Background: Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low frequency mutations. We describe an evidence-based precision medicine program designed to bring whole exome sequencing into clinical practice and illustrate how this can be utilized to identify novel predictive biomarkers associated with exceptional systemic response.
Methods: Metastatic and treatment-resistant cancer patients are prospectively enrolled under an IRB approved protocol for paired metastatic tumor and normal WES through our Precision Medicine Clinic. Using a comprehensive computational pipeline, point mutations, indels and copy number alterations are detected. Mutations are categorized as Category I-III based on actionability and a report is generated and discussed in tumor board. Patients are followed prospectively for correlation of molecular information with clinical response and patient outcomes. A rapid response functional team follows on key findings to expand actionability based on the WES results.
Results: In the first year, 154 tumor-normal pairs from 97 patients were sequenced, with an average coverage of 95X of over 21,000 genes and 16 somatic alterations detected on average per patient. In total, 16 mutations were Category I, 98 were Category II, and 1474 were Category III. Tumor purity ranged from 14 to near 100%. Among unexpected findings, a prostate cancer exceptional responder was identified that harbored a somatic hemizygous deletion of the DNA repair gene FANCA and likely loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response.
Conclusions: The establishment of a clinical program for whole exome sequencing of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.
Citation Format: Himisha Beltran, Kenneth Eng, Juan Miguel Mosquera, Alexandros Sigaras, Alessandro Romanel, Hanna Rennart, Myriam Kossai, Chantal Pauli, Bishoy Faltas, Jacqueline Fontugne, Brian Robinson, David M. Nanus, Scott T. Tagawa, Jenny Z. Xiang, Francesca Demichelis, David Rickman, Andrea Sboner, Olivier Elemento, Mark A. Rubin. Precision cancer medicine program for whole-exome sequencing of metastatic tumors reveals biomarkers of response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4745. doi:10.1158/1538-7445.AM2015-4745