Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations

Schmid, Sabine; Omlin, Aurelius; Higano, Celestia S.; Sweeney, Christopher J.; Chanzá, Nieves Martínez; Mehra, Niven; Kuppen, Malou C.P.; Beltran, Himisha; Conteduca, Vincenza; Almeida, Daniel Vargas Pivato de; Maluf, Fernando C.; Oh, William; Tsao, Che‐Kai; Sartor, Oliver; Ledet, Elisa M.; Lorenzo, Giuseppe Di; Yip, Steven; N., Kim; Bianchini, Diletta; Giorgi, Ugo De; Hansen, Aaron Richard; Beer, Tomasz M.; Lavaud, Pernelle; Morales-Bárrera, Rafael; Tucci, Marco; Castro, Elena; Karalis, Kostas; Bergman, Andries M.; Le, Mo Linh; Zürrer-Härdi, Ursina; Pezaro, Carmel; Suzuki, Hiroyoshi; Zivi, Andrea; Klingbiel, Dirk; Schär, Sämi; Gillessen, Silke

doi:10.1001/jamanetworkopen.2020.21692

Cited by 91 publications

(75 citation statements)

References 36 publications

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“…Indeed, 75% of BRCA2 carriers have reported a PSA decline > 50% within 12 weeks of treatment initiation compared to 17% of non-carriers, with overall prolonged survival in the first cohort of 18.9 months versus 9.5 months [17]. Similarly, as reported by Schimd et al 63.9% of patients with BRCA2 mutations reported a PSA decline > 50% compared to 20-30% of non-carriers [18].…”

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confidence: 72%

BRCA Germline Mutations in Prostate Cancer: The Future Is Tailored

et al. 2021

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confidence: 72%

BRCA Germline Mutations in Prostate Cancer: The Future Is Tailored

et al. 2021

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“…Additionally, since an exploratory gene level subgroup analysis of the OS PROFOUND data suggests that patients with ATM alterations, in contrast to other homologous recombination repair alterations, may derive less benefit with olaparib PARPi, this may be a more elegant predictive biomarker to determine which patients with ATM alterations may benefit from PARPi and show OS and PCSM survival advantage [1] . Future studies will enhance our understanding of how outcomes of patients with altered ATM and PTEN expression can be enhanced further with PARPi, combinations of PARPi and AR-targeted therapies, as well as platinum-based chemotherapies [21] , [22] .…”

Section: Discussionmentioning

confidence: 99%

Decreased ATM Protein Expression Is Substantiated with PTEN Loss in Defining Aggressive Phenotype of Prostate Cancer Associated with Lethal Disease

Walker

Abdelsalam

Ghosh

et al. 2021

European Urology Open Science

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Background Ataxia Telangiectasia Mutated (ATM) serine/threonine protein kinase is a known tumor suppressor, involved in DNA damage repair. It has prognostic and predictive therapeutic implications and is associated with aggressive prostate cancer (PCa). Objective To investigate the prognostic value of ATM protein expression in PCa patients and assessed the combined value of ATM, ERG, and PTEN status. Design, setting, and participants This study consisted of 303 patients with incidental, locally advanced, and castrate-resistant PCa by transurethral resection of the prostate (TURP). Outcome measurements and statistical analysis TURP samples from 303 PCa patients were assessed by immunohistochemistry (IHC for ATM, ERG, and PTEN. Individual and combined marker status were correlated with International Society of Urological Pathology Gleason grade group, overall survival (OS), and PCa-specific mortality (PCSM). Results and limitations Decreased ATM expression (negative/weak intensity) occurred in 164/303 (54.1%) patients, and was associated with shorter OS and higher PCSM ( p = 0.015 and p = 0.001, respectively). Negative/weak ATM expression was significantly associated with PCSM with a hazard ratio of 2.09 (95% confidence interval 1.34–3.27, p = 0.001). Assessment of Combined ATM/PTEN expression showed improved prognostic power to predict OS and PCSM, independent of Gleason grade groups. Conclusions Decreased ATM protein expression is associated with poor outcomes in advanced PCa patients. Patients with combined low ATM/PTEN negative expression are at the highest risk for reduced OS and PCSM. Assessing the combined status of ATM/PTEN by IHC in PCa patients may aid in risk stratification relative to OS and PCSM. Moreover, since ATM plays an integral role in DNA damage response pathways, future studies will enhance our understanding of how outcomes of patients with altered ATM and PTEN expression can be improved further with poly-ADP ribose polymerase inhibitors (PARPi), combinations of PARPi and androgen receptor–targeted therapies, as well as platinum-based chemotherapies. Patient summary Lower ATM intensity is associated with increased cancer-specific mortality in prostate cancer patients. Patients with lower ATM and PTEN negative expression showed decreased overall survival and increased cancer mortality compared with controls.

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“…Incidence of this type of tumors is expected to rise upon increased use of novel anti-AR agents [54][55][56]. These tumors alike classical NEPC tumors [57] are likely to be challenging to treat as they are resistant to anti-AR agents and usually treated with platinum therapy subsequent to exhausting taxane therapy [55,[57][58][59].…”

Section: Novel Epithelial Mesenchymal Transition (Emt) Process To Delay Nmcrpcmentioning

confidence: 99%

Novel Target Opportunities in Non-Metastatic Castrate Resistant Prostate Cancer

Gleicher¹,

Porter²,

Nath³

et al. 2021

Preprint

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Nearly one third of men will incur biochemical recurrence after treatment for localized prostate cancer. Androgen deprivation therapy (ADT) is the therapeutic mainstay, however almost all patients will eventually transition to a castrate resistant state (castrate resistant prostate cancer, CRPC). Subjects with CRPC generally develop symptomatic metastatic disease (mCRPC) and incur mortality several years later. Prior to metastatic disease, men acquire non-metastatic CRPC (nmCRPC) which lends the unique opportunity for intervention to delay disease progression and symptoms. This review addresses current therapies for nmCRPC, as well as novel therapeutics and pathway strategies targeting men with nmCRPC.

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Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations

Cited by 91 publications

References 36 publications

BRCA Germline Mutations in Prostate Cancer: The Future Is Tailored

BRCA Germline Mutations in Prostate Cancer: The Future Is Tailored

Decreased ATM Protein Expression Is Substantiated with PTEN Loss in Defining Aggressive Phenotype of Prostate Cancer Associated with Lethal Disease

Novel Target Opportunities in Non-Metastatic Castrate Resistant Prostate Cancer

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