Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy.

PURPOSE: This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance. PATIENTS AND METHODS: Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors. RESULTS: ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts. CONCLUSION: Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

Development and validation of a colon cancer risk assessment tool for patients undergoing colonoscopy.

OBJECTIVES: Diagnostic criteria for hereditary colorectal cancer (CRC) are complex. "Open-access" colonoscopy makes it challenging to identify who needs genetic evaluation, intensive surveillance, and screening for extracolonic tumors. Our aim was to develop a simple, preprocedural risk assessment tool to identify who may be at highest risk for CRC. METHODS: A total of 631 outpatients undergoing colonoscopy at two academic practices completed a questionnaire assessing personal and family histories of CRC, polyps, and Lynch syndrome (LS)-associated malignancies. Subjects were considered to be high-risk if one of the nine prespecified characteristics of hereditary CRC syndromes was met. Through recursive partitioning analysis, an algorithm of fewest questions needed to capture the most high-risk individuals was developed. The results were validated in 5,335 individuals undergoing colonoscopy at five private endoscopy centers and tested in 285 carriers of mismatch repair mutations associated with LS. RESULTS: About 17.7% and 20.0% of individuals were classified as high-risk in the development and validation cohorts, respectively. Recursive partitioning revealed three questions that were most informative for identifying high-risk patients: (i) "Do you have a first-degree relative with CRC or LS-related cancer diagnosed before age 50?" (ii) "Have you had CRC or polyps diagnosed before age 50?" (iii) "Do you have > or =3 relatives with CRC?" When asked successively, these questions identified 77% of high-risk individuals in both cohorts and 271 of 285 (95%) of mutation carriers. CONCLUSIONS: Approximately one in five individuals undergoing colonoscopy would benefit from further risk assessment. We developed a simple, three-question CRC Risk Assessment Tool to identify the majority of patients who require additional assessment and possible genetic evaluation.

Genetic counseling program in familial breast cancer: analysis of its effectiveness, cost and cost-effectiveness ratio.

Women with a family history of breast cancer are at increased risk for developing this neoplasm. Starting surveillance more frequently at a younger age than the general population and the possibility of undergoing genetic testing are options for their medical management. We analyzed the benefits and costs of our clinical program in familial breast cancer (FBC) and carried out a cost-effectiveness analysis of such procedure. The benefits and costs of performing genetic counseling and a screening program in FBC based on 143 high-risk families registered in our database between June 1995 and December 2001 were analyzed. A decision tree was constructed to estimate the survival benefit and cost-effectiveness of the clinical genetic counseling program compared with the strategy of not performing any screening protocol. We estimated that the prevalence of a BRCA mutation in an unaffected relative of our high-risk cohort was 10% and that 53% of the mutations are found in the BRCA1 gene. We assigned a 58.5% lifetime risk of breast cancer for a 30-year-old mutation carrier according to the SEER data. The effectiveness of the screening was obtained from our experience and data for estimating survival were derived from other studies with longer follow-up. We used our local payment data to calculate the costs of the program. A mutation in the BRCA1 or BRCA2 genes was identified in 20% of the probands. Seventy primary breast cancer cases were recorded since the onset of the program. Thirty percent of the tumors were diagnosed through the screening program and 71% of them were lymph node-negative compared to 49% of the tumors diagnosed outside the program (p=0.1). The cost-effectiveness ratio of our FBC genetic counseling and screening program was 4,294 euros per life-year gained. The model was sensitive to the prevalence of mutation carriers, the lifetime risk of breast cancer and the effectiveness of the screening. In our setting and according to our model, this analysis suggests that a program of genetic testing and screening for breast cancer in a high-risk population may be cost-effective. These results need to be confirmed as more effective interventions for cancer prevention and screening are being implemented.