Adding Trastuzumab Helps Breast Ca Subset


Major Finding: Adding neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy was tied to a significantly higher 3-year event-free survival rate, compared with neoadjuvant chemotherapy alone.

Data Source: The open-label, phase III NOAH study of 235 women with HER2-positive locally advanced or inflammatory breast cancer.

Disclosures: The study was funded and the drug was provided by Hoffmann-La Roche, the manufacturer of trastuzumab. The 20 authors included a current and a past employee of Roche, and two others who disclosed having served as adviser and/or consultant to several pharmaceutical companies, including Roche. The rest had no disclosures.

Event-free survival at 3 years was significantly greater among women with HER2-positive locally advanced or inflammatory breast cancer who received trastuzumab as neoadjuvant and adjuvant therapy in the international, open-label, phase III NOAH trial, investigators reported.

“Our results suggest that neoadjuvant trastuzumab should be offered to patients with HER2-positive locally advanced or inflammatory breast cancer alongside neoadjuvant chemotherapy, in addition to the established use of adjuvant trastuzumab” post surgery, concluded Dr. Luca Gianni of the Fondazione IRCCS Instituto Nazionale Tumori in Milan and his coauthors.

The 235-patient study appeared in the Lancet (2010;375:377-84).

A monoclonal antibody, trastuzumab (Herceptin) targets HER2—which is overexpressed in about 22% of early breast cancers—in 35% of locally advanced and metastatic tumors, and in 40% of inflammatory breast cancers, according to the authors.

It is widely approved as a monotherapy and a combination therapy for HER2-positive breast cancer, both in its early operable stages and when it has metastasized.

But the authors noted that it has not been “specifically indicated” for patients with locally advanced or inflammatory breast cancer that is positive for HER2.

Patients in the NOAH (Neoadjuvant Herceptin) trial received either neoadjuvant trastuzumab plus a neoadjuvant chemotherapy regimen (doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil) followed by adjuvant trastuzumab, or neoadjuvant chemotherapy alone.

The primary end point was event-free survival, which was defined as the time from randomization to disease recurrence or progression (local, regional, distant, or contralateral), or death from any cause.

After a median follow-up of 3.2 years, 71% of 117 women who received trastuzumab were event free, compared with 56% of 118 women in the chemotherapy-only group—a significant difference that represented a 41% reduction in the risk of recurrence, progression, or death (hazard ratio, 0.59; P = .013).

Pathological complete response, a secondary end point, was also significantly higher among those in the trastuzumab group, compared with the chemotherapy-only group (38.5% vs. 19.5%).

The 3-year overall survival rate was not significantly different at the time of the report (87% with trastuzumab vs. 79% with chemotherapy alone).

These results indicate that in patients with HER2-positive locally advanced or inflammatory breast cancer, adding 1 year of trastuzumab—starting as neoadjuvant and continuing as adjuvant therapy—to neoadjuvant chemotherapy “improved response rates, almost doubled rates of pathological complete response, and reduced risk of relapse, progression, or death compared with patients who did not receive trastuzumab,” the authors wrote.

Trastuzumab showed benefit in all the subgroups tested, including those with inflammatory disease, “who benefited substantially from trastuzumab,” they added.

Adverse events were similar in both groups, and the incidence of symptomatic heart failure was lower than expected among those in the trastuzumab group (less than 2%), which supports “the accumulating evidence that trastuzumab can be given concurrently with anthracyclines with a low frequency of symptomatic cardiac dysfunction, provided that low cumulative doses or less cardiotoxic anthracyclines are used, and careful cardiac monitoring is done,” the authors said.

In an accompanying editorial entitled “Challenging the Dogma on Trastuzumab: A Matter of the Heart,” Dr. Melanie Seal and Dr. Stephen Chia of the division of medical oncology at the British Columbia Cancer Agency, Vancouver, also noted that study results go against the dogma that anthracyclines and trastuzumab should not be given concurrently because of cardiac safety concerns.

“Because HER2-positive breast cancers are sensitive to anthracyclines and preclinical data suggest additive or synergistic effects for the combination of anthracyclines and trastuzumab, … the concomitant delivery of these drugs should be considered with an apparently favourable risk-to-benefit ratio” in patients who present with high-risk disease, such as locally advanced or inflammatory breast cancer, Dr. Seal and Dr. Chia wrote.

Furthermore, they advocated that with “the ability to assess response to systemic treatment and the additional opportunity of correlative studies, neoadjuvant trials should be further exploited in the search for new therapeutic strategies.”

Noting that “almost all new systemic agents being studied in cancer are targeted agents,” they added, “understanding the target, and downstream and redundant effects, is essential if we truly are moving to personalized medicine.”

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