THE PROGNOSTIC ROLE OF CLINICAL HISTOLOGICAL AND BIOLOGICAL MARKERS IN OPERABLE NON-SMALL CELL LUNG CANCER

Validation of a biological prognostic staging system using immunohistochemistry for EGFR, MMP-9, CA IX, MVD and bcl-2 by Laboratory Based Project:

Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in Ireland with a five-year survival rate of <10%. Few patients diagnosed with lung cancer are still alive five years after diagnosis. An increased understanding of the clinical and molecular biology of the disease may identify novel targets for drug development. The aim of the current thesis is to conduct a 10-year review of a consecutive series of patients undergoing curative-intent surgical resection at the largest tertiary referral centre in the Republic of Ireland in order to identify prognostic factors, the expansion of existing retrospective bio-bank of resected lung cancer patients to include all patients treated at SJH between 1998 and 2008 with audit of patient outcome and correlation, and finally validation of a biological prognostic staging system using immunohistochemistry for bcl-2, EGFR, MMP-9 and CAIX by laboratory based project.

I identified several factors that predicted outcome for NSCLC patients undergoing curative-intent surgical resection in Ireland. Survival rates in this series are comparable to those reported from other European thoracic surgery centres. Female sex, younger age, history of smoking, smaller tumour size and lower T & N status were identified as important independent prognostic factors for survival. Excising a greater number of lymph nodes in early stage NSCLC treated with resection improves survival. The number of metastatic lymph nodes adds more information to the pN category of the current TNM classification system. I recommend a minimum of 18 lymph nodes should be removed regardless of location or station. Vascular and lymphatic invasion can serve as independent prognostic factors in completely resected NSCLC. In stage I & II NSCLC, the presence of intra-tumoral vascular invasion was adversely affected long-term survival. The presence of lymphatic space involvement was correlated both to lymph nodes involvement and intra-tumoral invasion and it did serve as predictor of tumour recurrence.

I have found a strong association between EGFR and MMP-9 expression in NSCLC, which suggests that the EGFR signalling pathway may up-regulate MMP-9 expression. Although not significant, a trend towards a poor outcome was seen in patients with tumour cell MMP-9 expression and co-expression of EGFR and MMP-9 in keeping with previous reports. I have demonstrated an association between EGFR and different patterns of tumour cell CA IX and MMP-9 expression. Although these relationships were not prognostic in this patient series, there was a trend in all observations towards a poor outcome in keeping with previous observations. I have hypothesised that cases with co expression of EGFR with either MMP-9 or CA IX or both represent cases with activated EGFR promoting an aggressive NSCLC phenotype. By developing an assay to select cases with activated EGFR, a cohort of patients may be identified that are highly responsive to anti-EGFR therapy. Further large-scale studies with more recent patient cohorts and refined histological and molecular techniques are warranted.