rates (0% and 10%, respectively). 114 Triple negativity is the most commonly used IHC surrogate for basal-like tumors. 11 Immunohistochemical analysis of BLBC cases that had been defined by GEP demonstrated that added IHC testing for CK5/6 and EGFR was better able to define this subtype than triple negativity alone.…”

Predictive biomarkers for triple negative breast cancer treated with platinum-based chemotherapy

“…53 Retrospective trials have found that molecular profiles of TNBC have clinical utility in predicting chemotherapy response. 29,54 In a clinical research of 1055 patients with TNBC, BLBC or both, only when TNBC can be stratified into BLBC subtype could patients be identified with notably better response after chemotherapy. 55 Previous studies show that BLBC harbors the hallmarks of BRCAness.…”