Chemotherapy Less Toxic to the Heart May Be Option for Some Women with HER2-Positive Breast Cancer

Adapted from the NCI Cancer Bulletin.

A nonanthracycline-containing chemotherapy regimen combined with the targeted therapy trastuzumab (Herceptin®) may be an option for some women with HER2-positive breast cancer, according to results from the Breast Cancer International Research Group 006 (BCIRG-006) trial. These results, the first from a large randomized breast cancer trial to test nonanthracycline chemotherapy with trastuzumab, were reported October 6, 2011, in the New England Journal of Medicine.

Anthracyclines are effective anticancer drugs, but they can produce long-term side effects, including heart damage and second primary cancers. Because trastuzumab can also cause heart damage, combining the two drugs may further increase the risk to the heart.

The nonanthracycline regimen tested in BCIRG-006 was based on laboratory data that showed synergy between trastuzumab and docetaxel or platinum -based chemotherapy drugs. “It was also anticipated that [the regimen] might circumvent the cardiac toxicity seen with anthracycline-based regimens,” wrote the study authors, led by Dennis Slamon, M.D., Ph.D., director of Clinical/Translational Research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

Researchers in 41 countries enrolled 3,222 women with HER2-positive breast cancer in the trial. Participants were randomly assigned to receive one of three chemotherapy regimens after surgery: doxorubicin (an anthracycline), cyclophosphamide, and docetaxel (AC-T); AC-T plus trastuzumab; or docetaxel and carboplatin plus trastuzumab (TCH). The trial was sponsored by Sanofi-Aventis, the maker of docetaxel, with additional support from Genentech, the maker of trastuzumab.

At a median follow-up of 5.4 years, women in both groups receiving trastuzumab had better 5-year disease-free survival rates (84 percent for AC-T plus trastuzumab and 81 percent for TCH) than women who received AC-T alone (75 percent). The differences for both trastuzumab-containing regimens were statistically significant. (The researchers defined disease-free survival as the length of time without a breast cancer recurrence, a second primary cancer, or death from any cause.)

Although no significant difference in the rate of disease-free or overall survival was seen between the two trastuzumab-containing regimens, the study was designed to test both trastuzumab-containing regimens against treatment without trastuzumab, not against each other.

Therefore, there is no definitive answer to whether one of the trastuzumab-containing regimens is better than the other, explained Sally Hunsberger, Ph.D., an investigator with the Biometric Research Branch in NCI’s Division of Cancer Treatment and Diagnosis (DCTD). Instead, the authors looked at the tradeoff between disease-free events and cardiac events by comparing the excess of breast cancer events to the excess of high-grade congestive heart failure events.

A total of 144 women receiving TCH had a distant recurrence of their cancer compared with 124 women receiving AC-T plus trastuzumab (a difference of 20 events). However, 21 women receiving AC-T plus trastuzumab had high-grade congestive heart failure compared with 4 women who received TCH (a difference of 17 events). In addition, 18.6 percent of women receiving AC-T plus trastuzumab had a nonsymptomatic loss of heart function compared with 9.4 percent of women who received TCH.

Patients who receive TCH probably have a few more cancer recurrences, “but is it worth the cardiac events to use an anthracycline?” asked Dr. Hunsberger. Individual women and their doctors will need to decide which treatment is more relevant to their circumstances, balancing the risk of late side effects with the risk of recurrence, she said. “If a woman has heart disease, then TCH is probably a valid regimen to use.”

Taken together, the data from this trial “do not clearly favor one regimen over the other,” wrote Daniel F. Hayes, M.D., of the University of Michigan Comprehensive Cancer Center in an accompanying editorial. “These observations establish TCH as another (but not ‘the’) standard of care for adjuvant treatment of HER2-positive early-stage breast cancer,” he concluded.

“I agree that both trastuzumab-containing regimens could be considered ‘standard’,” said Jo Anne Zujewski, M.D., head of Breast Cancer Therapeutics in DCTD. “This study confirms again that trastuzumab-based therapy—whether combined with TC or AC-T as a chemotherapy backbone—has marked benefits in patients with tumors that overexpress HER2.”

It will be important, said Dr. Slamon, to keep following these and other women who have received the combination of an anthracycline and trastuzumab to better understand the long-term effects on the heart. “We don’t have long-term safety data on a lot of these studies, and that’s a real problem,” he explained.

The BCIRG-006 researchers plan to follow their participants for a median of 10 years to gather additional data on efficacy and safety.