Integrated clinical, whole-genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer

Bova, G. Steven; Kallio, Heini; Annala, Matti; Kivinummi, Kati; Högnäs, Gunilla; Häyrynen, Sergei; Rantapero, Tommi; Kivinen, Virpi; Isaacs, William B.; Tolonen, Teemu; Nykter, Matti; Visakorpi, Tapio

doi:10.1101/mcs.a000752

Cited by 28 publications

(29 citation statements)

References 57 publications

(62 reference statements)

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“…It has been previously demonstrated that [28] that metastasis to metastasis spread of prostate tumor clones is common. This may explain the small heterogeneity seen in HRstatus of multiple metastases.…”

Section: Discussionmentioning

confidence: 99%

Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

Sztupinszki

Dióssy

Krzystanek

et al. 2019

Preprint

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Background: Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. It is not clear, however, whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, rendering them sensitive to HR-directed therapies.To identify a more comprehensive set of prostate cancer cases with homologous recombination deficiency (HRD) including those cases that do not harbor mutations in known HR genes.HRD levels can be estimated using various mutational signatures derived from nextgeneration sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed.Results: Known BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR related genes. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD. Conclusions:These findings may expand the number of cases likely to respond to PARPinhibitor treatment. Based on the HRD associated mutational signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).3 Key words: BRCA1, BRCA2, DNA repair genes, homologous recombination deficiency, PARP inhibitors, Prostate cancer somatic mutations in BRCA1/2 or other HR related genes. This likely defines a subset of prostate cancer patients that will likely benefit from PARP inhibitor or platinum-based therapy.

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Section: Discussionmentioning

confidence: 99%

Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

Sztupinszki

Dióssy

Krzystanek

et al. 2019

Preprint

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“…Biomarker driven clinical trials for mCRPC have been hampered by the difficulty of obtaining metastatic tissue (11). Also, profiling a single metastatic lesion is not capable of providing the full spectrum of the molecular heterogeneity that may exist within the patient (12,13). A liquid biopsy, either in the form of circulating tumour cells (CTCs) or tumour-derived cell-free DNA (circulating tumor DNA, ctDNA), is an attractive alternative (14,15).…”

Section: Background and Rationalementioning

confidence: 99%

The ProBio Trial: Molecular Biomarkers for Advancing Personalized Treatment Decision in Patients with Metastatic Castration-Resistant Prostate Cancer

Crippa

Laere

Discacciati

et al. 2020

Preprint

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Background: Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression free survival (PFS) remains modest, potentially explained by tumour molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment decision and prolong PFS. We designed a platform trial to test this hypothesis.Methods: The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC.Discussion: Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study.Conclusions: The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care.

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Section: Background and Rationalementioning

confidence: 99%

The ProBio Trial: Molecular Biomarkers for Advancing Personalized Treatment Decision in Patients with Metastatic Castration-Resistant Prostate Cancer

Crippa

Laere

Discacciati

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression free survival (PFS) remains modest, potentially explained by tumour molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis.Methods: The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC.Discussion: Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study.Conclusions: The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care.Trial registration: ClinicalTrials.gov Identifier: NCT03903835Date of registration: April 4, 2019URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT03903835Status: Recruiting

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Integrated clinical, whole-genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer

Cited by 28 publications

References 57 publications

Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

The ProBio Trial: Molecular Biomarkers for Advancing Personalized Treatment Decision in Patients with Metastatic Castration-Resistant Prostate Cancer

The ProBio Trial: Molecular Biomarkers for Advancing Personalized Treatment Decision in Patients with Metastatic Castration-Resistant Prostate Cancer

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