When does the presence of the target predict response to the targeted agent

摘要: The last decade has been marked by major advances in the field of biologically based therapies for solid tumors and approval several new therapeutic strategies. Despite rational basis these treatments, identification validation markers prognostic predictive value remains a challenge. Correlative data from studies with imatinib, trastuzumab, epidermal growth factor receptor inhibitors suggest that presence target does not guarantee response to therapy. successful determination accurate hinges on establishing reproducible, sensitive methods marker detection unraveling key components molecular pathways affected specific Angiogenesis is required tumor metastasis an attractive cancer It complicated, multistep process regulated balance endogenous stimulatory inhibitory factors elaborated cells other cell types. Because its seemingly pivotal role tumorassociated angiogenesis across wide range malignancies, vascular endothelial factor-A (VEGF-A; commonly referred as VEGF) emerged central cancer. VEGF potent, direct acting regulator signals through tyrosine kinases. Its expression upregulated virtually all types cancer, tumor-associated levels frequently correlate microvascular density predict disease recurrence decreased survival. Multiple isoforms are coexpressed cancers, but relative importance individual splice variants ill defined. Bevacizumab (BV), recombinant humanized monoclonal antibody directed against was approved US Food Drug Administration 2004 use patients previously untreated metastatic colorectal (mCRC). This suggesting addition BV chemotherapy improves rate, progression-free survival, overall survival compared alone. generally well tolerated, associated hypertension small, clinically significant, increases GI perforations arterial thromboembolic events. Recently, phase III have further validated impact mCRC, determinants clinical benefit level remain undefined. Given recent our understanding biology strong scientific rationale underlying this strategy, it follows valid treated should be feasible. In accompanying article issue Journal Clinical Oncology, Jubb et al explore expression, thrombospondin-2 microvessel (MVD) treatment effect choice potential reflects reports 50% 70% cancers express VEGF, correlates MVD inversely prognosis. family members, number regulators (both positive negative) although unknown. Thrombospondin (THBS)-1 THBS-2 antiangiogenic activity, both expressed human CRC. implicated inhibition angiogenesis, even setting high mRNA reported metastases. authors performed retrospective subset analysis using samples available 813 CRC (mCRC) randomly assigned receive (irinotecan, fluorouracil, leucovorin [IFL]) or without BV. Samples were approximately 35% patients, 90% primary tumors. Epithelial stromal assessed at protein (overall maximal intensity) tissue microarrarys whole sections. scored stroma. “hot spots” immunohistochemistry continuous variable, varying cutoffs define low MVD. Although score correlated none proved significant factors. Thus, IFL mCRC regardless MVD; discriminate between more less likely first-line chemotherapy. Assuming characteristics subgroup reflected those group whole, larger sample size would probably changed conclusion. At first glance, findings appear odds published related concept However, results consistent generated JOURNAL OF CLINICAL ONCOLOGY E D I T O R A L VOLUME 24 NUMBER 2 JANUARY 1