Evaluation of the MammaTyper® as a molecular predictor for pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) and outcome in patients with different breast cancer (BC) subtypes (2018)

Background: According to molecular and genetic features BC can be divided into subtypes which show differences in the response to systemic therapy and in long-term outcome. Thus, effective and reliable molecular analysis of tumor material at the time of BC diagnosis is needed. Methods: Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor samples of BC patients (pts) enrolled in the single arm phase II TECHNO (Untch et al. JCO 2011) and the randomised phase III PREPARE (Untch et al. Ann Oncol. 2011) trials. MammaTyper®, a molecular in vitro diagnostic RT-qPCR test, was used to assess the expression of ERBB2 (HER2), ESR1 (ER), PGR (PR) and MKI67 (Ki67) genes as continuous and binary variables using predefined cutoffs. Pts were classified into 6 intrinsic BC subtypes according to St Gallen guidelines (Goldhirsch et al. Ann Oncol. 2013). In both trials the ER, PR, HER2 and Ki67 expression was assessed by immunohistochemistry (IHC). Predefined cutoffs for increased ESR1 (+1.8 Cq) and PGR (+3.7 Cq) expression defined a subgroup of ultra-high tumors. The study aimed to evaluate the MammaTyper® test for predicting pCR (ypT0 ypN0) after NACT and outcome in the BC subtypes. The degree of agreement between the MammaTyper® and the IHC test for determining BC subtypes was also estimated. Results: A total of 418 pts were assessed. The BC subtypes defined by MammaTyper® and IHC showed good agreements (ERBB2/HER2, kappa [κ]=0.674; ESR1/ER, κ = 0.815; PGR/PR, κ = 0.648). MKI67 significantly predicted pCR (AUC=0.686, p < 0.001). In HER2+ pts from the TECHNO trial the ERBB2 significantly predicted pCR in ESR1-positive sybtype (n = 59, AUC=0.708, p = 0.006). HER2-negative pts from the PREPARE trial with ultra-high ESR1 and/or PGR expression had significantly better disease-free (DFS) and overall survival (OS) than the non-ultra-high pts (n = 153; DFS HR = 1.80, [95%CI 1.18-2.76], p = 0.007; OS HR = 2.54 [95%-CI 1.50-4.31], p = 0.001). Conclusions: The MammaTyper® significantly predicts response after NACT in BC subtypes. A subgroup of pts with ultra-high ESR1/PGR expression had a good prognosis. Further analysis is required. Legal entity responsible for the study: GBG Forschungs GmbH and BioNTech Diagnostics GmbH. Funding: This study was financially supported by BioNTech Diagnostics GmbH, Mainz, Germany. Disclosure: P.A. Fasching: Grants: Biontech, during the conduct of the study; Grants and personal fees: Novartis; Personal fees: Pfizer, Roche, Teva, Celgene, outside the submitted work. M. Laible: Patent WO 2015/024942, Commercialized as MammaTyper(TM) Kit; Relevant financial activities outside the submitted work: BioNTech Diagnostics GmbH (Employee of BioNTech Diagnostics GmbH). K.E. Weber: Grants and non-financial support: BioNTech Diagnostics GmbH, Mainz, Germany, during the conduct of the study; Patent EndoPredict issued. C. Denkert: Personal fees: Teva, Novartis, Pfizer, Roche, Amgen, MSD Oncology; Other: Sividon Diagnostics, outside the submitted work. K. Schlombs: Personal fees: BioNTech Diagnostics GmbH, outside the submitted work; Patent WO 2015/024942 pending; New Patent application pending. F. Marme: Personal fees: Roche, AstraZeneca, Pfizer, Tesaro, Novartis, Amgen, PharmaMar, GenomicHealth, CureVac, Eisai, outside the submitted work. S. Loibl: Grants: AbbVie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, Roche, Teva, Vifor during the conduct of the study and outside the submitted work. All other authors have declared no conflicts of interest.