Anthracyclines in early breast ca: Is the end near?

SAN ANTONIO-Studies presented at the 2007 San Antonio Breast Cancer Symposium raise new questions about the role of anthracycline-based regimens as adjuvant therapy in early breast cancer, suggesting that these regimens may be appropriate only for a small subset of patients.

"The use of anthracyclines in the adjuvant treatment of all breast cancer patients is not supported by the existing data. Other approaches should now be adopted," said UCLA's Dennis Slamon, MD, PHD, who presented a new analysis of the phase III Breast Cancer International Research Group (BCIRG) 006 trial at the meeting (abstract 13).

His analysis showed that anthracyclines are beneficial only in patients with HER2-positive disease who also have amplification or overexpression of the topoisomerase II alpha (topo IIa) gene. Topo IIa amplification occurs only in about one-third of the HER2-positive patient population, or "a subset of a subclass," Dr. Slamon said.

Given that fact, he questioned the preferential use of anthracyclines in the HER2-negative population, which represents about 75% of all breast cancers.

And in the HER2-positive population, he said, "we now have trastuzumab [Herceptin] and lapatinib [Tykerb], one of which, thus far, appears to replace the gained efficacy of anthracyclines in patients with co-amplification of HER2 and topo IIa (about 8% of all breast cancers), without risking their known and well-established toxicities."

BCIRG 006 randomized 3,222 patients to doxorubicin/cyclophosphamide followed by docetaxel (Taxotere) (AC-T), to AC-T plus trastuzumab (AC-TH), or to an experimental non-anthracycline-based regimen of docetaxel, carboplatin, and trastuzumab (TCH).

The efficacy observed with AC-TH was restricted to patients with co-amplification of HER2 and topo IIa. In non-co-amplified patients, 4-year disease-free survival was 83% for AC-TH, 81% for TCH, and 71% for AC-T. But in co-amplified patients, disease-free survival was similar for all groups (83% to 85%). In other words, the inclusion of an anthracycline provided no additional benefit over the non-anthracycline-based TCH regimen.

What the anthracycline-based regimens did provide, however, was more toxicity. There was considerably more congestive heart failure (20 cases with AC-TH vs 4 with TCH) and leukemia (4 in AC-T + AC-TH vs 0 with TCH).

Improved survival with TC

With 7 years of follow-up, US Oncology Adjuvant Trial 9735 has shown that docetaxel plus cyclophosphamide (TC) significantly improved both disease-free and overall survival, compared with standard AC. Stephen Jones, MD, medical director of US Oncology Research, Houston, presented the data at SABCS 2007 (abstract 12). Five-year results, presented at SABCS 2005, had shown improved disease-free but not overall survival with TC.

"TC is a highly effective, modestly toxic, non-anthracycline adjuvant chemotherapy regimen. With longer follow-up, it has stood the test of time and now shows a survival advantage. TC should be considered a standard regimen for early breast cancer," Dr. Jones said.

A total of 1,016 patients with stage I, II, or operable stage III invasive breast cancer were randomized to four cycles every 21 days of doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² or to docetaxel 75 mg/m² plus cyclophosphamide 600 mg/m².

Disease-free survival was 81% for the TC arm and 76% for the AC arm, for a relative risk reduction of 26% favoring TC (P = .03). Overall survival was 87% for TC and 82% for AC, for a 31% relative risk reduction at 7 years (P = .03), Dr. Jones reported.

Regardless of age (< 65 or ≥ 65) TC improved disease-free and overall survival as compared with AC. The worst outcomes were observed in patients ≥ 65 receiving AC. At 7 years, disease-free survival was approximately 65% for that group of patients, compared to approximately 75% for patients ≥ 65 receiving TC.

All subgroups benefited

Furthermore, TC was efficacious in patients with HER2-positive as well as HER2-negative disease, though this was based on a limited sample of patients. An exploratory analysis of all key subgroups showed better outcomes for TC across the board, he added.

TC was well tolerated in both age groups. In the older patients, TC was associated with slightly more febrile neutropenia (8% vs 4%) but with less anemia than AC (< 1% vs 5%). It was also associated with less long-term toxicity to the heart and bone marrow.

The three long-term fatal toxicities (heart failure, myelodysplastic syndrome, and myelofibrosis) all occurred in the AC arm.

Dr. Jones indicated that he would be "comfortable" recommending TC for node-negative patients or those with one to three positive nodes, but might still prefer the anthracycline-based regimen in patients at higher risk, ie, those with locally advanced disease or with four or more positive nodes.

US Oncology is now involved in a new study that will further evaluate the need for anthracyclines by comparing six cycles of TC against six cycles of TAC (doce-taxel/doxorubicin/cyclophosphamide).

'An interesting dichotomy'

In an interview, John Cole, MD, head of hematology/oncology at the Ochsner Cancer Institute, New Orleans, noted the emergence of "an interesting dichotomy" between the overview data from earlier studies showing the superiority of anthracycline therapy, and subsequent trials, such as those presented at the San Antonio meeting, that call this approach into question.

"The studies by Jones and Slamon have indicated that non-anthracycline combination regimens are at least equivalent. I think the question now is, 'What subpopulation of patients needs which agents?'" Dr. Cole said.

The Early Breast Cancer Trialists' Collaborative Group overview study, involving 350,000 women from 400 clinical trials, showed improvement in local breast cancer recurrence and breast cancer mortality in women treated with anthracycline-based regimens, compared with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF).

"This gives us a broad look, but the whole field is going in the direction of individualized care," Dr. Cole said. "The problem is, we don't yet have all the answers."

Moving toward individualization of treatment regarding the other common class of cytotoxics, the taxanes, for example, he cited a study by Hayes et al (N Engl J Med 357:1496-1506, 2007) showing that patients with HER2-negative, ER-positive, node-positive breast cancer may gain little benefit from the administration of paclitaxel after adjuvant chemotherapy with AC.

In the case of anthracyclines, he said, Dr. Slamon showed in the BCIRG 006 trial that in HER2-positive, node-positive (or high-risk) patients, six cycles of TCH provided similar benefit to eight cycles of AC-TH, with much less cardiotoxicity.

"The best responders to anthracyclines were patients with amplification of both the topo IIa gene and HER2. Outside of this subset, one could argue that HER2-positive, node-positive patients do not need an anthracycline," Dr. Cole said.

He further noted that "there are groups of patients who clearly don't need anthracyclines. So you can avoid this drug in patients for whom you have cardiotoxicity concerns, and you can find regimens that are equally effective. You can use TCH in this case, or you can use TC instead of AC. We now have data in support of alternatives to anthracyclines when you want to avoid the potential for toxicity."

He added, however, that "in talking with my colleagues, I find that oncologists are not yet willing to give up anthracyclines completely. They still feel strongly that they are very effective agents and are leery of not using them."

Dr. Cole said he would like to see a comparison of the TC regimen with a regimen containing both an anthracycline and a taxane, which for node-positive patients is still standard treatment. And he would like to see the TC regimen compared with an anthracycline/taxane in node-negative patients.