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. 2024 Apr 3;2(1):28.
doi: 10.1038/s44276-024-00049-7.

Genomic profiling and clinical utility of circulating tumor DNA in metastatic prostate cancer: SCRUM-Japan MONSTAR SCREEN project

Masaki Shiota  1 , Nobuaki Matsubara  2 , Taigo Kato  3 , Masatoshi Eto  4 , Takahiro Osawa  5 , Takashige Abe  5 , Nobuo Shinohara  5 , Koshiro Nishimoto  6 , Yota Yasumizu  7 , Nobuyuki Tanaka  7 , Mototsugu Oya  7 , Takao Fujisawa  8 , Satoshi Horasawa  9 , Yoshiaki Nakamura  10 , Takayuki Yoshino  10 , Norio Nonomura  3
Affiliations

Genomic profiling and clinical utility of circulating tumor DNA in metastatic prostate cancer: SCRUM-Japan MONSTAR SCREEN project

Masaki Shiota et al. BJC Rep. .

Abstract

Background: Circulating tumor DNA (ctDNA) testing has emerged as a novel tool for cancer precision medicine. This study investigated the genomic profiling and clinical utility of ctDNA in metastatic prostate cancer.

Methods: This is a nation-wide prospective observational study. Patients treated with systemic treatment for metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC) were included. ctDNA was analyzed using FoundationOne Liquid®CDx at enrollment. In a subset of patients, ctDNA after disease progression and tissue prior to the initiation of treatment were examined using FoundationOne Liquid®CDx and FoundationOne®CDx, respectively.

Results: The frequency of AR alterations and homologous recombination repair (HRR) defect was higher in mCRPC compared with mCSPC. Tumor mutational burden was correlated between tissue and ctDNA at pre-treatment, as well as ctDNA between at pre-treatment and at post-treatment. Patients with HRR defect were associated with shorter time to castration resistance in androgen deprivation therapy/combined androgen blockade, but not in androgen receptor pathway inhibitor, compared with patients without HRR defect in mCSPC. Time to treatment failure in patients with AR amplification or AR mutation was shorter compared with patients without AR alterations in mCRPC.

Conclusions: This study revealed valuable findings for the clinical care of metastatic prostate cancer. Especially, predictive factors such as HRR defect in mCSPC should be validated in the future.

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Conflict of interest statement

M. Shiota received honoraria from Janssen Pharmaceutical, AstraZeneca, Astellas Pharma, Sanofi, and Bayer and research funding support from Daiichi Sankyo. N. Matsubara received honoraria from Sanofi, and research funding from Janssen, AstraZeneca, Bayer, Roche, MSD, Taiho, Astellas, Amgen, Eisai, Eli Lilly, PRA Health Science, Takeda, Pfizer, Seagen and Chugai. M. Eto received honoraria from Takeda Pharmaceutical, Janssen Pharmaceutical, AstraZeneca, and Astellas Pharma and research funding support from Astellas Pharma, Sanofi, and Takeda Pharmaceutical. N. Nonomura received honoraria from Takeda Pharmaceutical, Janssen Pharmaceutical, AstraZeneca, Merck Biopharma, Ono Pharmaceutical, and Bristol Myers Squibb. M. Shiota is an Associate Editor at BJC Reports. He was not involved in any aspect of handling of this manuscript or any editorial decisions.

Figures

Fig. 1
Fig. 1. Genomic landscape by F1LCDx® in metastatic prostate cancer.
Genomic alterations observed in multiple cases with variant allele frequency of over 2% were listed. Patients are sorted by tumor fraction (top). Genes are grouped by pathway. Frequency of alterations in each gene among 68 patients with metastatic castration-sensitive prostate cancer (mCSPC) and 95 patients with metastatic castration-resistant prostate cancer (mCRPC) is provided on the right. *statistical significance (mCSPC vs mCRPC).
Fig. 2
Fig. 2. Concordance between tissue and ctDNA.
a Correlation of tumor mutational burden (TMB) in tissue and blood TMB (bTMB) in ctDNA from matched patients (n = 37). b Venn diagram on of concordance and discordance of genomic alterations between paired tissue and ctDNA from matched patients (n = 38). c Altered genes with frequency of over 5% in paired tissue or ctDNA from matched patients (n = 38). T tumor, B blood.
Fig. 3
Fig. 3. Clonal evolution during treatment.
a Change of tumor fraction in paired ctDNA at pre-treatment and post-treatment from same patients (n = 46). Blue bar, metastatic castration-sensitive prostate cancer; red bar, metastatic castration-resistant prostate cancer. b Correlation of blood tumor mutation burden (bTMB) in paired ctDNA at pre-treatment and post-treatment from matched patients (n = 46). c Venn diagram on of concordance and discordance of genomic alterations in ctDNA between pre-treatment and post-treatment from matched patients (n = 46). d Altered genes with frequency of over 5% in ctDNA at pre-treatment or post-treatment from matched patients (n = 46). The data on tumor tissue genotyping was available in patients in red.
Fig. 4
Fig. 4. Predictive impacts of genomic alterations in metastatic castration-sensitive prostate cancer (mCSPC).
Time to castration-resistant prostate cancer (CRPC) according to presence or absence of homologous recombination repair (HRR) defect in mCSPC patients treated with androgen deprivation therapy (ADT)/combined androgen blockade (CAB) (left) or ADT plus androgen receptor pathway inhibitor (ARPI) (right).
Fig. 5
Fig. 5. AR alterations in metastatic castration-resistant prostate cancer (mCRPC).
a AR mutations, amplification, and rearrangement in F1LCDx® at pre-treatment in mCRPC (n = 95) are indicated. Each colored circle represents a single mutation with variant allele frequency (VAF) and copy number. b Change of VAF of AR mutation (left) and copy number of AR gene (right) in paired ctDNA at pre-treatment (blue bar) and post-treatment (red bar) from matched patients. c Time to treatment failure according to treatment (abiraterone or enzalutamide) (left), and AR gene alterations (right) in mCRPC patients.
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