Small Cell Lung Cancer Transformation as a Mechanism of Resistance to PD-1 Therapy in KRAS-Mutant Lung Adenocarcinoma: A Report of Two Cases
Authors: Wade T. Iams, Kathryn E. Beckermann, Karinna Almodovar, Jennifer Hernandez, Cindy Vnencak-Jones, Lee P. Lim, Christopher K. Raymond, Leora Horn, Christine M. Lovly
Journal: Journal of Thoracic Oncology (2018)

KRAS G12C–mutant metastatic lung adenocarcinoma was diagnosed in a 67-year-old woman with a 50-pack-year smoking history (Fig. 1). The patient responded to first-line carboplatin and paclitaxel but then progressed 19 months after diagnosis. At first progression she declined a biopsy and started taking nivolumab. Two weeks after her 36th cycle of nivolumab she experienced widespread progression, including development of a pericardial effusion with tamponade requiring pericardiocentesis. The pericardial fluid and pleural fluid from a new effusion revealed SCLC. Next-generation sequencing from pleural and pericardial fluid at the time of transformation revealed no KRAS mutation, a tumor protein p53 (TP53) S315S frameshift mutation in both the pleural and pericardial fluid, and a retinoblastoma 1 gene (RB1) splice site mutation in the pleural fluid. The patient was treated first with carboplatin and etoposide and then with paclitaxel; she died 11 months after SCLC transformation and 4 years after her initial diagnosis. KRAS G12C–mutant metastatic lung adenocarcinoma was diagnosed in a 75-year-old woman with a 30-pack-year smoking history (Fig. 2). The patient responded to first-line carboplatin, paclitaxel, and bevacizumab and progressed 24 months after diagnosis. A repeat clinical trial–related biopsy revealed lung adenocarcinoma, and she received 33 cycles of nivolumab with stable disease according to the Response Criteria in Solid Tumors 1.1. After an 11-month treatment holiday, she experienced asymptomatic progression with biopsy-proven transformation to SCLC. Peripheral blood cell-free DNA analysis at the time of SCLC transformation revealed conservation of the KRAS G12C mutation at an allele frequency of 19.47% and a TP53 R273C mutation with an allele frequency of 0.55%; no RB1 mutation was detected. The patient was treated in sequence with carboplatin and etoposide, nivolumab and ipilimumab, and irinotecan monotherapy. She died 16 months after SCLC transformation and 5.5 years after the initial diagnosis. The transformation of lung adenocarcinoma to SCLC has been observed in 5% to 15% of patients treated with EGFR inhibitors.1Lee 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 (266) Google Scholar, 2Oser 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 (552) Google Scholar In contrast, the transformation of lung adenocarcinoma to SCLC during nivolumab therapy has been reported only once.3Imakita T. Fujita K. Kanai O. Terashima T. Mio T. Small cell lung cancer transformation during immunotherapy with nivolumab: a case report.Respir Med Case Rep. 2017; 21: 52-55Crossref PubMed Scopus (25) Google Scholar Many cases have been thought to represent SCLC transformation rather than a mixed histologic type at diagnosis as a result of their response to initial therapy and less aggressive clinical course than is seen with SCLC2Oser 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 (552) Google Scholar; both of these attributes are recapitulated in our cases. In our first case, loss of the initial KRAS G12C driver mutation at SCLC diagnosis raises the possibility that SCLC was a second primary malignancy; however, the initial KRAS G12C mutation was conserved in our second case, supporting the transformation hypothesis. Our cases suggest that dedifferentiation from lung adenocarcinoma to SCLC may be a mechanism of resistance to programmed death 1 blockade, an intriguing finding that links the potential shared cell of origin theory (alveolar type II cells4Sutherland K.D. Proost N. Brouns I. Adriaensen D. Song J.Y. Berns A. Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung.Cancer Cell. 2011; 19: 754-764Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar) of lung adenocarcinoma and SCLC.2Oser 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 (552) Google Scholar, 5Norkowski E. Ghigna M.R. Lacroix L. et al.Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology.J Thorac Oncol. 2013; 8: 1265-1271Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar In these two cases we do not have information about TP53 and RB1 mutations at diagnosis; however, it may be speculated that the presence of these mutations at diagnosis increases the risk of SCLC transformation in patients with lung adenocarcinoma treated with programmed death 1 blockade, similar to the recently published observation in patients with EGFR-mutant lung adenocarcinoma.1Lee 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 (266) Google Scholar As the clinical applications of checkpoint inhibitors in patients with lung adenocarcinoma expand, all clinicians must be aware of the potential for transformation to SCLC as a potential mechanism of resistance. Dr. Iams was supported by the National Institutes of Health and National Cancer Institute Vanderbilt Clinical Oncology Research Career Development Award (2K12CA090625-17) and an American Society of Clinical Oncology/Conquer Cancer Foundation Young Investigator Award. Dr. Lovly was supported by a Vanderbilt-Ingram Cancer Center Young Ambassadors Award, a Damon Runyon Clinical Investigator Award, a LUNGevity Career Development Award, a V Foundation Scholar-in-Training Award, a Lung Cancer Foundation of America/International Association for the Study of Lung Cancer Lori Monroe Scholarship, and National Institutes of Health and National Cancer Institute grants (R01CA121210, U10CA180864, P01CA129243, and U54 CA217450). Dr. Beckermann was supported by a Merck–Cancer Research Institute Irvington Postdoctoral Fellowship and a Lung Cancer Foundation of America/International Association for the Study of Lung Cancer and Bristol-Myers Squibb Joint Young Investigator Award for Translational Immuno-oncology. We would like to thank Kelli Boyd, Sherry Smith, and Yingjun Yan for their help with project coordination and slide review. We would also like to thank Seyed Ali Hosseini, Samantha Henderson, and Kristy Potts for their help with sequencing.