Expert Weighs in on Debate Over Cardiotoxicity Effects in Breast Cancer Treatment

A debate among health care providers has ensued over the cardiotoxicity risk that is associated with anthracycline regimens for patients with breast cancer.

“Some physicians feel you should not worry about heart risk for patients when the risks themselves tend to be less than 5 percent in the short term,” explained Sara A. Hurvitz, M.D., who discussed the pros and cons of anthracycline treatment in a talk at the 2017 Miami Breast Cancer Conference.

Other physicians worry about their use, Hurvitz said, because they argue that the long-term risks of anthracyclines tend to be unknown because there are few, if any, studies that follow the women long term.

The BCIRG 006 study compared anthracycline regimens with nonanthracycline regimens. The trial aimed to describe and compare health-related quality of life in patients with high-risk, node-negative, HER2-positive early breast cancer receiving docetaxel and Herceptin (trastuzumab)­—based regimens compared with docetaxel-based regimens alone. The main safety concern with Herceptin-based regimens, particularly in combination with anthracyclines, is the cardiotoxicity. The BCIRG 006 study was one of few adjuvant Herceptin trials to include a nonanthracycline arm to compare these cardiotoxicities.

There were three treatment arms in the study: (1) 60 mg/m² of adjuvant doxorubicin and 600 mg/m² of cyclophosphamide every three weeks for four cycles followed by 100 mg/m² of docetaxel for four cycles; (2) cyclophosphamide and doxorubicin followed by docetaxel with 4-mg/kg loading dose and 2 mg/kg weekly of Herceptin during chemotherapy and 6 mg/kg every three weeks after chemotherapy for one year; and (3) six cycles of carboplatin and 75 mg/m² of docetaxel every three weeks with Herceptin for one year.

The two distinct Herceptin-containing regimens in the BCIRG 006 trial, one with and one without an anthracycline base, demonstrated improved survival with a more favorable safety profile. Although anthracyclines are a standard therapy in the treatment of adjuvant breast cancer, the cardiac and marrow toxicity risks affect long-term use, whereas the nonanthracycline regimen resulted in better adverse event change scores at the end of chemotherapy, and better health-related quality-of-life findings.

The cardiotoxicity related to anthracyclines has been shown to be dose-dependent, occurring more frequently with higher doses than with doses administered in the adjuvant setting. However, some acute cardiac events can occur after the first dose.

An additional serious adverse event related to anthracyclines is the development of myelodysplastic syndrome (MDS) and acute myelogenous leukemia. Multiple cytotoxic agents, such as cyclophosphamide, doxorubicin, daunorubicin and epirubicin, have been implicated.

“The benefits of using these nonanthracycline-based regimens is they have been consistently shown to be relatively safe in terms of the cardiac safety perspective,” Hurvitz said.

Another trial that compared an anthracycline with a nonanthracycline regimen was the MA.5 trial. The trial enrolled 710 patients with node-positive breast cancer who were randomly assigned to receive cyclophosphamide/epirubicin/fluorouracil or cyclophosphamide/methotrexate/fluorouracil. Although this trial was completed many years ago, the nonanthracycline regimen is still frequently used in patients who are not candidates for anthracycline-based regimens.

Where do we stand on exploring the potential to omit anthracyclines in adjuvant treatment for patients with breast cancer?

What are the benefits of nonanthracycline-based regimens?

How would nonanthracycline-based regimens affect patient outcomes?

In an interview with CURE, Hurvitz, director of the Hematology/ Oncology Breast Cancer Program and an associate professor in the Department of Medicine at the University of California, Los Angeles, discussed anthracycline versus nonanthracycline treatments for patients with breast cancer.There have been a few studies relating the relative efficacy of anthracycline-and- Herceptin—based regimens versus a nonanthracycline regimen. The typical docetaxel/carboplatin/Herceptin regimen is the backbone that has been studied in about 5000 patients in different clinical trials. There is a more recent regimen of weekly paclitaxel and Herceptin that Sara M. Tolaney, M.D., evaluated for small, lymph node–negative tumors. Then another regimen of docetaxel/Cytoxan/Herceptin was evaluated by Stephen E. Jones, M.D.The benefit of using these nonanthracycline-based regimens is that they have been consistently shown to be relatively safe in terms of the cardiac safety perspective. When we are talking about early-stage disease, where many of the patients with breast cancer will be cured of their disease by surgery and radiation, we have to carefully weigh the therapies we give them because of the risk of short-term and long-term safety. If we have regimens that are as effective, or appear to be very effective, compared with anthracycline-based regimens, and they are a lot safer in terms of the heart risk, then that is going to be a very attractive way to go.There are two different viewpoints to that. Some physicians feel that you should not worry about heart risk for patients when the risks themselves tend to be less than 5 percent in the short term and that we should be most worried about increasing the woman’s odds for a cure. I believe the counterpoint is that the long-term risk of anthracyclines is not well appreciated because studies have not followed women out for many years. There are only a couple of studies that have followed women for five years after their therapy by doing echocardiograms. Long-term risk is a real problem that we are underestimating in our clinical trials.

Are there any ongoing trials that you are particularly excited about?

Is there anything else you'd like to highlight about this topic?

At the conference, I discussed data relating to potential long-term risks and reviewed data that indicate that a nonanthracycline-based regimen is probably as effective in the majority of patients compared with an anthracycline.There are no trials that I am aware of that are comparing anthracycline to nonanthracycline regimens as a primary endpoint. The last large study that compared using an anthracycline versus not was the BCIRG 006 study. The final analysis of the 10-year outcome data was presented at the 2016 San Antonio Breast Cancer Symposium, but I think people have moved on to other issues, looking at HER2-targeted therapies, Kadcyla (T-DM1), Perjeta (pertuzumab) and the adjuvant setting. People will believe what they believe in terms of the safety of anthracyclines, but I think that more people are paying attention to the risk in terms of heart failure as well as leukemia and myelodysplasia, which is also a potentially deadly outcome of these drugs.The safety of outcome versus disease recurrence and the data that we have today do not indicate that disease recurrence outcomes were harmed by avoiding anthracyclines. We have good evidence that safety outcomes are affected in a bad way by the use of an anthracycline.