Neoadjuvant Anthracyclines Do Not Affect Survival Outcomes for Patients with ERBB2-Positive Breast Cancer

Neoadjuvant anthracyclines for patients with early ERBB2-positive breast cancer had no effect on survival outcomes compared with patients who were not treated with the chemotherapy. Moreover, the anthracycline group had a greater risk of febrile neutropenia, cardiac toxicity, and secondary leukemia, an extended follow-up of the TRAIN-2 trial found.

In a group of 438 patients with stage II and stage III ERBB2-positive breast cancer, an event had occurred in 10.5% of anthracycline recipients at three years compared with 9.6% of those who did not receive an anthracycline, senior author Gabe Sonke, MD, PhD, The Netherlands Cancer Institute, Amsterdam, the Netherlands, and colleagues reported in JAMA Oncology.

At three years, the estimated event-free survival (EFS) rate was almost identical—92.7% (95% CI, 89.3-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4-96.9%) in the nonanthracycline group. Similarly, at three years, 97.7% (95% CI, 95.7-99.7%) of anthracycline recipients were still alive compared with 98.2% (95% CI, 96.4—100%) of nonathracycline recipients.

The study authors also reported a decline of 10% or more in the left ventricular ejection fraction (LVEF) from baseline and a LVEF of less than 50% at any time was reported in 7.7% of the anthracycline group compared to 3.2% of those in the nonanthracycline group (P=0.04), and two patients treated with anthracyclines developed secondary leukemia.

“The 3-year follow-up of the TRAIN-2 study showed high EFS… and OS (overall survival)… in patients with stage II and III ERBB2-positive breast cancer treated with or without anthracyclines,” the study authors wrote, adding that, “These results add to the literature on omitting anthracyclines in early-stage ERBB2-positive breast cancer.”

The TRAIN-2 study was a multicenter, phase III trial in which patients were randomized to an anthracycline-containing regimen or one that did not contain an anthracycline.

Some 219 patients were randomized to each group, at a median age of 49 years (interquartile range [IQR], 43-55 years) in the anthracycline group and a median age of 48 years (IQR, 43-56 years) in the nonanthracycline group. A total of 33.6% of the cohort had hormone receptor-positive disease while slightly over one-third had stage III disease.

Patients in the anthracycline group received three cycles of fluorouracil, 500 mg/m², epirubicin, 90 mg/m², and cyclophosphamide, 500 mg/m² intravenously for three weeks followed by six cycles of paclitaxel, 80 mg/m² on days one and eight and carboplatin, at an area under the concentration-time curve [AUC] 6 mg/mL/min on day one or at an AUC of 3 mg/mL/min on days one and eight.

Patients in the nonanthracycline group received nine, three-week cycles of paclitaxel and carboplatin given in the same schedule as those who also received anthracyclines.

Both groups received trastuzumab (Herceptin, Roche), 6 mg/kg after a loading dose of 8 mg/kg as well as pertuzumab (Perjeta, Genentech), 430 mg, after a loading dose of 840 mg, concurrently with chemotherapy every three weeks.

The primary analysis of TRAIN-2 showed a high pathologic complete response (pCR) rate in the breast and axilla after treatment regardless of whether patients had been treated with anthracyclines at 67% versus 68% for the nonanthracycline group.

The median follow-up of this secondary analysis was 48.8 months (IQR, 44.1-55.2 months). Subgroup analyses showed a similar risk of an event regardless of lymph node status, tumor stage, disease stage or grade, investigators noted. However, pCR was associated with disease-free survival (DFS) risk.

For those who did not achieve a pCR in the breast and axillary lymph nodes, 15.3% progressed or had died by study endpoint compared with 7.1% of those who did achieve a pCR, at a Hazard Ratio (HR) of 0.42 (95% CI, 0.23-0.78; P=0.006).

“This association seemed more pronounced in hormone receptor-negative patients (HR, 0.25 (95% CI, 0.08-0.75) than in hormone receptor-positive patients (HR, 0.56 [95% CI, 0.26-1.20; P=0.23]) but did not differ within the treatment groups,” Sonke and colleagues noted.

Most grade 3 or higher adverse events (AEs) occurred during the neoadjuvant chemotherapy interval where anthracycline use was associated with an increased risk of hematologic and non-hematologic toxicities which led to the premature discontinuation of trastuzumab.

Commenting on the TRAIN-2 update, Sara Hurvitz, MD, David Geffen School of Medicine, University of California, Los Angeles, noted that it made “perfect sense” to use an anthracycline in the original adjuvant trastuzumab trials.

“At the time these large, randomized studies were being planned, almost a quarter century ago, anthracycline-taxane combinations were the accepted standard for treating high-risk breast cancer,” she pointed out. Given that why, she asked, would anyone try to develop an alternative regimen that did not contain an anthracycline?

The main argument against anthracycline use in patients scheduled to also receive trastuzumab is the elevated risk of cardiac toxicity and a small but serious risk of secondary leukemia—”toxic effects to seriously consider when treating patients in the curative setting where overtreatment is the rule, not the exception,” Hurvitz noted.

There has not been a large, randomized trial proving that nonanthracycline regimens are equally effective to those containing an anthracycline. “While that is true, there has also been no demonstration for any randomized trial showing that anthracyclines are superior to nonanthracycline-based regimens in the trastuzumab era,” she wrote. Furthermore, oncologists now have access to an expanding armamentarium of biologically targeted therapies for patients at highest risk of relapse.

Although not free of adverse effects in and of themselves, “their risk of life-threatening toxic effects is smaller than that seen with anthracyclines,” Hurvitz noted, adding that, “Data from studies like TRAIN-2 have played a critical role in redefining how we approach the use of anthracyclines in this setting.”

The National Comprehensive Cancer Network recently argued against the routine use of anthracyclines in ERBB2-positive breast cancer although they still suggested that the drugs may be useful in certain situations.

1. Neoadjuvant anthracyclines had no effect on survival outcomes in ERBB2-positive breast cancer compared with no anthracyclines but they did increase toxicity.

2. Evidence is increasing that neoadjuvant anthracyclines can be omitted in the treatment of ERBB2-positive breast cancer without compromising survival outcomes.

Pam Harrison, Contributing Writer, BreakingMED™

Cat ID: 22

Topic ID: 78,22,730,22,691,192,925