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