Cardiotoxicity Debated for Anthracyclines and Trastuzumab in Breast Cancer

When the U.S. Food and Drug Administration approved trastuzumab to treat HER2-positive breast cancer in 1998, the drug received wide acclaim for increasing survival and reducing recurrence—especially in combination with chemotherapy—for the 20%–30% of women who are HER2 positive. But in 2001, a pivotal trial showed that combining trastuzumab with anthracyclines (and cyclophosphamide) caused severe heart failure in 27%, compared with 13% taking paclitaxel and trastuzumab, and less than 7% expected taking anthracyclines alone (Slamon 2001, New England Journal of Medicine).For 35 years, researchers have known that anthracyclines are cardiotoxic, increasing by fivefold the risk of developing chronic heart failure or reduced left-ventricular ejection fraction. And risks with trastuzumab have been documented as use of the targeted drug increased, said Michael Ewer, M.D., M.P.H., professor of medicine at the University of Texas M. D. Anderson Cancer Center in Houston, one of a growing number of cardiologists devoting considerable time to cardio-oncology. Although researchers now know more about ways to reduce cardiotoxicity, including extending infusion time, giving the drugs sequentially, and limiting the cumulative dose of anthracyclines, new research indicates that cardiotoxicity may be more of a problem than thought. But researchers are debating just how damaging the drugs are. Two studies from late 2012 indicated that women taking both drugs experienced elevated risk of heart failure or cardiomyopathy. However, a third, which monitored women for 7 years who had received the anthracycline doxorubicin, and cyclophosphamide, followed by paclitaxel, with and without trastuzumab, found that late development of congestive heart failure was rare. Although many anticancer drugs are cardiotoxic to various degrees, most attention focuses on anthracyclines—especially doxorubicin—and trastuzumab, said Nancy Davidson, M.D., director of the University of Pittsburgh Cancer Institute. These new studies and older reports are generating concern and controversy among oncologists, some of whom are replacing anthracyclines with taxanes, especially the adjuvant setting, and in older patients who have greater incidence of extant cardiovascular disease, said Charles Geyer, M.D., associate professor of medicine at the University of Texas Southwestern Medical School in Dallas. “At M. D. Anderson we tend to stay away from anthracyclines.” Many disagree with this strategy, however. “Strong data to support these changes are lacking, and replacing anthra cyclines with taxanes for use with trastuzumab is the result of incredibly successful marketing,” including the conduct of many taxane trials, said Ewer and others. Larry Norton, M.D., deputy physician in chief for breast cancer programs at Memorial Sloan–Kettering Cancer Center in New York, and others concur that changes are unsupported by data. “The risks from anthracyclines [with and without trastuzumab] are tremendously overestimated,” Norton said, citing a 2008 study in the Journal of Clinical Oncology. “There are no really good long-term studies showing better safety and equal outcomes with taxanes,” said Edith Perez, deputy director at large at the Mayo Clinic Cancer Center in Tampa, Fla. With dissent concerning cardiovascular risks of these drugs, treatment regimens also vary. Nancy Davidson, M.D. “Depending on a patient’s disease characteristics, comor bidities, overall health, and preferences, there is some wiggle room in what is prescribed for individual patients,” said Davidson. The first study, led by Jersey Chen, M.D., Ph.D., of Yale University in New Haven, Conn., found higher rates of heart failure in older women with early-stage disease taking both drugs separately and together than reported in clinical trials, or about a 4% increase over 3 years (November 2012 online, European Journal of Cardiology). Using data from the SEER (Surveillance, Epidemiology, and End Results) program, Chen found that incidence of heart failure and cardiomyopathy were higher among women taking trastuzumab (32.1 per 100 patients), trastuzumab plus anthracyclines (41.9 per 100 patients) than among women taking no adjuvant therapy (18.1 per 100 patients) (online Nov. 20, 2012, Journal of the American College of Cardiology). Adding trastuzumab to anthracyclines added 12.1, 17.9, and 21.7 cases per 100 of heart failure or cardiomyopathy at 1, 2, and 3 years of follow-up, respectively. In the second report, a population-based, “real world” retrospective study of 12,500 women with invasive breast cancer, Erin Bowles, M.P.H., of the Group Health Research Institute in Seattle, also found that risk of heart failure was highly increased over 5 years in those taking trastuzumab alone or with an anthracycline as adjuvant therapy, compared with those given chemotherapy or anthracyclines alone, with risk rising with age (JNCI, Sept. 5, 2012). Risk of anthracycline-associated cardiac problems among women younger than 65 years was similar to that seen in randomized clinical trials, but trastuzumab-associated risk was greater than reported previously. Most studies are done in the context of clinical trials, with patients selected for few comorbidities, and show fairly low rates of cardiotoxicity, about a 2% increase with anthracyclines, and 4% over 3–5 years adding trastuzumab, Bowles said. Her study indicates that damage increases in the last year, with no evidence of plateau, Ann Geiger, Ph.D., M.P.H., of Wake Forest School of Medicine in Winston-Salem, N.C., commented in an editorial. The risk of heart failure in women with nonmetastatic disease taking trastuzumab is equivalent to or greater than that reported by clinical trials, Geiger concurred. But a third study, a phase III 7-year follow-up trial part of the National Surgical Adjuvant Breast and Bowel Project (B-31), analyzed a younger, healthier population. E.H. Romond, M.D., professor of medicine at the University of Kentucky Medical Center in Lexington, found that risk of cardiotoxicity increased only for those on trastuzumab or anthracyclines plus trastuzumab, and late heart failure was uncommon (online Sept. 17, 2012, Journal of Clinical Oncology). Perez, an author, noted that the first two studies were retrospective, with limitations. “We don’t see those high rates in our clinic, and we believe that the combination provides an edge for patients in survival and recurrence,” she said, adding that much more data are needed before one can change regimens from anthracycline to taxanes and that evaluation of ejection fraction should be done before starting therapy. Anthracyclines and trastuzumab act synergistically to damage the heart, but in different ways, and risk and damage from both may be modifiable. Type I damage from anthracyclines generally produces irreversible, dose-dependent death to heart muscle cells, which increases over time, taking months to years to manifest, but may be reversible when caught early. Risk factors for anthracycline damage include prior use of these drugs, hypertension, and age. Monitoring cardiac function before, during, and after anthracycline and/or trastuzumab helps physicians detect early damage, enabling regimen modifications—but this too is controversial, and practice varies widely, less so in patients with preexisting risk factors. Monitoring no- or low-risk patients after four to five cycles of doxorubicin treatment could help identify patients with asymptomatic decrease in systolic function, Ewer said. The iron chelator dexrazoxane may be given to protect against anthracycline cardiotoxicity, as can other cardioprotective drugs, including ACE (angiotensin-converting enzyme) inhibitors and statins. Researchers believe that trastuzumab affects cell repair mechanisms of the heart, which expresses HER2. Type II heart damage from trastuzumab is not tied to cumulative dose but to number of treatment sessions, manifesting as an asymptomatic decrease of left ventricular function, and is more reversible than anthracycline damage. Used sequentially, especially 3 months after an anthracycline, it causes less damage than when given with or near the same time as anthracyclines. Researchers are investigating echocardiography as a means to both detect presymptomatic damage and evaluate cardioprotective treatments. Biomarkers such as cardiac troponins may someday be used to predict and detect early chemotherapy-induced damage. “Ultimately, these drugs have been shown to extend survival,” said Bowles. “We just need to be careful whom we give these drugs to, because there are risks, which shouldn’t be ignored,” she said.