Small Benefit, Persistent Toxic Risk With Adjuvant Anthracycline in Breast Cancer

Adding an anthracycline to adjuvant chemotherapy for TOP2A-normal early breast cancer significantly improved disease-free survival (DFS) but not overall survival (OS) at 10 years, and doubled the risk of heart failure, a randomized trial showed.

Patients who received epirubicin and cyclophosphamide prior to docetaxel (EC-D) had a 21% reduction in the hazard for distant disease-free survival (DDFS) and a 17% reduction in the DFS hazard. Patients randomized to EC-D had a 10-year cumulative heart failure risk of 2.1% versus 1.1% for patients who received only cyclophosphamide and docetaxel (DC), but the difference did not translate into an increased risk of heart failure mortality.

TOP2A testing had no overall clinical value, and unexpectedly, patients with a TOP2A/CEN17 ratio Journal of Clinical Oncology.

“Benefit from anthracycline has been demonstrated among patients with TOP2A-amplified tumors, whereas the association with deletions has been less clear,” the authors stated. “The exploratory subgroup analyses of Ki-67 and TOP2A did not support that epirubicin preferentially benefits highly proliferating tumors.”

The recent Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis of 5-year data from the Danish READ study and seven other trials showed no reduction in the risk of recurrence with sequential anthracycline-taxane therapy as compared with DC. The analysis did show a benefit with concurrent anthracycline-taxane therapy when the cumulative taxane dose was the same as with DC.

The long-term results did not make a compelling case for continued use of anthracyclines as adjuvant breast cancer therapy, according to the authors of an accompanying editorial.

“A persistent dilemma in the judicious use of anthracyclines has been the lack of a clinical, pathological, or biological marker for treatment selection,” wrote Thomas Grinda, MD, and Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston. “To date, neither the READ trial nor the [EBCTCG] meta-analysis has suggested that identifying cohorts by patient age or tumor stage, grade, or estrogen receptor or HER2 status, uniquely defines individuals warranting anthracyclines.”

“The READ trial, open only to patients with TOP2A-normal tumors, showed comparable outcomes with anthracyclines regardless of the range of TOP2A expression,” they added.

Once a standard of care for breast cancer, anthracyclines remain foundational to cancer treatment around the world, particularly in low-resources areas with less access to newer, more expensive treatments, the editorialists continued. With good supportive care, anthracyclines are tolerable for most patients but still carry a risk of rare but significant late side effects.

“However, the era of anthracycline-based chemotherapy is waning,” Grinda and Burstein wrote in conclusion. “Incremental improvements in other treatment options and the use of biomarkers to define whether chemotherapy is indicated have diminished the chance that anthracyclines offer meaningful benefit to many patients with early-stage breast cancer. The burning red devil of anthracycline-based care has clearly passed its zenith and begun a long goodbye.”

The primary objective of the READ trial was to determine whether adjuvant EC-D improved outcomes versus DC in early breast cancer. Investigators enrolled a biomarker-selected patient population, namely TOP2A-normal node-positive or high-risk node-negative breast cancer. Results after 5 years of follow-up showed no difference in DFS or OS. The primary objective of the 10-year follow-up was to evaluate survival outcomes and late toxicity.

From June 2008 to December 2012, investigators throughout Denmark randomized 2,012 patients to EC-D or DC. After a median follow-up of 10 years, 170 patients in the EC-D arm and 204 in the DC arm had DDFS events, which translated into a statistically significant advantage for the anthracycline-containing arm, with an adjusted hazard ratio (HR) of 0.79 (95% CI 0.64-0.98, P=0.03). Additionally, 467 DFS events were recorded, and comparison of the two groups yielded an adjusted HR of 0.83 (95% CI 0.69-0.99, P=0.04).

The adjusted mortality HR of 0.88 in favor of EC-D did not achieve statistical significance (95% CI 0.70-1.10, P=0.25).

Toxicity analyses showed that heart failure was uncommon, with a total of 34 cases during long-term follow-up, but occurred twice as often in the EC-D arm (23 vs 11 cases). The difference translated into an adjusted HR of 2.12 (95% CI 1.03-4.35, P=0.04). However, six of the 11 patients in the DC arm subsequently died as compared with five of the 23 allocated to EC-D. Heart failure was associated with a sixfold higher mortality risk (adjusted HR 6.16, 95% CI 3.36-11.30).

Obesity and hypercholesterolemia increased the risk of heart failure, but not treatment with trastuzumab, left-sided radiotherapy, or prior diagnosis of diabetes or hypertension.

Second non-breast primary cancers developed in 67 patients treated with EC-D and in 76 treated with DC. No specific type of cancer occurred more often in one group than the other, including leukemia (two in the EC-D arm, one in the DC arm).

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