Ten Years Later, Trastuzumab Survival Advantages March On

Neil Osterweil

December 07, 2012

SAN ANTONIO, Texas — A decade of data continue to demonstrate that adding trastuzumab (Herceptin, Genentech) to standard chemotherapy in women with HER2-positive breast cancer improves both overall and disease-free survival.

Furthermore, the benefits conferred by trastuzumab are not waning over time.

At a median follow-up of 8.4 years, women randomly assigned to receive doxorubicin and cyclophosphamide (AC) followed by paclitaxel plus trastuzumab had a 37% lower relative risk for death than women who received AC alone, reported Edward H. Romond, MD, professor of medicine at the University of Kentucky Medical Center in Lexington.

For women with high-risk HER2-positive disease, the trastuzumab-containing regimen also reduced the risk of having a disease event by 40%.

These relative risk-reduction benefits were seen across nearly all subgroups, Dr. Romond said.

He presented data from the final planned joint analysis of overall survival from the NSABP B-31 and NCCTG N9831 trials here at the 35th Annual San Antonio Breast Cancer Symposium (SABCS).

"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% 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% at 7 years, after which distant recurrence from breast cancer is unlikely," Dr. Romond said.

A breast cancer specialist who was not involved in the study told Medscape Medical News that the long-term data are welcome but not surprising.

...there was a real plateauing out in terms of the risk of recurrence... Dr. Claudine Isascs

"There continues to be a growing benefit [of trastuzumab ] over time, and in the ER [estrogen-receptor]-negative subset of patients, it was nice to see that there was a real plateauing out in terms of the risk of recurrence after about 7 years, which is reassuring, as we're following some of these patients beyond that," said Claudine Isascs, MD, professor of medicine and codirector of the breast cancer program at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

Dr. Romond presented data on 2018 women assigned to AC and paclitaxel, and to 2028 assigned to AC, paclitaxel, and trastuzumab. In each arm, about 45% of women were both ER-positive and PR-positive, and the remainder had tumors that were ER- or PR-positive, or both. About one half of all women in the studies had tumors ranging from 2.1 to 5.0 cm in size, and about 40% had tumors measuring 2 cm or less. Roughly 10% in each group had tumors larger than 5 cm.

In all, 102 women (5%) assigned to receive trastuzumab did not get the drugs because of cardiac symptoms or a decrease over baseline in left ventricular ejection fraction following AC. These patients were included in the intention-to-treat (ITT) analysis.

In the control arm, 413 women (20.4%) received trastuzumab after the first interim analysis of the trials in 2005 showed positive results; these patients are also included in the ITT analysis.

Ten-Year Data Similar to 6-Year Data

Six years after randomization, disease-free survival was 81.4% for patients assigned to trastuzumab vs 69.5% among those assigned to AC. Similar results were seen at 8 years (76.8% vs 64.9%, respectively) and at 10 years (73.7% vs 62.2%), for an absolute difference at 10 years of 11.5%.

Trastuzumab was associated with a hazard ratio [HR] of 0.60 (95% confidence interval [CI], 0.53 - 0.68, P < .0001).

Disease-free survival events included distant recurrences in 11.2% vs 19.4%, local regional recurrences in 4.1 vs 6.1%, contralateral breast disease in 2.3% vs 2.0%, and other second primary cancers in 3.3% vs 3.7%. In all, 1.9% of patients receiving trastuzumab died without recurrence, compared with 1.5% of patients receiving AC-paclitaxel only.

Among ER- and/or PR-positive patients, distant recurrence as a first event occurred in 12.7% of those who had taken trastuzumab, and in 22.3% of those who had not. Among ER- and PR-negative patients, the respective rates were 11.9% and 21.5%, and as noted above by Dr. Isaascs, the events in both groups began to level out at about 7 years but remained substantially better for trastuzumab-treated patients.

Dr. Romond noted that the absolute differences in overall survival between trastuzumab-treated patients and control patients has increased gradually over the last decade, from 2.9% at 4 years after randomization to 5.5% at 6 years, 7.8% at 8 years, and 8.8% at 10 years.

There were 286 deaths in the trastuzumab arm, and 418 in the standard chemotherapy arm. Deaths from the primary breast cancer occurred in 10.3% and 16.8%, respectively, and from a second primary cancer in 1.2% vs 2.0%.

Survival rates were comparable between ER- and/or PR-positive patients (HR, 0.61; 95% CI, 0.49 - 0.76) and ER- and PR-negative patients.(HR, 0.64; 95% CI, 0.52 - 0.79).

NSABP B-31 and NCCTG N9831 were supported by the National Cancer Institute. Dr. Romond has disclosed no relevant financial relationships. Dr. Isaacs reported that she is on the speaker's bureau of AstraZeneca.

35th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S5-5. Presented December 7, 2012.