347PCASPASE ACTIVATION AND RESPONSE TO NEO-ADJUVANT CHEMOTHERAPY (NAC) IN LOCALLY ADVANCED BREAST CANCER (LABC)

ABSTRACT Aim: Caspase 3 activation is the final common pathway of apoptosis and is thought to be a major mechanism of tumour cell death due to conventional chemotherapy. This study aimed to investigate the relationship between NAC induced complete pathologic response (pCR) and caspase 3 expression in pre-treatment tumours. Methods: Between 2004 and 2013 women with locally advanced invasive ductal carcinoma were randomised to either drug sequence A (fluorouracil, epirubicin, cyclophosphamide (FEC) followed by docetaxel) or drug sequence B; the reverse order. Tumour samples were collected at baseline, after 4 cycles and 8 cycles of NAC. Immunohistochemistry expression of caspase 3, 8, 9 and BCL-2 were obtained as well as ER, PR, HER2, BRE grade, lymphovascular invasion & %ki-67. Using a digital high-resolution slide scanner, caspase 3, 8 & 9 were scored by 2 independent pathologists. Pathologic response was measured in the primary and lymph nodes, pCR was defined as absence of invasive cancer. Analysis involved correlating biomarkers with pCR and survival estimates using Kaplan-Meier method. Results: 132 women were enrolled into the study (101 samples analysable). 55 (54%) were randomized to drug sequence A and 46 (46%) to sequence B. 20 (20%) achieved a pCR, this correlated with ER negative, grade 3, higher ki-67 and HER2 subtype. Caspase 3 was activated in 57 (56%) of initial samples, of these, 52 (92%) had caspase 9 activation and 11 (19%) had caspase 8 activation. Initial BCL2 expression was strongly associated with ER positivity (p = 0.001) and was inversely related to response to NAC (p = 0.003). However, there was no association of caspase 3 with pCR rate or ER, PR, HER2, tumour grade, Ki-67, sequence of NAC or survival. Conclusions: Caspase 3 signal is activated in a high proportion of cases of untreated LABC. In most cases this is due to the intrinsic apoptotic pathway (caspase 9). Activation of Caspase 3 is not explained by tumour subtype or receptor status. Caspase activation does not correlate with pathologic outcomes or survival in this study, suggesting mechanisms other than classical apoptosis may be involved in chemotherapy related cancer cell death. Disclosure: All authors have declared no conflicts of interest.