Treatment of HER2-positive cancers has improved rapidly over the past decade, and the pace of progress continues to accelerate. The advances have been fueled in part by the conduct of neoadjuvant studies, which have aided in the development of novel therapies and more effective combination regimens. Neoadjuvant systemic therapy serves several functions in research as well as in clinical care. Neoadjuvant therapy offers the potential to render inoperable cancers operable, and can facilitate breast conservation in situations that would otherwise require mastectomy. Neoadjuvant therapy also can provide unique prognostic information, as it is clear from multiple studies that in all subtypes of breast cancer, patients who achieve a pathologic complete response (pCR) have a very favorable long-term outcome. From a research perspective, the neoadjuvant setting provides investigators with the opportunity to quickly compare the efficacy of different regimens, explore predictive and pharmacodynamic biomarkers, and identify mechanisms of resistance.
There are disadvantages to the neoadjuvant approach. Neoadjuvant treatment is more complicated than standard adjuvant approaches—it requires close coordination between surgical oncologists, medical oncologists, radiation oncologists, pathologists, and, frequently, plastic surgeons. Neoadjuvant treatment can also make treatment decisions more complex, primarily because some information about the initial presentation, including precise tumor size and nodal status, cannot be definitively determined prior to starting systemic therapy and may be altered by the systemic therapy. Because of this ambiguity, guidelines suggest that neoadjuvant therapy should only be used in situations in which it is clear whether chemotherapy is or is not warranted based on the data available preoperatively.
These positive and negative aspects of neoadjuvant therapy are comprehensively reviewed in the article by Gunter von Minckwitz and colleagues in this issue of ONCOLOGY. As they point out, HER2-positive breast cancers are typically well suited for a neoadjuvant approach, at least in part because the decision to use chemotherapy is generally straightforward—a chemotherapy/trastuzumab (Herceptin) regimen is used in most HER2-positive cancers greater than 1 cm.
What is the optimal neoadjuvant regimen for HER2-positive disease outside of a clinical trial? Unfortunately, there is not a simple answer. While a number of studies demonstrate high pCR rates and good tolerability with a variety of chemotherapy/trastuzumab combinations, there is no clear consensus on the length of therapy or whether to include an anthracycline, and if an anthracycline is included, on whether it should be given concurrently or sequentially with trastuzumab. There does seem to be a trend toward higher pCR rates with longer chemotherapy/trastuzumab regimens (eg, 24 weeks of therapy) compared with those extending only for 12 weeks. In terms of published guidelines, Dr. von Minckwitz notes that the National Comprehensive Cancer Network (NCCN) recommends paclitaxel plus trastuzumab followed by FEC (fluorouracil [5-FU], epirubicin, cyclophosphamide) plus trastuzumab, but this is based on a small study.[2,3] The German AGO (Arbeitsgemeinschaft Gynaekologische Onkologie) guidelines suggest EC plus trastuzumab followed by docetaxel plus trastuzumab, which was the control arm for the large GeparQuattro and GeparQuinto studies,[4,5] but neither of these trials has reported long-term outcome data. In the absence of definitive data, it is reasonable to use one of the standard adjuvant regimens (TCH [docetaxel, carboplatin, trastuzumab] or ACTH [doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab]) based on extrapolation of data indicating no difference in long-term outcomes when the same regimen is used neoadjuvantly or adjuvantly. If a physician chooses to employ a regimen of concurrent anthracycline and trastuzumab, great care should be taken with regard to cardiac toxicity (in spite of the very favorable results to date), and both the physician and patient should be aware that concurrent anthracycline-trastuzumab therapy has not been shown to be superior to standard sequential anthracycline-trastuzumab regimens in terms of long-term outcomes.
As noted earlier, neoadjuvant clinical trial designs have had a significant role in the rapid progress that has been made in developing novel HER2-directed therapies. By using a surrogate efficacy endpoint (pCR), neoadjuvant trial designs allow the comparison of different regimens much more quickly and with far fewer patients than can be done using a conventional adjuvant design. This is particularly true in the HER2-positive setting, in which the generally favorable outcomes associated with standard therapy require trials with very large sample sizes to demonstrate superiority of a novel regimen. Many neoadjuvant studies also allow patients who receive investigational therapy preoperatively to receive standard-of-care therapy postoperatively. This design allows novel therapies to be tested earlier in their development, further accelerating the development process. Neoadjuvant designs also provide ample pre-treatment and post-treatment tissue samples for correlative studies.
The European oncology community has focused on the opportunities of the neoadjuvant setting, enrolling more than 2000 patients with HER2-positive cancers to recent trials. These studies have produced a number of important findings, most notably that combining chemotherapy with dual HER2 blockade using pairs of HER2-directed agents such as trastuzumab/lapatinib (Tykerb) and trastuzumab/pertuzumab leads to significantly improved efficacy compared with using a single HER2-directed agent.[7,8]
A major potential weakness of the neoadjuvant trial design is that it is not known whether an agent that improves pCR rates will necessarily improve long-term outcomes. While there was a direct correlation between improved pCR and improved event-free survival with the addition of trastuzumab in the NOAH (NeOAdjuvant Herceptin) study, there have been other neoadjuvant studies (eg, with chemotherapy) in which such a correlation has not held true. Already it is clear that pCR does not have nearly as strong a prognostic effect in hormone receptor–positive HER2-positive cancers as it does in hormone receptor–negative HER2-positive cancers. At the very least, this observation suggests that studies need to analyze subgroups of HER2-positive cancers separately. It will be reassuring if the long-term efficacy results from ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) and APHINITY (Pertuzumab and Herceptin IN IniTial TherapY of Breast Cancer)—the adjuvant studies evaluating trastuzumab/lapatinib and trastuzumab/pertuzumab, respectively—confirm the results of the neoadjuvant studies.
The success of the neoadjuvant studies in HER2-positive breast cancer has had a great impact on the field in terms of facilitating drug development and providing guidance and experience regarding treating patients off-study with neoadjuvant therapy. These types of clinical trials will undoubtedly help resolve some of the ongoing challenges, including identifying which patients will benefit from specific novel therapies. Already, new trial designs are being developed that build on the neoadjuvant designs. One approach is the so-called post-neoadjuvant study, which will evaluate alterative therapeutic strategies in patients who fail to achieve a pCR after neoadjuvant therapy. Ultimately, it is hoped that studies in the neoadjuvant setting will allow us to determine which patients may be safely treated with targeted therapy alone in the absence of chemotherapy.
Financial Disclosure: Dr. Krop receives clinical trial support from Genentech.
1. Kaufmann M, Hortobagyi GN, Goldhirsch A, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: an update. J Clin Oncol. 2006;24:1940-9.
2. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2011. Available from: www.nccn.org.
3. Buzdar AU, Valero V, Ibrahim NK, et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007;13:228-33.
4. Untch M, Rezai M, Loibl S, et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol. 2010;28:2024-31.
5. von Minckwitz G, Eidtmann H, Loibl S, et al. Integrating bevacizumab, everolimus, and lapatinib into current neoadjuvant chemotherapy regimen for primary breast cancer. Safety results of the GeparQuinto trial. Ann Oncol. 2011;22:301-6.
6. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008;26:778-85.
7. Gianni L, Pienkowski T, Im Y-H, et al. Neoadjuvant pertuzumab (P) and trastuzumab (H): antitumor and safety analysis of a randomized phase II study ('NeoSphere'). Presented at the CTRC-AACR San Antonio Breast Cancer Symposium, San Antonio, Texas, December 8-12, 2010; abstract S3-2.
8. Baselga J, Bradbury I, Eidtmann H, et al. First results of the NeoALTTO trial (BIG 01-06 /EGF 106903): a phase III, randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer. Presented at the CTRC-AACR San Antonio Breast Cancer Symposium, San Antonio, Texas, December 8-12, 2010; abstract S3-3.
9. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377-84.
10. Loibl S, von Minckwitz G, Blohmer J, et al. pCR as a surrogate in HER2-positive patients treated with trastuzumab. Presented at the CTRC-AACR San Antonio Breast Cancer Symposium, San Antonio, Texas, December 6-10, 2011; abstract S5-4.