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Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: A systematic review and pooled analysis
Accepted Manuscript Systematic or Meta-analysis Studies Outcome of patients with lung adenocarcinoma with transformation to smallcell lung cancer following tyrosine kinase inhibitors treatment: A Systematic Review and Pooled Analysis Elisa Roca, Cristina Gurizzan, Vito Amoroso, William Vermi, Vittorio Ferrari, Alfredo Berruti PII: DOI: Reference:
S0305-7372(17)30121-4 http://dx.doi.org/10.1016/j.ctrv.2017.07.007 YCTRV 1656
To appear in:
Cancer Treatment Reviews Cancer Treatment Reviews
Received Date: Revised Date: Accepted Date:
29 July 2016 21 July 2017 22 July 2017
Please cite this article as: Roca, 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 Treatment Reviews Cancer Treatment Reviews (2017), doi: http://dx.doi.org/10.1016/j.ctrv.2017.07.007
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Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: A Systematic Review and Pooled Analysis. Elisa Roca, Cristina Gurizzan, Vito Amoroso, William Vermi, Vittorio Ferrari, Alfredo Berruti University of Brescia, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology and Department of Molecular and Translational Medicine Section of Pathology, at Spedali Civili Hospital, Brescia (Italy).
Corresponding author: Alfredo Berruti Oncologia Medica Università degli Studi di Brescia Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica Azienda Ospedaliera Spedali Civili Piazzale Spedali Civili, 1 25123 BRESCIA ( Italy) tel +39 030 3995410 email: [email protected]
ABSTRACT Background Lung adenocarcinoma can transform to small-cell lung cancer (SCLC) when resistance to tyrosine kinase inhibitors (TKIs) develops. This phenomenon has repeatedly been described in several case reports and small patient series. The characteristics and treatment outcomes of this population, however, have not been comprehensively reported. Methods We performed a systematic review of the published literature to obtain explorative information on the clinical and pathological features and prognosis of the reported cases. Results Twenty-five eligible publications were identified, contributing to 39 patients. The median time from initial diagnosis of lung adenocarcinoma to the transformation to SCLC (ttSCLC) was 19 months (range 1-61 months). The median survival after SCLC diagnosis was 6 months. Female gender was significantly associated with longer ttSCLC at the multivariable analysis. Smoking status seemed to be associated with worse prognosis after the diagnosis of SCLC. Conclusion In this series of published cases, the transformation to a SCLC phenotype after an initial diagnosis of lung adenocarcinoma following TKI therapy appeared to be a late phenomenon. The prognosis after SCLC diagnosis is poor and current treatment strategies derived from primary SCLC seem to be largely inefficacious. New therapies are needed in the management of transformed SCLC.
INTRODUCTION Lung cancer is the leading cause of cancer-related death. It accounts for 353,000 deaths in the European Union and about 160,000 deaths in the United States1. In the past decades, only two different lung cancer subtypes were recognized: non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC, which represents about 85% of all cases, arises from the respiratory epithelium, and it is further divided into two major histological subtypes: adenocarcinoma and squamous-cell carcinoma. SCLC, accounting for the remaining 15% of cases, is a highly aggressive tumor of neuroendocrine origin, which is characterized by rapid disease progression and early development of 2-4
metastases . Adenocarcinoma is nowadays the most common histological subtype, it represents about one-half of all lung tumors. The discovery of the epidermal growth factor receptor (EGFR) mutations and the anaplastic lymphoma kinase (ALK) rearrangements led to the development of novel targeted therapies, acting as specific EGFR and ALK tyrosine kinase inhibitors (TKIs). These drugs have consistently improved the patient outcomes but are not curative, and disease progression inevitably occurs after a median time of about 12 months5,6. Several mechanisms underlie the development of acquired resistance to TKIs, and among them, the transformation from adenocarcinoma to a SCLC phenotype was recently reported4,7. The potential mechanisms underlying the SCLC phenotype conversion after TKI therapy have been discussed in details elsewhere4,7. Historically, SCLC was believed to develop from neuroendocrine cells of central airways, whereas adenocarcinoma derives from the alveolar type II cells located in the alveolar surface area. Several studies have shown that alveolar type II cells may be common precursors of both lung adenocarcinoma and SCLC4,7. Therefore, lung adenocarcinoma arising from these alveolar type II cells and harboring EGFR mutations might transdifferentiate to SCLC under the selective pressure of TKI therapy. Genomic sequencing of tumor samples from repeated biopsies of lung adenocarcinoma progressing on TKIs revealed, in fact, that SCLC retained the same EGFR mutation type of the adenocarcinoma counterpart 8,9. Of course, these SCLC transformed tumors also harbored activating mutations in PIK3CA, inactivating 8
mutations of TP53 , and RB1 loss that are common features associated with the SCLC phenotype. Due of the rarity of this phenomenon, only few case reports and small series have been published so far
8-32
.
In this study, we reviewed the literature of all reported cases of SCLC diagnosed in patients treated with TKIs for EGFR-mutated or ALK-rearranged lung adenocarcinoma. The aim was to obtain explorative information on the clinical and pathological characteristics and the prognosis of the identified patients with a transformed SCLC phenotype.
PATIENTS AND METHODS Search Strategy A systematic search of the literature was applied using PubMed/Medline (US National Library of Medicine National Institutes of Health) database (2006 to present) with the following keywords: “transformation from
NSCLC to SCLC”, “NSCLC transformation in SCLC”, “resistance to TKIs”, “TKIs treatment”. Search results were limited to human studies without restriction for language. A manual review of reference lists in relevant publications was also carried out to identify additional articles. Conversely, abstracts from scientific meetings were not included in the systematic literature search. For duplicated publications, we selected the most recent version. The PRISMA flow diagram showing the selection process for this systematic review is depicted in Figure 1. Inclusion and Exclusion Criteria Case studies were eligible if they reported a histopathological transformation to SCLC after a prior history of lung adenocarcinoma treated with TKIs (gefitinib, erlotinib or crizotinib). SCLC should be diagnosed in highquality tumor biopsies or well-preserved cytological samples according to the 2015 WHO classification33. In a fraction of the reported cases, data of SCLC transformation has been supported by morphological and phenotypic characteristics. Specifically, reactivity for TTF-1, a typical adenocarcinoma marker, was found to combine with classical neuroendocrine markers (i.e CD56, synaptophysin and chromogranin) and a high proliferation index by ki67, confirming the occurrence of SCLC. Statistical Analysis Demography, tumor characteristics, treatment modalities and outcomes of all published patients were extracted from the full-length articles by two of the authors (E.R. and C.G.). Data were included in a specific database and analyzed as a case series. We defined the time to SCLC transformation (ttSCLC) as the time elapsing from the initial pathologic diagnosis of advanced-stage lung adenocarcinoma to the additional biopsy revealing the metachronous SCLC phenotype. Survival curves were computed using the Kaplan-Meier method and compared with the log-rank test. Exploratory analyses were performed using Cox proportional hazards regression models to test the prognostic value of patient and tumor characteristics (hazard ratios and 95% CIs) for overall survival (OS). P values <.05 (two-sided) were considered statistically significant. All statistical analyses were performed using Statistica software version 8 (StatSoft Inc., Tulsa, OK) and SPSS version 17.0 (SPSS, Chicago, IL).
RESULTS Search results and characteristics of the included studies Our search strategy identified a total of 398 articles (Figure 1). Among these, 25 articles were relevant reports of patients with histopathological transformation from lung adenocarcinoma to SCLC after TKI 9-16, 18-32
therapy
8-26, 28-32
. Of these 25 articles, 24 were in English language
, and one was in Japanese
language27. A total of 39 patients with transformed SCLC from a prior adenocarcinoma were therefore identified.
Patients characteristics Table 1 summarizes the characteristics of the 39 identified patients; seven were males (19.4%) and 29 females (80.6%). Median age was 56 yrs (range 36-80). All had a diagnosis of advanced-stage lung adenocarcinoma (TNM stage IIIb or IV) with EGFR mutation positivity (37/39) or ALK rearrangement (2/39). The EGFR mutation profile at diagnosis was as following: exon 19 mutations were observed in 19 patients (57.5%), and exon 21 mutations in nine patients (27.3%). Three patients had multiple mutations (one patient in exons 19, 20, 21, and T790M mutation, and two patients in exons 19 and T790M mutation). In one case the EGFR status was wild-type at diagnosis but become mutated on exon 19 at disease progression suggesting a false negative result at first diagnosis. In six patients an EGFR mutation was generically reported without specifying the exon involved. No mutation was described in exon 18 or 20. The remaining two patients (6%) presented an ALK rearrangement. The smoking status, available in 29 patients, was positive in six patients (20.7%): five patients were current smokers, and one was a former smoker. Twenty-three patients (79.3%) were never smokers. Among the 37 patients with EGFR-positive disease (including the patient with EGFR wild-type disease at diagnosis that became mutated at exon 19 at progression), 26 patients (66.7%) received a TKI as first-line therapy, eight patients (20.5%) as second-line therapy, and one patient (2.6%) as third-line therapy. In 35 patients (89.7%) the TKI was interrupted at disease progression and never re-introduced. In four patients (10.2%) the TKI treatment was subsequently re-introduced as a third-line approach. Thirty-seven patients (94.9%) received 1st and 2nd generation TKIs, while only 2 patients were treated with a 3rd generation TKI (Osimertnib)24. The median duration of TKI therapy was 18.0 months (range 1-47 months). Predictors of SCLC transformation The estimated median time to SCLC transformation was 19 months (range 1-61 months) (Figure 2). In the univariate analysis, female gender was a significant predictor of longer ttSCLC (HR, 0.21; 95% CI, 0.08-0.54; p = 0.001). TKI therapy administered as first-line treatment was associated with a non-significant delayed in SCLC onset as opposed to second-line treatment (HR, 0.59; 95% CI, 0.26-1.31; p = 0.192), while tobacco smoking (either former or current) was associated with an earlier occurrence of SCLC phenotype of borderline significance (HR, 2.32; 95% CI, 0.88-6.13; p = 0.09). Age and mutation type (exon 19 vs. exon 21) were not associated with ttSCLC (Figure 4). The association between female gender and SCLC transformation was maintained in the multivariate analysis after adjusting for smoking status and line of TKI therapy. Survival after SCLC transformation Information on survival status after SCLC diagnosis was available in 17 patients (43.6%). Sixteen were st
nd
treated with 1 and 2
generation TKIs before the SCLC transformation and only one received Osimertinib.
The calculated median OS after SCLC diagnosis was 6 months (range, 1 to 11 months) (Figure 3a). Sixteen patients (84.2%) were treated with systemic chemotherapy (platinum plus etoposide) and two patients (10.5%) with combined chemo-radiotherapy. The remaining patient was referred to palliative care early after pathologic conversion to SCLC.
st
nd
The median survival after SCLC transformation was 6 months in the sixteen patients treated with 1 and 2 generation TKIs. The only patients treated with Osimertinib survived 2 months.
Smoking status was the only factor significantly associated with shorter survival after diagnosis of SCLC (Figure 3b). Sex, age, and line of TKI therapy did not predict the patients’ outcome. Moreover, the ttSCLC (dichotomized at the median value) failed to impact patient survival from the time of SCLC transformation.
DISCUSSION SCLC is an aggressive subtype of lung cancer that often arises de novo. Metachronous SCLC has also been diagnosed in repeated biopsies from NSCLC patients who had previously received cytotoxic chemotherapy 810, 12-15
. Although the transformation from one phenotype to another cannot be ruled out in principle, a
plausible interpretation of these observations is that a combined-histology may be present at diagnosis (not revealed by the first biopsy), and the appearance of a pure SCLC could be a consequence of a treatmentinduced clonal selection. Since the introduction in clinical practice of therapies targeting EGFR, such as gefitinib, erlotinib or afatinib, the occurrence of the SCLC phenotype has been described as a mechanism of resistance to these agents4,7. In the present analysis that included 39 patients from published case studies, the proportion of female patients (80%) seemed to be higher as compared with the general population diagnosed with EGFR-mutated or ALK-rearranged lung cancer (ranging from 57% to 79.5%). Median age (55.5 years) was also lower than EGFR-mutated NSCLC patients treated with TKIs in clinical trials (ranging from 57 to 65 years)5, 34-46. It is well-known that patients with EGFR mutations are usually non-smokers, so the proportion of smoking patients in our series (17.2%) appears to be not negligible. As mentioned above, all SCLC cases maintained the same EGFR mutation present in the former adenocarcinomas. The persistence of the same EGFR mutation suggests that the SCLC phenotype is clonally derived from the primary adenocarcinoma, and distinguishes these transformed tumors from primary SCLC, in which EGFR mutations are extremely rare4. EGFR mutations, however, involved only exons 19 and 21, while no mutation on exons 18 or 20 was reported in our study population. Moreover, the T790M mutation was detected in a lower proportion of cases (3.8%) than reported in the literature47. In 16 out of 39 patients, for whom survival outcome after SCLC diagnosis was available, the estimated median survival was poor (6 months), and apparently inferior to what expected in primary SCLC with extensive-disease (median survival ranging from 8 to 13 months)48. On the contrary, the time from the first diagnosis of lung adenocarcinoma to the onset of SCLC phenotype was remarkably long (19 months, range 1-61 months), and appears to be longer than the progression-free survival (PFS) reported in patients treated with TKIs in prospective clinical trials (8-11 months). This observation suggests that long-term exposure to TKI may be required for SCLC transformation and patients obtaining a long-term benefit with these drugs are at higher risk of to transdifferentiation to a SCLC phenotype at progression. Thus, SCLC transformation might be favored by the novel TKIs targeting the 4
T790M mutation, as these drugs consistently prolong the tumor exposure to TKI therapy . Moreover, since
NSCLC patients harboring mutations on exons 18 and 20 are destined to obtain a limited benefit from TKIs
49-
52
, this could be one of the reasons why these rare mutations were not present in our identified cases.
In this study, we also analyzed factors potentially predicting SCLC transformation and showed that female gender was an independent variable associated with longer ttSCLC. In a recent meta-analysis of randomized 4
trials comparing TKI inhibitors with chemotherapy in EGFR-mutated lung adenocarcinoma , the PFS improvement with TKI therapy was greater in women than in men. Our data, therefore, suggest that gender correlates with the occurrence of TKI resistance but is not specifically associated with the transformation to a SCLC phenotype. 4
In the same meta-analysis , smoking status and exon 19 mutations were two additional predictors of PFS improvement with TKIs. In our case series, smoking status was associated with a trend for an earlier appearance of the SCLC phenotype at progression to TKI therapy. However, we did not show any predictive effect of exon 19 or 21 mutations. The smoking status was the only variable that seems to predict overall survival after SCLC transformation. The negative prognostic value of smoking had been previously reported in a series of primary SCLC patients undergoing chemotherapy53. The low number of cases included in our study, however, limits the generalization of the results. The mechanisms underlying the NSCLC-to-SCLC transformation after TKI therapy still remains unclear and there is a need of predicting markers. In a recently published paper, Lee et al provided novel and interesting insights54. These authors found that in patients destined to develop the SCLC phenotype after TKI, inactivation of p53 and Rb1 was frequent in tumor biopsies performed at baseline conditions (before TKI start), while it was uncommon in tumor tissues of patients in which the subsequent SCLC transformation was not observed. These data suggest that assessing p53 and Rb1 status of patients with EGFR mutant lung adenocarcinoma at diagnosis may be of help to predict which tumors most likely will transform to SCLC. However, as correctly pointed out in the editorial accompanying this article55, it is unclear why in patients with tumor harboring p53 and Rb1 mutations the SCLC development take several months to occur (17 months on average in the present study). The authors suggest that a subsequent epigenetic changes may favor the outgrowth of the SCLC sub-clone. If confirmed, these data provide a rationale to study epigenetic modifiers as a potential treatment strategy in patients with transformed SCLC, in whom currently available treatments are unefficacious, as shown in this paper. A major limitation of the present study is that the patient data were retrospectively collected from published articles. The optimal approach is to analyze a prospective cohort of patients with SCLC transformation according to standardized diagnostic criteria from a prior lung adenocarcinoma to gather information on the conversion rate to SCLC during TKI therapy. In conclusion, our pooled analysis shows that the achievement of the SCLC phenotype is a late phenomenon during TKI therapy and the prognosis of patients after SCLC diagnosis is poor. Current treatment strategies, adopted in the management of primary SCLC, appear to be largely inefficacious in transformed SCLC, and novel treatment approaches are needed.
Acknowledgements This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors. The study was supported in part by donations of ‘‘gli Amici di Carlo’’ in memory of Carlo Ridon and ‘‘gli Amici di Andrea’’ in memory of Andrea Gadeschi. Conflict of interests
The authors declare no conflict of interest.
Legends to figures
Figure 1: PRISMA Flow Chart Flow chart of study selection
Figure 2: Time to Small Cell Lung Cancer
Kaplan-Meier estimates of time from initial diagnosis of lung adenocarcinoma to development of neuroendocrine lung cancer (SCLC= Small Cell Lung Cancer)
Figure 3: Overall Survival after occurrence of SCLC
Kaplan-Meier estimates of overall survival after SCLC diagnosis (3A). Overall survival after SCLC diagnosis according to the smoking status (current and previous smokers vs never smokers) (3B). (SCLC= Small Cell Lung Cancer)
Figure 4: Forest Plots
Forest plots of the effect of several factors on time from start of TKI treatment to development of SCLC phenotype. (TKI= Tyrosine Kinase Inhibitors, SCLC= Small Cell Lung Cancer)
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: A Cancer Journal for Clinicians. 2016;66:7-30. 2. Ettinger DS, Aisner J. Changing face of small-cell lung cancer: real and artifact. J Clin Oncol. 2006;24:4526-7. 3. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med. 2011;32:605-44. 4. Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. The Lancet Oncology. 2015;16:e165-e72. 5. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. The New England journal of medicine. 2009;361:947-57. 6. Engelman JA, Janne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res. 2008;14:2895-9. 7. Shi X, Duan H, Liu X, Zhou L, Liang Z. Genetic alterations and protein expression in combined small cell lung cancers and small cell lung cancers arising from lung adenocarcinomas after therapy with tyrosine kinase inhibitors. Oncotarget. 2016. 8. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26. 9. Norkowski E, Ghigna MR, Lacroix L, Le Chevalier T, Fadel E, Dartevelle P, et al. Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology. J Thorac Oncol. 2013;8:1265-71. 10. Popat S, Wotherspoon A, Nutting CM, Gonzalez D, Nicholson AG, O'Brien M. Transformation to "high grade" neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma. Lung Cancer. 2013;80:1-4. 11. Cha YJ, Cho BC, Kim HR, Lee HJ, Shim HS. A Case of ALK-Rearranged Adenocarcinoma with Small Cell Carcinoma-Like Transformation and Resistance to Crizotinib. J Thorac Oncol. 2016;11:e55-8. 12. Zakowski MF, Ladanyi M, Kris MG, Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome G. EGFR mutations in small-cell lung cancers in patients who have never smoked. The New England journal of medicine. 2006;355:213-5. 13. van Riel S, Thunnissen E, Heideman D, Smit EF, Biesma B. A patient with simultaneously appearing adenocarcinoma and small-cell lung carcinoma harbouring an identical EGFR exon 19 mutation. Ann Oncol. 2012;23:3188-9. 14. Morinaga R, Okamoto I, Furuta K, Kawano Y, Sekijima M, Dote K, et al. Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation. Lung Cancer. 2007;58:411-3. 15. Watanabe S, Sone T, Matsui T, Yamamura K, Tani M, Okazaki A, et al. Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma. Lung Cancer. 2013;82:370-2. 16. Kim WJ, Kim S, Choi H, Chang J, Shin HJ, Park CK, et al. Histological transformation from non-small cell to small cell lung carcinoma after treatment with epidermal growth factor receptor-tyrosine kinase inhibitor. Thorac Cancer. 2015;6:800-4. 17. Zhang Y, Li XY, Tang Y, Xu Y, Guo WH, Li YC, et al. Rapid increase of serum neuron specific enolase level and tachyphylaxis of EGFR-tyrosine kinase inhibitor indicate small cell lung cancer transformation from EGFR positive lung adenocarcinoma? Lung Cancer. 2013;81:302-5. 18. Fujita S, Masago K, Katakami N, Yatabe Y. Transformation to SCLC after Treatment with the ALK Inhibitor Alectinib. J Thorac Oncol. 2016;11:e67-72. 19. Kuiper JL, Heideman DA, Thunnissen E, Paul MA, van Wijk AW, Postmus PE, et al. Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. Lung Cancer. 2014;85:19-24. 20. Alam N, Gustafson KS, Ladanyi M, Zakowski MF, Kapoor A, Truskinovsky AM, et al. Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinib-responsive adenocarcinoma of the lung. Clin Lung Cancer. 2010;11:E1-4. 21. Tatematsu A, Shimizu J, Murakami Y, Horio Y, Nakamura S, Hida T, et al. Epidermal growth factor receptor mutations in small cell lung cancer. Clin Cancer Res. 2008;14:6092-6. 22. Varghese AM, Zakowski MF, Yu HA, Won HH, Riely GJ, Krug LM, et al. Small-cell lung cancers in patients who never smoked cigarettes. J Thorac Oncol. 2014;9:892-6. 23. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-7. 24. Jun Soo Ham SK, Hee Kyung Kim, Seonggyu Byeon, Jong-Mu Sun, Se-hoon Lee, Jin Seok Ahn, Keunchil Park,
Yoon-La Choi, Joungho Han, Woongyang Park, Myung-Ju Ahn. Two cases of small cell lung cancer transformation from EGFR mutant adenocarcinoma during AZD9291 treatment. Journal of Thoracic Oncology.11(1):e1-e4. 25. Xue S, Yu T, Zhang Y, Shan L. [Clinical Observation of Translating to Small Cell Lung Cancer Following Treatment with EGFR-Tyrosine Kinase Inhibitors in Lung Adenocarcinoma]. Zhongguo Fei Ai Za Zhi. 2015;18:656-60. 26. Furugen M, Uechi K, Hirai J, Aoyama H, Saio M, Yoshimi N, et al. An Autopsy Case of Two Distinct, Acquired Drug Resistance Mechanisms in Epidermal Growth Factor Receptor-mutant Lung Adenocarcinoma: Small Cell Carcinoma Transformation and Epidermal Growth Factor Receptor T790M Mutation. Intern Med. 2015;54:2491-6. 27. Haruna Masaki SI, Yuichiro Takeda, Sho Watanabe, Masayuki Hojo, Haruhito Sugiyama. A case of lung adenocarcinoma that transformed to small cell carcinoma. Annals of The Japanese Respiratory Society. 2014;3:7. 28. Jiang SY, Zhao J, Wang MZ, Huo Z, Zhang J, Zhong W, et al. Small-Cell Lung Cancer Transformation in Patients With Pulmonary Adenocarcinoma: A Case Report and Review of Literature. Medicine (Baltimore). 2016;95:e2752. 29. Suda K, Murakami I, Sakai K, Mizuuchi H, Shimizu S, Sato K, et al. Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer. Sci Rep. 2015;5:14447. 30. Hwang KE, Jung JW, Oh SJ, Park MJ, Shon YJ, Choi KH, et al. Transformation to small cell lung cancer as an acquired resistance mechanism in EGFR-mutant lung adenocarcinoma: a case report of complete response to etoposide and cisplatin. Tumori. 2015;101:e96-8. 31. Piotrowska Z, Niederst MJ, Karlovich CA, Wakelee HA, Neal JW, Mino-Kenudson M, et al. Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor. Cancer Discov. 2015;5:713-22. 32. Fallet V, Ruppert AM, Poulot V, Lacave R, Belmont L, Antoine M, et al. Secondary resistance to erlotinib: acquired T790M mutation and small-cell lung cancer transformation in the same patient. J Thorac Oncol. 2012;7:1061-3. 33. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JH, Beasley MB, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015;10:1243-60. 34. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-34. 35. Yang JC-H, Wu Y-L, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. The Lancet Oncology. 2015;16:141-51. 36. Wu Y-L, Zhou C, Hu C-P, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. The Lancet Oncology. 2014;15:213-22. 37. Park K, Tan E-H, O'Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. The Lancet Oncology. 2016;17:577-89. 38. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29:2866-74. 39. Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014;110:55-62. 40. Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30:1122-8. 41. Mitsudomi T. Dacomitinib: another option for EGFR-mutant lung cancer? The Lancet Oncology. 2014;15:1408-9. 42. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for nonsmall-cell lung cancer with mutated EGFR. The New England journal of medicine. 2010;362:2380-8. 43. Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013;24:54-9. 44. Zhou C, Wu Y-L, Chen G, Feng J, Liu X-Q, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. The Lancet Oncology. 2011;12:735-42. 45. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 2015;26:1877-83. 46. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. The Lancet Oncology. 2012;13:239-46. 47. Kawamura T, Kenmotsu H, Taira T, Omori S, Nakashima K, Wakuda K, et al. Rebiopsy for Patients with NonSmall-Cell Lung Cancer after Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Failure. Cancer Sci. 2016.
48. Sculier JP, Chansky K, Crowley JJ, Van Meerbeeck J, Goldstraw P, International Staging C, et al. The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumors and the proposals for the 7th Edition. J Thorac Oncol. 2008;3:457-66. 49. Baek JH, Sun JM, Min YJ, Cho EK, Cho BC, Kim JH, et al. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer except both exon 19 deletion and exon 21 L858R: a retrospective analysis in Korea. Lung Cancer. 2015;87:148-54. 50. Kobayashi S, Canepa HM, Bailey AS, Nakayama S, Yamaguchi N, Goldstein MA, et al. Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2013;8:45-51. 51. Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. The Lancet Oncology. 2012;13:e23-e31. 52. Peng L, Song ZG, Jiao SC. Efficacy analysis of tyrosine kinase inhibitors on rare non-small cell lung cancer patients harboring complex EGFR mutations. Sci Rep. 2014;4:6104. 53. Rossi A, Garassino MC, Cinquini M, Sburlati P, Di Maio M, Farina G, et al. Maintenance or consolidation therapy in small-cell lung cancer: a systematic review and meta-analysis. Lung Cancer. 2010;70:119-28. 54. June-Koo Lee, Junehawk Lee, Sehui Kim, Soyeon Kim, Jeonghwan Youk, Seongyeol Park, Yohan An, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Young Tae Kim, Jin-Soo Kim, Se Hyun Kim, Jong Seok Lee, Se-Hoon Lee, Keunchil Park, Ja-Lok Ku, Yoon Kyung Jeon, Doo Hyun Chung, Peter J. Park, Joon Kim, Tae Min Kim, and Young Seok Ju. Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas. Journal of Clinical Oncology. 2017;12. 55. Farago AF, Piotrowska Z, Sequist LV. Unlocking the Mystery of Small-Cell Lung Cancer Transformation in EGFR Mutant Adenocarcinoma. J Clin Oncol. 2017; 73.
Case no.
Report year
Age (years)
Gender
Smoking status
TKI therapy line
Time to SCLC transformation
1
2013
46
M
2nd line
28 months
2
2015
72
M
Non smoker Ex smoker
2nd line
8 months
3
2006
45
F
1st line
22 months
4
2011
40
F
1st line
38 months
5
2011
67
F
1st line
22 months
6
2011
54
F
Non smoker Non smoker Non smoker Smoker
1st line
35 months
7
2011
56
F
1st line
14 months
8
2011
61
F
Non smoker Smoker
1st line
18 months
9
2011
42
F
2007
46
F
2nd and 4th line 3rd line
24 months
10 11
2013
60
F
Non smoker Non smoker Non smoker
1st line
31 months
12
2013
50
F
1st line
14 months
13
2013
52
F
2nd line
20 months
14
2015
73
M
Non smoker Non smoker Smoker
1st line
6 months
15
2013
80
M
Non
2nd line
1 months
31 months
Mutational status of metachronous tumor sample EGFR+ exon 19 ALK rearrangment EGFR+ exon 19 EGFR+ exon 19 EGFR+ exon 21 EGFR+ exon 19 EGFR+ exon 21 EGFR+ exon 21 EGFR+ exon 19 EGFR+ exon 19 EGFR+ exon 19+20+ 21+T790M EGFR+ exon 19 EGFR+ exon 19 EGFR+ exon 21 EGFR+
Treatment Survival after SCLC time after diagnosis SCLC diagnosis RT+CT 8 months
Reference no.
na
1 months
13
CT
7 months
14
na
na
10
na
na
10
na
na
10
na
na
10
na
na
10
na
9 months
15
CT
6 months
16
CT
8 months
11
CT
9 months
11
CT
3 months
17
CT
3 months
18
CT
6 months
19
12
16
2016
67
F
17
2014
na
na
18
2010
73
F
19
2008
36
F
20
2014
na
F
21
2014
na
F
22
2014
na
F
23
2014
na
24
2013
25
smoker Non smoker na
rd
3 and 7 line 1st line
th
38 months na
Non smoker Non smoker Non smoker Non smoker Non smoker
2nd and 3rd line 2nd line
61 months
1st line
15 months
1st line
na
1st line
na
F
Non smoker
1st line
na
67
F
na
1st line
22 months
2013
54
F
na
1st line
36 months
26
2013
56
F
na
1st line
14 months
27
2013
40
F
na
1st line
24 months
28
2013
61
F
na
1st line
18 months
29
2015
57
F
1st line
36 months
30
2015
58
F
2nd line
51 months
31
2015
49
F
Non smoker Non smoker na
1st line
na
na
exon 19 ALK rearrangment EGFR+ exon 19 EGFR+ exon 21 na EGFR+ exon 19 EGFR+ exon 19 EGFR+ exon 19+T790M EGFR+ exon 19+T790M EGFR+ exon 21 EGFR+ exon 19 EGFR+ exon 21 EGFR+ exon 19 EGFR+ exon 21 EGFR+ exon 21 EGFR+ exon 19 na
CT
na
20
CT
na
21
CT
4 months
22
na
23
CT
na
24
CT
na
24
na
na
24
na
na
24
na
na
25
na
na
25
na
na
25
na
na
25
na
na
25
CT
2 months
26
CT
na
26
na
na
27
32
2015
63
M
Non smoker
1st line
10 months
na
33 34
2014 2016
59 46
F M
2nd line 1st line
na 14 months
na na
35
2015
76
F
2nd line
8 months
36
2015
61
M
na Non smoker Non smoker Smoker
1st line
12 months
37 38 39
2015 2015 2012
na na 44
na na F
na na Smoker
1st line 1st line 2nd, 5th and 6th line
7 months 12 months 15 months
EGFR+ exon 19 EGFR+ exon 19 na na EGFR+ exon 19
Supportive care (no CT or RT) na RT+CT
11 months
28
na 11 months
29 30
na
na
31
CT
2 months
32
na na CT
na na 4 months
33 33 34
Table 1 Patients Characteristics Clinical characteristics and outcome of patients with EGFR-mutated lung adenocarcinoma transforming to SCLC. (EGFR= epidermal growth factor receptor; SCLC= small cell lung cancer; TKI= tyrosine kinase inhibitor)
PRISMA flow-chart Records identified through database searching (n=398) Records excluded, with reasons 1. SCLC harboring de novo EGFR mutations (n=48) Records screened on basis of title and abstract (n=248)
2. Transition from SCLC to NSCLC (n=5) 3. Animal model studies (n=17)
N
4. Cell line studies (n=55)
(n=248)
5. Did not meet inclusion criteria (n=123)
(n=286)
6. Not in vivo study (n=5)
Articles excluded, with reasons Full-text articles assessed for eligibility (n=150)
Studies included in the pooled analysis (n=25)
1. Duplicates (n=100) 2. Transformation to SCLC cytotoxic therapy (n=25)
after
Fig 2
Fig 3a
Fig 3b
Figure 4
P value
Gender
0,211
,001
Age
0,917
,825
Smoke
2,318
Exon 19 vs 21
,090
0,992
TKI line (1st vs subsequent)
0
,985
0,586
0,25 0,5
0,75 1
,192
2
3
4
5
6
Highlights
The occurrence of small cell lung cancer (SCLC) is one of the mechanisms by which non small cell
lung carcinomas (NSCLCs) with epidermal growth factor (EGFR) mutation or ALK rearrangement achieve resistance to specific TKI inhibitors. The mechanism underlying this transition has not been elucidated in detail yet and could based on a clonal selection or on a real transdifferentiation.
SCLC phenotype occurs after a long term exposure of TKI therapy.
The prognosis of patients with transformed SCLC from NSCLC after TKI treatment is poor (6 months
on average) and is influenced by the smoking status.
Current treatment strategies adopted for primary SCLC are largely unefficacious in transformed
SCLC patients.
S0305-7372(17)30121-4 http://dx.doi.org/10.1016/j.ctrv.2017.07.007 YCTRV 1656
To appear in:
Cancer Treatment Reviews Cancer Treatment Reviews
Received Date: Revised Date: Accepted Date:
29 July 2016 21 July 2017 22 July 2017
Please cite this article as: Roca, 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 Treatment Reviews Cancer Treatment Reviews (2017), doi: http://dx.doi.org/10.1016/j.ctrv.2017.07.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: A Systematic Review and Pooled Analysis. Elisa Roca, Cristina Gurizzan, Vito Amoroso, William Vermi, Vittorio Ferrari, Alfredo Berruti University of Brescia, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology and Department of Molecular and Translational Medicine Section of Pathology, at Spedali Civili Hospital, Brescia (Italy).
Corresponding author: Alfredo Berruti Oncologia Medica Università degli Studi di Brescia Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica Azienda Ospedaliera Spedali Civili Piazzale Spedali Civili, 1 25123 BRESCIA ( Italy) tel +39 030 3995410 email: [email protected]
ABSTRACT Background Lung adenocarcinoma can transform to small-cell lung cancer (SCLC) when resistance to tyrosine kinase inhibitors (TKIs) develops. This phenomenon has repeatedly been described in several case reports and small patient series. The characteristics and treatment outcomes of this population, however, have not been comprehensively reported. Methods We performed a systematic review of the published literature to obtain explorative information on the clinical and pathological features and prognosis of the reported cases. Results Twenty-five eligible publications were identified, contributing to 39 patients. The median time from initial diagnosis of lung adenocarcinoma to the transformation to SCLC (ttSCLC) was 19 months (range 1-61 months). The median survival after SCLC diagnosis was 6 months. Female gender was significantly associated with longer ttSCLC at the multivariable analysis. Smoking status seemed to be associated with worse prognosis after the diagnosis of SCLC. Conclusion In this series of published cases, the transformation to a SCLC phenotype after an initial diagnosis of lung adenocarcinoma following TKI therapy appeared to be a late phenomenon. The prognosis after SCLC diagnosis is poor and current treatment strategies derived from primary SCLC seem to be largely inefficacious. New therapies are needed in the management of transformed SCLC.
INTRODUCTION Lung cancer is the leading cause of cancer-related death. It accounts for 353,000 deaths in the European Union and about 160,000 deaths in the United States1. In the past decades, only two different lung cancer subtypes were recognized: non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC, which represents about 85% of all cases, arises from the respiratory epithelium, and it is further divided into two major histological subtypes: adenocarcinoma and squamous-cell carcinoma. SCLC, accounting for the remaining 15% of cases, is a highly aggressive tumor of neuroendocrine origin, which is characterized by rapid disease progression and early development of 2-4
metastases . Adenocarcinoma is nowadays the most common histological subtype, it represents about one-half of all lung tumors. The discovery of the epidermal growth factor receptor (EGFR) mutations and the anaplastic lymphoma kinase (ALK) rearrangements led to the development of novel targeted therapies, acting as specific EGFR and ALK tyrosine kinase inhibitors (TKIs). These drugs have consistently improved the patient outcomes but are not curative, and disease progression inevitably occurs after a median time of about 12 months5,6. Several mechanisms underlie the development of acquired resistance to TKIs, and among them, the transformation from adenocarcinoma to a SCLC phenotype was recently reported4,7. The potential mechanisms underlying the SCLC phenotype conversion after TKI therapy have been discussed in details elsewhere4,7. Historically, SCLC was believed to develop from neuroendocrine cells of central airways, whereas adenocarcinoma derives from the alveolar type II cells located in the alveolar surface area. Several studies have shown that alveolar type II cells may be common precursors of both lung adenocarcinoma and SCLC4,7. Therefore, lung adenocarcinoma arising from these alveolar type II cells and harboring EGFR mutations might transdifferentiate to SCLC under the selective pressure of TKI therapy. Genomic sequencing of tumor samples from repeated biopsies of lung adenocarcinoma progressing on TKIs revealed, in fact, that SCLC retained the same EGFR mutation type of the adenocarcinoma counterpart 8,9. Of course, these SCLC transformed tumors also harbored activating mutations in PIK3CA, inactivating 8
mutations of TP53 , and RB1 loss that are common features associated with the SCLC phenotype. Due of the rarity of this phenomenon, only few case reports and small series have been published so far
8-32
.
In this study, we reviewed the literature of all reported cases of SCLC diagnosed in patients treated with TKIs for EGFR-mutated or ALK-rearranged lung adenocarcinoma. The aim was to obtain explorative information on the clinical and pathological characteristics and the prognosis of the identified patients with a transformed SCLC phenotype.
PATIENTS AND METHODS Search Strategy A systematic search of the literature was applied using PubMed/Medline (US National Library of Medicine National Institutes of Health) database (2006 to present) with the following keywords: “transformation from
NSCLC to SCLC”, “NSCLC transformation in SCLC”, “resistance to TKIs”, “TKIs treatment”. Search results were limited to human studies without restriction for language. A manual review of reference lists in relevant publications was also carried out to identify additional articles. Conversely, abstracts from scientific meetings were not included in the systematic literature search. For duplicated publications, we selected the most recent version. The PRISMA flow diagram showing the selection process for this systematic review is depicted in Figure 1. Inclusion and Exclusion Criteria Case studies were eligible if they reported a histopathological transformation to SCLC after a prior history of lung adenocarcinoma treated with TKIs (gefitinib, erlotinib or crizotinib). SCLC should be diagnosed in highquality tumor biopsies or well-preserved cytological samples according to the 2015 WHO classification33. In a fraction of the reported cases, data of SCLC transformation has been supported by morphological and phenotypic characteristics. Specifically, reactivity for TTF-1, a typical adenocarcinoma marker, was found to combine with classical neuroendocrine markers (i.e CD56, synaptophysin and chromogranin) and a high proliferation index by ki67, confirming the occurrence of SCLC. Statistical Analysis Demography, tumor characteristics, treatment modalities and outcomes of all published patients were extracted from the full-length articles by two of the authors (E.R. and C.G.). Data were included in a specific database and analyzed as a case series. We defined the time to SCLC transformation (ttSCLC) as the time elapsing from the initial pathologic diagnosis of advanced-stage lung adenocarcinoma to the additional biopsy revealing the metachronous SCLC phenotype. Survival curves were computed using the Kaplan-Meier method and compared with the log-rank test. Exploratory analyses were performed using Cox proportional hazards regression models to test the prognostic value of patient and tumor characteristics (hazard ratios and 95% CIs) for overall survival (OS). P values <.05 (two-sided) were considered statistically significant. All statistical analyses were performed using Statistica software version 8 (StatSoft Inc., Tulsa, OK) and SPSS version 17.0 (SPSS, Chicago, IL).
RESULTS Search results and characteristics of the included studies Our search strategy identified a total of 398 articles (Figure 1). Among these, 25 articles were relevant reports of patients with histopathological transformation from lung adenocarcinoma to SCLC after TKI 9-16, 18-32
therapy
8-26, 28-32
. Of these 25 articles, 24 were in English language
, and one was in Japanese
language27. A total of 39 patients with transformed SCLC from a prior adenocarcinoma were therefore identified.
Patients characteristics Table 1 summarizes the characteristics of the 39 identified patients; seven were males (19.4%) and 29 females (80.6%). Median age was 56 yrs (range 36-80). All had a diagnosis of advanced-stage lung adenocarcinoma (TNM stage IIIb or IV) with EGFR mutation positivity (37/39) or ALK rearrangement (2/39). The EGFR mutation profile at diagnosis was as following: exon 19 mutations were observed in 19 patients (57.5%), and exon 21 mutations in nine patients (27.3%). Three patients had multiple mutations (one patient in exons 19, 20, 21, and T790M mutation, and two patients in exons 19 and T790M mutation). In one case the EGFR status was wild-type at diagnosis but become mutated on exon 19 at disease progression suggesting a false negative result at first diagnosis. In six patients an EGFR mutation was generically reported without specifying the exon involved. No mutation was described in exon 18 or 20. The remaining two patients (6%) presented an ALK rearrangement. The smoking status, available in 29 patients, was positive in six patients (20.7%): five patients were current smokers, and one was a former smoker. Twenty-three patients (79.3%) were never smokers. Among the 37 patients with EGFR-positive disease (including the patient with EGFR wild-type disease at diagnosis that became mutated at exon 19 at progression), 26 patients (66.7%) received a TKI as first-line therapy, eight patients (20.5%) as second-line therapy, and one patient (2.6%) as third-line therapy. In 35 patients (89.7%) the TKI was interrupted at disease progression and never re-introduced. In four patients (10.2%) the TKI treatment was subsequently re-introduced as a third-line approach. Thirty-seven patients (94.9%) received 1st and 2nd generation TKIs, while only 2 patients were treated with a 3rd generation TKI (Osimertnib)24. The median duration of TKI therapy was 18.0 months (range 1-47 months). Predictors of SCLC transformation The estimated median time to SCLC transformation was 19 months (range 1-61 months) (Figure 2). In the univariate analysis, female gender was a significant predictor of longer ttSCLC (HR, 0.21; 95% CI, 0.08-0.54; p = 0.001). TKI therapy administered as first-line treatment was associated with a non-significant delayed in SCLC onset as opposed to second-line treatment (HR, 0.59; 95% CI, 0.26-1.31; p = 0.192), while tobacco smoking (either former or current) was associated with an earlier occurrence of SCLC phenotype of borderline significance (HR, 2.32; 95% CI, 0.88-6.13; p = 0.09). Age and mutation type (exon 19 vs. exon 21) were not associated with ttSCLC (Figure 4). The association between female gender and SCLC transformation was maintained in the multivariate analysis after adjusting for smoking status and line of TKI therapy. Survival after SCLC transformation Information on survival status after SCLC diagnosis was available in 17 patients (43.6%). Sixteen were st
nd
treated with 1 and 2
generation TKIs before the SCLC transformation and only one received Osimertinib.
The calculated median OS after SCLC diagnosis was 6 months (range, 1 to 11 months) (Figure 3a). Sixteen patients (84.2%) were treated with systemic chemotherapy (platinum plus etoposide) and two patients (10.5%) with combined chemo-radiotherapy. The remaining patient was referred to palliative care early after pathologic conversion to SCLC.
st
nd
The median survival after SCLC transformation was 6 months in the sixteen patients treated with 1 and 2 generation TKIs. The only patients treated with Osimertinib survived 2 months.
Smoking status was the only factor significantly associated with shorter survival after diagnosis of SCLC (Figure 3b). Sex, age, and line of TKI therapy did not predict the patients’ outcome. Moreover, the ttSCLC (dichotomized at the median value) failed to impact patient survival from the time of SCLC transformation.
DISCUSSION SCLC is an aggressive subtype of lung cancer that often arises de novo. Metachronous SCLC has also been diagnosed in repeated biopsies from NSCLC patients who had previously received cytotoxic chemotherapy 810, 12-15
. Although the transformation from one phenotype to another cannot be ruled out in principle, a
plausible interpretation of these observations is that a combined-histology may be present at diagnosis (not revealed by the first biopsy), and the appearance of a pure SCLC could be a consequence of a treatmentinduced clonal selection. Since the introduction in clinical practice of therapies targeting EGFR, such as gefitinib, erlotinib or afatinib, the occurrence of the SCLC phenotype has been described as a mechanism of resistance to these agents4,7. In the present analysis that included 39 patients from published case studies, the proportion of female patients (80%) seemed to be higher as compared with the general population diagnosed with EGFR-mutated or ALK-rearranged lung cancer (ranging from 57% to 79.5%). Median age (55.5 years) was also lower than EGFR-mutated NSCLC patients treated with TKIs in clinical trials (ranging from 57 to 65 years)5, 34-46. It is well-known that patients with EGFR mutations are usually non-smokers, so the proportion of smoking patients in our series (17.2%) appears to be not negligible. As mentioned above, all SCLC cases maintained the same EGFR mutation present in the former adenocarcinomas. The persistence of the same EGFR mutation suggests that the SCLC phenotype is clonally derived from the primary adenocarcinoma, and distinguishes these transformed tumors from primary SCLC, in which EGFR mutations are extremely rare4. EGFR mutations, however, involved only exons 19 and 21, while no mutation on exons 18 or 20 was reported in our study population. Moreover, the T790M mutation was detected in a lower proportion of cases (3.8%) than reported in the literature47. In 16 out of 39 patients, for whom survival outcome after SCLC diagnosis was available, the estimated median survival was poor (6 months), and apparently inferior to what expected in primary SCLC with extensive-disease (median survival ranging from 8 to 13 months)48. On the contrary, the time from the first diagnosis of lung adenocarcinoma to the onset of SCLC phenotype was remarkably long (19 months, range 1-61 months), and appears to be longer than the progression-free survival (PFS) reported in patients treated with TKIs in prospective clinical trials (8-11 months). This observation suggests that long-term exposure to TKI may be required for SCLC transformation and patients obtaining a long-term benefit with these drugs are at higher risk of to transdifferentiation to a SCLC phenotype at progression. Thus, SCLC transformation might be favored by the novel TKIs targeting the 4
T790M mutation, as these drugs consistently prolong the tumor exposure to TKI therapy . Moreover, since
NSCLC patients harboring mutations on exons 18 and 20 are destined to obtain a limited benefit from TKIs
49-
52
, this could be one of the reasons why these rare mutations were not present in our identified cases.
In this study, we also analyzed factors potentially predicting SCLC transformation and showed that female gender was an independent variable associated with longer ttSCLC. In a recent meta-analysis of randomized 4
trials comparing TKI inhibitors with chemotherapy in EGFR-mutated lung adenocarcinoma , the PFS improvement with TKI therapy was greater in women than in men. Our data, therefore, suggest that gender correlates with the occurrence of TKI resistance but is not specifically associated with the transformation to a SCLC phenotype. 4
In the same meta-analysis , smoking status and exon 19 mutations were two additional predictors of PFS improvement with TKIs. In our case series, smoking status was associated with a trend for an earlier appearance of the SCLC phenotype at progression to TKI therapy. However, we did not show any predictive effect of exon 19 or 21 mutations. The smoking status was the only variable that seems to predict overall survival after SCLC transformation. The negative prognostic value of smoking had been previously reported in a series of primary SCLC patients undergoing chemotherapy53. The low number of cases included in our study, however, limits the generalization of the results. The mechanisms underlying the NSCLC-to-SCLC transformation after TKI therapy still remains unclear and there is a need of predicting markers. In a recently published paper, Lee et al provided novel and interesting insights54. These authors found that in patients destined to develop the SCLC phenotype after TKI, inactivation of p53 and Rb1 was frequent in tumor biopsies performed at baseline conditions (before TKI start), while it was uncommon in tumor tissues of patients in which the subsequent SCLC transformation was not observed. These data suggest that assessing p53 and Rb1 status of patients with EGFR mutant lung adenocarcinoma at diagnosis may be of help to predict which tumors most likely will transform to SCLC. However, as correctly pointed out in the editorial accompanying this article55, it is unclear why in patients with tumor harboring p53 and Rb1 mutations the SCLC development take several months to occur (17 months on average in the present study). The authors suggest that a subsequent epigenetic changes may favor the outgrowth of the SCLC sub-clone. If confirmed, these data provide a rationale to study epigenetic modifiers as a potential treatment strategy in patients with transformed SCLC, in whom currently available treatments are unefficacious, as shown in this paper. A major limitation of the present study is that the patient data were retrospectively collected from published articles. The optimal approach is to analyze a prospective cohort of patients with SCLC transformation according to standardized diagnostic criteria from a prior lung adenocarcinoma to gather information on the conversion rate to SCLC during TKI therapy. In conclusion, our pooled analysis shows that the achievement of the SCLC phenotype is a late phenomenon during TKI therapy and the prognosis of patients after SCLC diagnosis is poor. Current treatment strategies, adopted in the management of primary SCLC, appear to be largely inefficacious in transformed SCLC, and novel treatment approaches are needed.
Acknowledgements This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors. The study was supported in part by donations of ‘‘gli Amici di Carlo’’ in memory of Carlo Ridon and ‘‘gli Amici di Andrea’’ in memory of Andrea Gadeschi. Conflict of interests
The authors declare no conflict of interest.
Legends to figures
Figure 1: PRISMA Flow Chart Flow chart of study selection
Figure 2: Time to Small Cell Lung Cancer
Kaplan-Meier estimates of time from initial diagnosis of lung adenocarcinoma to development of neuroendocrine lung cancer (SCLC= Small Cell Lung Cancer)
Figure 3: Overall Survival after occurrence of SCLC
Kaplan-Meier estimates of overall survival after SCLC diagnosis (3A). Overall survival after SCLC diagnosis according to the smoking status (current and previous smokers vs never smokers) (3B). (SCLC= Small Cell Lung Cancer)
Figure 4: Forest Plots
Forest plots of the effect of several factors on time from start of TKI treatment to development of SCLC phenotype. (TKI= Tyrosine Kinase Inhibitors, SCLC= Small Cell Lung Cancer)
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: A Cancer Journal for Clinicians. 2016;66:7-30. 2. Ettinger DS, Aisner J. Changing face of small-cell lung cancer: real and artifact. J Clin Oncol. 2006;24:4526-7. 3. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med. 2011;32:605-44. 4. Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. The Lancet Oncology. 2015;16:e165-e72. 5. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. The New England journal of medicine. 2009;361:947-57. 6. Engelman JA, Janne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res. 2008;14:2895-9. 7. Shi X, Duan H, Liu X, Zhou L, Liang Z. Genetic alterations and protein expression in combined small cell lung cancers and small cell lung cancers arising from lung adenocarcinomas after therapy with tyrosine kinase inhibitors. Oncotarget. 2016. 8. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26. 9. Norkowski E, Ghigna MR, Lacroix L, Le Chevalier T, Fadel E, Dartevelle P, et al. Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology. J Thorac Oncol. 2013;8:1265-71. 10. Popat S, Wotherspoon A, Nutting CM, Gonzalez D, Nicholson AG, O'Brien M. Transformation to "high grade" neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma. Lung Cancer. 2013;80:1-4. 11. Cha YJ, Cho BC, Kim HR, Lee HJ, Shim HS. A Case of ALK-Rearranged Adenocarcinoma with Small Cell Carcinoma-Like Transformation and Resistance to Crizotinib. J Thorac Oncol. 2016;11:e55-8. 12. Zakowski MF, Ladanyi M, Kris MG, Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome G. EGFR mutations in small-cell lung cancers in patients who have never smoked. The New England journal of medicine. 2006;355:213-5. 13. van Riel S, Thunnissen E, Heideman D, Smit EF, Biesma B. A patient with simultaneously appearing adenocarcinoma and small-cell lung carcinoma harbouring an identical EGFR exon 19 mutation. Ann Oncol. 2012;23:3188-9. 14. Morinaga R, Okamoto I, Furuta K, Kawano Y, Sekijima M, Dote K, et al. Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation. Lung Cancer. 2007;58:411-3. 15. Watanabe S, Sone T, Matsui T, Yamamura K, Tani M, Okazaki A, et al. Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma. Lung Cancer. 2013;82:370-2. 16. Kim WJ, Kim S, Choi H, Chang J, Shin HJ, Park CK, et al. Histological transformation from non-small cell to small cell lung carcinoma after treatment with epidermal growth factor receptor-tyrosine kinase inhibitor. Thorac Cancer. 2015;6:800-4. 17. Zhang Y, Li XY, Tang Y, Xu Y, Guo WH, Li YC, et al. Rapid increase of serum neuron specific enolase level and tachyphylaxis of EGFR-tyrosine kinase inhibitor indicate small cell lung cancer transformation from EGFR positive lung adenocarcinoma? Lung Cancer. 2013;81:302-5. 18. Fujita S, Masago K, Katakami N, Yatabe Y. Transformation to SCLC after Treatment with the ALK Inhibitor Alectinib. J Thorac Oncol. 2016;11:e67-72. 19. Kuiper JL, Heideman DA, Thunnissen E, Paul MA, van Wijk AW, Postmus PE, et al. Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. Lung Cancer. 2014;85:19-24. 20. Alam N, Gustafson KS, Ladanyi M, Zakowski MF, Kapoor A, Truskinovsky AM, et al. Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinib-responsive adenocarcinoma of the lung. Clin Lung Cancer. 2010;11:E1-4. 21. Tatematsu A, Shimizu J, Murakami Y, Horio Y, Nakamura S, Hida T, et al. Epidermal growth factor receptor mutations in small cell lung cancer. Clin Cancer Res. 2008;14:6092-6. 22. Varghese AM, Zakowski MF, Yu HA, Won HH, Riely GJ, Krug LM, et al. Small-cell lung cancers in patients who never smoked cigarettes. J Thorac Oncol. 2014;9:892-6. 23. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-7. 24. Jun Soo Ham SK, Hee Kyung Kim, Seonggyu Byeon, Jong-Mu Sun, Se-hoon Lee, Jin Seok Ahn, Keunchil Park,
Yoon-La Choi, Joungho Han, Woongyang Park, Myung-Ju Ahn. Two cases of small cell lung cancer transformation from EGFR mutant adenocarcinoma during AZD9291 treatment. Journal of Thoracic Oncology.11(1):e1-e4. 25. Xue S, Yu T, Zhang Y, Shan L. [Clinical Observation of Translating to Small Cell Lung Cancer Following Treatment with EGFR-Tyrosine Kinase Inhibitors in Lung Adenocarcinoma]. Zhongguo Fei Ai Za Zhi. 2015;18:656-60. 26. Furugen M, Uechi K, Hirai J, Aoyama H, Saio M, Yoshimi N, et al. An Autopsy Case of Two Distinct, Acquired Drug Resistance Mechanisms in Epidermal Growth Factor Receptor-mutant Lung Adenocarcinoma: Small Cell Carcinoma Transformation and Epidermal Growth Factor Receptor T790M Mutation. Intern Med. 2015;54:2491-6. 27. Haruna Masaki SI, Yuichiro Takeda, Sho Watanabe, Masayuki Hojo, Haruhito Sugiyama. A case of lung adenocarcinoma that transformed to small cell carcinoma. Annals of The Japanese Respiratory Society. 2014;3:7. 28. Jiang SY, Zhao J, Wang MZ, Huo Z, Zhang J, Zhong W, et al. Small-Cell Lung Cancer Transformation in Patients With Pulmonary Adenocarcinoma: A Case Report and Review of Literature. Medicine (Baltimore). 2016;95:e2752. 29. Suda K, Murakami I, Sakai K, Mizuuchi H, Shimizu S, Sato K, et al. Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer. Sci Rep. 2015;5:14447. 30. Hwang KE, Jung JW, Oh SJ, Park MJ, Shon YJ, Choi KH, et al. Transformation to small cell lung cancer as an acquired resistance mechanism in EGFR-mutant lung adenocarcinoma: a case report of complete response to etoposide and cisplatin. Tumori. 2015;101:e96-8. 31. Piotrowska Z, Niederst MJ, Karlovich CA, Wakelee HA, Neal JW, Mino-Kenudson M, et al. Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor. Cancer Discov. 2015;5:713-22. 32. Fallet V, Ruppert AM, Poulot V, Lacave R, Belmont L, Antoine M, et al. Secondary resistance to erlotinib: acquired T790M mutation and small-cell lung cancer transformation in the same patient. J Thorac Oncol. 2012;7:1061-3. 33. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JH, Beasley MB, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015;10:1243-60. 34. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-34. 35. Yang JC-H, Wu Y-L, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. The Lancet Oncology. 2015;16:141-51. 36. Wu Y-L, Zhou C, Hu C-P, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. The Lancet Oncology. 2014;15:213-22. 37. Park K, Tan E-H, O'Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. The Lancet Oncology. 2016;17:577-89. 38. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29:2866-74. 39. Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014;110:55-62. 40. Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30:1122-8. 41. Mitsudomi T. Dacomitinib: another option for EGFR-mutant lung cancer? The Lancet Oncology. 2014;15:1408-9. 42. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for nonsmall-cell lung cancer with mutated EGFR. The New England journal of medicine. 2010;362:2380-8. 43. Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013;24:54-9. 44. Zhou C, Wu Y-L, Chen G, Feng J, Liu X-Q, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. The Lancet Oncology. 2011;12:735-42. 45. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 2015;26:1877-83. 46. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. The Lancet Oncology. 2012;13:239-46. 47. Kawamura T, Kenmotsu H, Taira T, Omori S, Nakashima K, Wakuda K, et al. Rebiopsy for Patients with NonSmall-Cell Lung Cancer after Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Failure. Cancer Sci. 2016.
48. Sculier JP, Chansky K, Crowley JJ, Van Meerbeeck J, Goldstraw P, International Staging C, et al. The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumors and the proposals for the 7th Edition. J Thorac Oncol. 2008;3:457-66. 49. Baek JH, Sun JM, Min YJ, Cho EK, Cho BC, Kim JH, et al. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer except both exon 19 deletion and exon 21 L858R: a retrospective analysis in Korea. Lung Cancer. 2015;87:148-54. 50. Kobayashi S, Canepa HM, Bailey AS, Nakayama S, Yamaguchi N, Goldstein MA, et al. Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2013;8:45-51. 51. Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. The Lancet Oncology. 2012;13:e23-e31. 52. Peng L, Song ZG, Jiao SC. Efficacy analysis of tyrosine kinase inhibitors on rare non-small cell lung cancer patients harboring complex EGFR mutations. Sci Rep. 2014;4:6104. 53. Rossi A, Garassino MC, Cinquini M, Sburlati P, Di Maio M, Farina G, et al. Maintenance or consolidation therapy in small-cell lung cancer: a systematic review and meta-analysis. Lung Cancer. 2010;70:119-28. 54. June-Koo Lee, Junehawk Lee, Sehui Kim, Soyeon Kim, Jeonghwan Youk, Seongyeol Park, Yohan An, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Young Tae Kim, Jin-Soo Kim, Se Hyun Kim, Jong Seok Lee, Se-Hoon Lee, Keunchil Park, Ja-Lok Ku, Yoon Kyung Jeon, Doo Hyun Chung, Peter J. Park, Joon Kim, Tae Min Kim, and Young Seok Ju. Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas. Journal of Clinical Oncology. 2017;12. 55. Farago AF, Piotrowska Z, Sequist LV. Unlocking the Mystery of Small-Cell Lung Cancer Transformation in EGFR Mutant Adenocarcinoma. J Clin Oncol. 2017; 73.
Case no.
Report year
Age (years)
Gender
Smoking status
TKI therapy line
Time to SCLC transformation
1
2013
46
M
2nd line
28 months
2
2015
72
M
Non smoker Ex smoker
2nd line
8 months
3
2006
45
F
1st line
22 months
4
2011
40
F
1st line
38 months
5
2011
67
F
1st line
22 months
6
2011
54
F
Non smoker Non smoker Non smoker Smoker
1st line
35 months
7
2011
56
F
1st line
14 months
8
2011
61
F
Non smoker Smoker
1st line
18 months
9
2011
42
F
2007
46
F
2nd and 4th line 3rd line
24 months
10 11
2013
60
F
Non smoker Non smoker Non smoker
1st line
31 months
12
2013
50
F
1st line
14 months
13
2013
52
F
2nd line
20 months
14
2015
73
M
Non smoker Non smoker Smoker
1st line
6 months
15
2013
80
M
Non
2nd line
1 months
31 months
Mutational status of metachronous tumor sample EGFR+ exon 19 ALK rearrangment EGFR+ exon 19 EGFR+ exon 19 EGFR+ exon 21 EGFR+ exon 19 EGFR+ exon 21 EGFR+ exon 21 EGFR+ exon 19 EGFR+ exon 19 EGFR+ exon 19+20+ 21+T790M EGFR+ exon 19 EGFR+ exon 19 EGFR+ exon 21 EGFR+
Treatment Survival after SCLC time after diagnosis SCLC diagnosis RT+CT 8 months
Reference no.
na
1 months
13
CT
7 months
14
na
na
10
na
na
10
na
na
10
na
na
10
na
na
10
na
9 months
15
CT
6 months
16
CT
8 months
11
CT
9 months
11
CT
3 months
17
CT
3 months
18
CT
6 months
19
12
16
2016
67
F
17
2014
na
na
18
2010
73
F
19
2008
36
F
20
2014
na
F
21
2014
na
F
22
2014
na
F
23
2014
na
24
2013
25
smoker Non smoker na
rd
3 and 7 line 1st line
th
38 months na
Non smoker Non smoker Non smoker Non smoker Non smoker
2nd and 3rd line 2nd line
61 months
1st line
15 months
1st line
na
1st line
na
F
Non smoker
1st line
na
67
F
na
1st line
22 months
2013
54
F
na
1st line
36 months
26
2013
56
F
na
1st line
14 months
27
2013
40
F
na
1st line
24 months
28
2013
61
F
na
1st line
18 months
29
2015
57
F
1st line
36 months
30
2015
58
F
2nd line
51 months
31
2015
49
F
Non smoker Non smoker na
1st line
na
na
exon 19 ALK rearrangment EGFR+ exon 19 EGFR+ exon 21 na EGFR+ exon 19 EGFR+ exon 19 EGFR+ exon 19+T790M EGFR+ exon 19+T790M EGFR+ exon 21 EGFR+ exon 19 EGFR+ exon 21 EGFR+ exon 19 EGFR+ exon 21 EGFR+ exon 21 EGFR+ exon 19 na
CT
na
20
CT
na
21
CT
4 months
22
na
23
CT
na
24
CT
na
24
na
na
24
na
na
24
na
na
25
na
na
25
na
na
25
na
na
25
na
na
25
CT
2 months
26
CT
na
26
na
na
27
32
2015
63
M
Non smoker
1st line
10 months
na
33 34
2014 2016
59 46
F M
2nd line 1st line
na 14 months
na na
35
2015
76
F
2nd line
8 months
36
2015
61
M
na Non smoker Non smoker Smoker
1st line
12 months
37 38 39
2015 2015 2012
na na 44
na na F
na na Smoker
1st line 1st line 2nd, 5th and 6th line
7 months 12 months 15 months
EGFR+ exon 19 EGFR+ exon 19 na na EGFR+ exon 19
Supportive care (no CT or RT) na RT+CT
11 months
28
na 11 months
29 30
na
na
31
CT
2 months
32
na na CT
na na 4 months
33 33 34
Table 1 Patients Characteristics Clinical characteristics and outcome of patients with EGFR-mutated lung adenocarcinoma transforming to SCLC. (EGFR= epidermal growth factor receptor; SCLC= small cell lung cancer; TKI= tyrosine kinase inhibitor)
PRISMA flow-chart Records identified through database searching (n=398) Records excluded, with reasons 1. SCLC harboring de novo EGFR mutations (n=48) Records screened on basis of title and abstract (n=248)
2. Transition from SCLC to NSCLC (n=5) 3. Animal model studies (n=17)
N
4. Cell line studies (n=55)
(n=248)
5. Did not meet inclusion criteria (n=123)
(n=286)
6. Not in vivo study (n=5)
Articles excluded, with reasons Full-text articles assessed for eligibility (n=150)
Studies included in the pooled analysis (n=25)
1. Duplicates (n=100) 2. Transformation to SCLC cytotoxic therapy (n=25)
after
Fig 2
Fig 3a
Fig 3b
Figure 4
P value
Gender
0,211
,001
Age
0,917
,825
Smoke
2,318
Exon 19 vs 21
,090
0,992
TKI line (1st vs subsequent)
0
,985
0,586
0,25 0,5
0,75 1
,192
2
3
4
5
6
Highlights
The occurrence of small cell lung cancer (SCLC) is one of the mechanisms by which non small cell
lung carcinomas (NSCLCs) with epidermal growth factor (EGFR) mutation or ALK rearrangement achieve resistance to specific TKI inhibitors. The mechanism underlying this transition has not been elucidated in detail yet and could based on a clonal selection or on a real transdifferentiation.
SCLC phenotype occurs after a long term exposure of TKI therapy.
The prognosis of patients with transformed SCLC from NSCLC after TKI treatment is poor (6 months
on average) and is influenced by the smoking status.
Current treatment strategies adopted for primary SCLC are largely unefficacious in transformed
SCLC patients.