Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study

Background: This study aimed to describe the aberrations of DNA damage repair genes and other important driving genes in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating tumor (ctDNA) sequencing and to evaluate the associations between the clinical outcomes of multiple therapies and key genomic alterations in mCRPC, especially DNA damage repair genes. Patients and Methods: A total of 292 Chinese patients with mCRPC enrolled from 8 centers. Multigene targeted sequencing was performed on 306 ctDNA samples and 23 matched tumor biopsies. The frequency of genomic alterations were compared with the Stand Up to Cancer–Prostate Cancer Foundation (SU2C-PCF) cohort. The Kaplan-Meier method was used to evaluate progression-free survival (PFS) following standard systemic treatments for mCRPC. Cox regression analyses were performed to determine prognostic factors associated with PFS resulting from treatments for mCRPC. Results: In total, 33 of 36 (91.7%) mutations were found consistently between ctDNA and paired biopsy samples. The most common recurrent genomic alterations were found in AR (34.6%), TP53 (19.5%), CDK12 (15.4%), BRCA2 (13%), and RB1 (5.8%). The frequency of CDK12 alterations (15.4%) in our cohort was significantly higher than that in Western populations (5%–7%). AR amplification and TP53 and/or RB1 alterations were associated with resistance to abiraterone or docetaxel. Patients with a CDK12 defect showed rapid disease progression after abiraterone treatment. However, the clinical outcome after docetaxel treatment was similar between patients with and without CDK12 defects. In multivariate Cox regression analysis, a CDK12 defect was significantly associated with inferior PFS after abiraterone treatment. Patients with a BRCA2 defect showed marked response to both PARP inhibitors and platinum-based chemotherapy. Conclusions: Our study explored the genomic landscape of Chinese patients with mCRPC at different treatment stages using minimally invasive methods and evaluated the clinical implications of the driver genomic alterations on patients’ response to the most widely used therapies for mCRPC. We observed a significantly higher alteration frequency of CDK12 in our cohort compared with the SU2C-PCF cohort.

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Platinum-based chemotherapy in metastatic prostate cancer with alterations in DNA damage repair genes.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5038 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5038-5038

Author(s):

Jose Mauricio Mota ◽

Ethan Barnett ◽

Jones Nauseef ◽

Konrad Hermann Stopsack ◽

Andreas Georg Wibmer ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Parp Inhibitor ◽

Dna Damage Repair ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Damage Repair ◽

Platinum Based Chemotherapy ◽

Before And After ◽

Repair Genes

5038 Background: Platinum-based chemotherapy has shown palliative and radiographic benefit in small unselected studies of metastatic castration-resistant prostate cancer (mCRPC). Alterations in DNA damage repair genes (DDRmut), which occur in ~25% of patients with mCRPC, may sensitize to platinum-based chemotherapy, and may aid in the selection of patients for this therapy. We sought to evaluate the efficacy of platinum-based chemotherapy in DDRmut mCRPC. Methods: We performed a retrospective review of patients with prostate cancer who underwent tumor genomic profiling and received platinum-based chemotherapy. Deleterious alterations in a panel including BRCA2, BRCA1, ATM, FANCA, CDK12 or PALB2 were classified as DDRmut. Absence of deleterious alterations in those genes was classified as DDRwt. MSI-H cases were excluded from analysis. Electronic charts, PSA values, and scans were reviewed to assess for outcomes. Results: From October 2013 to July 2018, 109 patients with mCRPC received platinum-based chemotherapy. 64/109 had prior taxane progression and were PARP inhibitor (PARPi) naïve at the time of platinum-based chemotherapy. DDRmut was found in 16/64 (25%) of patients ( BRCA2, n = 6; ATM, n = 2; CDK12, n = 4; FANCA, n = 4; PALB2, n = 1). Visceral metastasis occurred in 4/16 (25%) of DDRmut patients and in 22/48 (46%) of DDRwt patients. PSA50 responses were more common among DDRmut (8/15 evaluable = 53%, 95% CI, 30-75%) than among DDRwt patients (5/42 evaluable = 12%, 95% CI, 5-25%). Time on platinum-based chemotherapy tended to be longer in the DDRmut group (median 3.1 vs 1.8 months; HR 0.73, 95% CI 0.42-1.26). Of 8 DDRmut patients ( BRCA2, n = 6; BRCA1, n = 1; ATM, n = 2) who received platinum-based chemotherapy after progression on a PARPi, 3/7 evaluable patients (43%) had RECIST response or stable disease, and 2/7 evaluable patients (29%) had a PSA50 response. Of 4 patients with ATM deleterious mutations, none had a radiographic or PSA50 response to platinum-based chemotherapy. Conclusions: Platinum-based chemotherapy showed activity in DDRmut mCRPC patients before and after PARPi treatment.

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Impact of DNA damage repair defects and aggressive variant features on response to carboplatin‐based chemotherapy in metastatic castration‐resistant prostate cancer

International Journal of Cancer ◽

10.1002/ijc.33306 ◽

2020 ◽

Vol 148 (2) ◽

pp. 385-395

Author(s):

Peter H. J. Slootbeek ◽

Marleen L. Duizer ◽

Maarten J. Doelen ◽

Iris S. H. Kloots ◽

Malou C. P. Kuppen ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Dna Damage Repair ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Damage Repair ◽

Aggressive Variant

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Comment on: ‘Impact of DNA damage repair defects on response to radium-223 and overall survival in metastatic castration-resistant prostate cancer’ by De Vincentis et al

European Journal of Cancer ◽

10.1016/j.ejca.2020.09.041 ◽

2020 ◽

Cited By ~ 1

Author(s):

Giuseppe De Vincentis ◽

Viviana Frantellizzi

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Overall Survival ◽

Dna Damage Repair ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Radium 223 ◽

Damage Repair

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Response to comment on “Impact of DNA damage repair defects on response to radium-223 and overall survival in metastatic castration-resistant prostate cancer”

European Journal of Cancer ◽

10.1016/j.ejca.2020.11.041 ◽

2020 ◽

Author(s):

Maarten J. van der Doelen ◽

Peter H.J. Slootbeek ◽

Niven Mehra

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Overall Survival ◽

Dna Damage Repair ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Radium 223 ◽

Damage Repair

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614MO Cabazitaxel (CBZ) activity in men with metastatic castration resistant prostate cancer (mCRPC) with and without DNA damage repair (DDR) defects

Annals of Oncology ◽

10.1016/j.annonc.2020.08.873 ◽

2020 ◽

Vol 31 ◽

pp. S510

Author(s):

M. Aldea ◽

L. Lam ◽

C. Llacer Perez ◽

M. Saint-Ghislain ◽

G. Gravis Mescam ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Dna Damage Repair ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Damage Repair

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Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making

JCO Precision Oncology ◽

10.1200/po.17.00029 ◽

2017 ◽

pp. 1-16 ◽

Cited By ~ 56

Author(s):

Wassim Abida ◽

Joshua Armenia ◽

Anuradha Gopalan ◽

Ryan Brennan ◽

Michael Walsh ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Clinical Decision Making ◽

Dna Damage Repair ◽

Genomic Profiling ◽

Castration Resistant Prostate Cancer ◽

Disease States ◽

Castration Resistant ◽

Damage Repair ◽

Increased Risk

Purpose A long natural history and a predominant osseous pattern of metastatic spread are impediments to the adoption of precision medicine in patients with prostate cancer. To establish the feasibility of clinical genomic profiling in this disease, we performed targeted deep sequencing of tumor and normal DNA from patients with locoregional, metastatic noncastrate, and metastatic castration-resistant prostate cancer. Patients and Methods Patients consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based clinical assay was used to identify single-nucleotide variations, small insertions and deletions, copy number alterations, and structural rearrangements in more than 300 cancer-related genes in tumors and matched normal blood. Results We successfully sequenced 504 tumors from 451 patients with prostate cancer. Potentially actionable alterations were identified in DNA damage repair, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase pathways. Twenty-seven percent of patients harbored a germline or a somatic alteration in a DNA damage repair gene that may predict for response to poly (ADP-ribose) polymerase inhibition. Profiling of matched tumors from individual patients revealed that somatic TP53 and BRCA2 alterations arose early in tumors from patients who eventually developed metastatic disease. In contrast, comparative analysis across disease states revealed that APC alterations were enriched in metastatic tumors, whereas ATM alterations were specifically enriched in castration-resistant prostate cancer. Conclusion Through genomic profiling of prostate tumors that represent the disease clinical spectrum, we identified a high frequency of potentially actionable alterations and possible drivers of disease initiation, metastasis, and castration resistance. Our findings support the routine use of tumor and germline DNA profiling for patients with advanced prostate cancer for the purpose of guiding enrollment in targeted clinical trials and counseling families at increased risk of malignancy.

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