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Heterogeneity or transformation? A whack-a-mole case of EGFR-mutant lung adenocarcinoma and small cell carcinoma: A case report.

ABSTRACT: Histological transformation from adenocarcinoma to small cell lung cancer (SCLC) occurs ~10% after acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. Transformed SCLC generally responds well to chemotherapy regimens for SCLC such as platinum plus etoposide. After the response, histological nature and clinical course could be complicated by possible heterogeneity or transformation. Therefore, monitoring rebiospy is desirable to seize its histological nature at that moment. We report a case of EGFR-mutated adenocarcinoma, where histological transformations from adenocarcinoma and SCLC alternated. In this case, first rebiopsy after gefitinib revealed adenocarcinoma, but second rebiopsy after osimertinib identified SCLC transformation. After failure of platinum plus etoposide, adenocarcinoma-induced leptomeningeal metastases were controlled by osimertinib reintroduction. Optimal therapies could be provided according to the result of monitoring rebiopsy.

SUBMITTER: Ninomaru T

PROVIDER: S-EPMC9376156 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Heterogeneity or transformation? A whack-a-mole case of EGFR-mutant lung adenocarcinoma and small cell carcinoma: A case report.

Ninomaru Taira T Hata Akito A Hara Shigeo S Komatsu Masato M

Thoracic cancer 20220706 16

Histological transformation from adenocarcinoma to small cell lung cancer (SCLC) occurs ~10% after acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. Transformed SCLC generally responds well to chemotherapy regimens for SCLC such as platinum plus etoposide. After the response, histological nature and clinical course could be complicated by possible heterogeneity or transformation. Therefore, monitoring rebiospy is desirable to seize its histological nature ...[more]

PMID: 35793695

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Project description:IntroductionNSCLC transformation to SCLC has been best characterized with EGFR-mutant NSCLC, with emerging case reports seen in ALK, RET, and KRAS-altered NSCLC. Previous reports revealed transformed SCLC from EGFR-mutant NSCLC portends very poor prognosis and lack effective treatment. Genomic analyses revealed TP53 and RB1 loss of function increase the risk of SCLC transformation. Little has been reported on the detailed clinicogenomic characteristics and potential therapeutic targets for this patient population.MethodsIn this study, we conducted a single-center retrospective analysis of clinical and genomic characteristics of patients with EGFR-mutant NSCLC transformed to SCLC. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. Kaplan-Meier analyses were used to estimate survival outcomes. Next generation sequencing-based assays was used to identify EGFR and co-occurring genetic alterations in tissue or plasma before and after SCLC transformation. Single-cell RNA sequencing (scRNA-seq) was performed on a patient-derived-xenograft model generated from a patient with EGFR-NSCLC transformed SCLC tumor.ResultsA total of 34 patients were identified in our study. Median age at initial diagnosis was 58, and median time to SCLC transformation was 24.2 months. 68% were female and 82% were never smokers. 79% of patients were diagnosed as stage IV disease, and over half had brain metastases at baseline. Median overall survival of the entire cohort was 38.3 months from initial diagnoses and 12.4 months from time of SCLC transformation. Most patients harbored EGFR exon19 deletions as opposed to exon21 L858R alteration. Continuing EGFR tyrosine kinase inhibitor post-transformation did not improve overall survival compared with those patients where tyrosine kinase inhibitor was stopped in our cohort. In the 20 paired pretransformed and post-transformed patient samples, statistically significant enrichment was seen with PIK3CA alterations (p = 0.04) post-transformation. Profiling of longitudinal liquid biopsy samples suggest emergence of SCLC genetic alterations before biopsy-proven SCLC, as shown by increasing variant allele frequency of TP53, RB1, PIK3CA alterations. ScRNA-seq revealed potential therapeutic targets including DLL3, CD276 (B7-H3) and PTK7 were widely expressed in transformed SCLC.ConclusionsSCLC transformation is a potential treatment resistance mechanism in driver-mutant NSCLC. In our cohort of 34 EGFR-mutant NSCLC, poor prognosis was observed after SCLC transformation. Clinicogenomic analyses of paired and longitudinal samples identified genomic alterations emerging post-transformation and scRNA-seq reveal potential therapeutic targets in this population. Further studies are needed to rigorously validate biomarkers and therapeutic targets for this patient population.

Project description:IntroductionAdenocarcinoma of the lung is the most common subtype of non-small cell lung cancer, and epidermal growth factor receptor (EGFR) mutations are the most common driver genes in the development of cancer (NSCLC). Among them, mutations in exons 18-21 are the most frequent, especially the deletion of exons 19 and 21, where L858R mutations are the most common. Other mutations such as S768I, G719X, and 20ins are relatively rare. In the population of lung adenocarcinoma patients with EGFR mutations, some common mutations may occur, especially TP53.Case presentationHere, this study presents a retrospective analysis of neoadjuvant therapy for lung adenocarcinoma and reviews relevant literature. The patient was diagnosed with T4N3M1a, stage IVa. After 1 month of chemotherapy with 860 mg of pemetrexed and 480 mg of carboplatin, and immunotherapy with 200 mg of sintilimab, good response to conventional chemotherapy, but a follow-up CT scan showed disease progression. Next-generation sequencing showed EGFR exon 20 missense mutation (p.S768I and p.V774M) combined with tumor protein p53 (TP53) (p.Y220C) missense mutation, with mutation abundance of 48.6%/49.7% and 49.2%, respectively. Subsequently, chemotherapy with paclitaxel albumin 400 mg and treatment with pembrolizumab 200 mg were administered, followed by targeted treatment with oral afatinib (PFS: 12 months). And then, brain metastasis occurred, and targeted treatment with osimertinib was used instead (PFS: 9 months). The therapeutic effect is significant, but due to severe side effects, the patient stopped taking the medication on their own. Five months later, the patient became seriously ill again and CEA levels increased. Targeted treatment with furmonertinib (PFS: 3 months) and sunvozertinib (PFS: 3 months) was used instead. Three months later, the blood CEA level briefly decreased and then continued to increase, indicating the patient's critical condition.ConclusionThe results indicate that targeted therapy with afatinib and osimertinib for EGFR S7688I/V774M and TP53 mutations has better PFS than targeted therapy with furmonertinib and sunvozertinib. Simultaneously, the combination of platinum-based chemotherapy and immunotherapy may be a potential neoadjuvant therapy for NSCLC IVa stage patients.

Dataset Information

Heterogeneity or transformation? A whack-a-mole case of EGFR-mutant lung adenocarcinoma and small cell carcinoma: A case report.

Publications

Heterogeneity or transformation? A whack-a-mole case of EGFR-mutant lung adenocarcinoma and small cell carcinoma: A case report.

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