Cancers · 2026
Real-World Outcomes of DNA Damage Repair Altered Metastatic Castration-Resistant Prostate Cancer: Insights from FFPE-Based Genomic Profiling.
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Lai Eleonora, Pierantoni Francesco, Zampiva Ilaria, Bimbatti Davide, Ballestrin Melissa, Pretto Greta, Milani Anna, Erbetta Elisa, Jubran Salim, Pittarello Chiara, Di Marco Andrea, Cavasin Nicolò, Zamuner Carolina, Msaki Aichi, Moserle Lidia, Curtarello Matteo, Boldrin Elisa, Montagna Marco, Varano Veronica, Mourmouras Vasileios, Cataldo Ivana, Claps Francesco, Amodeo Antonio, Stragliotto Silvia, Maruzzo Marco, Basso Umberto
Аннотация
BACKGROUND: Germline and somatic variants in DNA Damage Repair (DDR) genes are found in approximately one-fourth of patients with metastatic prostate cancer (PC). However, their precise prognostic role and predictive impact on standard therapies remain controversial.
METHODS: This retrospective, single-center study evaluated the prevalence of germline/somatic DDR aberrations in 287 eligible patients with metastatic prostate cancer (mPC), treated between 2017 and 2022. Clinical characteristics and treatment outcomes (PFS and OS) for chemotherapy (taxanes) or next-generation hormonal therapies (NHT) were compared between DDR-mutated (DDRmut) and wild-type (DDRwt) cohorts.
RESULTS: Sixty-three patients (21.9%) were DDRmut, with BRCA2 (12.5%), ATM (3.1%), and BRCA1 (1.39%) being the most common alterations. A family history of breast, ovarian, or prostate cancer strongly predicted DDRmut status (47.0% vs. 14.0%, p = 0.0001). Tissue samples remained evaluable for sequencing up to 180 months from collection. Overall baseline characteristics were similar between cohorts, and BRCA1/2- and ATM-mutated patients treated with first-line taxanes for mCRPC presented with non significantly highermedian OS compared to DDRwt patients (70 vs. 36 months; p = 0.30). On the contrary, the DDRmut subgroup showed a trend toward shorter PFS (12 vs. 18 months; p = 0.04) when treated with first-line NHT. No significant differences were observed with third-line Cabazitaxel.
CONCLUSIONS: Formalin-fixed paraffin-embedded (FFPE) prostate tissue is highly reliable for DDR, possibly integrating novel liquid biopsy approaches for DDR evaluation. In a real-world setting, BRCA1/2 and ATM variants identify a distinct molecular subgroup that derives preferential survival benefit from first-line taxanes over standard hormonal intensification.
METHODS: This retrospective, single-center study evaluated the prevalence of germline/somatic DDR aberrations in 287 eligible patients with metastatic prostate cancer (mPC), treated between 2017 and 2022. Clinical characteristics and treatment outcomes (PFS and OS) for chemotherapy (taxanes) or next-generation hormonal therapies (NHT) were compared between DDR-mutated (DDRmut) and wild-type (DDRwt) cohorts.
RESULTS: Sixty-three patients (21.9%) were DDRmut, with BRCA2 (12.5%), ATM (3.1%), and BRCA1 (1.39%) being the most common alterations. A family history of breast, ovarian, or prostate cancer strongly predicted DDRmut status (47.0% vs. 14.0%, p = 0.0001). Tissue samples remained evaluable for sequencing up to 180 months from collection. Overall baseline characteristics were similar between cohorts, and BRCA1/2- and ATM-mutated patients treated with first-line taxanes for mCRPC presented with non significantly highermedian OS compared to DDRwt patients (70 vs. 36 months; p = 0.30). On the contrary, the DDRmut subgroup showed a trend toward shorter PFS (12 vs. 18 months; p = 0.04) when treated with first-line NHT. No significant differences were observed with third-line Cabazitaxel.
CONCLUSIONS: Formalin-fixed paraffin-embedded (FFPE) prostate tissue is highly reliable for DDR, possibly integrating novel liquid biopsy approaches for DDR evaluation. In a real-world setting, BRCA1/2 and ATM variants identify a distinct molecular subgroup that derives preferential survival benefit from first-line taxanes over standard hormonal intensification.