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J. Xiang
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Best abstracts selected from submissions 4 (ID 4)
- Event: ACLC 2018
- Type: Oral Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 11/09/2018, 10:50 - 11:30, Crystal Ballroom
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OA07 - Clinical Characterization Of ERBB2 Exon 20 Insertions and Heterogeneity of Outcomes to Afatinib in Chinese Lung Cancers (ID 188)
10:50 - 11:30 | Author(s): J. Xiang
- Abstract
Background:
Human epidermal growth factor 2 (HER2, ERBB2) gene alterations have been identified as oncogenic drivers in 2-5% of lung cancers. ERBB2 In-frame insertions in exon 20 (20ins) lead to constitutive activation of receptor and downstream pathways. However, response heterogeneity of different exon 20 insertions to ERBB2 inhibitor afatinib exists. In vitro and structural modeling results suggested that Glycine778 may facilitate inhibitor binding to ERBB2. In this study, our aim was to improve our understanding of clinical characteristics in ERBB2-mutated Chinese lung cancer and investigate the clinical outcomes of specific ERBB2 exon 20 insertions in response to afatinib.
Method:
We reviewed 7520 lung cancer patients whose tissue or plasma biopsies were sequenced in a CLIA-certified sequencing laboratory between 2015 to 2018. Clinical records of 19 patients (18 adenocarcinomas and 1 squamous cell carcinoma) with several different ERBB2 20ins after afatinib treatment were collected for clinical outcomes evaluation.
Results:
ERBB2 20ins were identified in 2.27% (171/7,520) in this Chinese lung cancer cohort. It occurred with a high proportion in females with adenocarcinoma histology. 11.7% (20/171) ERBB2 20ins-positive patients harbored concomitant ERBB2 amplification. Y772_A775dup (119/171, 69.6%) was the most frequently occurred 20ins subtype, followed by G778_P780dup (18/171, 10.5%). For the 19 patients treated with afatinib, they had a median PFS of 4.5 months and median OS of 11.5 months. The overall response rate in this cohort was 15.8% (3/19) and disease control rate was 68.4% (13/19). Next, we interrogated the clinical outcomes of specific 20ins subtype responding to afatinib. We found that patients harboring G778_P780dup (G778) achieved longer median PFS (10 vs 3.3 months, p=0.32) and median OS (19.7 vs 7 months, p=0.16) than non-G778 patients, consisting with in vitro results. Although statistical significance was not achieved due to limited number of G778_P780dup patients, this result warranted further investigation into this phenomenon. Moreover, to the best of our knowledge, we identified the first case of a lung squamous cell carcinoma patient harboring ERBB2 20ins from this cohort. He displayed favorable response to afatinib and achieved partial response with significant tumor shrinkage.
Conclusion:
We interrogated the characteristics of ERBB2 exon 20 insertions in a large cohort from single ethnicity. It demonstrated the response heterogeneity to afatinib among different ERBB2 exon 20 insertion subtypes. It highlighted the importance to correlate drug efficacy with specific ERBB2 exon 20 insertion variants in clinical application.
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Poster Session (ID 8)
- Event: ACLC 2018
- Type: Poster Session
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 11/07/2018, 00:00 - 00:00, Poster Hall
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P011 - Concurrent ALK/EGFR Alterations in Chinese Lung Cancers: Frequency, Clinical Features, and Differential Response to Therapy (ID 152)
00:00 - 00:00 | Author(s): J. Xiang
- Abstract
Background:
ALK rearrangement and EGFR alterations are oncogenic driver mutations in lung cancers. Generally considered mutually exclusive, some studies suggested that these two mutations might occur concomitantly. Limited studies have reported the underlying association of molecular features and drug response to EGFR-TKIs in lung cancers with such co-alterations. Here, we performed next-generation sequencing (NGS) analysis in Chinese lung cancer patients, and evaluated distinct features of EML4- vs. non-EML4-ALK fusions in EGFR-mutated cases.
Method:
A retrospective review was performed on genomic profiling data from either tissue or plasma of 419 ALK-rearranged lung cancer patients, sequenced in a CLIA-certified laboratory from 2015 to 2017. Patient characteristics (n=21) and clinical outcomes of patients harboring concurrent EGFR and ALK alterations were collected.
Results:
Among the 419 ALK-rearranged lung cancers, a total of 21 patients (5.01%) were detected harboring concurrent ALK and EGFR (exon 18-20) genomic alterations. The concomitant rate of EGFR in patients harboring EML4-ALK (3.06%, 11/359) was dramatically lower than in non-EML4-ALK patients (16.67%, 10/60, p<0.001). Four EML4-ALK and 1 non-EML4-ALK patients were found to have de novo ALK/EGFR co-mutations whereas 1 EML4-ALK and 3 non-EML4-ALK patients acquired their ALK alterations after EGFR TKI treatment. For dual-positive patients who received past EGFR-TKI with unknown ALK status before the treatment, EML4-ALK/EGFR patients (n=6) commonly had shorter PFS to EGFR-TKI as well as higher relative ALK/EGFR allele frequency compared to non-EML4-ALK/EGFR (n=6; mPFS, 5.45 vs 15 months, p=0.11; mRAF, 1.52 vs 0.41, p=0.01), suggesting that EML4-ALK was more likely to be de novo whereas non-EML4-ALK acquired after EGFR-TKI. In addition, we found that for 9 dual-positive patients who had prior first-generation EGFR-TKI treatment, the clinical efficacy of single TKI use varied greatly, and patients might benefit from combination therapy of ALK+EGFR TKIs.
Conclusion:
This study revealed that EML4-ALK/EGFR and non-EML4-ALK/EGFR co-alterations displayed distinct prevalence in Chinese lung cancer patients. Our analyses suggested that non-EML4-ALK might be an acquired gene alteration and function as a resistance mechanism to EGFR-TKI, which might explain the observed discrepancy in prevalence as our sequencing cohort consisted of both previously treated or untreated patients. In addition, we observed that patients with dual ALK/EGFR alterations may benefit from combinatorial TKIs therapy. -
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P020 - Characterization of Met Exon 14 Skipping and Association with Clinical Outcomes of Crizotinib in Chinese Lung Cancers (ID 192)
00:00 - 00:00 | Author(s): J. Xiang
- Abstract
Background:
Mesenchymal-to-epithelia transition (MET) exon 14 skipping (METex14) has been recognized as a potential driver alteration in lung cancers, and represents an emerging molecular target for lung cancer treatment. However, most studies about patient characterization and clinical outcomes of METex14-positive lung cancer were conducted in Caucasians, relevant data in Chinese patients were lacking. Here, we retrospectively characterized the clinical and molecular features of patients harboring MET mutations causing exon 14 skipping in a large cohort of Chinese lung cancers, and interrogated relevant clinical parameters associated with clinical outcomes of crizotinib treatment.
Method:
Genomic profiling data obtained from either plasma or tissue of 7,507 lung cancer patients with various histological types were screened to identify patients harboring METex14.
Results:
A total of 68 patients (0.91%), different from the frequency of Western population (3%), were identified to carry DNA alterations predicted to cause METex14 with a median age of 67.5, which is statistically significantly older than the whole cohort (p<0.001, t-test). In addition, METex14 has a female predominance (p=0.036, Fisher -
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P081 - Clinical Characteristics and Molecular Patterns Of RET-Rearranged Lung Cancer in Chinese Patients (ID 191)
00:00 - 00:00 | Author(s): J. Xiang
- Abstract
Background:
Rearrangement of RET is identified as an oncogenic alteration in lung cancer. However, studies about characteristics of RET rearrangement in lung cancers are still limited, and several reports were conflicting. Our aim was to demonstrate the clinical and molecular features of RET rearrangement in Chinese lung cancers.
Method:
We reviewed genomic profiling data of biopsies (including either tissue or plasma) from 6125 lung cancer patients sequenced in a CLIA-certified laboratory from 2015 to 2017. Patient characteristics, including age, gender and histology classification were collected.
Results:
A total of 106 RET rearrangements in 84 patients (1.37%, 84/6125) were identified. RET rearrangement had a tendency to occur in female, adenocarcinoma, with a median age of 58 years. KIF5B-RET fusion was the most frequently occurred subtypes, identified in 53.8% (57/106) RET rearrangements and 67.9% (57/84) of patients, followed by CCDC6-RET and NCOA4-RET. Besides, several rare and novel RET fusion partners were identified, to the best of our knowledge, including TSSK4, SORBS1, SIRT1, PTPRK, ADD3-AS1, PRKG1, IL2RA, CCNYL2, CCDC186 and ANKS1B. We further investigated the concurrent and exclusive genomic alterations in RET-rearranged patients. TP53 was the most commonly seen concurrent mutation, occurring in 42.5% (20/47) of patients, which was followed by EGFR (14.9%, 7/47). KIF5B-RET subtype was fully mutual exclusive with EGFR mutation, suggesting that KIF5B-RET was a strong oncogenic driver mutation. RET fusion partners of the 7 patients harboring concurrent EGFR and RET rearrangement were all non-KIF5B. In addition, we observed that allelic fraction of first-generation EGFR-TKI sensitizing mutation was higher than non-KIF5B-RET in each individual patient, indicating that non-KIF5B-RET fusion might function as a potential acquired resistance mechanism to EGFR tyrosine kinase inhibitors. Clinical outcomes of cabozantinib, a RET kinase inhibitor, were available in six patients with RET-rearrangement, and the median treatment period of cabozantinib for these patients was 5 months. A stage IV adenocarcinoma patient developed resistance to osimertinib and followed NGS revealed that he harbored concurrent CCNYL2-RET fusion and EGFR mutation. After the combinatorial treatment of osimertinib and cabozantinib, he achieved stable disease (SD) with a PFS of 5 months before disease progression.
Conclusion:
Lung cancer patients with RET-rearrangement displayed identifiable clinical characteristics and heterogeneous molecular distribution. The investigation of clinical and molecular pattern of RET-rearrangements might be helpful to provide basic knowledge for personalized diagnosis and clinical considerations. Further investigations are needed in the fields of potential sensitivities among different fusion variants and resistance mechanism to RET inhibition.
