Abstract IA17: Non-invasive detection of somatic mutations in the management of CRC

Abstract

Abstract Somatic mutations are exquisitely specific cancer biomarkers that are not merely associated with cancer, rather they are the root cause of cancer. The realization that this markers are present in bodily fluids of individuals with cancer and the development of digital methods for their detection ushered a new era in the management of cancer patients providing opportunities for the development of noninvasive methods for early detection, detection of minimal residual disease, monitoring of response to therapy, early detection of resistance and diagnosis. There are both technical and biological challenges for the development of noninvasive tests for the detection of somatic mutations. The number of circulating tumor DNA (ctDNA) molecules is very low compared to that of DNA molecules with wild-type sequence and requires very sensitive methods for their detection. To this end, we have developed a method called SafeSeqS that is able to reliably resolve mutations at 0.01% in background of wild-type DNA across multiple regions of interest. To determine the spectrum of cancers in which ctDNA measurements could prove clinically useful, we evaluated the detection of ctDNA in plasma (liquid biopsy) from patients with a large number of tumor types. ctDNA was detectable in the plasma of most patients with advanced tumor, but in less than 50% in patients with certain tumor types, like primary brain cancers. More than half of the patients with localized colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, had detectable ctDNA in their plasma. The sensitivity of detection of advanced colorectal cancer (CRC) was close to 100% and greater than 75% for localized cancers indicating that liquid biopsy could be utilized for a number of clinical applications. One such application is the detection of minimal residual disease after surgery or therapy with curative intent. Currently, there are not efficient ways to determine which patients are cured and which have residual disease that will result in recurrence. In a prospective cohort of 230 patients with resected stage II colon cancer, ctDNA detection after surgery provided direct evidence of residual disease and identified patients at very high risk of recurrence. Another application of liquid biopsy in CRC is monitoring resistance to therapies, like EGFR, providing an early indication that resistance ensues. The holy grail of non-invasive detection of cancer is early detection. Most tumors are incurable because they are detected at a late stage. Early detection of cancer, before symptoms appear, at a stage curable by surgery, holds great promise for decreasing the rate of deaths due to cancer. We will share our efforts on the development of tests for the early detection of cancer. Our overall vision is that non-invasive, somatic mutation based tests become routine in the clinical management of cancer patients. Citation Format: Nickolas Papadopoulos, Yuxuan Wang, Joshua Cohen, Ralph Hruban, Peter Gibbs, Jeanne Tie, Luis Diaz, Kenneth Kinzler, Bert Vogelstein. Non-invasive detection of somatic mutations in the management of CRC. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA17.