Impact of BRCA mutation status on tumor infiltrating lymphocytes (TILs), response to treatment, and prognosis in breast cancer patients treated with neoadjuvant chemotherapy
Authors: Grandal Beatriz , Evrevin Clémence , Laas Enora , Jardin Isabelle , Rozette Sonia , Laot Lucie , Dumas Elise , Coussy Florence , Pierga Jean-Yves , Brain Etienne , Saule Claire , Stoppa-Lyonnet Dominique , Frank Sophie , Sénéchal Claire , Lae Marick , De Croze Diane , Bataillon Guillaume , Guerin Julien , Reyal Fabien , Hamy Anne-Sophie 
Published: September 2020

AbstractIntroductionFive to 10% of breast cancers (BCs) occur in a genetic predisposition context (mainly BRCA pathogenic variant). Nevertheless, little is known about immune tumor infiltration, response to neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) and adverse events according to BRCA status.Material and methodsOut of 1199 invasive BC patients treated with NAC between 2002 and 2012, we identified 267 patients tested for a germline BRCA pathogenic variant. We evaluated pre-NAC and post-NAC immune infiltration (TILs). Response to chemotherapy was assessed by pCR rates. Association of clinical and pathological factors with TILs, pCR and survival was assessed by univariate and multivariate analyses.ResultsAmong 1199 BC patients: 46 were BRCA-deficient and 221 BRCA-proficient or wild type (WT). At NAC completion, pCR was observed in 84/266 (31%) patients and pCR rates were significantly higher in BRCA-deficient BC (p= 0.001), and this association remained statistically significant only in the luminal BC subtype (p= 0.006). The interaction test between BC subtype and BRCA status was nearly significant (Pinteraction=0.056). Pre and post-NAC TILs were not significantly different between BRCA-deficient and BRCA-proficient carriers; however, in the luminal BC group, post-NAC TILs were significantly higher in BRCA-deficient BC. Survival analysis were not different between BRCA-carriers and non-carriers.ConclusionBRCA mutation status is associated with higher pCR rates and post-NAC TILs in patients with luminal BC. BRCA-carriers with luminal BCs may represent a subset of patients deriving higher benefit from NAC. Second line therapies, including immunotherapy after NAC, could be of interest in non-responders to NAC.Translational relevanceHigh lymphocytic infiltration (TILs) seem to reflect favorable host antitumor immune responses. In breast cancer, the variation of TILs before and after neoadjuvant chemotherapy (NAC) according to BRCA status has been poorly described. Little data is available on their value after treatment. We investigated TIL levels before and after NAC and response to treatment in 267 paired biopsy and surgical specimens.In our study, luminal BCs were associated with pathologic complete response (pCR) and higher TIL levels after chemotherapy completion in patients with BRCA pathogenic mutations. Our data supports that (i) NAC should be reconsidered in luminal BCs with BRCA pathogenic mutation, (ii) TILs could be a biomarker for response to immune checkpoint blockade in luminal BCs with BRCA pathogenic variant who did not achieve a pCR and (iii) exploiting the antitumor immune response in luminal BCs could be an area of active research.