Germline Findings in Tumor-Only Sequencing: Points to Consider for Clinicians and Laboratories.

Precision oncology holds great potential to improve patient therapies and outcomes. Tumor sequencing is rapidly moving into clinical care as our understanding of the cancer genome and the availability of targeted therapies increase. Analysis of the cancer genome is most informative when paired with germline genomic DNA to delineate inherited and somatic variants. Although tumor-only analysis remains the most common methodology for numerous reasons, it holds the potential to identify clinically significant germline variants. Here, we provide anticipatory guidance and points to consider for laboratories and clinicians regarding the potential for germline findings in tumor sequencing.

The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine.

BACKGROUND: The diversity of clinical tumor profiling approaches (small panels to whole exomes with matched or unmatched germline analysis) may engender uncertainty about their benefits and liabilities, particularly in light of reported germline false positives in tumor-only profiling and use of global mutational and/or neoantigen data. The goal of this study was to determine the impact of genomic analysis strategies on error rates and data interpretation across contexts and ancestries. METHODS: We modeled common tumor profiling modalities-large (n = 300 genes), medium (n = 48 genes), and small (n = 15 genes) panels-using clinical whole exomes (WES) from 157 patients with lung or colon adenocarcinoma. We created a tumor-only analysis algorithm to assess germline false positive rates, the impact of patient ancestry on tumor-only results, and neoantigen detection. RESULTS: After optimizing a germline filtering strategy, the germline false positive rate with tumor-only large panel sequencing was 14 % (144/1012 variants). For patients whose tumor-only results underwent molecular pathologist review (n = 91), 50/54 (93 %) false positives were correctly interpreted as uncertain variants. Increased germline false positives were observed in tumor-only sequencing of non-European compared with European ancestry patients (p < 0.001; Fisher's exact) when basic germline filtering approaches were used; however, the ExAC database (60,706 germline exomes) mitigated this disparity (p = 0.53). Matched and unmatched large panel mutational load correlated with WES mutational load (r(2) = 0.99 and 0.93, respectively; p < 0.001). Neoantigen load also correlated (r(2) = 0.80; p < 0.001), though WES identified a broader spectrum of neoantigens. Small panels did not predict mutational or neoantigen load. CONCLUSIONS: Large tumor-only targeted panels are sufficient for most somatic variant identification and mutational load prediction if paired with expanded germline analysis strategies and molecular pathologist review. Paired germline sequencing reduced overall false positive mutation calls and WES provided the most neoantigens. Without patient-matched germline data, large germline databases are needed to minimize false positive mutation calling and mitigate ethnic disparities.

The impact of disclosing financial ties in research and clinical care: a systematic review.

BACKGROUND: Despite increased demand for disclosure of physician and researcher financial ties (FTs) to industry, little is known about patients', research participants', or journal readers' attitudes toward FTs. METHODS: We systematically reviewed original, quantitative studies of patients', research participants', or journal readers' views about FTs to pharmaceutical and medical device companies. The MEDLINE, Scopus, and Web of Knowledge databases were searched for English-language studies containing original, quantitative data on attitudes toward FTs. We screened 6561 citations and retrieved 244 potentially eligible abstracts. Of these, 20 met inclusion criteria. RESULTS: Eleven studies assessed FTs and perceptions of quality. In clinical care, patients believed FTs decreased the quality and increased the cost of care. In research, FTs affected perceptions of study quality. In 2 studies, readers' perceptions of journal article quality decreased after disclosure of FTs. Eight studies assessed the acceptability of FTs. Patients were more likely to view personal gifts to physicians as unacceptable, compared with professional gifts. In 6 of the 10 studies that assessed the importance of disclosure, most patients and research participants believed FTs should be disclosed; in the other 4, approximately one-quarter believed FTs should be disclosed. Among the 7 studies assessing willingness to participate in research, approximately one-quarter of participants reported less willingness after disclosure of FTs. CONCLUSIONS: Patients believe that FTs influence professional behavior and should be disclosed. Patients, physicians, and research participants believe FTs decrease the quality of research evidence, and, for some, knowledge of FTs would affect willingness to participate in research.

Self-reported practices and attitudes of US oncologists regarding off-protocol therapy.

PURPOSE: Investigational cancer therapies being tested in clinical trials may be available outside of trials, or off-protocol (OPRx). We evaluated the practices and attitudes among US oncologists with regard to this controversial practice. METHODS: We mailed an anonymous survey to a random sample of US medical oncologists evaluating frequency and prevalence of OPRx and evaluated the correlation between demographic factors, attitudes, and practice. RESULTS: One hundred forty-six (31%) of 471 oncologists responded. Ninety-three percent reported ever discussing and 81% ever prescribing OPRx. Academic oncologists were more likely than community oncologists to have ever provided OPRx (89% v 75%; P = .06), to discuss OPRx at least once/month (41% v 19%; P = .0004), and to deny requests for OPRx at least once/month (16% v 2%; P = .004). While 61% of oncologists believed that patients should be discouraged from OPRx, only 31% felt it should not be available. With regard to trial recruitment, 53% felt that informed consent requires discussion of OPRx, 34% disagree, and 26% feel that patients should be provided OPRx on request, while 56% disagree. There was lack of consensus on access to OPRx in scenarios based on open trials at the time of the survey, such as adjuvant trastuzumab, which 41% would provide, 59% would not. CONCLUSION: US oncologists report common discussion and use of OPRx, but attitudes and practices may vary substantially. There is need for greater debate regarding OPRx in oncology, further definition of the ethical and clinical issues at stake, and development of guidelines in this area.