Lung cancer is a common type of carcinoma and is the leading cause of cancer-related deaths worldwide. The two broad histological subtypes of lung cancer are non-small-cell lung cancer (NSCLC), which accounts for 85% of cases and includes adenocarcinoma and squamous-cell carcinoma, and small-cell lung cancer (SCLC), which accounts for 15% of cases.[1–3] Substantial improvements and refinements in the treatment have led to remarkable progress and changed outcomes for many patients. However, with an increase in the awareness of repeat biopsy, more and more patients with lung cancer have been found to undergo a histological transformation during treatment, with lung adenocarcinoma (LAdC) to SCLC transformation being the most frequent.[4–7]
MECHANISM OF THE TRANSFORMATION OF LUNG ADENOCARCINOMA TO SMALL-CELL LUNG CANCER
Acquired drug resistance in the transformation of EGFR-mutant LAdC to SCLC
Somatic activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain are present in 15%–50% of patients with NSCLC.[8–11] Treatment with EGFR tyrosine kinase inhibitors (EGFR–TKIs) extend the progression-free survival (PFS) compared with that observed with chemotherapy.[12–16] Thus, EGFR–TKIs are the standard therapy for patients with EGFR mutations. However, acquired resistance inevitably develops 10–12 months after treatment when detecting the T790M mutation.[17–22] Repeat biopsy showed that several mechanisms might account for the acquired resistance including the rare (approximately 3%–10%) LAdC to SCLC histological transformation, which affects the prognosis of patients with lung cancer.[23–25]
SCLC develops from neuroendocrine cells in the central airway, whereas LAdC derives from alveolar-type II cells located on the alveolar surface. Alveolar-type II cells may be common precursors of LAdC and SCLC.[26–29] Therefore, LAdC cells with EGFR mutations originating from alveolar-type II cells may transdifferentiate into SCLC under the selective pressure of treatment.[23,28–35]
However, there are different findings about the LAdC to SCLC conversion against TKI therapy. Norkowski et al. found that SCLC transformation is not associated with TKIs but might be related to carrying an EGFR mutation because only two out of six patients developing SCLC after adenocarcinoma were treated with TKIs after adenocarcinoma. Chu et al. demonstrated the occurrence of neuroendocrine transformation in NSCLC in the absence of TKI targets or other treatments.
Correlations between tumor protein 53 (TP53), RB transcriptional corepressor 1 (RB1), and transformed SCLC
The TP53 gene is located on chromosome 17 short arm (17p13). Mutated or inactivated TP53 loses its tumor suppressor function.[38–41]The antiproliferative role of the p53 protein makes it a primary target for inactivation in cancer. However, it may also drive oncogenes. RB1 is an important tumor suppressor gene. RB1 mutations or deletions cause the upregulation of pluripotent stem cell reprogramming factors and promote cell proliferation.[43,44] Studies have evaluated the role of the loss of TP53 and RB1 expression in neuroendocrine and alveolar-type cells and found that this loss led to SCLC.
Nearly 50% of NSCLC patients have EGFR/TP53 co-mutations, which are an independent risk factor for poor PFS and overall survival (OS) in patients treated with EGFR–TKIs.[46–48]
Most lung cancers with EGFR/RB1 co-mutants are associated with TP53 mutations. TP53 is the most frequently mutated gene in lung cancer cells, with similar mutation frequencies in SCLC and NSCLC.[49,50]
The ontogeny and molecular pathogenesis of SCLC transformation with TP53 and/or RB1 mutation remain poorly understood. A high incidence of aggressive lung tumors similar to SCLC was found in mice with conditional inactivation of RB1 and TP53 in lung epithelial cells, suggesting that RB1 and TP53 inactivation is a prerequisite for SCLC pathogenesis.Additionally, the EGFR/TP53/RB1 triple mutation had a six times higher risk of conversion to SCLC than that of patients with EGFR without TP53 or RB1 co-mutation, and other researchers found this rate even 42.8 times higher. However, not all NSCLCs with triple mutations undergo SCLC transformation. Additionally, reduced RB1 expression in EGFR-mutant LAdC is not enough to cause SCLC transformation.
LAdC and SCLC resistant to EGFR–TKIs have a common clonal origin. Indeed, resistant SCLCs differentiate early from LAdC clones with fully inactivated RB1 and TP53. The transformation of LAdC with EGFR mutations to SCLC is associated with the inactivation of RB1 and TP53 genes.
NOTCH signaling dysregulation is crucial for SCLC tumorigenesis, disease progression, and chemoresistance.[53–57] neurogenic locus notch homolog (NOTCH) and achaete-scute homolog 1 (ASCL1) pathways are master regulators of the neuroendocrine differentiation in small-cell lung carcinoma.[58–63] Koba proposed that the NOTCH–ASCL1 axis might also play a role in the transformation of SCLC with inactivated TP53 and RB1. Meder identified a novel pathway driving the pathogenesis of secondary SCLC. It involves NOTCH inactivation mutations, the activation of the NOTCH target ASCL1, and the canonical wingless-type (WNT) signaling in the context of mutual bi-allelic RB1 and TP53 lesions. The authors experimentally verified the involvement of the NOTCH–ASCL1–RB–p53 signaling axis in vitro and validated its activation by genetic alterations in vivo. Moreover, ASCL1 activation may cooperate with the biallelic RB/TP53 loss in neuroendocrine precursors in primary SCLC and contribute to secondary SCLC arising from NSCLC upon cancer therapy.[65–67]
Other hypotheses of the research
Telomerase reverse transcriptase amplification is another common genetic mechanism of SCLC transformation in patients with EGFR-mutant LAdC.
A whole-genome sequencing study of LAdC to SCLC transformation revealed that the somatic mutation profile changes in SCLC after transformation, with fewer C > T and more C > A mutations. Additionally, the copy number variants (CNVs) burden of the transformed SCLC is increased compared with that in the initial LAdC (61.1 in SCLC vs. 39.0 in LAdC, Wilcoxon P = 0.4). A greater CNV burden in LAdC is associated with a shorter time to SCLC transformation, and a greater CNV burden in the transformed SCLC results in a shorter OS after transformation. A clonal evolution analysis showed different clonal components between the initial LAdC and transformed SCLC.
CLINICAL CHARACTERISTICS OF THE LADC TO SCLC TRANSFORMATION
A systematic review and pooled analysis of reported cases of SCLC diagnosed in patients with EGFR-mutated (37/39) or ALK-rearranged (2/39) LAdC treated with TKIs were performed. Changes in EGFR exon 19 were observed in 19 cases and exon 21 in 9 cases. The median time to transform to SCLC was 19 months, and the median survival after transformation was 6 months. All SCLC cases had the same EGFR mutation as that present in the former adenocarcinoma.
Marcoux et al. retrospectively analyzed 67 patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas treated with one or more EGFR–TKIs before transformation to SCLC. The transformation can occur at any time point in the course of the disease. Typically, the time to conversion ranged from 2 months to 5 years, with a median time of 17.8 months. The median OS was 31.5 months (95% confidence interval [CI], 24.8–41.3 months) since the initial diagnosis and 10.9 months (95% CI, 8.0–13.7 months) since lung cancer transformation. Tissues from 59 patients were genotyped as the first evidence of SCLC. The initial EGFR mutation was maintained in all patients, and 15 out of the 19 EGFR T790M-positive mutants were converted to wild-type. Re-emergence of NSCLC clones was also found in some cases.
Ferrer et al. analyzed 48 cases of EGFR-mutated NSCLC and 13 cases of non-EGFR-mutated NSCLC that were converted to SCLC. Most EGFR-mutated tumors retained the EGFR mutation after transformation. The median time to SCLC transformation in the EGFR-mutant group was shorter than that in the non-EFGR-mutant group (16 months vs. 26 months). The median OS rate was 28 months in the EGFR-mutant group and 37 months in the non-EFGR-mutant group. After transformation, the median OS was 10 months in the EGFR-mutant group and 9 months in the non-EGFR-mutant group.
Central nervous system (CNS) metastases are frequent after transformation. Among 59 patients, 38 (64%) experienced CNS progression at some point after the SCLC diagnosis. The median follow-up time after conversion to SCLC was 8.1 months (range of 0–26.9 months), and 45 deaths (67%) occurred. The median OS of patients with metastatic lung cancer was 31.5 months since the first diagnosis and 10.9 months since SCLC formation.
THERAPEUTIC STRATEGIES AGAINST TRANSFORMED SCLC
The molecular characterization of NSCLC biomarkers significantly improved global outcomes for patients. Despite the recent understanding of SCLC biology, effective biomarkers for SCLC are lacking.[52,73] The clinical treatment of NSCLC after histological transformation remains challenging, and little data are available to guide clinical decision-making.
Platinum–etoposide is the most commonly used regimen after transformation to SCLC or de novo diagnosis of SCLC. The clinical response rate in patients treated with platinum–etoposide is 54%. A high response rate (eight [80%] out of 10 patients) was achieved in patients previously receiving platinum chemotherapy for adenocarcinoma. Estimated median PFS with platinum–etoposide treatment was 3.4 months (95% CI, 2.4 to 5.4 months). No responses are observed among patients receiving checkpoint inhibitors, such as programmed death-1 or programmed death-ligand 1 inhibitor, either as a single agent or in combination with the ipilimumab–nivolumab regimen. Accordingly, we speculated that NSCLC cells sensitive to taxanes exist in patients presenting transformed SCLC with an EGFR mutation. Additionally, transformed SCLC with EGFR mutations might be more sensitive to taxanes than de novo-formed SCLC. Another group proposed that, although EGFR mutations are found in SCLC after transformation, the EGFR protein expression is significantly reduced, rendering the transformed tumors unresponsive to EGFR–TKIs.
A multicenter retrospective study reported that anlotinib is effective in patients with small-cell transformation after third-generation TKI treatment. These patients have a better prognosis than patients with transformation after first or second-generation treatment (49.4 months vs. 20.0 months, P = 0.013).
Furthermore, the C797S and T790MEGFR mutations were shown to guide the selection of TKIs for the treatment of transformed SCLC. Indeed, cells with C797S and T790M mutations in trans are resistant to third-generation EGFR–TKIs but sensitive to a combination of first- and third-generation TKIs. In contrast, the activity of EGFR with cis mutations cannot be inhibited by EGFR–TKIs alone or in combination. T790M wild-type cells with C797S mutation (for which third-generation TKIs are the preferred treatment) are resistant to third-generation TKIs but remain sensitive to first-generation TKIs.
PREDICTORS OF SCLC TRANSFORMATION
Neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (ProGRP) serum levels are increased at the time of the second biopsy and decreased following EGFR–TKI treatment. Thus, ProGRP and NSE may be useful for the early detection of SCLC transformation in patients with resistance to EGFR–TKIs and in whom secondary biopsy should be performed.
The EGFR/TP53/RB1 triple mutation may increase the risk of SCLC transformation. Patients with EGFR/RB1/TP53-mutant lung cancer have a largely higher incidence of whole-genome doubling compared with that in NSCLC and SCLC. They also show further enrichment in triple-mutant cancers with eventual small-cell histology. A mutation in activation-induced cytidine deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like is enriched in transformed triple-mutant lung cancers. Thus, activation-induced cytidine deaminase hypermutation might be an early predictor of SCLC transformation.[46,78]
However, not all LAdC-transformed SCLCs harbor the EGFR mutation. Fujita et al. described SCLC transformation in an ALK-positive patient treated with alectinib for 9 months. Another case of SCLC transformation was reported by Toyokawa in a 70-year-old male patient smoker with advanced rectal cancer who received 5-fluorouracil-based chemotherapy.
LAdC to SCLC transformation might be a mechanism of TKI treatment resistance. However, ALK-positive LAdC treated with the targeted drug or LAdC without mutations but subjected to chemotherapy might also be converted into SCLC. We hypothesize that LAdC to SCLC transformation is a common event resulting from the breakthrough in drug development against LAdC that significantly improves patients’ survival. When LAdC progresses or has a poor prognosis, repeat biopsies are often performed for choosing a new therapeutic regimen, and are very likely to reveal altered histopathology. It can also be inferred that LAdC and SCLS have a common origin, and even that SCLC might be a worse differentiation stage of LAdC.
Financial support and sponsorship
The study was funded by the National Natural Science Foundation of China (Nos. 81901851 and 82072028).
Conflicts of interest
There are no conflicts of interest.
The Institutional Review Board of the First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Public Health Clinical Center has approved this study. Informed consent was obtained from all individuals included in the study. The work has not been published elsewhere. All the authors listed have seen and approved the manuscript that is enclosed, and contributed significantly to the work.
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