Using next‐generation sequencing to redefine BRCAness in triple‐negative breast cancer

Abstract

This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractBRCAness is considered a predictive biomarker to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors. However, recent trials showed that its predictive value was limited in triple-negative breast cancer (TNBC) treated with platinum. Moreover, tumors with mutations of DNA damage response (DDR) genes, such as homologous recombination (HR) genes, could be sensitive to platinum and PARP inhibitors. Thus, we aim to explore the relationship between mutation status of DDR genes and BRCAness in TNBC. We sequenced 56 DDR genes in 120 TNBC and identified BRCAness by array comparative genomic hybridization. The sequencing results showed that 13, 14, and 14 patients had BRCA, non-BRCA HR, and non-HR DDR gene mutations, respectively.Array comparative genomic hybridization revealed that BRCA-mutated and HR genemutated TNBC shared similar BRCAness features, both having higher numbers and longer length of large-scale structural aberration (LSA, >10 Mb) and similar altered chromosomal regions of LSA. These suggested non-BRCA HR gene-mutated TNBC shared similar characteristics with BRCA-mutated TNBC, indicating non-BRCA HR gene-mutated TNBC sensitive to platinum and PARP inhibitors. Among tumors with mutation of non-HR DDR genes, 3 PTEN and 1 MSH6 mutation also contained significant LSAs (BRCAness); however, they had different regions of genomic alteration to BRCA and HR gene-mutated tumors, might explain prior findings that PTEN-and MSH6-mutated cancer cells not sensitive to PARP inhibitors. Therefore, we hypothesize that the heterogeneous genomic background of BRCAness indicates different responsiveness to platinum and PARP inhibitors. Direct sequencing DDR genes in TNBC should be applied to predict their sensitivity toward platinum and PARP inhibitors.

Biomarkers in Triple-Negative Breast Cancer: State-of-the-Art and Future Perspectives

“…As a result, 22.2% of 158 patients in TNBC group carried mutations in genes involved in DNA repair by HR [ 38 ]. Confirming data have been reported by other group [ 39 ] and it has been demonstrated that homologous recombination deficiency (HRD) can occur in sporadic cancer through genetic and epigenetic inactivation of other components such as PALB2, BARD1, BRIP1, RAD51, RAD51C, RAD51D, ATM, FAAP20, CHECK2, FAM1, FANCE, FANCM, POLQ [ 5 , 34 ]. These findings confirm the hypothesis that HRD TNBC, shares similar characteristics with gBRCAm TNBC, identifying new possible biomarkers of response to PARPi [ 40 ].…”

Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations

“… 9 On the other hand, alterations in other non–homologous recombination DNA damage response genes, such as PTEN (OMIM 601728 ), are not associated with response to the same extent. 9 …”

Recent Advances in Integrative Multi-Omics Research in Breast and Ovarian Cancer

“…More recently, CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have been approved and, in conjunction with hormone therapy, have become the primary treatment regimen for HR+/HER2- treatment naïve or hormone therapy treated metastatic breast cancer patients [ 34 ]. Finally, the treatment of TNBC tumors has begun to evolve to include immune checkpoint inhibitors while patients with BRCA mutations are treated with PARP inhibitors in conjunction with chemotherapy [ 28 , 35 , 36 ].…”

“…More recent studies have indicated that these tumors demonstrate high homologous recombination deficiency (HRD) scores, accumulation of large-scale state transitions, increased loss of heterozygosity (LOH), and telomeric allelic imbalance scar signatures. Clinically, these alterations have been shown to be significantly correlated with pathologic complete response and minimal residual disease in TNBC patients treated with platinum-based therapies and with a better prognosis in HGSOC [ 36 , 135 , 136 ].…”