The first generation of clinical trials addressing adjuvant treatment questions in breast cancer has confirmed the important role of endocrine manipulations and chemotherapy, improving disease-free and overall survival. Subsequent generations of clinical trials have led to the current treatment paradigm for properly selected women: multiagent adjuvant chemotherapy that contains anthracyclines and/or taxanes, 5 to 10 years of adjuvant endocrine therapy, trastuzumab (Herceptin), or a combination of one or more of these treatment strategies.[1,2] With concurrent optimization of early detection and local therapy, breast cancer–related mortality has declined in recent years.[3,4] As a result, most women are now expected to survive their breast cancer.
In his review, Dr. Sledge first provides a historical perspective of the changes that he has observed since he first joined the Breast Committee at the Eastern Cooperative Oncology Group (ECOG) in the 1980s, chaired by the late Dr. Martin Abeloff. At the time, studies focused primarily on chemotherapy-related questions. Dr. Sledge then presents an overview of current trials, unresolved questions, and a glimpse into likely future treatment options.
In the new millennium, when I joined the ECOG Breast Committee (chaired by Dr. Sledge), the flavor of ongoing and planned trials was very different. While early trials targeted women with a specific nodal or hormone receptor status, more recent trials have been tailored to narrower subgroups of women.
Early trials informed us about the importance of tumor biology, an insight that has produced several changes in current practice. For example, we now recognize that endocrine manipulations are effective only in women whose tumors express estrogen or progesterone receptors (ER/PR), and yet, we also know that endocrine therapy does not benefit all women with this tumor expression. Unlike endocrine therapy, chemotherapy has less specific application to tumor subtypes, but the benefit is greater in tumors that do not express ER/PR and that are rapidly proliferating.[3,5] A new generation of clinical trials considers risk estimates based on these and other intratumoral characteristics. As Dr. Sledge explains, today’s studies parallel these subtypes, testing treatments that target hormone-sensitive, HER2-positive, or “triple-negative” tumors.
As we design new trials that target specific tumor subtypes, we continue to learn from the studies conducted by the cooperative groups a decade or two ago. Results from past trials not only guide our daily treatment recommendations, but also provide patient populations with long-term follow-up, tumor tissues, and other samples that can be used to test new hypotheses. For example, Oncotype DX was tested and validated in cohorts of women included in node-negative trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) 2 decades ago.[6,7] Moreover, the value of Oncotype DX has been studied in node-positive women who were included in a large study conducted by the Southwest Oncology Group (SWOG 8814) and the Breast Intergroup in the late 1980s.
We must regard current trials in a similar fashion. Ongoing trials will not only help answer today’s questions, but will also provide a wealth of information and samples that can be used to answer tomorrow’s inquiries.
Old and New Questions
The advances made in just a few decades of prospective clinical trials have clearly led to fewer recurrences. Since metastatic breast cancer is rarely curable, efforts should be made to optimize adjuvant treatments. Dr. Sledge lists some of today’s main questions in the adjuvant setting: In women with tumors that express hormone receptor, what is the role of aromatase inhibitors and ovarian suppression, and what is the optimal treatment duration? Ongoing studies, along with those already completed, will help answer some of these questions. At the same time, a clearer understanding of intratumoral characteristics and host factors invite new questions: Who will benefit from endocrine manipulation alone, and if a given patient would benefit, what is the optimal agent and duration? Who should be recommended chemotherapy and who should be offered other treatments in addition to or instead of endocrine therapies?
In women with HER2-positive tumors, what is the optimal duration and sequence of trastuzumab? Who may be resistant to this agent, and what is the role of new agents that target the pathway? Are there intratumoral and host characteristics that can help optimize trastuzumab-based treatments for individual patients? Since only about 20% of women with a newly diagnosed breast cancer develop HER2-positive tumors, it is encouraging that cooperative groups across the world have joined forces to ask the next question in the adjuvant setting, launching the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial in women with early high-risk HER2-positive breast cancer. Such collaborations will bring advances rapidly to the clinical arena. Other studies target only women with so-called triple-negative breast cancer, a group that comprises about 15% to 20% of all breast cancers, but for whom adjuvant treatment is limited to chemotherapy. Optimization of current treatments and new agents are required for this group. It is also possible that there are smaller subgroups within the category such as women with sporadic basal-like tumors or BCRA1-mutation carriers who may require different treatment approaches.
Prioritizing New Approaches
Several questions apply to all tumor subtypes: Who should be treated, and what are the optimal agents, sequences, and durations of treatment? Perhaps more importantly, we must recognize who does not require adjuvant therapy, either due to favorable tumor biology or due to resistance to current treatments. Better prognostic and predictive factors and an understanding of host factors will help individualize therapy. With the wealth of new knowledge and dozens of novel agents, a welcome problem that we are now facing is how to prioritize the use of promising new treatments and approaches.
We must also enhance our understanding of who is at risk for treatment-related side effects that may compromise the ability to complete a prescribed course of treatment or that may alter a woman’s long-term quality of life. Since it is likely that almost every woman diagnosed with an early breast cancer will be offered adjuvant therapy, and the majority of women will survive their disease, we must prospectively study the endocrine, genetic, inflammatory, and other factors that may determine long-term tolerance, with an overall goal of enhancing efficacy while minimizing toxicity.
This issue of ONCOLOGY is devoted to the memory of Dr. Martin Abeloff, a scientist, leader, mentor, and deeply compassionate man who treated all people with great dignity and respect. Marty was proud of the incremental improvements that he had observed over the many years of clinical investigations during his career. His passion for the future was to improve breast cancer prevention and health policy.
We have made several strides in identifying women who are at highest risk of developing breast cancer, but at this point, approaches to reducing the incidence of the disease are few and suboptimal. I am hopeful that in the new millennium, the strides we have made in the adjuvant setting will be translated to the prevention setting, where novel screening and risk-reduction strategies are greatly needed.
1. Carlson RW, Brown E, Burstein HJ, et al: NCCN task force report: Adjuvant therapy for breast cancer. J Natl Compr Canc Netw 4(suppl 1):S1-S26, 2006.
2. Goldhirsch A, Wood WC, Gelber RD, et al: Progress and promise: Highlights of the International Expert Consensus on the Primary Therapy of Early Breast Cancer 2007. Ann Oncol 18:1133-1144, 2007.
3. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005.
4. Berry DA, Cronin KA, Plevritis SK, et al: Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353:1784-1792, 2005.
5. Berry DA, Cirrincione C, Henderson IC, et al: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658-1667, 2006.
6. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004.
7. Paik S, Tang G, Shak S, et al: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726-3734, 2006.
8. Albain K, Barlow W, Shak S, et al: Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, node-positive, ER-positive breast cancer (S8814,INT0100) (abstract 10). Breast Cancer Res Treat 108, 2007.