Histologically Transformed SCLC From EGFR-Mutant NSCLC: Understanding the Wolf in Sheep’s Clothing
Authors: Sanjay Popat
Journal: Journal of Thoracic Oncology (2019)

The identification of somatic EGFR mutations in advanced NSCLC sensitizing to gefitinib marked a therapeutic landscape step change in defining a patient group with metastatic disease with previously poor survival that could then be effectively be treated with a well-tolerated simple oral therapy, resulting in rapid symptom resolution that is often compatible with a return to normal life and a median survival in excess of 2 years. This paradigm for EGFR-mutant NSCLC has been replicated for other oncogene-addicted subtypes, such as ALK receptor tyrosine kinase gene (ALK) and ROS1 fusions, thereby fracturing previously homogeneous advanced NSCLC adenocarcinoma into a group of molecularly defined diseases that had previously been rapidly lethal but are now orally druggable into a chronic plateau for many. Despite this major advance, acquired drug resistance to EGFR tyrosine kinase inhibitors (TKIs) is universal. Rebiopsy studies aiming to identify new therapeutic vulnerabilities have observed several on- and off-target molecular resistance mechanisms. Most surprising, initially identified with first-generation EGFR TKIs was the histological transdifferentiation into mesenchymal and high-grade neuroendocrine histological subtypes, which occurred at rates of 5% to 14%1Oser M.G. Niederst M.J. Sequist L.V. Engelman J.A. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin.Lancet Oncol. 2015; 16: e165-e172Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar and demonstrated for the first time the NSCLC cellular plasticity from drug-mediated evolutionary selection pressures, with transformation confirmed by retention of the retained parental adenocarcinoma EGFR-mutant allele. Initially identified by Zakowski et al.2Zakowski M.F. Ladanyi M. Kris M.G. EGFR mutations in small-cell lung cancers in patients who have never smoked.N Engl J Med. 2006; 355: 213-215Crossref PubMed Scopus (132) Google Scholar and subsequently verified by Sequist et al.,3Sequist L.V. Waltman B.A. Dias-Santagata D. et al.Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.Sci Transl Med. 2011; 3 (75ra26–75ra26)Crossref PubMed Scopus (2707) Google Scholar our group,4Popat S. Wotherspoon A. Nutting C.M. Gonzalez D. Nicholson A.G. O'Brien M. Transformation to "high grade" neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma.Lung Cancer. 2013; 80: 1-4Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar and others, such transformed SCLC tumors do not retain EGFR sensitivity and behave aggressively, typically consistent with their transdifferentiated histology, with a step change progression rate on imaging; neuroendocrine carcinomas being generally sensitive to platinum-etoposide, albeit transiently, but resistant to immune checkpoint inhibitors5Tokaca N. Wotherspoon A. Nicholson A.G. Fotiadis N. Thompson L. Popat S. Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer.Lung Cancer. 2017; 111: 65-68Abstract Full Text Full Text PDF Scopus (13) Google Scholar, 6Marcoux N. Gettinger S.N. O'Kane G. et al.EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes.J Clin Oncol. 2019; 371: 278-285Google Scholar and with a markedly poor prognosis.7Roca E. Gurizzan C. Amoroso V. Vermi W. Ferrari V. Berruti A. Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: a systematic review and pooled analysis.Cancer Treat Rev. 2017; 59: 117-122Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Indeed, a previous large pooled series of 67 cases identified an excess of SCLC transformation for the del19 over the L858R allele, with a median time to transformation of 17.8 months (although cases were also identified at time of diagnosis) and a median survival from time of transformation of 10.9 months.6Marcoux N. Gettinger S.N. O'Kane G. et al.EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes.J Clin Oncol. 2019; 371: 278-285Google Scholar Such transdifferentiation has now also been identified in patients progressing while taking first-line osimertinib, with a recent small series identifying histological changes in 15% of patients, including in those with SCLC (4%), the squamous histological subtype (7%), and the histological pleomorphic subtype (4%), thereby warning against sole reliance on circulating tumor DNA analyses for therapy decision making.8Schoenfeld A. Chan J. Rizvi H. et al.Tissue-based molecular and histological landscape of acquired resistance to osimertinib given initially or at relapse in patients with EGFR-mutant lung cancers [abstract].J Clin Oncol. 2019; 37: 9028Crossref Google Scholar Thus, the key to managing patients with EGFR-mutant NSCLC is a better understanding of the biological and clinical basis of this transdifferentiation so as to identify potential preventive strategies and tailored monitoring strategies and, ultimately, to best guide individualized prognostication, allowing patients maximal survival, ideally with the backbone of simple oral TKI therapy. Three major large-scale genomic sequencing projects have now been completed for SCLC, characterizing SCLC by ubiquitous somatic variants resulting in tumor protein p53 gene (TP53) and retinoblastoma 1 gene (RB1) loss-of-function against the background of other variants at, for example, SRY-box 2 gene (SOX2), notch gene (NOTCH), and v-myc avian myelocytomatosis viral oncogene homolog gene (MYC), potentially molecularly subclassifying the disease into four broad subtypes (SCLC-A, SCLC-N, SCLC-Y, and SCLC-P) driven by different transcriptional regulators (achaete-scute family bHLH transcription factor 1, neuronal differentiation 1, Yes associated protein 1 Yes associated protein 1, and POU class 2 homeobox 3, respectively) with potentially different therapeutic vulnerabilities.9Rudin C.M. Poirier J.T. Byers L.A. et al.Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.Nat Rev Cancer. 2019; 19: 289-297Crossref PubMed Scopus (418) Google Scholar How this subclassification impacts on transformed EGFR-mutant cases has not yet been defined. In parallel, a subset of nine tumors from four patients in a Korean series of patients with transformed EGFR-mutant SCLC were subjected to whole genome sequencing to better understand genomic trajectories.10Lee J.-K. Lee J. Kim S. et al.Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas.J Clin Oncol. 2017; 35: 3065-3074Crossref PubMed Scopus (268) Google Scholar Here, loss-of-function TP53 and RB1 aberrations were identified by immunohistochemistry in 83% of transformed cases versus in 3% of nontransformed EGFR-mutant controls, translating to a 43-fold greater relative risk of SCLC transformation with inactivation of both key alleles. Importantly, this common clonal origin was identified early in adenocarcinoma evolution and before TKI therapy. Some of these findings were previously identified by Niederst et al.,11Niederst M.J. Sequist L.V. Poirier J.T. et al.RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.Nat Commun. 2015; 6Crossref PubMed Scopus (410) Google Scholar who identified low or absent EGFR expression and universal Rb loss in SCLC-transformed EGFR-mutant cases and discovered that this alone was insufficient for transformation, suggesting that a pluripotent stem cell population influenced by other factors (e.g., p53 loss of function) was most susceptible to gradual epigenetic reprogramming into a neuroendocrine state resistant to EGFR signaling. It is therefore against this backdrop that in this issue of the Journal of Thoracic Oncology, Offin et al.12Offin M. Chan J.M. Tenet M. et al.Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes.J Thorac Oncol. 2019; 14: 1784-1793Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar present clinical and molecular findings of an institutional series of patients with advanced EGFR-mutant NSCLC, especially those with triple-mutant (EGFR, TP53, and RB1) disease (n = 43 [5% of EGFR-mutant cases]), alongside 142 controls with EGFR-mutant, TP53, and RB1 wild-type NSCLC. Here, the median time to transformation while taking a TKI for adenocarcinoma was 1.1 years, and again an excess of the del19 allele was observed in transformed cases. In all seven SCLC-transformed cases, the triple mutation was identified and an 18% transformation rate for triple-mutants was observed versus 0% for EGFR single mutants, to date, again confirming that TP53 and RB1 mutations are required, but not sufficient, for SCLC transformation. A much shorter median duration of TKI therapy for triple-mutants versus for EGFR-mutant–only controls was observed (9.5 versus 36.6 months, respectively), translating to significant survival differences (a median of 29.1 months versus 56.4 months, respectively), confirming the poorer prognosis. Importantly, a reduced rate of the acquired EGFR T790M mutation was observed for the triple mutants versus for single mutants (17% versus 47%, respectively), aiding in decision making between osimertinib use upfront versus on relapse for this former group. Genomic analyses using Memorial Sloan Kettering–integrated mutation profiling of actionable cancer targets were performed, and key genomic aberrations were identified before histological transformation; functional inactivation of TP53 and RB1, predominantly through loss of the wild-type allele and a significant excess of mutations in mitogen-activated protein kinase, Janus kinase–signal transducer and activator of transcription, erb-b2 receptor tyrosine kinase, fibroblast growth factor receptor, mechanistic target of rapamycin, and phosphoinositide 3-kinase–Akt signaling pathways was identified, potentially representing future therapeutic targets for transformation prevention, as well as those identified in established SCLC (e.g., phosphoinositide 3-kinase–Akt signaling). Although baseline EGFR expression was not assessed, EGFR amplification was less commonly seen in pretransformed specimens, perhaps suggesting that genomic markers of EGFR signaling dependence alongside other genomic changes of transformation occur early before histological changes—findings that are again consistent with that previously identified. Finally, triple mutants before transformation were characterized by enrichment for an apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like signature compared with those that never transformed—findings mirroring those previously.10Lee J.-K. Lee J. Kim S. et al.Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas.J Clin Oncol. 2017; 35: 3065-3074Crossref PubMed Scopus (268) Google Scholar And in these triple-mutant tumors both TP53 and RB1 mutations preceded whole genome doubling, which is an established truncal phenomenon fueling intratumoral heterogeneity and perhaps suggesting a transdifferentiation causative mechanism. Despite needing to be corroborated by larger cohorts, these findings are an important step in further defining the molecular heterogeneity of EGFR-mutant NSCLC. Transdifferentiation to SCLC is a real and significant risk for patients with EGFR-mutant NSCLC, transforming a controllable disease with excellent quality of life and long-term survival to a sudden, unstable, clinical scenario and dismal prognosis, destroying any promises of a chronic disease. Several questions remain unanswered. Will rates of transdifferentiation rise with the use of frontline osimertinib owing to its more durable EGFR kinase inhibition? What additional molecular events are required in addition to biallelic inactivation of TP53 and RB1 to cause transdifferentiation, and importantly, can it be prevented? Two large phase 3 randomized clinical trials have now unequivocally demonstrated a marked survival benefit for combination EGFR TKI and chemotherapy,13Noronha V. Joshi A. Pateil V. et al.Phase III randomized trial comparing gefitinib to gefitinib with pemetrexed-carboplatin chemotherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+C) [abstract].J Clin Oncol. 2019; 37: 9001Google Scholar, 14Nakamura A. Inoue A. Morita S. et al.Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009) [abstract].J Clin Oncol. 2018; 36: 9005Google Scholar and a survival benefit has been suggested for locally ablative consolidation.15Xu Q. Zhou F. Liu H. et al.Consolidative local ablative therapy improves the survival of patients with synchronous oligometastatic NSCLC harboring EGFR activating mutation treated with first-line EGFR-TKIs.J Thorac Oncol. 2018; 13: 1383-1392Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Perhaps this multimodality approach may be optimal for this group of triple mutants at high risk of transdifferentiation. Having unequivocally established EGFR TKIs as standard first-line therapy for EGFR-mutant NSCLC, we must now better predict and prevent this wolf masquerading in sheep's clothing. We are now in the era of routine predictive biomarker testing through combined genomic and immunohistochemical testing. Implementing routine testing and reporting of this p53 and Rb loss-of-function signature at time of diagnosis of an EGFR mutant to better appreciate the genomic context of the EGFR-mutant driver is now key to identifying this wolf. Only then will we be able to prospectively define this group of patients as a separate molecular entity, to better understand and further investigate the natural history of this disease, and to implement and stratify for therapeutic strategies most likely to result in enduring survival. Dr. Popat acknowledges National Health Service funding to The Royal Marsden Hospital–Institute of Cancer Research National Institute for Health Research Biomedical Research Centre. Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical OutcomesJournal of Thoracic OncologyVol. 14Issue 10PreviewEGFR-mutant lung cancers are clinically and genomically heterogeneous with concurrent RB transcriptional corepressor 1 (RB1)/tumor protein p53 (TP53) alterations identifying a subset at increased risk for small cell transformation. The genomic alterations that induce lineage plasticity are unknown. Full-Text PDF Open Archive