Aiming at the target: improved adjuvant medical therapy.
The 2007 St. Gallen Expert Panel recognized the existence of molecular tools for risk stratification, but recommended the use of high-quality standard pathological testing alone for risk allocation and treatment selection. Over the last two years, much has been learned about these novel molecular tools: they demonstrate similar prognostic power; their performance appears to be driven by improved quantification of cellular proliferation; tumour burden remains an important determinant of long-term outcome; and their prediction of responsiveness to systemic therapy is suboptimal. In the meantime, great effort has continued to be invested in evaluating individual predictive markers to guide treatment selection. A number of putative targets that showed early promise--such as HER-2 and TOP2A gene amplification for anthracyclines, Myc amplification for trastuzumab, and Tau expression for taxanes--have yielded disappointing results when subjected to subsequent validation. These failings underscore the difficulty of accurate, reproducible target measurement and the inherent complexity of early breast cancer which is unlikely to be captured by a single gene or protein alteration. Future progress in adjuvant treatment tailoring will require a fundamental shift towards multi-dimensional thinking--with the development of multi-parameter assays that integrate tumour biology, disease burden, and host-related factors. The traditional model of post hoc predictive marker validation appears unlikely to produce tangible gains in the era of targeted systemic therapy. It is hoped that coupling prospective biomarker discovery with new drug development in earlier stages of disease will yield additional targets that can be used to guide clinical decision-making in the future.
Bedard
Philippe L
PL
Department of Medical Oncology, Jules Bordet Institute, Rue Heger-Bordet 1, Brussels, Belgium.
Dinh
Phuong
P
Sotiriou
Christos
C
Piccart-Gebhart
Martine J
MJ
D018943:Anthracyclines / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017024:Chemotherapy, Adjuvant / Q000379:methods*; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D016503:Drug Delivery Systems; D005260:Female; D005784:Gene Amplification; D006801:Humans; D000075223:Poly-ADP-Ribose Binding Proteins; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab
D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D043823:Taxoids; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; D000068878:Trastuzumab