MSI Status: Actionable Mutations in Advanced Endometrial Cancer

David Hyman, MD and patient

Sequencing advanced endometrial tumors with the MSK-IMPACT™ assay provides an effective method for detecting microsatellite instability (MSI) and germline cancer predisposition syndromes, which are collectively present in 16 percent of patients, as well as potentially actionable somatic variants, according to our recent retrospective analysis.

Overall, MSK-IMPACT identified potentially actionable mutations in 68 percent of patients. Twenty-seven percent of these patients were enrolled in matched clinical trials, of which 47 percent achieved clinical benefit. (1) Our findings indicate that characterizing the underlying genomics of advanced endometrial cancer on a prospective basis can help refine prognoses and inform treatment selections, leading to improved patient outcomes.

The results represent a conservative estimate of the percentage of patients with advanced endometrial cancer who could benefit from a personalized treatment plan guided by this molecular testing strategy. Since the US Food and Drug Administration’s recent approval of pembrolizumab for MSI-high or mismatch repair deficient (dMMR) solid tumors, detection of tumors harboring these alterations has become of immediate therapeutic importance. As the cost and operational efficiency of next-generation sequencing continue to increase, we expect it will be rapidly and broadly adopted in the treatment of endometrial cancer.

Defective Mismatch Repair and Microsatellite Instability

Mismatch repair is a biological response that recognizes and reverses base mismatches and insertion and deletion mistakes in a single strand of DNA. A defective MMR response results in MSI, a state of hypermutation in the genome that is associated with resistance to chemotherapy but sensitivity to immunotherapy. (2)

In May 2017, the FDA granted accelerated approval to the anti-PD1 agent pembrolizumab as the first drug approved for solid tumors with dMMR regardless of tissue type. (3) However, emerging clinical data show that dMMR cancer does not always respond to immunotherapy, and cancer that responds to immune checkpoint inhibitors is not always correctly classified as dMMR with conventional immunohistochemistry (IHC) and polymerase chain reaction assays. (4) Therefore, more-advanced approaches have been developed to characterize the mutational signatures associated with dMMR, (5) such as evaluating MSI through next-generation sequencing. (6), (7), (8)

New Insights for Characterizing Endometrial Cancer

Endometrial cancer is a collection of several cancer subtypes that arise in the uterus and together constitute the most common gynecologic cancer. In 2018, an estimated 63,000 new cases will be diagnosed in the United States, resulting in more than 11,000 deaths. (9) Prognosis has typically been based on histological grade and clinical stage. Previous retrospective comprehensive profiling studies have identified four distinct molecular subtypes of endometrial cancer based on the pattern of somatic copy-number alterations: POLE mutant or ultramutated, MSI high or hypermutated, copy-number low, and copy-number high. (10) Recent genomic analyses have also identified important possible therapeutic targets in endometrial cancer, such as the P13K pathway, cell-cycle inhibition, and epigenetic regulation. (11)

The present study is the first to evaluate the clinical utility of the molecular characterization of tumors and matched normal specimens in patients with active advanced endometrial cancer.
David Hyman Chief, Early Drug Development Service

The present study is the first to evaluate the clinical utility of the molecular characterization of tumors and matched normal specimens in patients with active advanced endometrial cancer. A multidisciplinary research team of Memorial Sloan Kettering researchers analyzed clinical and treatment histories and prospective clinical sequencing and IHC data for 197 tumors profiled with MSK-IMPACT from 189 patients with advanced endometrial cancer. (1) The data were generated within the context of an ongoing pan-cancer clinical trial (NCT01775072), which is evaluating the utility of genomic profiling in patients with solid and hematologic cancers and comparing molecular findings with patient outcomes and responses to targeted and other cancer treatments.

Tumor mutational burden has emerged as a predictive biomarker for immune checkpoint inhibitors in several cancer types. In this endometrial cancer cohort, samples with a high mutational burden were characterized as having MSI (n = 28), POLE (n = 1), or MSI and POLE-mediated hypermutation (n = 1), confirming that MSI accounts for the vast majority of high tumor burden cases in patients with endometrial cancer. Notably, in several MSI-H tumors identified by MSI-IMPACT testing, standard IHC failed to identify the loss of an MMR protein. (1)

Compared to the previously identified molecular subtypes of endometrial cancer based on the patterns of copy-number alterations, we also found three distinct clusters: Cluster A comprised predominantly high-grade tumors with various histologies, was enriched for TP53 mutation, and underwent whole-genome doubling; Cluster B consisted of mostly FIGO grade 1/2 endometrioid tumors, which were enriched for PTEN mutations; and Cluster C comprised high-grade endometrioid tumors and nonendometrioid tumors with loss of 1q gains and heterozygous losses across the genome. Patients in Cluster C had a significantly lower median progression-free survival of 9.6 months compared to 17.0 and 17.4 months for Clusters A and B, respectively (p = 0.006). (1)

Therapeutically Actionable Mutations

Overall, 67 percent of patients (127/189) had at least one potentially actionable mutation, for which there is an FDA-approved therapy available or an investigational agent under clinical investigation. The most common potentially actionable mutations included mutations in the P1K3CA (n = 66/189 cases, 35 percent) and PTEN (n = 54/189, 29 percent) genes, MSI high (any evidence; n = 30/189, 16 percent), and ERBB2 amplifications (n = 16/189, 8 percent). (1)

Twenty-seven percent of patients (34/127) with potentially actionable mutations were enrolled in matched clinical trials. The alteration that most commonly led to the administration of a matched therapy was a P1K3CA mutation (n = 12). Thirty-one of the 34 matched patients (91.2 percent) were enrolled in clinical trials involving targeted therapies alone, and three (8.8 percent) were enrolled in studies that also included chemotherapy. Overall, the rate of clinical benefit to patients in molecularly matched clinical trials was 47 percent (n = 16/34), exceeding historical rates. (1)

With respect to germline mutations, clinical sequencing identified three patients with rare mutations in the BRCA2 gene and one patient with a grade 2 endometrioid tumor harboring a Lynch-syndrome-associated germline MLH1 splice site mutation. The irreversible anonymization process required to conduct the germline analysis prevented further clinical characterization of germline-positive patients, however, such studies are planned in the future. (1)

Advancing Molecular Cancer Research

Developed by bioinformaticians, molecular pathologists, and genome scientists at MSK, MSK-IMPACT has been employed to analyze tumors in patients with advanced cancer since January 2014. MSK-IMPACT, which received FDA authorization in November 2017, is currently available for MSK patients and those in the MSK Alliance network. To date, we have compiled tumor and matched normal sequence data from a unique cohort of more than 30,000 patients with advanced cancer, as well as available pathological and clinical data. These data are now being studied by clinical and laboratory researchers at MSK to identify clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that are shared by common and rare tumor types. (12) As our knowledge base grows, we continue to expand the panel. Currently, MSK-IMPACT analyzes 468 cancer-associated genes. To further accelerate the discovery of new drug targets and biomarkers predictive of drug response, all patient-level clinical and genomic data have been de-identified and shared with the scientific community via the cBioPortal for Cancer Genomics, a portal developed originally at MSK and hosted by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at MSK. We are also sharing data through AACR Project GENIE (a project by the American Association for Cancer Research called the Genomics Evidence Neoplasia Information Exchange), a collaboration among eight leading cancer centers that are pooling resources to take advantage of genomic sequencing of tumors to advance precision oncology.

At MSK, we continue to pioneer the translation of molecular insights into clinical research. Close collaboration among teams of physician-scientists with diverse clinical and scientific training has led to internationally recognized advances in the treatment of lung cancer, melanoma, thyroid cancer, and prostate cancer, among other tumor types.

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Dr. Solit is a consultant and advisory board member for Loxo Oncology, Pfizer, and Illumina. Dr. Hyman is a consultant and advisory board member for Atara Biotherapeutics, Chugai Pharmaceutical, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, and Genentech.

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