A "Direct Assault" on Anthracycline-Based Therapy for Breast Cancer?

Nick Mulcahy

December 15, 2009

December 15, 2009 (San Antonio, Texas) — Most women with HER2-positive early breast cancers should not receive an anthracycline-based adjuvant chemotherapy, suggested a presenter here at the 32nd Annual San Antonio Breast Cancer Symposium.

Dr. Dennis Slamon

This treatment guidance was offered by Dennis Slamon, MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, and is partly rooted in new 5-year data from the ongoing phase 3 trial known as Breast Cancer International Research Group (BCIRG) 006.

However, another breast cancer expert approached by Medscape Oncology disagreed with this conclusion.

Dr. Gary Lyman

"That's going beyond the data," said Gary Lyman, MD, from the Duke Comprehensive Cancer Center in Durham, North Carolina. He also disagreed with several other comments made by Dr. Slamon, who is well known for his advocacy against anthracyclines.

The results that Dr. Slamon presented are the third analysis of the BCIRG 006 trial, which is being conducted in more than 3000 women and compares chemotherapy alone with 2 experimental regimens of chemotherapy plus trastuzumab (Herceptin, Genentech-Roche): 1 with anthracycline-based chemotherapy and 1 with taxane-based chemotherapy.

Dr. Slamon highlighted the findings that came from the 2 trastuzumab groups.

He noted that, at 5 years, there were 29 fewer events in the anthracycline-based group (185 events among 1074 women) than in the taxane-based group (214 events among 1074 women).

However, this "numerical advantage came at the cost of 21 cases of congestive heart failure and 8 acute leukemias," he pointed out, referring to the anthracycline-based therapy.

The efficacy differences are outweighed by the toxicity differences.

"The efficacy differences are outweighed by the toxicity differences," Dr. Slamon said at a press briefing.

Furthermore, the study data show that the "incremental benefit" conferred by the anthracycline-based therapy is based on the effect seen in a subgroup of HER2-positive women — those with tumors containing alterations in the topoisomerase II alpha (TOP2A) gene. This group, which comprises about one third of HER2-positive breast cancers, is the only one in which anthracyclines "make sense," said Dr. Slamon.

Consideration for a nonanthracycline-based regimen should be high.

"Consideration for a nonanthracycline-based regimen should be high" for most HER2-positive early breast cancers, Dr. Slamon explained.

Provocatively, Dr. Slamon called evidence of the limitations of anthracyclines, including data from the new study, a "direct assault on anthracycline-based regimens."

However, Dr. Lyman had a different perception of the efficacy and safety findings of the anthracycline-based regimen in the study.

"Many oncologists will differ with his opinion," said Dr. Lyman. So will many patients, he suggested.

"When I show the data to my patients, they will be more concerned about what is most effective in treating their breast cancer than about the hypothesized long-term risk of cardiac effects and second malignancies," he told Medscape Oncology.

Dr. Lyman emphasized the fact that, in the BCIRG 006 trial, the anthracycline-based regimen has an evolving superiority compared with the taxane-based therapy. ''If you look at the disease-free survival and overall survival curves, they have widened since the last analysis, favoring the anthracycline regimen," he observed.

Furthermore, Dr. Slamon's recommendation to not use anthracyclines is not appropriate, Dr. Lyman said, because although the study "may justify leaving out anthracyclines in patients with HER2-positive breast cancer and significant cardiac risk, it was clearly not powered to answer the question of whether anthracyclines are unnecessary in all HER2-positive disease."

Dr. Lyman explained that the study showed a statistically significant superiority for both chemotherapy-plus-trastuzumab regimens over chemotherapy alone in disease-free survival and overall survival.

Also, these are only 5-year data, said Dr. Lyman, adding: "We'd like to see more mature data." Dr. Slamon, in his press conference, agreed with the need for longer-term data.

As previously reported by Medscape Oncology, Dr. Slamon is an advocate for using nonanthracycline-containing regimens in most HER2-positive patients. He has also argued that TOP2A is a proven biomarker for predicting response to adjuvant anthracycline-based treatment. However, both of these ideas are contended by other experts and reportedly conflicting data.

Overall Results From the Study

BCIRG 006 was conducted in 3222 women with Her2/neu-positive early breast cancer who were randomized to 1 of 3 treatment group:

  • The control group — chemotherapy with doxorubicin (Adriamycin, Bedford Laboratories) and cyclophosphamide followed by docetaxel (Taxotere, Sanofi-Aventis) (n = 1072)

  • The anthracycline-based experimental group (AC→TH) — doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (n = 1074)

  • The taxane-based experimental group (TCH) — docetaxel, carboplatin, and trastuzumab (n = 1074).

Patients were prospectively stratified by the number of positive nodes (0, 1 to 3, and 4+) and hormone-receptor status. Patients with estrogen-receptor- and/or progesterone-positive tumors received hormonal therapy for 5 years after chemotherapy (about 50% of all patients in each group). About 60% of all patients in each group underwent mastectomy and about 68% of each group received radiotherapy.

One of the distinguishing features of the trial is that, when trastuzumab efficacy results were announced in 2005, only 23 patients (2.1%) crossed over to an experimental group to receive the drug, noted Dr. Slamon. Thus, the statistical power of the study was not affected.

These new data are from a third protocol-specified analysis, which was conducted after 650 events, said Dr. Slamon.

At 5 years, there were 656 events among the patients: 257 in the control group, 185 in the AC→TH group, and 214 in the TCH group.

For the primary end point of disease-free survival, both of the trastuzumab-containing groups were statistically superior to the control group. Compared with the control group, the AC→TH group had a hazard ratio of 0.64 (95% confidence interval [CI], 0.53 – 0.78; < .001), and the TCH group had a hazard ratio of 0.75 (95% CI, 0.63 - 0.90; = .04).

The same held true for the secondary end point of overall survival.

There were 348 deaths among the patients: 141 in the control group; 94 in the AC→TH group; and 113 in the TCH group.

Compared with the control group, the AC→TH group had a hazard ratio of 0.63 (95% CI, 0.48 - 0.81; < .001) and the TCH group had a hazard ratio of 0.77 (95% CI, 0.60 - 0.99; P = .038). Both were statistically significant improvements.

The advantages in the 2 experimental groups were also seen in low- and high-risk patients, said Dr. Slamon.

Differences in Interpretation

In terms of safety, the TCH group was generally better tolerated and, when compared with both the control and AC→TH groups, had statistically significantly lower rates of grade 3/4 nonhematological toxicities for arthralgia, myalgia, hand-foot syndrome, stomatitis, and vomiting, and of grade 3/4 hematological toxicities for neutropenia and leucopenia.

However, Dr. Slamon focused on the differences in grade 3/4 cardiac left ventricular function (LVEF) and congestive heart failure. The AC→TH group had 21 such events, whereas the TCH group had only 4 events.

However, as Dr. Lyman pointed out, a graph presented by Dr. Slamon showing mean LVEF in the different groups over 5 years revealed "trends that indicated a recovery of cardiac function among patients treated with anthracyclines."

But Dr. Slamon suggested that the damage is not reversible. "The damage we are doing to the heart is ongoing," he told reporters.

Dr. Slamon also emphasized that there were 8 total treatment-related leukemias, and 7 were among the patients treated with anthracyclines (both the AC→TH and control groups), whereas there was only 1 such event among patients in the TCH group (this patient also received an anthracycline for treatment of B-cell lymphoma). "These treatment-related leukemias are well known in the literature," he noted.

There can be, among intelligent people, very different conclusions about the same data.

However, Dr. Lyman pointed out that most of the cases of leukemia (6 of the 8 cases) were in the control group. There was no difference in the number of cases of leukemia among the patients in the AC→TH group and the TCH group (both had 1 case apiece), observed Dr. Lyman. "That's the real comparator here," he said.

"Bottom line, there can be, among intelligent people, very different conclusions about the same data," said Dr. Lyman about the ways his perspective differs from Dr. Slamon's.

The study was sponsored by Sanofi-Aventis with support from Genentech. Dr. Slamon reports receiving a research grant from Amgen, is a member of the speakers' bureaus for Genentech and Sanofi-Aventis, and is a consultant to Pfizer. Dr. Lyman has disclosed no relevant financial relationships.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract 62. Presented December 12, 2009.

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