Achievement of therapeutic mitotane concentrations in management of advanced adrenocortical cancer: a single centre experience in 47 patients

Introduction: Multi-modal therapy for adrenocortical carcinoma (ACC) includes surgery, therapy with the adrenolytic agent mitotane and systemic chemotherapy. Achievement of therapeutic mitotane concentrations (≥14 mg/l) has been related to improved outcomes. Aim: To evaluate the effectiveness of a defined* high dose protocol mitotane therapy in patients with advanced ACC (stages III and IV). Methods: Review of patients presenting to KCH with stage III or IV ACC and the mitotane concentration achieved through the Lysosafe monitoring service. Results: N=57 patients were referred and first diagnosed with ACC (2008-17) of whom 44 patients had stage III or IV disease at diagnosis and were managed actively with surgery and/or mitotane therapy. 40/44 patients underwent surgical resection of the primary tumour;11/22 patients with stage IV disease subsequently received systemic chemotherapy [10 patients received a combination of etoposide, doxorubicin and cisplatin (EDP) and 1 patient received a combination of carboplatin and etoposide]. 38/44 patients were initiated on mitotane therapy. The median overall survival of patients with stage IV disease was 25.3 months. The median survival for stage III has not been reached. An additional 9 patients had prior management, including surgery, elsewhere and were referred for mitotane initiation. A total of 47 patients were therefore included in the mitotane pharmacokinetic analysis. Six patients were excluded: 3 patients died shortly after mitotane initiation, 1 patient withdrew due to a severe reaction and 2 patients had not completed 12 weeks therapy at the time of submission. Of the remaining 41 patients, 33 commenced the ‘high dose’ protocol and the remainder the ‘low dose’ protocol. For patients on the high dose protocol, 25/33 (76%) reached a mitotane concentration ≥14 mg/l within 12 weeks of initiation of therapy, compared to 3 patients from the low dose protocol group (P=0.084). In the high dose protocol group, 21 patients (84%) maintained therapeutic drug concentrations in ≥50% of the subsequent follow-up samples and 12 patients (48%) maintained therapeutic drug concentrations in ≥75% of subsequent samples. Conclusion: The use of high dose protocol mitotane therapy is a successful strategy to achieve and maintain therapeutic drug concentrations when treating patients with advanced ACC (stages III and IV). In combination with an assertive surgical approach and optimal chemotherapy, this has resulted in outcomes that compare favourably (median OS 25.5 months in stage IV disease) with previously published series which describe a median OS <12 months

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 G12 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