Search

BRCA1 and BRCA2 are the most frequently mutated genes in ovarian cancer (OC) crucial both for the identification of cancer predisposition and therapeutic choices. However, germline variants in other genes could be involved in OC susceptibility. We characterized OC patients to detect mutations in genes other than BRCA1/2 that could be associated with a high risk of developing OC and permit patients to enter the most appropriate treatment and surveillance program. Next-generation sequencing analysis with a 94-gene panel was performed on germline DNA of 219 OC patients. We identified 34 pathogenic/likely pathogenic variants in BRCA1/2 and 38 in other 21 genes. The patients with pathogenic/likely pathogenic variants in the non-BRCA1/2 genes mainly developed OC alone compared to the other groups that also developed breast cancer or other tumors (p = 0.001). Clinical correlation analysis showed that the low-risk patients were significantly associated with platinum sensitivity (p < 0.001). Regarding PARP inhibitors (PARPi) response, the patients with pathogenic mutations in the non-BRCA1/2 genes had worse PFS and OS. Moreover, a statistically significantly worse PFS was found for every increase of one thousand platelets before PARPi treatment. To conclude, knowledge about molecular alterations in genes beyond BRCA1/2 in OC could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies for OC patients.

Background: Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain identify mCRPC patients with worse outcomes. This study aimed to assess if ctDNA associates with PSA kinetics. Methods: In this prospective biomarker study, we evaluate ctDNA fraction and AR CN from plasma samples. We divided patients into high and low ctDNA level and in AR gain and AR normal. Results: 220 baseline samples were collected from mCRPC treated with abiraterone (n = 140) or enzalutamide (n = 80). A lower rate of PSA decline ≥ 50% was observed in patients with high ctDNA (p = 0.017) and AR gain (p = 0.0003). Combining ctDNA fraction and AR CN, we found a different median PSA progression-free survival (PFS) among four groups: (1) low ctDNA/AR normal, (2) high ctDNA/AR normal, (3) low ctDNA/AR gain, and (4) high ctDNA/AR gain (11.4 vs. 5.0 vs. 4.8 vs. 3.7 months, p < 0.0001). In a multivariable analysis, high ctDNA, AR gain, PSA DT, PSA DT velocity remained independent predictors of PSA PFS. Conclusions: Elevated ctDNA levels and AR gain are negatively and independently correlated with PSA kinetics in mCRPC men treated with abiraterone or enzalutamide.

Gynecological tumors are malignancies with both high morbidity and mortality. To date, only a few chemotherapeutic agents have shown efficacy against these cancer types (only ovarian cancer responds to several agents, especially platinum-based combinations). Within this context, the discovery of immune checkpoint inhibitors has led to numerous clinical studies being carried out that have also demonstrated their activity in these cancer types. More recently, following the development of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, this strategy was also tested in solid tumors, including gynecological cancers. In this article, we focus on the molecular basis of gynecological tumors that makes them potential candidates for immunotherapy. We also provide an overview of the main immunotherapy studies divided by tumor type and report on CAR technology and the studies currently underway in the area of gynecological malignancies.

The therapeutic landscape of prostate cancer has expanded rapidly over the past 10 years, and there is now an even greater need to understand the biological mechanisms of resistance and to develop noninvasive biomarkers to guide treatment. The androgen receptor (AR) is known to be involved in the pathogenesis and progression of prostate cancer. Recently, highly sensitive next-generation sequencing and PCR-based methods for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma were established in cell-free DNA (cfDNA) of patients with castration-resistant prostate cancer (CRPC) treated with different drugs. The study of cfDNA holds great promise for improving treatment in CRPC, especially in the advanced stage of the disease. Recent findings showed the significant association of plasma AR aberrations with clinical outcome in CRPC patients treated with AR-directed therapies, whereas no association was observed in patients treated with taxanes. This suggests the potential for using plasma AR as a biomarker for selecting treatment, i.e., hormone therapy or chemotherapy, and the possibility of modulating taxane dose. In recent years, plasma AR status has also been investigated in association with novel agents, such as 177Lu-PSMA radioligand therapy and PARP inhibitors. This review will focus on AR testing in plasma that may have clinical utility for treatment selection in advanced prostate cancer.

In the last few years, substantial progress has been made in the treatment of ovarian cancer, with increased knowledge about the biology of the disease. Ovarian cancer is a neoplasm strongly linked to defects in DNA repair mechanisms, where deficiency in the homologous recombination (HR) system results in a better response of ovarian cancers to therapy, whether platinum-based chemotherapy, anthracyclines, or poly (ADP-ribose) polymerase (PARP) inhibitors. More recently, it has been demonstrated that different ovarian cancer histotypes may have different immunogenicity. Interestingly, defects in HR systems are associated more frequently with higher tumor infiltrating lymphocytes, providing a rationale for developing combination therapy with immune-modulating agents and PARP inhibitors. Again, locoregional therapies combining heat shock and chemotherapy delivery have been shown to induce an anticancer immune response in vitro. Thus, the potential for locoregional therapeutic approaches that may impact the immune system, perhaps in combination with immune-modulating agents or PARP inhibitors, needs to be further explored. With this premise, we reviewed the main biological and clinical data demonstrating a strict interplay between the immune system, DNA repair mechanisms, and intraperitoneal therapies in ovarian cancer, with a focus on potential future therapeutic implications.

Prostate cancer is one of the most common malignant neoplasms in men worldwide, and is the fifth cause of cancer-related death. In recent years, a new generation of therapies have been approved for the management of metastatic disease. Moreover, the development of new immunotherapeutic drugs has become a novel frontier for the treatment of several tumor types; to date, numerous studies have investigated their potential activity, including in prostate cancer. In this article, we discuss the role of emerging immunotherapeutic drugs in prostate cancer patients.