Features of potentially predictive biomarkers of chemotherapeutic efficacy in small cell lung cancer.
BACKGROUND
One-size-fits-all chemotherapy does not improve survival in patients with small cell lung cancer (SCLC). Excision repair cross-complementing group 1 (ERCC1), ribonucleotide reductase 1 (RRM1), thymidylate synthase (TS), and topoisomerase 2alpha (Topo2alpha) expression levels are predictive of chemotherapeutic efficacy in some malignancies. Our aim was to determine the expression levels of these proteins to assess their potential clinical utility in SCLC.


METHODS
We used an immunofluorescence-based automated quantitative technique to score RRM1, ERCC1, TS, and Topo2alpha levels in tumor specimens from 100 patients with SCLC and immunohistochemistry to semiquantitatively score levels of TS, 5-phosphoribosyl-glycinamide formyl-transferase, and folyl-polyglutamate synthase expression. Confocal microscopy was used for subcellular localization in SCLC cells.


RESULTS
RRM1, ERCC1, and Topo2alpha staining was predominantly nuclear and TS mainly cytoplasmic. Using immunohistochemistry, we found that TS (antibody 106) and TS (antibody 4H4) scores were strongly correlated (r = 0.82, p < 0.0001). By automated quantitative technique, RRM1 and Topo2alpha levels were highly correlated (r = 0.56, p < 0.0001). ERCC1 and TS levels had a narrow and low range of expression. There was no correlation between any of these biomarkers and patients' age or sex.


CONCLUSIONS
Considering this clinical evidence, expression levels of RRM1 and Topo2alpha may have utility for chemotherapy customization. Clinical validation of their predictive power is desirable in a prospective clinical trial.
Chiappori
Alberto A
AA
Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. alberto.chiappori@moffitt.org
Zheng
Zhong
Z
Chen
Tingan
T
Rawal
Bhupendra
B
Schell
Michael J
MJ
Mullaney
Brian P
BP
Bepler
Gerold
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012262:Ribonucleoside Diphosphate Reductase; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000378:metabolism; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D013940:Thymidylate Synthase; C071447:ERCC1 protein, human; D004720:Endonucleases; D004250:DNA Topoisomerases, Type II