INVESTIGATION OF CIRCULATING-TUMOR DNA (ctDNA) IN PATIENTS WITH NON-METASTATIC TRIPLE-NEGATIVE BREAST CANCER (TNBC) SUBMITTED TO NEOADJUVANT CHEMOTHERAPY
Rafael Canfield Brianese1, Giovana Tardin Torrezan1, Marina de Brot Andrade2, Vladmir Claudio Cordeiro de Lima3, Solange Moraes Sanches3, Maria Nirvana da Cruz Formiga4, Fabiana Baroni Alves Makdissi5, Dirce Maria Carraro1
1Laboratory of Clinical and Functional Genomics – A. C. Camargo Cancer Center, São Paulo (SP) – Brazil
2Pathology Department – A.C. Camargo Cancer Center, São Paulo (SP) – Brazil
3Clinical Oncology Department – A.C. Camargo Cancer Center, São Paulo (SP) – Brazil
4Oncogenetics and Clinical Oncology Department – A.C. Camargo Cancer Center, São Paulo – Brazil
5Breast Surgery Department – A. C. Camargo Cancer Center, São Paulo (SP) – Brazil
Objective: 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. Our aim is to characterize the resistance to chemotherapy in patients with germline-characterized TNBC by investigating somatic mutations in ctDNA.
Methodology: 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.
Results: We enrolled 96 TNBC patients of which 88 were tested for germline variants: 23% (20/88) of cases were Hereditary – BRCA1 (16%), BRCA2 (4%), PALB2 (1%), RAD51D (1%) and TP53 (1%). Tumor mutation burden (TMB) analysis (43 cases) showed that 11.6% had high and 89.4% low TMB, not associated with Hereditary status. We found, on average, 3 somatic variants per tumor (range 1-7) and used them as tumor marks for screening ctDNA in plasma. Somatic mutations in TP53 were identified in most tumors (71%). In ctDNA before treatment, detection of at least one tumor mutation was observed in 24 out of 30 patients (80%) and no association was observed regarding Hereditary status and TMB score. Although ctDNA was not associated to the residual cancer burden (RCB) score, ctDNA- positive patients were associated with clinical progression, either at baseline and during monitoring (post-neoadjuvant chemo) and ctDNA identification anticipated progression detected by imaging.
Conclusion: 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.
Keywords: hereditary tumor; triple-negative breast cancer; ctDNA; liquid biopsy