The clinical options available to treat HER2-positive breast cancer, in both the early and late stage setting, have been informed by the results of large, pivotal clinical trials. These trials have not only provided guidance to the optimal way to utilize adjuvant trastuzumab, but also expanded therapeutic options with new agents available for treatment of metastatic, HER2-positive breast cancer. The 2012 San Antonio Breast Cancer Symposium highlighted several important presentations that add to our body of knowledge and re-affirm the impact of anti-HER2 agents.
Two large adjuvant trials investigating the optimal duration of trastuzumab and conducted largely outside the U.S. were updated. The HERA trial had previously confirmed that treatment with one year of trastuzumab following adjuvant chemotherapy was superior to chemotherapy alone in patients with HER2-positive, early stage breast cancer, both in terms of disease-free survival (DFS) and overall survival (OS).
The other key question that was addressed in HERA was whether two years of trastuzumab offered additional benefit compared with one year of adjuvant trastuzumab therapy. Patients who were disease-free for at least one year following the start of trastuzumab were eligible to continue on for two years of therapy (1,553 patients for two years; 1,552 for one year). The final analysis was planned for 725 disease-free events and the current analysis was reported with 734 DFS events. With a median follow-up of eight years there were no differences in DFS, DFS by estrogen receptor expression, or OS. These results confirm that durations of adjuvant trastuzumab longer than one year should not be recommended.
Piccart-Gebhart MJ, Goldhirsch A, et al. HERA trial: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median followup. SABCS 2012 S5-2.
At the other end of the duration question is how short a duration of adjuvant trastuzumab can be recommended to attain the optimal benefit in terms of reduction in disease recurrence and mortality. Several years ago a Scandinavian trial, FinHer, demonstrated that as little as nine weeks of exposure to trastuzumab along with chemotherapy could confer similar benefit as was reported in large randomized cooperative group trials, including HERA. The FinHer trial by itself was not convincing because of its small size and non-standard chemotherapy regimen.
Nevertheless, the possibility of being able to achieve significant improvement in patient outcome with short exposures to trastuzumab became an important research question from a patient standpoint as well as from a societal resource expenditure perspective. The PHARE (Protocol of Herceptin Adjuvant Reduced Exposure) randomized patients with HER2-positive, early stage breast cancer (node-negative or -positive tumors larger than 1 cm), following six months of trastuzumab therapy to no further trastuzumab or continuation to a full year.
The trial was statistically designed as a non-inferiority trial, with non-inferiority established for six months of therapy if the HR of 1.15 was not crossed. A total of 1,690 patients were enrolled into each group (~50% of tumors were node-negative and ≥ 2 cm; ~75% received anthracycline/taxane-based chemotherapy).
With a median follow-up of 42.5 months, there was no statistical difference in DFS between the group receiving six months of therapy versus 12 months of trastuzumab, but there was a trend favoring 12 months of trastuzumab. A pre-planned subset analysis suggested that 12 months of trastuzumab was more effective than six months in patients with ER-negative tumors who completed chemotherapy prior to initiating trastuzumab (e.g., sequential).
The results from PHARE support one year of adjuvant trastuzumab as the standard of care. Longer follow-up of the PHARE trial, will be required and other randomized trials addressing shorter durations of trastuzumab will report in the next year.
Pivot X, et al. PHARE trial result of subset analysis comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer. SABCS 2012 S5-3
The final planned survival analysis from the combined analysis of the NSABP B-31 trial and NCCTG 9831 was presented. These two practice-changing randomized clinical trials were first reported over six years ago, establishing the role of trastuzumab as an essential component of adjuvant therapy regimens in HER2-positive breast cancer. Treatment arms that were similar (those with a chemotherapy backbone of AC [doxorubicin/cyclophosphamide] followed by T [paclitaxel] or AC followed by T with concurrent trastuzumab) between the trials were combined in an agreement with the NCI.
Now, with the requisite number of survival events and a median follow-up of 8.4 years, the addition of trastuzumab to paclitaxel following AC chemotherapy is associated with a significant and substantial improvement in OS with a relative risk reduction of 37% (HR 0.63). For patients with high-risk HER2-positive breast cancer, treatment with this regimen reduced the risk of a DFS event at 10 years by 40 percent (0.60).
The improvement in DFS and OS occurred in almost all subsets of patients analyzed. For patients with hormone receptor positive disease, the absolute reduction in the rate of distant recurrence as a first event continues to improve over time with the addition of trastuzumab and reaches 9.6 percent at 10 years.
For patients with hormone receptor negative disease the absolute risk of distant recurrence as a first event is reduced by 9.6 percent at seven years, after which distant recurrence from breast cancer is unlikely. These results should reassure patients and clinicians about the durability of the benefit derived from adjuvant trastuzumab.
Romond E, et al. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: Final planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. SABCS 2012 S5-5.
The final presentation that focused on HER2 therapy was an update of the Cleopatra study published earlier this year in the NEJM by Baselga et al.
Based on the results from Cleopatra, pertuzumab was approved by the FDA for first-line treatment of HER2-positive, metastatic breast cancer in combination with docetaxel and trastuzumab. An extensive biomarker analysis was undertaken as a companion to the trial in an effort to identify: Predictive markers that would provide qualitative association with pertuzumab benefit, and prognostic markers independent of treatment arm. The analyses confirmed HER2 as the only marker for selecting patients for HER-targeted therapy.
One area of particular interest was the analysis of PIK3CA mutations that were found not to be associated with resistance to pertuzumab. However, patients with tumors harboring a PIK3CA mutation, with or without pertuzumab, had a somewhat worse prognosis compared with their counterparts not having such a mutation. The added benefit of pertuzumab was similar whether a mutation was present or not.
Baselga J, et al. Biomarker analyses in CLEOPATRA: A phase III, placebo-controlled study of pertuzumab in HER2-positive, first-line metastatic breast cancer. SABCS 2012 S5-1. Baselga J, et al. Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer. N Engl J Med 2012; 366:109-119
The results from SABCS 2012 clearly show that clinical investigations of how best to utilize anti-HER2 therapy have translated into better outcomes for patients with both early and late stage breast cancer. As we go forward, we can anticipate additional agents becoming available for this subset of breast cancer and further refinement of how we manage patients.