Identification of Hypermutation and Defective Mismatch Repair in ctDNA from Metastatic Prostate Cancer

Ritch, Elie; Fu, Simon; Herberts, Cameron; Wang, Gang; Warner, Evan W.; Schönlau, Elena; Taavitsainen, Sinja; Murtha, Andrew J.; Vandekerkhove, Gillian; Beja, Kevin; Loktionova, Yulia; Khalaf, Daniel; Fazli, Ladan; Kushnir, Igal; Ferrario, Cristiano; Hotte, Sébastien J.; Annala, Matti; N., Kim; Wyatt, Alexander W.

doi:10.1158/1078-0432.ccr-19-1623

Cited by 61 publications

(75 citation statements)

References 51 publications

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“…In a retrospective study, MSI-H/dMMR mCRPC patients responded poorly to first-line treatment with abiraterone acetate or enzalutamide, with a median PFS of 9.9 months (15). Ritch et al reported that the median duration for first-line androgen receptor pathway inhibitor therapy was only 3.9 months in 11 dMMR patients (21). Our findings are highly consistent with these results.…”

Section: Discussionsupporting

confidence: 93%

“…A whole-exome analysis of 150 metastatic site biopsies from castration-resistant patients showed that 2.0% had aberrations in MSH2, and 0.7% had aberrations in MLH1 (20). A recent study identified 3.7% of metastatic prostate cancers with deleterious alterations in MSH2, MSH6, or MLH1 from cfDNA samples (21). Previous studies reported that dMMR prostate cancer is an aggressive disease with a higher Gleason score, lower differentiation, and a higher rate of distant metastasis (16,22,23).…”

Section: Discussionmentioning

confidence: 99%

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Clinical Characterization of Mismatch Repair Gene-Deficient Metastatic Castration-Resistant Prostate Cancer

Wang

et al. 2020

Front. Oncol.

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Mismatch repair-deficient (dMMR) prostate cancer is rare and has not been well studied. We aimed to evaluate the clinical characterization of dMMR metastatic castrationresistant prostate cancer (mCRPC) patients. The MMR genes include MLH1, MLH3, MSH2, MSH6, PMS1, PMS2, and EPCAM, and were analyzed by targeted sequencing of plasma cell-free DNA samples. A total of 109 mCRPC patients were identified, including 50 patients with MMR alterations (pathogenic alterations, n = 7; alterations of unknown significance, n = 43) and 59 patients with wild-type MMR. For the seven patients with pathogenic MMR alterations, the median age at diagnosis was 63.5 years, and 42.9% had a Gleason score ≥8. The median time from androgen deprivation therapy (ADT) initiation to CRPC was 24 months. Compared with the wild-type MMR subgroup, patients with MMR alterations, pathogenic MMR alterations, or MMR alterations of unknown significance showed higher rates of hotspot missense mutations or copy number amplifications in the AR gene (24/50 vs. 10/59, P = 7.8 × 10 −4 ; 7/7 vs. 10/59, P = 2.5 × 10 −5 ; 17/43 vs. 10/59, P = 0.013). The presence of any MMR alterations was associated with an inferior response to abiraterone [median progression-free survival (PFS): 5.0 vs. 10.9 months, P = 0.022]. Shorter PFS times were observed in both the pathogenic MMR alteration subgroup (median PFS: 5 months) and the MMR alterations of unknown significance subgroup (median PFS: 5.3 months), compared with the PFS of those with wild-type MMR genes (median PFS: 10.9 months, P = 0.052). There was no statistically significant difference in response to docetaxel chemotherapy between the MMR alterations of unknown significance and the wild-type MMR subgroups (median PFS: 8.2 vs. 8.1 months, P = 0.23). Our results demonstrate that dMMR mCRPC patients have an equivalent response to standard ADT and taxanebased chemotherapy treatments compared with wild-type MMR patients. Patients with both pathogenic and unknown significance alterations of MMR genes had poorer responses to abiraterone therapy.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Clinical Characterization of Mismatch Repair Gene-Deficient Metastatic Castration-Resistant Prostate Cancer

Wang

et al. 2020

Front. Oncol.

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“…16 MMR have also been associated with aggressive features and more advanced disease at diagnosis. 34,35 However, conflicting results have been reported on the clinical outcomes of MMRdeficient prostate tumours. 34 While a study suggests favourable responses to ADT, others have found that MMR-deficient patients develop castration-resistant disease earlier than the MMRproficient ones.…”

Section: Genementioning

confidence: 99%

“…34 While a study suggests favourable responses to ADT, others have found that MMR-deficient patients develop castration-resistant disease earlier than the MMRproficient ones. 35,36 These differences in outcomes between studies may be related to the limited number of patients included and the different assays used to detect these alterations (targeted sequencing vs. immunohistochemistry). Further studies are needed to completely elucidate the clinical implications of these and other DDR alterations in prostate cancer.…”

Section: Genementioning

confidence: 99%

Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer

et al. 2020

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Over the past years, several studies have demonstrated that defects in DNA damage response and repair (DDR) genes are present in a significant proportion of patients with prostate cancer. These alterations, particularly mutations in BRCA2, are known to be associated with an increased risk of developing prostate cancer and more aggressive forms of the disease. There is growing evidence that certain DDR gene aberrations confer sensitivity to poly-(ADP ribose) polymerase inhibitors and/or platinum chemotherapy, while other defects might identify cases that are more likely to benefit from immune checkpoint inhibition. The potential prognostic impact and relevance for treatment selection together with the decreasing costs and broader accessibility to next-generation sequencing have already resulted in the increased frequency of genetic profiling of prostate tumours. Remarkably, almost half of all DDR genetic defects can occur in the germline, and prostate cancer patients identified as mutation carriers, as well as their families, will require appropriate genetic counselling. In this review, we summarise the current knowledge regarding the biology and clinical implications of DDR defects in prostate cancer, and outline how this evidence is prompting a change in the treatment landscape of the disease.

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“…However, only a small proportion of prostate cancers exhibit dMMR, with estimates ranging from 3 to 8% (11)(12)(13)(14)(15). Thus, our best estimates of the efficacy of anti-PD1 therapy in dMMR or MSI-H prostate cancer are derived from retrospective case series with small numbers and short follow-up (15)(16)(17)(18)(19). More data are needed to define depth and durability of responses to anti-PD1 therapy for men with dMMR prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Tumor Frameshift Mutation Proportion Predicts Response to Immunotherapy in Mismatch Repair-Deficient Prostate Cancer

et al. 2020

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Background. Genomic biomarkers that predict response to anti-PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti-PD1 therapy in prostate cancer. Methods. To enrich for response to anti-PD1 therapy, we assembled a multi-center cohort of 65 men with mismatch repair-deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden (FSB) and frameshift mutation proportion (FSP), which were correlated to outcomes on anti-PD1 treatment. We subsequently utilized data from a clinical trial of pembrolizumab in patients with non-prostatic dMMR cancers of various histologies as a biomarker validation cohort. Results. Nineteen of 65 patients with dMMR metastatic castration-resistant prostate cancer were treated with anti-PD1 therapy and demonstrated a PSA 50 response rate of 65% and a median progression-free survival (PFS) of 24 (95%CI, 16-54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti-PD1 treatment, and with density of CD8+ tumor infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti-PD1 therapy in a validation cohort. Conclusions. Tumor FSP correlated with prolonged efficacy of anti-PD1 treatment among patients with dMMR cancers, and may represent a new biomarker of immune checkpoint inhibitor sensitivity. The Oncologist 2020;9999:• • Implications for Practice: Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, we assembled a cohort of patients with DNA mismatch repair-deficient (dMMR) prostate cancer as these patients are enriched for responses to ICI. We observed a high response rate to anti-PD1 therapy in these patients, however these responses were not durable in most patients. Notably, we identified tumor frameshift mutation proportion (FSP) as a novel biomarker that was associated with prolonged response to anti-PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti-PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts.

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Identification of Hypermutation and Defective Mismatch Repair in ctDNA from Metastatic Prostate Cancer

Cited by 61 publications

References 51 publications

Clinical Characterization of Mismatch Repair Gene-Deficient Metastatic Castration-Resistant Prostate Cancer

Clinical Characterization of Mismatch Repair Gene-Deficient Metastatic Castration-Resistant Prostate Cancer

Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer

Tumor Frameshift Mutation Proportion Predicts Response to Immunotherapy in Mismatch Repair-Deficient Prostate Cancer

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