National Breast Cancer Coalition

Anthracyclines

All breast cancers are not the same, so it makes sense that treatments can no longer be one-size-fits all. However, once a treatment regimen is in place and becomes standard, it can take a long time to remove it from practice, even when scientific evidence no longer supports its use.

Many women diagnosed with invasive breast cancer of different subtypes continue to receive the same adjuvant chemotherapy regimen, one including a controversial class of drugs called anthracyclines, though evidence shows that the drugs may only provide benefit to a small group of patients, and could be replaced with a less toxic substitute. 

The class of chemotherapy drugs called anthracyclines includes doxorubicin (Adriamycin®)  and epirubicin (Ellence®). Side effects include short term nausea and hair loss and potential long-term effects such as heart damage (1-2% of patients) and leukemia (less than 1% of patients) (Barlett-Lee, 2009).

History

During the 1990s, chemotherapy regimens containing anthracyclines largely replaced previous regimens of cyclophosphamide, methotrexate, and 5-FU (CMF) for the treatment of breast cancer, based primarily on a meta-analysis of 11 clinical trials, done by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Results of individual studies were inconclusive, but when the results were pooled, the Group found that regimens containing anthracyclines slightly improved disease-free and overall survival (EBCTCG, 1998).

Data published from as far back as 1994 has suggested that the benefit of anthracyclines in the adjuvant setting is limited to the HER2-positive molecular subtype of breast cancer, which accounts for 25% or less of breast cancers (Muss, 1994; Paik, 1998). More recently, a meta-analysis of 5,354 early breast cancer patients in Italy came to similar conclusions (Gennari, 2008).

The Impact of Trastuzumab

The development of a targeted treatment for HER2-positive cancers, trastuzumab (Herceptin®), decreases the importance of previous evidence on anthracyclines. Recent evidence shows that for those whose tumors are HER2-positive, treatment with trastuzumab, along with a non-anthracycline chemotherapy regimen, provides the same benefit as an anthracycline-containing regimen and trastuzumab, with less toxicity (Slamon, 2009). On the basis of these results, the US Food and Drug Administration approved trastuzumab for adjuvant treatment of early breast cancer, in combination with other drugs, with or without an anthracycline.

Progress and improvements in treatment require that adjustments be made as new evidence becomes available.

Recent Research

Recent research continues to support a move away from anthracyclines. The U.S. Oncology's 9735 trial randomized 1,016 women to four cycles of docetaxel (Taxotere®)-cyclophosphamide or doxorubicin-cyclophosphamide. After 7 years, there was a statistically significant improvement in overall survival in the taxane (docetaxel) group compared with the anthracycline (doxorubicin) group (Jones, 2009).

For women who are HER2-positive, evidence for a move away from anthracyclines comes from a Breast Cancer International Research Group trial (BCIRG 006) that has been following 3,222 women with node-positive, or high-risk node-negative, HER2-positive breast cancer, since 2001. Women were randomized to receive an anthracyline-containing regimen alone, an anthracycline-containing regimen with trastuzumab, or a non-anthracycline regimen with trastuzumab. The third efficacy analysis of this trial was presented at the 2009 San Antonio Breast Cancer Symposium (Slamon, 2009).

After 65 months on the study, the disease-free survival rate was 84% for the group receiving an anthracycline regimen with trastuzumab, 81% for the group receiving a non-anthracycline regimen with trastuzumab, compared to 75% for those receiving an anthracycline regimen and no trastuzumab.

Women receiving the anthracycline-containing regimen with trastuzumab had slightly less chance of metastasis or spread of the breast cancer, compared to those receiving the non-anthracycline containing regimen and trastuzumab. The difference was not statistically significant and came with a higher cost in toxicity. The group receiving anthracyclines and trastuzumab had five times as many cases of congestive heart failure as the group not receiving anthracyclines (2% vs. 0.4%). The difference was statistically significant.

There were eight cases of leukemia in the study, six (0.6%) in the non-trastuzumab group, and one (0.1%) in each of the trastuzumab groups, but the difference was not statistically significant. All patients who developed leukemia had received an anthracycline at some point during their treatment.

Results from BCIRG 006, along with results from several other studies, have suggested that a smaller subset of patients gain benefit from anthracycline based therapy – those with HER2-positive tumors that also show amplification of another gene – the topoisomerase IIα or topo IIα, about 35% of the HER2-positive cancers (Slamon, 2009; O'Malley, 2009; Tubbs, 2009). Even within this subset, a comparable benefit was seen in the BCIRG 006 trial with the non-anthracycline regimen with trastuzumab, without the long-term toxicities.

Treatment regimens must keep pace with the increasing knowledge of different subtypes of breast cancer and the variation in responses to treatment within the different subtypes. Patient-centered care requires that removing a treatment from standard care should happen as quickly and easily as adding a new one, once the evidence supports a change.

Citations

Barlett-Lee PJ, Dixon JM, Farrell C et al. Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk. Annals Oncology 2009 May;20:816-827.

Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 1998;352(9132):930-42.

Gennari, A, Sormani MP. HER2 Status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 2008;100:14-20.

Gianni L, Norton L, Wolmark N et al. Role of anthracyclines in the treatment of early breast cancer. J Clin Oncol 2009;27:4798-4808.

Harris LN, Broadwater G, Abu-Khalaf M et al. Topoisomerase IIα amplication does not predict benefit from dose-intense cyclophosphamide, doxorubicin, and fluorouracil therapy in Her2-amplified early breast cancer: Results of CALGB 8541/150013. J Clin Oncol 2009; 27:3430–3436.

Jones S, Holmes FA, et al. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol 2009 Mar 10: 1177-1183.

Knoop A, Kudsen H, Baslev E et al. Retrospective analysis of topoisomerase IIα amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluoouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Group. J Clin Oncol 2005;23:7483-7490.

MacArthur HL, Tan LK, Patil S et al. High resolution representational oligonucleotide microarray analysis (ROMA) suggests that TOPO2 and HER2 co-amplification is uncommon in human breast cancer. 2008 San Antonio Breast Cancer Symposium.

Muss HB, Thor AD, Berry DA, et al. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 1994 May 5; 330(18): 1260-6.

O'Malley FP, Chia S, Tu D et al. Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J NCI 2009; 101:644-650.

Paik S, Bryant J, Park C, et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 1998 Sep 1 6; 90(18): 1361-70.

Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients: BCIRG 006 Study. San Antonio Breast Cancer Symposium, December 12, 2009. Abstract #62.

Tubbs R, Barlow WE, Budd GT et al. Outcome of patients with early –stage breast cancer treated with doxorubicin-based adjuvant chemotherapy as a function of HER2 and TOP2A status. J Clin Oncol 2009;27:3881-3886.

Young P. Anthracycline War: No victor yet. J Natl Cancer Inst 2009;101:1171-1173.