Widespread Benefit of Anthracyclines in Early BC Comes into Question

Anthracyclines are widely used in the adjuvant treatment of breast cancer, but this practice is being questioned as emerging data show benefits to be restricted to certain subsets of patients.

Dennis J. Slamon, MD, PhD
Photo Courtesy @ SABCS/Todd Buchanan 2007

"The use of anthracyclines in the adjuvant treatment of all breast cancer is not supported by the existing data. Other approaches should now be adopted," said Dennis Slamon, MD, PhD, professor of medicine and director of clinical/translational research at the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles. Dr. Slamon noted that the superior efficacy benefits for anthracyclines, when present, appear to derive from the effect of these agents on amplification or overexpression of the topoisomerase IIα (topo IIα) gene. The topo IIα gene encodes an enzyme that is critical in DNA replication and function, and the topo IIα protein is a major target of the anthracyclines. Given that topo IIα amplification occurs only in about one-third of the HER2+ patient population, or "a subset of a subclass," Dr. Slamon questioned the preferential use of anthracyclines in the HER2– population, which represents about 75% of all breast cancers. He and colleagues performed a systemic review of published data from randomized controlled adjuvant trials that classified patients by HER2 subtype, and they reclassified the BCIRG 005 and 006 trials according to topo IIα coamplification. These analyses of published data demonstrated "a remarkably consistent finding," according to Dr. Slamon. "Specifically, the incremental efficacy benefit attributed to anthracycline-based therapies is restricted to the HER2+ subgroup," he said. According to in vivo and in vitro studies, this is apparently not due to a unique and/or inherent sensitivity to anthracycline caused by HER2 overexpression. Rather, the current data indicate that it is the topo IIα gene amplification and not HER2 that is responsible for the improved sensitivity to anthracyclines, he said. A recent analysis of the BCIRG 006 (HER2+ patients) and BCIRG 005 (HER2-normal patients) trials revealed that topo IIα amplification is observed in about 35% of HER2+ patients and is confined to cancers that contain the HER2 amplicon. "In over 1600 patients in the HER2-normal BCIRG 005 population, there was not a single case of topo IIα amplification," he said. "This does not appear to occur without HER2 amplification." BCIRG 006 randomized 3222 patients to doxorubicin/cyclophosphamide followed by docetaxel (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 coamplification of HER2 and topo IIα. In noncoamplified patients, 4-year disease-free survival was 83% for AC-TH, 81% for TCH, and 71% for AC-T. But in coamplified 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 TCH, which does not contain an anthracycline. "The differences were larger in the topo IIα noncoamplified patients. When topo IIα was coamplified, the outcomes were essentially identical," Dr. Slamon said. What the anthracycline-based regimens did provide, however, was more toxicity. There was considerably more congestive heart failure (n = 20 with AC-TH vs. 4 with TCH) and leukemia (n = 4 in AC-T + AC-TH vs. 0 with TCH). "Moreover, for HER2+ breast cancers, we now have trastuzumab and lapatinib, one of which, thus far, appears to replace the gained efficacy of anthracyclines in the one-third of patients with coamplification of HER2 and topo IIα (about 8% of all breast cancers), without risking their known and well established toxicities," Dr. Slamon said.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.