Sometimes referred to as massively parallel sequencing, next-generation sequencing evaluates millions of DNA sequences simultaneously, representing a true revolution compared with traditional, labor-intensive methods in which far less DNA could be sequenced at once.
Lucy Langer, MD
Lucy Langer, MD
Over the past decade, tremendous progress has been made in the development of DNA sequencing technologies. Of particular use to the cancer community is next-generation sequencing (NGS), the newer technique of higher throughput evaluation of genetic sequences. Sometimes referred to as massively parallel sequencing, this advanced technology evaluates millions of DNA sequences simultaneously, representing a true revolution compared with traditional, labor-intensive methods in which far less DNA could be sequenced at once.1
This powerful new technology holds great potential in our efforts to offer patients with cancer the most effective treatments and preventive strategies. Although CMS has expanded coverage to include NGS tumor testing, not all patients who could benefit from this potentially lifesaving technology are covered, fueling a growing debate within the cancer community.
The Predictive Value of Germline Data
Today NGS is used to evaluate both germline and somatic genetic alterations. In germline testing, NGS technologies are employed to examine the genes an individual inherited and that are present in every cell of the body. White blood cells, skin cells, and cells from the lining of the mouth are commonly used to identify any inherited DNA alterations. By contrast, somatic genetic alterations are found in tumors and require a tumor sample for testing.
Only a few years ago, germline information was thought of as just a useful prognostic tool for estimating the risk of a cancer. As a predictive tool, aiding in the selection of the appropriate therapies for a cancer, germline information had not reached prime time. Even the decision to undergo bilateral mastectomy for breast cancer was more of a choice to prevent a future cancer than a change in management of the present cancer.
Our understanding of targeted therapies has evolved, and we now realize that knowledge of an underlying germline mutation can play a vital role in selecting treatments for several cancers. For example, patients with ovarian cancer and a germline mutation in a BRCA gene have responded well to the class of drugs called PARP inhibitors. Similarly, in patients with breast cancer, BRCA mutations can drive the choice of a PARP inhibitor. Further, patients with colon cancer who have a mutation in a gene associated with Lynch syndrome have a different response to the classical drug used for this, fluorouracil, compared with those without the mutation.
The American Society of Breast Surgeons recommends that all women with breast cancer be tested for a germline mutation, and, because PARP inhibitors are available, the National Comprehensive Cancer Network (NCCN) guidelines promote consideration of BRCA testing in all women with metastatic breast cancer.
All women with ovarian cancer should also be tested, not only because PARP inhibitors are available but also because there is a higher likelihood of carrying a deleterious mutation if the patient has ovarian cancer. In general, 5% to 10% of cancers may be caused by an inherited mutation. However, in ovarian cancer, the likelihood of a harmful mutation being identified can be as high as 20%. This information is important not only for an individual woman but also her family.
Many organizations have their own guidelines about which patients should be tested for germline mutations. These include the American Society of Clinical Oncology, the Society of Gynecologic Oncology, the American Society of Breast Surgeons, and the National Society of Genetic Counselors. Most in the cancer world follow NCCN guidelines, which are most commonly adopted by payers. Much can be said about how these guidelines are written and what goes into them, but generally, the NCCN guidelines are considered the gold standard.
The Medicare Controversy Over Germline Testing
In recent years, CMS has taken steps to expand access to care for patients with cancer. A national coverage determination (NCD) was made last year to allow coverage for NGS tumor tests. This included approval for a comprehensive panel test from Foundation Medicine and companion diagnostic tests for specific therapies. As the NCD has been applied, coverage for this kind of testing is supported for patients with advanced or stage IV cancer to help determine treatment options; however, it excludes testing for germline mutations in patients who do not have advanced disease.
Prior to this rule, CMS covered germline genetic testing (with NGS technologies) only for patients with a diagnosis of cancer who met specific criteria, largely based on the published NCCN guidelines. Now, the specific stage and diagnosis are being brought into play. This has the effect of excluding a large population of patients for whom knowledge of an underlying germline mutation could alter their treatment course and potentially help prevent future cancers.
It is also worth noting that master’slevel trained certified genetic counselors are currently not recognized by Medicare. Consequently, in our practice, Medicare patients undergoing genetic counseling must be seen by either a physician or a nurse practitioner who has advanced specialty training in genetics. In states like Oregon, where we practice, it seems counterproductive to direct a group of patients away from the practitioner with master’s level expertise specifically in genetic risk evaluation, counseling, and testing. Last October, the National Society of Genetic Counselors presented a bill to Congress to recognize certified genetic counselors as Medicare practitioners.2 Hopefully, these uniquely trained professionals will soon be acknowledged by CMS.
Precision Medicine May Drive Germline Coverage
Tremendous advances are occurring in sequencing tumor genomes and identifying and targeting individual oncogenic driver mutations. We applaud CMS’ efforts to expand access to this potentially lifesaving technology. As our understanding of the cancer genome as defined by NGS broadens, great progress will undoubtedly occur in personalized therapeutics and diagnostics. However, misapplying the NCD to exclude patients with earlier-stage cancers from germline testing sets us back and hinders the pace of growth in knowledge about the interplay between germline and somatic genetics. As our ability to treat cancer grows and more cancers become chronic diseases, the information provided by germline testing will be critical in our ability to offer all patients the most effective therapies and cancer prevention plans.