Impact of BRCA Mutation Status on Tumor Infiltrating Lymphocytes (TILs), Response to Treatment, and Prognosis in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

INTRODUCTION: Five 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 METHODS: Out 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. RESULTS: Among 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. CONCLUSIONS: BRCA 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.

No Impact of Smoking Status on Breast Cancer Tumor Infiltrating Lymphocytes, Response to Neoadjuvant Chemotherapy and Prognosis.

Tobacco use is associated with an increase in breast cancer (BC) mortality. Pathologic complete response (pCR) rate to neoadjuvant chemotherapy (NAC) is influenced by tumor-infiltrating lymphocyte (TIL) levels and is associated with a better long-term survival outcome. The aim of our study is to evaluate the impact of smoking status on TIL levels, response to NAC and prognosis for BC patients. We retrospectively evaluated pre- and post-NAC stromal and intra tumoral TIL levels and pCR rates on a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012 at Institut Curie. Smoking status (current, ever, never smokers) was collected in clinical records. We analyzed the association between smoking status, TIL levels, pCR rates and survival outcomes among the whole population, and according to BC subtype. Nine hundred and fifty-six BC patients with available smoking status information were included in our analysis (current smokers, n = 179 (18.7%); ever smokers, n = 154 (16.1%) and never smokers, n = 623 (65.2%)). Median pre-NAC TIL levels, pCR rates, or median post-NAC TIL levels were not significantly different according to smoking status, neither in the whole population, nor in any BC subtype group. With a median follow-up of 101.4 months, relapse-free survival (RFS) and overall survival (OS) were not significantly different by smoking status. We did not find any significant effect of tobacco use on pre- and post-NAC TILs nor response to NAC. Though our data seem reassuring, BC treatment should still be considered as a window of opportunity to offer BC patients accurate smoking cessation interventions.

Prognostic value of the Residual Cancer Burden index according to breast cancer subtype: Validation on a cohort of BC patients treated by neoadjuvant chemotherapy.

INTRODUCTION: The Residual Cancer Burden (RCB) quantifies residual disease after neoadjuvant chemotherapy (NAC). Its predictive value has not been validated on large cohorts with long-term follow up. The objective of this work is to independently evaluate the prognostic value of the RCB index depending on BC subtypes (Luminal, HER2-positive and triple negative (TNBCs)). METHODS: We retrospectively evaluated the RCB index on surgical specimens from a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012. We analyzed the association between RCB index and relapse-free survival (RFS), overall survival (OS) among the global population, after stratification by BC subtypes. RESULTS: 717 patients were included (luminal BC (n = 222, 31%), TNBC (n = 319, 44.5%), HER2-positive (n = 176, 24.5%)). After a median follow-up of 99.9 months, RCB index was significantly associated with RFS. The RCB-0 patients displayed similar prognosis when compared to the RCB-I group, while patients from the RCB-II and RCB-III classes were at increased risk of relapse (RCB-II versus RCB-0: HR = 3.25 CI [2.1-5.1] p<0.001; RCB-III versus RCB-0: HR = 5.6 CI [3.5-8.9] p<0.001). The prognostic impact of RCB index was significant for TNBC and HER2-positive cancers; but not for luminal cancers (Pinteraction = 0.07). The prognosis of RCB-III patients was poor (8-years RFS: 52.7%, 95% CI [44.8-62.0]) particularly in the TNBC subgroup, where the median RFS was 12.7 months. CONCLUSION: RCB index is a reliable prognostic score. RCB accurately identifies patients at a high risk of recurrence (RCB-III) with TNBC or HER2-positive BC who must be offered second-line adjuvant therapies.