Pain predicts overall survival in men with metastatic castration-resistant prostate cancer treated with radium-223

Giandomenico Roviello,1 Rosj Gallicchio,2 Giovanni Bozza,1 Maria Grazia Rodriquenz,1 Michele Aieta,1 Giovanni Storto2 1Division of Medical Oncology, Department of Onco-Hematology, IRCCS CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy; 2Nuclear Medicine Department, IRCCS CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy Background: Radium-223 dichloride is an alpha emitter approved for metastatic castration-resistant prostate cancer (mCRPC). Unfortunately, little data are available on the prognostic factors during radium-223-based therapy.Patients and methods: Patients with histologically confirmed progressive CRPC with two or more bone metastases and symptomatic disease were eligible. Previous therapy with a novel hormonal therapy was allowed. The patients received six intravenous injections of radium-223 every 4 weeks. A visual analog scale (VAS) was adopted to evaluate patients’ basal pain.Results: A total of 25 patients were evaluated. Of these, 6 (24%) reported VAS <4. After a median follow-up of 8 months, all patients died with a median overall survival of 8.3 months (95% CI: 5.2–11.8 months), 12.6 months in the patients with VAS <4 vs 6.6 months in the patients with VAS ≥4 (P=0.03).Conclusion: The present study suggests that VAS could be prognostic of the survival of mCRPC treated with radium-223 irrespective of the limitations of a small number of patients and the retrospective nature of the data. Keywords: radium-223, pain, prostate cancer, radioactive therap

Association of IL-8 and eNOS polymorphisms with clinical outcomes in bevacizumab-treated breast cancer patients: an exploratory analysis

Background: The role of bevacizumab in metastatic breast cancer is controversial. Identification of predictive biomarkers could help to select patients who really benefit from it. We evaluated the association of angiogenesis-related gene polymorphisms with the treatment outcome of bevacizumab in metastatic breast cancer patients. Patients and methods: eNOS-786T/C and -894G/T, IL-8-251T/A genomic polymorphisms were assessed in 31 metastatic breast cancer patients treated with bevacizumab plus chemotherapy in the first-line setting. Testing for association between each polymorphism and treatment outcome was performed. Results: Patients with IL-8 251 AA genotype showed a significantly lower progression-free survival in each combination comparison: "TT" vs "AA" (13 vs 8 months; p = 0.008); TT vs TA vs AA (13 vs 11 vs 8 months; p = 0.02); TT vs TA +AA (13 vs 11 months; p = 0.01); TT + TA vs AA (12 vs 8 months; p = 0.01) and a lower overall survival when compared with TT +TA genotype (26 vs 51 months, p = 0.04). Patients carrying eNOS 894 TT genotype showed a statistically significant lower progression-free survival than patients with GG genotype (11.5 vs 26.5 months; p = 0.04) with no differences in the overall survival. No association with response rate was found with any of the polymorphisms analyzed. Conclusion: These findings suggest that IL-8 251T/A and eNOS-894 G/T polymorphisms might have a role in predicting treatment outcome of bevacizumab in metastatic breast cancer. Our results are hypothesis generating and need to be confirmed in larger clinical trials

Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer.

Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies