In 2004, Dr. Leisha Emens and I reviewed the use of trastuzumab (Herceptin), the monoclonal antibody directed against the HER2 protein, in the treatment of breast cancer. At that time, trastuzumab as monotherapy or in combination with chemotherapy was established as a standard of care for women with advanced HER2-overexpressing metastatic breast cancer. Much new information has emerged in the ensuing seven years. Below I summarize seven things that we have learned and seven things that we still seek to understand to optimize anti-HER therapy in breast cancer.
What Have We Learned?
1. The utility of trastuzumab in high-risk early-stage breast cancer has been unequivocally established. Several randomized trials suggest that the administration of trastuzumab concurrent with or after adjuvant chemotherapy decreases recurrence by about 50%, and it seems likely that this will translate into a survival advantage.
2. The importance of accurate ascertainment of HER2 status has been recognized, and testing guidelines have been widely promulgated by the College of American Pathologists and the American Society of Clinical Oncology. Use of immunohistochemistry or fluorescent in situ hybridization (FISH) to assess HER2 status in breast tumor is now widely accepted, and recommendations regarding what are viewed as positive or negative results have been disseminated.
3. The short- and long-term toxicities of trastuzumab have been extensively studied. The principal short-term toxicity appears to be the infusion reaction that is associated with several monoclonal antibodies. The short- and moderate-term cardiotoxic effects of trastuzumab alone and in combination with chemotherapy have been evaluated. Trastuzumab alone appears to be associated with a small but real risk of cardiac dysfunction, as judged by echocardiography or nuclear medicine testing for ejection fraction. This risk is increased in patients who received adjuvant chemotherapy, particularly anthracycline-containing regimens. Guidelines for cardiac monitoring and treatment adjustment have been promulgated.
4. The success of trastuzumab has spawned the development of a number of other HER2-targeted therapies. Among these, the small molecule receptor tyrosine kinase inhibitor, lapatinib (Tykerb), has entered clinical care as treatment for advanced HER2-positive breast cancer that is resistant to trastuzumab. Other HER-targeted agents, such as pertuzumab, neratinib, and TDM1, are at earlier stages of clinical development. The availability of these agents enables us to test combination HER-targeted strategies.
5. Provocative clinical trials in advanced breast cancer suggest that trastuzumab should be continued beyond clinical progression. Separate clinical trials in the same setting have suggested that trastuzumab plus lapatinib gives superior outcome compared with lapatinib alone after trastuzumab failure. Similarly, trastuzumab plus capecitabine (Xeloda) leads to better results than capecitabine alone in those whose disease progresses on a trastuzumab-containing regimen. These results are not in keeping with the usual approach in metastatic breast cancer of discontinuation of a therapy at the time of disease progression.
6. Recently reported trials that used trastuzumab and lapatinib in the preoperative setting in early-stage HER2-overexpressing breast cancer have suggested that trastuzumab may be slightly more active than lapatinib and that the combination of trastuzumab and lapatinib leads to better results (as judged by response and pathological complete response) than are achieved with either agent alone.
7. The rapid pace of these developments has demonstrated the power of using a molecular target for the enrichment of patients who are more likely to respond, and it has shown the ability of large collaborative trials focused on a specific molecularly-defined subset of patients to accelerate progress.
What Is Left to Learn?
1. An obvious question is what the role of combination HER-targeted therapy versus monotherapy should be in early-stage breast cancer. ALTTO—an international trial of chemotherapy with trastuzumab, lapatinib, the combination of trastuzumab and lapatinib, or the sequence of trastuzumab followed by lapatinib—is nearing completion of its accrual. The results of this trial are eagerly awaited, both because of the implications for clinical care and on account of the opportunity they will provide to compare the results of ALTTO with those of its preoperative counterpart, NEOALTTO, which suggested improved outcome with dual therapy.
2. Another area of uncertainty is the optimal duration of anti-HER therapy in the adjuvant setting. Trastuzumab for one year is currently viewed as the standard of care in the United States. Other trials will shed light on whether longer durations of therapy (up to two years) or shorter durations (several months) will give similar or better results. These trials have enormous practical implications and may also contribute to our understanding of underlying cancer biology.
3. A third question is whether all women with HER2-overepressing tumors should receive HER-targeted therapy. Better predictive markers that can refine patient selection are sorely needed. In addition, the role of anti-HER therapy in T1cN0 tumors or ductal carcinoma in situ has not been assessed.
4. A related question is whether some women with early-stage HER2-overexpressing breast cancer might benefit from anti-HER therapy in the absence of chemotherapy. Clinical trials to date have not evaluated this important question.
5. Success in developing anti-HER therapy rests in large part on our ability to enrich the population of patients through HER2 testing. However, provocative data from two adjuvant trials raise the possibility that trastuzumab may provide benefit even in women whose tumors were judged to have normal HER2 expression on central testing after initial local testing was felt to show HER2 overexpression. Although the weight of the evidence favors limitation of anti-HER therapy to those patients whose tumors overexpress HER2 by established assays, this remains an area of uncertainty.
6. How and when to integrate anti-HER therapy with other biologically targeted agents are questions of keen interest. Studies in metastatic breast cancer show that trastuzumab plus letrozole (Femara) gives better results that letrozole alone. Early data suggest that the combination of trastuzumab and bevacizumab (Avastin) is active and well tolerated in advanced breast cancer.
7. A final sobering observation is that a large fraction of individuals who receive anti-HER therapy for breast cancer manifest either primary or secondary resistance. A better understanding of mechanisms of action and of resistance for the anti-HER therapies is clearly required.
Just over 25 years have passed since the HER2/c-erbB-2 gene was identified by several investigators. Recognition of its importance as a prognostic and predictive factor in breast cancer has followed. With this understanding, several strategies for targeting this growth pathway have emerged. Two HER-targeted therapies, trastuzumab and lapatinib, are viewed as standard treatments for metastatic breast cancer that overexpresses HER2, and trastuzumab has entered clinical practice as a part of the adjuvant therapy regimen for many women with early-stage HER2-overexpressing breast cancer. Ongoing and planned clinical trials over the next decade should contribute to further optimization of anti-HER therapy.