A Durable Response to Pembrolizumab in a Patient with Uterine Serous Carcinoma and Lynch Syndrome due to the <i>MSH6</i> Germline Mutation

Danley, Kelsey; Schmitz, Karen; Ghai, Ritu; Sclamberg, Joy S.; Buckingham, Lela; Burgess, Kelly; Kuzel, Timothy M.; Usha, Lydia

doi:10.1002/onco.13832

Cited by 6 publications

(2 citation statements)

References 30 publications

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“…Similarly, a range of clinical studies led by Dr. Diaz Jr. confirmed the strong association between responses to CPI and dMMR tumor status in a tissueagnostic fashion (60,61). Further investigation suggested dMMR status or MSI-H score to being predictive to CPI responses in solid tumors (62)(63)(64). These results led to the fast-track approval of dMMR as a biomarker for CPI by FDA and initiation of prospective stage II/III clinical trials, e.g., NCT02563002 or NCT04008030, to evaluate dMMR as a predictive biomarker.…”

Section: Msi-h Cancer and Clinical Managementmentioning

confidence: 83%

Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines

et al. 2021

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Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. Lynch syndrome – a hereditary cause of dMMR – confers increased lifetime risk of malignancy in different organs and tissues. These Lynch syndrome pathogenic alleles are widely present in humans at a 1:320 population frequency of a single allele and associated with an up to 80% risk of developing microsatellite unstable cancer (microsatellite instability – high, or MSI-H). Advanced MSI-H tumors can be effectively treated with checkpoint inhibitors (CPI), however, that has led to response rates of only 30-60% despite their high tumor mutational burden and favorable immune gene signatures in the tumor microenvironment (TME). We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. These frameshifts might serve as targets for off-the-shelf cancer vaccine designs. In this review we discuss the current state of research around MSI-H cancer vaccine development, its application to MSI-H and Lynch syndrome cancer patients and the utility of MSI-H as a biomarker for CPI therapy. We also summarize the tumor intrinsic mechanisms underlying the high occurrence rates of certain frameshifts in MSI-H. Finally, we provide an overview of pivotal clinical trials investigating MSI-H as a biomarker for CPI therapy and MSI-H vaccines. Overall, this review aims to inform the development of novel research paradigms and therapeutics.

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Section: Msi-h Cancer and Clinical Managementmentioning

confidence: 83%

Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines

et al. 2021

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“…At this time, data specific for patients with Lynch syndrome treated with pembrolizumab are largely limited to case reports. In one such report, a patient with uterine serous carcinoma and Lynch syndrome sustained a partial response to pembrolizumab and has remained asymptomatic and stable for 2 years at the time of publication [14] . In 2021, Bellone et al [15] published data from a phase 2 study of single-agent pembrolizumab for recurrent “Lynch-like” (i.e., somatically acquired MMR mutations) and sporadic endometrial cancer (i.e., biallelic methylation of MLH1 gene promoter).…”

Section: Discussionmentioning

confidence: 99%

Exceptional Response to Pembrolizumab for Treatment of Metastatic Chemorefractory Endometrial Carcinoma in a Patient with Lynch Syndrome: A Case Report

Batman¹,

Rauh‐Hain²,

Grinsfelder³

et al. 2023

Case Rep Oncol

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Advanced endometrial cancer is associated with poor outcomes and few treatment options exist. Recently, the US Federal Drug Administration approved pembrolizumab for the treatment of endometrial cancers that are deficient in mismatch repair and have high microsatellite instability (MSI). Lynch syndrome is an autosomal dominant disease that causes MSI-high endometrial cancer. We report a case of a 46-year-old woman with Lynch syndrome and advanced endometrial cancer who experienced progressive disease after treatment with chemotherapy with carboplatin and paclitaxel. She was then treated with single-agent pembrolizumab and had an exceptional response. She was noted to have a significant decrease in the size of a large uterine mass extending into the vagina and vulva, as well as decrease in the size of lymphadenopathy. Data are limited at this time for patients with Lynch syndrome treated with single-agent pembrolizumab. Our case report seeks to add to the body of literature that suggests that this patient population may particularly benefit from this novel therapy.

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Context-dependent environmental associations with endometrial cancer histotype and genotype

Borrego

Kurnit

Turner

et al. 2023

Int J Gynecol Cancer

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ObjectiveMLH1 loss due toMLH1methylation, detected during Lynch syndrome screening, is one of the most common molecular changes in endometrial cancer. It is well established that environmental influences such as nutritional state can impact gene methylation, both in the germline and in a tumor. In colorectal cancer and other cancer types, aging is associated with changes in gene methylation. The objective of this study was to determine if there was an association between aging or body mass index onMLH1methylation in sporadic endometrial cancer.MethodsA retrospective review of patients with endometrial cancer was performed. Tumors were screened for Lynch syndrome via immunohistochemistry, withMLH1methylation analysis performed when there was loss of MLH1 expression. Clinical information was abstracted from the medical record.ResultsThere were 114 patients with mismatch repair deficient tumors associated withMLH1methylation, and 349 with mismatch repair proficient tumors. Patients with mismatch repair deficient tumors were older than those whose tumors were proficient. Mismatch repair deficient tumors had a higher incidence of lymphatic/vascular space invasion. When stratified by endometrioid grade, associations with body mass index and age became apparent. Patients with endometrioid grades 1 and 2 tumors and somatic mismatch repair deficiency were significantly older, but body mass index was comparable with that of the mismatch repair intact group. For endometrioid grade 3, patient age did not significantly vary between the somatic mismatch repair deficient group and the mismatch repair intact group. In contrast, body mass index was significantly higher in the patients with grade 3 tumors with somatic mismatch repair deficiency.ConclusionThe relationship ofMLH1methylated endometrial cancer with age and body mass index is complex and somewhat dependent on tumor grade. As body mass index is modifiable, it is possible that weight loss induces a ‘molecular switch’ to alter the histologic characteristics of an endometrial cancer.

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A Durable Response to Pembrolizumab in a Patient with Uterine Serous Carcinoma and Lynch Syndrome due to the MSH6 Germline Mutation

Cited by 6 publications

References 30 publications

Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines

Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines

Exceptional Response to Pembrolizumab for Treatment of Metastatic Chemorefractory Endometrial Carcinoma in a Patient with Lynch Syndrome: A Case Report

Context-dependent environmental associations with endometrial cancer histotype and genotype

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