BACKGROUND:The global lapatinib expanded access programme provided access to lapatinib combined with capecitabine for women with HER2-positive metastatic breast cancer (MBC) who previously received anthracycline, taxane and trastuzumab. METHODS: Progression-free survival (PFS) and safety data for 356 patients recruited from the United Kingdom are reported. Efficacy was assessed in 162 patients from the five lead centres, including objective tumour response rate (ORR), time to disease progression (TTP) and efficacy in those with central nervous system (CNS) metastases. Correlation of PFS and ORR with previous capecitabine treatment was also documented. RESULTS: Overall, PFS for the 356 UK patients was 21 weeks (95% CI: 17.6 -24.7). In the 162 assessable patients, ORR was 21% (95% CI: 15 -27%) and median TTP was 22 weeks (95% CI: 17 -27). Efficacy was greater in capecitabine-naive patients (ORR 23 vs 16.3%, P ¼ 0.008). For 34 patients with CNS metastases, ORR was 21% (95% CI: 9 -39%), with evidence of improvement in neurological symptoms, and median TTP was 22 weeks (95% CI: 15 -28). CONCLUSIONS: Lapatinib combined with capecitabine is an active treatment option for women with refractory HER2-positive MBC, including those with progressive CNS disease.

BACKGROUND: Altered DNA repair may be associated with aggressive tumour biology and impact upon response to chemotherapy and radiotherapy. We investigated whether expression of human AP endonuclease (APE1), a key multifunctional protein involved in DNA BER, would impact on clinicopathological outcomes in ovarian, gastro-oesophageal, and pancreatico-biliary cancer. METHODS: Formalin-fixed human ovarian, gastro-oesophageal, and pancreatico-biliary cancers were constructed into TMAs. Expression of APE1 was analysed by IHC and correlated to clinicopathological variables. RESULTS: In ovarian cancer, nuclear APE1 expression was seen in 71.9% (97 out of 135) of tumours and correlated with tumour type (P ¼ 0.006), optimal debulking (P ¼ 0.009), and overall survival (P ¼ 0.05). In gastro-oesophageal cancers previously exposed to neoadjuvant chemotherapy, 34.8% (16 out of 46) of tumours were positive in the nucleus and this correlated with shorter overall survival (P ¼ 0.005), whereas cytoplasmic localisation correlated with tumour dedifferentiation (P ¼ 0.034). In pancreatico-biliary cancer, nuclear staining was seen in 44% (32 out of 72) of tumours. Absence of cytoplasmic staining was associated with perineural invasion (P ¼ 0.007), vascular invasion (P ¼ 0.05), and poorly differentiated tumours (P ¼ 0.068). A trend was noticed with advanced stage (P ¼ 0.077). CONCLUSIONS: Positive clinicopathological correlations of APE1 expression suggest that APE1 is a potential drug target in ovarian, gastro-oesophageal, and pancreatico-biliary cancers.

The calpain family, and their endogenous inhibitor calpastatin, has been implicated in cancer progression, and recent in vitro data have indicated a role in trastuzumab resistance. The aims of our study were to examine expression levels of calpastatin, calpain-1 and calpain-2 in breast tumours from patients treated with trastuzumab following adjuvant chemotherapy to determine their potential as biomarkers to predict therapeutic response. The expression of calpastatin, calpain-1 and calpain-2 was determined, using immunohistochemistry (IHC), in tumours from a series of 93 patients with primary breast cancer treated with surgery and adjuvant chemotherapy with or without trastuzumab followed by trastuzumab to complete 1 year of therapy. IHC was performed using tissue microarrays constructed from cores taken from intratumour and peripheral tumour areas. Expression was correlated with clinicopathologic variables and patient outcome. Calpastatin expression was correlated with Nottingham prognostic index (p 5 0.003) and lymph node status (p 5 0.007). Trastuzumab resistance was defined as disease relapse during therapy. Calpain-1 expression is associated with relapse-free survival (p 5 0.001) and remained significant in multivariate analysis accounting for confounding pathological and treatment variables (hazard ratio 4.60, 95% confidence interval 1.05-20.25; p 5 0.043). Calpain-1 may be a useful biomarker to predict relapse-free survival in breast cancer patients treated with adjuvant trastuzumab and chemotherapy. A larger verification study is warranted.

Increased CD14(+) monocytes with loss of HLA expression were seen in patients with higher stage disease, more aggressive pathology, and in relapse or refractoriness to treatment. Identifying therapeutic strategies to overcome the suppressive properties of these monocytes could be of value.

Neoadjuvant chemotherapy has become the standard of care for locally advanced primary breast cancer. Anthracycline-based regimens have proven to be one of the most effective treatments in this setting. As certain cytotoxic antineoplastic agents, such as anthracyclines, generate reactive oxygen species as a by-product of their mechanism of action, we examined whether redox protein expression was involved in the response to anthracycline-based chemotherapy and with clinical outcome. Pre-treatment needle core biopsy and post-anthracycline treatment tumour sections were analysed from 98 cases. In all, 32 individuals had a complete clinical response and 17 had a complete pathological response. Immunohistochemical staining was performed for eight redox proteins: thioredoxin, thioredoxin reductase, thioredoxin interacting protein (TxNIP), glutathione S-transferase (GST) π, θ and α, catalase and manganese superoxide dismutase. GST π (P=0.05) and catalase (P=0.045) were associated with pathological complete response in pre-chemotherapy samples. TxNIP (P=0.017) and thioredoxin reductase (P=0.022) were independent prognostic factors for distant metastasis-free survival and TxNIP for overall survival (P=0.014). In oestrogen receptor negative patients that are known to have a poor overall survival, a considerably worse prognosis was seen in cases that exhibited low expression of TxNIP (P=0.000003), stratifying patients into more defined groups. This study indicates the importance of redox regulation in determining breast cancer response to anthracycline-based chemotherapy and provides ways of further stratifying pre-chemotherapy patients to potentially allow more tailored treatments.