Association of SPOP Mutations with Outcomes in Men with De Novo Metastatic Castration-sensitive Prostate Cancer

Swami, Umang; Velho, Pedro Isaacsson; Nussenzveig, Roberto; Chipman, Jonathan; Santos, Víctor Sacristán; Erickson, Stephanie; Dharmaraj, Divya; Alva, Ajjai; Vaishampayan, Ulka N.; Ealing, John; Hahn, Andrew W.; Maughan, Benjamin L.; Antonarakis, Emmanuel S.; Agarwal, Neeraj

doi:10.1016/j.eururo.2020.06.033

Cited by 56 publications

(41 citation statements)

References 15 publications

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“…Furthermore, studies using both mouse-and human-derived PC cell lines have shown that mutant SPOP (including SPOP-F133V) in concert with CHD1 loss exhibits increased double-strand break repair and sensitivity to DNA-damaging agents such as poly ADP-ribose polymerase inhibitors [40]. Recent multicenter data from men with mHSPC treated with ADT suggest that SPOP mutations confer a favorable long-term prognosis on progression free and overall survival, which aligns with the current excellent outcome of our current patient [41].…”

Section: Significance Of Spop Mutationssupporting

confidence: 81%

Molecular medicine tumor board: whole-genome sequencing to inform on personalized medicine for a man with advanced prostate cancer

Armstrong

Tucker

et al. 2021

Prostate Cancer Prostatic Dis

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Purpose Molecular profiling of cancer is increasingly common as part of routine care in oncology, and germline and somatic profiling may provide insights and actionable targets for men with metastatic prostate cancer. However, all reported cases are of deidentified individuals without full medical and genomic data available in the public domain. Patient and methods We present a case of whole-genome tumor and germline sequencing in a patient with advanced prostate cancer, who has agreed to make his genomic and clinical data publicly available. Results We describe an 84-year-old Caucasian male with a Gleason 10 oligometastastic hormone-sensitive prostate cancer. Whole-genome sequencing provided insights into his tumor’s underlying mutational processes and the development of an SPOP mutation. It also revealed an androgen-receptor dependency of his cancer which was reflected in his durable response to radiation and hormonal therapy. Potentially actionable genomic lesions in the tumor were identified through a personalized medicine approach for potential future therapy, but at the moment, he remains in remission, illustrating the hormonal sensitivity of his SPOP-driven prostate cancer. We also placed this patient in the context of a large prostate-cancer cohort from the PCAWG (Pan-cancer Analysis of Whole Genomes) group. In this comparison, the patient’s cancer appears typical in terms of the number and type of somatic mutations, but it has a somewhat larger contribution from the mutational process associated with aging. Conclusion We combined the expertise of medical oncology and genomics approaches to develop a molecular tumor board to integrate the care and study of this patient, who continues to have an outstanding response to his combined modality treatment. This identifiable case potentially helps overcome barriers to clinical and genomic data sharing.

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Section: Significance Of Spop Mutationssupporting

confidence: 81%

Molecular medicine tumor board: whole-genome sequencing to inform on personalized medicine for a man with advanced prostate cancer

Armstrong

Tucker

et al. 2021

Prostate Cancer Prostatic Dis

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“…In the future, predictive clinical parameters such as the ones identified in our analysis might be used in conjunction with emerging molecular markers for therapeutic decisions. SPOP mutations appear to identify a group of mCPSC patients with excellent response to ADT alone (35). Conversely, Harshman et al showed that elevated IL-8 levels predict shorter time to CRPC and OS independent of DOC administration, tumor burden, and recurrent versus de novo metastatic presentation, using baseline serum samples from CHAARTED (36).…”

Section: Discussionmentioning

confidence: 99%

Population-Based Study of Docetaxel or Abiraterone Effectiveness and Predictive Markers of Progression Free Survival in Metastatic Castration-Sensitive Prostate Cancer

et al. 2021

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BackgroundBoth Docetaxel (DOC) and Abiraterone (ABI) improve the survival of men with metastatic, castration sensitive prostate cancer (mCSPC). However, the outcome among mCSPC patients is highly variable, while there is a lack of predictive markers of therapeutic benefit. Furthermore, there is limited data on the comparative real-world effectiveness of adding DOC or ABI to androgen deprivation therapy (ADT).MethodsWe conducted a retrospective analysis of 121 mCSPC patients treated at Odette Cancer Centre (Toronto, ON, Canada) between Dec 2014 and Mar 2021 (DOC n = 79, ABI n = 42). The primary endpoint studied was progression free survival (PFS), defined as the interval from start of ADT to either (i) biochemical, radiological, or symptomatic progression, (ii) start of first-line systemic therapy for castration-resistant prostate cancer (CRPC), or (iii) death, whichever occurred first. To identify independent predictive factors for PFS in the entire cohort, a Cox proportional hazard model (stepwise selection) was applied. Overall survival (OS) was among secondary endpoints.ResultsAfter a median follow-up of 39.6 and 25.1 months in the DOC and ABI cohorts, respectively, 79.7% of men in the DOC and 40.5% in the ABI group experienced a progression event. PFS favored the ABI cohort (p = 0.0038, log-rank test), with 78.0% (95%CI 66.4–91.8%) of ABI versus 67.1% (57.5–78.3%) of DOC patients being free of progression at 12 months. In univariate analysis superior PFS was significantly related to older age at diagnosis of mCSPC, metachronous metastatic presentation, low-volume (CHAARTED), and low-risk (LATITUDE) disease, ≥90% PSA decrease at 3 months (PSA90), and PSA nadir ≤0.2 at 6 months. Age (HR = 0.955), PSA90 (HR = 0.462), and LATITUDE risk stratification (HR = 1.965) remained significantly associated with PFS in multivariable analysis. OS at 12 months was 98.7% (96.3–100%) and 92.7% (85.0–100%) in the DOC and ABI groups (p = 0.97), respectively.ConclusionsIn this real-world group of men undergoing treatment intensification with DOC or ABI for mCSPC, we did not find a significant difference in OS, but PFS was favoring ABI. Age at diagnosis of mCSPC, PSA90 at 3 months and LATITUDE risk classification are predictive factors of PFS in men with mCSPC.

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“…The notion that SPOP mutations may impart a favorable prognosis to hormonal therapies in the context of mHSPC is supported by prior studies and is thought to be related to decreased proteasomal degradation of the AR protein in SPOP-mutant cancers leading to enhanced AR addiction in these tumors. 15,16 Data has been emerging on the importance of combined mutations in RB1, TP53, and PTEN. Previous triple-knockout mouse models showed an aggressive disease variant with ADT resistance and a high potential for metastases.…”

Section: Discussionmentioning

confidence: 99%

Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone‐sensitive prostate cancer

et al. 2021

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Background Clinical outcomes may differ among patients presenting with primary (de novo) metastatic hormone‐sensitive prostate cancer (mHSPC) versus secondary (metachronous) mHSPC occurring after local therapy. It is unknown what molecular features distinguish these potentially distinct presentations. Methods A single‐center retrospective study of mHSPC patients classified as primary mHSPC (n = 121) or secondary mHSPC (n = 106). A targeted set of genes was analyzed: BRCA2, PTEN, RB1, TP53, SPOP, CDK12, any two out of PTEN/RB1/TP53 alterations, and homologous recombination deficiency mutations. TP53 mutations were categorized as loss‐of‐function (LOF) versus dominant‐negative (DN). The impacts of genetic features on progression‐free survival (PFS) and overall survival (OS) were assessed using univariate and multivariate Cox proportional hazards regression. Results Median PFS was 15 and 30 months for men with primary and secondary mHSPC, respectively (hazard ratio: 0.57, 95% confidence interval: 0.41–0.78; p < .01). OS did not show a significant difference between groups. There were more men with Gleason 8–10 disease in the primary versus secondary mHSPC groups (83% vs. 68%; p < .01). In univariate and multivariate analyses, TP53 DN mutations showed a statistically significant association with OS for the entire mHSPC population. Conversely, SPOP mutations were associated with improved OS. Additionally, TP53 mutations (DN and LOF) were associated with worse OS for secondary mHSPC. A combination of PTEN/RB1/TP53 mutations was associated with worse OS and PFS for secondary mHSPC, while no genomic alteration affected outcomes for primary mHSPC. Conclusions TP53 DN mutations, but not all TP53 alterations, were the strongest predictor of negative outcomes in men with mHSPC, while SPOP mutations were associated with improved outcomes. In subgroup analyses, specific alterations were prognostic of outcomes in secondary, but not primary, mHSPC.

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Association of SPOP Mutations with Outcomes in Men with De Novo Metastatic Castration-sensitive Prostate Cancer

Cited by 56 publications

References 15 publications

Molecular medicine tumor board: whole-genome sequencing to inform on personalized medicine for a man with advanced prostate cancer

Molecular medicine tumor board: whole-genome sequencing to inform on personalized medicine for a man with advanced prostate cancer

Population-Based Study of Docetaxel or Abiraterone Effectiveness and Predictive Markers of Progression Free Survival in Metastatic Castration-Sensitive Prostate Cancer

Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone‐sensitive prostate cancer

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