Potentially targetable alterations identified in circulating tumor DNA (ctDNA) from patients (pts) with advanced rare cancers.

Abstract

e15540 Background: People with rare cancers have limited treatment options. In April 2017, the MASTER KEY Project, a prospective registry study with multiple clinical trials embedded, was established to promote treatment development for rare cancers. ctDNA analysis by next-generation sequencing (NGS) has provided new insight into personalized medicine; however, reports are focused on common cancers. Using our platform, we examined the feasibility of ctDNA NGS analysis for rare solid cancers. Methods: Prospectively consented pts with advanced rare cancers enrolled in MASTER KEY had ctDNA NGS testing (Guardant360, Guardant Health). Alterations were assessed for incidence according to cancer type, functional impact, and therapeutic implications. Results: From Nov 2018 to Jan 2019, 98 samples from 100 consented pts were analyzed. Diseases included soft tissue sarcoma (39); cancers of the ovary (12) and salivary gland (9); neuroendocrine tumors (8); carcinoma of unknown primary (6); carcinosarcoma (5); mesothelioma (4); gastrointenstinal stromal tumor (3); and olfactory neuroblastoma (2). All pts were Japanese, male/female = 40/58, median age 53, ECOG performance status 0/1/2/3 = 56/41/0/1, prior pharmacotherapy yes/no = 77/21. 76% of pts (75/98) had at least 1 alteration detected (median 2.8/pt; range: 0-9), with variant allelic frequency of 0.1-73.3%; 61%(60/98) of pts had a likely pathogenic variant, most commonly TP53 (43), KRAS (11), and NRAS (6); 36% (36/98) had a potentially actionable variant, such as BRCA1/2 (6), EGFR (6), PIK3CA (6), ARID1A (5), FGFR1/2/3 (4), and other homologous recombination deficiency genes. Known resistant mutations such as ROS1 G2032R and RAS mutations were detected in patients on a ROS inhibitor and a BRAF inhibitor, respectively, which suggested drug resistance prior to clinical diagnostic imaging. Mean turn-around-time from blood collection was 9.5 days. Conclusions: ctDNA testing is capable of rapidly identifying alterations that lead to clinical decision making in pts with advanced rare cancers, who have a crucial lack of treatment options compared to common cancer pts. Clinical trial information: UMIN000034394.