Optimizing Adjuvant Chemotherapy in Early-Stage Breast Cancer

Improvements in early diagnosis and treatment of breast cancer over the past few decades have clearly reduced disease-related mortality. The 2000 Oxford Overview published recently by the Early Breast Cancer Trialists' Cooperative Group (EBCTCG) highlights some of the widely practicable adjuvant drug treatments that were under investigation in the 1980s, and have substantially reduced 5-year recurrence rates as well as 15-year mortality rates.[1] Optimal adjuvant hormone therapy is associated with a substantial improvement of disease outcomes in hormone receptor-positive women. Chemotherapy is also associated with considerable benefits in women with breast cancer, regardless of age, stage, or hormone receptor status. However, chemotherapy is not without risks. The treatment is associated with many adverse events that may significantly affect a patient's quality of life while she is receiving treatment. Other effects may be longstanding, permanent, and, rarely, lifethreatening. Tailoring Treatment
Two decades of research have demonstrated that not all patients benefit from adjuvant chemotherapy equally. Knowledge of who is most likely to benefit from chemotherapy will reduce risks and costs to those who are not likely to benefit from the treatment. Techniques and improvements have evolved to predict a patient's likelihood of disease recurrence, and this information can be a significant aid in evaluating and optimizing treatment options. In their excellent review, Drs. Perez and Muss highlight the many treatment options that are available for our breast cancer patients today. One size does not fit all, and in fact, we are moving toward an era when we will be able to tailor treatment for the best response on an individual basis. The challenge is to figure out who will do well with a standard "cookie-cutter" treatment plan, and who needs the benefit of a customdesigned regimen. The article also provides a comprehensive summary of the multitude of clinical trials in which-while the questions posed during the design phase were seemingly different-the ultimate question was the same: What regimen works best for our patients, with the fewest adverse effects? Challenges in the next decade include the large number of patients and followup required to evaluate new regimens and treatments in definitive trials, largely due to the early diagnosis and successful treatments that are already in use. Researchers and clinicians will need to carefully consider what questions may be most important to answer and whether alternate designs can be used to evaluate new treatments more efficiently. Is There an Optimal Adjuvant Chemotherapy Regimen?
Following definitive breast surgery, whether it is mastectomy or lumpectomy, methods to identify women with microscopic metastatic disease are needed. Currently, clinicians utilize models to predict probability of recurrence for a population with similar characteristics such as age, stage, tumor grade, and receptor status. The role of adjuvant chemotherapy is to treat this probable residual disease. The models, however, cannot predict whether an individual will or will not suffer disease recurrence. As Drs. Perez and Muss so clearly state, "Adjuvant chemotherapy is a work in progress." While many individual clinical trials have been reported, the Oxford Overview has provided us with several important conclusions that could not be answered in studies with a limited sample size. Based on the Overview, we can conclude that polychemotherapy is superior to single-agent chemotherapy, and that anthracycline-based chemotherapy is superior to non-anthracycline-based therapy.[1] In an attempt to choose regimens with the best outcomes, it is interesting that there have not been any head-to-head trials evaluating the different formulations of anthracyclines such as doxorubicin(Drug information on doxorubicin) and epirubicin(Drug information on epirubicin) (Ellence). Recent data suggest modest benefit with the addition of taxanes to anthracycline- based therapy. Until new data are available, the decision to add a taxane to anthracycline-based therapy should be made based on estimates of relapse and the absolute benefit that is expected for an individual. As is the case with anthracyclines, direct data comparing the different taxanes in the adjuvant setting are not currently available.[2] Genomics and Proteomics in Treatment Decision-Making
The completion of the human genome project and advances in DNA sequencing and proteomic technologies are promising tools that may ultimately help tailor treatment. Perez and Muss point out the crucial role gene array technology and proteomics will likely play in the future. Several groups have reported early results suggesting that gene-expression profiling may not only be used to determine prognosis but may also separate patients who are more likely to benefit from chemotherapy from those who will not benefit. With the advent of the 21-gene reverse transcriptasepolymerase chain reaction (RT-PCR) assay we can calculate a recurrence score for each patient with node-negative and hormone-receptor-positive tumor. This score may serve as an aid in the decision to prescribe adjuvant hormone therapy, chemotherapy, or both.[3,4] Other investigators have demonstrated that a 70-gene profile is a strong independent factor in predicting disease outcome.[5] Indeed, large prospective clinical trials are planned to validate these tools and to investigate new ones. It is also possible that tumor signatures or profiles may be used to predict response to specific regimens. It has been suggested that clinical response to the taxane docetaxel(Drug information on docetaxel) or to anthracycline- and taxanebased regimens can be predicted by gene-expression profiling.[6,7] The advent of proteomics provides the hope of discovering novel biologic markers that can be used for early detection and disease diagnosis, to determine prognosis, and to predict response to therapy. The ultimate goal is to characterize protein pathways, networks, and signaling events that are relevant in disease.[8] In the future, this type of analysis offers the ability to further subgroup patients and identify those who may or may not benefit from adjuvant therapies.[9] Investigators are also equipped to examine relationships between germ-line genetic variants and response or toxicity to specific treatments of breast cancer.[10] With the ability to predict how a tumor responds to a particular therapy, and whether the individual is likely to suffer serious adverse events, we will truly be able to tailor an individual patient's treatment. Incorporating Targeted Therapy
A targeted therapy should attack a biologically important process, preferably one central to a hallmark of cancer. It should be measurable in the clinic, and that measurement should correlate with clinical outcome when administered.[11] In this review article, Perez and Muss point to inhibitors of epidermal growth factor receptor, HER2 tyrosine kinase, and angiogenesis as targets for therapy, as well as the many agents in the drug development pipeline. Experimental studies are needed, but there are many obstacles to using these agents in clinical trials.[12] Patient selection, proper dosing and scheduling, and the combination of these agents with conventional treatments all prompt difficult questions that need to be answered in order to integrate the many promising compounds in the most appropriate manner. Conclusions
Chemotherapy, although not necessarily targeted, has clearly improved disease-free survival and overall survival. Drs. Perez and Muss highlight the evolution of standard of care in breast cancer treatment by pointing out the regimens associated with the best outcomes and noting the promise of future regimen selection based on individual patient characteristics. Further improvements in long-term survival could well be available from newer drugs, or through the better use of older drugs.