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Likun Chen
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P35 - Pathology - Genomics (ID 105)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P35.01 - Genomic Origin and Immune-related Status of Pulmonary Sarcomatoid Carcinoma (ID 1695)
00:00 - 00:00 | Presenting Author(s): Likun Chen
- Abstract
Introduction
Pulmonary sarcomatoid carcinoma (PSC), composed of sarcomatous component (SaC) and carcinomatous component (CaC), is a rare and highly aggressive subtype of poorly differentiated non-small cell lung cancer (NSCLC) with poor survival compared to other type of NSCLC. Here, we explored the genetic origin, intratumor heterogeneity (ITH), driver mutations, tumor mutation burden (TMB), and PD-L1 status of PSC.
Methods
31 immunohistochemically (IHC) diagnosed PSCs were enrolled and surgical tumors were separated by laser capture microdissection to obtain SaC and CaC. Independent components were subjected to targeted sequencing with a 1021-gene-panel. Shared and private alterations were investigated to explore the genetic origin and evolutionary event. Somatic mutations were used to assess TMB and construct phylogenetic tree. PD-L1 expression level was determined by IHC. Independent cohorts of 67 lung adenocarcinomas (LUAD) and 265 sarcomas were used for genomic and PD-L1 comparison.
Results
87% of patients (pts) were male, with a median age of 58.0 years. 64.5% were smokers. The most recurrently mutated genes were TP53 (74%), MET (23%), NF1 (19%), EGFR (19%), and KRAS (19%) in SaCs, similarly, TP53 (74%), MET (19%), NF1 (19%), EGFR (19%), KRAS (19%) and MAP3K1 (19%) in CaCs. 30 (97%) cases had component-shared (trunk) alterations between SaC and CaC implying the genetically monoclonal origin of the majority of PSCs. TP53, MET, NF1, and KRAS were mostly frequently found in common mutations. Driver mutations of EGFR (L858R and 19del), KRAS (G12X), MET (amplification and exon 14 skipping), PIK3CA (E545K and amplification), and EML4-ALK fusion were tend to be located in trunk and with predominant cancer cell fraction. 27 PSCs had component-private alterations, including MET amplification, PIK3CA amplification, EGFR amplification, TP53 mutations, CDKN2A mutations, and EGFR rare mutations, suggesting the common branch evolution event and genetic ITH. Compared with LUAD, adenocarcinoma component of PSC showed the differentially mutational features, especially with lower EGFR incidence (21% vs 45%, p = 0.051). Compared with typical sarcomas, MET, EGFR, NF1 were detected with higher mutated frequently in SaCs, indicating the differentially mutational features. CaC and SaC had equivalent and proportional TMB and PD-L1 level. Compared with LUAD, SaC had significant higher TMB (p = 0.029), while CaC with not fully significant (p = 0.086). SaC possibly had more patients with high PD-L1 expression (TPS > 50%) (27% vs 12%, p = 0.080), while CaC similar (13%, p = 1.000). We found that patients with lower proportion of component-shared alterations (trunk ratio) had prolonged DFS (Log-rank test, p = 0.006). Multivariate cox regression analysis indicated that trunk ratio as an independent prognostic factor (p = 0.011).
Conclusion
The majority of PSCs share a monoclonal origin between CaC and SaC, with common branch evolutionary event leading to mutational ITH. PSC is a particular subgroup of NSCLC. Targetable trunk driver mutations, high TMB and positive PD-L1 expression may provide the treatment options. Mutational ITH may be an independently prognostic indicator.
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P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P84.04 - HIP1-ALK Positive Non-Small-Cell Lung Cancer: Clinicopathological Characteristics and Prognosis (ID 2947)
00:00 - 00:00 | Author(s): Likun Chen
- Abstract
Introduction
Anaplastic lymphoma kinase (ALK) fusions were identified in 2-7% of non-small cell lung cancer (NSCLC), and the most frequently occurring ALK fusion partner was EML4. Huntingtin interacting protein 1 (HIP1)-ALK fusion was rarely reported in NSCLC cases. This study is aimed to summarize clinicopathological characteristics and prognosis and to describe the efficacy and safety of ALK inhibitors in HIP1-ALK positive NSCLC.
Methods
We queried cases of NSCLC from multi-center and screened for patients who harbored HIP1-ALK. Meanwhile, adequate document retrieval was performed to identify published cases of HIP1-ALK positive NSCLC. Then we reviewed medical records or case descriptions of all patients retrospectively. Moreover, efficacy and safety of ALK inhibitors were evaluated based on RECIST v1.1 and CTCAE v5.0, respectively.
Results
A total of 9 patients (6 from multi-center and 3 from published cases) with HIP1-ALK were identified by next-generation sequencing (NGS). Female accounted for 77.8% with a median age of 56 years (range, 33-73 years). The median follow-up period was 13 months (range, 4 months-34 months). In addition, all patients were non-smokers with histological types of adenocarcinoma. Stage distribution included 22.2% stage I, 22.2% stage Ⅲ, and 55.6% stage IV (Table 1). In all cases, HIP1-ALK fusion did not incorporate other common driver genetic alterations. 8 cases received crizotinib or alectinib and all responded. 2 patients (25%) had a complete remission to crizotinib or alectinib with progression-free survival (PFS) beyond 9 months. Furthermore, 3 patients (37.5%) got a partial response to crizotinib or alectinib. 2 patients (25%) treated with crizotinib showed stable disease for at least 13 months. 1 patient (12.5%) was treated with adjuvant crizotinib after complete surgical resection with disease-free survival beyond 15 months. Among 8 patients, 2 patients switched to alectinib after crizotinib resistance, and both showed remarkable response. None died during the follow-up. Adverse events included grade-Ⅰ constipation, grade-Ⅰ localized edema, grade-Ⅰ alanine aminotransferase and aspartate aminotransferase elevation.
Conclusion
We firstly report a case series of HIP1-ALK positive NSCLC, whose clinicopathological characteristics are similar to EML4-ALK fusion NSCLC. Secondly, HIP1-ALK fusion may be mutually exclusive of other driver alterations. NGS is essential for detecting HIP1-ALK. Thirdly, ALK inhibitors should be recommended for advanced NSCLC harboring HIP1-ALK, and crizotinib-resistant patients could benefit from alectinib. Long follow-up and large-sample study are needed to determine the long-term prognosis.
