Small-cell lung cancers in patients who never smoked cigarettes.
BACKGROUND
We describe clinical, pathologic, and molecular characteristics of never-smoker patients with small-cell lung cancers (SCLCs).


METHODS
We identified cases of SCLCs evaluated at our institution from 2005 to 2012. We collected smoking history, demographic, treatment, and survival data. EGFR, KRAS, PIK3CA, ALK testing, RB protein expression, and next generation sequencing were performed on available samples.


RESULTS
Two percent (23 of 1040) of patients with SCLCs were never-smokers. Eighty-three percent (19 of 23) had de novo SCLCs, whereas 17% had SCLC transformation as acquired resistance to erlotinib after treatment for EGFR-mutant lung carcinomas. Median survival from SCLC diagnosis was 23 months. Of de novo SCLCs, ALK rearrangement, KRAS mutations, EGFR mutations, and RB loss were identified in zero of five, zero of eight, two of eight, and six of seven, respectively. Two de novo samples underwent next generation sequencing. One had mutations in p53 and RB1 with amplification in TERT, and a second had mutations in CBL and GNAS with amplification in MYCL1.


CONCLUSIONS
Two percent of patients with SCLCs are never-smokers. Although transformation to SCLC can rarely occur in acquired resistance to erlotinib, 83% of never-smokers with SCLCs had de novo SCLC. RB loss was noted in 86% of cases. Multiplexed genotyping can be performed on tissues to identify potentially actionable oncogenic drivers.
*Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; †Department of Medicine, Weill Cornell Medical College; ‡Department of Pathology; and §Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY.
Anna M
AM
Varghese
Maureen F
MF
Zakowski
Helena A
HA
Yu
Helen H
HH
Won
Gregory J
GJ
Riely
Lee M
LM
Krug
Mark G
MG
Kris
Natasha
N
Rekhtman
Marc
M
Ladanyi
Lu
L
Wang
Michael F
MF
Berger
M Catherine
MC
Pietanza
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002864:Chromogranins; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D005784:Gene Amplification; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D012189:Retrospective Studies; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics*; D012907:Smoking; D015996:Survival Rate; D019098:Telomerase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
D000970:Antineoplastic Agents; D002864:Chromogranins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D000069347:Erlotinib Hydrochloride; D050721:Proto-Oncogene Proteins c-cbl; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C509186:TERT protein, human; D019098:Telomerase; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C067419:CBL protein, human