Reduce Recurrence Breast Cancer Without Cardio Toxicity by Adding Herceptin (Trastuzumab) with Chemotherapy

Reduce Recurrence Breast Cancer Without Cardio Toxicity by Adding Herceptin (Tra

THE MANAGEMENT of patients with invasive breast cancer has changed substantially over the past few decades. A large proportion of such patients is now treated with breast-conserving surgery rather than mastectomy. Increasing numbers of patients (including those with histologically negative axillary lymph nodes) receive systemic therapy.

Diseases like breast cancer usually affect adult women - teen girls are unlikely to get this form of cancer. But of all the different kinds of cancer, there are some types that teens are more likely to get. Testicular cancer, for example, tends to affect younger guys rather than older men.In 2007, breast cancer is expected to cause 40,910 deaths (7% of cancer deaths; almost 2% of all deaths) in the U.S.Women in the U.S. have 1 in 8 lifetime chance of developing invasive breast cancer and a 1 in 33 chance of breast cancer causing their death.Each breast disease should be treated according to the stage of the disease in the particular breast.

The management of breast cancer continues to be one of the most controversial subjects in the field of oncology. There has been no universal consensus regarding the extent of surgery. The role of adjuvant radiotherapy is likewise highly debatable.

Adjuvant chemotherapy has been shown to prolong the disease-free interval in premenopausal patients and improve overall survival. It has been less effectiveness in postmenopausal patients. Because of the availability of hormone receptor assays and the production of anti-estrogen medications during the last decade, there is a trend to use endocrine therapy as adjuvant treatment. The use of tamoxifen in postmenopausal women with operable breast cancer has improved disease-free and overall survival.

Between 20 and 25 percent of breast cancers make too much of (overexpress) a protein called HER2, which also is made by normal breast cells. Tumors that overexpress HER2 (called HER2-positive) tend to grow faster and are more likely to come back than tumors that don’t overexpress the protein.If you are one of the 25% of women with metastatic breast cancer with tumors that have too many copies of the HER2 gene or too many HER2 receptors, Herceptin may work to slow down or stop the growth of the cancer.

The human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor (EGFR) family of transmembrane tyrosine kinases and is normally involved in the regulation of cell proliferation.The HER2 gene, located on the short arm of chromosome 17, was discovered and cloned in 1983 and found to be related to, albeit distinct from, the EGFR.

Amplification (an excess number of gene copies) or overexpression (excess production of protein) confers on the affected cancer cell aggressive behavioral traits, including enhanced growth and proliferation, increased invasive and metastatic capability, and stimulation of angiogenesis.

The Food and Drug Administration (FDA) has approved the first novel targeted therapy for use in early-stage HER2-positive breast cancers. The drug, trastuzumab (Herceptin), offers hope of a cancer-free future to the thousands of women diagnosed worldwide each year with HER2-positive breast tumors. Herceptin previously was approved only for women with advanced (metastatic) HER2-positive breast cancer.

Recently reported research found the targeted drug Herceptin given along with chemotherapy to women with HER2-positive breast cancer cut the risk of recurrence in half. Here, researchers found Herceptin may also play a role in treating HER2-postive bladder cancer.

The adverse prognosis of HER2-positive breast cancer led to the development of clinical trials to assess the efficacy and safety of trastuzumab in patients with primary breast cancer. Although there was concern about the possibility of inducing longterm cardiac dysfunction with this agent, experience in the metastatic setting suggested that cardiac dysfunction was potentially reversible.

Trastuzumab (Herceptin, Roche), a humanized monoclonal antibody against the extracellular domain of HER2, has been shown to benefit patients with HER2-positive metastatic breast cancer when administered weekly or every three weeks, alone or in combination with chemotherapy.Trastuzumab is not associated with the adverse events that typically occur with chemotherapy, such as alopecia, myelosuppression, and severe nausea and vomiting.9 With the exception of hypersensitivity, which has been seen mainly and occasionally with the first infusion, cardiotoxicity (principally congestive heart failure) is the most important adverse effect of trastuzumab. Cardiotoxicity has been reported in 1.4 percent of women who received the drug as a single agent for metastatic disease.

he chances of developing congestive heart failure as a result of using Herceptin in early-stage breast cancer treatment does not increase over time, new research finds.

When added to standard chemotherapy, Herceptin (trastuzumab) reduces the risk of breast cancer recurrence by 52 percent after three years. The compound has proven to be effective in the 20 percent to 25 percent of breast cancer cases that test positive for the HER2/neu receptor.

Trastuzumab can cause heart failure and other heart problems, especially for women with pre-existing heart conditions. Patients who take this drug need to have regular heart check-ups.

But this benefit comes at a cost: 4.1 percent of people taking Herceptin developed heart failure over a three-year period, vs. 0.8 percent of patients who only received chemotherapy.

This latest study, reported at the American Society for Clinical Oncology meeting in Chicago, found that after five years, the incidence of heart failure was 3.8 percent.

"With an additional two years of follow-up for a cumulative five years, the incidence of heart failure in the available group numbers was essentially unchanged," said Dr. Priya Rastogi, assistant director of medical affairs for the National Surgical Adjuvant Breast and Bowel Project (NSABP), which oversaw the study. "There was a substantial recovery in cardiac function in all three groups who had clinically relevant declines in heart function."

Updated results on the drug's cardiac risk over time have also resulted in a risk profile that should help determine which patients might want to steer clear of Herceptin. For instance, women who were older, used hypertensive medications and had a low normal baseline left ventricular ejection-fraction (a measure of heart function) were more likely to develop heart failure while taking the drug.

"A model of prediction of risk for heart failure was developed that could support a more individualized assessment of cardiac risk," Rastogi, an assistant professor of medicine at the University of Pittsburgh Cancer Institute, said. "The choice of trastuzumab-containing regimens should be based on an individualized assessment of risk and benefit in women with HER2-positive breast cancer. We want to make this an easy formula for physicians to use. We're in the process of doing that."

In other good news out of the meeting for women with early-stage breast cancer, a British study found that delivering fewer but larger doses of radiation to women with early breast cancer is as effective as the conventional schedule of 25 doses in reducing the risk of recurrence, even though the total dose of radiation was lower.

"It's likely that patients can be effectively and safely treated to a lower total dose with fewer larger fractions [doses] than the current standard," said study author Dr. John Dewar, a clinical oncologist at the University of Dundee in Scotland. "This should encourage further studies and will help radiation oncologists individualize patients." Those further studies need to determine if recurrence rates stay low over time.

The main benefit of the approach, called hypofractionation, is that it is easier on the patient. It also resulted in fewer adverse changes in the appearance of patients' breasts.

"This is very exciting news for patients, as radiation is very disruptive to life," said Dr. Julie Gralow, the moderator of a news conference on the new research and an assistant oncology professor at the University of Washington in Seattle. "If we could achieve the same outcome with fewer trips to the radiation center, this would be a tremendous benefit for patients."

Another study presented at the meeting found magnetic resonance imaging (MRI) was better than mammography for detecting "high-grade" ductal carcinoma in situ (DCIS), a form of pre-invasive breast cancer. These lesions are most likely to progress to aggressive invasive cancer, and therefore need to be diagnosed early.

"High-grade DCIS is easily curable by resection, but, if left untreated, will progress to high-grade invasive cancer," said study author Dr. Christiane K. Kuhl, vice chairman and a radiology professor at the University of Bonn in Germany.

Forty percent of DCIS lesions were only found by MRI, and 78 percent of those were high grade, according to the study. On mammography, only 8 percent of DCIS were visible, and all but one were low grade.

The question is how quickly MRIs will be used for regular screening, or if they will be used at all. MRIs are routine in Germany, where the study was conducted, but not in the United States.

"MRI is a great tool when used in the right hands, but we don't have quality control anywhere in the world for MRI as we do for screening mammography," Gralow noted. "We hope soon to have a partial rectification of this, as the American College of Radiology is starting a voluntary accreditation program in the U.S. for breast MRI. At that point, it will be fair to say that programs that choose to undergo this accreditation are doing breast MRI in a similar manner. All breast MRIs are not the same. We need to have standards and reproducibility."

Mammography has been found to be a useful procedure for early detection in elderly women but is not economically feasible as a means of mass screening in this Region, particularly because about two thirds of breast cancer patients in the EMR are premenopausal. Thus public and professional education is needed for early detection.

Women at high risk for breast cancer should have an MRI scan along with their annual mammogram, according to new guidelines from the American Cancer Society.

Guidelines from the American College of Physicians recommend women with a low risk for breast cancer talk to their doctor before starting to have mammogram screening at age 40.

Kuhl added, "Our study proves that MRI is better. Whether we use MRI or mammogram is more a question of finances and availability than a medical question."

But there are other issues not considered in this study, said Dr. Stephen Sener, past president of the American Cancer Society. "The issue of whether MRI improves survival is not answered yet," he said.

There is also a high rate of false-positive results, he added, which can drive up costs as women go for additional tests.

A study of total of 392 patients with advanced, HER2-positive breast cancer were enrolled in this international phase III clinical trial. All of the patients had disease that had begun to progress after treatment with trastuzumab. Patients were randomly assigned to receive either the drug capecitabine alone or capecitabine in combination with lapatinib.

Researchers found 70 percent of patients responded to the chemotherapy and Herceptin treatment and saw their tumors shrink. Only 7 percent saw their cancer progress, or worsen. Patients lived an average of 15 months, comparable to overall survival rates for advanced bladder cancer. But, Hussain points out, the patients participating in this study had a more aggressive disease.

Breast tissue can be tested for HER2, and routine testing is recommended for most women with breast cancer because the results may affect treatment recommendations and decisions. Whenever breast cancer recurs or spreads, the cancer cells should be tested for HER2.

The good news is that women are living longer with breast cancer, and at this time more than 2 million American women are survivors. Survivors must live with the uncertainties of possible recurrent cancer and some risk for complications from the treatment itself.

Recurrences of cancer usually develop within 5 years of treatment. However, 25% of recurrences and half of new cancers in the opposite breast occur after 5 years. One study suggested that the risk factors for a first breast cancer do not necessarily place a woman at any higher risk for recurrence.


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