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L.M. Krug

Moderator of

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    MS 08 - BAP1 Cancer Syndrome and Mesothelioma (ID 26)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 4
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      MS08.01 - Mesothelioma and BAP1 Germline Mutations (ID 1877)

      14:20 - 14:40  |  Author(s): M. Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS08.02 - BAP1 and Ubiquitination (ID 1878)

      14:40 - 15:00  |  Author(s): E.B. Affar

      • Abstract
      • Presentation

      Abstract:
      The deubiquitinase (DUB) BAP1 recently emerged as a major tumor suppressor inactivated in several malignancies notably mesothelioma. With the aim of defining the BAP1 mechanism of action, we previously conducted a tandem affinity immunopurification of BAP1-associated proteins and found that most of the interacting partners are transcription factors and cofactors. Notably, BAP1 forms a complex with the Host Cell Factor (HCF-1), the O-linked N-acetyl-Glucosamine Transferase (OGT), the Lysine Specific Demethylase KDM1B, the Additional Sex Comb Like proteins ASXL1 and ASXL2 (ASXL1/2), the Forkhead Box transcription factors FOXK1 and FOXK2 as well as the zinc finger transcription factor Yin Yang 1 (YY1). We found that BAP1 regulates the expression of genes involved in cell proliferation and is recruited to gene regulatory regions to activate transcription. BAP1 is also recruited to the site of DNA double strand breaks to promote repair by homologous recombination. Moreover, this DUB appears to be also finely regulated by post-translational modifications including phosphorylation and ubiquitination. Interestingly, the ortholog of BAP1 in drosophila, named Calypso, deubiquitinates histone H2A on lysine 119 (H2Aub). H2Aub is a critical epigenomic modification involved in transcriptional and DNA repair, and is associated with stem cell function, development, cell proliferation and cancer. Calypso associates with Additional Sex Comb (ASX) and forms the Polycomb Repressive DUB (PR-DUB) complex. Recently, we provided insights into the importance of BAP1-interacting partners, ASXL1 and ASXL2 (two orthologs of ASX) in promoting H2A deubiquitination. We found that BAP1 forms two mutually exclusive complexes with ASXL1 and ASXL2. ASXL1 and ASXL2 use their highly conserved ASXM domain to interact with the C-terminal domain (CTD) of BAP1, and these factors regulate each other’s protein stability. Significantly, through mutational analysis, we found that ASXM enhances BAP1 binding to ubiquitin and stimulates its DUB activity. Importantly, these functions require intramolecular interactions in BAP1 that generate a Composite Ubiquitin Binding Interface (CUBI). Gain and loss of function studies indicated that BAP1, ASXL1 and ASXL2 play critical roles in the coordination of cell cycle progression. Notably, overexpression of BAP1 or ASXL2 trigger the p53/p21 DNA damage response and cellular senescence, and these effects are abolished by mutations of the CTD or ASXM interaction domains. Furthermore, we showed that cancer-associated inactivation of BAP1/ASXL1/2 DUB activity disrupts coordination of cell proliferation. Altogether, our results indicate that the mammalian BAP1 is an authentic DUB for H2A that regulates chromatin function and exerts a tight control on cell cycle progression. Moreover, our studies provide a mechanistic link between H2A deubiquitination, BAP1 interacting partners and tumor suppression.

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      MS08.03 - Screening for BAP1 in Danish Families (ID 1879)

      15:00 - 15:20  |  Author(s): K. Wadt, L. Aoude, N.K. Hayward, A. Gerdes

      • Abstract
      • Slides

      Abstract:
      Background: BRCA1 associated protein-1 (BAP1) is a tumor suppressor gene that encodes a deubiquitinase involved in cell cycle regulation, cellular differentiation, and cell death (Carbone et al., 2013; Murali, Wiesner, & Scolyer, 2013). BAP1 is recruited to double-stand DNA breaks and promotes error-free DNA-repair (Yu et al., 2014). Germline BAP1 mutations have been identified in around 40 families with accumulation of mesothelioma, uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and basal cell carcinoma (BCC) (Carbone et al., 2013; Wadt et al., 2014; Wiesner et al., 2011). Speculation exists as to whether BAP1 germline mutation carriers with mesothelioma, UM or RCC have different prognosis compared to non-carriers with the same types of cancer. Somatic BAP1 mutations have been identified in approximately 20% of pleural malignant mesotheliomas (Zauderer MG, Bott M, McMillan R, Sima CS, Rusch V, Krug LM, Ladanyi M, 2013), with most studies reporting no significant differences in the histopathological features or survival of patients with BAP1 mutant compared to wild-type tumors. A recent study of Portuguese siblings discovered a germline BAP1 mutation as the possible cause of the only known familial clustering of well-differentiated papillary mesothelioma (WDPM), a rare subtype of epithelioid mesothelioma (Ribeiro et al., 2013), and there has since been another report of WDPM in a carrier of a germline BAP1 mutation (Pilarski et al., 2014). Previously, some patients with germline BAP1 mutations and malignant mesotheliomas have been reported as long-term survivors, which is very rare for mesotheliomas, raising the possibility that such tumors may be associated with more favorable prognosis (Ribeiro et al., 2013; Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, Kutzner H, Lax S, Smolle-Jüttner F, Geigl JB, 2014). In contrast, somatic BAP1 mutations or loss of BAP1 have been associated with high-grade tumors or disseminated disease in sporadic RCC and UM patients, which could indicate a worse prognosis for carriers of germline BAP1 mutations with these tumor types. Clearly, further studies are necessary to clarify whether BAP1 germline mutation carriers with various cancers have altered prognosis relative to individuals who acquire somatic mutations in BAP1. Here, we sought to determine the frequency of germline BAP1 mutations in cancer prone families with accumulation of mesothelioma, UM, CM and RCC. Methods: Families were collected through the Danish melanoma registry and through Clinical Genetic Departments in Denmark. Families, who previously had received genetic counselling regarding mesothelioma, CM, UM, and RCC, were contacted. Results: In total we analysed 152 Danish families and found five with BAP1 mutations, which are described in Table 1. We analysed 127 CM patients, who were either young onset (<40 years), had multiple primary CM, or had a family history of melanoma, and found no BAP1 mutation. We analysed 22 sporadic cases of UM or familial cases of CM, with one case of UM in the family and found no BAP1 mutation. However, in 6 melanoma families with two cases of UM, we found 4 families with BAP1 mutation, and 2 of 3 families analysed with 2 or more cases of mesothelioma carried BAP1 mutations. We found that the strongest indicator of a germline BAP1 mutation, were families with two or more cases of mesotheliomas or UM. In 40% of families with the occurrence of mesothelioma and CM we also found BAP1 mutations but did not find BAP1 mutations in families with only CM or RCC, or families with CM and RCC. Table 1: Characterization of Danish BAP1 mutation-positive families

      Family Mutation Cases of UM/No. of mutation carriers Cases of mesothelioma/ No. of mutation carriers Cases of CM/No. of mutation carriers Other types of cancer in mutation carriers
      A c.1708C>G p.L570V 3/14 2/14 1/14 Paraganglioma, Sarcoma
      B c.581-2A>G Splice defect 7/9 0/9 1/9 Lung
      C c.1209_1210dupT p.D404X 0/8 3/8 2/8 BCC, Breast, unknown primary
      D c.178C>T p.R60X 3/10 0/10 2/10 BCC, ovary
      E c.178C>T p.R60X 2/4 1/4 0/4 BCC
      Total 15/45(33%) 6/45(13%) 6/45(13%)
      13% of BAP1 mutation carries developed mesothelioma, 33% developed UM, and 13% developed CM. There were no cases of RCC in the 5 Danish BAP1 mutation-positive families. Conclusion: In the Danish BAP1 mutation carriers we observed rare tumor types (pericardial paraganglioma and malignant fibrous histiocytoma) and three cases of unknown primary tumors. At present there is no international consensus about a surveillance program for BAP1 mutation carriers. Since BAP1 contributes to a rare, recently discovered cancer syndrome, there is as yet no documented reduction of morbidity or mortality to persons following surveillance. To obtain such empirical data we offer persons carrying a pathogenic BAP1 mutation a surveillance program consisting of yearly ophthalmological and dermatological examination from the age of 15. In addition, from the age of 25, we offer ultrasound examination of the kidneys every second year. We inform the patient and their general practitioners of the increased cancer risk, and signs which should prompt further symptom-related investigations. At the moment, we have not established a surveillance program for mesothelioma. References: Carbone, M., Yang, H., Pass, H. I., Krausz, T., Testa, J. R., & Gaudino, G. (2013). BAP1 and cancer. Nature Reviews. Cancer, 13, 153–9. doi:10.1038/nrc3459 Murali, R., Wiesner, T., & Scolyer, R. a. (2013). Tumours associated with BAP1 mutations. Pathology, 45, 116–26. doi:10.1097/PAT.0b013e32835d0efb Pilarski, R., Cebulla, C. M., Massengill, J. B., Rai, K., Rich, T., Strong, L., … Abdel-Rahman, M. H. (2014). Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. Genes Chromosomes and Cancer, 53, 177–182. doi:10.1002/gcc.22129 Ribeiro, C., Campelos, S., Moura, C. S., Machado, J. C., Justino, A., & Parente, B. (2013). Well-differentiated papillary mesothelioma: Clustering in a Portuguese family with a germline BAP1 mutation. Annals of Oncology, 24, 2147–2150. doi:10.1093/annonc/mdt135 Wadt, K. A. W., Aoude, L. G., Johansson, P., Solinas, A., Pritchard, A., Crainic, O., … Hayward, N. K. (2014). A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma. Clinical Genetics. doi:10.1111/cge.12501 Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, Kutzner H, Lax S, Smolle-Jüttner F, Geigl JB, S. M. (2014). J OURNAL OF C LINICAL O NCOLOGY Toward an Improved Definition of the Tumor Spectrum Associated With BAP1. Journal of Clinical Oncology, 30(32), 2012–2015. Wiesner, T., Obenauf, A. C., Murali, R., Fried, I., Griewank, K. G., Ulz, P., … Speicher, M. R. (2011). Germline mutations in BAP1 predispose to melanocytic tumors. Nature Genetics, 43(10), 1018–21. doi:10.1038/ng.910 Yu, H., Pak, H., Hammond-Martel, I., Ghram, M., Rodrigue, A., Daou, S., … Affar, E. B. (2014). Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proceedings of the National Academy of Sciences of the United States of America, 111, 285–90. doi:10.1073/pnas.1309085110 Zauderer MG, Bott M, McMillan R, Sima CS, Rusch V, Krug LM, Ladanyi M. (2013). Clinical Characteristics of Patients with Malignant Pleural. Journal of Thoracic Oncology, 8(11), 1430–1433.

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      MS08.04 - BAP1: Lessons from Renal Cell Carcinoma (ID 1880)

      15:20 - 15:40  |  Author(s): J. Brugarolas

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MINI 27 - Biology and Other Issues in SCLC (ID 152)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      MINI27.11 - Comprehensive Mutation Analysis of Never-Smokers with Small Cell Lung Cancer (SCLC) (ID 3135)

      17:45 - 17:50  |  Author(s): L.M. Krug

      • Abstract
      • Presentation
      • Slides

      Background:
      Although most patients with SCLC are current or former smokers, this disease has been reported in never-smokers. In our prospective genomic profiling of SCLC patients, we have identified four never-smokers. Here, we report next generation sequencing (NGS) results for these four SCLC patients and describe how they differ from those of smokers.

      Methods:
      We are evaluating pathologically confirmed SCLC tumors in patients undergoing treatment. Formalin-fixed, paraffin-embedded surgical resections, core biopsies, and fine needle aspirates are being evaluated using a targeted, hybrid capture-based, NGS assay, MSK-IMPACT, which identifies single nucleotide variants, indels, and copy number alterations in 341 cancer-associated genes. We determined never-smoking status prospectively: all smoked <100 cigarettes in their lifetime. Clinical data on stage [extensive (ES), limited (LS)], treatment, and response were collected.

      Results:
      Four never-smokers have been identified within the 50 patient samples that have undergone NGS evaluation thus far. The median age at diagnosis of the four never-smokers is 58 (range, 47-75); 50% are male; and one presented with LS-SCLC. None of these four patients developed SCLC as acquired resistance to EGFR tyrosine kinase inhibitors after treatment for EGFR-mutant lung cancers. The tumors from the four never-smokers displayed a median of 3 non-synonymous somatic mutations, while those from moderate (<20 pack years) and heavy (20+ pack years) smokers contained 4.5 and 8 mutations, respectively (P<0.05). None of the four never-smoker samples contained smoking associated G-to-T transversions (see Table). Inactivation of RB1 and TP53 occurred in 75% and 50% of the samples, respectively. Only patient 4 had platinum-refractory disease. The median survival of these patients was 20.7 months (range, 17 to 25).

      Sample Gene altered Alteration Present Protein Alteration Base Pair Alteration
      Patient 1 PHOX2B Missense Mutation P82L G-to-A
      NOTCH1 Frame-Shift Insertion P2485fs
      RB1 Splice Site R500_splice G-to-A
      TP53 Frame-Shift Deletion V218fs
      TP53 Frame-Shift Deletion V73fs
      TERT Amplification
      Patient 2 CBL Missense Mutation C401S G-to-C
      GNAS Missense Mutation M102V A-to-G
      MYCL Amplification
      Patient 3 TP53 Nonsense Mutation R342 G-to-A
      RB1 Frame-Shift Insertion T197fs
      CDKN2C Amplification
      MYCL Amplification
      Patient 4 RB1 Nonsense Mutation C666
      ETV1 Amplification


      Conclusion:
      Using a targeted NGS assay, we have shown that the molecular characteristics differ between never-smokers and smokers, while the majority of the tumors demonstrate RB loss. Whole exome sequencing of the tumors from these never-smokers is underway. Ongoing comprehensive, multiplexed genotyping is needed to fully characterize the molecular diversity of SCLC in this unique population.

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    MINI 38 - Biology and Prognosis (ID 167)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 2
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      MINI38.02 - BAP1 Inactivation in Mesothelioma Is Highly Prevalent (ID 657)

      18:35 - 18:40  |  Author(s): L.M. Krug

      • Abstract
      • Presentation
      • Slides

      Background:
      Efforts to elucidate tumorigenic mutations in mesothelioma are essential to advance therapy. Prior efforts to characterize the molecular heterogeneity of this disease have been limited by sample condition and testing platforms. Herein, we describe efforts to prospectively test patients using next-generation sequencing with matched patient germline controls.

      Methods:
      Sequential mesothelioma patients were approached for consent to our IRB protocol NCT01775072 to perform MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a comprehensive molecular profiling platform based on solution-phase exon capture and next generation sequencing to detect somatic genetic alterations in FFPE tumor specimens. MSK-IMPACT involves hybridization capture and deep sequencing of all protein-coding exons of 341 key cancer-associated genes, including all genes that are druggable by approved therapies or are targets of experimental therapies being investigated in clinical trials at MSKCC.

      Results:
      51 patients with mesothelioma underwent MSK-IMPACT testing (see Table 1). 12 samples had low tumor content. Among 39 samples with reliable results, BAP1 was the most common alteration (46%). Another 3 samples had changes also thought to inactivate BAP1 (2 samples had gene copy number changes just below the cutoff for whole gene deletions and 1 had an inversion of LIMD-BAP1 thought to inactivate BAP1), making the incidence of BAP1 alterations possibly as high as 56%. In 4 samples with sufficient tumor content, no alterations were identified. Table 1

      N=39 (%)
      Gender M/F 26/13 (67/33)
      Primary site of disease * Pleural * Peritoneal * Testicular 32 (82) 6 (15) 1 (3)
      # identified alteration, average 3
      Alterations present in >6% * BAP1 * NF2 * CDKN2Ap16INK4A * SETD2 * CDKN2Ap14ARF * LATS1 * CREBBP * WT1 * CDKN2B * PI3KCA * PBRM1 * TP53 18 (46) 8 (21) 5 (13) 5 (13) 4 (10) 4 (10) 4 (10) 4 (10) 3 (8) 3 (8) 3 (8) 3 (8)


      Conclusion:
      Using MSK-IMPACT, BAP1 inactivation is the most common alteration. Other aberrations previously reported at high frequency were identified but albeit at lower frequencies (NF2 and p16, previously reported as 40% and 75% respectively). For multiple samples with deep coverage, no alterations were identified. The high incidence of BAP1 mutations in this systematic testing makes this pathway ideal for developing and testing targeted therapies.

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      MINI38.08 - Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma (MPM) (ID 1745)

      19:10 - 19:15  |  Author(s): L.M. Krug

      • Abstract
      • Presentation
      • Slides

      Background:
      The CALGB and EORTC have previously developed prognostic scoring systems for patients with MPM, but these included patients managed surgically and predated the use of pemetrexed. We sought to identify prognostic factors in a contemporary cohort of patients with unresectable MPM.

      Methods:
      We retrospectively reviewed the charts of patients with histologically proven MPM managed non-surgically at MSKCC from 2000-2012. Variables analyzed and correlated with overall survival (OS) included: sex, age at diagnosis, smoking history, asbestos exposure, tumor laterality, initial performance status (PS), tumor histology, clinical TNM, initial PET maximum Standardized Uptake Value (SUVmax), hemoglobin level, platelet, lymphocyte and neutrophil counts, treatment type (chemotherapy and/or radiotherapy), and response to treatment. OS was analyzed by Kaplan-Meier method, and significance (p<0.05) of prognostic factors was analyzed by log-rank test and Cox regression.

      Results:
      191 patients met study criteria: median age 71 years (range 46-90), 147 (77%) male, 128 (67%) epithelioid , 20 (10.5%) biphasic, and 28 (14.6%) sarcomatoid. 34 patients were stage I-II at presentation and 157 (82%) stage III-IV. First line chemotherapy included pemetrexed in 159 (90.3%) patients. Median time from diagnosis to treatment was 1.2 months. With a median follow-up of 13.2 months, median OS for all patients was 13.4 months. By univariate analysis, histology (p<0.001), platelet count (≤450 vs. >450, p<0.001), initial PS, maximum PET SUV (> or ≤8.1, p=0.037) were significant. Clinical staging (I/II vs III/IV) did not correlate with OS (p=0.35). By multivariable analyses, only histology, platelet count and PS were independent prognostic factors. 1-year OS was 69% (95%CI 62%-78%) for epithelioid versus 30% (95%CI 15%-59%) and 29% (95%CI 16%-51%) for biphasic and sarcomatoid tumors, respectively. Patients with PS 0-1 had a 1-year OS of 64% (95%CI 56%-73%) versus 42% (95%CI 31%-57%) for PS 2 or greater. Epithelioid histology, PS 0-1 and elevated neutrophil count at diagnosis were significantly associated with response to first line chemotherapy. Patients with response or stable disease after the first two cycles of chemotherapy had significantly better OS, median OS was 16.8 (95% CI 14.8 – 20.1) versus 6.5 (95% CI 5.4-8.5) months (p<0.001). Patients receiving more than one line of chemotherapy had better OS, median OS 14.2 (95% CI 12.1 – 16.8) versus 8.7 (95% CI 6.6 – 11.0 ) months (p=0.013). There was no significant association between use of radiotherapy and OS (p=0.058), but patients who received radiotherapy showed a 1-year OS of 60.5% vs 44.0% of patients who did not receive radiotherapy.

      Conclusion:
      This analysis in patients with unresectable MPM confirms that some elements of the CALGB and EORTC prognostic scoring systems (platelet count, PS, histology) correlate with OS, and identifies factors (PS, elevated neutrophil count, histology) associated with response to chemotherapy. Our analysis emphasizes the impact of histology and response to first-line chemotherapy on outcomes, but also the lack of predictability with the use of clinical staging.

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    P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P3.08-014 - COMMAND: A Phase 2 Randomized, Double-Blind, Study of Defactinib (VS-6063) as Maintenance Therapy in Malignant Pleural Mesothelioma (ID 2847)

      09:30 - 09:30  |  Author(s): L.M. Krug

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung. Median OS with frontline chemotherapy of pemetrexed/cisplatin (pem/cis) is ~12 months. There is no established second line therapy. Pem/cis has been shown to enrich cancer stem cells (CSCs) in tumors. Focal adhesion kinase (FAK) inhibitors have been found to decrease CSCs in mesothelioma models. The use of a FAK inhibitor in a maintenance setting after frontline chemotherapy may therefore extend survival of MPM patients. Furthermore, approximately 40% of MPM tumors exhibit disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Mesothelioma cell lines that lack merlin are more sensitive to FAK inhibitors than those with wild type merlin. This Phase 2 study will determine if defactinib (VS-6063), an oral inhibitor of FAK, provides superior clinical benefit compared with placebo as maintenance treatment in patients with MPM following frontline pem/platinum therapy.

      Methods:
      COMMAND is a multinational, randomized, double-blind, placebo-controlled trial. Approximately 370 patients with PR or SD following ≥4 cycles of frontline pem/platinum therapy will be enrolled. Patients will receive defactinib 400 mg BID or matched placebo. Randomization will be stratified by merlin status, as determined by immunohistochemistry. Primary endpoints include OS and PFS. An adaptive enrichment design at the interim analysis (projected to occur in Q2 2015) may restrict patients to those with low merlin protein expression if greater benefit is observed among this subpopulation. Secondary endpoints include patient-reported outcomes, objective response and safety and tolerability. The study is currently enrolling across 15 countries. Clinical trial: NCT01870609.

      Results:
      Not applicable

      Conclusion:
      Not applicable