Dados do Resumo

Título

Multigenic NGS panel testing in triple negative breast cancer: homologous recombination DNA repair genes beyond BRCA1/2

Introdução

Triple Negative Breast Cancer (TNBC) is strongly associated with germline BRCA1 gene mutations but mutations in other homologous recombination (HR)-related genes may also cause HR deficiency (HRD) and lead to increased cancer risk. Tumors with HRD are sensitive to PARP inhibitors and platinum agents. A genetic evaluation including HR-related genes in TNBC may refine the TNBC genetic context and provide better stratification of patients benefiting from targeted therapies.

Objetivo

Investigate germline pathogenic variants (GPV) in HR-related and other breast cancer predisposing genes in TNBC and its association with clinical data.

Métodos

TNBC patients attending A. C. Camargo Cancer Center were screened for GPVs in constitutive DNA using diverse multigenic panels (26 to 113 genes – 20 genes covered in all panels) and next generation sequencing on illumina’s platforms (MiniSeq or NextSeq500) or by external certified laboratories. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. A subgroup of patients was investigated for ancestry markers with the PMDA-plus microarray kit. Clinical data were retrieved from electronic medical records. The Fisher’s Exact/Qui-square test and Mann-Whitney tests were used for categorical and numerical variables, respectively. Survival curves were calculated using the Kaplan-Meir method with Log-rank (Mantel-Cox) test for comparisons. The significance level was set at 95%.

Resultados

A total of 329 women diagnosed with TNBC were included. The mean age at diagnosis was 45.7 years of age (range 17-83;median=44), most patients were self-declared white (77%- 191/248) most tumors were stage 2 (53%- 162/306) and received neoadjuvant treatment (66%- 208/316). GPV were identified in 31% (105/329) of patients, being BRCA1 the most frequently altered gene (16%- 54/329), followed by BRCA2 (6%- 19/329), MUTYH (2%- 7/229), PALB2 (2%- 6/329) and other less frequent genes. Moreover, the rate of GPVs combining all HR-related genes was 27.1% (89/329). HR-Hereditary tumors were diagnosed at younger age (median 40 vs 45;p=0.0011) and were more often bilateral tumors (17% vs 5%;p=0.0011) compared with sporadic tumor. No association was observed between germline status and ancestry or self-declared ethnicity. Moreover, HR-hereditary tumor exhibited better 3-year progression free survival (p=0.005) and a trend to better 5-year overall survival (p=0.0563) compared with sporadic tumors.

Conclusões

Germline HRD plays an important role in TNBC cases, mainly due to BRCA1 gene GPVs but also other HR-related genes. Multigenic panel testing is an important approach to better characterize breast cancer predisposing genes in TNBC with potential implications in treatment strategies.

Financiador do resumo

PRONON (2500.055.121\2015-12), FAPESP (2013/23277-8); CNPq (305464/2013-2)

Palavras Chave

triple-negative breast cancer; germline pathogenic variants; homologous recombination DNA repair