Dr. Lajos Pusztai, a professor in the department of breast medical oncology at M.D. Anderson, agrees with Dr. Fehrenbacher’s conclusion. "I think the findings are correct, as several other studies have also indicated a very low risk of recurrence for very small HER2-positive cancers," he said in an interview.
"It may also be important to remember that HER2 has not been considered by the ASCO biomarker review panels [to be] an important prognostic marker, but rather a predictive marker for trastuzumab therapy."
Review Warns of Cardiotoxicity
In a recent review article looking into whether the existing data supports a definitive treatment threshold for patients with T1aN0M0 or T1bN0M0 HER2-positive breast cancer, Dr. Pusztai, along with lead author Dr. Catherine M. Kelly of Waterford Regional Hospital in Waterford, Ireland and colleagues, wrote that "a blanket recommendation to treat all small HER2 positive breast cancer with trastuzumab-based therapy will almost certainly lead to clinically significant cardiotoxicity in some without any benefit in breast cancer recurrence."
Similarly, they noted, "withholding this form of adjuvant therapy from all small HER2 positive cancers will result in some otherwise avoidable breast cancer recurrence. Unfortunately, today we do not have accurate tools to identify precisely the subset of patients for whom the risks of trastuzumab outweigh the benefits."
Lacking such tools, shared medical decision making based on estimates achieved using established risk calculators and discussion of the risks with patients should be the order of the day, they said, with the decision depending upon the patients’ perspective and risk tolerance level. If trastuzumab-based treatment is an option, the authors stressed that regimens with the lowest risk of cardiotoxicity should be pursued (Ann. Oncol. 2011 Mar. 15 [doi:10.1093/annonc/mdq786]).
In the absence of randomized controlled trials to establish or refute the benefit from adjuvant trastuzumab in this patient subset, the authors called for the development of molecular predictors of prognosis within HER2 positive disease to further optimize risk/benefit estimates. The development of better prediction tools for more precise estimations of the risk of death from comorbid illnesses and the risk of cardiac death, in particular, are important, they said.
Level 1 Evidence Lacking
The lack of level 1 evidence from large, prospective trials contributes to the overall uncertainty surrounding the role of adjuvant chemotherapy in early HER2 breast cancer, according to Dr. Gabriel Hortobágyi, professor and chair of the department of Breast Medical Oncology at M.D. Anderson.
Studies examining the prognostic value of HER2 are limited by their reliance on retrospective database analyses and small cohort sized, Dr. Hortobágyi said in an interview. "I think it is critically important to perform a couple of larger trials with prospective collection of patients, HER2 checked centrally in a high-volume lab, and long enough follow-up to determine the real outcomes of these patients."
In this regard, the Southwest Oncology Group’s breast committee, chaired by Dr. Hortobágyi, is trying to activate a clinical trial for HER2 positive T1a and T1b patients comparing trastuzumab alone and in combination with lapatinib "to determine whether treatment with targeted chemotherapy would be effective enough for these patients." Additionally, he said investigators at Dana Farber Cancer Institute are completing recruitment to a single-arm trial for patients with small, HER2 positive breast cancer treated uniformly with paclitaxel and trastuzumab.
"Both trials will give us prospective data and should contribute significantly to our assessment of the real prognosis of this group of patients," he said.
In the meantime, Dr. Hortobágyi said that his group, and many others, "considers that risk of recurrence exceeding about 10% deserves adjuvant chemotherapy, and in the HER2 positive group we believe the risk exceeds, by far, that level. Therefore, we discuss trastuzumab and chemotherapy with all patients without significant comorbid conditions if they have any size-invasive, HER2 positive breast cancer."
The uncertainty regarding the role of adjuvant chemotherapy in early HER2 breast cancer touches on a "fascinating aspect of medicine: how to deal with and communicate uncertainty in diagnosis and treatment benefit," observed Dr. Pusztai.
"Medicine is a very imprecise science and the handling of imprecision is what makes it, as some would call it, an art," he said. "I suspect that what patients perceive as a ‘good’ vs. ‘not so good’ doctor often comes down to how efficiently one can make decisions under uncertainty of information and how effectively one communicates this uncertainty and the decision that is based on it."
Dr. Fehrenbacher, Dr. Pusztai, and Dr. Hortobágyi reported no relevant conflicts of interest with respect to the information presented.
Susan London contributed to this report.