Breast Cancer Prevention, Breast Cancer Treatment, Cancer News : Info Centre

Radiation Benefit for Breast Cancer Shown-(Washington Post- 16/12/2005)

The radiation treatments that millions of patients with early-stage breast cancer receive significantly reduce their chances of dying from the disease, according to a large international study that for the first time documents that the therapy saves lives. The analysis of data collected from more than 42,000 women with early breast cancer worldwide found that those who underwent radiation after having a lumpectomy and mastectomy were about 5 percent less likely to die from the disease over the next 15 years. Although previous studies have found that radiation reduces the risk of a recurrence, some women still do not have the treatment because of possible side effects and lingering doubt about whether that relapse reduction translates into a reduced risk of dying from the disease. The new findings -- from the largest and most authoritative examination of that question -- should dispel any remaining uncertainty, the researchers said.

"There's been a lot of questions about this. We've, for the first time, shown very clearly that there is a benefit," said Sarah Darby of Oxford University in England, who led the analysis being published in tomorrow's issue of the journal the Lancet. "The message for women is that if their doctors are offering them radiotherapy, they should consider it very seriously. It does save lives." The findings should also reassure those who have had the treatment that the risks were worthwhile, the researchers said, and women who recently opted against the treatment may want to have it now.

"It might be worth considering . . . for some women who, within just the last year or two, have had lumpectomy for breast cancer or who have had mastectomy for cancer that had spread to the armpit and who didn't get radiotherapy after their surgery because of the side effects," Darby said. Breast cancer is diagnosed in more than 211,000 U.S. women each year, killing more than 40,000. It is the most common cancer among women and the second-leading cancer killer, after lung cancer.

Doctors recommend that women whose tumors are detected early and are removed through a lumpectomy have the affected breast radiated to kill any remaining cancer cells. In addition, many women who have had a breast removed and whose cancer has spread to their lymph nodes are offered radiation. But some patients do not have the follow-up treatment, often because of fears of side effects, including swollen arms and increased risk of heart attack and other cancers later.

The new study was conducted by the Early Breast Cancer Trialists' Collaborative Group, based at Oxford, which has been assessing the effectiveness of treatments. In May, the group reported the first data demonstrating that chemotherapy and hormone treatment had dramatically reduced the death rate from early breast cancer.

In the new analysis, the group analyzed data from all 78 studies involving radiation treatment for early breast cancer conducted worldwide through 1995, which included data from 42,080 women. "This is reassuring," said Susan Love, a breast cancer expert at UCLA. "This confirms the benefits of radiation." In addition to a reduced risk of recurrence in the first five years after treatment, the study found the risk of dying from breast cancer was 30.9 percent among those who received radiation, compared with 35.9 percent among those who did not -- the first demonstration that the treatment lowers the mortality risk.

Women who received radiation were also less likely to die for any reason, showing that any increased risk was outweighed by the reduced risk of dying from breast cancer, Darby said. For women who underwent a mastectomy but whose cancer had spread to the lymph nodes under their arms, the 15-year breast cancer mortality risk was 54.7 percent with radiation vs. 60.1 percent without -- a reduction of 5.4 percentage points, the researchers found. There was a similar reduction in overall death risk. Radiation was previously shown to reduce the breast cancer mortality rate, but the new study is the first to show a decrease in overall mortality, Darby said.

For years, doctors have known exactly what to do with breast cancer patients like Eva Ossorio: Poison them. Blasting women with toxic chemicals was considered the best way to save their lives. The bigger the cancer or the more it had spread, the more vile liquid doctors pumped into their veins to try to kill it. But there's been a sea change in the last year. Guidelines recently adopted in Europe and similar ones unveiled this weekend at a conference in Texas will result in far fewer women getting chemotherapy in the future.

The new advice calls for choosing a treatment based on each woman's particular type of tumor. "In the past, we made all decisions based on how big the tumor was and whether the lymph nodes were involved. If you had a lot of cancer, you got treated one way, and if you had a little cancer, you got treated another way," said Dr. Eric Winer of the Dana-Farber Cancer Center in Boston.

Under the new rules, hormone status — whether a tumor's growth depends on estrogen or progesterone — becomes the single most important factor in picking treatment. That is why Ossorio, a 62-year-old nurse in San Antonio, last week was started on a hormone blocker rather than the chemo she formerly would have been given for her relatively large tumor. She was relieved. "I don't care if I die tomorrow. I decided I didn't want chemotherapy," she said.

Women have reason to dread it. Chemo is a sledgehammer, killing all rapidly dividing cells whether they are out-of-control cancerous ones or healthy ones that naturally grow quickly, like those lining the mouth and stomach. That's why chemo causes hair loss, nausea and mouth sores. But the worst part is, it only helps about 15% of those who get it after the usual surgery to remove their tumors. Roughly 25% get worse despite chemo. A whopping 60% would have been fine with hormones alone.

"For the vast majority of patients, we probably overtreat," said Dr. William Gradishar of Northwestern University in Chicago. "It's not that chemotherapy is not of value, it's that the value is smaller in women with hormone-driven disease," said Dr. Robert Carlson, a Stanford University physician who led the U.S. guideline-writing group. "We're trying to determine if the benefit is so small that we should not be recommending chemotherapy."

Several developments in recent years help doctors pick who really needs it. First is the realization that breast cancers have different causes, arise from different types of cells, are driven by different genes, and tend to be different in women before or after menopause. "Breast cancer must be understood as an umbrella of diseases," said Dr. Antonio Wolff of Johns Hopkins Medical Institute in Baltimore.

For example, three-fourths of postmenopausal women have tumors fueled by estrogen, called ER-positive disease. Drugs that block this hormone, like tamoxifen and a newer class of medications called aromatase inhibitors, work against those cancers — whether they have spread to lymph nodes or not. On the other hand, women before menopause often have tumors that are ER-negative and orchestrated by bad genes. Hormones don't help in that case; these women benefit most from chemotherapy. If hormone drugs are ball-peen hammers compared to chemotherapy, a medication like Herceptin is an even more refined tool. It targets the one-fourth of breast cancers that have too much of a protein on cell surfaces called HER-2 and leaves healthy cells alone.

A woman's HER-2 status is the next factor doctors will consider, after hormone status, in choosing treatments under the new guidelines. You can see the possibilities: half of HER-2 tumors are ER-positive, but only 10% of ER-positive tumors are HER-2-negative. These aren't black-and-white distinctions, either. Tumors can be weakly ER-positive or negative; same thing for HER-2. New high-tech lab tests help doctors sort it out. They measure the activity of dozens of genes and reveal which ones are most active and what treatments would work best. One such test, Oncotype DX, has found its way into more and more doctors' offices since presentations at the Texas cancer meeting last year showed its ability to predict which women benefit from tamoxifen and which do best on chemo.

Ossorio's doctor ordered the test because she thought it would convince Ossorio to have chemo. Surprisingly, it revealed chemo was very unlikely to help. The test is expensive — $3,400 — but many insurers cover it because it often prevents even more costly and unnecessary chemo, as it did for Ossorio. Dr. Larry Norton, breast cancer chief at Memorial Sloan-Kettering Cancer Center in New York, uses it when situations are complex and treatment choices aren't obvious. He compares it to lab tests that pinpoint a germ so the right antibiotic can be prescribed. "In the old days, people just said 'pneumonia.' Now we say 'what organism?' and that lets us identify how to treat the disease," he said. But relying on factors like hormone and HER-2 status makes the accuracy of lab tests a life-or-death matter. Doctors warn about the wide variation in the quality of such tests, whether low- or high-tech. "The right (test) is the one that is done right," not which type of test is chosen, Wolff told doctors at the Texas meeting who had come to learn about the U.S. guidelines. The new guidance was developed by the National Comprehensive Cancer Network, a group of leading cancer treatment centers, in cooperation with the American Cancer Society.

Breast cancer trials set for second phase-(Staff Writer- 9/12/2005)

Dr. Debu Tripathy is gearing up for the second phase of clinical trials on a new drug to treat advanced breast cancer. The trials will start in January and are expected to receive between $5 million and $10 million in funding. Much of that money will go to Tripathy and the University of Texas Southwestern Medical Center at Dallas, where Tripathy is a professor of internal medicine and director of the Komen/UT Southwestern Breast Cancer Research Program . Also participating in the trial and receiving funding are the University of California at San Francisco, the University of California at Berkeley and the University of Colorado Health Sciences Center. Ultimately, up to 10 institutions could participate in the trials, but the others have not yet been selected.

Tripathy is a principal investigator of a new oral drug for advanced-stage breast cancer called BZL101. The drug uses botanical extracts -- a growing field in medicine. It works by targeting diseased cells but not disturbing the healthy cells that often are destroyed by current cancer treatments. The trials likely will last about 18 months, and the data will be analyzed for about a year after that, Tripathy said. Getting approval for the drug from the U.S. Food and Drug Administration could be three to four years from now if all proceeds as planned.

The first phase of clinical trials of BZL was funded by $1 million from Emeryville, Calif.-based Bionovo Inc. and the California Breast Cancer Research Fund. Bionovo is funding the second phase of clinical trials of BZL 101 using venture capital dollars. Dr. James Willson said Tripathy's work reflects a growing trend in research. "He is bridging the gap between scientific discovery and applying that discovery to impact on patients," said Willson, director of the Simmons Comprehensive Cancer Center at UT Southwestern. "It is a high priority for development and major investments are being made to realize this."

Adjuvant Trastuzumab (Herceptin®) Combined with Chemotherapy Increases Disease-free Survival and Overall Survival for Women with HER2-Positive Early Breast Cancer. Data published in the Oct. 20, 2005, online edition of The New England Journal of Medicine show significant and clinically important improvements in disease-free survival and overall survival for women with HER2 positive early breast cancer who were given trastuzumab (Herceptin®) in combination with adjuvant chemotherapy. These data were derived from two randomized, prospective Phase III clinical trials that involved 3,351 women. In April 2005, the trials were stopped early after their first interim data analyses showed better-than-expected results for groups getting trastuzumab.

The studies
Trastuzumab is a "targeted" treatment, meaning it is designed to attack specific cancer cells. It is a monoclonal antibody that targets the HER2 protein, which is overexpressed in approximately 25 percent of breast cancers. Trastuzumab has not been shown to be effective in women with HER2-negative tumors.

The trials, NSABP B-31 and NCCTG N-9831 began enrolling patients in 2000. Although the trials were conducted independently of one another, both looked at the use of trastuzumab in combination with chemotherapy in early-stage node positive or high-risk node negative breast cancer. The basic design for each trial was:

NSABP B-31

Control arm/Group 1: Four cycles of doxorubicin (Adriamycin®) and cyclophosphamide (Cytoxan®) (AC) followed by four cycles of paclitaxel (Taxol®)

Experimental arm/Group 2: Same chemotherapy as control arm plus 52 weeks of trastuzumab beginning at the start of the paclitaxel chemotherapy
NCCTG N-9831

Control arm/Group A: Four cycles of doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel for 12 weeks

Experimental arms:
Group B: Four cycles of AC followed by 52 weeks of trastuzumab after the completion of paclitaxel therapy. Group C: Four cycles of AC followed by 52 weeks of trastuzumab beginning at the start of the paclitaxel therapy. Because the trials had similar designs, the National Cancer Institute and the Food and Drug Administration took an unprecedented step and approved a combined data analysis from the B-31 and the N-9831 trials. In this analysis, data from B-31's Group 1 and N-9831's Group A were combined to serve as the control arm. Data from B-31's Group 2 and N-9831's Group C combined to become the experimental arm.

After an average follow-up of 2.4 years for the B-31 study and 1.5 years for N-9831, these results have been reported from the combined data analysis: The relative risk of recurrence was reduced by 52 percent among women getting chemotherapy with trastuzumab compared with those getting chemotherapy alone. The risk reduction was unrelated to age, hormone-receptor status, tumor size and lymph node involvement. The absolute difference in disease-free survival between the two groups was 12 percent at three years from randomization and 18 percent at four years - in favor of those getting trastuzumab plus chemotherapy. Trastuzumab with chemotherapy compared with chemotherapy alone produced an absolute difference in distant disease-free survival of 9 percent at three years after randomization and 16 percent after four years.

In the combined analysis, a 33 percent increase in overall survival was reported among women getting the combination therapy. The absolute difference in number of deaths between the trastuzumab-containing regimens and the control groups was 2 percent at three years and 4 percent after four years. More time will be needed to determine whether these early differences hold steady, increase or decrease. A 3-4 percent absolute increase in the rate of "cardiac dysfunction" was reported for the women getting the AC followed by paclitaxel and trastuzumab treatment compared with those getting AC followed by paclitaxel without trastuzumab. The incidence of isolated brain metastasis as first event was higher in the trastuzumab group. However, the imbalance is attributed to earlier failure at other organ sites among patients in the control group.

NBCCF is impressed by the efficacy results reported in these trials, which have demonstrated the value of combining trastuzumab with chemotherapy for early breast cancers that are HER2-positive. However, while the studies show substantive improvements in recurrence-free survival and in overall survival among those who were treated with the trastuzumab, it is premature and irresponsible to call this a "cure" for breast cancer. Long-term follow-up of study participants is necessary to fully assess the impact of trastuzumab on breast cancer in this population. In addition, we have the following concerns:

Safety: The combination of trastuzumab with AC followed by paclitaxel produces a substantial risk of cardiac toxicity. While it may prove that the breast cancer benefit outweighs the cardiac risk in this adjuvant application of trastuzumab, it is also clear that, because of this risk, trastuzumab must not be used in the adjuvant setting without very vigorous monitoring. Moreover, we are not convinced that such increased cardiac risk needs to be accepted. In fact, data released after the first interim analysis of BCIRG 006, a trial in which NBCC is collaborating, showed that patients who were given trastuzumab with a different chemotherapy combination (docetaxel and carboplatin 1) obtained a comparable benefit to that obtained when trastuzumab is given in combination with AC and docetaxel (Taxotere®), but without added toxicity to the heart. (See NBCCF analysis of BCIRG 006 trial.) We eagerly await publication of these data.

Early stopping: When clinical trials are stopped early, important information about the long-term effects of the treatments involved may be unknown for many more years - even beyond the originally planned duration of the trial. And, in that time, more women are exposed to the treatment. While investigators in these studies plan to continue monitoring patients' progress, the loss of the control arm of the study due to crossover will make full assessment of any long-term toxicities of adjuvant use of trastuzumab much less feasible. If women are advised on the basis of these studies to consider these treatments, they will be doing so without the benefit of much of the data that prospective randomized clinical trials are designed to provide. (See NBCCF fact sheet Early Stopping of Clinical Trials.)

The National Breast Cancer Coalition Fund is a grassroots organization dedicated to ending breast cancer through the power of action and advocacy. NBCCF's main goals are to increase federal funding for breast cancer research and collaborate with the scientific community to implement new models of research, improve access to high-quality health care and breast cancer clinical trials for all women and expand the influence of breast cancer advocates in all aspects of the breast cancer decisionmaking process.

The BCIRG 006 trial has three arms: AC followed by docetaxel, AC followed by docetaxel and trastuzumab, and docetaxel with platinum salts (TCH) with trastuzumab.

Added Illnesses May Explain Breast Cancer 'Race Gap'- (HealthDay- 11/10/2007)

Researchers are unraveling the mystery of why black women stricken with breast cancer often have shorter survival times than white women diagnosed with the disease. According to a new study, black patients are more likely than whites to have other disorders such as high blood pressure and diabetes, and those disorders may help explain their poorer survival, said researcher David Nerenz, acting director of the Center for Health Services Research at the Henry Ford Health System, in Detroit. "For the past 10 or 15 years, researchers have known that black patients do worse with breast cancer when it comes to survival," Nerenz said. Several reasons have been identified, he said, such as a lower socioeconomic status, a lack of access to medical care and inferior treatment.

In their study, the researchers tracked the 10-year post-diagnosis outcomes of more than 900 breast cancer patients -- 264 of whom were black and 642 of whom were white.They found that nearly 62 percent of black patients died during the follow-up period, compared to 50 percent of whites, and that more black patients than whites died of breast cancer -- nearly 25 percent compared to just over 18 percent of whites. The researchers also collected information on the presence of other health problems such as diabetes, high blood pressure, respiratory problems and other ailments. They found that, on average, black patients had about 2.5 additional illnesses, while white patients experienced two additional health problems. Overall, about 86 percent of black patients faced at least one health problem besides breast cancer, compared to around 66 percent of whites. In all, 37 percent of blacks died from non-breast cancer causes compared to 32 percent of whites.

Compared with white patients, black patients had shorter overall survival, breast cancer survival and other-causes survival, the researchers found. "The presence of other health problems accounted for most of the difference in deaths between African-Americans and whites," said Nerenz. "African-Americans were more likely to die of something else other than breast cancer, but also from breast cancer." "The study is a reminder to us that even with the diagnosis of breast cancer, women are whole human beings and they continue to have other health problems. It's important for us not to lose sight of other health conditions and focus only on the breast cancer," he said. "They are able to look specifically at the effects of other health problems on survival," she said. "Few studies have done this because such information is difficult to get." However, she worried that the study's' focus on deaths due to illnesses besides breast cancer will take the spotlight away from the early detection and treatment of breast malignancies. "It therefore remains very important to continue to research the gap between black women and white women with respect to breast cancer treatment and survival," Ward said.

Another expert, Dr. Nancy Keating, an assistant professor of medicine and health care policy at Harvard Medical School, called the new report an important study. "We have long known that there are racial differences in breast cancer survival that aren't explained by the racial differences in stage at diagnosis and treatment," she said. "The study measured numerous comorbid [accompanying] illnesses, including many that are typically not captured in other studies of breast cancer care, and found that these comorbid illnesses help to explain differences in survival. "Studies examining cancer patients' survival should include information about comorbidity," she said.

FDA Issues Warning on Breast Cancer Drug By Amanda Gardner
(HealthDay News-31/08/2005)

Federal health authorities today issued a warning about the potential heart problems associated with use of the breast cancer drug Herceptin. While experts had already known of the potential problems, the warning, along with a letter from Genentech, the drug's maker, constitutes a more formal acknowledgement of the issue. "Herceptin is known to have adverse effects on the heart in a certain number of patients. That information in itself is not new," said Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society in Atlanta. "I suspect that many oncologists who were using the drug were already aware of it, but it is still nonetheless important that this be put into some more formal language and process."

The U.S. Food and Drug Administration reported in their warning that in a randomized phase III trial, women taking Herceptin were at more than triple the risk of congestive heart failure and cardiac death than women receiving chemotherapy alone. The absolute numbers were still low, however, with 4.1 percent of women in the Herceptin arm experiencing heart problems versus only 0.8 percent in the other arm. The FDA warning went on to say that there were no cardiac deaths in patients in the Herceptin-only arm, whereas there was one cardiac death in the control arm. This apparently means that most of the problems seen were congestive heart failure. Lichtenfeld said it was unlikely that this news would change the status of Herceptin, which, in recent months, had been emerging as a major weapon in the fight against HER-2 positive breast cancers. "This will do nothing to change people's decisions about using the drug," he said. "This is information that was readily available, and doctors are already aware of it."

HER-2 positive breast cancers produce too much of the HER-2 protein, which stands for human epidermal growth factor receptor 2 and is found on the surface of the cells. These tumors tend to grow faster and are more likely to recur than tumors that are HER-2 negative. About 40,000 to 50,000 of the 200,000 women who develop breast cancer annually in the United States have HER-2 positive tumors. Herceptin was approved in 1998 to treat metastatic breast cancer. Earlier this year, two trials of the drug in women with early-stage breast cancer showed such promising results that they were halted early.

In these cases, patients with early stage HER-2 positive breast cancer who were given Herceptin in combination with chemotherapy had a 52 percent decrease in their risk for a recurrence compared with patients who received chemotherapy without the drug. Herceptin, also known as trastuzumab, is a targeted therapeutic antibody, meaning it has a specific mechanism of action, and is already approved for metastatic breast cancer. The current warning concerned women with early-stage breast cancer, meaning that the FDA is effectively issuing a warning on an off-label usage of a drug. No matter what the usage, experts pointed out, treatment decisions always need to involve weighing the risks and benefits.

"Everything is relative to the condition that you're treating," Lichtenfeld said. "This is a situation that can be life-threatening for a substantial number of women. The use of Herceptin in that situation reduces the chance of recurrence significantly. It's also appropriate, given the degree of adverse heart-related events, that doctors make patients aware of the risks. Herceptin has a significant chance of reducing the risk of recurrence, but it does come at a cost." "This is a clarity issue, an acknowledgement that the extent of the problem was really nothing to be ignored. It's not an inconsequential event, it's not uncommon event for that matter," added Dr. Stephen Malamud, an attending physician at the Beth Israel Medical Center in New York City. "Herceptin has become now almost a routine drug. The issue is going to be that these patients should be looked at and monitored for the development of cardiac events, and we don't know what the long-term ramifications are going to be."

Type of Benign Breast Disease and Family History Influence Subsequent Risk of Breast Cancer-(Susan Komen Foundation-07/22/2005)

Among women with benign breast disease, subsequent risk of breast cancer varies by type of benign breast disease and by family history of breast cancer, according to a study in the New England Journal of Medicine. Benign breast disease refers to several types of noncancerous changes in breast tissue. Benign breast disease is often categorized as nonproliferative (a category which includes breast cysts), proliferative without atypia (an overgrowth of cells in the breast without the presence of cells which look abnormal) and atypical hyperplasia (a condition with certain abnormal features). Women with proliferative breast disease without atypia and those with atypical hyperplasia have been found to be more likely to develop breast cancer than women without these conditions. The extent to which nonproliferative breast conditions increase the risk of breast cancer is still uncertain. It’s also unclear whether family history of breast cancer affects the likelihood that a woman with benign breast disease will develop breast cancer.

The study evaluated 9087 women who were diagnosed with benign breast disease at the Mayo Clinic between 1967 and 1991. Sixty-seven percent of the women had non-proliferative breast disease, 30 percent had proliferative breast disease without atypia and four percent had atypical hyperplasia. The women were followed for a median of 15 years after their diagnosis of benign breast disease. The researchers compared the number of breast cancers that developed among the women with benign breast disease to the number of breast cancers that would be expected to occur among women in the general population.

During follow-up, 707 of the 9087 women with benign breast disease were diagnosed with breast cancer; this is significantly more than the 453 breast cancers that would be expected to occur in the general population. Risk of breast cancer varied across the categories of benign breast disease. Compared to an expected five cases of breast cancer per 100 women in the general population, breast cancer occurred in six per 100 women with nonproliferative conditions, 10 per 100 women with proliferative conditions without atypia, and 19 per 100 women with atypia. Having a family history of breast cancer also increased the risk of breast cancer. Furthermore, among women with nonproliferative conditions, risk of breast cancer was increased only among women with a strong family history of breast cancer. Among women with other types of benign breast disease, risk of breast cancer was increased whether or not the woman had a family history of breast cancer. The authors conclude that type of benign breast disease and family history of breast cancer play an important role in determining the breast cancer risk of a woman with benign breast disease.

Traces of malignant cells in the bone marrow of newly diagnosed breast cancer patients are a significant indicator of a poor prognosis, researchers report. They add that this "micrometastasis" could be used to monitor the extent of the cancer and also to evaluate the success of chemotherapy. "The presence of tumor cells in the bone marrow of breast cancer patients is a poor sign for patients," said lead author Dr. Stephan Braun, a professor of obstetrics and gynecology at Innsbruck Medical University in Austria. In addition, using this marker will change the design of clinical trials, Braun said. Their report appears in the Aug. 25 issue of the New England Journal of Medicine. In their study, Braun and his colleagues collected data on more than 4,700 women with invasive breast cancer from nine other studies. They evaluated patient outcomes over a period of 10 years.

The researchers found micrometastasis in 30.6 percent of the patients. Women who had signs of cancer cells in their bone marrow had significantly poorer outcomes over the follow-up period compared with women who did not, Braun's team found. Outcomes were poorer in terms of both disease-free survival and overall mortality. "The next step will be to design clinical trials to demonstrate that this marker is valuable," Braun said. "The marker is a way to see if the tumor has responded to chemotherapy, or if chemotherapy is needed." Braun noted that right now 90 percent of breast cancer patients are given chemotherapy. But only 25 percent may actually need chemotherapy, since 75 percent are cured by surgery alone, he said. "Actually, it's an over-treatment of at least 60 percent of the patients, given that we have identified, more or less by chance, those patients who need chemotherapy," Braun said. Moreover, Braun believes that this marker may identify patients who need chemotherapy after surgery, and it also provides a way to see whether chemotherapy has been successful. "This marker can be used to identify patients at risk and to see if tumor cells are cleared or not after chemotherapy," Braun said. "In addition, if the tumor cells are cleared after chemotherapy, we believe we have successfully treated patients."

One expert is skeptical of the value of using micrometastasis as a marker for deciding how to treat patients, however. "Knowing that someone has a worse prognosis is valuable primarily if it results in a change of therapy to improve prognosis," said Dr. George W. Sledge, a professor of medicine, pathology and oncology at Indiana University. "Since we offer adjuvant therapy (chemotherapy or hormonal therapy) to most patients with tumors bigger than one centimeter, I'm not sure how this helps. The other potential means by which an indicator of bad prognosis might be of potential help would be if it eliminated certain patients from needing therapy. I'm not at all certain that this test accomplishes this either," he added.

Researchers to investigate links between insulin, vitamin D and breast cancer-(Yahoo News 25/07/2005)

Five research groups from across Canada will get $2.9 million in funding to investigate the roles of insulin and vitamin D in breast cancer risk. Although osteoporosis and diabetes have most often been considered the main diseases associated with vitamin D deficiency and insulin control in women, there are indications from the medical community that there is also a possible link to breast cancer risk. "Recent data suggest that, particularly in northern countries such as Canada, lower than required levels of vitamin D in many women may increase breast cancer risk - and confirmation of this would suggest interesting and novel approaches for risk reduction," Dr. Michael Pollak, an oncology expert with McGill University, said in a news release.

The five groups will examine thousands of breast cancer specimens and take a variety of approaches to the topic. Among the areas the groups will examine are the role of supplements, the implications of insulin resistance and an exploration of new drug treatments. "As an oncologist who treats breast cancer patients, I am reminded every day of the need to improve current prevention and treatment methods," said Pollak. He will collaborate with Laval University's Jacques Brisson, Sandra Dunn from the University of British Columbia, Ivan Fantus from Toronto's Mount Sinai Hospital and McGill University's Nahum Sonenberg. The funding comes from the Canadian Breast Cancer Research Alliance, in conjunction with the Canadian Institutes of Health Research.

The project was selected for funding on the recommendation of a specially convened panel of international scientists with broad knowledge and expertise in the proposed areas of study. The Canadian Breast Cancer Research Alliance is the primary granting agency for breast cancer research in Canada. It was founded in 1993, and has so far awarded $138 million to support 399 research grants.

A new study should help women who have benign breast biopsies understand their cancer risk. As mammography use increases, so does the frequency of breast biopsies, which usually are benign, or cancer-free, the authors write today in The New England Journal of Medicine. Each year, they say, more than 1 million U.S. women have benign breast biopsies. The new study focused on 9,087 women 18 to 85 who had a benign breast biopsy at the Mayo Clinic in Rochester, Minn., from 1967 through 1991. During 15 years' follow-up on average, 707 were diagnosed with breast cancer.

A breast pathologist who did not know the original findings or the women's current health classified stored slices of their biopsies into one of three categories: non-proliferative (no cell overgrowth), proliferative (overgrowth of normal cells) and atypical (overgrowth of abnormal cells). Scientists also asked the women about their family history of breast cancer. About two-thirds of the biopsies contained non-proliferative changes, while 30% had an overgrowth of normal cells and 4% had an overgrowth of abnormal cells. Women with non-proliferative changes such as a cyst did not have an increased breast cancer risk as long as they did not have a strong family history.

If they did have a strong family history, they were about 60% more likely to be diagnosed with the disease than women in the general population. Strong family history was defined as having a first-degree relative — mother, sister or daughter — diagnosed before age 50 or at least two affected relatives, with at least one a first-degree relative.

Among women with an overgrowth of normal cells, those without a strong family history also were about 60% more likely to be diagnosed with breast cancer than women in the general population. If they had a strong family history, their breast cancer risk was about twice that of the general population. Family history did not significantly affect breast cancer risk in women whose biopsies contained abnormal cells. Overall, they were about 300% more likely to be diagnosed with the disease than women in the general population.

An accompanying editorial points out the need to explain that these risk levels translate into relatively few cancer cases. In the study, about five out of 100 women in the general population developed breast cancer within 15 years, write editorial authors Joann Elmore of the University of Washington and Gerd Gigerenzer of Berlin's Max Planck Institute. So doubling the risk raises the number of cases to 10 out of 100.

What should women at increased risk do? They could take tamoxifen, shown to reduce the risk of a breast cancer diagnosis, or enter a study of another drug or a screening tool, says Mayo cancer doctor Lynn Hartmann, lead study author. Vanderbilt University cancer pathologist David Page, who published similar findings in 1985, says his advice to higher-risk women — "because we don't know to do anything better" — has been to get regular mammograms.

A study shows that men with breast cancer are not at increased risk for relapse after mastectomy compared to women with breast cancer and therefore should be treated using the same guidelines as women. Yes, men do develop breast cancer, but it is fairly rare. In most countries, about 1 of every 100 cases of breast cancer occur in men. In women with breast cancer, post-mastectomy radiation is guided by specific indications such as tumor size. But in men with breast cancer, radiation is routinely given after mastectomy because the smaller male breast makes it harder for surgeons to leave a clear margin of healthy tissue when they remove the cancer, so men are thought to be at increased risk for cancer recurrence in the breast area.

The outcome of the current study "challenges the idea that males with breast cancer should be treated with more aggressive local therapy purely on the basis of sex," Dr. Graham Macdonald told Reuters Health. Macdonald, from the Aberdeen Royal Infirmary, UK, and Canadian colleagues, examined data on 4181 women and 60 men with invasive breast cancer who had undergone total mastectomy as primary therapy.

Men were almost 6 times more likely than women to have radiotherapy after mastectomy, even when other "confounding" factors were accounted for, the authors report in the Annals of Oncology, a medical journal. Of note, gender was not a prognostic factor for recurrence, breast-cancer specific survival or overall survival. Local recurrence was significantly associated with tumor size and grade, involvement of the lymph nodes and the presence of vascular space invasion. These findings, Macdonald concluded, should "reassure physicians involved in breast cancer care that the indications for post-mastectomy radiotherapy should be the same for males and females."

The combination of the anti-cancer drugs Herceptin and Taxotere appears to work better than Taxotere alone in women with advanced breast cancer that has spread beyond the breast, research shows. Moreover, there is little added toxicity when Herceptin is given. Herceptin (trastuzumab) is a monoclonal antibody, meaning that it binds to one specific protein, HER2, which helps regulate cell growth. Overexpression of HER2, a sign of more aggressive cancer, occurs in about 25 percent to 30 percent of breast tumors. Taxotere (docetaxel) is a chemotherapy drug widely used to treat breast cancer and other cancers as well.

Previous studies indicate "synergy" between the two agents in women with breast cancer. To investigate further, Dr. Michel Marty, from Innovative Therapeutics in Paris, and colleagues treated 186 women with HER2-positive advanced breast cancer with six cycles of Taxotere with or without Herceptin. Women treated with the combination regimen had a higher response rate (61 percent vs. 34 percent) and survived significantly longer (31.2 vs. 22.7 months) than women given Taxotere alone. These findings, along with previous findings, support the use of Herceptin with a taxane such as Taxotere as first-line therapy for HER2-positive advanced breast cancer, the researchers conclude in the Journal of Clinical Oncology.

Overall, the number and severity of side effects seen in both groups were similar, aside from a higher incidence of neutropenia in the combination group. Neutropenia is a condition characterized by a drop in infection-fighting white blood cells that can occur with frequent chemotherapy. Cardiac toxicity with Herceptin and Taxotere combination therapy, a concern in earlier trials, is "manageable," the authors conclude, based on the low incidence of heart problems seen in women in the study.

In a commentary, Drs. Charles L. Vogel and Elizabeth Tan-Chiu, from the Cancer Research Network in Plantation, Florida, comment that while they "fully endorse" first-line Herceptin in these women, "a lingering question" remains regarding the survival benefit of Herceptin combination therapy compared with a sequential treatment approach

Novartis Submits Applications in U.S. and Europe for Femara as Adjuvant Treatment for Postmenopausal Women With Early Breast Cancer-(Yahoo News-11/07/2005)

Pre-Planned Subset Analyses Show Femara Reduces Risk of Cancer Returning by Up to 30% in Node-Positive and Chemotherapy-Treated Patients. Novartis has submitted marketing authorization applications in the United States and Europe for the use of Femara (letrozole) in the adjuvant (post-surgery) treatment of postmenopausal women with hormone receptor-positive early breast cancer. Once approved for this indication, Femara will become the only breast cancer treatment available to significantly reduce the risk of recurrence in the adjuvant setting as well as in extended adjuvant treatment following tamoxifen.

"Femara represents an important advance to help increase a woman's chance of staying cancer free after initial treatment for early breast cancer," said Diane Young, MD, vice president and global head, Clinical Development, Novartis Oncology. "The data filed today add to the already substantial body of evidence supporting the use of Femara in breast cancer."

The submissions are based on data from the Breast International Group (BIG) 1-98 study, a Phase III, randomized, double-blind study that compared the safety and efficacy of adjuvant Femara vs. tamoxifen in more than 8,000 postmenopausal women with hormone receptor-positive early breast cancer. The overall results of BIG 1-98 demonstrated that at a median follow-up of 26 months, Femara prolonged disease-free survival by reducing risk of recurrence by an additional 19% (p=0.003)(a) over the reduction offered by tamoxifen. Women who were treated with Femara experienced a 27% reduction in the risk that their cancer would spread to other parts of the body (distant metastases) compared with tamoxifen (p=0.001), a clinically relevant finding since women who develop distant metastases may be at greater risk of dying from their disease. Femara also provided a 14% reduction in the risk of death, although this did not reach statistical significance (p=0.155).

In two separate pre-planned subset analyses, Femara also reduced the risk of cancer returning by 29% among patients whose initial cancer had already spread to the lymph nodes at the time of diagnosis (node-positive breast cancer) and by 30% in those who had received chemotherapy, two groups that are at increased risk of recurrence. Additionally, in node-positive patients and in patients who received adjuvant chemotherapy, the risk of distant metastases was reduced by more than 30% with Femara compared to tamoxifen.

BIG 1-98 is the only clinical trial designed to incorporate both a head-to-head comparison of Femara with tamoxifen during the first five years following breast cancer surgery and a sequencing of both agents to determine the most effective approach to minimizing the risk of recurrence. Patients were randomized to the following arms: tamoxifen for five years, Femara for five years, tamoxifen for two years followed by Femara for three years, and Femara for two years followed by tamoxifen for three years. Results from the ongoing arms of the study, which are expected to determine whether monotherapy or sequential therapy is more effective, and if sequential therapy, which sequence is more effective, are expected in 2008.

BIG 1-98 was conducted by the International Breast Cancer Study Group (IBCSG), with participation of the Danish Breast Cancer Group, the French FNCLCC group, the Yorkshire Group and many independent centers. The study was supported by Novartis.

The data upon which the filings are based were initially presented at the Primary Therapy of Early Breast Cancer 9th International Conference in St. Gallen, Switzerland, in January 2005. Updated data from this analysis, presented in May at the annual meeting of the American Society for Clinical Oncology (ASCO) in Orlando, Florida, clarified the safety of Femara as compared with that of tamoxifen.

The adverse events in the BIG 1-98 study were consistent with published data on both Femara and tamoxifen. In the BIG 1-98 study, the two treatments were generally well tolerated and the safety profile in the two treatment arms was similar. Only arthralgia/arthritis, bone fractures and osteoporosis were significantly more common in the Femara arm as compared to tamoxifen. Hot flashes/flushes, night sweats, vaginal bleeding and thromboembolic events in turn were significantly more frequent in the tamoxifen group.

Overall, more deaths were reported on tamoxifen (n=192) than on Femara (n=166). More patients on tamoxifen (n=135) died from breast cancer than Femara (n=100). In patients whose breast cancer did not recur, more deaths due to cardiac causes were reported in Femara-treated patients than tamoxifen-treated patients.

The frequency of bone fractures and osteoporosis on both treatments was low but the numbers were higher in the Femara arm (6.4%) compared to tamoxifen (4.8%). Endometrial hyperplasia or cancer was reported more often for tamoxifen (2.1%) than for Femara (0.4%).

In the trial, the number of all cardiovascular events was overall lower in the Femara arm than in the tamoxifen arm (9.7% vs. 10.5%). Irrespective of causality, the following adverse events occurred in the Femara and tamoxifen groups respectively: thromboembolic events (1.2% vs. 2.8%), angina pectoris (0.7% vs. 0.6%), myocardial infarction (0.6% vs. 0.4%) and cardiac failure (0.9% vs. 0.4%). Tamoxifen slightly decreased the cholesterol values, whereas Femara treatment resulted in no relevant overall changes over time in serum total cholesterol.

Femara is a leading once-a-day oral aromatase inhibitor currently available in more than 90 countries worldwide. Femara is approved for extended adjuvant treatment of early breast cancer in postmenopausal women who have completed standard adjuvant tamoxifen therapy in 57 countries worldwide, including Europe as well as the United States. In addition, it is indicated for first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer and for the treatment of advanced breast cancer in postmenopausal women with disease progression following anti-estrogen therapy, and as neo-adjuvant (pre-operative) therapy. Not all indications are available in every country.

In previous clinical trials, the most common adverse events experienced with Femara have been hot flashes/flushes, arthralgia/arthritis and myalgia. Other commonly reported adverse reactions are: nausea, fatigue, anorexia, appetite increase, peripheral edema, headache, dizziness, vomiting, dyspepsia, constipation, diarrhea, alopecia, increased sweating, rash, bone pain, weight increase, osteoporosis and bone fracture. Femara is contraindicated in women who are pregnant or breast-feeding as well as in premenopausal women. Femara is contraindicated in patients with known hypersensitivity to Femara or any of its excipients.

Women diagnosed with a relatively rare and aggressive type of breast cancer tend to be younger, have larger tumors and a lower survival rate, according to a study in the July 6 issue of the Journal of the National Cancer Institute. Inflammatory breast cancer (IBC) is characterized by redness, warmth and swelling, often without an underlying palpable mass in the breast. It's estimated to account for between less than 1 percent and 10 percent of all breast cancer cases. The wide range is due to variations in case definitions of IBC.

In this National Cancer Institute study, researchers analyzed data from the Surveillance, Epidemiology, and End Results (SEER) program on more than 180,000 breast cancer cases. The researchers estimated that IBC comprised about 2 percent of all of these cases. The study found the average age for diagnosis with IBC was just under 59 years. That's about three to seven years younger than the average age of women diagnosed with other forms of breast cancer. IBC patients had a median survival of 2.9 years, compared with 6.4 to 10 years for women with other types of breast cancer. Black women with IBC had a lower survival rate than white women with IBC.

IBC tumors also tended to be larger than tumors in other forms of breast cancer, the researchers added. IBC cases seem to be on the increase, the study group found. Between 1988 and 1999, the IBC incidence rate increased from two cases per 100,000 women to 2.5 per 100,000. Over the same period, the incidence of more common forms of breast cancer decreased, from 108 cases per 100,000 women to 101 per 100,000. Changing patterns of risk factor exposure and heightened clinical awareness are possible explanations for the increase in reported IBC cases, the study authors said.

Cancer Comes Full Circle-(Yahoo News-28/06/2005)

Researchers in the Life Sciences Division of the Department of Energy's Lawrence Berkeley National Laboratory have discovered a key molecular pathway by which an enzyme that normally helps remodel tissues initiates the pathway to breast cancer. The same molecular pathway, the researchers found, links both the loss of tissue organization in cancerous organs and the loss of genomic stability in individual cancer cells. "This study demonstrates how structure and function in a tissue are intimately related, and how loss of structure could itself lead to cancer," says Mina Bissell, who pioneered the view that a cell's environment is as important as its genes in determining the formation and progression of tumors. "Thus the unit of function in organs — which are made of tissues — is the organ itself."

Enzymes known as matrix metalloproteinases (MMPs) are important during an organism's development and during wound healing, but they can also promote carcinogenesis. The new study shows that one type, MMP-3, causes normal cells to express a protein, Rac1b, that has previously been found only in cancers. Rac1b stimulates the production of highly reactive oxygen molecules, which promote cancer in two ways — by leading to tissue disorganization and by damaging genomic DNA. "What comes first in cancer, the mutations within the genome of the tumor cells or the loss of tissue organization?" asks Derek Radisky, a postdoctoral fellow in Bissell's laboratory who has focused on the molecular pathways mediating interactions between tumors and their surrounding tissues. "It's a chicken-and-egg problem. Our study shows that the relationship is reciprocal."

Lead author Radisky, with Bissell and their colleagues Dinah Levy, Hong Liu, Celeste Nelson, and Jimmie Fata of Berkeley Lab; Laurie Littlepage, Donna Albertson, and Zena Werb of the University of California at San Francisco; Devin Leake and Elizabeth Godden of Dharmacon, Inc.; and M. Angela Nieto of the Instituto de Neurociencias de Alicante, Spain, report their findings in the 7 July issue of Nature.

Epithelial cells are the source of the majority of cancers; the investigators thus concentrated on factors controlling epithelial cell organization. Epithelial tissues are specialized for managing the flow of substances into and out of the body and for protecting underlying organs. To form these tissues, epithelial cells are tightly interconnected in sheets that line hollow organs and glands, including the breast, prostate, colon, and lung, as well as external surfaces of the body. Epithelial cell organization is determined by a specialized structure known as the basement membrane, a form of the ubiquitous extracellular matrix (ECM) that acts as both a structural scaffold for cells in a tissue and a medium through which the cells communicate. Breakdown of the basement membrane is associated with the spread of tumors; in earlier studies with transgenic mice, Bissell and her colleagues, including UCSF's Werb, showed that loss of integrity of the basement membrane can itself cause tumors. But the mechanism was not understood.

Among the chief agents controlling the configuration of the basement membrane are the matrix metalloproteinases, digestive enzymes that normally act as bulldozers to clear the way for building new organ structures or repairing old ones. Breast tumors have an increased amount of MMPs, however, and this promotes the spread of tumors by degrading the basement membrane and digesting the contacts that bind the epithelial cells into sheets. In cancers MMPs also wreak havoc in another way, as Bissell and her colleagues showed previously: MMPs induce the so-called epithelial-mesenchymal transition (EMT). This transition from one cell state to another causes epithelial cells to disassociate from their neighbors, break free, and acquire the ability to move through the body. In the embryo, EMT is essential for normal organ development. In breast cancer, however, the process renders tumor cells mobile and helps them penetrate barriers like the walls of lymph and blood vessels, facilitating metastasis.

In the present study, the researchers demonstrate that the link between MMPs and the epithelial-mesenchymal transition lies in a family of proteins called Rho GTPases, which control the proteins that define the cell skeleton. They found that treating normal cells with a particular MMP, MMP-3, causes the cells to express an unusual form of Rho GTPase, previously found in cancers, called Rac1b. Rac1b dramatically alters the cell skeleton, making it easier for epithelial cells to separate and move away from surrounding cells. Changes in the cell skeleton induced by Rac1b trigger the formation of extremely reactive molecules known as reactive oxygen species, or ROS. In turn, the increased amount of ROS activates key genes that control the epithelial-mesenchymal transition — the first slippage in an avalanche of tissue disorganization. The reactive oxygen species induced by Rac1b also stimulate the development of cancer by directly affecting genomic DNA. "Reactive oxygen species can damage DNA directly," says Radisky, "and we found that this was the case in cells exposed to MMPs. Examining the genomes of these cells showed that huge regions of DNA were either duplicated or missing altogether. These sorts of changes are a key characteristic for development of cancer."

Much effort in cancer research has gone into identifying and investigating the key genes known as oncogenes; when mutated to high activity, oncogenes stimulate the cell to form cancers. But a number of investigators, including Bissell and her colleagues, have shown that genetic alterations of oncogenes are not, as once believed, sufficient in themselves to cause cancer. "Even activated oncogenes require changes in the tissue structure to produce cancer," Bissell says. "By altering the tissue structure, MMPs accomplish both functions: activating oncogenes and compromising genomic integrity."

The fact that cells exposed to MMP-3 express Rac1b "presents both a challenge and an opportunity," says Radisky. "Rac1b is produced through a process known as alternative gene splicing, through which a single gene can produce many different proteins with dramatically different activities. Alternative splicing is emerging as a key mechanism for controlling cellular function, and identification of MMPs as influencing these processes provides a unique tool for understanding their regulation."

Finding new mechanisms of cancer control can lead to specific opportunities for targeting cancer development. In the course of defining the pathways by which MMP-3 induces malignancy, the researchers developed a method for specifically blocking the formation of the highly active Rac1b, using a recently discovered process known as RNA interference, or RNAi. Reducing the levels of Rac1b by RNAi completely blocked the effects of MMP-3, they found — suggesting a possible method for intervening in this particular pathway of tumor development.

Targeting Rac1b in this fashion is now being investigated for therapeutic potential. Besides inhibiting Rac1b, the study suggests additional therapeutic possibilities, for example by suppressing alterations of the cell skeleton, or blocking the effects of reactive oxygen species, or targeting the process by which the reactive oxygen species activate genes that induce the epithelial-mesenchymal transition. "Many people are discouraged by the extra complexity demonstrated by this study, but personally I find it encouraging," says Radisky. "It suggests many more points for intervention in the treatment of cancer."

AstraZeneca's Arimidex Cancer Drug Gets EU Approval for New Use-(Yahoo News-28/06/2005)

AstraZeneca Plc, Europe's third- biggest drugmaker, said U.K. regulators approved its Arimidex drug for use in postmenopausal women who have undergone surgery for a type of breast cancer fuelled by the hormone estrogen. About 75 percent of all postmenopausal cases of breast cancer fall into this category, London-based AstraZeneca said in an e-mailed statement. The Medicines and Healthcare Products Regulatory Agency's approval means more women can now get Arimidex after surgery, the company said.

Early Stage Breast-cancer Rates Are Rising As Incidence Of Invasive Cases Are Leveling-(Science Daily, 25/06/2005)

Since 1980, the incidence of ductal carcinoma in situ, or DCIS, one of the most common kinds of early stage breast cancer, has increased more than sevenfold. This sharp increase in DCIS -- which is a tumor that contains cancer-like cells but is not considered "true" cancer because the cells have not invaded normal breast tissue -- has been accompanied by a flattening in the incidence of true invasive breast cancer. Both trends suggest that widespread mammography screening, along with improvements in imaging technology and increased biopsy rates, among other factors, are catching breast cancer earlier, before it starts to spread and becomes more life-threatening, according to a new study by Christopher Li, M.D., Ph.D., and colleagues at Fred Hutchinson Cancer Research Center, published in the April issue of Cancer Epidemiology, Biomarkers and Prevention.

"The results of this study suggest that our public-health efforts to increase the use of breast-cancer screening -- mammography, primarily -- appear to have altered the types of breast cancer that are being diagnosed most frequently in the United States, as we have found that the number of invasive cases being diagnosed has stabilized, while more cases of in situ breast cancer are being diagnosed," said Li, an assistant member of Fred Hutchinson's Public Health Sciences Division. Li and colleagues also found a sixfold increase in a less aggressive form of ductal carcinoma in situ, a condition called noncomedo DCIS, while incidence rates of a potentially more aggressive type, called comedo DCIS, have declined during the last five years. "This suggests a further downshifting of severity within in situ cancers themselves," Li said.

The researchers also found that rates of a less common precancerous condition called lobular carcinoma in situ, or LCIS, has increased nearly fourfold in postmenopausal women since 1980. These findings, based on the most comprehensive assessment to date of age-specific incidence rates of in situ breast cancer, while encouraging, also pose a particular challenge to health-care professionals.

"There is good news in that it appears we are detecting breast cancer at an earlier stage. However, the increasing number of in situ cancers presents an important clinical challenge, since in some cases the treatments that should be given to women with these conditions, primarily LCIS, is unclear," Li said. "Another problem is that we are not very good at predicting which women with these precancerous lesions will develop invasive breast cancer and which will not," said Li, also a research assistant professor in the Department of Epidemiology at the University of Washington School of Public Health and Community Medicine.

Since lobular carcinoma in situ, or LCIS, is very rare, accounting for only about 4,200 cases annually in the United States, it has not been possible to gather enough cases to conduct randomized clinical trials to determine whether women would benefit from treatment. "Some small studies do indicate that women with LCIS are equally likely to develop cancer in one or both breasts, so oftentimes it is considered a nonsurgical disease, because the only logical treatment would be a bilateral mastectomy, which would be unnecessary in the vast majority of cases," Li said. "However, if we could develop new tools to predict which women with LCIS are more likely to develop invasive cancer we could better counsel them on what might be appropriate treatment options," he said.

LCIS is characterized by precancerous changes in the cells that line the milk-producing lobules, or lobes, of the breast. The condition cannot be felt during an exam or seen on a mammogram, and so it is typically found by chance during a breast biopsy performed for another reason.

In contrast, because ductal carcinoma in situ, or DCIS, is common, accounting for more than 14 percent of U.S. breast-cancer cases, clinical randomized trials have shown that women benefit from treatment. The most common treatments for DCIS are either breast-conserving surgery with radiation or total mastectomy.

In DCIS, the cells lining the milk ducts have cancer-like characteristics. If left untreated, DCIS may, over time, become cancerous and begin to spread, or invade, the surrounding milk ducts.

"Given that rates of DCIS and LCIS continue to increase in the United States, clinically useful tools that improve our abilities to stratify these patients based on their risk of invasive cancer are needed," Li and colleagues wrote.

According to the American Cancer Society, more than 58,400 new cases of in situ breast cancer are expected to occur among women this year. Of these, approximately 85 percent will be DCIS.

The study was based on data from 32,990 women diagnosed with DCIS and 5,462 women diagnosed with LCIS between 1980 and 2001. Cases were identified through nine population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results, or SEER, Program, which is funded by the National Cancer Institute. The registries represented women from Connecticut, Hawaii, Iowa, New Mexico, Utah, and the metropolitan areas of Atlanta, Detroit, San Francisco-Oakland and Seattle-Puget Sound. The NCI funded the research.

Sixty percent of doctors are using chemotherapy doses that are too low for their heavier breast cancer patients, according to a study released today. This may be one reason overweight women face a greater risk of breast cancer recurrence than their thinner counterparts. The study, published in the Archives of Internal Medicine, looked at breast cancer treatment practices to determine if discrepancies in chemotherapy doses could be the cause of the 1.3-times greater risk of cancer recurrence in overweight and obese women.

The researchers looked at data from over 9,000 women treated at over 900 practices across the United States who received adjuvant chemotherapy between 1990 and 2001. Adjuvant chemotherapy is given to women after their cancer is successfully treated and there is no evidence of metastasis, or spread of the tumor. Administering adjuvant therapy decreases the likelihood of recurrence and improves overall survival. Generally, chemotherapy doses are determined by body surface area (BSA), which plays a role in determining how quickly a drug will be cleared from the body. BSA takes both the patient's height and weight into account, giving doctors an idea of how much chemotherapy should be used. Therefore, a greater BSA because of a high weight results in a greater calculated dose. However, many physicians are hesitant to give this higher calculated dose for fear of causing toxic side effects. The right dose must be properly balanced: give too little and the chemotherapy will be ineffective; give too much and the patient will suffer from many toxic side effects.

While the chemotherapy doses that were given to an overweight or obese woman were still higher than what is normally given a thin person, many doctors decided to lower the recommended dose because they were wary about the side effects. As such, 60 percent of the practices surveyed reduced the therapy dose by more than 10 percent. "We're uncertain of what happens to chemotherapy drugs in the body of a heavy person," said Jennifer Griggs, MD, lead author of the study from the University of Rochester, "And physicians feel better if something happens because of the disease, rather than from the treatment."

Despite concerns of side effects, women in the study who were given full doses of chemotherapy were subsequently found to be less likely to be admitted for neutropenia than women of normal weight. Neutropenia is serious side effect of chemotherapy where the body fails to produce enough white blood cells; a lack of white blood cells results in an inability to fight off infections. It was shown that many doctors even add an additional round of chemotherapy for patients with reduced doses, extending the time that patients will have to cope with side effects. However, doctors have good techniques for managing the basic side effects of chemotherapy, like hair loss and nausea, and Griggs advises her colleagues not to reduce the dose, but to "give the patient support through the side effects."

In fact, previous studies have shown that using actual body weight for calculating chemotherapy doses is associated with improved survival rates in overweight and obese women. These findings suggest that the recommended doses based on BSA would not affect heavy women in an excessively negative way and may even lower the rate of recurrence. Griggs hopes that this study will stimulate the creation of more specific guidelines for chemotherapy dosing. In the meantime, she advises overweight and obese women to insist that their doctor give them their full chemotherapy dose.

Today, an international survey of the attitudes of over 1,500 women towards breast cancer, has revealed that up to one third would consider the removal of both breasts to help prevent the development of the disease(1). But a new breast cancer prevention trial, IBIS-II (International Breast Cancer Intervention Study)*, being launched globally today could reveal an alternative option.The need for an effective way of helping women to reduce their risk of developing breast cancer was confirmed by the outcomes of a major global survey of 1,588 women age of 45 and over. The survey revealed that nearly half of women are concerned about developing breast cancer and up to one third of women surveyed felt so strongly about reducing their chances of developing the disease that they would be prepared to undergo radical surgery to remove both breasts (double mastectomy) prior to diagnosis, if they were known to be at "high risk".

"This important survey will set the agenda for healthcare professionals around the world. That so many women would consider a double mastectomy to reduce their risk of developing breast cancer demonstrates the importance of providing women with alternative options," said Professor John Forbes, IBIS-II co-chairman and chairman of the Australia and New Zealand Breast Cancer Trials Group. "We as oncologists must respond to these findings by not only offering women the best treatments for their breast cancer, but by identifying and investigating approaches that can avert the disease altogether."

IBIS-II is investigating the potential of using a once-a-day hormonal therapy to prevent breast cancer in women who are at an increased risk of developing the disease. The IBIS-II Study will evaluate whether the established breast cancer treatment anastrozole ('Arimidex') can also help to prevent the development of the disease, based on the encouraging results of the recently completed and published ATAC (Arimidex, Tamoxifen Alone or in Combination) Trial (2). Results from the ATAC Trial suggest that anastrozole may have the potential to prevent up to 80% of hormone-sensitive breast tumours. It is currently estimated that each year over 1.2 million women worldwide will be diagnosed with breast cancer and over 400,000 will die from the disease(3).

Professor Tony Howell, IBIS-II co-chairman and Professor of Medical Oncology at the Christie Hospital, Manchester, commented. "We found out from the ATAC trial that anastrozole was effective at preventing breast cancer recurrence and even more effective at preventing new breast cancers in the opposite breast. This, plus a good side effect profile, makes anastrozole a suitable candidate for use in the preventive setting."

Almost half of the women surveyed said that they would be prepared to take a daily tablet to prevent breast cancer, with a similar proportion indicating that they would be willing to participate in a study which evaluated such a medicine. The IBIS-II centres are now open to recruit women into the trial, which will help to provide answers about preventive treatment for breast cancer, potentially giving women at high risk of developing the disease more choice than a double mastectomy.

"The IBIS-II study is extremely important for women, especially those at an increased risk of developing breast cancer," commented Jack Cuzick, John Snow Professor of Epidemiology at Queen Mary, University of London, leading researcher from Cancer Research UK and IBIS-II Steering Committee co-chairman. "It is vitally important that women come forward to participate in the trial - not just for themselves, but for their daughters, their families and for other women around the world. Many of us already take preventive medicines for heart disease and stroke and this is a major attempt to extend this successful approach to cancer."

The IBIS-II study is currently recruiting in 26 countries worldwide. The IBIS-II trial is designed to investigate the value in a preventive setting of the new breast cancer drug, anastrozole, which works by preventing the production of oestrogen, in 10,000 women who are at an increased risk of breast cancer. To be eligible for IBIS-II, women must be aged between 40-70 years, been through the menopause, not be taking HRT, have a family history of breast cancer and other risk factors.

IBIS-II, Cancer Research UK, Wolfson institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, UK

2. ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005, 365 (9453): 60-62.

3. J. Ferlay, F. Bray, P. Pisani and D.M. Parkin. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No. 5. version 2.0, IARCPress, Lyon, 2004.

* Cancer Research UK are organising IBIS II and Queen Mary, University of London are the sponsors.

About the survey-Research was carried out by NOP World, a global market research agency, in April 2005. The nationally representative surveys were conducted in six countries (Australia, Belgium, Brazil, Germany, Italy and the United Kingdom) via the telephone with 1,588 women aged 45+.

- The International Breast Cancer Intervention Study II (IBIS-II) has been designed to investigate the new breast cancer drug, anastrozole, in women in 26 countries, who are at an increased risk of breast cancer.

- The study is currently recruiting women and will run for 4-6 years.

i. The IBIS-II Prevention part of the study aims to recruit 6,000 postmenopausal women who are at increased risk of developing breast cancer. A number of factors for increased risk can make a woman eligible to enter the study and these are set according to the different age groups. Women can take part in the trial if they are aged between 40-70 years and are not on HRT.

ii. The second part of the study, IBIS-II (DCIS), will recruit 4,000 women who have been diagnosed with and had surgery to remove a particular early form of breast cancer, which is not growing or spreading, known as DCIS (Ductal carcinoma in situ). As well as being at high risk of developing more advanced forms of breast cancer, these women are also more likely to develop a new tumour in the opposite breast. This part of the trial is designed to determine which of the two drugs, anastrozole or tamoxifen, can best prevent new cancers, both in the breast affected by DCIS and in the opposite breast.

CONTACT: Mark Haydon, Shire Health International +44-207-108-6500, Mark.Haydon@Shirehealthinternational.com

Test Accurately Predicts Aggressiveness Of Breast Cancer-(Yahoo News-10/06/2005)

A test that measures how quickly cells are dividing is an accurate way for doctors to predict the aggressiveness of breast cancer tumors, even among women with very early stages of the disease, researchers told the 2nd ESMO Scientific & Educational Conference (ESEC) in Budapest, Hungary. The findings will help clinicians decide which patients will benefit most from treatment with more intensive chemotherapy. For most women whose invasive breast cancer is detected early, research shows that prognosis is generally excellent. But the group includes dramatically different subgroups of patients who need to be identified in order to perform the most effective treatment.

Clinicians know that the molecule Ki67 is a good indicator of cell proliferation rate, and the marker is already used to define the aggressiveness of later stages of breast cancer. But it was not clear how effective it would be in very early stages of the disease. Dr. Monica Gionvannini and colleagues from the University of Verona in Italy analyzed 4,250 patients with early invasive breast cancer and correlated Ki67 levels with tumor size, nodal status, and other parameters. "We found that high cell proliferation rate, measured as Ki67 levels, correlates with larger tumor size, axillary nodal involvement, higher grading, lymphovascular invasion, ER and PgR negativity, c-erbB2 overexpression, p53 mutation, younger age at diagnosis and symptomatic presentation," Dr. Giovannini said. "All these factors are well known markers of poor prognosis."

The same findings were valid also when the 'pT1' subgroup of the very earliest stage cancers was considered. "This means that very early invasive breast cancer gathers very different tumors in terms of prognosis and Ki67 could be a reliable and easily obtainable marker in order to identify which pT1 have worse prognosis," Dr. Giovannini said.

Commenting on the data, Dr. Ahmad Awada from Jules Bordet Institute, Brussels, Belgium, said the data presented by Dr. Giovannini confirm that Ki67 is a prognostic indicator in early breast cancer. "What is interesting in the analysis is that Ki67 showed the same prognostic indication in small tumors such as pT1. Furthermore, in clinical practice, tumors with pathological size of <1cm are a true challenge in term of therapeutic decision (mainly chemotherapy indication). Consequently, it will be important to correlate Ki67 expression and prognostic in these very small tumors (<1 cm), which ultimately could help us to use this 'easy-to-perform' parameter in the selection of therapeutic approach."

In another presentation at the conference, Dr. Uwe Langsenlehner and colleagues from Medical University Graz in Austria showed that a specific genetic variation in a cytokine gene is associated with lower breast cancer risk. Cytokines are molecules that act as signals between cells. The authors were examining the cytokine IL 10, which is involved in the development of various tumors. "In breast cancer risk, IL-10 may be a two-edged sword," Dr. Langsenlehner said. "On one hand, higher IL-10 levels could facilitate development of cancer by supporting tumor escape from the immune response. On the other hand, the anti-angiogenic effects of IL-10 are supposed to prevent or reduce tumor growth and spread."

Specifically, the Austrian team examined a particular genetic arrangement, or haplotype, in the promoter region of the gene, which has been associated with increased IL-10 expression. The researchers call this the TCATA haplotype. In a study comparing 500 women with breast cancer against 500 health controls, they found that breast cancer patients were significantly less likely to have two versions of the TCATA haplotype. "Our study suggests that high levels of IL-10 may be protective against breast cancer," Dr. Langsenlehner said. "The mechanism for this remains to be determined, but may likely include anti-angiogenic functions of IL-10. If this result can be confirmed in additional studies, determination of IL 10 genotypes may help to obtain a more precise individual breast cancer risk profile."

The chemotherapy drug Taxotere may help women with breast cancer live longer while keeping the disease at bay. That's in comparison to an older drug, fluorouracil, say researchers in The New England Journal of Medicine's June 2 edition. Taxotere "significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer," write researchers. Aventis Pharmaceuticals, Taxotere's maker, funded the study.

Doctors working on the study included Miguel Martin, MD, of the Hospital Universitario San Carlos in Madrid. Nearly 1,500 women with breast cancer took part. The women lived in 20 countries, were 18-70 years old, and were followed for about 4.5 years (on average). The women had "node-positive" breast cancer, meaning the cancer had spread to their lymph nodes. Like millions of women with early breast cancer, they first got surgery and then chemotherapy. These anticancer drugs have been repeatedly shown to reduce the risk of the cancer coming back and the risk of death in women with breast cancer. They stop cancer growth by killing cancer cells that have spread to other parts of the body.

The women all got six cycles -- a day of chemotherapy treatment with periods of days or weeks off between treatments. They either got Taxotere or fluorouracil, along with two other standard chemotherapy drugs. Each group had similar numbers of women, and most completed all of the cycles (91 percent with Taxotere and 97 percent with fluorouracil).

After five years, three out of four women that received Taxotere had survived without cancer's return, compared with 68 percent of those that received fluorouracil. That amounts to a 28 percent cut in the risk of relapse with Taxotere, the study notes. The reduction in breast cancer's return did not seem to be driven by certain risk factors that would make it more likely such as lymph node status or by HER2/neu status, they write. Disease-free survival was also independent of menopausal status, they say.

Overall five-year survival was 87 percent with Taxotere and 81 percent with fluorouracil, giving the Taxotere group a 30 percent lower risk of death.

Taxotere was not without side effects. Significantly more women who got Taxotere had low levels of infection-fighting white blood cells (neutropenia), a common side effect of chemotherapy. Infections were also more common in the Taxotere group, but none were fatal. Two women in each group died during treatment. Congestive heart failure, a side effect seen with some cancer-fighting drugs, affected 1.6% of those who received Taxotere and 0.7 percent of the fluorouracil group. Two women in the Taxotere group and one in the fluorouracil group developed acute myeloid leukemia.

Understandably, quality of life dipped for women in both groups during chemotherapy. Their scores fell from 72 (out of 100) before treatment to 62 at the end of chemotherapy with Taxotere and 69 with fluorouracil. But the women had bounced back to or surpassed their original scores at follow-up, says Martin.

Chemotherapy with Taxotere can be considered a standard of care, says Edith Perez, MD, of the Mayo Clinic in Jacksonville, Fla. However, she notes that Martin's study didn't include any women older than 70, so it's not clear if they stand to gain the same benefits. Other studies are in the works and breast cancer treatments will keep evolving as new information becomes available, writes Perez in a journal editorial.

Adjuvant Trastuzumab (Herceptin) Increases Disease Free Survival and Overall Survival for Women with HER2 Positive Early Breast Cancer-(NBCCF Website-05/2005)

Data reported at the 2005 annual meeting of the American Society of Clinical Oncology (ASCO) show significant and clinically important improvements in disease free survival and overall survival for women with HER2 positive early breast cancer who were given trastuzumab (Herceptin) in combination with adjuvant chemotherapy. These data were derived from three randomized, prospective Phase III clinical trials involving more than 8000 women. In April 2005 the trials were stopped early after their first interim data analyses showed better than expected results for the groups getting the trastuzumab.

The studies
Trastuzumab is a "targeted" treatment designed to attack specific cancer cells. It is a monoclonal antibody that targets the HER2/neu protein, which is overexpressed in approximately 25% of breast cancers. Trastuzumab has not been shown to be effective in women with HER2 negative tumors.

The trials, NSABP B-31, NCCTG N-9831, and BIG HERA, conducted independently of one another, all looked at the use of trastuzumab in combination with chemotherapy in early stage node positive or high-risk node negative breast cancer. The three trials began enrolling patients in 2000 and 2001, and details about the patient populations and the chemotherapy and trastuzumab regimens vary between them. Most significantly, all patients in the two North American trials (B-31 and N-9831) got anthracycline and cyclophosphamid (AC) chemotherapy, while those in the 39-country HERA trial got either AC or any other approved chemotherapy regimen¹. The data from the B-31 and the N-9831 trials were combined for a single analysis, and data from the worldwide HERA trial were reported separately. Regardless of trial origin, the results for all groups treated with trastuzumab were very similar.

The results
After follow-up of 2.4 years for the B-31 study and 1.5 years for N-9831, the following results have been reported from the combined data analysis:

The relative risk of recurrence was reduced by 52% among women getting chemotherapy with trastuzumab compared with those getting chemotherapy alone.
The risk reduction was unrelated to age, hormone receptor status, tumor size, and lymph node involvement.
The absolute difference in disease free survival between the two groups at three years from randomization was 12%, and 18% at four years, in favor of those getting trastuzumab plus chemotherapy.
Trastuzumab with chemotherapy compared with chemotherapy alone produced an absolute difference in distant disease free survival of 9% at three years after randomization, and 16% after four years.
In the combined analysis, a 33% increase in overall survival was reported among women getting the combination therapy. The absolute difference in number of deaths between the trastuzumab-containing regimens and the control groups was 2% at three years, and 4% after four years. More time will be needed to determine whether these early differences hold steady, increase, or decrease.
Administration of trastuzumab along with AC+paclitaxel produced greater improvement in disease free survival than giving trastuzumab after completion of the AC+paclitaxel treatment.
A 3-4% absolute increase in the rate of cardiac dysfunction was reported for the women getting the AC+paclitaxel and trastuzumab treatment, compared to those getting AC+paclitaxel without trastuzumab.
NBCC analysis
These very encouraging results appear to support the use of trastuzumab in adjuvant treatment with AC+paclitaxel chemotherapy for early breast cancers that are HER2/neu positive. These data also underscore the importance of getting an accurate assessment of HER2/neu activity in the post-surgery assessment of all breast tumors.

The results reported for these trials are impressive. However, publication in a peer-reviewed journal will provide the information needed to assess the methodologies and data analyses, and to more fully evaluate the benefits and limitations of this use of trastuzumab. In the meantime, we have the following concerns and reservations:

Safety: Even though trastuzumab is a targeted therapy, these studies combine it with a chemotherapy regime that is known to be toxic and known to increase cardiac risk. Together, the combination produces an even more substantial risk of heart problems. While it may turn out that the breast cancer benefit outweighs this risk, it is also clear that trastuzumab must not be used in the adjuvant setting without very vigorous cardiac monitoring.

Moreover, we are not convinced that such increased cardiac risk needs to be accepted. Testing the cardiac toxicity of adjuvant trastuzumab in combination with other chemotherapy regimens will allow evaluation of alternative strategies. For example, an ongoing trial (BCIRG 006), in which NBCC is collaborating, includes an arm in which patients are given trastuzumab in combination with docetaxel and carboplatin². While efficacy data are not yet available, preliminary safety data presented at the 2005 ASCO meeting suggest that this combination does not elevate cardiac toxicity when compared to the chemotherapy treatment alone.

Data: The joint analysis of data from the two North American trials is highly unorthodox. Although the decision to do a single joint interim analysis of results from the combined total of 3,300 women was approved in advance by the FDA, the appropriateness and adequacy of the unprecedented joint analysis of data generated from two separate studies will need to be evaluated carefully to determine whether the conclusions drawn from it can be trusted statistically. This is especially true in light of the fact that the analysis did not include data from all of the randomized patients, and it will be necessary to determine whether this omission introduces error into the obtained results. Although it may be tempting to conclude, on the basis of the consistency in the results from this data set and the data from the HERA trial, that this joint analysis is justified, such a conclusion would be premature. Furthermore, adoption of such analyses might lead to flawed analyses and conclusions in the face of less robust effects in future studies.

In addition, we are concerned about how two such similar clinical trials were conducted simultaneously in North America. With resources scarce, the need to ensure that every trial addresses clinically relevant questions without duplication is especially important.

Early stopping: When clinical trials are stopped early, important information about the long-term effects of the treatments involved may not come to light for many more years, even beyond the originally planned duration of the trial, and in that time, more women are exposed to the treatment. While the investigators in these studies plan to continue following the patients' progress, the loss of the control arm of the study will make full assessment of any long-term toxicities of adjuvant use of trastuzumab much less feasible. If women are advised, on the basis of these studies, to consider these treatments, they will be doing so without the benefit of much of the data that prospective randomized clinical trials are designed to provide. [See NBCCF fact sheet: "Early Stopping of Clinical Trials"].

About NBCCF
The National Breast Cancer Coalition Fund is a grassroots organization dedicated to ending breast cancer through the power of action and advocacy. The Coalition's main goals are to increase federal funding for breast cancer research and collaborate with the scientific community to implement new models of research; improve access to high quality health care and breast cancer clinical trials for all women; and expand the influence of breast cancer advocates in all aspects of the breast cancer decision making process.

Reference
American Society of Clinical Oncology, 2005 ASCO Annual Meeting, May 13-17, 2005, Orlando, FL. Advances in Monoclonal Antibody Therapy for Breast Cancer (Scientific Symposium). www.asco.org

Footnote:
¹ Although the patterns of administration varied between trials, both the B-31 and the N-9831 trials included a control group treated with AC followed by paclitaxel, and an experimental group that got trastuzumab in addition to paclitaxel. A third experimental group, included in the NCCTG N-9831 trial but not the NSABP B-31 trial, got AC followed by paclitaxel followed later by trastuzumab. Data from this group were not included in the joint analysis. With the decision to stop the trial early, some patients from this group will now be eligible to begin getting trastuzumab treatments earlier instead of waiting until the end of their chemotherapy as originally planned.

² The BCIRG 006 trial has three arms: AC followed by docetaxel, AC followed by docetaxel and trastuzumab, and docetaxel with platinum salts (TCH) with trastuzumab

Bevacizumab (Avastin) in First-Line Treatment of Metastatic Breast Cancer-(05/2005)

Adding bevacizumab (Avastin) to paclitaxel chemotherapy has been found to significantly improve disease free survival among women being treated for the first time for recurrent or metastatic breast cancer, compared with those who got paclitaxel alone. These results, reported at the 2005 annual meeting of the American Society of Clinical Oncologists (ASCO), are from a randomized, prospective Phase III clinical trial (ECOG E2100). The trial was stopped early because of better-than-expected results among the women getting the experimental treatment. Bevacizumab is a "targeted", anti-angiogenic therapy designed to inhibit tumor growth by stopping the formation of new blood vessels that are needed to nourish the tumor. It is a monoclonal antibody that attacks specific cancer cells - in this case inhibiting vascular endothelial growth factor (VEGF) and interfering with the blood supply necessary for tumor growth and metastasis. Bevacizumab is already approved by the FDA for treatment of colorectal cancer.

Summary of Results
The trial enrolled 722 patients between December 2001 and March 2005. It compared paclitaxel chemotherapy with or without bevacizumab in 722 women with recurrent or metastatic breast cancer whose tumors tested negative for the HER2/neu protein¹ and who had not received previous chemotherapy for their recurrence. The median age of women in the trial was 55. About 64% had had estrogen receptor positive tumors, and 41% had experienced recurrence or metastatic progression within 24 months of initial treatment.

At the first interim data analysis, which led to the early stopping decision, about twice as many patients were found to have responded to paclitaxel + bevacizumab as to paclitaxel alone (28.2% vs. 14.2%; or a 7% absolute difference). Progression free survival increased from about 6 months to about 11 months in the group of patients getting the combination treatment with bevacizumab (HR = 0.498, p<.001). More time will be needed to assess the effects of the drug on the secondary endpoint of overall survival, but initial data analysis indicates a 49% improvement (HR = 0.67, p<.01) on that measurement as well.

While hypertension (high blood pressure) was not a common side effect for women getting standard paclitaxel treatment alone, 13% of those receiving the combination of bevacizumab and paclitaxel had this side effect. Also, slightly more than 2% of this group experienced proteinuria, a condition in which protein is excreted in the urine² . There was increased neuropathy³ in the bevacizumab group (21% vs 14%), possibly due to the longer survival and therefore greater exposure to paclitaxel.

NBCCF Analysis
This study demonstrates another encouraging application of a targeted breast cancer therapy, this time in recurrent or metastatic disease. Publication of the study in a peer reviewed journal will provide details of the methodology and data analysis so that a full assessment of the findings can be made. Until that time it will not be possible to determine the full extent of the promise and limitations of this use of bevacizumab.

Endpoints: This trial met its primary endpoint of progression free survival, and there was a statistically significant increase in overall survival among women getting the bevacizumab treatment. More time will be needed to confirm this important effect. We will also await more data from this study on measures of quality of life during the disease free interval. [See NBCCF fact sheet: "Outcomes in Breast Cancer Clinical Trials"].

Early stopping: When clinical trials are stopped early, important information about the long-term effects of the treatments involved may not come to light for many more years and in that time, more women are exposed to the treatment. If women are advised, on the basis of these studies, to consider these treatments, they will be doing so without the benefit of much of the data that prospective randomized clinical trials are designed to provide. [See NBCCF fact sheet: "Early Stopping of Clinical Trials"].

Between 2000 and 2002 when the trial ended, NBCCF worked collaboratively with Genentech on the first study of the application of Herceptin in breast cancer. This was a Phase III clinical trial in which Avastin did not meet the primary endpoint of increased progression-free survival in relapsed metastatic breast cancer. [See NBCCF fact sheet: "Completion of Avastin Treatment for Women with Metastatic Breast Cancer"].

Reference
American Society of Clinical Oncology, 2005 ASCO Annual Meeting, May 13-17, 2005, Orlando, FL. Advances in Monoclonal Antibody Therapy for Breast Cancer (Scientific Symposium). www.asco.org

Footnotes

¹Exceptions were made for patients with HER2/neu positive tumors who had previously been treated with trastuzumab or who could not take trastuzumab because of a contraindication.

²Proteinuria is an indicator that the kidneys are damaged in some way.

³ Neuropathy is a general term referring to disorders of peripheral nerves, which branch out of the spinal cord to the arms, legs, and other parts of the body.

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