Quadruple Primary Malignancies over 2 Years with Germline Mutation in Krebs Cycle Enzyme Gene Fumarate Hydratase.

Multiple primary cancers (MPCs) are defined as the presence of more than one cancer in an individual that is not due to recurrence, metastasis, or local spread. Different factors such as copathogenic genetic mutations, environmental factors, lifestyle, and first cancer treatment increase the possible occurrence of subsequent malignancies. In recent years, the risk of MPCs has increased due to improved treatment; however, quadruple primary malignancies are still rare and require further investigation and treatment of the underlying cause. Here, we present a 64-year-old man with a 40-year history of cigarette smoking who developed quadruple primary malignancies of the epiglottis, kidney, pancreas, and lung. To investigate the possible genetic cause, we performed WES, and a variant of c.580G > A (Ala194Thr) was discovered in exon 5 of the Krebs cycle enzyme gene, fumarate hydratase (FH). This substitution was classified as VUS in Clinvar and likely pathogenic by Varsome and Franklin software. The structural analysis showed that the variation found was localized in a highly conserved alpha helix in the D2 domain near the FH hinge region (<6 Å), suggesting that enzyme activity was affected by a perturbation in protein quaternary structure. Because of the well-established role of FH mutations in renal cancer risk, it was possible that the FH mutation could have led to the development of renal cell carcinoma in this case. The biological mechanisms of MPCs suggest that subsequent primary malignancies are triggered by the combined effects of environmental factors, such as smoking and genetics.

Predictive factors for response to abiraterone in metastatic castration refractory prostate cancer.

BACKGROUND: Management of metastatic castration refractory prostate cancer (CRPC) is rapidly evolving. Rationalisation of treatment requires identification of those patients more likely to benefit from a particular therapy. We reviewed the outcome of patients treated with abiraterone at our Institution to describe factors predictive for response. PATIENTS AND METHODS: Patients with CRCP treated with abiraterone were identified. Baseline variables and potential prognostic factors were extracted from electronic records. Outcome measures included overall survival (OS), prostate-specific antigen (PSA) response and time to PSA progression (TTPP). The Kaplan-Meier method and Cox proportional hazards model were used to analyze survival data. RESULTS: A total of 61 patients met the inclusion criteria. In multivariate analysis, three independent predictors of OS were identified: Duration of response to androgen deprivation therapy (ADT) (hazard ratio(HR)=0.95, p=0.006), performance status (HR=7.4, p=0.013), and baseline haemoglobin (HR=0.47, p≤0.001). CONCLUSION: This study has identified three factors predictive for response to abiraterone in CRPC. Duration of response to ADT has not been previously shown to be a predictive factor for patients with CRCP. We suggest that a prospective validation is required.