CCNE1 Amplifications Tied to Racial Disparities in Serous Endometrial Cancer Outcomes

Julian Schink, MD

Black women with serous endometrial cancer are less likely than White women to harbor PIK3CA mutations, and are more likely to harbor CCNE1 amplification, according to Julian Schink, MD, who added that the latter alteration has been linked with racial disparities in cancer outcomes.

Data from a retrospective study reported during the 2022 ASCO Annual Meeting showed that among 86 patients analyzed, 94% had at least 1 genomic alteration; the majority, or 93%, of patients harbored TP53 mutations. Alterations predicted to activate the PI3K pathway, such as PIK3CA, PIK3R1, and PTEN, were significantly more common in White patients compared with Black patients, at 41% (n = 13/32) and 16% (n = 8/50), respectively (P = .019).

Moreover, a larger percentage of Black patients were found to harbor CCNE1 amplifications vs White patients, at 22% (n = 11/50) and 13% (n = 4/32), respectively (P = .38). Schink noted that these amplifications have been associated with racial disparities in cancer outcomes and could potentially explain the disparities observed in endometrial cancers.

“[This research] is a reminder that outcomes for Black women with endometrial cancer are worse [than White women],” said Schink, who is the chief medical officer of the Cancer Treatment Centers of America, part of City of Hope. “It is up to us to begin to identify why. We know that CCNE1 [amplifications] are a possible explanation, and we need to begin to identify clinical trials that address [those] specific mutations.”

In an interview with OncLive^®, Schink further discussed findings from the retrospective study evaluating racial differences in the mutational landscape of serous endometrial cancer, underscored the need for appropriate genomic testing and treatment for Black women with the disease, and explained the importance of equity in racial representation across clinical trials.

OncLive^®: What were the key objectives of the retrospective study presented during the 2022 ASCO Annual Meeting?

Schink: [During the 2022 ASCO Annual Meeting,] we presented a poster looking at racial disparities in serous endometrial cancer. It is well known that Black women are twice as likely to die of endometrial cancer [vs other populations], and there are a few reasons we believe [contribute to this disparity]. One of them is that [Black women] are more likely to have aggressive forms of endometrial cancer.

Another possibility is other causes of racial disparities and health outcomes, such as access to health care. We chose to home in on the genomic alterations in these uterine cancers, then look at them in [White] women and Black women to see where there were differences.

What did the analysis reveal?

We found that CCNE1 [amplifications] are more common in Black women than in White women. That is important because those mutations predict drug resistance and chemotherapy resistance. Those CCNE1 amplifications are associated with worse outcomes in general. That helps, in part, to explain why there might be a difference and why we may see those racial disparities.

It is also important because [CCNE1 is also] potentially a targetable or treatable amplification. Some of the new drugs, such as the WEE1 inhibitors, which are being [evaluated] in clinical trials, may target [CCNE1]. Now that we have identified a potential cause, or a contributing cause, for these disparities, we can then say that this is a group of women who deserve to be in clinical trials studying [WEE1 inhibitors] to see whether, in the future, we can overcome those disparities.

Did you find any of the data from the analysis to be surprising?

We found an excess of mutations in the PI3K pathway. Those [mutations] were more common in White women with the disease. [PI3K mutations] predict that anti-HER2 drugs will not work as well, and they are a part of a pathway that disrupts the benefit of HER2[-targeted] drugs. In breast cancer, worse outcomes [are associated with] women who have [PI3K] mutations.

[The prevalence of PI3K mutations] had not been described at all in serous endometrial cancers. [PI3K] is also a potential treatment target. There are drugs that can treat that pathway and may restore the efficacy of anti-HER2 therapy.

What should be taken away from this research?

This is a cohort of women who deserve clinical trials that target their specific mutations. We try to do genomic testing on all these women, [and what we found] is that there are targetable mutations that do not [currently] have FDA approved drugs. If you don't have an approved drug, you need to have a [clinical] trial that you can test against that mutation. In other cancers, some of those drugs are effective. Now we know we have a new group of patients [with endometrial cancer] who may also benefit [from new targeted therapies].

Could you expand on the importance of enrolling underserved populations in clinical trials?

[The enrollment of underserved populations into clinical trials] is critical for several reasons. Everyone in America deserves access to the best and newest treatments. We talk about social disparities in health care, and a key one is access to clinical trials. We need to enroll these [underserved populations], and we need to find ways to get the clinical trials to women who might not otherwise be offered [that opportunity].

What steps can community oncologists take to assist in closing these gaps in their own practices?

A key step is to offer genomic testing to all patients. It may likely help you make a treatment decision. [Genomic testing is now FDA] approved in endometrial cancer, and clinicians should be testing all these patients.

[Community oncologists] need to be aware that for those patients who have a targetable mutation, either find a clinical trial or appeal to the drug company that makes the treatment for that target for those drugs. These drugs are available, and drug companies are certainly benevolent about providing effective treatments when they make sense and the targetable mutation is there.

Have you been involved in any other efforts examining the mutational landscapes of patients with endometrial or other gynecologic cancers?

We also examined low-grade serous carcinomas of the ovary and looked at the genomic profiles for those patients. We found some interesting things, and the most important one was that there were almost 10 different targetable mutations for that cancer that we could address. That is certainly a new finding. In the past, [researchers] have focused on just RAS mutations in low-grade serous carcinoma. We found that there are several other targetable mutations in these patients.

Reference

Schink JC, Garg R, Buttin B, et al. Racial differences in the mutational landscape of serous endometrial cancer. J Clin Oncol. 2022;40(suppl 16):5600. doi:10.1200/JCO.2022.40.16_suppl.5600