HER2-positive breast cancers tend to be more aggressive than HER2-negative breast cancers. The studies reviewed here found that even small (1 cm or smaller), early-stage, HER2-positive breast cancers are more likely to come back (recur) and spread to parts of the body away from the breast (metastasize) than small, early-stage, HER2-negative breast cancers.
The results suggest that treating small, early-stage, HER2-positive breast cancers with the targeted therapy medicine Herceptin (chemical name: trastuzumab) may make sense.
HER2-positive cancers make too much of the HER2 protein. The HER2 protein sits on the surface of cancer cells and receives signals that encourage cancer to grow and spread. About one out of every four breast cancers is HER2-positive.
Herceptin works by attaching to the HER2 protein and blocking it from receiving growth signals. By blocking the signals, Herceptin can slow or stop the growth or spread of the cancer.
Treating HER2-positive, early-stage breast cancer with Herceptin after surgery has been shown to lower the risk of recurrence. Current treatment guidelines recommend using Herceptin only when the cancer is larger than 1 cm because the risk of recurrence is higher for cancers of that size. The guidelines do say that using Herceptin to treat smaller cancers may be considered.
In these studies, the researchers compared the outcomes of two groups of women. All the women were diagnosed with small (1 cm or smaller), early-stage breast cancer that hadn't spread to lymph nodes. One group of women was diagnosed with HER2-positive cancer and the other group with HER2-negative cancer. None of the women were treated with Herceptin.
The researchers found:
Based on these and other results, the researchers said that doctors should consider using Herceptin to treat smaller, early-stage, HER2-positive breast cancers after surgery to lower the risk of recurrence. One researcher estimated that the number of women who had a recurrence would be reduced by 4% to 5% if Herceptin were used to treat these smaller, early-stage, HER2-positive cancers.
Herceptin can cause side effects, some of them serious. It's also expensive compared to some other cancer medicines. Because of these concerns, some doctors suggest only using Herceptin to treat small, HER2-positive cancers with specific "personality" factors. One suggestion is to use Herceptin only if the cancer is 0.5 cm or larger. Another is to give Herceptin for a shorter time than is done with larger cancers: 6 months instead of 12 months, for example.
While these results are promising, the official Herceptin treatment guidelines haven't been changed. Still, using Herceptin to lower the risk of recurrence for some smaller, early-stage, HER2-positive breast cancers is currently an option that can be considered.
If you've been diagnosed with early-stage, HER2-positive breast cancer and your doctor isn't recommending Herceptin treatment, you might want to ask why. The treatment recommendation may be based on the size of the cancer and because it hasn't spread to any lymph nodes. If those are your doctor's reasons, you may want to ask your doctor about these results and whether using Herceptin after surgery might make sense for you.
Learn more about Herceptin in the Breastcancer.org Targeted Therapies section.
Small, early-stage breast cancers that are HER2-positive carry a substantial risk of recurrence and metastasis that may suggest a need for trastuzumab (Herceptin) therapy, researchers said.
For node-negative tumors of 1 cm or smaller diameter, overexpression of HER2 increased risk of recurrence two- to five-fold, with absolute five-year risks of 10% to 23% in two separate studies reported online in the Journal of Clinical Oncology.
In one study, the small HER2-positive cancers were also associated with a distant recurrence risk more than five times as high as HER-2 negative tumors, according to Ana M. Gonzalez-Angulo, MD, of the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues.
A second study, led by Giuseppe Curigliano, MD, PhD, of the Istituto Europeo di Oncologia in Milan, Italy, estimated that trastuzumab would be expected to reduce recurrence risk by an absolute 4% to 5%.
Both research groups recommended that trastuzumab be considered for these HER2-positive tumors despite their small size.
However, an accompanying editorial cautioned that this therapy should generally be limited to patients with tumors of at least 0.5 cm in diameter (stage T1b or higher), since smaller size is associated with lower risk -- even within the 1-cm-and-under tumor category.
Trastuzumab has only been directly tested in larger, higher-risk breast cancers and is recommended in consensus guidelines only for patients with tumors larger than 1.0 cm.
For tumors 0.6 to 1.0 cm, the guidelines suggest trastuzumab as an option. But for those under 0.5 cm, guidelines call for no additional therapy after surgery and radiation.
Abbreviating the course of adjuvant trastuzumab could also be considered to minimize risk of adverse events, wrote editorialists Harold J. Burstein, MD, PhD, and Eric P. Winer, MD, both of the Dana-Farber Cancer Institute and Brigham and Women's Hospital in Boston.
Given the increasing number of smaller and earlier stage tumors found with modern screening, the fine line between aggressive treatment and overtreatment is elusive, according to Jennifer Obel, MD, a spokesperson for the American Society of Clinical Oncology.
"We don't want to subject patients to the side effects and costs of unnecessary therapy," she said in a statement.
Since only one of the landmark studies of trastuzumab in early stage breast cancer included patients with small tumors, Gonzalez-Angulo's group retrospectively reviewed outcomes for 965 patients with 1 cm or smaller, node-negative, nonmetastatic breast cancers diagnosed at their institution between 1990 and 2002.
The 10% of patients with HER2-positive tumors had significantly worse recurrence-free survival at five years than patients with HER-negative tumors (77.1% versus 93.7%, P<0.0001).
For distant recurrence-free survival, HER2-positive cancers had worse five-year rates than those with HER2-negative status (86.4% versus 92.7%, P<0.0001).
Even after adjustment for hormone receptor status, age at diagnosis, T stage, and nuclear grade, HER2-positive breast cancer significantly increased risk of recurrence (hazard ratio 2.68, P=0.002) and distant recurrence (HR 5.3, P=0.0002) compared with HER2-negative tumors.
These findings were reproduced in a cohort of 350 patients from European institutions.
HER2-positive, early stage, node negative, 1-cm or smaller breast tumors again had significantly lower recurrence-free survival risk than those that were HER2-negative (87.4% versus 97.0% at five years, P=0.043). Metastasis also tended to be more common with HER2-positive status (92.3% versus 97.0%, P=0.449).
Similar findings were seen in another European cohort, the 150 consecutive patients with node-negative, 1-cm or smaller breast tumors in Curigliano's study.
The 7% of patients with HER2-positive tumors had a 2.4-fold higher risk of recurrence than HER2-negative tumors (P=0.09), with five-year disease-free survival rates of 92% versus 99% in hormone receptor positive cases and 91% versus 92% in the hormone receptor-negative cases.
After adjustment for stage, tumors that overexpressed both hormone receptors and HER2 had a significant, 5.1-fold increase in risk of recurrence (95% confidence interval 1.0 to 25.7).
"The lack of prognostic value for HER2 status in women with estrogen receptor-negative tumors is most likely caused by the high risk of disease recurrence for patients who have triple-negative tumors compared with women who have estrogen receptor-positive and HER2-negative disease," the researchers wrote.
Both research groups noted that their studies included only patients not treated with trastuzumab. The M.D. Anderson study also excluded patients who got chemotherapy.
Although both were limited by their retrospective design, randomized trials seem unrealistic at the present because of clinician and patient biases, low event rates, and the large samples that would be needed, Burstein and Winer noted.
Curigliano's group reported no conflicts of interest. Burstein and Winer reported no conflicts of interest.
Gonzalez-Angulo's study was supported in part by an award from ASCO, a grant from the National Cancer Institute, and the Nellie B. Connally Breast Cancer Research Fund. Gonzalez-Angulo's co-authors reported conflicts of interest with AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Pfizer, Roche, sanofi-aventis, Schering-Plough, Eli Lilly, and Amgen.
Primary source: Journal of Clinical Oncology Source reference: Gonzalez-Angulo AM, et al "High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2–positive, node-negative tumors 1 cm or smaller" J Clin Oncol 2009; DOI: 10.1200/JCO.2009.23.2025.Additional source: Journal of Clinical Oncology Source reference: Curigliano G, et al "Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer" J Clin Oncol 2009; DOI: 10.1200/JCO.2009.22.0962. Additional source: Burstein HJ, Winer EP "Refining therapy for human epidermal growth factor receptor 2–positive breast cancer: T stands for trastuzumab, tumor size, and treatment strategy" J Clin Oncol 2009; DOI: 10.1200/JCO.2009.24.2222. Source reference: Burstein HJ, Winer EP "Refining therapy for human epidermal growth factor receptor 2–positive breast cancer: T stands for trastuzumab, tumor size, and treatment strategy" J Clin Oncol 2009; DOI: 10.1200/JCO.2009.24.2222.
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