By ecancer reporter Jo Armstrong

Biomarkers were the buzz word for this year's ESMO meeting and featured across all cancer types and therapeutic advancements. In the ESMO/JSMO joint symposium the implication of biomarkers and their potential application to personalised treatment of lung and GI cancer was discussed.

In lung cancer, tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), gefitinib and erlotinib, were the first molecularly targeted agents to be developed for the clinical treatment of non-small cell lung cancer (NSCLC). These inhibitors have had a significant impact on the treatment of advanced disease, prompting the investigation of their potential role in first-line treatment in molecularly selected patients. In the IPASS study, which investigated gefitinib or carboplatin and paclitaxel in patients with advanced NSCLC, biomarker analysis revealed EGFR tumour cell mutations in a proportion of the patients enrolled. In this EGFR mutation-positive group, first-line gefitinib resulted in significantly improved response rates (71.2% versus 47.3%, p<0.001) and longer progression free survival (p<0.001) compared to treatment with carboplatin and paclitaxel. Two recently completed Japanese randomised phase III trials (WJTOG3405, NEJ002) comparing platinum-based chemotherapy with gefitinib in chemotherapy-naïve NSCLC patients with sensitising EGFR mutations have provided further strong evidence that first-line treatment with EGFR-TKIs should be considered as important standard therapeutic option for such patients. The use of biomarker analysis will enable clinicians to personalise therapy, so improving outcomes for patients with advanced NSCLC. In a phase II trial of customised cisplatin-based chemotherapy based on BRCA1, median survival has been shown to be influenced by RAP80 expression. In patients with both low BRCA1 and low RAP80, survival is significantly improved. Chemotherapy response is based on the fact that DNA repair genes require a series of molecular recognition steps that enable DNA damage response proteins to localise at and near DNA lesions. Binding of the mediator of DNA damage checkpoint 1 (MDC1) protein to the phosphorylated tail of histone H2AX (gH2AX) facilitates the formation of BRCA1 nuclear foci at double strand breaks induced by irradiation or chemotherapy. By dimerising with BARD1 protein through the RING domain, BRCA1 forms an E3 ubiquitin ligase. Recently, it has been shown that RAP 80 targets the BRCA1-BARD1 E3 ligase to MDC1-gH2AX-dependent lysine 63-linked ubiquitin proteins at double-strand breaks. The BREC (BRCA1 RAP80 Expression Customisation) trial, a phase III trial of personalised chemotherapy based on BRCA1 and RAP80 expression, is being carried out in Spain, France, Belgium, Luxembourg and Saudi Arabia. Two treatment approaches for advanced NSCLC patients can be carried out in large clinical studies of treatment customised by molecular analyses: for patients without EGFR mutations, customised chemotherapy based on the BRCA1-RAP80 model; for patients with EGFR mutations, EGFR tyrosine kinase inhibitors. At present, gene expression profiles are mainly analysed by QPCR. However, this technique is limited to samples with sufficient tissue for RNA amplification and can provide reliable results in only 70% of formalin-fixed paraffin-embedded NSCLC tumour samples. The novel NanoString nCounter System can provide direct digital readouts of each mRNA using a small amount of total RNA. The validation of this technique could be useful for its universal application in customised clinical trials.

When our attention is turned to the treatment of gastric cancer, the ToGA trial of trastuzmab, an anti-HER2 antibody, in combination with capecitabine/cisplatin showed significant survival prolongation compared with chemotherapy alone in patients with HER2 positive advanced gastric cancer. In the subset analysis of the study, the difference in survival became more prominent in patients with high HER2 expression (IHC2+/FISH+ or IHC3+). Lapatinib (HER1/2 dual inhibitor) is also being investigated in combination with capecitabine/oxaliplatin as first-line (LOGIC trial) or with paclitaxel as second-line (TYTAN trial) in patients with HER2 positive tumours. In the AVAGAST trial, which compared capecitabine/cisplatin plus placebo with or without bevacizumab, the primary endpoint of overall survival was not met. However, adding bevacizumab to chemotherapy significant improved the secondary endpoints of progression-free survival and response rate. In this trial, marked differences in efficacy results for the placebo arm were observed between geographical regions, with the lowest survival benefit seen in Asia and the highest in Pan-America, which confounded the interpretation of the results.

The prognosis of metastatic colorectal cancer (mCRC) remains poor in spite of the advances obtained in recent years with new therapeutic agents, surgical procedures and diagnostic methods. New treatments directed to molecular targets have emerged but there is a need to optimise and define the best use of these new approaches. Clinical data shows that the efficacy of cetuximab and panitumumab, two monoclonal antibodies (mAb) targeting the EGFR, is confined to patients bearing tumours with K-Ras wildtype. K-Ras mutation is detected in approximately 40-45% of mCRC and its analysis is now considered a new standard of care in the selection of patients for EGFR-targeted therapy. Recent data suggest that other markers of oncogenic activation of EGFR downstream effectors such as B-Raf (mutated in 10% of tumours), PIK3CA (mutated in 15-20% of tumours) and loss of function of PTEN also predict for response to anti-EGFR therapies. Tumours with wild-type K-Ras, B-Raf and PIK3CA and without loss of expression of PTEN (named "quadruple-negative") have the highest probability of response to anti-EGFR therapies. Up to 70% of patients with mCRC unlikely to respond to these agents can be identified. Early reports suggest that responders also show increased levels of EGFR ligands (epiregulin and amphiregulin) and specific inherited polymorphisms of EGF or EGFR gene and in proteins involved in antibody dependent cell-mediated cytotoxicity. Attempts to discover molecular or pathological predictive factors for efficacy of bevacizumab, which targets the VEGF in host endothelial cells, have not been successful. To date, no predictive markers that can determine benefit from the addition of bevacizumab to frontline therapy have been identified. The most promising candidate biomarkers include hypertension development, imaging parameters, such as diffusion contrast-enhanced magnetic resonance imaging (DCE-MRI) and some circulating measurements, as VEGF, VEGFR2 and circulating endothelial cells.