For some solid tumors, identification of genomic alterations susceptible to drug therapy has improved clinical outcomes. This has led to increased interest in next-generation sequencing (NGS) testing to identify patients who qualify for enrollment in biomarker-selected clinical trials. In the Michigan Oncology Sequencing Program (Mi-ONCOSEQ), a cohort study of 1015 patients who underwent integrative genomic profiling, Dr E.F. Cobain and colleagues identified a high rate of pathogenic germline variants and a subset of patients who derived substantial benefit from sequencing information. In this study, the majority (80.5%) of tumors sequenced had at least 1 potentially actionable alteration, and 70.2% harbored a somatic molecular alteration that was potentially actionable and provided rationale for the use of investigational targeted or off-label therapy. Among the alterations, nearly all (94.8%) were identified by DNA sequencing and two-thirds were identified by RNA sequencing. Sequencing-directed therapy (SDT) was initiated in 16.2% of patients with actionable alterations; of those, 37.1% of patients experienced clinical benefit, primarily those with sarcoma, prostate cancer, or cancer of unknown primary (CUP) origin. Of the patients receiving SDT, nearly 20% had exceptional response and received treatment for 12 months or longer. None of these therapies would have been recommended per standard-of-care guidelines, thus highlighting the value of sequencing information.
NGS testing contributed to more-definitive diagnoses for some patients, helping to establish a treatment paradigm for some patients with CUP. About half of the cases with CUP were reclassified to an alternative cancer diagnosis. This enabled 23.6% of patients originally diagnosed with CUP to receive SDT, with clinical benefit achieved in half.
Pathogenic germline variants (PGVs) were identified and designated as having potential therapeutic implications in 4.8% of the cohort. PGVs associated with therapeutic targets were identified, 76% of which had not been determined prior to enrollment. Many of the PGVs were ascertained as having therapeutic relevance, leading to administration of targeted therapies with clinical benefit. PGVs were identified in malignant tumors not typically associated with common hereditary cancer syndromes. In an editorial response to the original investigation, Dr Timothy Yap and colleagues reinforced that matched tumor-normal testing discovers previously unknown PGVs.
The authors concluded that genomic profiling of tumor and normal specimens was found to be a clinically powerful tool. The findings of this study provide rationale for directed germline testing for inherited cancer predisposition in all patients with advanced cancer. They also support use of integrative genomic profiling as part of standard of care for patients with CUP and other rare malignant tumors. On the basis of the research, precision medicine strategies have the greatest potential in cancer types that currently do not have clear standard-of-care options (eg, CUP and other rare tumors), to enable delivery of personalized therapies to those patients.
The study authors suggest that germline testing of DNA repair genes should be standard practice in patients with metastatic solid tumors, as well as comprehensive NGS profiling at diagnosis for patients with CUP. Further discovery of genomic biomarkers predictive of clinical benefit from anticancer therapies will lead to broader clinical applicability of this technology. Continued efforts are needed to identify genomically matched treatments for key cancer drivers, and timely availability of these therapies will be essential to their success.
If resources allow, it is suggested that institutions establish a dedicated clinical decision support team to facilitate successful practice of precision medicine. These teams can interpret molecular profiling results, identify matched therapies, and provide treatment recommendations to ensure that the data and therapeutic options are up to date at the point of care. To allow time for an integrated analysis, this approach requires that testing be done early in the metastatic course.
Accurate readout and interpretation of PGV test results is crucial to decision-making, and should be done by trained specialists who can help clinicians choose the best treatment for their patients. When interpreting PGV test results, oncologists should consider whether the variant alters the function or expression of the protein to promote tumor growth, whether there are clinically available therapies that target the alteration, and the level of evidence for use of a specific therapy within a given molecular profile and tumor type. The identification of PGVs also has implications for patients’ family members, who may be offered genetic testing and enhanced screening, with risk-reducing interventions if appropriate. As NGS moves toward becoming a standard-of-care diagnostic tool, informed consent and genetic counseling may be needed to ensure that patients and their families understand the possibility and potential impact of PGV discovery.