Somatic Testing Could Be Standard Approach in Endometrial Cancer

Somatic mutation testing should be more widespread among patients with endometrial cancer, as a significant percentage of them are found to harbor BRCA1/2 mutations and could benefit from PARP inhibitors, explained Julia Fehniger, MD.

In a study presented during the 2020 SGO Winter Meeting, investigators evaluated 89 women who were treated for advanced or recurrent endometrial cancer at NYU Langone Health’s Perlmutter Cancer Center from January 2013 to July 2019. Genomic alterations, including microsatellite instability (MSI) and tumor mutational burden (TMB), were recorded and compiled with descriptive statistics of patients both with and without somatic BRCA1/2 mutations. Thirteen (15%; 95% CI, 8-24) patients had BRCA1/2 somatic mutations.

“Although you may think that patients with endometrial cancer don't necessarily have a BRCA-associated cancer, their tumors can harbor mutations in BRCA1/2,” said Fehniger. “We identified 15% of patients [with these mutations], suggesting that there's not an insignificant percentage of patients who may be able to benefit from PARP inhibitors. It is important to further characterize tumors with clinical trials in the future.”

In an interview with OncLive, Fehniger, a third-year oncology fellow at NYU Langone Health’s Perlmutter Cancer Center, discussed emerging strategies in the treatment paradigm for patients with BRCA1/2-mutant endometrial cancer.

OncLive: Why could somatic testing be important in patients with endometrial cancer?

Fehniger: In 2018, the Centers for Medicare and Medicaid Services included molecular testing for advanced [recurrent, metastatic, relapsed/refractory, or stage III/IV] tumors. With that, there has been a lot [of research] with interesting molecular profiling of endometrial cancers. There are relatively few treatment options for patients with advanced endometrial cancer. That is changing rapidly. The use of PARP inhibitors in other solid tumors, such as breast cancer, ovarian cancer, prostate cancer, has been very successful. With these data, we're finding that some patients have BRCA1/2 mutations, and we are wondering if those can be targeted.

Do we have earlier data looking at outcomes for patients with BRCA1/2-mutant endometrial cancer who were treated with PARP inhibitors?

We actually don't know the answer to that. For patients with less-common cancers, there are ongoing trials that are investigating the role of PARP inhibitors—usually in combination with other treatments. The goal of our study was to characterize the problems of the patient with BRCA mutations who had advanced, neuroendocrine endometrial cancer, in order to get a sense of how many patients could potentially benefit from these strategies in the context of future clinical trials or clinical practice.

Could you provide an overview of the study that was presented at the 2020 SGO Winter Meeting?

We reviewed the Foundation Medicine results from our institution from 2013 to 2019. We had 89 patients who underwent profiling and had advanced recurrent endometrial cancer. We identified that 13 of those patients, or 15%, had BRCA1/2 mutations. We also looked at MSI-high and tumor mutation burden (TMB) status in those patients.

We characterized the patients with BRCA mutations compared to the ones who did not. Most patients were non-Hispanic or white. They had predominantly endometrioid tumors and advanced stage at the time of diagnosis. When we looked more carefully at the characteristics of the mutations, the majority of patients had either tumors with high-TMB or MSI-H status, suggesting that somatic BRCA1/2 mutations in their tumors may be passengers.

We had a subset of patients who received germline genetic testing. Of the 6 patients in the cohort who underwent germline genetic testing, 4 were found to have germline BRCA1/2 mutations. With additional research into the presence of homologous recombination deficiency or loss of heterozygosity (LOH). We'll have more information about whether we think that exploiting these mutations in these patients would be successful—similar to the way [they are exploited] in ovarian cancer.

How do you expect the role of PARP inhibitors to evolve in endometrial cancer?

[PARP inhibitors will play a role] In patients that have BRCA1/2 mutations once we better characterize them with an LOH score or quantifying this combination deficiency. We will see a role for PARP inhibitors in patients with this mutation profile, and it will probably in combination with other types of therapies, such as antiangiogenic agents, similar to the way that strategy has been actively investigated [in ovarian cancer]. It provides a potential rationale for a non-insignificant number of patients.

Overall, in gynecologic cancer, what has been your experience with PARP inhibitors?

I use PARP inhibitors in my practice for patients with ovarian cancer in the maintenance or treatment settings. In general, they are well tolerated and patients like the convenience of having them as an [oral] medication. Even though they have to come in for their lab work, you don't necessarily have to be tied to [an infusion chair], which is great for them. In my practice, we had some very nice responses and we are able to keep people off of chemotherapy for a period of time. It's exciting to think about expanding the use of them in other tumor types, in ways that we may not have expected.

Fehniger J, Levine DA, Pothuri B. BRCA1/2 somatic mutations in patients with advanced or recurrent endometrial cancer. Presented at: SGO 25th Annual Winter Meeting; February 6-8; 2020; Snowmass, CO.