Locally advanced breast cancer is breast cancer that has spread to tissue near the breast, but not to parts of the body away from the breast, such as the bones or brain.
Inflammatory breast cancer is an uncommon but aggressive form of breast cancer with symptoms that include swelling, redness, and tenderness of the breast.
The study reviewed here suggests that giving Herceptin (chemical name: trastuzumab) at the same time as chemotherapy BEFORE surgery for HER2-positive locally advanced or inflammatory breast cancer can lengthen the time before the cancer comes back (recurrence) or grows (called event-free survival) compared to chemotherapy alone. Treatments given before surgery are called neoadjuvant therapies. Treatments given after surgery are called adjuvant therapies. Neoadjuvant and adjuvant therapies are used to reduce the risk of the cancer coming back or growing.
Herceptin is a targeted therapy medicine commonly used to treat HER2-positive breast cancers AFTER surgery. HER2-positive cancers have too many copies of the HER2/neu gene, which make too much of the HER2 protein. About 35% of locally advanced and 40% of inflammatory breast cancers are HER2-positive. HER2-positive breast cancers tend to be more aggressive than HER2-negative breast cancers.
In this study, called the NOAH trial, half of 235 women diagnosed with HER2-positive locally advanced or inflammatory breast cancer got standard chemotherapy before surgery. The other women got standard chemotherapy AND Herceptin before surgery. Because all the breast cancers were HER2-positive, all the women were treated with Herceptin after surgery. The women were followed for 3 or more years.
Women who got chemotherapy and Herceptin before surgery were 41% more likely to be alive without the cancer coming back or growing 3 years after surgery compared to women who got only chemotherapy before surgery.
Women who got chemotherapy and Herceptin before surgery had better overall survival compared to women who got only chemotherapy before surgery.
Still, the overall survival difference wasn't statistically significant, which means it could have been due to chance and not because of the different treatment plans.
The researchers also followed a different group of 99 women who were diagnosed with HER2-negative locally advanced or inflammatory breast cancer for 3 years. The women got chemotherapy before and after surgery, but no Herceptin because the cancer was HER2-negative. HER2-positive breast cancers are usually more aggressive than HER2-negative cancers. Still, after 3 years, the women in the study diagnosed with HER2-positive breast cancer who got Herceptin and chemotherapy before surgery had outcomes that were similar to the women diagnosed with HER2-negative breast cancer.
Most of the women who got Herceptin before surgery didn't have any serious side effects. Herceptin is given intravenously and can cause flu-like symptoms in about 40% of the people who receive it. Any side effects are usually less severe after the first treatment. Herceptin also has a 5% to 30% risk of damaging the heart's ability to pump blood. The risk of serious heart damage goes up when Herceptin is given with chemotherapy medicines known to cause heart damage, such as Adriamycin (chemical name: doxorubicin). In this study, four of the women who got Herceptin with chemotherapy before surgery had decreased heart function -- two of the women had no symptoms; the other two women got better after Herceptin treatment was done.
Herceptin is approved by the U.S. Food and Drug Administration (FDA) to treat metastatic, HER2-positive breast cancers and to lower the risk of recurrence of early-stage, HER2-positive breast cancer with a high risk of recurrence. Herceptin has not been approved by the FDA to treat locally advanced or inflammatory breast cancer before surgery. Still, based on the results of this study, using Herceptin to treat HER2-positive locally advanced or inflammatory breast cancer before surgery may make sense for many women.
If you've been diagnosed with HER2-positive locally advanced or inflammatory breast cancer, Herceptin will likely be a part of your treatment plan after surgery. You may want to talk to your doctor about this study and ask if Herceptin and chemotherapy BEFORE surgery is a good choice for you. Together, you and your doctor can decide on the best treatment plan for your unique situation.
Visit the Breastcancer.org Targeted Therapies section to learn more about Herceptin and other targeted therapies used to treat breast cancer.
The addition of trastuzumab (Herceptin) before and after surgery significantly improved event-free survival compared with neoadjuvant chemotherapy alone in women with HER2-positive locally advanced or inflammatory breast cancer, investigators in a multicenter European trial reported.
Patients treated with trastuzumab had a 40% reduction in the hazard ratio for the composite endpoint of recurrence, progression, or death from any cause.
"Although locally advanced breast cancer is relatively infrequent in affluent countries compared with nonaffluent countries, it is still an area of medical need, especially in regions of the world where diagnosis tends to occur late for cultural or economic reasons," Luca Gianni, MD, of the National Cancer Institute in Milan, Italy, and colleagues wrote in the Jan. 30 issue of The Lancet.
Neoadjuvant chemotherapy has a key role in the management of patients with locally advanced and inflammatory cancers. Anthracycline- and taxane-based regimens have produced high response rates and rates of breast-conserving surgery for patients with operable breast cancer, the authors wrote.
About 35% of locally advanced and 40% of inflammatory breast cancers are associated with HER2 amplification or overexpression. Trastuzumab, which targets HER2, has demonstrated efficacy as monotherapy and in combination with chemotherapy for patients with HER2-positive metastatic and early operable breast cancer, the authors continued.
Trastuzumab does not have specific approval for treatment of locally advanced or inflammatory breast cancer and has not been studied extensively for those indications. So the investigators designed the neoadjuvant Herceptin (NOAH) study to assess the efficacy of neoadjuvant chemotherapy plus trastuzumab followed by adjuvant trastuzumab.
The randomized trial compared the regimen versus neoadjuvant chemotherapy alone in 235 patients with newly diagnosed HER2-positive locally advanced or inflammatory breast cancer.
The investigators conducted a parallel observational study involving 99 patients with newly diagnosed HER2-negative locally advanced or inflammatory breast cancer. Those patients too were treated with chemotherapy alone, which consisted of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and 5-FU.
The primary endpoint was event-free survival, defined as the time from randomization to disease recurrence or progression or death from any cause.
After a median follow-up of 3.2 years, the three-year event-free survival was 71% in the trastuzumab arm and 56% in the patients who received chemotherapy without trastuzumab. The difference translated into an unadjusted hazard ratio of 0.59 (95% CI 0.38 to 0.90, P=0.013).
Regression analysis confirmed that treatment with trastuzumab was the only factor that significantly affected event-free survival, resulting in a hazard ratio of 0.58 compared with the chemotherapy-only arm (P=0.126).
Three-year overall survival was not significantly different between the treatment arms of HER2-positive patients but trended in favor of the trastuzumab arm (87% versus 79%). The authors noted that the 17% crossover to treatment with trastuzumab may have lessened the observed survival difference.
The HER2-negative patients had a three-year event-free survival of 67% and overall survival of 86%.
Rates and severity of noncardiac adverse events were similar in all three treatment groups, the authors reported. Fewer patients in the trastuzumab arm maintained normal left ventricular ejection fraction (LVEF) throughout the study, but most reductions in LVEF were grade 1 in severity. Two patients had grade 2 (asymptomatic) reductions in LVEF, and two had reversible grade 3 decreases.
Gianni and colleagues acknowledged that the benefit in the trastuzumab arm could have occurred as a result of both neoadjuvant and adjuvant use of trastuzumab. However, the magnitude of the benefit (HR 0.59) was greater and the number needed to treat was lower compared with adjuvant trials of trastuzumab, Melanie D. Seal, MD, and Stephen K. Chia, MD, of the British Columbia Cancer Agency in Vancouver, wrote in a commentary.
"Adjuvant studies require thousands of women to show survival benefits, at high cost and often long follow-up," Seal and Chia wrote. "Studies such as NOAH illustrate the benefits and potential of neoadjuvant trials and should challenge the dogma of our current strategies of therapeutic trials in early-stage breast cancer."
The study was supported by F. Hoffmann-La Roche.
Gianni disclosed relationships with Roche, Genentech, GlaxoSmithKline, Wyeth, Novartis, Millennium, Biogen Idec, and Eisai. Co-author Jose Baselga disclosed relationships with Exelixis, Merck, Novartis, Roche, and GlaxoSmithKline. Co-author Andrea Feyereislova is a Roche employee. Co-author Claire Barton disclosed relationships with Roche, ONO Pharma, Cellact, Acadia, Michelangelo, BTG Ltd, Kuros Biosurgery, Micromet AG, Bioenvision, Norgine, Piramed, and GlaxoSmithKline.
Primary source: The Lancet Source reference: Gianni L, et al "Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locallly advanced breast cancer (the NOAH trial): A randomzied controlled superiority trial with a parallel HER2-negative cohort" Lancet 2010; 375: 377-84.Additional source: The LancetSource reference: Seal MD, Chia SK "Challenging the dogma on trastuzumab: A matter of the heart" Lancet 2010; DOI: 10.1016/S0140-6736(09)62069-9.
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