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Mutational Profile Evaluates Response and Survival to First-Line Chemotherapy in Lung Cancer.

ABSTRACT: Evaluating the therapeutic response and survival of lung cancer patients receiving first-line chemotherapy has always been difficult. Limited biomarkers for evaluation exist and as a result histology represents an empiric tool to guide therapeutic decision making. In this study, molecular signatures associated with response and long-term survival of lung cancer patients receiving first-line chemotherapy are discovered. Whole-exome sequencing is performed on pretherapeutic tissue samples of 186 patients [145 non-small cell lung cancer (NSCLC) and 41 small cell lung cancer (SCLC)]. On the basis of genomic alteration characteristics, NSCLC patients can be classified into four subtypes (C1-C4). The long-term survival is similar among different subtypes. SCLC patients are also divided into four subtypes and significant difference in their progression free survival is revealed (P < 0.001). NSCLC patients can be divided into three subtypes (S1-S3) based on TMB. A trend of worse survival associated with higher TMB in subtype S3 than in S1+S2 is found. In contrast, no significant correlations between molecular subtype and therapeutic response are observed. In conclusion, this study identifies several molecular signatures associated with response and survival to first-line chemotherapy in lung cancer.

SUBMITTER: He Y

PROVIDER: S-EPMC7887584 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Mutational Profile Evaluates Response and Survival to First-Line Chemotherapy in Lung Cancer.

He Yayi Y Song Lele L Wang Hao H Chen Peixin P Liu Yu Y Sun Hui H Li Xiaobin X Dang Shiying S Liu Guifeng G Liu Xinyi X Chen Shifu S Zhang Xiaoni X Hofman Paul P Uchino Junji J Park Henry S HS Pacheco Jose M JM Tabbò Fabrizio F Xu Mingyan M Dai Jiawei J He Kan K Yang Yang Y Zhou Caicun C

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20201230 4

Evaluating the therapeutic response and survival of lung cancer patients receiving first-line chemotherapy has always been difficult. Limited biomarkers for evaluation exist and as a result histology represents an empiric tool to guide therapeutic decision making. In this study, molecular signatures associated with response and long-term survival of lung cancer patients receiving first-line chemotherapy are discovered. Whole-exome sequencing is performed on pretherapeutic tissue samples of 186 p ...[more]

PMID: 33643802

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Project description:Nivolumab, an anti PD-1 checkpoint inhibitor has demonstrated efficacy in metastatic non-small-cell lung cancer (NSCLC) patients after failure to standard chemotherapy. Standard chemotherapy agents could promote antitumor immune response. We thus examined whether the response to first line chemotherapy could impact on nivolumab benefit. One hundred and 15 patients with NSCLC were included in this retrospective study from 4 different French centers. Forty-three squamous cell carcinomas (SCC), and 72 non-SCC received nivolumab between 2015 and 2016 (3 mg/kg IV Q2W). Response to first-line chemotherapy and to nivolumab was retrospectively assessed on CT-scan by central review. The association between RECIST response to first-line chemotherapy and nivolumab efficacy were determined using Fisher's exact test and Cox proportional hazard model. Respectively 46 (40%), 44 (38%) and 25 (22%) patients experienced partial response (PR), stable disease (SD), or progressive disease (PD) in response to first-line platinum- based chemotherapy. Twenty 5 (21%), 34 (30%), 56 (49%) respectively experienced PR, SD and PD in response to nivolumab. 60% (54/90) of patients who experienced clinical benefit (PR + SD) after first-line chemotherapy also had clinical benefit after nivolumab, while only 20% (5/25) of patients with initial PD subsequently experienced clinical benefit with nivolumab (Fisher's exact test, P = 0.001). The type of first-line doublet chemotherapy did not influence the response rate to nivolumab. Univariate and multivariate analyses showed that patients with clinical benefit from first-line chemotherapy had higher second-line PFS (P = 0.003) (median PFS on nivolumab of 5, 3.3 and 1.9 months for patients with PR, SD and PD in response to first-line therapy, respectively). Similar results were obtained for OS. Thus this study suggests that the efficacy of first-line chemotherapy may be a valuable surrogate marker of the benefit of nivolumab in terms of PFS and OS.

Project description:BackgroundChemotherapy has been the standard treatment for small-cell lung cancer (SCLC) for decades. Nonetheless, patients are usually responsive to initial chemotherapy but quickly suffer from relapse, resulting in a poor long-term outcome. Treating advances that greatly ameliorate survival outcomes are historically finite, and credible biomarkers for therapeutic evaluation are deficient. As the genetic biology emerges, investigating biomarkers to optimize individualized treatment for SCLC is necessary.MethodsBased on following inclusion criteria: (I) patients diagnosed as SCLC by pathology; (II) patients treated with first-line etoposide/cisplatin (EP) chemotherapy; (III) patients who received long-term follow-up and signed informed consent, a total of 24 SCLC patients receiving first-line standard chemotherapy were divided into progressive disease (PD) and partial response (PR) groups. They were regularly followed every 3 months with computed tomography (CT) scan until recurrences determined by CT scan results. Next-generation sequencing (NGS) with a panel of 1,406 cancer-related genes was conducted on the tumor tissue-derived DNA of patients to compare genetic variations, including deletions (indels), single nucleotide variations (SNVs), copy number variations (CNVs), and copy number instability (CNI) between the two groups.ResultsFor the clinical characteristics of enrolled SCLC patients, except for significant differences in sex, age, clinical stage, and limited or extensive stage, PD patients showed distinctly shorter overall survival than those with PR (6.5 vs. 14.0 months, respectively, P=0.007). Genetic variations analysis discovered several common genes with CNV mutations between the PR and PD groups, and increased epidermal growth factor receptor (EGFR) gene copy numbers gain was found in PR groups in comparing with PD patients (P=0.006). However, no significant differences in terms of SNVs, indels, genotypes associated with first-line chemotherapy, CNI of tumor tissue-derived DNA, and tumor mutational burden of tumor tissues were observed between two groups. Additionally, the relationship between EGFR gene mutation and clinicopathological features of SCLC indicated that EGFR gene mutation may be an independent indicator for SCLC patients.ConclusionsIncreased EGFR gene CNVs may be an independent indicator influencing the survival time and PR in SCLC patients receiving standard first-line chemotherapy.

Dataset Information

Mutational Profile Evaluates Response and Survival to First-Line Chemotherapy in Lung Cancer.

Publications

Mutational Profile Evaluates Response and Survival to First-Line Chemotherapy in Lung Cancer.

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