BRCA gene mutations do not shape the extent and organization of tumor infiltrating lymphocytes in triple negative breast cancer

Solinas, Cinzia; Marcoux, Diane; Garaud, Soizic; Vitória, Joel Rodrigues; Eynden, Gert Van den; Wind, Alexandre de; Silva, Pushpamali De; Boisson, Anaïs; Craciun, Ligia; Larsimont, Denis; Piccart‐Gebhart, Martine; Detours, Vincent; Roodenbeke, Daphné t'Kint de; Willard-Gallo, Karen

doi:10.1016/j.canlet.2019.02.027

Cited by 37 publications

(27 citation statements)

References 48 publications

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“…42 Solinas et al analyzed TN tumors of 44 patients with BRCA1 or BRCA2 germline mutations and 41 patients with BRCA-wild-type breast cancers and did not observe differences in TIL density and PD-L1 expression according to BRCA1 or BRCA2-mutation status. 43 These results suggest that other mechanisms different from, or in addition to, high mutation rate and BRCA1-deficiency may regulate immune infiltration in TN breast cancer. We observed a lower level of TILs and PD-L1 expression in lobular carcinomas compared with ductal carcinomas, regardless of other pathological variables and also within the ER+HER2− group.…”

Section: Discussionmentioning

confidence: 85%

Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival

et al. 2018

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To better understand the expression pattern of programmed death-ligand 1 (PD-L1) expression in different breast cancer types, we characterized PD-L1 expression in tumor and tumor-infiltrating immune cells, in relation to mutation rate, BRCA1-like status and survival. We analyzed 410 primary treatment-naive breast tumors comprising 162 estrogen receptor-positive (ER+) and HER2−, 101 HER2+ and 147 triple-negative (TN) cancers. Pathologists quantified tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in tumor cells and TILs using whole slides and tissue microarray. Mutation rate was assessed by DNA sequencing, BRCA1-like status using multiplex ligation-dependent probe amplification, and immune landscape by multiplex image analyses of CD4, CD68, CD8, FOXP3, cytokeratin, and PD-L1. Half of PD-L1 scores evaluated by tissue microarray were false negatives compared to whole slide evaluations. We observed at least 1% of PD-L1-positive (PD-L1+) cells in 53.1% of ER+HER2−, 73.3% of HER2+, and 84.4% of TN tumors. PD-L1 expression was higher in ductal compared to lobular carcinomas, also within ER+HER2− tumors (p = 0.04). High PD-L1+ TILs score (> 50%) was independently associated with better outcome in TN tumors (HR = 0.27; 95%CI = 0.10-0.69). Within TN tumors, PD-L1 and TIL scores showed a modest but significant positive association with the number of silent mutations, but no association with BRCA1-like status. Multiplex image analyses indicated that PD-L1 is expressed on multiple immune cells (CD68+ macrophages, CD4+, FOXP3+, and CD8+ T cells) in the breast tumor microenvironment, independent of the PD-L1 status of the tumor cells. We found no evidence that levels of PD-L1 + TILs in TN breast cancer are driven by high mutation rate or BRCA1-like status.

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Section: Discussionmentioning

confidence: 85%

Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival

et al. 2018

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“…TNBC tumors have been associated with high TIL-levels (signaling immunogenicity) which are also prognostically favorable 52 , 53 . A recent study has suggested a higher frequency of TIL-positive tumors in BRCA1/2 -mutated patients than in wild-type cases 54 . In the SCAN-B cohort, TIL-levels did not differ between hypermethylated and BRCA1 -null cases, which is consistent with the similar prognosis in these groups after adjuvant chemotherapy.…”

Section: Discussionmentioning

confidence: 97%

“…In the SCAN-B cohort, TIL-levels did not differ between hypermethylated and BRCA1-null cases, which is consistent with the similar prognosis in these groups after adjuvant chemotherapy. PD-L1 expression is also frequent in TNBC, including BRCA1 hypermethylated tumors 19 , but studies have not found that levels of PD-L1-positive TILs in TNBC cancers are driven by a high mutation rate or by BRCA1 mutation status 52,54 . This lack of association may now be appreciated through our delineation of the BRCA1/2-wt subgroup by BRCA1 hypermethylation, forming a major subgroup of TNBC with similar genetic and immune cell phenotypes as BRCA1-null cases.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers

et al. 2020

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Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.

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“…The impairment of HRR activity is known as HRR deficiency (HRD). HRD may drive tumorigenesis, increasing the number of tumor mutations and, potentially, the neo-Ag rate in BC [17]. Thus, HRD tumors may hold the biological prerequisites for eliciting neo-Ag–directed adaptive immune response.…”

Section: Introductionmentioning

confidence: 99%

Homologous Recombination Repair Deficiency and the Immune Response in Breast Cancer: A Literature Review

Pellegrino

Musolino

Llop‐Guevara³

et al. 2020

Translational Oncology

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The success of cancer immunotherapy with immune checkpoint blockade (ICB) has demonstrated the importance of targeting a preexisting immune response in a broad spectrum of tumors. This is particularly novel and relevant for less immunogenic tumors, such as breast cancer (BC), where the efficacy of ICB was more evident in the triple-negative (TNBC) subtype, in earlier stages, and in association with chemotherapy. Tumors harboring homologous recombination DNA repair (HRR) deficiency (HRD) are supposed to have a higher number of mutations, hence a higher tumor mutational burden, which could potentially make them more sensitive to immunotherapy. However, the mechanisms involved in ICB sensitivity and patient selection are still yet to be defined in BC: whether the innate system could play a role and how the adaptive immunity could be linked with HRR pathways are the two key points of debate that we will discuss in this article. The aim of this review was to close the loop between what was found in clinical trial results so far, go back to laboratory theory and preclinical results and point out what needs to be clarified from now on.

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BRCA gene mutations do not shape the extent and organization of tumor infiltrating lymphocytes in triple negative breast cancer

Cited by 37 publications

References 48 publications

Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival

Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival

Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers

Homologous Recombination Repair Deficiency and the Immune Response in Breast Cancer: A Literature Review

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