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M.G. Zauderer



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    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 1
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      MO09.04 - Defining BAP1 Syndrome: Preliminary results from an epidemiologic ascertainment study (ID 3437)

      16:15 - 17:45  |  Author(s): M.G. Zauderer

      • Abstract
      • Presentation
      • Slides

      Background
      Identifying tumorigenic mutations in malignant pleural mesothelioma (MPM) is essential to advance therapy. Somatic mutations in the BRCA-1 associated protein-1 (BAP1) gene occur in about 20% of MPM tumors (Bott et al., Nature Genetics, 2011). In a retrospective analysis evaluating demographics, exposures, and survival, a history of smoking was the only clinical feature associated with the presence of BAP1 mutations (Zauderer et al., in press, J Thorac Oncol, 2013). Germline BAP1 mutations have also been identified in families predisposed to MPM (Testa et al., Nature Genetics, 2011). BAP1 germline mutations have also been associated with other tumors including atypical Spitz nevi, uveal melanoma, and renal cell carcinoma. These discoveries suggest that BAP1 mutations in mesothelioma represent part of a new hereditary cancer syndrome but the exact clinical phenotype remains unclear. To establish the frequency of germline BAP1 mutations in MPM patients and to accurately assess exposure history and family histories in these patients, we have undertaken a clinical trial to prospectively collect this information from patients with MPM.

      Methods
      All consenting patients provide a saliva or blood specimen from which germline DNA is extracted. Existing tumor samples are collected and analyzed for BAP1 mutation. Everyone completes a questionnaire regarding asbestos exposure, personal cancer history, and family history of malignancy. First, we will perform a de-identified assessment of the prevalence of germline BAP1 mutation. Patients whose tumors harbor BAP1 mutation and/or meet prespecified high risk criteria will be approached for identified germline testing after appropriate pre-test counseling. Mutations identified through research testing with be confirmed with clinical testing and additional genetic counseling will be undertaken. Testing will be offered to family members of patients with identified BAP1 germline mutations. Please see Figure 1 for study flow. Figure 1

      Results
      During the first 3 months that this protocol was open, we accrued 26 patients with mesothelioma, 15 of whom qualify for identified research testing. We will present results from ongoing testing at the meeting.

      Conclusion
      Recruiting patients to perform both de-identified and identified germline testing is feasible. Given the paucity of information regarding penetrance and appropriate screening interventions, BAP1 germline testing should continue only in the context of research programs. Additional preclinical work is ongoing to exploit this potential therapeutic target. Supported, in part, by a grant from the Mesothelioma Applied Research Foundation.

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    P1.14 - Poster Session 1 - Mesothelioma (ID 194)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P1.14-002 - Lack of response to chemotherapy for previously treated malignant pleural mesothelioma (MPM) (ID 656)

      09:30 - 16:30  |  Author(s): M.G. Zauderer

      • Abstract

      Background
      After initial therapy with pemetrexed/platinum, second-line therapy options are not well established. Gemcitabine and vinorelbine are often used based on small trials and first-line data. To augment the existing data, we examined our institutional experience using vinorelbine and gemcitabine in patients with previously treated MPM.

      Methods
      We reviewed the records of all patients treated with vinorelbine and/or gemcitabine as second- or third-line therapy for MPM between 2003 and 2010. Vinorelbine was administered at a dose of 25 mg/m[2] days 1 and 8 in a 3-week cycle and gemcitabine was given at 1000 mg/m[2] days 1, 8, and 15 in 28 day cycles. CT scans were generally performed after every two cycles. Imaging studies were reviewed with a radiologist according to the modified RECIST criteria.

      Results
      60 patients were identified: 33 treated with vinorelbine, 15 with gemcitabine, and 12 with both. Patient characteristics are as follows: 78% men: median age 67 (range 41-85); 63% epithelioid, 19% mixed histology, and 18% sarcomatoid; 83% received first-line pemetrexed-platinum therapy and 10% gemcitabine-platinum therapy. One partial radiographic response was identified among the 56 patients with follow up imaging available for review (Figure 1) giving a response rate of 2% (95% CI 0-5%). With gemcitabine, 10 patients (37%) had radiographic progression, 6 (22%) had clinical progression, 6 (22%) had radiographic stable disease, 4 (15%) had clinically stable disease, and 1 (4%) had radiographic partial response. With vinorelbine, 20 patients (43%) had radiographic progression, 2 (4%) had clinical progression, 19 (42%) had radiographic stable disease, 4 (8%) had clinically stable disease, and there were no responses. 53% experienced at least one episode of grade 3-4 toxicity, most commonly anemia, neutropenia, fatigue, and neutropenic fever. 24 patients received more than 2 cycles. Median progression free survival was 1.6 months and median overall survival was 5 months. Figure 1

      Conclusion
      Response to second-line therapy with gemcitabine or vinorelbine is rare. The rate of stable disease suggests some level of activity of these agents. Therefore, it remains a reasonable standard therapeutic option. However, survival was comparable to the placebo arm in the phase III vorinostat trial (Krug, ECCO/ESMO, 2011). This lack of efficacy supports the use of placebo control arms in randomized second-line MPM trials. Novel therapies are desperately needed for this patient population.