Exome Analysis Of Oncogenic Pathways And Tumor Mutational Burden (Tmb) In Triple-Negative Breast Cancer (Tnbc): Results Of The Translational Biomarker Program Of The Neoadjuvant Double-Blind Placebo Controlled Geparnuevo Trial.

509 Background: GeparNuevo (G9) showed a numerical increase in pCR rate of 53% vs 44%; p = 0.287 compared to placebo in TNBC with the addition of the anti-PD-L1 antibody durvalumab (D) to a neoadjuvant anthracycline-taxane containing chemotherapy (Loibl S et al. ASCO 2018). Somatic mutations in malignant cells manifest over the evolutionary history of a tumor. Reports in selected tumor types suggest that TMB may predict clinical outcomes on immune-checkpoint inhibitors (ICI). The clinical relevance of TMB in breast cancer has not been studied widely. Here, we investigated the hypothesis that TMB predicts response to ICI. Methods: Whole exome sequencing was conducted on patient-matched fresh-frozen core biopsies and blood samples with Illumina (n = 149/174). SNVs and indels were called with Mutect and pureCN was used for copy number calls. Mutational signatures were identified as described by Alexandrov et al. (Cell Rep. 3, 2013). Data from G9 were compared to The Cancer Genome Atlas (TCGA) TNBC cohort. Results: A similar genomic landscape was observed between G9 and TCGA with primary mutations in TP53 (69%), c-MYC (26%), BRCA1 (13%), BRCA2 (6%), PIK3CA (11%) and PTEN (11%). Median TMB was 1.52 mut/MB. TMB in G9 was slightly lower than TCGA TNBC. TMB correlated with older age, higher mutation rates in BRCA2, ARID1A, and TP53, and higher burden in variant signatures such as DDR, HRD, GFRs, APOBEC and Alexandrov’s signatures 3 and 6. Continuous TMB predicted pCR in univariate (OR = 1.62, 95%-CI: 1.20 - 2.20, p = 0.0018) and multivariate (OR = 2.06, 95%-CI: 1.33 - 3.20, p = 0.0012) logistic regression models, but did not predict a D effect. After dichotomisation of TMB at the top tertile, 50 patients had high TMB and 29 of these (58%) achieved a pCR, while 99 had low TMB and only 38 of these (38%) had a pCR (p = 0.0242). Conclusions: Results show that TMB may predict pCR in primary TNBC. The trial was financially supported by Astra Zeneca and Celgene. Clinical trial information: NCT02685059.