Profiling Prostate Tumors for MSI May Inform Better Treatment Selection

Howard Scher

Profiling prostate cancer tumors for microsatellite instability (MSI) status with targeted next-generation sequencing can identify patients who may respond better to PD-1/PD-L1 agents, according to data we presented at the American Society of Clinical Oncology’s annual meeting in 2018.

Our preliminary results indicate that favorable responses to PD-1/PD-L1 therapy may occur in about 50 percent of patients with tumors that have a defective mismatch repair (dMMR) status and a high MSI score. However, longer follow-up and prospective studies are needed to confirm these findings. (1)

Using next-generation sequencing to characterize the underlying genomics of prostate cancer tumors may inform immune therapy selection, combination therapy selection, and the choice of predictive biomarkers, leading to improved patient outcomes in the future.

Defective Mismatch Repair and Microsatellite Instability

Understanding the relationship between tumor genomics and the immune response in advanced cancer has gained more attention with the advent of immunotherapy. The mismatch repair system is a single-strand DNA repair mechanism that recognizes and reverses DNA base mismatches, insertions, and deletions. Defective MMR results in MSI, a state of hypermutability of short repetitive sequences in the genome that have been associated with resistance to chemotherapy but sensitivity to immunotherapy. (2)

In 2014 and 2017, two large clinical trials in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) failed to find a benefit for the immunotherapy ipilimumab compared to placebo.(3),(4) Other research has found that mismatch repair–defective cancers may benefit from immune checkpoint inhibitor therapies, (5) regardless of tissue of origin, but mCRPCs typically have lower detectable mutation loads. (6)

In May 2017, the US Food and Drug Administration granted accelerated approval for the anti-PD-1 agent pembrolizumab as the first antitumor drug approved for solid malignancies with dMMR regardless of tissue type.(5),(7) However, emerging clinical data have shown that dMMR cancers do not always respond to immunotherapy, and cancers that respond to immune checkpoint inhibitors are not necessarily identified as dMMR with conventional immunohistochemistry and polymerase chain reaction assays.(5),(7),(8) Multiple advanced approaches have been developed to characterize the mutational signatures associated with dMMR (9) and evaluate MSI using next-generation sequencing (MSINGS). (10)

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Preliminary Study Results

To better understand the frequency of MSI-high prostate cancer and its response to PD-1/PL-L1 agents, we performed targeted next-generation sequencing of tumors and matched normal tissue control samples for 839 patients, then tracked treatment responses. We characterized somatic mutations, copy number alterations, and germline mutations (with specific consent), and determined MSI status. We also calculated tumor mutation burden, mutational signatures, and MMR status for select cases. (1)

Our preliminary results indicate that favorable responses to PD-1/PD-L1 therapy may occur in about 50 percent of patients with tumors that have a defective mismatch repair (dMMR) status and a high MSI score.
Howard I. Scher
Howard I. Scher Co-Chair, Center for Mechanism Based Therapy; Head of the Biomarker Development Initiative; D. Wayne Calloway Chair in Urologic Oncology

Of 839 patients with prostate cancer, 20 (2.4 percent) had MSI-high, dMMR tumors with an MSI sensor score of greater than or equal to 3 and a tumor mutation burden of greater than or equal to 10, as confirmed by immunohistochemistry analysis and mutational signature analysis. Within a group of ten patients with MSI-high tumors who received a PD-1/PD-L1 targeting agent, two patients had a radiographic partial response, with a PSA decline greater than 80 percent, and three patients early in their treatment regimen showed a PSA decline greater than 60 percent. (1)

Interestingly, for 13 of 20 patients who consented to germline analysis, three (23 percent) had a germline MMR gene mutation. Three of five MSI-high patients who underwent tumor profiling for more than two matched tumors showed MSI in the later tumor, indicating the importance of profiling the most recent tumor when possible. (1)

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Hunting Signature Genetic Mutations

Recently, we participated in another study investigating the impact of MSI and dMMR status on overall survival rates in patients with advanced prostate cancer. Results unveiled a discrete subset of lethal prostate cancer with a defective mismatch repair status that is associated with decreased overall survival. (11)

The landmark research provides the first integrated examination of genomic, transcriptomic, and clinical data of two large cohorts of mCRPC. It represents a three-year collaboration with prostate cancer clinicians and scientists at Memorial Sloan Kettering Cancer Center and other institutions comprising the 2012 Stand Up To Cancer (SU2C)–Prostate Cancer Foundation Prostate Cancer Dream Team. (11) The study was funded by Movember, Prostate Cancer UK, Prostate Cancer Foundation, SU2C, and Cancer Research UK.

Results showed that 8.1 percent of a cohort of 124 patients with mCRPC had some evidence of loss of mismatch repair protein expression or MSI. The median overall survival for the dMMR group was significantly shorter than the MMR-proficient group (3.8 versus 7.0 years, respectively). Higher MSI scores were associated with dMMR, and advanced prostate cancers with higher MSI scores had higher T cell infiltration and PD-L1 protein expression. Notably, the defects were usually present at diagnosis. (11)

Only a portion of dMMR tumors had a high mutational load and PD-L1 expression found on immunohistochemistry staining, confirming that characterizing dMMR with clinically available assays has limitations. A multipronged approach with next-generation sequencing more effectively identifies patients who may potentially benefit from immunotherapy with immune checkpoint inhibitors. (11)

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Advancing Prostate Cancer Research

The SU2C–Prostate Cancer Foundation Prostate Cancer Dream Team brought together world expert physicians, geneticists, biologists, and bioinformatics specialists to focus on studying the heterogeneity of prostate cancer with next-generation sequencing technology. The goal was to more effectively stratify patients toward precision medicines that are most likely to achieve better responses and outcomes.

At MSK, we continue to investigate how molecular insights can be translated 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.

Dr. Scher is on the board of Asterias Biotherapeutics; has served in a consulting or advisory role for Clovis Oncology, Ferring Pharmaceuticals, Janssen (research and development), OncLive, Physicians’ Education Resource, Sanofi, and the WIRB-Copernicus Group; has received research funding from Illumina, Innocrin Pharmaceuticals, and Janssen; and has had travel, accommodations, and other expenses provided by Asterias Biotherapeutics, OncLive, Physicians’ Education Resource, Sanofi, and the WIRB-Copernicus Group. Dr. Abida has received honoraria from CARET; has served in a consulting or advisory role for Clovis Oncology; has received research funding from AstraZeneca, Clovis Oncology, GlaxoSmithKline, and Zenith Epigenetics; and has had travel, accommodations, and other expenses provided by GlaxoSmithKline.

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  1. Abida W, Cheng ML, Armenia J, et al. J Clin Oncol. 36, 2018 (suppl; abstr 5020).

  2. Nilbert M, Planck M, Fernebro E, Borg A, Johnson A. Microsatellite instability is rare in rectal carcinomas and signifies hereditary cancer. Eur J Cancer. 1999;35(6):942–945.

  3. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700–712.

  4. Beer TM, Kwon ED, Drake CG, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol. 2017;35(1):40–47.

  5. Le DT, Uram JN, Bartlett BR, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520.

  6. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–1228.

  7. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–413.

  8. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–567.

  9. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–421.

  10. Salipante SJ, Scroggins SM, Hampel HL, et al. Microsatellite instability detection by next generation sequencing. Clin Chem. 2014;60(9):1192–1199.

  11. Nava Rodrigues D, Rescigno P, Liu D, et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest. 2018;128(10):4441–4453.