Predictive markers in early research and companion diagnostic developments in oncology.

Predictive biomarkers are discovered and used in oncology research to formulate hypotheses aimed at the identification of patients benefiting from specific therapeutic intervention(s). They pave the way to the development of companion diagnostic tests which are tools readily implemented in the clinic and serve to qualify a patient for treatment with a particular targeted drug or the continued use of a particular drug, thus maximizing the benefit to risk ratio of the medical intervention to the patient. Predictive biomarkers are defined by biological characteristics of the patient's or tumor status that can be measured objectively and correlated with clinical outcome: these can be molecular, cellular or biochemical features. Predictive markers need extensive analytical validation - specific for the tool utilized for their assessment - as well as rigorous clinical qualification in the context of the drug treatment for which they define clinical utility. The process of companion diagnostic development is a highly interdisciplinary and complex one, driven by key crucial milestones and accompanying the same and typical process of a whole drug discovery and development continuum, from marker discovery and validation, assay development, clinical qualification until test approval and commercialization.

Clinicopathologic characteristics of patients with stage III/IV (M(0)) advanced gastric cancer, according to HER2 status assessed by immunohistochemistry and fluorescence in situ hybridization.

Despite recent advances in chemotherapy, the prognosis for patients with advanced gastric cancer (GC) or gastroesophageal junction cancer remains poor. Human epidermal growth factor receptor 2 (HER2) is a novel target for biologic therapy in metastatic GC. We analyzed the association between HER2 overexpression and the clinicopathologic characteristics of advanced GC. Formalin-fixed, paraffin-embedded tumor samples were collected from patients with stage III or to IV (M(0)) GC who subsequently underwent curative surgery followed by adjuvant chemotherapy with 5-fluorouracil and cisplatin. All the samples were analyzed for HER2 status by immunohistochemistry (IHC) and fluorescence in situ hybridization. Of 142 samples analyzed, 7.1% scored IHC 2+ and 8.6% scored IHC 3+, whereas 9.3% were HER2-amplified. Of HER2-amplified cases, 76.9% (10/13) scored IHC 3+, showing the correlation between HER2 amplification and overexpression (P=0.01). HER2 IHC 3+ cases were more common in the intestinal-type tumors compared with diffuse-type tumors (16.7% vs. 5.1%, respectively; P=0.049), and a nonsignificant trend was observed using fluorescence in situ hybridization (14.3% vs. 9.2%, respectively; P=0.399). HER2 gene amplification was more frequent in stage IV (M(0)) than stage III disease (15.4% vs. 4.0%, respectively; P=0.037). Interestingly, HER2-amplified disease was more common than nonamplified disease in patients with nodal stage 3 tumors (76.9% vs. 38.6%, respectively; P=0.009); a similar pattern was observed using IHC. HER2 overexpression correlated with nodal stage, and a lymph node ratio greater than 0.5 was more common in HER2-amplified tumors than HER2-nonamplified tumors (69.2% vs. 43.3%, respectively; P=0.086). These findings suggest that further investigations of adjuvant therapy with HER2-targeted therapy for advanced GC are warranted.