ABSTRACT
More than 20% of metastatic prostate cancer carries genomic defects involving DNA damage repair pathways, mainly in homologous recombination repair-related genes. The recent approval of olaparib has paved the way to precision medicine for the treatment of metastatic prostate cancer with PARP inhibitors in this subset of patients, especially in the case of BRCA1 or BRCA2 pathogenic/likely pathogenic variants. In face of this new therapeutic opportunity, many issues remain unsolved. This narrative review aims to describe the relationship between homologous recombination repair deficiency and prostate cancer, the techniques used to determine homologous recombination repair status in prostate cancer, the crosstalk between homologous recombination repair and the androgen receptor pathway, the current evidence on PARP inhibitors activity in metastatic prostate cancer also in homologous recombination repair-proficient tumors, as well as emerging mechanisms of resistance to PARP inhibitors. The possibility of combination therapies including a PARP inhibitor is an attractive option, and more robust data are awaited from ongoing phase II and phase III trials outlined in this manuscript.
Subject(s)
Poly(ADP-ribose) Polymerase Inhibitors , Prostatic Neoplasms , Recombinational DNA Repair , Humans , Male , Prostatic Neoplasms/genetics , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , BRCA2 Protein/genetics , BRCA2 Protein/deficiency , Neoplasm Metastasis , BRCA1 Protein/genetics , BRCA1 Protein/deficiency , Phthalazines/therapeutic use , Phthalazines/pharmacology , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , PiperazinesABSTRACT
Endometrial cancer (EC) incidence and mortality rates have been increasing, particularly among young females. Although more than 90% of ECs are sporadic, 5-10% are hereditary, a majority of which occurs within Hereditary Non-Polyposis Colorectal Cancer syndrome (HNPCC) or Lynch syndrome. The traditional histopathological classification differentiates EC between two main groups: type I (or endometrioid) and type II (including all other histopathological subtypes). However, this classification lacks reproducibility and does not account for the emerging molecular heterogeneity. In 2013, The Cancer Genome Atlas (TCGA) project proposed EC molecular classification defining four groups with different prognostic and predictive values and the current international guidelines are progressively establishing EC risk stratification and treatment based on both histopathological and molecular criteria. Our manuscript aims to summarize the current state of EC molecular characterizations, including germline alterations at the basis of hereditary EC predisposition, to discuss their clinical utility as prognostic and predictive markers.
Subject(s)
Endometrial Neoplasms , Female , Humans , Biomarkers, Tumor/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/therapy , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Endometrial Neoplasms/genetics , Endometrial Neoplasms/therapy , Endometrial Neoplasms/pathology , PrognosisABSTRACT
BACKGROUND: Ovarian cancer is metastatic at presentation in about 62% of cases, but brain metastases are rare, reported in 3.3-4% of patients. Brain metastasis seems to be more frequent in advanced stages at diagnosis and in patients with BRCA1/2 mutation. CASE PRESENTATION: We present a case of a 47-year-old Caucasian woman, BRCA wild type, with an ovarian cancer that started with single cerebellar metastasis. CONCLUSION: Brain metastases in ovarian cancer are rare and complex for diagnosis and management. This case focuses both on diagnosis and treatment, emphasizing the importance of a multimodal approach in a multidisciplinary team.
Subject(s)
Brain Neoplasms , Ovarian Neoplasms , Humans , Female , Middle Aged , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Ovarian Neoplasms/pathology , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/therapy , Brain Neoplasms/geneticsABSTRACT
Clinically relevant bone metastases are a major cause of morbidity and mortality for prostate cancer patients. Distinct phenotypes are described: osteoblastic, the more common osteolytic and mixed. A molecular classification has been also proposed. Bone metastases start with the tropism of cancer cells to the bone through different multi-step tumor-host interactions, as described by the "metastatic cascade" model. Understanding these mechanisms, although far from being fully elucidated, could offer several potential targets for prevention and therapy. Moreover, the prognosis of patients is markedly influenced by skeletal-related events. They can be correlated not only with bone metastases, but also with "bad" bone health. There is a close correlation between osteoporosis-a skeletal disorder with decreased bone mass and qualitative alterations-and prostate cancer, in particular when treated with androgen deprivation therapy, a milestone in its treatment. Systemic treatments for prostate cancer, especially with the newest options, have improved the survival and quality of life of patients with respect to skeletal-related events; however, all patients should be evaluated for "bone health" and osteoporotic risk, both in the presence and in the absence of bone metastases. Treatment with bone-targeted therapies should be evaluated even in the absence of bone metastases, as described in special guidelines and according to a multidisciplinary evaluation.
