Expanding Germline Analyses to Prevent and Treat Cancers

Alexander M. Castellino, PhD

September 06, 2017

Precision medicine targets actionable mutations in tumors to appropriate therapies, but finding those mutations can be a challenge. A new approach developed at Memorial Sloan Kettering (MSK) Cancer Center, New York City, which includes a germline mutation analysis, finds more of them.

The MSK team used paired tumor-normal sequencing and found that more than half of the inherited cancer gene mutations that they detected cannot be found using traditional methods (ie, phenotypic testing) based on family history, age, and tumor type.

In a case series of 1040 patients with advanced cancers, 101 of the 182 (55.5%) patients with clinically actionable mutations would not have been detected through guideline based "traditional" genetic testing approaches - which translates to 9.7% of the entire cohort of 1040 patients.

The study was published online September 5 in JAMA.

"We found that at the time of tumor diagnosis, information obtained from looking at germline and tumors allows for a more powerful window into hereditary cancers than the traditional approach," senior author Kenneth Offit, MD, MPH, chief of the Clinical Genetics Service and Robert and Kate Niehaus Chair in Inherited Cancer Genomics, MSK, told Medscape Medical News.

"The conventional way of assessing cancer risk will not detect a significant proportion of inherited mutations that are clinically actionable," he added. In addition, passing these findings to patients and their families allows them to take action on the information, which facilitates precision cancer prevention, he pointed out.

"This timely study in a large patient population questions the somatic-only approach of precision medicine, which matches treatment to the actionable mutation in the tumor," medical oncologist Eliezer M. Van Allen, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, told Medscape Medical News.

"In routine clinical practice, tumor-normal paired samples are genetically tested to filter out the 'noise' and to determine actionable targets in the tumor," he said. "The MSK study illustrates that there is indeed an important role for germline testing. It impacts therapeutic decision making that was not thought of even a few years ago," he added.

"However, treatment changes based on the MSK approach were instituted in only a small number of patients. Precision oncology will need a fair amount of studies to determine the therapeutic utility of this approach," Dr Van Allen said.

Dr Van Allen authored an accompanying editorial, which also raises questions about the clinical use of the MSK approach to the general cancer population.

The MSK Study

Between January 2014 and May 2016, 10,336 cancer patients at MSK consented to undergoing tumor and normal DNA sequencing using the MSK-IMPACT (MSK-Integrated Mutation Profiling of Actionable Cancer Targets) 410-gene panel.

Since May 2015, 1040 patients consented to a prospectively offered secondary germline analysis of 76 cancer predisposition genes (a subset of the MSK-IMPACT panel), which also included those identified in the American College of Medical Genetics and Genomics guidelines.

Of the 1040 patients, more than 80% had stage IV cancer, the most common of which were prostate, pancreatic, renal, breast, and colon cancers.

The MSK researchers estimated results after adjusting the population to change the case mix and by excluding Ashkenazi and European founder mutations in BRCA1/2, APC, MSH2, MSH6, CHEK2, or MUTYH.

Patients with advanced prostate cancer also had mutations in ATM, BAP1, BARD1, BRCA1/2, BRIP1, CHECK2, FAM175A, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, and RAD51D, some of which are known to be associated with this disease phenotype.

The protocol allowed the germline findings in the context of tumor-normal sequencing to be returned to patients and their families, and offered genetic counseling and recommendations when appropriate.

The MSK Study Findings

Of 1040 patients who consented to secondary germline testing, 205 patients (19.7%) had pathogenic variants conferring cancer risk. Of these, 182 had clinically actionable mutations, of which 81 were consistent with family history and phenotype, but 101 had additional mutations not predicted by family history or phenotype, which translates to 55.5% of the 182 cases.

Dr Offit pointed out some of the factors that contributed to the higher-than-expected prevalence of actionable mutations using the 76-gene MSK-IMPACT panel ― the high proportion of patients in the mix who share the founder mutations and the types of cancers enriched with these mutations. "Our cohort had more patients with pancreatic, prostate, colorectal, and breast cancers, which have a strong familial component, and less of lung cancer cases, which have less of a familial component," he said.

"However, even when we adjust the population to change the case mix and exclude founder mutations, about a third of actionable mutations are missed by traditional family history-based approaches, and this is still quite high," Dr Offit said.

Of the 76 genes tested, each patient had an average of 1.8 variants of uncertain significance, with 833 of 1040 patients having at least one variant of uncertain significance.

Pathogenic variants involved in DNA repair pathways were found in 49 of 362 (13.5%) patients with prostate cancer and in 87 of 678 (12.8%) patients with other cancers.

The MSK study also identified genes that contributed to the incremental actionable findings (eg, BRCA2, MSH2, MSH6), which would have been missed in guideline-directed approaches. In addition, patients with more advanced types of cancer had a greater proportion of hereditary mutations. "This is an interesting finding and suggests that inherited cancers may be more aggressive," Dr Offit noted.

This is an interesting finding and suggests that inherited cancers may be more aggressive. Dr Kenneth Offit

The germline findings were returned to 193 of 205 (94.1%) of patients, with pathogenic variants detected in 175 of 182 (96.2%) patients. Germline testing was offered to relatives of 29 patients with actionable mutations ― 13 of these mutations would not have been detected through guideline-based testing. In half the families tested (15/29), the mutation was found in at least one relative.

For 20 relatives with mutations, the MSK researchers offered increased surveillance or recommended risk-reduction procedures. For example, the daughter of a patient with advanced prostate cancer chose oophorectomy as a preventive option.

"Actionable mutations opened the window for discussing treatment options with patients," Dr Offit said. For example, of 132 patients with mutations in DNA repair genes, approved targeted therapies or their off-label use was discussed with 38 patients; 11 chose to be treated with PARP inhibitors.

Clinical Significance of the MSK Findings

Dr Offit explained the significance of their study especially in the context of detecting genetic defects in DNA repair genes and DNA mismatch repair genes, which may not be found using the traditional phenotypic approach.

Prostate cancer with BRCA1/2 mutation is typically seen in patients with cancers of Gleason grade 7 or higher, and these patients may benefit from PARP inhibition, he pointed out. "With the clinical advancement of PARP inhibitors, the MSK protocols for PARP inhibitors in pancreatic cancers increasingly allow for their use in this set of patients," he told Medscape Medical News.

Another noteworthy observation relates to mutations in DNA mismatch repair genes, such as MLH1, MSH2, MSH6, and PMS2, that are associated with microsatellite instability (MSI). Recently, immunotherapeutic approaches have been approved for patients with MSI-high tumors. "These agents are being actively investigated in patients with MSI-H prostate cancer," Dr Offit said. Indeed, in the case of a patient with advanced prostate cancer with more than 20 somatic mutations and a germline PMS2 mutation, immunotherapy was planned at the time this study went to press.

MSK is encouraged with the reported findings. The study is now scaled to test all patients with pancreatic, prostate, ovarian, and breast cancers for DNA repair mutations, Dr Offit told Medscape Medical News.

With respect to returning the mutational analyses to patients and their families, Dr Offit said in a statement: "At the time of a diagnosis of advanced cancer, we have a vital opportunity, through comprehensive genetic testing, to set the stage for precision prevention for patients' families. The major message for patients is that out of the challenges of a cancer diagnosis can come the opportunity for prevention in the family."

Germline testing across all cancer patients can create a vital opportunity for precision prevention to treat cancer preemptively in the next generation through increased surveillance or risk-reducing surgical procedures, the MSK researchers point out. For example, following an identification of MSI-H tumors in patients, family members identified with the same mutations are considered to have Lynch syndrome and can then be managed with increased surveillance.

Determining germline mutations allows for targeted treatment for patients and precision prevention for families. Dr Kenneth Offit

"Determining germline mutations allows for targeted treatment for patients and precision prevention for families," Dr Offit told Medscape Medical News.

Challenges in Implementing the MSK Approach

Attractive as the approach is, there are challenges in expanding germline testing into clinical practice for all cancer patients, Dr Van Allen told Medscape Medical News. He noted that although the MSK researchers used the 76-gene panel to determine germline pathogenic events, the results of the study indicated that only 19 (25%) were associated with actionable events. He also noted that other academic laboratories and commercial vendors provide similar approaches using nonoverlapping gene sets.

"There is uncertainty about the right genes in the mix. Which is the right test for germline testing?" Dr Van Allen asked.

He told Medscape Medical News that most academic centers and commercial ventures do not test for germline mutations. "Somatic tumor profiling costs less money and, given the potential implications of germline testing, is less complex," he said.

Blanket germline testing has the potential to generate a huge amount of data, which may be difficult to interpret and has downstream implications for family members, Dr Van Allen noted. He explained that with the MSK approach, an implementation system needs to be in place - from the consenting process, to having counselors in place, to having the ability to manage it operationally.

Although some commercial ventures undertake paired analysis, the analysis is done as proprietary intellectual property, Dr Van Allen suggested to Medscape Medical News. In cases in which the testing results are returned to the physicians who ordered them, they are unlikely to be returned to the patients, owing to the anxiety they may cause patients and their families, he noted.

Dr Offit admits that a study such as this was a significant undertaking for MSK. "It required a large number of genetic counselors and an infrastructure to produce reports, incorporate them into medical records, and convey the findings to patients and family members," he said. He also indicated that, on the basis of these findings, his institution was committed to expanding this model of precision prevention.

"Future studies will determine the tangible importance of this undertaking in clinical decision making," Dr Van Allen said. He pointed out that although the MSK study included a huge patient population, the approach was biased toward a white population. A similar approach must be used in parallel to include other ethnic groups, he pointed out.

"The generalizability of the recurrent mutated genes and founder mutations described in this patient population require assessment in ancestrally diverse settings to select the appropriate gene panel that maximizes test characteristics for widespread use," he writes in his editorial.

Dr Van Allen also noted that about half (52%) of patients in the case mix had prostate or pancreatic cancer. The rest represented 16 different tumor types, several of which involved fewer than 10 patients. "Although the data may support universal screening for some cancer types, such as advanced prostate cancer and potentially pancreatic cancer, it is difficult to make firm conclusions about those cancer phenotypes with few studied cases," he writes.

The MSK researchers agree that their study had unique demographic characteristics and case mix - factors that will limit their generalizability to community practice. But Dr Offit pointed out that their case mix may be typical of cancer patients undergoing tumor-normal testing at a large cancer center.

"Germline testing for prevention requires a creative solution of the right test, a broader patient population, and empowering patients with that it actually means," Dr Van Allen said.

He also noted that the clinical utility of germline testing in expanded and heterogeneous clinical settings should be tested in prospective studies. "Comparing how this approach and a guideline-driven approach impact patient outcomes is important," Dr Van Allen said.

Dr Offit told Medscape Medical News that the 76-gene panel will not be licensed out. "The content of the MSK-IMPACT test is public and has been published and is open to all who want to use it," he said.

The study was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics at Memorial Sloan Kettering Cancer Center, the Andrew Sabin Family Foundation, the Sharon Levine Corzine Research Fund from the Memorial Sloan Kettering Cancer Center, the Breast Cancer Research Foundation, Marie-Josée and Henry R. Kravis, the J. Randall and Kathleen L. MacDonald Renal Cancer Research Fund, the David M. Rubenstein Center for Pancreatic Cancer Research, and a grant from the National Cancer Institute. Several authors of the study have disclosed relationships with industry, which are available in the original article. Dr Offit has disclosed no relevant financial relationships. Dr Van Allen has served as a consultant for Genome Medical and Invitae and has equity in Genome Medical and Synapse.

JAMA. Published online September 5, 2017. Abstract, Editorial

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