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A deficiency of mismatch repair (MMR) proteins in patients with early-stage endometrial cancer is associated with a worse outcome following vaginal brachytherapy, according to a new analysis.¹ In this multicenter, retrospective study, the recurrence rate for patients with MMR deficiency (dMMR) after a median of 42 months of follow-up was several times greater than it was for those with preserved MMR (17% versus 4%; P=.009). Five-year recurrence-free survival (RFS) was significantly lower for those with dMMR (61% versus 90%; P=.003).

In general, the prognosis for early endometrial cancer (grade 1 or 2) after surgical staging is favorable.¹ In a multicenter study comparing vaginal brachytherapy to pelvic external beam radiotherapy, the rate of vaginal recurrence at a median of 45 months of follow-up was 1.8% and 1.6%, respectively. Disease-free survival and overall survival at 5 years in this study exceeded 80%.²

Defining MMR deficiency

While previous investigators have reported that dMMR is often identified in tumors with other adverse prognostic characteristics, such as higher grade and presence of lymphovascular invasion (LVI),³ its independent prognostic importance remains unclear. The current study was conducted on the hypothesis that MMR status in early-stage endometrial cancer could provide meaningful information about risk of disease progression after patients had received adjuvant vaginal brachytherapy.¹

At the participating centers, MMR status has been assessed since 2013, providing a basis for this retrospective analysis.¹ The primary endpoint was RFS in long-term follow-up after controlling for a broad range of risk factors, including tumor grade and stage, depth of myometrial invasion (MMI), presence of LVI, and patient age. MMR deficiency was defined as lack of expression of at least 1 of the repair proteins hMLH1, hMSH2, hMSH6, or hPMS2.

Of the 141 patients in this analysis, 41 (29%) had dMMR; the rest had preserved MMR. The average ages of 69 years and 66 years in these two groups, respectively, was not significantly different. However, fewer of the dMMR patients had grade 1 tumors (42% versus 68%; P=.003) and more had grade 2 tumors (58% versus 32%). LVI was greater (42% versus 30%) in the dMMR group versus the preserved MMR group, but the difference did not reach statistical significance. There were also no significant differences in depth of MMI, tumor size, or number of lymph nodes removed.

In the 41 patients with dMMR, deficiency in MLH1 and PMS2 was identified in 37 (90%). No other repair protein was found to be deficient in more than two patients. With or without dMMR, all patients underwent adjuvant vaginal brachytherapy after surgery. The median dose was 21 Gy, delivered in three to six fractions.

A promising prognostic indicator

For median time to first recurrence, the hazard ratio (HR) indicated a more than fourfold increase in risk among those with stage II disease in a multivariate analysis (HR 4.3, 95% confidence interval 1.1 to 16.7; P=.03). In addition, dMMR had an independently negative influence on RFS in a multivariate analysis that included known risk factors, such as presence of LVI or tumor grade, stage, or size.

This suggests that dMMR might be a factor for determining when treatment should be intensified, according to the study鈥檚 lead author, Andrea L. Russo, MD, director of the Gynecologic Radiation Oncology Program at Massachusetts General Hospital, Boston. She told 口袋女优 that there鈥檚 a phase 3 trial called NRG-GY020 that is now randomizing dMMR patients to receive radiation with or without the immune checkpoint inhibitor pembrolizumab.

鈥淲e鈥檙e not changing our practice at this time as we await results of prospective data,鈥� Dr. Russo says. While her team will continue to treat endometrial cancer with radiation alone in the early-stage adjuvant setting, Dr. Russo considers dMMR a promising prognostic indicator that might allow a higher risk group of patients with early endometrial cancer to be identified for more-aggressive therapy.

Published: June 28, 2022