Over the past 20 years we have witnessed the emergence of a new generation of aromatase inhibitors as valuable antiestrogens in the management of both advanced and early-stage breast cancer. In addition, the list of cytotoxic chemotherapeutic agents useful in the control of breast cancer has grown considerably. The emergence of anthracyclines was a major chemotherapeutic step forward in the 1980s, and the taxanes have clearly been the agents with the greatest impact on breast cancer treatment over the past decade. The end of the past 2 decades has been characterized by a greater understanding of the molecular biology of breast cancer, rational drug design, and the development of agents that disrupt specific cellular targets and pathways. The development of better prognostic and predictive assays that employ a panel of genes involved in the malignant and metastatic phenotype promises to allow clinicians to better select patients who could forgo adjuvant chemotherapy. Finally, adjunctive and supportive therapy of breast cancer has evolved substantially over the past 20 years. This review will highlight some of the landmark accomplishments during this time, and offer a glimpse at where we might be 20 years from now.
In his article, Dr. Seidman gives a succinct and comprehensive review of the landmark events in the systemic therapy of breast cancer over the past 2 decades. The topics covered are germane to clinical practice. The next 20 years is presented with optimism, and there is reason for this. Systemic therapy, including targeted/biologic therapies, is exploding. The "beginning of the end of chemotherapy" is an era eagerly awaited by many patients hoping it will occur soon enough to impact them. Optimism, however, must be tempered. There are reasons to be cautionary, and herein the review can be improved. Dr. Seidman raised several important issues that need to be addressed as we move ahead. What is missing, in my opinion, are his insights on what we need to be vigilant about to realize the promise of the next 2 decades. What are the questions we must critically answer? What pitfalls must we avoid? What has the past taught us about drug development? How do we rationally develop targeted agents? Although these themes are difficult to craft and can be colored by one's perspective, his candid opinion(s) would have given the article a quality beyond the eloquent review of significant trials in breast cancer. Thus, I will focus more on these and less on trial results already substantively discussed by Dr. Seidman.
Targeted Therapy: Lessons Learned
From promising preclinical observations to pivotal trials in metastatic disease and most recently in adjuvant therapy, the development of trastuzumab (Herceptin) is a spectacular story. Development was rational, rapid, and practice-changing. What can we learn from this process? Some things were done well: (1) A target was identified, (2) the best way to assay that target was defined, (3) appropriate patients were selected based on presence of the target, and (4) pharmacokinetics was incorporated to make scheduling more convenient.
We could improve on/learn from some aspects: (1) Is continuing trastuzumab after disease progression valuable? (2) Did we need that many trials to see the benefit of trastuzumab in early-stage disease? Could we have come to a conclusion with fewer? (3) By allowing only patients 6 months from their adjuvant therapy to get trastuzumab, we may have lost an opportunity to determine the benefit of delayed initiation of adjuvant trastuzumab. In a different population, MA.17, by allowing crossover to letrozole (Femara) regardless of when tamoxifen was completed, is providing evidence for benefit of delayed initiation of aromatase inhibitor therapy.
In contrast to trastuzumab, there is less enthusiasm for bevacizumab (Avastin) and uptake has not been as rapid. E2100 is no less spectacular than the pivotal trastuzumab trial and toxicity is manageable, so why the lack of enthusiasm? The initial phase III trial of bevacizumab was perceived as negative despite the doubling of response rate. Negative trials create less excitement, but this is not the sole reason for the slower uptake. E2100 accrued well, so there was enough faith in bevacizumab to put patients on the trial.
There are some legitimate reasons behind the slower uptake: (1) Lack of a marker to select the most appropriate patients for this therapy; (2) absence of a reliable test to determine if angiogenesis is being modulated by the therapy; and (3) cost. The cost issue is more profound when taken globally. There are patients world-wide that can benefit from this treatment but the cost is prohibitive. It is disturbing to envision a dichotomy where patients have worse outcomes simply because of economics. Breast cancer patients worldwide share the same aspirations regardless of their ability to pay-all hope for a cure, for fewer recurrences, and for less toxicity. The translational model must flow not only from bench to bedside but also to the global breast cancer community.
Metastatic disease is lethal; we continue to develop better therapies in the adjuvant setting where we have a better chance for cure. As we focus on improving cure, it is easy to forget a point of diminishing returns. Some patients' benefit from a given therapy is marginal at best. But can we afford to compromise the cure of a few to spare many from the toxicities of therapy? Thankfully, models such as Adjuvant! Online and molecular assays like the Oncotype DX have been developed to better predict benefit from a given adjuvant therapy. The Breast Intergroup's collaborative effort in the TAILORx study is laudable. Foretelling that it will validate the Oncotype DX assay, my enthusiasm is tempered by the prospect of a "poor man's recurrence score assay" and whether the Oncotype DX assay will perpetually be out of reach for patients in less affluent countries.
Clinical Trials: Can We Do Better?
Dr. Seidman's analogy of a "book of many chapters" for metastatic breast cancer is quite fitting. Although we would like to ultimately impact survival, it may not be the best endpoint to look at in the in the early chapters of the book. Pinning down the most suitable endpoint is complicated by the scenario of dissimilar endpoints for different therapies. For instance, response rate may be a reasonable early endpoint for chemotherapy but not for biologic therapy. It can get even more complicated when combining both therapies. A key attraction of TCH (docetaxel/cisplatin/trastuzumab) was that it was predicted to have the best synergy based on a preclinical model. So the results of BCIRG 006 and BCIRG 007 were, to some degree, a letdown. More importantly, there was a serendipitous victim of these results-the hope of preclinical model(s) helping with rational design of therapies to accelerate novel drug development.
The blemish of the Bezwoda trial has taught us not to be complacent. Many trials are sponsored by pharmaceutical companies with vested interests in the results. This in itself is not wrong and in an era of limited resources, should be encouraged. But the question of who controls the data and what constitutes appropriate restriction(s) to the data by the pharmaceutical company must be answered upfront. Consider that data in the public domain can be mined to generate a hypothesis that may result in subsequent practice-changing clinical trial(s). Will data from pharmaceutical-sponsored trials be readily available for such analysis? The fear is that if we are not sufficiently engaged, this issue it will be decreed for us. We acknowledge that clinical trials are critical in advancing knowledge into therapies that matter to patients.
Participation in clinical trials is less than ideal. One of the reasons for nonparticipation often cited by patients is that they were never even offered the option. This can easily be changed. Granted, it might occasionally result in "losing a patient" to another practice, but is this too steep a price to pay? Imagine if a trial could be completed in half the time it takes today. By simply completing trials in a timely fashion, we can have an impact of similar or greater magnitude as targeted therapies. We can apply results from positive trials earlier to improve outcomes of many more patients and discontinue ineffective therapies sooner to spare more patients from toxicities.
The declining mortality from breast cancer is noteworthy, but what if breast cancer were altogether uncommon? Is this achievable? Maybe, if we put as much effort into prevention as we do for treatment of established disease. But even that is insufficient; a buy-in from the population we would like to affect is essential. Despite the positive results of the NSABP P-1 trial, uptake of tamoxifen as a risk-reduction strategy was low. We will see what the uptake of raloxifene will be now that the STAR results have been reported. If it turns out to be similar to tamoxifen, what would it mean for the future chemoprevention trials? In designing prevention trials, have we relied solely on the "science"? Have we considered what women will or will not do to decrease their risk of developing breast cancer? How about trials that have little to do with a drug but may have similar benefits? Take, for instance, the Women's Intervention Nutrition study. Although in a different setting, a clinical benefit was seen with reduction in dietary fat intake. Such interventions have little to no toxicity, cost less, and may provide health benefits beyond breast cancer. Will more women undertake such interventions compared to chemoprevention strategies? If so, how do we foster, fund, and create expertise for the conduct of such studies?
Dr. Seidman predicts that the future will bring advances at an unprecedented rate, requiring "frequent, clear, and timely communication of such advances." I agree completely.
-Melanie E. Royce, MD, PhD
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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