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K. Aldape



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    Best of Posters - IASLC Selection - Part 2 (ID 263)

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 1
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      P2.06-032 - SMO mutations occur in non-small cell lung cancer (NSCLC) and may respond to hedgehog inhibitors (ID 2483)

      09:55 - 10:25  |  Author(s): K. Aldape

      • Abstract
      • Slides

      Background
      Smoothened (SMO) is a 7-membrane spanning receptor involved in the hedgehog signaling pathway. In the absence of Patched inhibition, SMO accumulates and inhibits proteolytic cleavage of transcription factors. We previously identified a lung cancer patient with SMO mutation (Patient A, Table 1) and successfully treated him with erivedge, a hedgehog inhibitor. We therefore sought to determine the incidence of SMO mutations in The Cancer Genome Atlas (TCGA) lung cohorts, identify additional NSCLC patients with SMO mutations, and initiate therapy with hedgehog inhibition as proof-of-concept.

      Methods
      TCGA databases for lung adenocarcinoma (n=230) and squamous cell carcinoma (n=178) were interrogated for SMO mutations and hedgehog pathway dyregulation. Mutations were determined by whole exome sequencing. Copy number was assessed by GISTIC 2.0 (scores of 2 considered high level amplification). The lung SMO mutation patients were undergoing treatment at M.D. Anderson Cancer Center Thoracic Clinic for metastatic/refractory disease. Mutations in hotspot regions of 46 cancer-related genes including SMO was performed as part of their clinical diagnostic evaluation (Ion AmpliSeq Cancer Panel; Life Technologies, CA).

      Results
      In TCGA lung adenocarcinomas, alterations in SMO (mutation, amplification, mRNA overexpression) were observed in 12.2% of tumors. The incidence of SMO mutations was 2.6% and SMO gene amplifications 5%. SMO mutations and amplifications strongly correlated with sonic hedgehog gene dysregulation (p<0.0001). In TCGA squamous cell, SMO was altered in 10.1% of tumors, primarily via mRNA upregulation. Only 1 SMO missense mutation was identified in the Lung SCC cohort (D209Y). We identified 3 NSCLC patients with SMO mutations (Table 1) by the 46-gene panel. Patient A was treated with erivedge as he had a concomitant localized basal cell carcinoma (BCC) with a significant reduction in tumor burden. He continues to respond to therapy after 14 weeks. It is possible that Patient A’s NSCLC-SCC was misidentified and that this was metastatic BCC or that this is a germline variant. Germ-line mutation analysis is underway. However, the precise SMO mutation in Patient A was also identified in a lung adenocarcinoma Patient C (Table 1). Two additional SMO-mutated patients have just initiated erivedge and updates on their status will be provided at WLCC.

      Table 1
      Patient Biopsy site SMO mutation Reported Histology Duration of Erivedge Therapy Response to Erivedge
      A Lung Codon 641, exon 11 (CCT to GCT) p. Pro641Ala NSCLC SCC 14 weeks PR
      A Skin lesion Codon 641, exon 11 (CCT to GCT) p. Pro641Ala BCC 14 weeks CR
      B AP window lymph node Codon 525, exon 9 (ATG to TTG) p.Met525Leu NSCLC Adenoca pending pending
      C Axillary lymph node Codon 641, exon 11 (CCT to GCT) p.Pro241Ala NSCLC Adenoca pending pending

      Conclusion
      SMO mutations and pathway alterations occur in NSCLC and may be an actionable target with hedgehog inhibitors; a clinical trial is under development. Screening lung SCC tumors for SMO mutations is recommended to prevent misdiagnosis of metastatic BCC. Additional analysis of hedgehog signaling pathway alterations is underway and will subsequently be reported.

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    O04 - Molecular Pathology I (ID 126)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O04.02 - Using NGS for Mutational Profiling of NSCLC in the Clinical Setting (ID 2571)

      10:30 - 12:00  |  Author(s): K. Aldape

      • Abstract
      • Presentation
      • Slides

      Background
      Recent advances in molecular characterization of lung cancer have led to the identification of potential therapeutic targets that play key roles in regulating cell growth and proliferation. With the introduction of new targeted therapies, it becomes increasingly important to accurately characterize mutation status in lung cancer patients to provide personalized care that define prognosis and predict response to therapy. The advent of next generation sequencing (NGS) platforms in the realm of clinical molecular diagnostics has made multi-gene mutational profiling an affordable and highly successful methodology for massively parallel sequencing using small quantities of DNA.

      Methods
      Tumor specimens from 262 distinct samples of primary lung carcinoma including adenocarcinoma (n=228), squamous cell carcinoma (n=15), non small cell cancer not otherwise specified (NSC-NOS) (n=8), poorly differentiated carcinoma (n=4), neuroendocrine carcinoma (n=2), small cell carcinoma (n=1) and pleomorphic carcinoma (n=4) were tested by NGS. Tumor samples included formalin-fixed paraffin-embedded surgical core needle biopsies, resection specimens, cytopathology cell blocks, as well as cytopathology direct smears. Ten ng of DNA from each sample was tested for mutations in hotspot regions of 46 cancer related genes (Ion AmpliSeq Cancer Panel) using either a 316 chip or a 318 chip on an Ion Torrent Personal Genome Machine (PGM) Sequencer (Life Technologies, CA).

      Results
      Mutations were detected in 222/240 (93%) patients with a histologic diagnosis of adenocarcinoma, NSC-NOS or PDC. EGFR mutations were detected in 47 (20%) of these patients and double EGFR mutations identified in 13 cases, including acquired resistance mutations T790M (n=6) and S768I (n=3). KRAS mutations were detected in 61 (25%) cases, most commonly involving codons 12 and 13 (n= 58) and less frequently involving codons 61 and 146 (n= 3). TP53 was most frequently mutated (n=65; 27%) and was often seen in conjunction with EGFR mutations (n=14; 5%) and KRAS mutations (n=15; 6%). Mutations were detected in 10/15 (67%) squamous cell carcinomas with mutations in TP53 (n=5), CDKN2A (n=3) and PIK3CA (n=2) most frequently seen. Additional mutations detected at a lower frequency from the entire dataset were STK11, ATM, BRAF, PIK3CA, CTNNB1, IDH1, NRAS, CDKN2A, KDR, RET, MET, FBXW7, APC, RB1, FLT3, GNAS, ABL1, HRAS, PTPN11, JAK3, NOTCH1, SMAD4, SMARCB1, SMO, MLH1, AKT1, and ERBB4.

      Conclusion
      In summary, our results show that NGS-based mutational profiling using small amounts of DNA derived from FFPE as well as cytology smears can provide important information regarding mutation status of genes that play key roles in growth and progression of tumor in lung cancer patients and can provide insight into directing personalized cancer therapy.

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