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Wallace Akerley



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    MA03 - Lung Cancer Screening - Next Step (ID 896)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 206 AC
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      MA03.10 - Population-Based Relative Risks for Lung Cancer Based on Complete Family History of Lung Cancer  (ID 11268)

      11:30 - 11:35  |  Author(s): Wallace Akerley

      • Abstract
      • Presentation
      • Slides

      Background

      Published risk estimates for diagnosis of lung cancer based on family history are typically focused on close relatives, rather than a more diverse or complete family history. This study provides relative risks (RR) for lung cancer based on comprehensive family history data obtained from a statewide Cancer Registry linked to a high quality genealogy data resource. Risk estimates presented avoid common recall, recruitment, ascertainment biases, and are based on an individual’s (proband’s) lung cancer family history constellation (pattern of lung cancer affected relatives).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A population-based genealogical resource linked to a statewide electronic SEER cancer registry estimated relative risk (RR) for lung cancer for an individual based upon their lung cancer family history. Family history data available for a proband included degree of relationship (first to third-degree), paternal or maternal family lung cancer history, number of lung cancer affected relatives and age at diagnosis of affected relatives. Over 1.3M probands probands with specific constellations of lung cancer were analyzed. To estimate RRs, the observed number of lung cancer cases among probands with a specific family history constellation was compared to the expected number using internal cohort-specific rates.

      4c3880bb027f159e801041b1021e88e8 Result

      5,048 lung cancer cases were identified. Significantly elevated RR was observed for any number of lung-cancer-affected relatives among first-, second-, or third-degree relatives. RRs for lung cancer were significantly elevated for each additional lung cancer first-degree relative (FDR) ranging from RR=2.57 (2.39, 2.76) for >= 1 FDR to RR=4.24 (1.56, 9.23) for ≥3 FDRs affected. In an absence of FDR family history, increased risk for lung cancer was significant for increasing numbers of affected second-degree relatives (SDR) ranging from 1.41 (1.30, 1.52) for ≥ 1 SDR to 4.76(1.55, 11.11) for ≥ 4 SDRs. This was also seen in the absense of FDRs and SDRs for affected third-degree relatives (TDR) ranging from 1.18 (1.11, 1.24) for ≥1 affected TDR to 1.55 (1.03, 2.24) for ≥ 4 affected TDRs. RRs were significantly increased with earlier age at diagnosis of a first degree relative, and equivalent risks for maternal compared to paternal history were observed.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study provides unbiased, population-based estimates of lung cancer risk based on a proband’s complete family history that can be 2-5+ times increased. Estimates of RR for lung cancer based on family history are arguably very relevant clinically. The constellation RR estimates presented could serve in individual decision making to direct resource utilization, and could be pivotal in decision making for screening, treatment, and post treatment surveillance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA12 - Novel Therapies in MET, RET and BRAF (ID 921)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 106
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      OA12.06 - Mutational Landscape of BRAF V600E Positive Lung Cancer Patients Following BRAF Directed Therapy Failure (ID 13540)

      16:10 - 16:20  |  Author(s): Wallace Akerley

      • Abstract
      • Presentation
      • Slides

      Background

      BRAF V600E mutation is identified as molecular drivers in 1-2% of lung adenocarcinomas and predicts response to combination BRAF and MEK inhibitors. Little is known about molecular mechanisms of acquired resistance to these therapies for lung cancer patients with BRAF V600E mutations, partially due to a lack of representative cancer models.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified patients with BRAF V600E mutated lung cancer who were progressing after initial response to a BRAF/MEK inhibitor combination in 5 academic institutions in the US. Potential molecular mechanisms of resistance were explored by comparing pre- and post-therapy results from comprehensive tissue and/or the Guardant360 and FoundationACT plasma-based next generation sequencing assays.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 6 patients. Prior to treatment with a BRAF/MEK inhibitor combination, four patients had received at least one line of chemotherapy and immune checkpoint inhibitor monotherapy, one had received chemotherapy only and one was treatment naïve. Five patients received dabrafenib/trametinib and one vemurafenib/cobimetinib combination. All 6 patients achieved a partial response. Progression free survival (PFS) ranged from 3 to 15 months (median 9.5 months). At the time of progression, all patients had the BRAF V600E mutation re-identified in their samples. Additionally, there was one patient with a new AKT1 E17K and a new KRAS G12A mutation, one patient with a new VHL R167Q mutation and one patient with a new TP53 splice site indel mutation at the time of progression. Another two patients had AKT1 E17K mutations that were present prior to BRAF/MEK inhibitor therapy. They both had oligoprogression, one in lymph nodes and one in the brain after 5.2 and 3 months, respectively; both continued on dabrafenib and trametinib combination therapy after radiation treatment to the progressing sites. Interestingly, co-occurrence of AKT1 E17K and BRAF V600E mutations is rare in the TCGA data, but was identified in three of six patients in our case series. Finally, we have established a BRAF V600E positive lung adenocarcinoma cell line from a TKI naïve patient for further functional studies of drug resistance.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Comprehensive molecular testing can identify potential resistance mechanisms following progression of BRAF V600E positive lung cancer to TKI therapy. AKT1 mutations were common as co-alterations in BRAF V600E mutated lung adenocarcinoma before and after targeted therapy and may contribute to drug resistance. The development of patient-derived cell line models may assist in the identification and validation of drug resistance mechanisms, and may help devise strategies to overcome drug resistance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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