FDA-approved Pembrolizumab for Treatment of Metastatic Chemo Refractory Endometrial Carcinoma
Dr. Monica Avila, a gynecologic oncologist in the Department of Gynecologic Oncology at Moffitt Cancer Center, co-authored “Exceptional Response to Pembrolizumab for Treatment of Metastatic Chemo Refractory Endometrial Carcinoma in a Patient with Lynch Syndrome: A Case Report” published in Case Reports in Oncology.
Microsatellite instability (MSI) is a molecular tumor phenotype associated with approximately 30% of endometrial cancers [1]. It is defined by the gain and/or loss of nucleotides from microsatellite tracts and these changes can arise from deficiencies in the mismatch repair (MMR) system [1]. MSI is typically the result of either a germline mutation in the MMR system, as in the case of Lynch syndrome, or a somatic hypermethylation of the MLH1 promoter. Thus, both MMR deficiency and MSI-high status are hallmark features of Lynch syndrome.
Lynch syndrome is an autosomal dominant disease that is caused by a germline mutation in MMR genes, including MLH1, MSH2, MSH6, and PMS2[2]. Women with Lynch syndrome have a 15–46% lifetime risk of developing colorectal cancer, a 43–57% lifetime risk of endometrial cancer, and a 10–17% lifetime risk of ovarian cancer, depending on which gene is mutated. For those with an MLH1 gene mutation, the risks are 46%, 43%, and 10%, respectively [3]. Prior studies have shown that the average age at diagnosis of Lynch syndrome-associated endometrial cancer is 47–49 years (range 26–87) [4], compared with 60 years in the general population. Lynch syndrome-associated endometrial cancers are typical of endometrioid histology, and the tumors are more often located in the lower uterine segment [5].
Treatment options for women with advanced endometrial cancer, both sporadic and Lynch syndrome-associated, are known to be limited, with a 5-year survival of 20% in those with distant metastatic disease [6]. As such, there has been ongoing interest in novel therapeutic targets for the treatment of advanced/metastatic endometrial cancer. One such target is the programmed death (PD-1) receptor which, when bound to programmed death ligands 1 and 2 (PD-L1 and PD-L2) on tumor cells, leads to inhibition of the immune response, including antitumor activity [7]. Pembrolizumab is a monoclonal anti-PD-1 antibody that blocks this interaction and has been shown to have response in patients with multiple tumor types, and was approved in May 2017 for the treatment of MSI-high solid tumors [7]. PD-L1 overexpression is a predictive biomarker for anti-PD1 therapy, and it is thought that endometrial cancer cells have this overexpression in 25–100% of cases [8]. Additionally, high tumor mutational burden, which increases the production of tumor-specific neoantigens, has also been a predictive biomarker for anti-PD-1 therapy, and this feature has been associated with MMR-deficient/MSI-high tumors [9]. We present a case of a patient with Lynch syndrome with advanced endometrial cancer who had an exceptional response to single agent pembrolizumab.
In summary, our case of a patient with MSI-high chemo refractory, advanced endometrial cancer with an exceptional response to pembrolizumab is notable given her history of Lynch syndrome. Tumors associated with Lynch syndrome are MSI-high and this therefore may be a patient population that can particularly benefit from immunotherapy treatment with pembrolizumab.
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