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Best treatment for small HER-2–positive, node-negative breast cancers unknown
Although there is little direct evidence showing efficacy, trastuzumab may be the best available option.
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About 25% of breast cancers diagnosed in the United States are HER-2–positive. Research has established that the HER-2 phenotype is associated with poor DFS and OS.
Despite this increased risk, most women with HER-2–positive node-positive breast cancer and node-negative tumors larger than 1 cm have an established and effective treatment method with the use of the HER-2–targeted monoclonal antibody trastuzumab (Herceptin, Genentech) — the only FDA-approved treatment for this patient population.
However, treatment options for women with very small, early stage HER-2–positive, node-negative breast cancers are still lacking. The National Comprehensive Cancer Network does not recommend treatment with trastuzumab because of a lack of clinical evidence that the drug can effectively treat these small tumors.
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Photo by Keith Moody |
In addition, data on the risk for recurrence in these small node-negative tumors are also lacking, making treatment decisions more complicated. Data from the European Institute of Oncology and The University of Texas M.D. Anderson Cancer Center recently published in the Journal of Clinical Oncology indicated that even in these smaller tumors, HER-2 positivity may increase risk for recurrence by as much as two- to fivefold.
Therefore, physicians and their patients with small HER-2–positive, node-negative tumors must choose between the small but known risks of cardiotoxicity associated with trastuzumab vs. the unknown risk for recurrence.
The experts who spoke to HemOnc Today said clear-cut answers about the proper treatment approach for these patients are overdue.
Treatment of small tumors
“There seems to be clear consensus for treating larger tumors with chemotherapy plus anti-HER-2 therapy. Where it becomes much more controversial is in these subcentimeter tumors,” said Norah Lynn Henry, MD, PhD, assistant professor of medicine at the University of Michigan.
“When a tumor is in the T1a range, 5 mm or less, it becomes difficult to know what to do. We know from some of the studies that have come out recently that T1a and T1b tumors tend to be much more aggressive when they are HER-2–positive rather than HER-2–negative, but because there are not that many 5 mm or smaller tumors that have been studied and included in the reports, it is difficult to know how best to treat that subset.”
Studies such as N9831, BCIRG 006, NASBP B-31 and HERA, which established the efficacy of trastuzumab in HER-2–positive patients, did not specifically evaluate trastuzumab in tumors smaller than 1 cm.
Edith A. Perez, MD, director of the breast cancer program at the Mayo Clinic in Jacksonville, Fla., and a HemOnc Today Editorial Board member, said women with these very small tumors were excluded from early studies of trastuzumab, in part because of the relatively recent introduction of HER-2 testing in this population.
“We did not know how good trastuzumab was going to be, and none of us had a good database to figure out the natural history of node-negative tumors smaller than 1 cm,” Perez said. “Those data had not been captured. HER-2 testing was approved by regulatory agents in 1998, so we did not have a long track record to understand what the outcome of those patients was in order to justify using adjuvant therapy.”
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Another issue in determining proper treatment approaches is the rarity of these smaller tumors. Fewer than 10% of breast cancers are HER-2–positive, node-negative and smaller than 1 cm. Henry said it would be nearly impossible to conduct the kind of prospective, randomized study necessary to show a definitive benefit with trastuzumab in these patients.
“We are seeing patients like this in the clinic every day, and for these patients with smaller tumors, we have to extrapolate from the data that is available in the larger node-positive studies,” she said. “We have to tell them, ‘To the best of our knowledge, based on retrospective studies at single institutions, we believe you have an elevated risk for recurrence. We know based on the adjuvant trials of trastuzumab that it seems to be beneficial in HER-2–positive tumors; therefore, we think you’ll get this much benefit.’”
Risk for recurrence
The two previously mentioned studies published in the Journal of Clinical Oncology may be able to provide more information about the recurrence risk in these small, HER-2–positive, node-negative tumors.
In the study conducted by the European Institute of Oncology, Curigliano and colleagues collected information on 2,130 consecutive patients with pT1a-b, node-negative breast cancer who had surgery between January 1999 and December 2006. Researchers identified 150 patients with HER-2 gene amplification or overexpression. Of that population, 56.6% of tumors were classified as pT1a and 43.3% were classified as pT1b.
Overall, five-year DFS was longer for the HER-2–negative group compared with the HER-2–positive group in both hormone-receptor–positive (99% vs. 92%) and hormone-receptor–negative tumors (92% vs. 91%).
A univariate analysis showed that, in all patients, HER-2 overexpression was associated with a HR for recurrence of 2.4. However, in patients with hormone-receptor–positive, node-negative disease, HER-2 expression substantially worsened prognosis (HR=5.2). At multivariable analysis, which adjusted for stage in HR–positive patients, HER-2 overexpression/amplification remained associated with a worse prognosis (HR=5.1).
From these findings, the researchers concluded these tumors have a low risk of recurrence after five years, although these patients have a poorer prognosis than women with similarly sized HER-2–negative tumors.
However, results of a study by Ana M. Gonzalez-Angulo, MD, associate professor in the departments of breast medical oncology and systems biology with M.D. Anderson Cancer Center, and colleagues found that patients with these types of tumors had an increased risk of recurrence at five years (HR=2.56; 95% CI, 1.05-6.23).
“Patients who had small tumors, even though they were node-negative and 1 cm or smaller, were at higher risk for developing recurrence in the first five years,” Gonzalez-Angulo said. “What we saw was that patients with HER-2–positive tumors had about 2.6-times the risk for recurrence compared with HER-2–negative disease.”
Gonzalez-Angulo and colleagues found that five-year recurrence-free survival for patients with HER-2–negative tumors was 93.7% vs. 77.1% for HER-2–positive tumors. Distant recurrence-free survival was 97.2% for patients with HER-2–negative tumors vs. 86.4% for those with HER-2–positive tumors.
In an editorial accompanying these two studies, Harold J. Burstein, MD, and Eric P. Winer, MD, suggested that outcomes were better in the Curigliano study because a significant number of those patients were treated with adjuvant hormonal therapy or chemotherapy. Nonetheless, between the two studies, the absolute risk for recurrence after five years was between 8% and 23%.
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Together, the results infer that HER-2–positive breast cancers measuring 1 cm or less carry sufficient risk that the anticipated benefit from chemotherapy plus trastuzumab — a reduction of at least 50% in the risk of disease recurrence — is worthy of serious consideration, they wrote.
However, Burstein and Winer instead suggested that this may not always be the case. “We suggest that consideration of trastuzumab plus chemotherapy generally should be limited to patients with T1b or larger cancers and selected patients with T1a tumor. … We believe that among patients with small T1a or microinvasive cancers, it is less likely that the trade-offs of risk and benefit warrant chemotherapy plus trastuzumab,” they said.
If trastuzumab is being considered as a treatment option for women with smaller, node-negative, HER-2–positive breast cancers, Burstein and Winer suggested that a less toxic regimen be considered, particularly as part of clinical trials.
The FinHer approach
In final results from the FinHer trial, also published by Journal of Clinical Oncology, researchers showed that nine weeks of treatment with trastuzumab could reduce the risk of recurrence.
In FinHer, women with axillary node-positive or high-risk node-negative breast cancer were assigned to three cycles of fluorouracil, epirubicin and cyclophosphamide with either docetaxel (n=502) or vinorelbine (n=508) from October 2000 to September 2003. A cohort of 232 women with HER-2–positive disease were further assigned therapy with (n=116) or without trastuzumab (n=116). Patients assigned to trastuzumab received nine infusions at one-week intervals.
Researchers said 19.1% of patients assigned to trastuzumab were diagnosed with distant recurrence or died without known cancer recurrence compared with 26.7% in the non-trastuzumab group (HR=0.65; 95% CI, 0.38-1.12). Twelve patients (10.4%) treated with trastuzumab died, compared with 21 patients (18.1%) in the comparison group (HR=0.55; 95% CI, 0.27-1.11).
Gonzalez-Angulo said the results from FinHer were interesting but not definitive because the cohort was too small.
In an interview with HemOnc Today, Winer, director of the Breast Oncology Center at Dana-Farber Cancer Institute, said the results of these three studies suggest that, for some women with these very small tumors, the risk for recurrence is high enough that the toxicity of treatment, including the small risk for cardiotoxicity associated with trastuzumab, is a fair trade.
“Although randomized trials have not been done in women with these small tumors, given everything we know about women with breast cancer, the risk of recurrence will be reduced with trastuzumab and chemotherapy,” he said. “For women who have T1b tumors, trastuzumab and chemotherapy probably does make sense. For women with the smallest tumors, treatment with a combination of chemotherapy and trastuzumab needs to be considered carefully, weighing the risks and benefits. This is another one of those many situations where, ultimately, it is up to each individual doctor to find the best treatment for their patient.”
Winer is part of a team conducting the phase-2 Adjuvant Paclitaxel and Trastuzumab for Node-Negative HER-2–Positive Breast Cancer trial (ClinicalTrials.gov; identifier NCT00542451). Researchers are recruiting 400 women into the single-arm, nonrandomized trial to study the safety and efficacy of a 12-week regimen of trastuzumab and paclitaxel.
“It’s hard to be dogmatic about this issue and say that all women with very small HER-2–positive tumors should have treatment with trastuzumab,” Winer said. “At best, we can conclude that women with tumors smaller than 1 cm should have a discussion with their oncologist to determine whether it makes sense to begin treatment with trastuzumab and chemotherapy.”
Many patients with small tumors would rather deal with the known cytotoxicity of trastuzumab than the somewhat less-defined risk for recurrence, Winer said. As noted by Curigliano et al in their study, patients are often willing to accept serious side effects in exchange for a relatively small clinical benefit.
“In all adjuvant trials, the use of trastuzumab was associated with an almost 50% reduction in the risk of recurrence,” Curigliano and colleagues wrote. “In this series of patients, the follow-up was short, and additional events may have occurred with additional follow-up. Even if none were to occur, a 50% reduction in risk of disease recurrence achieved by adjuvant trastuzumab would still lead to an absolute benefit in the range of 4% to 5%. For many women and their physicians, this benefit would justify the use of adjuvant trastuzumab.”
What’s next?
Perez said that Mayo Clinic data on outcome of patients with HER-2–positive tumors less than 1 cm are expected to be published later this year.
In addition, the BETH trial, a multicenter, phase-3 study, may shed some light on the efficacy of trastuzumab for these patients. The study was designed to determine the value of adding bevacizumab (Avastin, Genentech) to chemotherapy plus trastuzumab in patients with resected node-positive or high-risk node-negative, HER-2–positive breast cancer with tumors larger than 2 cm.
The ALTTO trial is currently recruiting 8,000 women from 50 countries with HER-2–positive breast cancer. That randomized, phase-3, multi-arm trial will compare DFS for patients assigned to trastuzumab for one year vs. lapatinib (Tykerb, GlaxoSmithKline) for one year vs. trastuzumab followed by lapatinib vs. trastuzumab in combination with lapatinib for one year.
However, final results for ALTTO will not be available until 2013, and Winer said he sees nothing in the immediate future that might be more effective than trastuzumab, either alone or in combination for these patients.
“This is an area where we had initial randomized studies, but as time has gone on, we have moved beyond the patient population included in those randomized studies,” he said. “Although we don’t have the absolute highest level of evidence for these patients, it does not change the fact that it probably makes sense to talk to patients about all treatment options, including trastuzumab.” – by Jason Harris
For more information:
- Burstein HJ. J Clin Oncol. 2009;doi:10.1200/JCO.2009.24.2222.
- Curigliano G. J Clin Oncol. 2009;doi:10.1200/JCO.2009.22.0962.
- Dinh P. Nature. 2008;doi:10.1038/ncponc1219.
- Gonzelez-Angulo A. J Clin Oncol. 2009;doi:10.1200/JCO.2009.23.2025.
- Joensuu H. J Clin Oncol. 2009;doi:10.1200/JCO.2008.21.4577.
- Piccart-Gebhart MJ. N Engl J Med. 2005;353:1659-1672.
- Romond EH. N Engl J Med. 2005;353:1673-1684.
- Tovey SM. British Journal of Cancer. 2009;doi:10.1038/sj.bjc.6604940.