Clinical Impact of Tumor DNA Repair Expression and T-cell Infiltration in Breast Cancers

Abstract

Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repair (ERCC1), base excision repair (XRCC1, pol β, FEN1, PARP1), and immune responses (CD8, PD-1, PD-L1, FOXP3) in 1269 breast cancers and validated our findings in an independent estrogen receptor (ER) -cohort (n = 279). Patients with tumors that expressed low XRCC1, low ATM, and low BRCA1 were not only associated with high numbers of CD8 + tumor-infiltrating lymphocyte (TILs), but were also linked to higher grades, high proliferation indexes, presence of dedifferentiated cells, ER -cells and poor survival (all P ≤ 0.01). PD-1 + or PD-L1 + breast cancers with low XRCC1 were also linked to an aggressive phenotype that was high grade, had high proliferation indexes, contained dedifferentiated cells and ER -(all with P values ≤ 0.01) and poor survival (P = 0.00021 and P = 0.00022, for PD-1 + and PD-L1 + cancers, respectively) including in an independent ER -validation cohort (P = 0.007 and P = 0.047, respectively). We conclude that the interplay between DNA repair, CD8, PD-L1, and PD-1 can promote aggressive tumor phenotypes. XRCC1-directed personalization of immune checkpoint inhibitor therapy may be feasible and warrants further investigation in breast cancer.4

Targeting PARP1 in XRCC1-Deficient Sporadic Invasive Breast Cancer or Preinvasive Ductal Carcinoma In Situ Induces Synthetic Lethality and Chemoprevention

“…Tumors that expressed low XRCC1 were associated with high CD8 þ tumor-infiltrating lymphocyte (TIL) counts, aggressive phenotype and reduced survival. Importantly, PD-1 þ or PD-L1 þ breast cancers with low XRCC1 were linked to aggressive cancers and reduced survival including in ERbreast cancers (13). As immune microenvironment (including PD-L1 þ TILs infiltration) in DCIS can influence aggressive phenotypes (28,29), we propose that PARP1 targeting may be a promising personalized approach either alone or in combination with immune checkpoint inhibitors in XRCC1deficient invasive cancers and in preinvasive DCIS.…”

“…However, biomarkers that could predict such an approach are currently unknown. We recently investigated XRCC1 and T-cell infiltration in invasive breast cancers (13). Tumors that expressed low XRCC1 were associated with high CD8 þ tumor-infiltrating lymphocyte (TIL) counts, aggressive phenotype and reduced survival.…”

“…The study was performed in a consecutive series of 1,650 patients with primary invasive breast carcinomas who were diagnosed between 1986 and 1999 and entered into the Nottingham Tenovus Primary Breast Carcinoma series. All patients were treated in a single institution and have been investigated in a wide range of biomarker studies (11)(12)(13)(14)(15). Supplementary Table S1 summarizes patient demographics.…”

“…The characteristics of this cohort are summarized in Supplementary Table S2. Tumors were arrayed in tissue microarrays and IHC profiled for XRCC1 (15), PARP1 (14) and other biological antibodies ( Supplementary-Table S3) as described previously (11)(12)(13).…”

BRCA1 mRNA expression modifies the effect of T cell activation score on patient survival in breast cancer

“…BRCA1 deficiency results in genomic instability and individual's susceptibility to breast and ovarian cancer [20][21][22]. Recently, Green and colleagues reported that low BRCA1 expression was associated with high numbers of CD8 + TILs and poor survival in patients with breast cancer [23].…”