A study of patients with early breast cancers expressing HER2 found that treatment with just 9 weeks of adjuvant trastuzumab was of “comparable efficacy” in terms of disease-free survival (DFS), had indistinguishable overall survival (OS) curves among patients, and cut rates of cardiac toxicity by two-thirds compared to the standard regimen of treatment with trastuzumab for 1 year (Abstract 501).
Pierfranco Conte, MD, Professor of Oncology at the University of Padova and Chief of Medical Oncology at the Veneto Cancer Institute in Padova, Italy, reported these findings after 5.2 years of follow up from the multi-center phase III Italian Short-HER study that randomized 1,254 patients—typical of those in everyday cancer clinics—to 9 weeks or 1 year of adjuvant trastuzumab in combination with usual chemotherapy.
“On the basis of the observed data, we can see that the probability that the short treatment is not inferior to the long one is 78 percent,” he noted.
Conte acknowledged that 1 year of trastuzumab remained the standard of care. “But in my view after these data, clinicians must be reassured that if they have patients who have to stop trastuzumab for any reason they can be reassured that you don't lose too much of its activity.”
Conte said that making the decision to start trastuzumab in patients with cardiovascular risk factors had always been problematic because of potential cardiotoxicity. The near-equivalent efficacy of the 9-week regimen (reported in the Short-HER trial by using Bayesian statistical analysis that gauged the overlapping area of Gaussian distribution curves of the treatment effects on DFS) implied that the shorter anti-HER2 regimen was a better choice for many of these patients.
More Patients Worldwide
Globally the cost savings from implementing shorter therapy was important because it could bring trastuzumab to more of the world's patients with HER2-positive early breast cancer, Conte said. “Cancer is a global issue, not just an issue for rich countries only. Access to trastuzumab is a problem for the majority of HER2-positive patients.”
Patients with HER2-positive breast cancer were randomly assigned to usual care with standard chemotherapies—including doxorubicin, cyclophosphamide, 5-fluorouracil, and epirubicin—followed by docetaxel. Patients in the standard therapy arm then received 14 additional three-weekly courses of trastuzumab. Patients on the abbreviated course of anti-HER2 therapy were treated with regimens, including the same chemotherapy agents along with nine weekly doses of trastuzumab and then further chemotherapy.
In both arms of the study, radiation therapy was added “when indicated.” After finishing chemotherapy, patients with hormone receptor-positive disease began their hormonal therapy.
At a median follow up of 5.2 years, the 5-year DFS was 87.5 percent in patients assigned to a year of trastuzumab and 85.4 percent in those treated for only 9 weeks—giving a hazard ratio of 1.15, which was not sufficient to claim “non-inferiority” on the basis of the “frequentist” approach to statistical analysis. The Bayesian analysis, however, yielded the probability that the short treatment was not inferior of 0.78.
There was significantly less cardiac toxicity in patients assigned to the short treatment with a hazard ratio of 0.32.
Conte explained why they chose an older group of patients. “It is important to have trials that include more elderly patients, patients who might have some kind of comorbidities, and patients who are more similar to a general population of patients seen in community hospitals,” Conte stated. And he explained this recruitment had differed from previous studies of adjuvant trastuzumab therapy.
“There were three large randomized trials [in which] there were only a few patients with node-negative disease. Most of them had a higher risk of relapse. While in daily practice, we see at least 50 percent of our patients with node-negative disease and a small tumor size.”
The median age of patients in the Short-HER study was 5-7 years older than in the earlier studies. “An elderly patient means a patient at high risk of toxicity and a patient with co-morbidities,” Conte said. “So we wanted to see if a shorter treatment might be as effective and less toxic then the long [treatment] in patients at lower risk of relapse and higher risk of cardiac events.”
He noted that the adoption of 1 year as standard duration for adjuvant trastuzumab therapy had only eventually been selected empirically. “There was no special biological reason to believe that 6 months or 1 year or 2 years would be the most appropriate duration.”
Up to now, the data on OS—the second primary outcome measure—had been reassuring, he said. “We haven't seen any difference at all in overall survival. The overall survivals were completely superimposable—you cannot really discriminate between the two curves.”
Previous Conflicting Data
The discussion of the Short-HER Study at ASCO was conducted by Carey K. Anders, MD, Associate Professor for the Department of Medicine in the Division of Hematology and Oncology at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, who confirmed that 1 year of adjuvant trastuzumab had been selected as standard amid conflicting data.
“There were fewer cardiac events in the Short-[HER] arm compared to the longer arm with the majority of the excess events being grade 2 in nature,” she noted.
The decision about whether to add to the standard 1 year of adjuvant trastuzumab—discussed in other papers at the same ASCO breast cancer session, or subtract from it—as in the Short-HER study needed to be discussed in the light financial implications, said Anders.
“Based on Medicare estimates, 1 year of adjuvant trastuzumab is approximately $55,000,” she said. Her thoughts were that switching from 1 year to 9 weeks of trastuzumab would save “close to $46 000.” Adding newer targeted agents caused a jump in costs, however. “The addition of pertuzumab is in excess of $100,000 and lapatinib $40,000,” she added.
She also noted that 1 year of adjuvant trastuzumb was still the standard of care in adjuvant treatment of HER2-positive breast cancer, and she reminded her audience that it had dramatically altered outcomes with this disease.
Anders was in favor of trying the newer targeted agents in some patients. “One may consider the addition of dual anti-HER2 targeted therapy for the higher-risk patient population—those with node-positive disease and hormone receptor-negative disease.”
But she acknowledged that a shorter duration of trastuzumab “may be reasonable in select patients who can't tolerate 12 months of therapy.” And she hoped predictive biomarkers would be found.
William M. Sikov, MD, from the Comprehensive Cancer Center at Miriam Hospital, Providence, R.I., doubted whether adding costly new treatments with marginal benefits was prudent in typical clinical settings. “The problem is we don't live in Utopia where treatments don't have any financial or toxicity costs. All these are patients who do very well with standard treatment,” he stated. “To treat 100 patients with pertuzumab on top of standard treatment would cost $10 million. And since there is a 2 percent improvement, that means we are paying $5 million for each patient who does not recur.”
For Conte, however, the findings of Short-HER carried a powerful message for the practicing clinician. “The take-home message is that there is now one more option: Nine weeks instead of 1 year trastuzumab. This option is—I would say—of comparable efficacy to 1 year of trastuzumab. There is essentially no difference—particularly for patients at low [and] medium risk of relapse. And by giving less trastuzumab, you also reduce the incidence of cardiac events. High-risk patients—patients who have high numbers of positive lymph nodes—still deserve more aggressive treatment,” he concluded.
Peter M. Goodwin is a contributing writer.