MMR Deficiency Linked to PD-L1 Expression in Endometrial Cancer

Kari L. Ring, MD

Mismatch repair (MMR)—deficient endometrial cancers exhibited significantly higher levels of PD-L1 expression compared with MMR-intact tumors, according to a poster presentation at the Society of Gynecologic Oncology meeting.

More than half of MMR-deficient tumors and 100% of immune stromal cells at the periphery of MMR-deficient tumors tested positive for PD-L1. That compared with 10% of MMR-intact tumors and 66% of associated immune stromal cells. Tumors associated with Lynch Syndrome had an even stronger association with PD-L1 expression.

Aside from the difference in PD-L1 expression, MMR-deficient and proficient tumors had similar clinicopathologic characteristics, although PD-L1 expression also had a strong association with MSH6 loss in Lynch Syndrome—associated tumors, reported Kari L. Ring, MD, assistant professor of gynecologic oncology at the University of Virginia in Charlottesville.

“MMR status, and whether this is a result of germline or somatic changes, may be an important determinant in the success of immune checkpoint therapy in endometrial cancer,” Ring and colleagues concluded.

MMR deficiency in endometrial cancer has been associated with an increased number of tumor-infiltrating lymphocytes and with increased neoantigen production induced by frameshift mutations resulting from microsatellite instability (MSI). Preliminary evidence suggested increased PD-L1 expression in the immune compartment of MSI-high tumors compared with microsatellite stable tumors. No data existed to differentiate between sporadic and heritable etiologies of MMR deficiency.

Studies to clarify the relationship between MMR status and PD-L1 expression have implications for treatment of endometrial cancer, as early clinical trials showed a therapeutic benefit of PD-1/PD-L1 inhibition in MMR-deficient cancers, Ring and colleagues noted.

Investigators conducted a study to: (1) evaluate tumoral and peritumoral PD-L1 expression in Lynch Syndrome—associated and sporadic MMR-deficient endometrial carcinomas; (2) correlate with histologic subtype, and (3) correlate with disease recurrence.

Immunohistochemical analysis of PD-L1 expression was performed for 67 retrospectively identified endometrial carcinomas, 38 that were MMR-deficient (20 associated with Lynch Syndrome and 18 associated with MLH1 promoter hypermethylation) and 29 that were MMR-intact. MMR deficiency was determined by loss of expression of MLH1, PM52, MSH2, or MSH6. Additionally, sporadically methylated tumors were identified by MLH1 methylation analysis.

The results demonstrated PD-L1 expression in 20 of 38 (52.6%) MMR-deficient tumors and in the peritumoral compartment, or immune stroma, of all 38 tumors. In contrast, 3 of 29 (10.3%) MMR-intact tumors exhibited PD-L1 expression (P = .0005) versus MMR-deficient tumors. PD-L1 expression was detected in the stroma of 19 tumors (but was minimal in 13 cases and moderate in the remaining 6).

Among the 20 Lynch Syndrome—associated tumors, PD-L1 expression was observed in 14, with expression levels ranging from 1% to 5% (n = 7) to 26% to 50% (n = 2). PD-L1 expression was detected in the immune stroma of all 20 tumors (minimal in 5, moderate in 12, and “brisk” in 3).

Among the 18 tumors with MLH1 promoter hypermethylation, 6 exhibited PD-L1 expression and all 18 exhibited PD-L1 expression in immune stroma (minimal in 6, moderate in 5, and brisk in 7).

MMR-deficient and proficient tumors did not differ with respect to FIGO stage or dedifferentiation. PD-L1 expression was identified in 5 of 8 tumors with MSH2/MSH6 loss, eight of eight with MSH6 loss, and three of four with PMS2 loss.

PD-L1 expression did not correlate with an increased risk of recurrence, as the recurrence rate was 13.6% for PD-L1-negative tumors and 13.0% for PD-L1-positive tumors.

Ring KL, Sloan EA, Willis BC, et al. One of these things is not like the others: PD-L1 expression in Lynch syndrome associated and sporadic mismatch repair deficient endometrial carcinomas. In: Proceedings from the Society for Gynecologic Oncology Annual Meeting on Women’s Cancer; March 12-14, 2017; National Harbor, MD. Featured poster presentation No. 68.

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