Breast cancer biology: Is it transforming the treatment paradigm?
30 January 2010—During the first day of the 4th International Breast Cancer Conference in Paris, presentations focused on emerging portraits of breast cancer in 2010.
Martine Piccart-Gebhart, MD, PhD (Institute Jules Bordet, Brussels, Belgium), introduced the program by stating there would be more of a focus on biology with the ultimate goal of offering more tailored therapies to breast cancer patients in daily clinical practice. With this purpose in mind, 54 faculty from 14 countries have assembled to address over 1100 delegates on a variety of topics, including management of endocrine-responsive breast cancer, triple-negative breast cancer, node-negative breast cancer, and individualizing treatment approaches.
International integration of data regarding early breast cancer Peter Ravdin, MD, PhD (University of Texas Health Science Center, San Antonio, United States), highlighted achievements of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). The first publication focused on the use of adjuvant chemotherapy in patients with ER-negative breast cancer (EBCTCG, et al. Lancet. 2008;371(9606):29-40.). This was the first meta-analysis to focus on a particular subtype of breast cancer, and it was found that adjuvant polychemotherapy significantly reduced breast cancer mortality in women younger than 50 years and those aged 50-59 years at entry into trial; there was less of an effect in patients 60 years and older. The second report evaluated the efficacy of radiotherapy in early breast cancer (Darby S, on behalf of the EBCTCG. Cancer Res. 2009;69(Suppl): Abstract MS3-1.). Results demonstrated that breast-conserving surgery (BCS) plus radiation resulted in better local control of disease, which was associated with less breast cancer mortality, for both pN0 and pN+ patients when compared to BCS alone. Conversely, it was found that better local control with mastectomy + axillary dissection (AD) + radiotherapy was not associated with less breast cancer mortality in pN0 patients, but patients with even 1 positive node seemed to benefit from the addition of radiation therapy. Dr Ravdin concluded his presentation by stating that, in order to be relevant in the modern era, meta-analyses must define subsets by biomolecular profiling as well as include questions relating to the value of taxanes and HER2-interacting agents.
Science woven into the art of oncology
As stated by Yosef Yarden, PhD (The Weitzmann Institute of Science, Rehovot, Israel), "Revolutions are often recognized in retrospect." In terms of cancer therapy, Dr Yarden was referring to the idea of targeted drug delivery developed by Dr Paul Ehrlich over 100 years ago. The revolution of molecular targeted cancer therapy inspired Dr Yarden’s presentation, which focused on the biologic framework necessary to take translational research from the bench to the clinic. As oncogenic networks are “trained” to resist common modifications, therapeutic interventions that create “uncommon perturbations” are needed to disrupt cancer progression and metastasis. Specifically, the following strategies to exploit oncogenic signaling were described: recruitment of the immune system, chaperone inhibition, double-hit drugs, and antibody combination. In his concluding remarks, Dr Yarden stated that evolution has transformed a simple linear cascade into a robust signaling network that is trained to overcome single perturbations; however, evolution did not train these networks to resist complex perturbations such as combination therapy targeting a single pathway.
Building on the biologic framework, Edith Perez, MD (Mayo Clinic, Jacksonville, United States), discussed a clinical framework toward an individual approach to breast cancer, focusing on current challenges and providing recommendations for solutions. It is believed that treatment individualization will allow for more precise diagnosis, optimal selection of treatment for disease, prediction of risk prior to occurrence of symptoms, and more effective disease management. Dr Perez reiterated the fact that new awareness of target complexity (ie, predicting sensitivity to anthracyclines/taxanes and optimal use of anti-estrogen therapy) requires new therapeutic strategies, specifically the use of gene expression profiles rather than molecular subtyping. While the clinical validity of gene profiling has been established, there are several hurdles, such as tissue handling, an incomplete understanding of biology/tumor microenvironment, and no definition of what is positive or negative for each predictive test, that must be overcome to establish clinical utility. Dr Perez concluded by stating her vision for the future of breast cancer involves multiple types of breast cancer based on molecular profile.
The question of whether or not we have finally approached the era of practical and applied genomics for the clinician was addressed by Norman Wolmark, MD (National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, United States). The changing portrait of breast cancer has been caused, in part, by the results of randomized prospective clinical trials and the National Surgical Adjuvant Breast and Bowel Project (NSABP); a dramatic example was demonstrated by images of radical mastectomy and breast conservation. Data supporting the use of genomics were reported from prospective validation of the 21-gene recurrence score in NSABP B-14, which demonstrated that a low recurrence score was associated with improved distant recurrence-free survival (DRFS), and could be used as a continuous variable to estimate patient risk. Results from NSABP B-20 demonstrated that recurrence score could predict the benefit of chemotherapy. These results have led to an increase in the use of the 21-gene recurrence score, and a concomitant decrease in administration of adjuvant chemotherapy for endocrine-responsive, node-negative breast cancer in postmenopausal patients. Additional data regarding the use of gene expression profiles are eagerly awaited from the TAILORx and MINDACT trials. Dr Wolmark concluded that we have, indeed, reached the era of therapy based on well-defined molecular signatures.
From the sanofi-aventis perspective
The International Breast Cancer Conference (IBCC) has been supported for the last four years by sanofi-aventis. In the opening presentation, Debasish Roychowdhury, MD (senior vice president of the sanofi-aventis Oncology division), stated the company is upholding its commitment to patient care by providing substantially beneficial treatments and access to medicine, as well as educating patients and healthcare providers regarding optimal cancer management. The shift toward development of novel molecules by truly integrating science and translational medicine is evidenced by clinical trials evaluating emerging therapeutics such as VEGF Trap, a PARP inhibitor, and a vascular disrupting agent. Based on ongoing clinical and preclinical studies and four years of IBCC, the company clearly has a focus on strengthening partnerships with the international breast cancer community. In addition, sanofi-aventis CEO, Chris Viehbacher, gave encouraging remarks at the end of Plenary Session I, reaffirming the company’s commitment to the care of patients with cancer even in the light of an economic recession.
Memorable quotes from IBCC4
Martine Piccart-Gebhart, MD, PhD (Jules Bordet Institute, Brussels, Belgium): "We can do a much better job at treatment individualization by better classification of each patient’s tumor characteristics."
Peter Ravdin, MD, PhD (University of Texas Health Sciences Center, San Antonio, United States):"Can future EBCTCG work identify the luminal B-like chemosensitive patients?"
Yosef Yarden, PhD (Weizmann Institute of Science, Rehovot, Israel):"First identify critical hubs, then target them simultaneously.”
Edith Perez, MD (Mayo Clinic, Jacksonville, United States): "The ‘one size fits all’ approach is over in the setting of breast cancer."
Norman Wolmark, MD (National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, United States): "We have the armamentarium to move forward; it is up to us to use it in a wise, definitive, and intrepid manner"
This activity is supported by an educational grant from sanofi-aventis Groupe.
