ASCO Breast: Breast Cancer Responds to Trastuzumab, But So Does Heart

SAN FRANCISCO, Sept. 11 -- Neoadjuvant trastuzumab (Herceptin) may improve breast cancer response rates in combination with anthracycline-based chemotherapy, but some oncologists remain skeptical about cardiac toxicity.

Pathologically complete tumor response was doubled when trastuzumab was added to neoadjuvant chemotherapy for HER2-positive breast cancer (43% versus 22%, P=0.002) in a large trial presented here at the American Society of Clinical Oncology's Breast Cancer Symposium.

But, more patients on trastuzumab developed heart failure (2.2% versus 0%) or had at least a 10% decrease in left ventricular ejection fraction (23% versus 16%) compared with those who did not receive trastuzumab, reported Luca Gianni, M.D., of the Istituto Nazionale Tumori in Milan, Italy, and colleagues.

While Dr. Gianni called this "acceptable cardiac safety," others were less convinced.

"I think the risk of heart failure is enormous," commented Daniel F. Hayes, M.D., of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

"I don't think patients should be treated with concurrent anthracycline and trastuzumab, especially outside of a trial," he added, noting that there is data suggesting that the combination is worse, whereas the data suggesting it is better is based on only about 40 patients.

But, argued Dr. Gianni, "whenever you achieve an eradication of breast cancer, a pathologically complete response, that predicts for long-term benefit and you may cure the patient in most instances."

"What we have here is two cases of congestive heart failure responsive to treatment" countered by 20 extra patients who achieved complete response, he said.

"I think we all agree this is a really important finding for this group of patients undergoing neoadjuvant chemotherapy," commented Julia R. White, M.D., of the Medical College of Wisconsin in Milwaukee, who was a discussant for the study.

"It suggests, just suggests, that a trastuzumab with anthracycline-based combination may have acceptable cardiac safety," she added.

Dr. Gianni and colleagues' interim analysis included 228 women with HER2-positive locally advanced breast cancer and an observational cohort of 99 women with HER2-negative cancer in the ongoing international phase III NeOAdjuvant Herceptin (NOAH) study.

HER2-positive women were randomized to three cycles of trastuzumab, doxorubicin (Adriamycin), and paclitaxel (Taxol) followed by four cycles of trastuzumab and paclitaxel then four cycles of trastuzumab with three cycles of cyclophosphamide (Cytoxan), methotrexate, fluorouracil (Adrucil), or to the same regimen without trastuzumab.

After chemotherapy, both groups had surgery and radiotherapy. The trastuzumab group continued to receive the drug for 52 weeks.

Among the intent-to-treat interim findings, the researchers reported:

• More complete responses in the trastuzumab-treated group than in those who did not receive the drug (60% versus 51%)
• A higher overall response rate with trastuzumab (81% versus 73%)
• More pathologically complete responses with trastuzumab (43% versus 22%, P=0.002)
• More total pathologically complete responses in both the breast and lymph nodes with trastuzumab (38% versus 20%, P=0.003)

The combination was "generally well tolerated and feasible," Dr. Gianni said.

Serious adverse events included a total of 15% of patients in the trastuzumab group and 8% of those who underwent chemotherapy without the drug. Serious cardiac toxicity was seen in 2% of patients in the trastuzumab group but in none of the other HER2-positive group.

Compared with those who did not receive the drug, the trastuzumab group had:

• More frequent absolute decrease of at least 10% but less than 20% in left ventricular ejection fraction (21% versus 15%).
• More frequent absolute decrease of at least 20% in left ventricular ejection fraction (2% versus 1%).
• More congestive heart failure responsive to treatment (2% versus 0%).
• A higher cumulative incidence of congestive heart failure (2.2% versus 0%).

Cardiac safety is an important issue that needs to be explored further, along with additional follow-up to see if the high pathologically complete response rates predict for improved disease-free and overall survival, Dr. White said.

Dr. White provided no information on conflicts of interest. Dr. Hayes reported conflicts of interest for Precision Therapeutics, Abraxis, American Biosciences, AviaraDx, Cytogen, Monogram Sciences, Siemens Medical Solutions Diagnostics, STemCapture, Veridex, Pfizer, Novartis, AstraZeneca, and GlaxoSmithKline.