Dados do Trabalho

Título

Update on the ADAMANT-NEO study: Monitoring treatment resistance using ctDNA analysis in non-metastatic Triple-Negative Breast Cancer (TNBC) treated with pre-operative chemotherapy

Introdução

Loss-of-function germline mutation in BRCA1 increases breast cancer risk, especially the TNBC subtype. BRCA1 impairment may confer benefit from treatment with DNA damage-inducing drugs and PARP1 inhibitors. Patients who respond to neoadjuvant chemotherapy tend to have good outcomes.

Objetivo

Our aim is to characterize the resistance to chemotherapy in patients with germline-characterized TNBC by investigating somatic mutations in ctDNA.

Métodos

Germline genetic testing using cancer-predisposing gene panels (26-126 genes) for classifying TNBC as Hereditary or Sporadic. Somatic mutation identification in tumor (409 cancer-related gene panel) and screening of ctDNA in plasma samples during treatment.

Resultados

We enrolled 108 TNBC patients of which 103 were tested for germline variants: 27% (28/103) of cases were Hereditary - BRCA1 (19%), BRCA2 (3%), PALB2 (1%), RAD51C (1%), RAD51D (1%) and TP53 (1%). Tumor mutation burden (TMB) analysis (59) showed that 8.5% had high and 91.5% low TMB, not associated with Hereditary status. Somatic mutations were identified in 95% (53/56) of tumors, with TP53 mutations being the most frequent (84%; 47/56). In ctDNA before treatment, detection of at least one tumor mutation was observed in 37/48 patients (77%) and no association was observed with TMB score. Sporadic tumors were more frequently ctDNA+ at diagnosis than Hereditary tumors (84% vs 50%, respectively, p=0.04), however after treatment no difference was observed. Although ctDNA was not associated to the residual cancer burden (RCB) score, ctDNA detection was associated with clinical progression at baseline (36% ctDNA+ progressed vs 0% of ctDNA-; p=0.02) and after curative-intended treatment (72% ctDNA+ vs 32% in ctDNA-; p=0.01) . ctDNA identification anticipated progression detected by imaging.

Conclusões

Hereditary tumors, markedly due to germline variants in BRCA1, are frequent in TNBC. Tumor-mark identification using gene panel and ctDNA screening in plasma samples provide valuable information regarding clinical progression of patients treated with pre-operative chemotherapy.

Palavras-chave

triple-negative breast cancer; ctDNA; liquid biopsy

Financiador do resumo

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