What is the role of anthracyclines in the adjuvant therapy for breast cancer?

Updated: May 21, 2019
  • Author: Erin V Newton, MD; Chief Editor: Neetu Radhakrishnan, MD  more...
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Anthracycline-containing adjuvant chemotherapy regimens have been used in the treatment of early-stage breast cancer for decades, although concerns regarding anthracycline-associated cardiotoxicity or leukemogenic potential remain. In the 2000 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview, anthracycline-based regimens were associated with an annual risk of cardiac mortality of 0.08% per year, as compared with 0.06% per year in patients treated with nonanthracycline-based regimens. However, the question of long-term cardiac safety remains, particularly for older women with early-stage breast cancer.

The US Oncology 9735 trial established TC (docetaxel/cyclophosphamide) as a viable option for treating women with early-stage breast cancer, especially those at high risk of cardiotoxicity or requiring only 12 weeks of therapy. [24] This study randomized 1016 women with operable breast cancer (stages I-III) to 4 cycles of TC versus 4 cycles of standard-dose AC (Adriamycin/cyclophosphamide).

After a median of 7 years’ follow-up, both disease-free survival (81% vs 75%) and overall survival (87% vs 82%) were superior in the TC arm. Grade 5 cardiotoxicity (resulting in death) was seen in 6 patients treated with AC (4 from myocardial infarction; 2 from congestive heart failure) versus 2 patients (myocardial infarction) in the TC group. [24]

Additionally, a meta-analysis of 8 trials, comprising 6564 women with early-stage breast cancer, of anthracycline-based versus nonanthracycline-based regimens, suggested a benefit with anthracycline administration only in patients with HER2-positive disease. [25]

Biologically, anthracyclines inhibit topoisomerase IIa, whose gene (TOP2A) lies adjacent to the HER2 gene on chromosome 17. TOP2A is co-amplified in approximately 35% of HER2-overexpressing breast cancers.

The original trials demonstrating superiority of anthracycline-based regimens over CMF (cyclophosphamide, methotrexate, fluorouracil) did not include TOP2A or HER2 testing. The BCIRG 006 trial, which randomized women with HER2-positive disease to AC followed by T, AC followed by TH (docetaxel/trastuzumab [Herceptin]), or TCH (docetaxel and carboplatin plus trastuzumab), did test for TOP2A and HER2 co-amplification. [14]

This group comprises only approximately 8% of the total breast cancer population and may be the only subgroup to benefit from anthracycline administration. The role of TOP2A as a predictive marker of response to anthracyclines needs further validation. Until then, patients should not be deprived of anthracycline-based adjuvant chemotherapy if their risk assessment so determines it.

However, final analysis of the BCIRG-006 trial confirmed the increased toxicity of anthracyclines and called their therapeutic value into question. The 10-year disease-free survival was 74.6% with AC-TH versus 73.0% with TCH, and overall survival at 10 years was 85.9% and 83.3%, respectively, but neither difference reached statistical significance.

Safety differences in BCIRG-006 proved significant. Grades 3/4 congestive heart failure occurred in 21 AC-TH patients but in only 4 TCH patients (P = 0.0005) and a sustained  ≥10% relative decline in left ventricular ejection fraction was seen in 200 AC-TH patients, compared with 97 in TCH patients (P< 0.0001). Seven treatment-related cases of acute leukemia occurred in patients receiving anthracyclines, compared with one case in a TCH patient. [14]

An anthracycline followed by or concurrent with a taxane is the optimal therapy for "triple-negative" breast cancer patients with no medical contraindications. However, it remains unclear what the optimal combination chemotherapy regimen is for ER-positive, HER2-negative tumors. Currently, CMF, TC, or an anthracycline-based regimen may all be reasonable options.

The drug combination uracil-tegafur (UFT) is not approved in the United States, but is used in many other countries worldwide. A study that compared the effectiveness of oral UFT with that of CMF given as a postoperative adjuvant to women with node-negative, high-risk breast cancer demonstrated that risk-free survival and overall survival were similar in the 2 groups, but the quality of life scores were higher for patients given UFT than for those given CMF. The study concluded that for women with node-negative, high-risk breast cancer, UFT is a promising alternative to CMF. [26]

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