Standard therapy‑resistant small cell lung cancer showing dynamic transition of neuroendocrine fate during the cancer trajectory: A case report

Abstract

While small cell lung cancer (SCLC) has been treated as a single disease historically, recent studies have suggested that SCLC can be classified into molecular subtypes based on the expression of lineage transcription factors such as achaete-scute homolog 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), POU domain class 2 transcription factor 3 (POU2F3) and transcriptional coactivator YAP1 (YAP1). These transcription factor-based subtypes may be specifically targeted in therapy, and recent studies have suggested that the SCLC subtypes represent different stages of dynamic evolution of SCLC rather than independent diseases. Nevertheless, evidence of shift in neuroendocrine differentiation during SCLC evolution has been lacking in the clinical setting. In the present study, a 60-year-old male was diagnosed with extensive SCLC. The tumor responded not to the standard SCLC regimen of carboplatin, etoposide and atezolizumab, but to the non-SCLC regimen of carboplatin, nab-paclitaxel and pembrolizumab. The patient succumbed 5 months after the initial diagnosis and a pathological autopsy was performed. The tumor was originally negative for all four transcription factors, ASCL1, NEUROD1, POU2F3 and YAP1, in the biopsy specimens at diagnosis. Loss of synaptophysin expression and emergence of Myc proto-oncogene protein and YAP1 expression was recorded in the autopsy specimens, suggesting the transition to a decreased neuroendocrine fate during the disease trajectory. This case provides clinical evidence of dynamic transition of neuroendocrine fate during SCLC evolution. In light of SCLC heterogeneity and plasticity, development of precision medicine is required.

Remarkable response to PD-1 inhibitor in a patient with extensive-stage small cell lung cancer: a case report and literature review

“…NLR peaked before immunotherapy then rapidly declined, mirroring his tumor regression. Elevated NLR is associated with poor prognosis across cancer types ( 13 , 14 ). The sharp drop in NLR following immunotherapy corresponds with the patient’s exceptional outcome.…”

Evolving role of seneca valley virus and its biomarker TEM8/ANTXR1 in cancer therapeutics

“…TEM8/ANTXR1 upregulation has been described in a variety of solid tumors types including triple negative breast cancer (Xu et al, 2021), prostate cancer (Li et al, 2021a), gastric cancer (Li et al, 2021b;Sun et al, 2021), pancreatic cancer (Alcalá et al, 2019), angiosarcoma (Kusaba et al, 2021(Kusaba et al, ), colon cancer (Ł et al, 2021, and NSCLC (Gong et al, 2021). Lineage plasticity with a transformation from adenocarcinomas to carcinomas with neuroendocrine differentiation has been described in a variety of solid tumors, including lung and prostate primary tumors (Farrell et al, 2017;Rubin et al, 2020;Ito et al, 2021). This transformation is often associated with the development of therapy resistance and portends poor outcomes for patients.…”

Diagnostic criteria and evolving molecular characterisation of pulmonary neuroendocrine carcinomas

“…Although the majority of SCLC do not respond to immunotherapy, alterations in NOTCH signalling may also influence tumour susceptibility to immunotherapy and allow for selection of patients who may respond 98,105 . Some studies have shown intratumoral heterogeneity of NOTCH signalling in mouse models, as well as shifts to increased NOTCH signalling and predominance of neuroendocrine marker‐low cell populations in cell lines exposed to chemotherapeutic agents, suggesting that the SCLC phenotype could also potentially be dynamically regulated within an individual tumour during therapy and require specific adjustments in patient management 96–98,100,106 . Further understanding of how the individual tumour phenotype evolves over the disease course could therefore be utilised to tailor therapy in patients with tumour persistence or recurrence.…”