RNA-based molecular tumor typing and immunological infiltrate as response predictors to neoadjuvant chemotherapy: Prospective validation in the GeparQuinto-PREDICT substudy.

Abstract

10526 Background: We have recently developed a standardized system and defined cutoffs for assessment of molecular tumor subtype based on RNA expression of ESR1 and HER2 in FFPE tissue. (Müller et al. Diagn Mol Pathol 2011). Furthermore we described intratumoral and stromal lymphocytes as well as lymphocyte-predominant breast cancer (LPBC) as new predictors of pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) (Denkert et al. J Clin Oncol 2010). Methods: The PREDICT substudy of the GeparQuinto trial (von Minckwitz et al. SABCS 2010) included a prospective independent validation of these 5 markers. RNA was extracted from 192 HER2neg FFPE breast cancer core biopsies using a fully-automated robot-based system. Expression of ESR1 and HER2 mRNA as well as control genes was determined by quantitative RT-PCR using predefined cutoffs. Test results were available in all cases before the patient underwent surgery. Results: 112 luminal tumors and 80 triple-negative (TNBC) tumors were defined by RNA-based subtyping. pCR rate was 40% in TNBC compared to 7.1% in luminal tumors. TNBC was predictive for response to NACT in logistic regression analysis (p<0.001) with an OR of 8.67 (95%CI [3.72-20.2]). LPBC had a pCR rate of 41%, compared to 14% for non-LPBC tumors (p<0.01). Intratumoral lymphocytes (p=0.005), stromal lymphocytes (p<0.005) and LPBC (p<0.005) were predictive for pCR in univariate logistic regression analysis. TNBC were more likely to contain an increased lymphocytic infiltrate compared to luminal tumors (p=0.001). Conclusions: This is the first report of a validated diagnostic test for mRNA based molecular subtyping. Distinct molecular subgroups according to the predefined cutoffs showed statistically significant different pCR rates. This standardized approach might be helpful to reliably define TNBCs as target population for clinical trials investigating new agents.