P59.03 Intratumoral Heterogeneity and Clonal Evolution in Large Non-Small Cell Lung Cancer (>7cm) Delineated by Multiregion Sequencing

e20603 Background: EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Clonal and clinical analyses of genetic alterations at baseline and progressive disease (PD), as well as differences between acquired T790M and T790M-negative patients in drug-resistant mechanisms, have not been systematically studied. Methods: We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Correlation between genomic features and patients’ progression-free survival (PFS) was evaluated. Ten additional patients were sequenced using whole exome sequencing to infer the clonal evolution patterns. Results: We observed new pathways limiting EGFR-inhibitor response, including NOTCH1/ STK11 co-deletion, and TGF-beta alterations. Besides acquired T790M mutation, chromosomal instability (CIN) related genes including AURKA and TP53 alterations were the most frequently acquired events. CIN significantly increased with TKI treatment in T790M-negative patients. Transcriptional regulators including HNF1A, ATRX and NKX2-1 acquired alterations were enriched in T790M-positive patients, and diverse oncogenic pathway alterations were more common in T790M-negative patients. T790M-positive patients had improved PFS compared to T790M-negative patients. We identified subgroups within T790M-positive or T790M-negative patients with distinct PFS. Interestingly, we observed a death-and-birth process of RTK-RAS mutations during TKI treatment, and baseline and acquired RTK-RAS mutations had opposite effects on PFS. Clonal evolution analysis indicated progression of T790M-positive patients depends on competition between T790M and non-T790M resistant subclones. Conclusions: T790M-positive and T790M-negative patients display divergent landscape of acquired somatic events. Subgroups of patients were identified within T790M-positive and T790M-negative patients with distinct survival. Our results point the importance of clonal competition between T790M and non-T790M resistant subclones.

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Intratumoral heterogeneity and tumor evolution of small cell lung cancer through multi-regional sequencing.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21103 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21103-e21103

Author(s):

Yaxiong Zhang ◽

Ningning Zhou ◽

Huaqiang Zhou ◽

Mengmeng Song ◽

Pansong Li ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Genetic Alterations ◽

Small Cell ◽

Intratumoral Heterogeneity ◽

Postoperative Treatment ◽

Tumor Evolution ◽

Small Cell Lung ◽

Tumor Tissues

e21103 Background: Small cell lung cancer (SCLC) is a type of aggressive malignancy with poor prognosis, accounting for 15% of lung cancers. Intratumoral heterogeneity (ITH) has been investigated in lung adenocarcinoma or squamous cell carcinoma, but its role in SCLC still remains unclear. Exploring ITH and tumor evolution of SCLC is essential for its treatment and prognosis. Methods: 102 multi-regional tumor tissues were collected from 34 operative SCLC patients (pts) before systemic therapy during Sep. 2009 to Sep.2018 from Sun Yat-sen University Cancer Center. All of the enrolled cases were confirmed as SCLC by immunohistochemistry. We performed whole-exome sequencing (WES) of all the tumor tissues and assessed the ITH using clonal and subclonal somatic mutations or copy number variants. ITH was defined as the proportion of subclonal genetic alterations of all. The relationship between ITH and overall survival (OS) was also explored. Results: Among the enrolled 34 SCLC pts, the median age was 64 year. 28 pts had the smoking history. 23 pts received adjuvant therapy after surgery. Stage I-II and III-IV pts accounted for 50% respectively. The most frequent mutated genes were TP53 (88%), RB1 (70%), TTN (68%), TCEB3CL (65%), MUC16 (56%), and all of them were clonal. The median overall ITH was 0.36 (ranging from 0 to 1), while the mutational ITH and the CNV ITH were 0.50 (0.22 to 1) and 0.49 (0.22 to 1). Univariate analysis revealed that postoperative treatment (HR = 0.27, 0.07-0.97, p= 0.006) and higher CNV ITH (HR = 0.28, 0.08-0.99, p= 0.009) were significant positive predictors of OS, while higher mutational heterogeneity was not associated with OS (HR = 3.34, 0.91-12.25, p= 0.21) significantly. Conclusions: TP53, RB1, TTN, TCEB3CL and MUC16 were probably clonal mutations as early events in SCLC evolution. CNV ITH might be a prognostic predictor in SCLC, which should be verified in a large-sample cohort.

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P2.04-53 Serial Ultra-Deep Sequencing of ctDNA Reveals the Clonal Evolution in Non-Small Cell Lung Cancer Patients Treated with Pembrolizumab

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2019.08.1558 ◽

2019 ◽

Vol 14 (10) ◽

pp. S728-S729

Author(s):

L. Li ◽

H. Yong

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Patients ◽

Deep Sequencing ◽

Cell Lung Cancer ◽

Clonal Evolution ◽

Small Cell ◽

Small Cell Lung ◽

Lung Cancer Patients

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Multi-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer

Nature Communications ◽

10.1038/s41467-021-25787-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Huaqiang Zhou ◽

Yi Hu ◽

Rongzhen Luo ◽

Yuanyuan Zhao ◽

Hui Pan ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Exome Sequencing ◽

Cell Lung Cancer ◽

Disease Free Survival ◽

Small Cell ◽

Intratumoral Heterogeneity ◽

Egfr Mutations ◽

Small Cell Lung ◽

Mutation Distribution

AbstractSmall cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment.

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Abstract 2899: Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer

10.1158/1538-7445.sabcs18-2899 ◽

2019 ◽

Author(s):

C. Allison Stewart ◽

Carl M. Gay ◽

Yuanxin Xi ◽

Junya Fujimoto ◽

Neda Kalhor ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Single Cell ◽

Cell Lung Cancer ◽

Treatment Resistance ◽

Small Cell ◽

Intratumoral Heterogeneity ◽

Small Cell Lung ◽

Essential Component

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Abstract 2899: Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer

10.1158/1538-7445.am2019-2899 ◽

2019 ◽

Author(s):

C. Allison Stewart ◽

Carl M. Gay ◽

Yuanxin Xi ◽

Junya Fujimoto ◽

Neda Kalhor ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Single Cell ◽

Cell Lung Cancer ◽

Treatment Resistance ◽

Small Cell ◽

Intratumoral Heterogeneity ◽

Small Cell Lung ◽

Essential Component

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Frequent intratumoral heterogeneity of EGFR gene copy gain in non-small cell lung cancer

Lung Cancer ◽

10.1016/j.lungcan.2012.11.009 ◽

2013 ◽

Vol 79 (3) ◽

pp. 221-227 ◽

Cited By ~ 13

Author(s):

Tobias J. Grob ◽

Tobias Hoenig ◽

Till S. Clauditz ◽

Djordje Atanackovic ◽

Alexandra M. Koenig ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Intratumoral Heterogeneity ◽

Gene Copy ◽

Small Cell Lung ◽

Egfr Gene

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Intratumoral Cellular Heterogeneity: Implications for Drug Resistance in Patients with Non-Small Cell Lung Cancer

Cancers ◽

10.3390/cancers13092023 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2023

Author(s):

Vanesa Gregorc ◽

Chiara Lazzari ◽

Mario Mandalá ◽

Stefania Ippati ◽

Alessandra Bulotta ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Protein Modification ◽

Small Cell ◽

Intratumoral Heterogeneity ◽

Response To Therapy ◽

Small Cell Lung ◽

Frequent Event ◽

Nsclc Patients

Tailored therapies based on the identification of molecular targets currently represent a well-established therapeutic scenario in the treatment of non-small cell lung cancer (NSCLC) patients. However, while aiming to improve patients’ response to therapy, development of resistance is frequently observed in daily clinical practice. Intratumoral heterogeneity is a frequent event in NSCLC, responsible for several critical issues in patients’ diagnosis and treatment. Advances in single-cell sequencing technologies have allowed in-depth profiling of tumors and attributed intratumoral heterogeneity to genetic, epigenetic, and protein modification driven diversities within cancer cell populations. This review highlights current research on the biological role of tumor heterogeneity and its impact on the development of acquired resistance in NSCLC patients.

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