Determining Clinical Relevance of Genomic Heterogeneity in an Ethnically Diverse Cohort of Newly Diagnosed Patients with Breast Cancer

ASCO Annual Meeting 2019 Presentation
Authors Padma Sheila Rajagopal, Nike Beaubier, Masaya Hattori, Lise Sveen, Galina Khramtsova, Taylor Abboushi, Mathew Barber, Fang Liu, Toshio Yoshimatsu, Yonglan Zheng, Kevin White, Dezheng Huo, and Olufunmilayo I. Olopade

Background: The trajectory from early breast cancer to distant metastasis has not been precisely characterized. We are building an ethnically diverse, longitudinal cohort of prospectively ascertained breast cancer patients with integrated genomic, transcriptomic, epidemiological and clinical data, with the goal of identifying biomarkers that can improve on clinical predictors.

Methods: Our goal is 500 histologically confirmed invasive cases with a minimum follow-up of 5 years. To date, Tempus Labs, Inc. has completed xT assays (595-gene panel DNA-seq and full-transcriptome RNA-seq) on 127 cases with matched tumor-normal samples. Clinical information was obtained from electronic health records and our cancer registry.

Results: Median age of diagnosis was 51, with 47% African-Americans. 73% had stage 2 or 3 disease (2 patients were stage 4). 24.4% had TNBC; 30% had HER2+ and 62.2% HR+ status. Somatic alterations were identified in 560 genes with most common mutations in TP53 (56%), MCL1 (35%), PIK3CA (30%) and ERBB2 (17%). Somatic mutations in BRCA1 (10%) and BRCA2 (5%) were associated with increased tumor mutation burden (TMB). 2 patients were MSI high; 6 were equivocal. After a median follow-up of 6.5 years, 46 patients died and 38 had recurrent disease. With adjustment for clinical factors, TMB showed a slight nonsignificant negative association with recurrence-free survival (HR: 0.97, 95% CI: 0.91-1.00, p = 0.31). TP53 was associated with recurrence-free survival (HR: 1.76, 95% CI 0.94-3.29; p = 0.08) as was MSI (HR: 0.24, 95% CI: 0.06-1.06, p = 0.06).

Conclusions: These data support the importance of integrating tumor sequencing in a diverse cohort with full clinical annotation to assess the diversity of actionable genomic alterations at the time of primary diagnosis to develop interventions for prevention of metastases.