Cancer risk panels -pro
There are several objections to widespread indiscriminate adoption of hereditary cancer profiles, with multiple genomic alterations done in the form of a panel. First, they indiscriminately mix high penetration and low penetration mutations. High-penetrance mutations usually result in a significant alteration in the function of the corresponding gene product and are associated with large increases in cancer risk. Other mutations (eg, APC*I1307K, CHEK2*1100delC) result in less dramatic increases in risk (intermediate penetrance). The identification of a high-penetrance mutation often justifies an adjustment of clinical care through the modification of surveillance or through preventive surgery, although the benefit of such intervention must be established through prospective clinical trials, which for most of such mutations had not been done. Germline testing for certain high-penetrance predispositions is now part of clinical guidelines and is reimbursed by most third-party payers. The impact of intermediate-penetrance mutations on clinical care is less clear. For low penetrance mutations, there seems to be no value and much downside for it to be tested. For example, rs13281615 confers a risk of breast cancer equivalent to that of delaying childbearing from age 30 to 35. This level of risk does not warrant changes in recommendations for screening or prevention. However, if not framed appropriately, clinically ambiguous test results could produce unjustified alarm and may lead patients to request unnecessary screening and other preventive care that can cause physical discomfort or harm and increase costs. Alternatively, ambiguous test results or results associated with minimal cancer risk can provide false reassurance that discourages individuals from taking appropriate preventive measures. Another objection arises from the fact that most inherited cancer susceptibility arises from a number of DNA sequence variants, each of which, in isolation, confers a limited increase in risk. There is simply no clinical experience on how to deal with more than one identified mutation. Therefore, genetic testing (Ambry Genetics Cancer Next panel) is not considered medically necessary.
A recent paper by Domchek and Bradbury (2013), “Pending the development of these new counseling approaches, we recommend that multiplex testing is performed in the context of carefully designed follow-up studies to limit the potential for harm and maximize benefit to patients.”
Finally, per SGO (2014), “The major drawback of cancer gene panels is the increased complexity of results. For many genes, clear risk reduction strategies for mutation carriers are not established. A major concern is the increased likelihood of identifying results of uncertain clinical significance.”
2. IS genetic testing in this clinical setting supported by NCCN or the appropriate medical society?
No. American Society of Clinical Oncology (ASCO) recommends genetic counseling both before and after the genetic test. Only in settings of high quality and easily available genetic counselling with easy access, should multi-gene assays even be considered. Therefore, genetic testing in this clinical setting is not supported by NCCN or the appropriate medical society
As stated per ASCO (2015), “In particular, there was an interest in addressing the opportunities and challenges arising from the application of massively parallel sequencing-also known as next-generation sequencing-to cancer susceptibility testing. This technology introduces a new level of complexity into the practice of cancer risk assessment and management, requiring renewed effort on the part of ASCO to ensure that those providing care to patients with cancer receive the necessary education to use this new technology in the most effective, beneficial manner.”
PEER REVIEWED PUBLICATION/LITERATURE
Domchek, S. M., and Bradbury, A. (2013). Multiplex Genetic Testing for Cancer Susceptibility: Out on the High Wire Without a Net? CO April 1, 2013 vol. 31 no. 10 1267-1270
Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, Lipkin SM, Syngal S, Wollins DS, Lindor NM. (2015). American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. doi: 10.1200/JCO.2015.63.0996.
Society of Gynecologic Oncology (SGO). Clinical Practice Statement: Next Generation Cancer Gene Panels Versus Gene by Gene. (2014). Retrieved from: https://www.sgo.org/clinical-practice/guidelines/next-generation-cancer-gene-panels-versus-gene-by-gene-testing/