Genomic Landscape in Prostate Cancer in a Latin American Population.

PURPOSE: This study aims to describe genomic characteristics of patients with metastatic prostate cancer (mPC). PATIENTS AND METHODS: This study is a retrospective, multicenter cohort study of patients with mPC and reports on genomic testing. Patients were included from 12 academic centers in five countries. RESULTS: A total of 349 patients with PC were included in this study. Most patients (209, 59.9%) were de novo metastatic. Genomic analysis was performed in 233 (66.6%) patients in the metastatic castration-resistant prostate cancer (mCRPC) setting, and only 115 (32.8%) patients had a tumor evaluation in the metastatic hormone sensitive prostate cancer scenario. The evaluation of somatic and/or germline mutations was performed through multigene panel analyses in 290 (83.09%) patients, and next-generation sequencing of BRCA1 and BRCA2 genes was performed in 59 (16.91%) patients. Analyzing the mCRPC subgroup, with a median follow-up of 15.6 months (IQR, 14-19.06), the median progression-free survival (PFS) was not reached (NR) and the PFS at 16 months was 58.7% (95% CI, 50.8 to 67.8). When comparing patients with BRCA mutations with those who are not BRCA-mutated in the mCRPC scenario, the median PFS was NR (95% CI, 14 to NR) and 26.3 months (95% CI, 16.7 to 36.5; P = .2), respectively. Two of six patients with BRCA mutations were treated with targeted therapies (poly-ADP-ribose polymerase inhibitors). CONCLUSION: Our study, to the best of our knowledge, represents one of the larger data sets for somatic testing in patients with PC in Latin America (LATAM). It adds valuable information to the growing body of knowledge about the genomic landscape of advanced PC in real-world daily practice scenarios in LATAM countries, which are not always well-represented in large-scale randomized clinical trials.

Cyclin-Dependent Kinase 4/6 Inhibitor Outcomes in Patients With Advanced Breast Cancer Carrying Germline Pathogenic Variants in DNA Repair-Related Genes.

PURPOSE: In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair-related genes. PATIENTS AND METHODS: We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair-related genes (gBRCA1/2-ATM-CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models. RESULTS: Among the total population (n = 217), 15 (6.9%) patients carried gBRCA1/2 (n = 10)-ATM (n = 4)-CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger (P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group (P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival (P = .020) and overall survival (P = .012). CONCLUSION: In this retrospective real-world study, gBRCA1/2-ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors.

Experience of bipolar androgen therapy (BAT) in Argentinian oncology centres.

Background: Previous studies with bipolar androgen therapy (BAT) have shown clinical activity in metastatic Castration Resistant Prostate Cancer (mCRPC) as well as the potential to re-sensitise prostate cancer cells to prior androgen receptor-targeted agents. None of these studies had tested BAT after chemotherapy. In this study, we gathered real-world evidence from three centres in Argentina where BAT is being used in castration-resistant prostate cancer (CRPC), not only prior to chemotherapy but also after several lines of treatment. Materials and methods: This retro-prospective nonrandomised multicentre cohort study included patients with mCRPC, who received BAT in different scenarios defined by the treating physician at three centres in Argentina. Results: A total of 21 asymptomatic patients with mCRPC were included. There was a median of two lines before BAT, with nine patients (42.8%) receiving three or more lines, and 13 patients (61.9%) receiving chemotherapy previously. Previous lines included next-generation hormonal agents (NHA) in 100% (abiraterone 33.3% and enzalutamide 71.4%), chemotherapy in 61.9%, Radium-223 in 47.6% and others in 4.8%. The progression free survival (PFS) after BAT was 3.5 months (95% CI: 3.06-7.97). PSA50 response rate (RR) was 28.5% and the overall RR was 14.3%. Of the 17 patients who had disease progression, 9 had a rechallenge to NHA, achieving a 55% RR, 6 received other treatment (chemotherapy in 5 and 177Lu-PSMA in 1) with a 66% RR and 2 best supportive care. The PFS2, calculated after the initiation of BAT in the 15 patients who received further therapy, was 7.93 months (95% CI: 6.73-NR). Treatment was overall well tolerated, with only two patients requiring hospitalisation and treatment interruption due to worsening pain. Conclusion: To the authors' knowledge, this is the first publication of BAT in later lines of therapy in mCRPC. BAT showed clinical activity in this scenario. Our data supports that BAT may play a role in CRPC re-sensitisation after multiple treatment lines.

PARP inhibitors as a radiosensitizer: a future promising approach in prostate cancer?

Poly (ADP-ribose) polymerase (PARP) inhibitors (iPARPs) have shown efficacy in homologous recombination (HR) deficiency patients with advanced castration resistant prostate cancer and have shown a radiosensitizing effect in preclinical and early clinical trials. Preclinical data in prostate cancer cells suggest a similar cytotoxic effect with half the radiation dose under the effect of Olaparib or Rucaparib irrespective of HR status. Due to the biologic synergy of radiotherapy (RT) and iPARPs, the risk of recurrence of high-risk prostate cancer and the morbidity associated with prostate cancer local treatment, this interesting strategy seems promising, and a better understanding of the clinical implications remains to be elucidated.

[Timely diagnosis of disseminated paracoccidioidomycosis in an immunocompetent adult]. / Diagnóstico oportuno de paracoccidioidomicosis diseminada en un adulto inmunocompetente.

Paracoccidioidomycosis is endemic in subtropical rainforests of Latin America. Acute/subacute presentations involve an aggressive dissemination throughout the lymphatic system, while chronic forms (more frequent) arise as differential diagnosis for other conditions involving lung, oropharynx, skin, and eventually the brain. We present the case of a man referred for evaluation and treatment of a possible lung tumor with brain metastasis. The finding of multibudded yeasts and the microbiological isolation of a dimorphic fungus identified as Paracoccidioides sp. from a brain biopsy prompted a cardinal change in prognosis and treatment. This case alerts on the importance of considering systemic fungal diseases as differential diagnosis of compatible clinical presentations in patients who had lived in, or visited, endemic areas.