Measurement of chemoresistance markers in patients with stage III non-small cell lung cancer: a novel approach for patient selection.
BACKGROUND
The long-term survival of patients with stage III non-small cell lung cancer treated with a combination of chemotherapy and radiation is 10% to 20%. Survival could potentially be increased and toxicity limited if one could identify patients most likely to respond to a particular treatment regimen. This project prospectively evaluated a panel of potential immunohistochemical markers of chemoresistance in a population of patients with pathology-confirmed stage III non-small cell lung cancer in order to determine the prognostic value of each marker in relation to response to chemotherapy or survival.


METHODS
Immunohistochemical staining was performed on histologically positive mediastinal nodal specimens obtained from 59 patients (mean age, 62 years; range, 41 to 79 years) without evidence of distant metastatic disease treated with navelbine-based chemotherapy and external beam radiation therapy between 1996 and 2001. Included were markers for apoptosis (p53, bcl-2), drug efflux/degradation (MDR, GST-pi), growth factors (EGFr, Her2-neu), and mismatch repair (hMLH1, hMSH2). After chemotherapy, patients underwent radiologic evaluation for response measured by standard criteria.


RESULTS
After a median 41 months of follow-up (range, 17 to 55 months), 43 patients had recurrent disease and 38 of these patients were dead of cancer (median cancer-free survival of 10 months and overall survival of 18 months). Patients who demonstrated a complete or partial response (n = 38) had a significantly improved survival (p = 0.002) compared with those with stable or progressive cancer (n = 21). Multivariable Cox step-wise regression analysis of marker expression associated overexpression of p53 and low expression of hMSH2 with poor treatment response and cancer death.


CONCLUSIONS
These preliminary data suggest that marker expression may allow the separation of patients into low- and high-risk groups with respect to survival after combined navelbine-based chemotherapy and XRT. This could represent a novel method of selecting patients for a particular treatment regimen if these data are reproduced in a larger prospective trial.
Brooks
Kelli R
KR
Thoracic Oncology Program, Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina 27710, USA.
To
Kathleen
K
Joshi
Mary-Beth Moore
MB
Conlon
Debbi H
DH
Herndon
James E
JE
D'Amico
Thomas A
TA
Harpole
David H
DH
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000097:blood*; D001707:Biopsy, Needle; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D015331:Cohort Studies; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005069:Evaluation Studies as Topic; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D018579:Patient Selection; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D011829:Radiation Dosage; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor