Implementation of Precision Cancer Medicine: Progress and the Path to Realizing the Promise of Tumor Sequencing

摘要

Precision medicine, as described by Jameson and Longo ~( 1 ) is a classic example of a disruptive innovation, one that challenges existing standards of practice and redefines how we classify cancer and select treatments. They noted that, given the complexity and volume of data that support this new paradigm of precision medicine, physicians will no longer be able to rely on memory or other traditional information sources to apply precision medicine in the clinic. Rather, precision medicine will need to rely on the development of robust informatics and decision supports to be effectively implemented in clinical practice. In the article that accompanies this editorial, Levit et al ~( 2 ) describe how three large, multisite community practices or networks have successfully incorporated precision cancer medicine (PCM) into their community oncology practices. Each of these practices has leveraged informatics and decision support as key components of successful implementation. They describe using standardized algorithms for testing, in-house sequencing, and molecular tumor boards, which provide guidance to physicians on how to interpret sequencing results. In addition, commercial or in-house clinical pathway programs and nurse navigators were used to match patients to clinical trials, and additional financial supports (eg, a drug navigation team) were used to interact with insurers to obtain approval for drugs. These are impressive implementation efforts that address many of the critical pain points for oncology providers who face a wide range of barriers as they implement PCM in their clinical practice. ADDRESSING EXPECTATIONS AND PROVIDING EDUCATION ABOUT TESTING As we continue down the path of implementing PCM in real-world practice, there are additional challenges that will be critical to address and that might benefit from similar technology and decision support systems. First, as the authors acknowledge, many patients have high expectations about the benefits of tumor sequencing, and providers need to clearly communicate its potential benefits as well as its risks and limitations. ~( 3 - 5 ) Although patients have high expectations for and interest in tumor sequencing, ~( 4 ) studies report that some patients are concerned about the complexity of the information, the potential for distress, and disappointment and loss of hope after testing, particularly when no actionable mutations are identified or clinical trials are not accessible. ~( 5 , 6 ) Studies have shown that only a subset of patients who have undergone tumor sequencing enroll in clinical trials. ~( 7 - 9 ) Addressing these expectations and possibilities at the time of testing could help mitigate negative patient outcomes. We do not know how best to approach pretest education and counseling for tumor sequencing, and it is likely not feasible or necessary for all patients to meet with a genetic counselor. ~( 10 ) Thus, the responsibility for pretest education and counseling presents an additional burden for oncology providers as they implement PCM in their practice. ADDRESSING THE POTENTIAL FOR SECONDARY GERMLINE FINDINGS Second, an important component of provider communication about tumor sequencing is sharing the potential for secondary germline findings, which will vary depending on which sequencing platform is used. In the setting of tumor-normal sequencing, the American College of Medical Genetics and Genomics (ACMG) has recommended that 59 genes (including those in both cancer and cardiovascular conditions) be actively evaluated for pathogenic mutations and reported back to patients, unless they specifically decline to receive secondary findings. ~( 11 , 12 ) ASCO and others have endorsed pretest communication to inform patients of the possibility of secondary germline findings and to determine their preference for receiving germline information. ~( 10 , 13 , 14 ) Studies suggest that 3% to 18% of patients undergoing tumor-normal sequencing have a pathogenic germline variant. ~( 15 - 19 ) Although most patients are likely to be interested in secondary germline findings, current studies suggest that a subset of patients may prefer not to receive information about secondary germline findings. ~( 20 - 22 ) Qualitative studies have reported patient concerns about receiving secondary germline information, such as the complexity of the information, potential negative emotional impact, additional burden in the setting of advanced cancer, concerns about sharing these results with relatives, and additional costs. ~( 5 , 6 , 14 , 20 , 23 , 24 ) The obligation to address secondary germline findings in tumor-normal sequencing introduces considerable challenges in implementing PCM, and many commercial and institutional laboratories have elected to offer tumor-only sequencing, in which the ACMG guidelines for returning secondary germline information do not apply. But tumor-only sequencing can still identify the potential for a germline mutation. Oncology