Targeting the Tumor Translating Genetic and Molecular Profiling into Clinical Reality
Targeting the Tumor Translating Genetic and Molecular Profiling into Clinical Reality
US Oncology Review 2006
Published: October 2008
Published: October 2008
Breast cancer is a heterogeneous disease with a complex molecular biology and a high level of inter- patient variability regarding response to therapy.
Understanding signal transduction pathways involved in breast cancer initiation, promotion, invasion, and metastasis has led to improved diagnostic and therapeutic approaches. Completion of the human genome project and development of high-throughput technologies have stimulated enthusiasm for their cancer treatment potential in academia and industry, resulting in steady progress toward the clinical applications of genetic and molecular profiling of human tumors.
The discovery of the estrogen receptor (ER) by Jensen1 et al. in the 1960s remains one of the most important achievements in understanding the biology of breast cancer. Multiple prospective clinical trials have validated the important clinical role of the ER as a predictive marker of response to tamoxifen and other endocrine therapies. Estrogen mediates its functions through two specific intracellular receptors, ER? and ER?, which act as hormone-dependent transcriptional regulators. Most of the available data regarding prognosis and response to hormone therapy are based on expression of ER?; the prognostic significance of ER? is not well defined. Although ER levels were initially measured by using radioactive ligand-binding assays, the ER status is currently determined by using immunohistochemistry (IHC).
The type I family of tyrosine kinase receptors (TKRs) plays an important role in the pathogenesis of a subset of breast cancers.This family consists of four receptors known as the epidermal growth factor receptor (EGFR) and human EGFRs 2 (HER-2), 3, and 4.
Slamon et al.2 showed that HER-2 overexpression was associated with poor disease-free survival in women with node-positive breast cancer.The role of HER-2 as a predictive marker of response to hormone therapy and chemotherapy is controversial. However, HER-2 is considered one of the best therapeutic targets in patients with breast cancer. The HER-2 status of a tumor can be determined by using IHC or fluorescence in situ hybridization.
Trastuzumab (Herceptin®) is a monoclonal antibody directed against the HER-2 oncoprotein. Clinical trials have shown that trastuzumab is effective against metastatic breast cancer when administered as a single agent and that its efficacy is improved when combined with chemotherapy.3 In the pivotal clinical trials, patients were initially selected for therapy with trastuzumab if their tumors were found to be HER- 2-positive by using IHC. On a scale of 0–3, tumors were considered HER-2-positive if their HER-2 expression level was scored as 2 or 3 and HER-2- negative if their HER-2 expression level was scored as 0 or 1. Subsequent retrospective studies showed that such patients were more likely to benefit from receiving trastuzumab if their tumors expressed the HER-2 protein at high levels (IHC score, 3+) or have HER-2 gene amplification (fluorescence in situ hybridization positive).4 Based on the success of trastuzumab use, numerous molecules targeting the epidermal growth factor family of growth factor receptors and their ligands are in clinical development. These molecules include antibodies, small molecules, and vaccines.5 Other tumor markers that have been studied as potential prognostic and/or predictive markers include Targeting the Tumor—Translating Genetic and Molecular Profiling into Clinical Reality
References:
- Jensen E V,“From Chemical Warfare to Breast Cancer Management”, Nat. Med. (2004);10: pp. 1,018–1,021.
- SlamonD J, Clark G M,Wong S G et al., “Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the HER-2/neu Oncogene”, Science (1987);235: pp. 177–182.
- Slamon D J, Leyland-Jones B, Shak S et al.,“Use of Chemotherapy Plus a Monoclonal Antibody Against HER2 for Metastatic Breast Cancer that Overexpresses HER2”, N. Engl. J. Med. (2001);344: pp. 783–792.
- Nahta R, Esteva F J,“HER-2-Targeted Therapy: Lessons Learned and Future Directions”, Clin. Cancer Res. (2003);9: pp. 5,078–5,084.
- Esteva F J, “Monoclonal Antibodies, Small Molecules, and Vaccines in the Treatment of Breast Cancer”, Oncologist (2004);9 (suppl. 3): pp. 4–9.
- Esteva F J, Hortobagyi G N, “Prognostic Molecular Markers in Early Breast Cancer”, Breast Cancer Res. (2004);6: pp. 109–118.
- Perou C M, Sorlie rT, Eisen M B et al.,“Molecular Portraits of Human Breast Tumours”, Nature (2000);406: pp. 747–752.
- van’t Veer L J, Dai H, van de Vijver M J et al.,“Gene Expression Profiling Predicts Clinical Outcome of Breast Cancer”, Nature (2002);415: pp. 530–536.
- Sorlie T,Tibshirani R, Parker J et al., “Repeated Observation of Breast Tumor Subtypes in Independent Gene Expression Data Sets”, Proc. Natl. Acad. Sci. USA (2003);100: pp. 8,418–8,423.
- Ayers M, Symmans W F, Stec J et al.,“Gene Expression Profiles Predict Complete Pathologic Response to Neoadjuvant Paclitaxel and Fluorouracil, Doxorubicin, and Cyclophosphamide Chemotherapy in Breast Cancer”, J. Clin. Oncol., (2004);22: pp. 2,284–2,293.
