Can Anthracyclines Be Withheld in High-Risk HER2-Negative Breast Cancer?

Kevin Kalinsky, MD, MS; Kathy D. Miller, MD


June 06, 2016

Editor's Note: Results of the ABC (Anthracyclines in Early Breast Cancer) adjuvant trials generated a considerable amount of early attention at ASCO 2016. Breast cancer specialists Kathy D. Miller, MD, and Kevin Kalinsky, MD, MS, each contributed their initial response to the trial's results in Medscape's ASCO 2016 Live Blog, which are excerpted below.

For a review of the most important ASCO 2016 sessions across all tumor types, visit Medscape's ASCO 2016 Live Blog.

Kathy D. Miller, MD: Persistence has paid off. US Oncology began a clinical trial to evaluate the role of anthracyclines in patients with HER2-negative disease over a decade ago. Initially funded by Sanofi and conducted entirely by US Oncology, the trial hoped to show that docetaxel plus cyclophosphamide (TC) was not inferior to anthracycline/taxane-based chemotherapy regimens (TAC). Both regimens were given for six cycles to isolate the anthracycline question. As accrual lagged and sponsorship evaporated, US Oncology partnered with NSABP to add a third arm, TC x 6 with bevacizumab. With new sponsorship from Genentech, the trial could continue. As the FDA approval for bevacizumab in breast cancer was withdrawn, the pattern repeated: Accrual again lagged, sponsorship cancelled. This time the NCI/CTEP came to the rescue, picking up sponsorship and broadening the anthracycline arm to allow sequential AC >T regimens. The TC + bevacizumab arm was eliminated and the trial had new life.

Despite the tortured history, the ABC suite of trials[1] combined to enroll 4156 patients; 41% were lymph node–negative. The trial was stopped at the first interim analysis as the noninferiority boundary was not met.

Let me say that more clearly in lay terms: TC was not as effective as anthracycline/taxane regimens. The hazard ratio was 1.23 (P = .04 for superiority) favoring use of anthracyclines. That's a 23% increase in recurrence with TC. As you might expect, the benefit was greatest in patients with hormone-negative disease and multiple lymph node involvement, but all groups favored anthracycline use.

Stop and think about the implications of this study for a minute. Practice pattern surveys have consistently shown a dramatic decrease in use of anthracyclines in patients with HER2-negative disease even though there was little data to support that shift. Dr Steve Jones' AC x 4 vs TC x 4 trial[2] is the only study in this population. While TC was superior, there was no comparison to sequential A > T or combination AT regimens. Fearful that TC x 4 was insufficient for high-risk patients, many had simply extended the duration of therapy with TC x 6. That practice, too, should be questioned. While not addressed in the ABC trial, a previous CALGB study found no improvement in efficacy and increased toxicity with six rather than four cycles of AC or paclitaxel. It seems unlikely that TC would fare any better.

So where does that leave us? Patients with high-risk disease should receive anthracycline and taxane therapy. TC might still have a role in lower-risk patients or those with significant underlying cardiac disease, but it can no longer be considered appropriate for most patients. There are some cautionary tales for all of us in this trial. First, the US Oncology and NSABP investigators should be congratulated for getting this done. It would have been easy and understandable had they simply closed the trial and moved on. Second, we should demand more of a study to claim that it is indeed practice-changing. Many took the results of the initial trial much further than the data justified, and they adopted TC as a new practice standard for all HER2-negative patients.

Kevin Kalinsky, MD, MS: Can we withhold an anthracycline in patients with high-risk node-negative or node-positive, HER2-negative breast cancer?

Based on results presented at ASCO, the current answer at this time is no.

This has been an important and frequently argued clinical question. Given the rare but serious adverse events of cardiotoxicity and secondary leukemia, the field has argued for some time whether (and in whom) we could withhold these agents. Predictive markers of anthracycline benefit have not been adopted into clinical practice.

In a joint analysis, three phase 3 trials were combined for a total of more than 4000 patients. The primary endpoint was invasive disease-free survival. This study was designed as a noninferiority trial. With a median follow-up of approximately 3 years, the study is reporting early based on futility. At this interim analysis, the study demonstrated that docetaxel + cyclophosphamide (TC) x 6 was not noninferior to anthracycline-containing regimens, meaning that an anthracycline should still be considered in these patients. In an exploratory analysis, the hormone receptor–positive/HER2-negative, node-negative cohort was the only subgroup for whom TC numerically favored anthracycline-based regimens; however, these analyses are hypothesis-generating. We will see how these data mature over time, but one could argue that, on the basis of today's session, anthracyclines remain an important class of agent for high-risk, node-negative or node-positive HER2-negative breast cancer.


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