A systematic liquid biopsy program identifies novel and heterogeneous mechanisms of acquired resistance in gastrointestinal (GI) cancer patients

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S3-S3
• Main Authors: Parikh, A, Kwak, E, Goyal, L, Blaszkowsky, L, Hazar-Rethinam, M, Siravegna, G, Russo, M, Van Seventer, E, Nadres, B, Shahzade, H, Clark, J, Allen, J, Iafrate, A.J, Bardellli, A, Ryan, D, Murphy, J, Zhu, A, Hong, T, Corcoran, R
• Format: Article
• Language: English
• Subjects: Antibodies; Biopsy; Cancer; Decision making; Deoxyribonucleic acid; Digestive system; DNA; Drug resistance; Epidermal growth factor receptors; ErbB-2 protein; Fibroblast growth factor receptor 2; Fibroblast growth factor receptors; Hematology, Oncology and Palliative Medicine; Heterogeneity; Inhibitors; MAP kinase; Metastases; Molecular chains; Mutation; Patients; Target acquisition; Therapy; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32610-7

Background: Understanding mechanisms of acquired resistance to targeted therapy can guide strategies to improve clinical outcome. Circulating tumor DNA (ctDNA) provides a non-invasive means to identify concurrent heterogeneous resistance mechanisms arising during therapy. Methods: Since January 2015, 31 patients (pts) with molecularly-defined Gl cancers (22 colorectal (CRC), 7 biliary, 2 gastroesophageal (GE)) achieving response or prolonged stable disease on targeted therapies had plasma collected at disease progression for next-generation sequencing of ctDNA. Molecular alterations identified were compared to ctDNA and/or tissue obtained pre-treatment to identify mechanisms of acquired resistance. When possible, post-progression tumor biopsies were also analyzed. Results: In 31 pts, at least one molecular mechanism of resistance was identified in progression ctDNA in 24 (77%) pts, with 11 (36%) exhibiting >1 resistance alteration (range 2-12, median 3). Overall, 62 total (35 distinct) resistance alterations were identified. 13 pts had matched progression tumor biopsies, and resistance alterations were identified in 9 (69%), all of which were detected in matched ctDNA. In 62% of these pts, additional resistance mechanisms not detected in the matched tumor biopsy were identified in ctDNA. In 7 pts with multiple progression tumor biopsies available, distinct metastases showed different resistance alterations, all of which were detectable in ctDNA, but in 6 (86%) of these pts, ctDNA detected additional resistance alterations not found despite multiple tumor biopsies, reflecting extensive heterogeneity. Several critical and/or novel resistance alterations were identified across tumor types treated with diverse therapies. In 12 of 15 RAS wildtype CRC pts receiving EGFR antibodies, 21 total (10 distinct) resistance alterations affecting KRAS. EGFR extracellular domain, MEK1, MET, and ERBB2 were detected. In 3 of 5 BRAF mutant CRC pts receiving BRAF inhibitor combinations, 10 total (9 distinct) resistance alterations affecting MAPK genes (KRAS, NRAS, BRAF, MEK1, MEK2) were detected. In a MET-amplified GE pt receiving a MET inhibitor, 2 novel secondary mutations in the MET kinase domain were identified. In 4 FGFR2 fusion-positive biliary pts receiving an FGFR inhibitor, all patients developed novel secondary FGFR2 kinase mutations (13 total. 8 distinct), with 2 pts harboring 5 concurrent mutations, and one harboring 2. Conclusions: Systematic ctDNA analysis at dis