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Risks, benefits must be balanced when choosing optimal therapy for node-negative, HER-2–positive breast cancer
On May 16, 2005, at about 1:30 p.m. local time, I was one of several hundred fortunate persons crowded into a conference hall at the ASCO Annual Meeting when the wide separation of the DFS curves in the joint analysis of NCCTG 9831 and NSABP B-31 was first shown.
The benefit of adjuvant trastuzumab was dramatic, and the results changed clinical practice that very next Monday morning.
Because there was a known cardiac risk of trastuzumab, patients with smaller lymph node-negative breast cancers either were excluded or underrepresented in the initial adjuvant trastuzumab studies, thus making extrapolation of these impressive results somewhat problematic for patients at lower risk for invasive recurrence.
Andrew D. Seidman
Since then, many patients at lower risk for recurrence and death in these trials have received adjuvant trastuzumab, and comparisons with historical controls seem to indicate that this may be associated with improved outcomes.
But: How to balance the upside with the potential downside? Anthracyclines, taxanes and trastuzumab for T1a or bN0 breast cancers? Really? Wouldn’t that be akin to hitting the metaphorical fly with a sledgehammer?
What about simply “targeting the targets?” Perhaps antiestrogen and trastuzumab alone, for example, would suffice for such a patient with HER-2–positive and ER-positive low-risk breast cancer?
The ‘sweet spot’
It was clear that a clinical trial examining the specific contribution of trastuzumab in this population would be a long and very large undertaking given the low expected event rate, and the very real possibility that by the time the results would be available, they could be irrelevant to clinical practice — particularly given the rapid pace of drug development in the management of HER-2–positive disease.
In this context, Tolaney and colleagues decided to employ the anthracycline- and carboplatin-free regimen of weekly paclitaxel plus trastuzumab previously demonstrated to be safe and very effective in HER-2–positive metastatic breast cancer, with the expectation of a better therapeutic index than more aggressive standard adjuvant regimens in a lower-risk population.
With a still-modest median follow-up of 4 years, only two of 406 patients have experienced distant metastases, two patients had reversible congestive heart failure, and 3.2% had reversible asymptomatic declines in left ventricular ejection fraction.
So, is the regimen “ready for prime time?” If so, which patients would make optimal candidates?
It is noteworthy that two-thirds of patients in the trial had hormone receptor-positive disease, and one-half had tumors not greater than a centimeter in diameter. The event rate distribution for patients with ER-positive disease is likely to be spread out over a longer horizon than this early report encompasses. Patients with T2 tumors represented only 9% of enrolled patients.
Nonetheless, the overall efficacy and safety of this regimen has made it an occasional treatment option that I do employ in selected patients in my own practice. My primary target group is patients with T1b and smaller T1c breast cancers, particularly — but not exclusively — when I have concerns about the safety and tolerability of regimens such as “AC-TH” or “TCH.” This is the “sweet spot” for this regimen in my mind, the place where — for patients with average comorbidities — the benefit of weekly paclitaxel with trastuzumab outweighs the harms and risks.
I have less/little enthusiasm for employing such therapy for the patient with T1aN0 breast cancers, for which — absent some combination of unique worrisome features, such as multifocality, extensive lymphovascular invasion and ER-negativity — the ratio of benefit to harm for even this reasonably well-tolerated regimen seems dubious.
Inflection point
Have we reached an inflection point in the management of small HER-2–positive tumors where “less is more,” paralleling the evolution of treatment for, say, testicular cancer? It would seem so.
In this context, studies of other well- or better-tolerated approaches — such as the ATEMPT trial, designed to compare weekly paclitaxel plus trastuzumab with ado-trastuzumab emtansine (Kadcyla, Genentech), a HER-2 drug–antibody immunoconjugate — are relevant. Despite relatively less data for trastuzumab monotherapy, one cannot help but wonder if patients with low-risk ER-positive, HER-2–positive disease might be best served by optimal endocrine therapy plus anti–HER-2 therapy. Data from the PERTAIN trial in metastatic disease will shed light on whether the addition of pertuzumab (Perjeta, Genentech) to an aromatase inhibitor plus trastuzumab offers incremental benefit.
Although longer follow-up on the current study is awaited, the data do inform a current rational and safe adjuvant treatment choice for selected patients with stage I, HER-2–positive breast cancers. The consideration of important host factors, such as age and comorbidities, also can contribute to optimized, tailored and nuanced adjuvant treatment selection.
References:
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Nichols CR, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2013.52.0858.
Oldenburg J, et al. Ann Oncol. 2015;doi:10.1093/annonc/mdu520.
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Seidman A, et al. J Clin Oncol. 2002;20:1215-1221.
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Seidman AD, et al. J Clin Oncol. 2008;doi:10.1200/JCO.2007.11.6699.
Tolaney SM, et al. N Engl J Med. 2015;doi:10.1056/NEJM0a1406281.
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For more information:
Andrew D. Seidman, MD, is an attending physician with the Breast Medicine Service at Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Cornell Medical College. He can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10021; email: seidmana@mskcc.org.
Disclosure: Seidman reports speakers bureau and consultant roles with Genentech/Roche.