These updated joint analysis data indicate that after 4-years of follow-up, the addition of adjuvant trastuzumab to chemotherapy maintains both a significant DFS and OS benefit compared with chemotherapy alone. At the time of the initial report (with median follow-up of 2 years),13
the relative reduction in DFS event rate was 52% (HR, 0.48; P
< .001), and at 2.9 years, the relative reduction in death rate was 35% (HR, 0.65; P
With the additional follow-up, the relative reduction in DFS event rate was 48% (P
< .001), and the relative reduction in death rate was 39% (P
< .001). Thus, our data demonstrate long-term continued benefit with trastuzumab administered concurrently with chemotherapy (anthracycline/cyclophosphamide followed by paclitaxel + trastuzumab, with 1 year of trastuzumab treatment). Absolute differences in DFS increased by number of nodes; it was most pronounced for patients with ≥ 10 involved nodes, who had an unprecedented 27% absolute improvement.
Cardiac safety in these trials has been studied extensively.17–20
In N9831, at a median follow-up of 3.75 years, the 3-year cumulative incidence of cardiac events (ie, symptomatic CHF or probable or definite cardiac death) was 0.3% without trastuzumab, 2.8% with sequential paclitaxel and trastuzumab, and 3.3% with concurrent paclitaxel and trastuzumab.18
There was no evidence of a significant increase in cardiac events over time.18
In B-31, the 5-year cumulative incidence of cardiac events was 0.9% without trastuzumab and 3.8% with concurrent paclitaxel and trastuzumab.19
There was no evidence of an increase in cardiac events over time.19
The findings of an independent board of cardiologists reviewing the data from patients reported to have had cardiac events (n = 173) in N9831 and B-31 have recently been reported.20
The panel concluded that the rate of symptomatic heart failure was 0.5% with chemotherapy alone and 2.0% with AC followed by paclitaxel and trastuzumab. Moreover, the panel reported that 86% of patients (31 of 36 patients) in the trastuzumab arms had either complete or partial resolution of the cardiac event in follow-up. Analyses of risk factors for cardiac events in N9831 have shown that patients ≥ 60 years old (P
= .003), patients with prior or current use of antihypertensive medication (P
= .005), and patients with LVEF near the LLN at registration (P
= .033) were at increased risk for such events.18
On the basis of our own data, we are reassured of the favorable therapeutic ratio (benefit over toxicity) of the AC followed by paclitaxel/trastuzumab adjuvant regimen as administered in NCCTG N9831 and NSABP B-31.12,13,17–20
A marked increase in the incidence of a DFS event was noted 1 year after random assignment in both treatment arms. This is an expected pattern in the clinical course of these patients, but the trastuzumab-containing arm continued to report a lower disease incidence after the discontinuation of trastuzumab compared with controls.
A number of phase III clinical trials have examined the impact of combining trastuzumab with chemotherapy on DFS, varying the type of chemotherapy, duration of trastuzumab, and timing of introduction of trastuzumab in relationship to chemotherapy.12,15,16,21
The Breast Cancer International Research Group 006 trial, with a median follow-up of more than 5 years, demonstrated significant improvements in DFS and OS with a nonanthracycline regimen (docetaxel, carboplatin, and trastuzumab [TCH]) and with AC followed by trastuzumab and concurrent docetaxel (AC-TH) compared with AC followed by docetaxel.12
The study was not powered to compare the two trastuzumab-containing arms. Notably, the number of deaths from any cause, number of deaths from breast cancer, and number of progression events were greater in the TCH arm relative to the AC-TH arm. The incidence of symptomatic CHF was greater in the AC-TH arm than in the TCH arm (2.0% v
0.4%, respectively; P
< .001). There were no reported cardiac deaths. The Herceptin Adjuvant (HERA) trial assessed the impact of 1 year of trastuzumab after standard chemotherapy in the neoadjuvant or adjuvant setting.15,16
At 2 years of follow-up, there was a significant DFS and OS benefit in patients receiving 1 year of trastuzumab compared with observation only.16
At 3.6 years of median follow-up, rates of cardiotoxicity were relatively low, but patients in the trastuzumab group, compared with the observation group, had a greater incidence of severe CHF (0.8% v
0%, respectively) and symptomatic CHF (1.9% v
The smaller Neoadjuvant Herceptin (NOAH) study evaluated the clinical benefit of chemotherapy alone (ie, doxorubicin plus paclitaxel followed by paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil) or with trastuzumab starting concurrently with doxorubicin in patients with HER2-positive locally advanced or inflammatory breast cancer.22
Patients in the trastuzumab arm received trastuzumab for a total of 1 year, starting in the neoadjuvant portion. At 3 years of follow-up, the addition of trastuzumab to chemotherapy significantly improved rates of pathologic complete response and event-free survival and reduced risks of recurrence, progression, or death compared with patients who did not receive trastuzumab. Trastuzumab therapy was well tolerated, with treatment-responsive symptomatic CHF in 2% of patients (two of 115 patients) being the most notable adverse event.
In conclusion, longer term analysis of N9831 and B-31 demonstrates continued benefit of adding 1 year of trastuzumab to standard anthracycline-based chemotherapy. A number of adjuvant treatment combinations of chemotherapy with trastuzumab are now available, allowing physicians to select a regimen they consider most appropriate for patients with early-stage invasive HER2-positive breast cancer. Longer-term follow-up and identification of predictive biomarkers will provide further insight into optimal trastuzumab adjuvant therapies. For patients with eligibility consistent with our adjuvant trastuzumab trials, the AC-TH regimen remains an excellent choice of treatment.