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Hairong Bao
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MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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MA26.01 - Accumulation of Concomitant Mutations Involved in Drug Resistance in the Sequential ALK TKI Treatments of ALK-Positive NSCLC (ID 12550)
13:30 - 13:35 | Author(s): Hairong Bao
- Abstract
- Presentation
Background
ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next-generation TKIs, have shown promising clinical outcomes for ALK-positive lung cancer patients. However, distinct resistant-mechanisms have been suggested for different ALK fusion variants in response to various TKIs. The genomic alterations associated with these heterogeneous resistant-mechanisms have not been adequately investigated, especially for patients received sequential ALK TKI treatments.
a9ded1e5ce5d75814730bb4caaf49419 Method
The distribution of ALK fusion variants in 475 ALK-positive lung cancer patients (cohort I) out of 11842 lung cancer patients (4%) tested by next-generation sequencing were analyzed. In addition, mutation profiles of 416 cancer-relevant genes in the post-ALK TKI treatment tumor samples from 52 non-small cell lung cancer (NSCLC) patients (cohort II) who represent the similar distribution of ALK fusion variants as in cohort I were analyzed. Thirty-five patients received crizotinib treatment only (crizotinib group), whereas the other 17 patients were treated with multiple lines of ALK TKIs (multi-TKI group), including lorlatinib, alectinib, ceritinib and brigatinib.
4c3880bb027f159e801041b1021e88e8 Result
EML4-ALK v3 and v1 are the two most common ALK fusion variants in both cohorts. In cohort II, 18 different ALK activating mutations were found in 17 patients (49%) of the crizotinib group and 10 patients (59%) of the multi-TKI group, although with different mutation patterns. In the multi-TKI group, G1202R was the most frequent ALK activating mutation found in 35% of the patients, while L1196M (14%) and G1269A (11%) were more common in the crizotinib cohort. Of note, there was a significant enrichment of concomitant ALK activating mutations in the multi-TKI group (p=0.031), as well as a trend of increased number of patients carrying activation of ALK by-pass/downstream pathways (p=0.056) in this group compared with the crizotinib group, resulting in a significantly higher recurrence of dual activation of ALK and ALK by-pass/downstream pathways in the multi-TKI group (29%) than that in the crizotinib group (6%) (p=0.031). Patients with concomitant TP53 mutation had significantly shorter progression free survival (PFS) compared with TP53 wildtype patients upon crizotinib treatment (median PFS: 8 vs 13 months, HR 1.494, p=0.019) regardless of fusion variant types.
8eea62084ca7e541d918e823422bd82e Conclusion
Significantly higher frequency of concomitant mutations, including concomitant ALK activating mutations, and dual activation of ALK and ALK by-pass/downstream pathways, was observed after multiple lines of ALK TKI treatments, indicating the diversity and complexity of resistance-mechanisms in response to next-generation ALK TKIs. Concomitant TP53 mutation might serve as a prognosis biomarker for worse clinical outcomes treated with crizotinib.
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P2.03 - Biology (Not CME Accredited Session) (ID 952)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.03-12 - EGFR and ERBB2 Germline Mutations in Chinese Lung Cancer Patients and Their Roles in Genetic Susceptibility to Cancer (ID 12560)
16:45 - 18:00 | Author(s): Hairong Bao
- Abstract
Background
Inherited genetic determinants of lung cancer risk remains relatively elusive. Rare germline mutations in EGFR and ERBB2 have previously been reported in lung cancer patients, which may be associated with the genetic susceptibility to lung cancer.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively analyzed the next-generation sequencing (NGS) results targeting 416 cancer-relevant genes, including the whole exons of EGFR and ERBB2, in a cohort of 9091 Chinese lung cancer patients.
4c3880bb027f159e801041b1021e88e8 Result
Of the 9091 Chinese lung cancer patients, nine germline mutations from 12 patients were identified within or adjacent to the kinase domain of EGFR: K757R (two patients), D1014N (two patients), I646S, G724S, V786M, T790M, L792F, R831H, and L844V, and one germline mutation was identified adjacent to the kinase domain of ERBB2: V1128I. The incidence of EGFR T790M germline mutation is much lower compared with the reported frequency in the Caucasian patients. Somatic mutations detected in the 12 patients carrying rare EGFR/ERBB2 germline mutations were most commonly EGFR exon19 deletion, L858R, and G719S mutations, and rare EGFR: S768I mutation and a novel D770delinsDNPH indel mutation. The superior response to afatinib of the patient carrying only EGFR L844V germline mutation suggests that this germline mutation might be sensitive to TKI treatment.
8eea62084ca7e541d918e823422bd82e Conclusion
Here we indentified eight novel EGFR germline mutations and the ERBB2: V1128I germline mutation were linked to the genetic susceptibility of lung cancer in Chinese population.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-46 - Comprehensive Investigation of ERBB2 Transmembrane Domain Mutations (V659/G660) in 12,833 Chinese Lung Cancer Patients (ID 13466)
16:45 - 18:00 | Author(s): Hairong Bao
- Abstract
Background
The ERBB2/HER2 receptor tyrosine kinase belongs to the human EGFR family and is a known oncogenic driver in many cancers including lung cancer. Majority of ERBB2 mutations are within its kinase domain in non-small cell lung cancer (NSCLC). Rare transmembrane domain (TMD) mutations of ERBB2 have also been identified at V659/G660 residues, which potentially stabilize ERBB2 heterodimerization with EGFR, favour a kinase activating conformation, and have shown to respond to afatinib (Ou et al, JTO 2017).
a9ded1e5ce5d75814730bb4caaf49419 Method
We interrogated next-generation sequencing data from 19,800 Chinese cancer patients, including 12,833 lung cancers between 2014 and 2017. Sample types include formalin-fixed paraffin-embedded (FFPE) or fresh tumor samples, and/or circulating tumor DNA (ctDNA) from pleural effusion or plasma. Patients’ demographic and clinical data were further analyzed.
4c3880bb027f159e801041b1021e88e8 Result
ERBB2 TMD mutations at V659 were identified in twelve adenocarcinomas patients (five with V659D and seven with V659E), accounting for 0.14% of lung adenocarcinomas and 0.09% of all lung cancers. However, no G660 mutations were observed in this patient cohort. There is no gender preference for patients carrying such mutations (50%:50%). The median age of these patients is 56 with a trend to be younger in female patients. Two cases also carry other known driver alterations, EGFR L858R mutation and PIK3CA amplification, respectively. One case has two tumor tissue samples from the right upper and lower lobe of the lung, respectively. One lobe harbors EGFR exon19del mutation and EGFR amplification, whereas the other lobe carries ERBB2 V596D and EGFR G719A mutation. No other driver mutations were identified in the remaining cases. Interestingly, a novel TMD mutation I649R on ERBB3 was found in two patients together with ERBB2 V659D mutation, which might involve in the regulation of heterodimerization between ERBB2 and ERBB3. All these ERBB2 TMD mutations present at a relatively high mutant allele frequency (MAF) in tumor tissues, ranging from 15% to 71%, as well as liquid biopsy samples up to 47.5% of MAF, indicating a high tumor burden in these patients and potential ERBB2 amplification. Three patients received afatinib treatment though with progressive disease for various potential reasons, and the details of their treatment course will be presented.
8eea62084ca7e541d918e823422bd82e Conclusion
Among Chinese patients, ERBB2 TMD mutation V659D/E is rare and unique to lung adenocarcinomas (0.14%). The efficacy of ERBB2-specific targeted therapy on these patients especially ERBB2 antibody and/or TKI need to be further investigated.
6f8b794f3246b0c1e1780bb4d4d5dc53
