Trial establishes neoadjuvant trastuzumab as standard for locally advanced disease

SAN ANTONIO-Neoadjuvant therapy that includes trastuzumab (Herceptin) prolongs event-free survival and has an acceptable safety profile in women with HER2-positive locally advanced breast cancer, based on results from the largest trial testing such therapy in this setting.

"The median survival for women with LABC ranges from three years for inflammatory breast cancer to six years in other cases, and is significantly worse than for women with a non-LABC diagnosis. This alone strongly suggests that LABC is an area of continuous medical need," said lead author Luca Gianni, MD. "In all treatment strategies, preoperative systemic drug therapy has a key role to allow for surgery and to improve outcomes among patients with LABC."

In the international phase III trial, known as the NeOAdjuvant Herceptin (NOAH) trial, women with HER2-positive LABC were randomly assigned to sequential neoadjuvant chemotherapy consisting of AT, T, and CMF, either with (n = 115) or without (n = 113) concomitant trastuzumab. After surgery and radiation therapy, women in the trastuzumab arm received that agent out to one year, whereas those in the other arm did not (SABCS abstract 31).

For additional assessment of the regimen and comparison, the trial also included a group of women with HER2-negative LABC who received just the neoadjuvant chemotherapy followed by surgery and radiation therapy (n = 99). All women in the trial with hormone receptor-positive disease also received adjuvant tamoxifen.

In the intent-to-treat analysis, the rate of pathologic complete response among the HER2-positive population was significantly higher in the group given trastuzumab than in the group not given this agent (43% versus 23%), according to Dr. Gianni, who is director of medical oncology at the Istituto Nazionale Tumori in Milan, Italy. The rate in the group not given trastuzumab did not differ from that in the HER2-negative group (23% versus 17%).

In the HER2-positive population, the patients who received trastuzumab were significantly less likely to experience events (progression on therapy, relapse after surgery, or death from any cause) than those in the group that did not receive this agent (hazard ratio, 0.56). The risk reduction was essentially the same after adjustment for potential confounders (hazard ratio, 0.55). In contrast, the risk of death did not differ between the HER2-positive groups. Median follow-up was three years,

Within the HER2-positive population, receipt of trastuzumab was associated with a reduction in the risk of events in all subgroups, Dr. Gianni noted. The reduction was significant among patients with inflammatory breast cancer, patients with hormone receptor-negative disease, and patients with a clinical N stage of 1 or greater.

Compared with the HER2-negative group, the HER2-positive group who did not receive trastuzumab did not have better event-free survival. In fact, the probability of events in that group increased over time and surpassed that in the former group.

"Overall, the treatment was very feasible and well tolerated," Dr. Gianni said.

Rates of grade 3/4 adverse events were low and generally similar in each of the three treatment groups. The most common were neutropenia (2.0% to 4.4%), febrile neutropenia (1.7% to 2.0%), diarrhea (0.9% to 3.5%), and stomatitis (0.9% to 3.5%).

The worst grade of left ventricular ejection fraction toxicity observed (according to Common Toxicity Criteria) was also generally similar across the three treatment groups.

"Most patients [showed] either a minimal or no effect on left ventricular ejection fraction," Dr. Gianni said.

Two patients (1.7%) in the HER2-positive group given trastuzumab developed symptomatic (grade 3) heart failure during treatment or follow-up, compared with none of those in the HER2-positive group not given trastuzumab and none of those in the HER2-negative group.

"Neoadjuvant trastuzumab therapy with an anthracycline- and paclitaxel-containing chemotherapy significantly extends event-free survival in patients with HER2-positive disease," Dr. Gianni asserted, summing up the trial's results. "The neoadjuvant regimen is well tolerated, with acceptable cardiac safety."

He added that the findings also show some activity of the same regimen without trastuzumab.

"We think these data establish neoadjuvant trastuzumab with chemotherapy as a standard treatment option in women with HER2-positive LABC," Dr. Gianni concluded.

Ongoing analyses are assessing associations between biomarkers and outcomes, he noted.