ASSOCIATION OF IMMUNOREACTIVE HEPATOCYTE GROWTH-FACTOR WITH POOR SURVIVAL IN RESECTABLE NONSMALL CELL LUNG-CANCER

We have shown previously that hepatocyte growth factor (HGF), which is produced by lung fibroblasts, is a potent mitogen and motogen for bot h normal and neoplastic bronchial epithelium, and that expression of t he HGF receptor, the c-met proto-oncogene protein, is uniformly found in the human bronchial epithelium and in non-small cell lung carcinoma s (NSCLCs; P. Singh-Kaw st at, Am, J, Physiol,, 268: L1012-L1020, 1995 ). Yamashita et al. have reported an association of HGF with poor surv ival in invasive ductal carcinoma of the breast (Cancer Res., 54: 1630 -1633, 1994). There are few prognostic markers for lung cancer, and th e high recurrence rate for stage I lung cancer suggests the frequent p resence of undetectable tumor burden in such patients, Criteria are ne eded to evaluate these patients for risk of recurrence. We have now ev aluated whether HGF present in resectable lung tumors has prognostic s ignificance. In this study, 56 primary NSCLCs, mainly adenocarcinomas, were examined for presence of HGF by quantitative Western blot. These tumors consisted of tissue from 34 stage I patients, 9 stage II patie nts, and 13 stage IIIa patients who underwent curative resection for p rimary NSCLC, Extracts of whole tumor tissue were analysed after separ ation of proteins by electrophoresis and transfer of proteins to nitro cellulose membranes, Immunoreactive (ir)-HGF was visualized by reactio n with a polyclonal anti-HGF antiserum and quantitated by densitometry . Lung tumor content of ir-HGF varied widely among individuals. Median ir-HGF content in tumor extracts was 15.3 ng/40 mu g of tumor protein ; mean ir-HGF was 27.2 ng/40 mu g of tumor protein, The median and mea n ir-HGF were both significantly higher in tumor tissue from patients who suffered a recurrence during the follow-up period compared with th ose with no evidence of residual disease; this was true of all patient s (P = 0.0001) and stage I patients analysed separately (P = 0.002), A nalysis of survival curves indicated that ir-HGF levels higher than th e median were associated with poor overall survival (P < 0.03). Univar iate analysis showed three factors related to poor overall survival in this set of patients: ir-HGF, tumor (T) status (a measure of primary tumor size and extent), and age, Nodal N status and stage were only ma rginally related to overall survival, most likely because the majority of the patients in the study were stage I. N status, stage, and T sta tus were related to disease-free survival, however, Multivariate Cox a nalysis showed that ir-HGF, T status, and age independently had a nega tive impact on overall survival, ir-HGF was a strong independent negat ive prognostic indicator (P = 0.0001) with a relative risk of 1.022 pe r unit of ir-HGF (ng/40 mu g of protein), This demonstrates that, in t his group of patients, the relative risk of ir-HGF content in creased continuously as ir-HGF increased, and exceeded 10 at units of ir-HGF o f 100 or more. In comparison, In this group of patients, the relative risk of a T status greater than 1 was 4.75 and that of age greater tha n 65 was 3.95. The combined negative effect of a T status greater than 1 and elevated ir-HGF on survival was also highly pronounced (P < 0.0 05), In addition, elevated ir-HGF had a negative impact on survival wh en patients were stratified by stage or N status. Stage I patients wit h high ir-HGF values had a worse outcome than stage II or stage IIIa p atients with low ir-HGF values. Elevated ir-HGF was strongly associate d with poor outcome for resectable NSCLC patients as a group, and also identified stage I patients with poor outcome, indicating that it cou ld be a useful indicator of risk of relapse and death in patients who have early lung cancer, The impact of elevated ir-HGF was especially p rominent in patients whose T status was greater than 1, suggesting tha t patients with both risk factors who are stage I should be treated as aggressively as stage , patients. Thus, measurement of ir-HGF could b e a useful prognostic indicator for both early and advanced NSCLC pati ents.