Phasing out anthracyclines in breast cancer: Is it time?

Experts continue to debate whether there is enough evidence to retire a successful therapy.

For decades, anthracyclines have been the gold standard of treatment for women with breast cancer, but that could be changing.

Ever since Dennis J. Slamon, MD, director of clinical/translational research at UCLA’s Jonsson Comprehensive Cancer Center, first released data at the 2007 San Antonio Breast Cancer Symposium that challenged the routine use of anthracyclines, several studies have shown that taxanes provide superior survival in some patients. Eric P. Winer, MD, of Dana-Farber Cancer Institute, has been quoted saying that anthracyclines will be phased out eventually. Slamon thinks that there is little reason to wait.

“The overwhelming data, and I do mean overwhelming, indicates there is only a small subpopulation of women who incrementally benefit from anthracyclines over non-anthracyclines in breast cancer,” he told HemOnc Today.

“That was initially thought to be all HER2-positive patients, about 20% to 25% of all breast cancer patients, leaving the other 75% to 80% not benefitting incrementally but certainly experiencing all the toxicities,” he said. “You can argue for their use if there is some incremental benefit, but when other drugs have the same or better effects without the toxicity, why is this even being discussed?”

Slamon’s opinion is further supported by the results of U.S. Oncology Research Trial 9735. In that trial, researchers showed that the combination of docetaxel and cyclophosphamide resulted in superior DFS compared with doxorubicin plus cyclophosphamide. After seven years of follow-up, DFS was 81% in the docetaxel/cyclophosphamide arm compared with 75% in the doxorubicin/cyclophosphamide arm (HR=0.74; 95% CI, 0.56-0.98). Similarly, patients in the docetaxel/cyclophosphamide arm had superior OS: 87% vs. 82% (HR=0.69; 95% CI, 0.50-0.97).

Dennis J. Slamon, MD, of UCLA, thinks the time to phase out anthracyclines is now. Photo courtesy of UCLA

“If physicians are being evidence-based and data-driven, then this fight is over,” Slamon said. At UCLA anthracyclines have been eliminated for the treatment of patients with breast cancer, he said.

Of course, not everyone is ready to dismiss a treatment that has been used effectively since the 1960s. Even some of the experts who do believe anthracyclines are on the way out do not believe that the class of drugs will disappear anytime soon. Kathleen Pritchard, MD, a senior scientist and medical oncologist at Sunnybrook Odette Cancer Centre in Toronto, sees no reason to eliminate an effective therapy.

“Why stop using some of the most successful drugs we’ve ever had? The argument doesn’t make sense,” she said. “Twenty-five years ago we were treating patients with CMF [cyclophosphamide, methotrexate and 5-FU] chemotherapy.

“Have those drugs gone out of fashion a little bit? Yes. Do we still use them? Yes. They are still active drugs. I don’t think drugs that are as active as anthracyclines will disappear from breast cancer care. I think they’ll still be used very widely for some time to come,” Pritchard said.

Trastuzumab vs. anthracyclines

Slamon argued that patients do not need anthracyclines because the same effects are possible with trastuzumab (Herceptin, Genentech) but without the increased risk for heart disease and leukemia that is associated with anthracyclines. Trastuzumab is an antibody that binds selectively to the HER2 protein and is approved for the treatment of HER2-overexpressing node-positive or –negative breast cancer.

He pointed to results of the BCIRG 006 study, for which he served as lead author. The Cancer International Research Group, which conducted the study, released a press release with the findings last year, and the study is under review for publication.

The FDA approved both the docetaxel/carboplatin/trastuzumab (TCH) and doxorubicin/cyclophosphamide/docetaxel/trastuzumab (AC-TH) treatment plans tested in the study based on the results.

BCIRG 006 recruited 3,222 women with HER2-positive node-positive and high-risk node-negative operable breast cancer. The AC-TH group (n=1,073) was randomly assigned doxorubicin plus cyclophosphamide every three weeks for four cycles, followed by docetaxel. The TCH group (n=1,075) was assigned docetaxel, carboplatin and trastuzumab every three weeks for six cycles, and then trastuzumab monotherapy to complete one year of trastuzumab treatment.

A control group of 1,074 patients was assigned doxorubicin plus cyclophosphamide every three weeks for four cycles, followed by docetaxel every three weeks for four cycles (AC-T).

The TCH regimen reduced the risk of disease recurrence by 33% compared with the AC-T arm (95% CI, 0.54-0.83). AC-TH reduced the risk of disease recurrence by 39% compared with the AC-T arm (HR=0.61; 95% CI, 0.49-0.77).

In addition, the study found that TCH and AC-TH improved DFS regardless of patient age, hormone receptor status or nodal status. There was no statistically significant difference in DFS between the two experimental arms.

TCH was also associated with a 34% reduced risk for death compared to the control group (95% CI, 0.47-0.93). AC-TH was associated with a 42% reduction in the risk of death (95% CI, 0.40-0.83). There was no statistically significant difference in OS between the two experimental arms.

“The only patients who benefited from an anthracycline (AC-T) over a non-anthracycline regimen (TCH or AC-TH) was a subset of the HER2- positives, the ones who are topoisomerase II-alpha co-amplified,” Slamon said.

“Those patients benefited equally; they have a Herceptin-like effect without Herceptin if you use anthracyclines, but they still have the toxicity of anthracyclines. Herceptin gives you the same benefit as anthracycline, so why would you use anthracycline unless you’re in a country where you don’t have access to the targeted agents?”

Hyman Muss, MD, a professor of medicine at the University of North Carolina and director of geriatric oncology at the Lineberger Comprehensive Cancer Center, agreed that the evidence for taxane-based non- anthracycline therapy is compelling for patients with

Hyman Muss

HER2-positive, node-positive disease; however, there is a “paucity of data with non-anthracycline regimens in patients with node-positive, HER2-negative disease.”

Based on NSABP-B30 trial results, presented last year at the San Antonio Breast Cancer Symposium by Sandra Swain, MD, medical director of the Washington Cancer Institute, the data supporting taxanes over anthracyclines are not clear cut.

“What she showed was that one of the arms in that study — one was an AC plus a taxane and one was TAC for four cycles — TAC was less effective than the ACT,” Muss said. “I don’t know if that was due to duration of therapy, but it seems to me that if four cycles of the TAC regimen were not as effective as the eight cycles of the anthracycline-containing regimen, the current style of giving people TC regimens, let’s say for four cycles, while omitting anthracycline is not ready for primetime in high-risk patients.”

Kevin R. Fox, MD, medical director of the Rena Rowan Breast Center at the University of Pennsylvania’s Abramson Cancer Center, said the percentage of breast cancer patients at his center assigned to anthracyclines has dropped from 100% five years ago to about 20% today. With a few qualifications, he said, he is convinced that some patients can be treated effectively without anthracyclines.

“If a patient has a HER2-positive cancer, regardless of its hormone receptor status, the evidence from BCIRG 006 is that those patients may be served well by a non-anthracycline regimen such as Taxotere/carboplatin/Herceptin,” Fox told HemOnc Today. “The only reservation we have at the moment is that the BCIRG 006 study is as yet unpublished. We have seen it presented on many occasions with results that appear to be convincing for the equivalence of the non-anthracycline arm and the anthracycline arm, but there is always some reassurance in seeing it published in a peer-reviewed journal.”

Pritchard argued that the only study to date that shows that trastuzumab can fully replace anthracyclines is BCIRG 006. And like many of the experts contacted for this story, she noted that those results have not been published.

Slamon, however, does not think that is particularly relevant. “Everyone has seen the data,” he said. “We made it public as soon as we generated it. It’s been downloaded by multiple people, and it’s been submitted to the FDA and approved. It’s pending review as we speak.”

Toxicity overblown?

Another reason for the discontinuation of treatment with anthracyclines is the increased risk for toxicities, specifically serious chronic heart failure, Slamon said. Although there is no doubt that anthracyclines can cause type 1 chemotherapy-related cardiac dysfunction, there is some question about how much anthracyclines increase the risk for cardiotoxicity.

In an expert opinion published in Annals of Oncology in January, researchers from several institutions in the United Kingdom noted that studies have used different definitions of cardiotoxicity, different methods of measurement for heart function and different estimates of the underlying risk to patients. They cautioned that most studies on the topic have been retrospective and long-term data are not yet available.

Citing a 1979 study by Von Hoff, Layard and Basa, the researchers said the incidence of chronic heart failure is about 3.0% for patients receiving a cumulative doxorubicin dose of 400 mg/m ². The incidence increased to 7.5% at a 550 mg/m² dose and 18.0% at a 700 mg/m² dose.

Another study, conducted in 1998 by Nielsen et al, showed that the cumulative risk for cardiotoxicity increased by 1.9% for patients assigned to 800 mg/m² epirubicin. The risk increased to 4.3% for those assigned to a 900 mg/m ² dose and to 15.0% at a 1,000 mg/m² dose.

“People worry about heart disease, but if you look at the papers that have explored the issue, like UCLA’s Patricia Ganz’s review of patients in an anthracycline trial, the incidence of serious heart disease is low, probably 0.5% to 1%,” Muss said. “If you actually look at what’s been published about anthracycline toxicity in the adjuvant studies in early breast cancer, it hasn’t been overly toxic.

“If you look at our study in older people we just published in The New England Journal of Medicine, we did AC for four cycles in the standard fashion, and it was well tolerated by older people. There’s been no leukemia and we haven’t reported any heart disease. This concept that anthracyclines are so overwhelmingly bad has been overstated,” Muss said.

“There is some concern about cardiotoxicity, but I think the doses and schedules used today cause a minimum of that problem,” said Fox. “It is not an overwhelming problem.”

Choosing the right patients

“We know some patients benefit from anthracyclines, but we can’t predict who they are,” Pritchard said. “The argument is that if patients are HER2-positive and they’re getting Herceptin, they don’t need anthracyclines. In fact, studies like the HERA trial show that patients who were treated with anthracyclines still get additional benefit from Herceptin. The fact that you can give Herceptin doesn’t mean you shouldn’t also give anthracyclines. Furthermore, I don’t think you can accurately select patients who will or won’t respond to Herceptin by using HER2.”

Slamon said one of the reasons BCIRG 006 has yet to be published is that researchers are still working on the role of topoisomerase as a biomarker for anthracycline sensitivity. Several studies support his contention that topoisomerase effectively predicts the subset of patients who will benefit from anthracyclines.

The Scandinavian Breast Group Trial 9401, for example, found that patients with topoisomerase II-alpha-amplified tumors had a superior relapse-free survival rate when treated with tailored and dose-escalated fluoroucil, epirubicin and cyclophosphamide (FEC) compared with standard FEC followed by bone marrow–supported cyclophosphamide, thiotepa and carboplatin (HR=0.45, P=.049). There was no such difference between the two treatments in patients with no topoisomerase II-alpha amplification (HR=0.95; P=.88).

Di Leo and colleagues concluded in a 2002 study published in Clinical Cancer Research that “TOP II Α could be the most attractive candidate for predicting the efficacy of an anthracycline-based regimen, and the predictive value of HER2 could be most likely be related to the concomitant amplification of these two genes located on the same arm of chromosome 17.”

They warned, however, that results were only hypothesis-generating because of a “limited number of patients in which both HER2 and TOP II Α gene amplifications could be evaluated.”

In a study published earlier this year, O’Malley and colleagues reported that patients with the topoisomerase II-alpha amplification were more responsive to anthracycline-based chemotherapy than treatment with a non-anthracycline. They said the response was similar to that of patients with the HER2 amplification.

“The default biomarker we have now that drives the perceived need for anthracyclines is nothing more than absence of hormone receptor and the absence of HER2. Other than topo, I don’t know if a biomarker exists that would drive the decision to use or not use anthracyclines,” Fox said. “The way that I view the current data regarding topoisomerase is that the presence or absence of topo activity has not been clearly linked with either the usefulness or lack of usefulness of anthracyclines in a conclusive way.

“I do not think we’re at a point where we can comfortably apply that to patient decision-making. In theory, patients with topo excess would be better candidates for anthracycline-based therapy, but I do not think that’s been proven conclusively enough in patients in clinical trials to be able to use that as a decision point. I just don’t think the data are robust enough to make that part of the care standards,” Fox said.

Francisco J. Esteva, MD, and Gabriel N. Hortobagyi, MD, both of The University of Texas M.D. Anderson Cancer Center, noted in an editorial published in The Journal of Clinical Oncology that the data supporting the use of topoisomerase II-alpha as a predictor for anthracycline sensitivity is fairly mixed.

“In summary, topo II Α expression can be used as a prognostic marker,” they wrote. “However, currently available evidence does not support use of thetopoisomerase II-alpha gene amplification or deletion to select patients for anthracycline-based chemotherapy in the adjuvant setting.”

TC TAC will connect the dots

The experts who spoke to HemOnc Today are eagerly awaiting the results of the TAC Versus TC for Adjuvant Breast Cancer trial, colloquially known as Tic Tac. The phase-3, randomized, open-label trial compares a combination of docetaxel, doxorubicin and cyclophosphamide vs. docetaxel and cyclophosphamide.

Final results are not expected until 2022, but Muss believes that they’ll be released earlier if “they’re a slam dunk.”

“In the meantime, for lower-risk patients — node-negative, patients with intermediate scores on Oncotype where you’re considering either randomizing them to the TAILOR X trial or treating them off trial — giving non-anthracycline regimens like TC is reasonable. For the higher-risk, node-positive patients it’s not reasonable to omit anthracyclines with the data we have right now,” Muss said.

Is topoisomerase II alpha a valid biomarker for taxane sensitivity?

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