Abstract
Small-cell lung cancer (SCLC) is an aggressive malignancy characterized by a rapid progression and a high resistance to treatments. Unlike other solid tumors, there has been a scarce improvement in emerging treatments and survival during the last years. A better understanding of SCLC biology has allowed for the establishment of a molecular classification based on four transcription factors, and certain therapeutic vulnerabilities have been proposed. The universal inactivation of TP53 and RB1, along with the absence of mutations in known targetable oncogenes, has hampered the development of targeted therapies. On the other hand, the immunosuppressive microenvironment makes the success of immune checkpoint inhibitors (ICIs), which have achieved a modest improvement in overall survival in patients with extensive disease, difficult. Currently, atezolizumab or durvalumab, in combination with platinum–etoposide chemotherapy, is the standard of care in first-line setting. However, the magnitude of the benefit is scarce and no predictive biomarkers of response have yet been established. In this review, we describe SCLC biology and molecular classification, examine the SCLC tumor microenvironment and the challenges of predictive biomarkers of response to new treatments, and, finally, assess clinical and molecular characteristics of long-term survivor patients in order to identify possible prognostic factors and treatment vulnerabilities.
Highlights
Lung cancer is the leading cause of cancer mortality worldwide
small-cell lung cancer (SCLC) is an aggressive and lethal disease characterized by an acquired chemoradiotherapy resistance, extraordinary metastatic potential, and poor overall survival in both limited and extended diseases
SCLC was considered to be an immunogenic tumor with high somatic mutation rates due to tobacco exposure, and, was predicted to induce strong T-cell responses
Summary
Lung cancer is the leading cause of cancer mortality worldwide. There are two major histologic subtypes, non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), which accounts for 13–15% of all lung cancers and is the sixth most common cause of cancer-related mortality [1]. III trial, which evaluated the addition of the PD-L1 inhibitor durvalumab with or without tremelimumab to a platinum-based ChT, versus standard of care treatment combining carboplatin or cisplatin with etoposide plus prophylactic intracranial irradiation. It showed a median OS of 13.0 months in the experimental arm vs 10.3 months in the control arm (HR 0.73, 95%CI: 0.59–0.91; p = 0.0047). Two phase III clinical trials that evaluated the combination of ICIs and ChT in newly diagnosed ES-SCLC patients do not show proved significant differences in OS. We assess clinical and molecular characteristics of long-term survivor patients in order to understand possible mechanisms involved in a better prognosis or treatment vulnerabilities
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