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In Latin America, prostate cancer is the third most common cancer overall and the most common in men, with the highest mortality rate of all cancers. In 2022, there were approximately 22,985 new prostate cancer cases and 61,056 deaths from prostate cancer in the region. Patients with metastatic disease that is resistant to cure by castration now have multiple therapeutic options, including poly-ADP ribose polymerase inhibitors. These treatment advances present new challenges, such as developing monitoring protocols for early detection of disease progression to castration resistance. The Americas Health Foundation organized a 3-day meeting with 8 regional oncologists and pathologists to create a paper on metastatic castration-resistant prostate cancer diagnosis and therapy, including the new poly-ADP ribose polymerase inhibitors. The panel examined metastatic castration-resistant prostate cancer in Latin America and recommended ways to improve patient care using published literature and their expertise. Gene mutations play an important role in prostate cancer development. Precision medicine innovations highlight the importance of genotyping DNA variants and tumor biomarkers for targeted treatment. Access to appropriate genetic testing is difficult, medications are available but expensive, and there is a lack of infrastructure and regulatory frameworks that prevent patients from benefiting from innovative therapies. The panel recommends developing a population database and biobank and creating tumor tissue collection, processing, and storage facilities. Multi-stakeholder collaboration is needed to integrate the information gathered, train staff, select target populations, improve patient accessibility, and reduce the cost burden of drugs, genetic counselors, and cancer geneticists in Latin America. Collaboration is essential among healthcare professionals, policymakers, patient advocacy groups, pharmaceutical companies, and international organizations to address these challenges and needs in Latin America.
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Inhibidores de Poli(ADP-Ribosa) Polimerasas , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , América Latina , Metástasis de la NeoplasiaRESUMEN
PURPOSE: Despite the success of immune checkpoint inhibitors (ICIs) across various cancers, their efficacy in metastatic castration-resistant prostate cancer (mCRPC) is modest, except for a subset of patients who experience significant, yet unpredictable, benefits. DNA repair defects (DRD) are associated with higher neoantigen load, which may predict response. Our study explored the potential of DRD for enhanced responsiveness to the ICI nivolumab. METHODS: We conducted a phase II, multi-center, single-arm trial evaluating nivolumab in post-docetaxel mCRPC patients. DRD was assessed using circulating tumor DNA (ctDNA). The primary endpoint was PSA50 response. Secondary endpoints included objective response rate (ORR), radiographic progression-free survival (rPFS), and overall survival (OS). Also, exploratory comprehensive genomic profiling was performed via whole-exome sequencing (WES) of tumor samples and matched normal tissue, alongside PD-L1 expression evaluation. RESULTS: Among the 38 enrolled patients, DRD was identifiable in 30.5% (11/36) through ctDNA and/or WES analysis. The overall PSA50 response rate was 10.5% (4/38). PSA50 response and ORR did not significantly differ between patients with and without DRD (18.2% vs. 8%; p = 0.57 and 50% vs. 17.6%, p= 0.27, respectively). Median PSA-PFS (1.9 vs. 2.8 months, p=0.52) and rPFS (3.4 vs. 5.5 months, p=0.7) were not statistically different between patients with and without DRD. Grade ≥ 3 adverse events were reported in 47.3% of participants. CONCLUSION: Nivolumab has clinical activity in a subset of mCRPC patients, however, DRD do not predicted response.These results highlight the necessity of identifying new biomarkers to more accurately determine mCRPC patients who might respond to ICIs.
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PURPOSE: The prevalence of homologous recombination repair gene mutations (HRRm) in patients with metastatic castration-resistant prostate cancer (mCRPC) in Latin America and the Caribbean (LAC) is unknown. Prevalence of homologous Recombination repair (HRR) gene mutatiOns in patientS with metastatic castration resistant ProstatE Cancer in LaTin America (PROSPECT) aimed to determine this prevalence and to describe the demographic and clinical characteristics of the participants. MATERIALS AND METHODS: This was a prospective, cross-sectional, multicenter study across 11 cancer centers in seven LAC countries. After informed consent, all eligible participants underwent genomic testing by provided blood samples for germline HRR testing; they also provided PC tissue blocks if available for somatic HRR testing. RESULTS: Between April 2021 and April 2022, 387 patients (median age, 70 years [49-89], 94.3% Eastern Cooperative Oncology Group 0-1) with mCRPC were enrolled in the study. Almost 40% of them had a family history of cancer, and the overall time from their initial PC and mCRPC diagnosis was 3 years and 1 year, respectively. The overall prevalence of germline HRRm was 4.2%. The mutations detected included the genes CHEK2 (n = 4, 1%), ATM (n = 3, 0.8%), BRCA2 (n = 3, 0.8%), BRIP1 (n = 2, 0.5%), RAD51B (n = 2, 0.5%), BRCA1 (n = 1, 0.3%), and MRE11 (n = 1, 0.3%). The prevalence of somatic HRRm could not be assessed because of high HRR testing failure rates (79%, 199/251) associated with insufficient DNA, absence of tumor cells, and poor-quality DNA. CONCLUSION: Despite the study's limitations, to our knowledge, PROSPECT was the first attempt to describe the prevalence of HRRm in patients with PC from LAC. Notably, the germline HRRm prevalence in this study was inferior to that observed in North American and European populations. The somatic HRR testing barriers identified are being addressed by several projects to improve access to HRR testing and biomarker-based therapies in LAC.
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Mutación , Neoplasias de la Próstata Resistentes a la Castración , Reparación del ADN por Recombinación , Humanos , Masculino , Anciano , Estudios Prospectivos , Persona de Mediana Edad , Estudios Transversales , América Latina/epidemiología , Anciano de 80 o más Años , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/epidemiología , Neoplasias de la Próstata Resistentes a la Castración/patología , Reparación del ADN por Recombinación/genética , PrevalenciaRESUMEN
BACKGROUND: Prostate cancer exhibits a very diverse behaviour, with some patients dying from the disease and others never needing treatment. Active surveillance (AS) consists of periodic PSA assessment (prostate-specific antigen), DRE (digital rectal examination) and periodic prostate biopsies. According to the main guidelines, AS is the preferred strategy for low-risk patients, to avoid or delay definitive treatment. However, concerns remain regarding its applicability in certain patient subgroups, such as African American men, who were underrepresented in the main cohorts. Brazil has a very racially diverse population, with 56.1% self-reporting as brown or black. The aim of this study is to evaluate and validate the AS strategy in low-risk prostate cancer patients following an AS protocol in the Brazilian public health system. METHODS: This is a multicentre AS prospective cohort study that will include 200 patients from all regions of Brazil in the public health system. Patients with prostate adenocarcinoma and low-risk criteria, defined as clinical staging T1-T2a, Gleason score ≤ 6, and PSA < 10 ng/ml, will be enrolled. Archival prostate cancer tissue will be centrally reviewed. Patients enrolled in the study will follow the AS strategy, which involves PSA and physical examination every 6 months as well as multiparametric MRI (mpMRI) every two years and prostate biopsy at month 12 and then every two years. The primary objective is to evaluate the reclassification rate at 12 months, and secondary objectives include determining the treatment-free survival rate, metastasis-free survival, and specific and overall survival. Exploratory objectives include the evaluation of quality of life and anxiety, the impact of PTEN loss and the economic impact of AS on the Brazilian public health system. DISCUSSION: This is the first Brazilian prospective study of patients with low-risk prostate cancer under AS. To our knowledge, this is one of the largest AS study cohort with a majority of nonwhite patients. We believe that this study is an opportunity to better understand the outcomes of AS in populations underrepresented in studies. Based on these data, an AS national clinical guideline will be developed, which may have a beneficial impact on the quality of life of patients and on public health. TRIAL REGISTRATION: Clinicaltrials registration is NCT05343936.
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Antígeno Prostático Específico , Neoplasias de la Próstata , Masculino , Humanos , Estudios Prospectivos , Brasil/epidemiología , Espera Vigilante/métodos , Calidad de Vida , Salud Pública , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/terapiaRESUMEN
Metastatic renal cell carcinoma (mRCC) encompasses a heterogeneous group of neoplasms with distinct clinical behavior and prognoses. As a result of the increasing number of therapeutic options in the metastatic setting, it is crucial to improve prognostic stratification ability. We aimed to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and combination platelet count and neutrophil lymphocyte ratio (COP-NLR) in patients with mRCC. We evaluated a cohort of mRCC patients treated with first-line pazopanib or sunitinib. Levels of NLR, PLR and COP-NLR were measured prior to systemic treatment and evaluated as prognostic predictors. Primary endpoint was overall survival (OS). Data from 276 patients were included, of which 54.7% received first-line pazopanib and 45.3%, sunitinib. Memorial Sloan-Kettering Cancer Center risk classification was intermediate and poor in 50% and 42.6% of patients, respectively. High NLR (> 3.5) was associated with inferior OS (median 9.6 vs 17.8 months, P < 0.001). A high PLR (> 200) was associated with inferior OS (median 10.3 vs 17 months, P = 0.002). The median OS in the COP-NLR 1, 2 and 3 groups were 19.0 months (95% CI 15.3-26.0), 13.1 months (95% CI 9.8-17.0) and 7.4 months (95% CI 3.6-11.9), respectively (P < 0.001). In the multivariate analysis, high NLR and high COP-NLR were associated with inferior OS. Both high NLR and high COP-NLR were associated with poorer OS in our cohort of patients with mRCC treated with first-line pazopanib or sunitinib.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Carcinoma de Células Renales/inmunología , Neoplasias Renales/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/tratamiento farmacológico , Niño , Femenino , Humanos , Indazoles/uso terapéutico , Inflamación/sangre , Neoplasias Renales/tratamiento farmacológico , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Neutrófilos , Recuento de Plaquetas , Pronóstico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Sunitinib/uso terapéutico , Adulto JovenRESUMEN
Purpose Sunitinib and pazopanib are multitargeted tyrosine kinase inhibitors (TKIs) that act against vascular endothelial growth factor receptors and are standard first-line treatment options for metastatic clear cell renal cell carcinoma (ccRCC). The Brazilian public health system diverges from the randomized clinical trials in the availability of first and subsequent lines of treatment and in clinical and demographic characteristics of patients. Therefore, it is essential to describe the history of advanced ccRCC during and after TKI treatment in this population. Methods We performed a retrospective analysis of patients with advanced ccRCC treated with a first-line TKI (either sunitinib or pazopanib) between February 2009 and March 2017 in a single academic Brazilian cancer center (Instituto do Câncer do Estado de São Paulo). Results Of the 222 patients, 109 were treated with sunitinib and 113 with pazopanib. The median duration of treatment and overall survival (OS) were 6.4 and 15.2 months for sunitinib and 6.7 and 14.2 months for pazopanib, respectively. Discontinuation of treatment occurred secondarily to progressive disease or death in 64.2% of patients using sunitinib and in 54.8% of patients using pazopanib. Adverse events were responsible for discontinuation of treatment in 28.4% of patients in the sunitinib group and in 22.1% in the pazopanib group. According to Memorial Sloan-Kettering Cancer Center risk categories, the OS was 32.9 months, 15.9 months, and 8.1 months for low risk, intermediate risk, and poor risk, respectively (hazard ratio, 1.72; 95% CI, 1.13 to 2.26; P < .001). Conclusion The use of TKI inhibitors as first-line treatment of metastatic RCC is effective and feasible in the Brazilian public health. However, the median OS of our population is considerably lower compared with the prospective trials that evaluated the same drugs.
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Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Sunitinib/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Brasil , Carcinoma de Células Renales/secundario , Supervivencia sin Enfermedad , Femenino , Humanos , Indazoles , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Based on currently available genomic data, most head and neck squamous cell carcinoma have few targetable aberrations and immediate clinical translation is challenging. However, potential therapeutic agents listed in this article need to be thoroughly evaluated because there are compelling scientific rationales supporting their development. Concerted effort is required to identify better predictive biomarkers of clinical benefit and improve the therapeutic index. Clinicians need to better understand resistance mechanisms, generate novel hypotheses for appropriate combination regimens and dosing schedules, develop more accurate model systems, and conduct innovative clinical trials.