What do patients think about being tested for many genes that may impact their hereditary risk for breast or ovarian cancer, beyond the well-known 

mutations? Getting a better understanding of patient attitudes toward multigene panel testing was among the goals of research recently reported at the 2016 ASCO Annual Meeting by Allison W. Kurian, MD, MSc, associate professor of Medicine and of Health Research and Policy, Stanford University School of Medicine.

In the first study she led of nearly 100,000 patients who were clinically tested for hereditary cancer risk, utilization of multigene panel sequencing was found to detect ovarian cancer—associated mutations in 11 genes.

Using a 25-gene panel test, 14% of the 95,561 women from the database were found to have a genetic mutation. One-third of patients harbored unexpected genes—such as breast cancer genes&mdash;which do not typically appear on standard tests.

Here second study, also presented at the ASCO meeting, examined the potential harms of multiplex testing for cancer risk, such as unwarranted surgery or adverse psychological effects. However, results showed that, at a 3-month follow-up after genetic testing, the rates of patient distress, intrusive thoughts, or regret of testing were found to be low.

In a recent interview, Kurian discussed these studies utilizing multigene panels to uncover previously undetected risks in patients with breast and ovarian cancer.

Can you give us an overview of your ongoing study on multigene panel testing?

: This is an interim report of a clinical trial that we've been doing, and that trial is evaluating a multiple-gene panel test. Instead of the older practice of testing for only one or two genes when people come in with a family history of breast cancer or colon cancer, this is a panel that tests 25 genes. This is quite a few more than we usually test.

The goals of this study are to understand the yield when we do this bigger panel and to determine what proportion of patients has harmful mutations, as well as variants of uncertain significance. We also want to very much understand the patient's perspective and the outcomes. Is this information that upsets patients? Does it drive them to do things that we would rather them not do, such as preventive surgery that might be unwarranted based on the results? Do they have high levels of distress? That's been the intention of the study.

This is an interim analysis where we've enrolled 1000 of the total 2000 patients. The study enrolled rather quickly—it was 1000 within the first year at 3 centers. One of the real strengths of the study that we see is the diversity of the patients, both in terms of ethnicity and sociodemographic background. One-third of the patients had no higher than high school as their level of education; I believe 30% to 40% were of Hispanic ethnicity, and about 29% were Spanish-speaking only. It's a nice, diverse population and one where we think we would have a good chance of really seeing the impact on a real-world population of genetic testing. This is not what we see often in a tertiary referral center, so we like that a lot.

What did you learn about patient attitudes surrounding multigene panel tests?

What we found was that about 3 months after genetic testing, which are the results we recently presented, the rates of distress, of intrusive thoughts, or regret of testing were really very low. We were encouraged that there doesn't seem to be an early signal for harm from this kind of testing from a psychological perspective. We also saw a very low use of preventive surgery among patients who had negative or uncertain results, which was encouraging to see, and we saw a good understanding of the results in terms of patients notifying their family members when a result was positive.

Those were the main findings. The caveats are that the follow-up is short at this point; it's only about 3 months follow-up. We're going to follow patients much longer, so really this is an early safety signal at this point and needs further follow-up.

Can you also talk about gene panel testing for possible ovarian cancer risks?

This is a study focused on understanding the level of cancer risk with gene mutations, again using one of these large multiple-gene panels. I think the significance here is that more and more patients are being tested with these panels, and much of the time the genes on the panels are associated with risks that are not really well-defined. For example, we might have a patient who had breast cancer and maybe we find a mutation in a gene like 

. We think we're beginning to understand the breast cancer risk, but we really don't know the associated ovarian cancer risks, and that's important because if the risk is high, this woman should be protected by being offered preventive surgery. So it would really change care.

Thus far, there have not been large, well-powered studies of penetrants for associated cancer risk with these mutations in general. What we did was use a large database from a testing laboratory to look at penetrants, or associated risk of ovarian cancer with these gene mutations. We had 95,531 total patients, so it was really a large sample size, and upward of 5000 ovarian cancer patients. That was a real strength of the study. We were able to use a few different statistical methods to analyze the risk of ovarian cancer, and we used the few different methods as sort of a backup check to make sure our results would be relatively consistent.

What we found was quite interesting. We found about 14% of ovarian cancer patients did have a genetic mutation on this panel, and about a third of these mutations were in what I would describe as unexpected genes, or genes that aren't typical for our standard testing. A number of them were genes we typically think of as breast cancer genes, not necessarily ovarian cancer genes. I think it'll be interesting to understand the ovarian cancer risk.

Caveats to this type of study is that it is a sample that is attained from clinical practice, which is not the same thing as a carefully controlled trial, so there are always questions there about data collection methods and those sorts of things. To the best of our ability, we think that these are reasonably valid based on prior work and based on what we see through different analytic methods. At this point I think this is going to be something that needs further study, but it is quite interesting in terms of the ovarian cancer risks that we see.

Kurian AW, Hughes E, Handorf E, et al. Association of ovarian cancer (OC) risk with mutations detected by multiple-gene germline sequencing in 95,561 women. 

Kurian AW, Idos G, Culver J, et al. Safety of multiplex gene testing for inherited cancer risk: Interim analysis of a clinical trial. 

Articles

What do patients think about being tested for many genes that may impact their hereditary risk for breast or ovarian cancer, beyond the well-known BRCA mutations?

Multigene Panel Tests Yield Clues to Breast and Ovarian Cancer Risk

National guidelines recommend that women with a personal history of ovarian cancer be tested for the 

 mutation. Approximately 1.3% of women will develop ovarian cancer, according to the National Cancer Institute, but that risk increases to an estimated 39% in women with the 

mutation and 11% to 17% in women who inherit the 

mutation. In addition to the importance of having this information for family members who may be impacted, early identification of 

 mutations in women with ovarian cancer can significantly help inform their future treatment choices.

, Leslie Randall, MD, associate professor, gynecology/ oncology at the University of California Irvine, discusses the importance of 

 testing and the generally accepted guidelines for these tests. She says the tests are strongly recommended for all patients with ovarian cancer.

: What is the importance of early BRCA testing?

: Early BRCA testing is very important for several reasons, the most important of which is identifying patients who have specific tumor biology. Patients with 

 mutations tend to be more platinum-sensitive than patients who don't have those mutations. They're also eligible for different clinical trials than patients who don't have those mutations. In addition to that, identifying these patients will identify them for later on in their treatment line for things like PARP inhibitor therapy, as well as identify those whose family members should maybe be tested for genetic mutations.

What are the current recommendations for 

 testing is recommended for all of our invasive ovarian cancer patients to include fallopian tube and peritoneal cancer. Those guidelines are endorsed by the NCCN, ASCO, the Society of Gynecologic Oncology, National Society of Genetic Counselors, and also the American Congress of Obstetrics and Gynecology. All of these came together in what we called the Genetic Summit to discuss how strongly we recommend 

 testing for our ovarian cancer patients. We all strongly recommend it, and are somewhat disenchanted that it hasn't been happening at the rates we would like to see, though I think it was significantly improved within the last year. The level of evidence to support it is about a Level B if you look at the US Preventive Services Task Force Levels of Evidence.

 mutations in patients with ovarian cancer?

I always say that the more we test, the more we'll learn that more patients have it. Currently, we think the prevalence of 

 mutations in ovarian cancer patients is about 20%.

What is the difference in terms of germline versus somatic 

 alterations, and is one more important than the other?

Germline and somatic mutations are both important. Germline mutations are the ones that are inherited, so you're born with a germline mutation in 

 you can pass that on to your offspring. Somatic mutations happen only in the tumor. Somatic mutations can't be inherited—they can't be passed on to future generations&mdash;so that's the very important distinction between germline and somatic mutations. I think they're both important because they are both associated with responses to 

-specific therapies like PARP inhibition.

National guidelines recommend that women with a personal history of ovarian cancer be tested for the BRCA mutation. Approximately 1.3% of women will develop ovarian cancer, according to the National Cancer Institute, but that risk increases to an estimated 39% in women with the BRCA1 mutation and 11% to 17% in women who inherit the BRCA2 mutation.

Why BRCA Testing Is So Important for Women With Ovarian Cancer

Encouraging findings for PD-1 inhibitor—based immunotherapies for the treatment of patients with metastatic head and neck cancer are emerging from clinical studies, making it important for clinicians to understand the optimal treatment settings and adverse events associated with these therapies.

In late January, the phase III CheckMate-141 trial investigating the anti—PD-1 agent nivolumab (Opdivo) in patients with platinum-refractory squamous cell carcinoma of the head and neck was stopped early, due to a substantial improvement in the primary endpoint of overall survival (OS), according to Bristol-Myers Squibb, the drug’s manufacturer.

The drug was examined against the investigator’s choice of cetuximab (Erbitux), methotrexate, or docetaxel following progression on a platinum-based therapy. At this time, data from the study have not yet been released but are being prepared for future presentation.

Additionally, the PD-1 inhibitor pembrolizumab (Keytruda) has demonstrated promising activity in patients with advanced PD-L1—positive esophageal carcinoma during the phase Ib KEYNOTE-028 study. Additionally, the agent was effective for patients with squamous cell carcinoma of the head and neck in the phase I KEYNOTE-012 study.

In the head and neck cancer population, the objective response rate with pembrolizumab was 24.8% in 117 evaluable patients. Tumor shrinkage was experienced by 56% of patients, and another 25% had stable disease. The response rate seen with pembrolizumab was similar, regardless of HPV infection status. In those with HPV-positive disease, the ORR was 20.6% compared with 27.2% in the negative group.

In a recent interview, head and neck cancer expert Barbara Burtness, MD, professor of Medicine (Medical Oncology), Clinical Research Program Leader, Head and Neck Cancers Program, co-director, Developmental Therapeutics Research Program, Yale Cancer Center, discussed the promise of immunotherapy in this setting.

Can you give us an overview of where immunotherapy is currently in head and neck cancer? 

BURTNESS: The first trials for immunotherapy in head and neck cancer began 2 or 3 years ago, and we now have sufficient reason to believe that these therapies are going to be active in the cancer. For example, there is the KEYNOTE-012 trial, which was a trial of pembrolizumab given to an expansion cohort of either HPV-positive or HPV-negative head and neck cancer. The response rate there was about 25%.

There is some reason to believe that if either PD-L1 or PD-L2 are expressed, this would predict for a higher response rate. There are now phase III trials going forward for both platinum-refractory disease and for first-line patients looking at pembrolizumab compared with chemotherapy.

There are also data with MEDI4736, which if a patient is expressing PD-L1, appears to have a pretty high response rate of about 50% in a small group of patients. There are currently ongoing trials looking at the combination of MEDI4736 with tremelimumab, though we don't have any data on that just yet.

Then there are novel strategies people have for trying to integrate immunotherapy with standard treatment. We have some reason to believe that when head and neck cancer is treated with radiation there is upregulation in tumor-infiltrating lymphocytes and PD-L1. There are trials now moving forward that are integrating immune checkpoint inhibitors together with chemoradiation, or taking patients who have completed their chemoradiation but have persistent disease and exposing them to pembrolizumab in that setting.

Finally, there is some evidence that siltuximab can upregulate a co-stimulatory molecule, CD137. There are some trials looking at co-targeting EGFR and CD137.

What adverse events are associated with immunotherapy in the head and neck cancer setting? 

The one thing community oncologists should be aware of is toxicities. As these drugs roll out, these toxicities that will be present are a lot different to manage than the usual cytotoxic agent toxicities. There are a lot of unusual or unexpected side effects that are autoimmune in nature.

The most common toxicity is fatigue. Across all the patients with head and neck cancer who received pembrolizumab, about 17% of them had grade 3 or 4 toxicities. This is a lot easier to tolerate than chemotherapy or chemoradiation. The other things that you might look for are pneumonitis, nephritis, pancreatitis with diabetic symptoms, thyroiditis, and a variety of unusual autoimmune side effects.

What do you see as the overall potential for immunotherapy in head and neck cancer? 

Everybody with biomarker expression of either the ligands or the targets in this pathway is likely to be exposed to these drugs in the future. The challenge for us is going to be to figure out, for those patients who are not PD-L1 expressing or who don't have tumor-infiltrating lymphocytes, other ways that we can prime patients for immunotherapy with our standard treatments. It's speculative—it's not something that people are doing in clinics now, but the first trials of those approaches are starting. There is also ADXS11-001 that is fused to the E7 oncogene from HPV. The idea is that that would increase antigenic presentation and then the immune checkpoint inhibitor could potentially be more effective. That treatment is still in phase I investigation.

Encouraging findings for PD-1 inhibitor–based immunotherapies for the treatment of patients with metastatic head and neck cancer are emerging from clinical studies.

Greg Kennelty

Articles

Multigene Panel Tests Yield Clues to Breast and Ovarian Cancer Risk

Why BRCA Testing Is So Important for Women With Ovarian Cancer

Studies Signal Role for Immunotherapy in Head and Neck Cancer