Whole-Exome Sequencing Identifies Biologically Informative Alterations in the Majority of Metastatic Cancers
In a study reported in JAMA Oncology, Beltran et al found that whole-exome sequencing of metastatic and treatment-resistant cancers revealed biologically informative alterations in the majority of cases. Although treatment recommendations could be made in the majority of cases, treatment was guided on the basis of such information in very few.
Study Details
Patients with metastatic and treatment-resistant cancers were prospectively enrolled at Weill Cornell Medical College between February 2013 and September 2014 for paired metastatic tumor and normal tissue whole-exome sequencing to detect point mutations, indels, and copy number alterations. Clinical reports were discussed in a precision tumor board, and patients were observed for 7 to 25 months for correlation of molecular information with clinical response.
High Yield of Actionable/Potentially Actionable Findings
A total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced with a mean coverage of 95X. An average of 16 somatic alterations were detected per patient. In total, 16 mutations were classified as category 1 (defined as having available targeted therapy), 98 were category 2 (defined as biologically relevant), and 1,474 were category 3 (defined as of unknown significance). Whole-exome sequencing provided informative results in 91 patients (94%), including alterations for which there is an approved drug or therapies in clinical or preclinical development and alterations that are considered mutational drivers and potentially actionable. The tumor board was able to make treatment recommendations in the majority of cases. However, treatment was guided in only five patients (5%) on the basis of the recommendations, due primarily to lack of access to clinical trials or off-label use of drugs.
Identification of Treatment Response Mechanism
As noted by the investigators, one unexpected finding was a dramatic response to treatment for prostate cancer in a patient with somatic hemizygous deletion of the DNA repair gene FANCA and putative partial loss of function of the second allele in association with a germline missense variant. Subsequent study showed that loss of FANCA function was associated with platinum hypersensitivity in vitro and in patient-derived xenografts, providing a biologic and functional explanation for the dramatic response.
The investigators concluded, “The majority of advanced, treatment-resistant tumors across tumor types harbor biologically informative alterations. The establishment of a clinical trial for whole-exome sequencing of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.”
Himisha Beltran, MD, and Mark A. Rubin, MD, of the Institute for Precision Medicine, Weill Cornell Medical College, are the corresponding authors of the JAMA Oncology article.
The study was supported by a Damon Runyon Cancer Research Foundation-Gordon Family Award, the Department of Defense, the Ann and William Bresnan Foundation, the Starr Cancer Consortium, the Prostate Cancer Foundation, the National Cancer Institute, Weill Cornell Medical College, the Canadian Institutes of Health Research, the National Science Foundation, the Leukemia and Lymphoma Society, and the Hirschl Trust.
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