BREAST CANCER

Breastfeeding protects against triple-negative breast cancer (MedWire News-28/08/2008)

Women who breastfeed for at least 6 months have a diminished risk for developing triple-negative breast cancer, US study results show. The research team, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, also found that certain other reproductive factors appeared to be differentially associated with certain breast cancer subtypes. Gene expression studies have identified and validated the existence of four "intrinsic" breast cancer subtypes: luminal A, luminal B, human epidermal growth factor receptor (HER)-2-overexpressing, and basal-like. Luminal tumors express hormone receptors while nonluminal subtypes lack these markers. The triple negative phenotype - which expresses neither estrogen receptor, progesterone receptor, nor HER-2 - is often used a surrogate marker for the basal subtype. The five-year survival rate for triple negative breast cancer is 15% lower than for other types of the disease, in part because the disease responds poorly to most breast cancer treatments. Notably, nearly 50% of Black women younger than 55 years who are diagnosed with breast cancer have the triple negative type, compared with 22% of White women with the disease. In the current study, lead researcher Amanda Phipps and colleagues sought to determine what puts women at risk for the triple negative type of breast cancer. The authors pooled two population-based, case-control studies of breast cancer in women aged 55 to 79 years for analysis. These included 1476 controls and 1023 cases of luminal breast cancer, 39 cases of HER-2-overexpressing breast cancer, and 78 cases of triple-negative breast cancer.

Clinical and lifestyle factors were obtained and analyzed using the polytomous logistic regression method. As reported in the journal Cancer, breastfeeding for at least 6 months was found to reduce the risk for triple-negative disease (odds ratio [OR]=0.5) and to a lesser extent luminal breast cancer (OR=0.80) compared with breastfeeding for less than 6 months. The researchers say it is unclear why breastfeeding influenced hormonal cancer risks. One possible explanation is that while women are breastfeeding, they are not menstruating and thus their hormones are not cycling. Alternatively, breastfeeding may alter the structure of breast cells in a way that makes them less prone to develop into cancer cells, Phipps and team said. Another finding of the study was that early age at menarche was associated with risk for HER-2-overexpressing disease only (OR=2.7, relative to population average menarche) whereas both late age at menopause and the use of estrogen plus progestin hormone therapy were found to be associated with risk of luminal disease only (OR=1.6, 1.7). Phipps and collegues comment: "Certain reproductive factors may have a greater impact on the risk of certain molecular subtypes of disease compared with others. "Future studies that further define the etiology of breast cancer subtypes will add to the biologic understanding of this disease."

[Back]

Telephone follow-up for breast cancer could ease burden on clinics (MedWire News-(29/08/2008)

An automated telephone follow-up system for breast cancer survivors has the potential to reduce the burden on outpatient clinics and may even help improve the detection of psychosocial concerns among women, a feasibility study has shown. In addition, many women in the study reported that the telephone questionnaire was less stressful and less embarrassing than the clinic and also saved on time, report David Montgomery (Glasgow Royal Infirmary, UK) and colleagues. The National Institute for Clinical Excellence in the UK recommend 2-3 years of follow-up after treatment for breast cancer before discharge to a general practitioner (GP). While clinicians are "reluctant" to implement these guidelines because of added strain on the system, they are also anxious over "perceived lack of GP training and experience in oncology and potential loss of patient outcome data." Furthermore, routine clinical examination is an "inefficient" way of detecting potentially treatable relapse after breast cancer: locoregional relapse, including new contralateral cancers, occurs at a rate of 1-1.5% with only 13% of such relapses detected by routine clinical examination in asymptomatic patients. Thus, there is a need for more effective and efficient methods of follow-up, Montgomery and colleagues say.

Recently, a semi-structured, automated telephone questionnaire has been developed which monitors symptoms associated with locoregional or metastatic relapse as well as treatment-related side effects and psychosocial concerns. Poor scores or deterioration from the last-recorded score can result in an email being sent to a designated person to ensure that the low score is followed up or a routine mammogram requested. The researchers performed a trial of this technology in 110 women with a previous breast cancer diagnosis. In all, 75 (71%) patients completed follow-up using the new automated system. Seventy-one percent found the system easy to use; 65.33% were happy to use it as their sole method of follow-up; and a further 12% were happy to use it as part of their follow-up. Only 10.66% of participants had concerns raised which led to clinic attendance. In addition, patients cited several benefits of this new follow-up method. Notably, one patient said they were able to complete the questions in their home environment, which they found "less threatening and less likely to drag up memories of their treatment." Commenting on the findings in the British Journal of Cancer, the team said: This [system] should provide increased capacity to help meet the demand to see new patients quickly, without compromising the care of our long-term patients, and should ensure that clinic visits are more focused on the needs of those attending."

[Back]

Obese breast cancer patients show poor response to chemotherapy (MedWire News-2/09/2008)

Breast cancer patients who are overweight or obese have a reduced response to neoadjuvant chemotherapy compared with their healthy-weight peers, study results show. Not surprisingly obese patients also had worse overall survival at 4 years of follow-up compared with their healthy-weight counterparts, and also had a higher proportion of hormone-unresponsive tumors. The researchers say their findings "may be attributed to the influence of BMI [body mass index] on the clinical effectiveness of chemotherapy or the underdosing of overweight and obese patients by clinicians because of fears of toxicity." As reported previously by MedWire News, studies show that obesity is an important predictor of outcome in breast cancer. It has been proposed that obesity influences breast cancer prognosis by increasing circulating plasma levels of estrogen, insulin, insulin-like growth factor, and other hormonal factors that act to promote the growth of occult metastatic disease. Alternatively, obesity may affect response to chemotherapy because the conversion to active metabolite and/or clearance of cytotoxic drugs such as doxorubicin and cyclophosphamide may be altered by higher body weight without a corresponding increase in toxicity. "An assessment of tumor response to neoadjuvant chemotherapy may serve as a surrogate measure for understanding how obesity influences breast cancer prognosis," study investigator Abenaa Brewster and co-workers from the University of Texas MD Anderson Cancer Center in Houston, USA, comment. The team therefore collected data on 1169 patients who were diagnosed with invasive breast cancer and treated with chemotherapy before surgery at the MD Anderson Cancer Center.

Overall, 30% of patients were obese (BMI =30 kg/m2), 32% were overweight (BMI of 25 to < 30 kg/m2), and 38% were normal or underweight (BMI< 25 kg/m2). Overweight and obese patients were significantly less likely to have a pathologic complete response than patients who were normal or underweight (odds ratio[OR]=0.59). "Clinicians should be aware of higher BMI status as a host risk factor influencing pathologic complete response to neoadjuvant chemotherapy and overall survival," the researchers write. They add: "Attention to chemotherapy dosing based on actual body weight, investigations into chemotherapy pharmacokinetics, and management of comorbidities may yield significant benefits in improving the outcome of breast cancer patients."

[Back]

HER2/neu vaccine shows promise in preventing breast cancer relapse (MedWire News-3/09/2008)

Breast cancer vaccines containing HER2/neu peptide fragments show "significant promise" when administered in the adjuvant setting for preventing disease recurrence in high-risk women, according to a clinical review of the evidence. The authors nevertheless caution that issues such as optimal dosing, booster inoculations, and the prospect of combination therapies need to be clarified before such vaccines come to the clinic. Interest in the development of cancer vaccines increased after the discovery of tumor-associated antigens (TAAs) that can be recognized and targeted by human T lymphocytes, George Peoples (Brooke Army Medical Center, Houston, Texas, USA) and colleagues note. One such tumor-associated antigen is produced by the HER2/neu (human epidermal growth factor receptor) gene, which is overexpressed in up to 30% of breast and ovarian cancers. This overexpression can result in a 100-200-fold increase in concentration of the HER2/neu protein in tumor versus normal tissue. In the early 1990s, one research group recognized the potential to create a vaccine to activate or reactivate an immune response against a HER2/neu expressing tumor. They developed the E75 epitope of the HER2/neu protein which is specifically recognized by host cytotoxic T-cells - sentinels of the immune system. Preclinical data and early clinical trials suggested that the E75 epitope did indeed provoke an immune reaction against HER2/neu overexpressing cancer cells.

In 2005, a pivotal phase II clinical trial was conducted in which 24 breast cancer survivors, who were rendered disease free through surgery, systemic therapy, and radiation, were given a E75 epitope vaccine and followed-up and compared with a similar control group of 29 patients. At a median follow-up of 26 months, the breast cancer recurrence rate was 8.3% in the vaccine group compared with 14.8% in the observation group, while mortality rates were 1.0% and 6.2%, respectively, for these groups. Notably, for patients whose disease recurred, the mortality rate for the control and vaccinated groups was 41.7% and 12.5%, respectively. While these results clearly suggest that the vaccine has a utility in the adjuvant setting for preventing disease recurrence, Peoples and colleagues point out some potential concerns. Because a single peptide vaccine targets one epitope from a TAA, lack of antigen diversity means the vaccine may "wear-off" in time. This may be overcome by booster inoculations or a multi-epitope vaccine, the researchers suggest. In addition, it is unclear how the vaccine would work in combination with other therapies that target HER2/neu. "We anticipate that peptide-based vaccines will be incorporated into adjuvant treatment algorithms using already determined standard therapeutics to include trastuzumab for women with HER2-overexpressing breast cancer," the team comment in the journal Cancer Immunology, Immunotherapy.

[Back]

Vitamin D exposure protects against breast cancer (MedWire News-3/09/2008)

Exposure to vitamin D through sunlight or dietary intake during adolescence and early adulthood appears to protect against the risk for breast cancer, study results show. The research team found that Vitamin D reduced the risk for both hormone receptor-negative and -positive tumors, although the effect appeared stronger in the latter group, leading the researchers to call for confirmatory mechanistic studies. Evidence supporting a role for vitamin D in the prevention of several cancers, including breast cancer, has recently emerged, note study co-author Kristina Blackmore (Mount Sinai Hospital, Toronto, Ontario, Canada) and colleagues. Vitamin D is primarily obtained through exposure of the skin surface to ultraviolet B radiation, but small amounts can be ingested through limited dietary sources (e.g., fortified milk, fatty fish) and supplements. The biologic mechanism by which vitamin D prevents breast cancer is thought to be mediated through its metabolite, 1,25-dihydroxyvitamin D (1,25(OH)2D)), which can inhibit cellular proliferation and induce differentiation and apoptosis in normal and cancerous breast cells. However, studies in humans have produced somewhat conflicting findings, Blackmore and colleagues note. To investigate, the researchers interviewed 759 women with breast cancer and 1135 controls regarding their sun exposure history and their dietary and supplemental vitamin D intake with respect to three age groups: 10-19, 20-29, and 45-54 years.

These age groups were chosen to capture exposures during breast development in adolescence and early adulthood and breast involution occurring around the time of menopause. Analysis revealed that women who reported the highest level of exposure to vitamin D (sunlight and dietary measure combined) between the ages of 10 and 29 years had a significantly reduced risk for estrogen receptor(ER)-positive/ progesterone receptor(PR)-positive tumors (odds ratio[OR]= 0.76) compared with those receiving less exposure. There was a similar association between vitamin D exposure and ER-negative/ PR-negative breast cancer (OR=0.74) and mixed ER-positive/PR-negative disease (OR=0.79), although the small numbers of women with hormone receptor negative-disease prevented this from reaching significance. Blackmore and colleagues comment in the American Journal of Epidemiology: "Some data support the concept that the antiproliferative and antitumor effects of vitamin D and its analogues (e.g., EB1089) on estrogen-responsive breast cancer cells are mediated via disruption of estrogen mitogenic and survival signals."

[Back]

Ethnicity gap for advanced breast cancer mortality worsening (MedWire News-4/09/2008)

Black patients with advanced-stage breast cancer are missing out on the gains in survival rates made in the last 20 years, study results suggest. Between 1988 and 2003 survival rates among White patients with advanced disease increased several points, but have, at best, remained static among their Black counterparts, report Sharon Giordano (The University of Texas MD Anderson Cancer Center, Houston, USA) and colleagues. Clearly, potential disparities in treatment have to be considered, say the researchers, however, another explanation could lie in the fact that most of the net survival gains made were among estrogen-receptor positive cancers, which are inherently less frequent in Black women. Overall, survival appears to be improving for patients with breast cancer of any stage, with mortality rates decreasing by approximately 2.3% annually. In part, this decline in mortality can be attributed to more widespread participation in screening programs, with a greater proportion of patients being diagnosed with in situ and early-stage breast cancer.

Furthermore, the decline in mortality rates is also a result of the increasing use of adjuvant anthracyline-based polychemotherapy regimens and the monoclonal antibody trastuzumab, both of which have been associated with improved survival in clinical trials. However, it is not known whether these gains in survival have been felt among patients who present with metstatic disease at diagnosis - a group which makes up around 10% of all diagnosed cases. The researchers investigated data on 15,438 women with stage IV breast cancer who were followed up for 16 months, 18 months, and 11 months in the time periods between 1988 and 1993, 1994 and 1998, and 1999 and 2003, respectively. Overall, 1-year survival rates in these respective time points for women of all ethnicities was 57.4%, 59.1%, and 61.3% - a statistically significant improvement. By contrast, stratifying the patients by ethnicity revealed that Black women had respective survival rates of 55.1%, 52.0%, and 54.8% - a non-significant trend for worsening survival. Giordano and colleagues comment in the Journal of Clinical Oncology: "Health policymakers need to be aware of this increasing gap in survival and study the possible causes of such evolving discrepancies and implement appropriate steps to halt and reverse this phenomenon."

[Back]

Prognostic factors linked to large breast tumors identified (MedWire News-5/09/2008)

Overweight breast cancer patients with high-grade tumors that are detected symptomatically are more likely to present with advanced stage disease than patients with other characteristics, an Australian study has found. The researchers urge greater participation in screening programmes and also emphasize the benefits of "maintaining a healthy weight throughout adult life - in this case to improve prospects of avoiding diagnosis with a large breast cancer." Despite the introduction of mammographic screening in Australia in 1991, women continue to present with advanced breast cancers, as elsewhere, Anne Kricker (University of Sydney, New South Wales) and colleagues note. While only 25% of cancers detected in 1997 by the national screening program, BreastScreen Australia, were 2 cm in diameter or larger, they account for a high proportion (41%) of all breast cancers diagnosed in the population. "Given the capacity for screening to detect cancers when they are small and before they progress, we asked why so many breast cancers in Australia are not diagnosed and treated definitively until they are 2 cm or larger," Kricker et al comment, adding: "In principle, the answer lies in 3 broad areas: the health system, the woman herself and the cancer." The researchers identified 1459 women, aged 22-69 years, diagnosed with breast cancer between March 2002 and December 2003 in the population-based cancer registries in the Australian States of Victoria, New South Wales, and Queensland.

In all, 35% of breast cancers were detected by a routine mammogram, with the remaining 65% being diagnosed after a clinical examination following a breast symptom. The likelihood of women being diagnosed with a tumor =2 cm in diameter were significantly reduced if that tumor was detected by mammogram rather than symptomatically (odds ratio[OR]=0.27). Most women (82%) reported at least one mammogram up to 4.5 years before diagnosis and 57% had one up to 2 years before, excluding diagnosis mammograms. Compared with patients with low-grade cancer, those with moderate-grade disease had an increased risk for being diagnosed with a =2 cm tumor (OR=2.00), as did those with high-grade cancers (OR=3.67). Relative to patients with a healthy body mass index (BMI) of =25 kg/m2, those who were overweight (BMI=25-29 kg/m2) or obese (BMI=30 kg/m2) were more likely to present with a tumor =2 cm in diameter. The population attributable fractions (PAF) for a =2 cm cancer was 42% for detection by clinical examination, 29% for having a moderate- or high-grade cancer, 11% for having a BMI =25 kg/m2, and 4% for lack of regular mammograms in the past 4.5 years. They explain: "Each PAF can be interpreted as the proportion of =2 cm breast cancers that would be eliminated if the level of exposure to the relevant risk factor in the whole study population was shifted from the high- to the low-risk level." Discussing their findings in the International Journal of Cancer, Kricker et al comment: "Although women need to be aware of the potential harms of screening, our study suggests that greater participation could help some women avoid diagnosis with a large breast cancer."

[Back]

HER-2-overexpressing breast tumors may switch in response to therapy (MedWire News-5/09/2008)

Breast cancer patients who overexpress the human epidermal growth factor receptor (HER)-2 and are treated with monoclonal antibody therapy may actually convert to HER-2-negative status during treatment, study findings show. "It's known that a small percentage of HER-2 positive patients develop a resistance during treatment, and there have been several described mechanisms," said study co-author Elizabeth Mittendorf (The University of Texas MD Anderson Cancer Center, Houston, USA) presenting the findings at the recent 2008 Breast Cancer Symposium in Washington, D.C. The researchers say they may have uncovered a new resistance mechanism through their work; alternatively, among patients who converted, HER-2-positive disease may have been eradicated allowing HER-2-negative disease to proliferate. Using the MD Anderson Breast Medical Oncology database, the team identified 143 breast cancer patients, all of whom had tumors that overexpressed HER-2 at the time of diagnosis. The women were treated with HER-2 monocloncal antibody treatment, in combination with taxane- and anthracycline-based chemotherapies, prior to surgery. At the time of surgery, 50% of all patients achieved a pathologic complete response (pCR). Of those who did not achieve pCR, pre- and post-treatment tissue samples were available for 23 patients which were analyzed using FISH, a laboratory technique that uses fluorescent probes to detect specific DNA sequences, in this case, additional copies of the HER-2 gene. Seven patients, or 30.4%, were found to be HER-2 negative at the time of surgery.

With a median follow-up of 10.2 months, the researchers also found that two patients (2.8 %) who had achieved a pCR had recurred, compared with eight patients (11.3%) who did not achieve a pCR. Of the second group, tumor samples were available for five; three had converted to HER-2-negative status. "At this stage, I think the findings advocate for reassessing HER-2 status at the time of surgery," said study co-author Ana Gonzalez-Angulo, also from the MD Anderson Cancer Center. She added: "However, it would be inappropriate for clinicians to conclude from our study that women with a change in HER-2 status should not receive their full course of [anti-Her-2 therapy] therapy. The team concluded: "Certainly, the study warrants further investigation of what might be the best adjuvant therapy for this sub-set of women and suggests that a clinical trial in the adjuvant setting would be appropriate."

[Back]

Can Breast MRI Help Evaluate Cancer? Study Weighs the Benefits, Risks of Routine Breast MRIs for Cancer Evaluation (Yahoo NEws-8/09/2008)

Routine use of breast MRI (magnetic resonance imaging) scans to help evaluate cancer after diagnosis is not as beneficial as some believed, according to a new study. "The bottom line is it doesn't help us as we thought it did," says Richard J. Bleicher, MD, a surgical oncologist at Fox Chase Cancer Center in Philadelphia and lead author of the study, presented Saturday at the American Society of Clinical Oncology Breast Cancer Symposium in Washington, D.C. But another expert who reviewed the study abstract for WebMD says the study was small and that the role of breast MRI to evaluate cancer is still evolving. On one point all sides seem to agree: More research is needed to determine if MRI can improve the outcomes of women with breast cancer. 
Breast MRI 
Bleicher and his colleagues reviewed the records of 577 breast cancer patients, including 130 who had MRIs before treatment and 447 who did not. The goal was to determine the effect, if any, of getting an MRI on the time to start treatment, the chances of removal of all the cancer, and other outcomes. "We wanted to ascertain whether routine MRIs [for cancer, not for screenings] are helpful and do they, in fact, assist us in treatment planning," Bleicher tells WebMD. The role of breast MRI for screening, he says, is clearer. The American Cancer Society, for instance, advises that MRIs be used in combination with mammograms for preventive screenings of certain women at especially high risk of breast cancer. But the role of the breast MRI to evaluate breast cancer is not as clear, he says. The thinking among experts, he says, is that MRIs, because they are so sensitive, may allow better visualization of the cancer, so using one when cancer is diagnosed or suspected should help guide treatment decisions. 
Breast MRI Study Findings
Among the findings:
Breast MRI was associated with a 22-day delay in the start of treatment. "We don't know why," Bleicher says. It could be because of the scheduling of the MRI itself, or perhaps MRI prompts other biopsies." Three weeks should not change a patient's survival chances, he says, but waiting can clearly add to a patient's anxiety. 
Those who got the breast MRI were nearly twice as likely to have a mastectomy as breast-conserving surgery, even after controlling for size and stage of the tumor. One reason, he says, may be that the MRI, being highly sensitive, picked up something that looked like cancer but turned out not to be -- a false positive. 
Those who got the breast MRI were slightly more likely to have what surgeons call positive margins, although this finding could have been a chance finding. The goal is negative margins. "The goal is to excise out the tumor so there is a margin of normal tissue around it, reassuring us the cancer has been completely removed," he says. 
Younger women were more likely than older women to have MRIs, but the use of the MRI did not correlate with other factors such as family history of breast or ovarian cancer. 
Breast MRI Research Evolving
Another expert, Constance Lehman, MD, PhD, professor and vice chair of radiology and head of breast imaging at the University of Washington Medical Center and director of imaging at the Seattle Cancer Care Alliance, reviewed the study for WebMD. She says the new study is "not the kind of study we need to make firm conclusions." She points out that the study was small and that only 130 women had breast MRIs. Research on the value of breast MRI when used in cancer treatment decision is evolving, she says, and not all the answers are in. The Bleicher study has inherent limitations, she says, because it wasn't a study that randomized people to get one treatment or not. Rather, it was a study that took a look backward, and it lacked some information, such as why some women got MRIs and others didn't. The findings from the current study, she says, don't hold up at her center. "This study shouldn't rule out a preoperative MRI,'' she says. "This is one abstract from one center that did one study in a very select group of patients." She points to another study, published in the Journal of Clinical Oncology, which reviewed the results of 19 studies and found the rate of mastectomy because of false positives on the MRI is 1%. 
Breast MRI: Advice for Women
If a woman has suspected or diagnosed breast cancer, Lehman says, she should ask about the potential benefits and risk of a breast MRI. "Go to a center with a high level of experience," she advises. 
Bleicher's advice: "Women who walk into their doctor's office with breast cancer should not be immediately thinking, 'I have to have an MRI.' There are false positives [to MRIs], unnecessary biopsies, a lot of anxiety ... and a three-week delay [to treatment]. All these disadvantages have not been offset by an improvement in our ability to choose the proper treatment." More study is needed, he says, to decide the best role for breast MRI in cancer diagnosis.

[Back]

In Asian Women Risk Of Breast Cancer Mutations Underestimated (Yahoo News-14/09/2008) 

Oncologist Allison Kurian, MD, and her colleagues at the Stanford University School of Medicine were perplexed. Computer models designed to identify women who might have dangerous genetic mutations that increase their risk of breast and ovarian cancer worked well for white women. But they seemed to be less reliable for another ethnic group. "We've been repeatedly surprised when Asian women who the models predicted would probably not have the mutations do in fact have them," said Kurian. She recently showed that in a head-to-head comparison between whites and Asians, two of the most commonly used models failed in predicting the presence of mutations in almost half of the Asian women studied. "Doctors and patients should have a higher level of suspicion when using these prediction models in Asian women, because they under-predicted the true number of clinically important mutations," said Kurian. "We may have to consider more subtle patterns of family cancer history when considering genetic testing in this ethnic group." Kurian, assistant professor of oncology and of health research and policy, is the first author of the research, which was published online in the Journal of Clinical Oncology. Mutations in two genes - BRCA1 and BRCA2 - are strongly associated with the development of breast or ovarian cancer in carriers. However, not every woman with a family history of cancer or who develops these cancers has these mutations. 

To determine who should be tested for the mutations, genetic counselors frequently use computer models that assess specific variables for each woman, such as the number of relatives affected by breast and ovarian cancer, the age of each relative at onset of the condition and how closely the woman is related to her affected relatives. Those women deemed by the models to be likely carriers of these mutations are referred for testing of their BRCA1 and BRCA2 genes. Kurian and her colleagues used two of the most widely used computer models, named BRCAPRO and Myriad II, to predict the presence of the mutations in 200 white women and 200 Asian-American women at cancer genetics clinics in four locations: Stanford, the University of California-San Francisco, Queen's Medical Center in Honolulu and the British Columbia Cancer Center in Vancouver. They sequenced the BRCA1 and BRCA2 genes of all of the study subjects and compared them to the models' predictions. The researchers found that the models were highly accurate in predicting the presence of mutations in white women; one program identified 24 of the 25 women with BRCA1 or BRCA2 mutations and the other identified all 25. However, both programs performed much worse in predicting the 49 Asian women in the study sample with mutations. One program predicted that only 25 of the 49 women would carry mutations, while the other recommended testing of 26 women. "It's clear that these models are far from foolproof," said Kurian, who is also a member of the Stanford Cancer Center. "These results emphasize the need for expert evaluation by a genetics professional to guide all clinical genetic testing." 

Because the Asian and white women reported similar numbers of affected relatives on average, it's possible that fewer Asians with the mutations go on to develop cancer. In that case, the family history would be a less accurate way to determine the presence of the mutations. Kurian and her colleagues are collaborating with researchers in Hong Kong to investigate these and other alternatives. The study results point out the need for further investigation into the genetic variability of different ethnic groups. In addition to previously identified, clinically important mutations of the genes, the researchers identified more "variants of unknown significance" in the BRCA1 and BRCA2 genes of Asian women than in white women. Many of these variants probably don't have any clinical effect," said Kurian. "We know a lot more about the normal variability of these genes in white women. Many of these variants are probably just normal for members of a particular ethnic group, but we haven't studied enough people in ethnic minority groups to know for sure, and further research needs to be done to distinguish variants of uncertain significance from truly harmful mutations."

[Back]

Recurrence Risk Low For Women Who Survive Breast Cancer Five Years After Treatment (Yahoo News-15/08/2008)

Women who survive breast cancer for at least five years after treatment have an 89% chance that they will not have a recurrence of the cancer after 10 years and an 81% chance after 15 years, according to a study published online Tuesday in the Journal of the National Cancer Institute, USA Today reports. The study involved 2,838 women diagnosed with breast cancer from 1985 to 2001 who had surgery to remove the original tumor, some of whom had radiation. All of the women also took medication to prevent the cancer from returning (Szabo, USA Today, 8/13). Cancer returned after five years in 7% of women treated for stage I breast cancer, 11% of women treated for stage II cancer and 13% of women treated for stage III cancer (Dunham, Reuters, 8/12). Study author Abenaa Brewster, an assistant professor at the University of Texas M.D. Anderson Cancer Center, noted that the study did not include women who relapsed before five years. She added that doctors now often prescribe aromatase inhibitors to post-menopausal women when they are diagnosed, which could lead to an even smaller number of relapses after five years (USA Today, 8/13).

[Back]

Drug Stops Bone Loss From Breast Cancer Chemo (HealthDay News-21/08/2008)

Zometa (zoledronic acid) prevented bone loss at 12 months in premenopausal women undergoing chemotherapy after they had surgery for early stage breast cancer, a new study found. The multicenter, phase III study is the first to evaluate the use of zoledronic acid in premenopausal breast cancer patients. The 101 women (85 completed the study) were divided into two groups that received either zoledronic acid or a placebo every three months for one year. All the women were given oral vitamin D and calcium supplements. Bone mineral density (BMD) was measured before the start of chemotherapy and again at six and 12 months. At six and 12 months, bone density was stable among patients who received zoledronic acid, but there were significant declines in spine and hip BMD among women in the placebo group. Side effects weren't significantly different between the two groups. The findings were published online Aug. 18 in the Journal of Clinical Oncology. "Our study confirms that women experience significant bone loss due to cancer treatments and that zoledronic acid can prevent this loss," study lead author Dr. Dawn L. Hershman, assistant professor of medicine at Columbia University's College of Physicians and Surgeons, said in a university news release. "While our findings are promising, it's too early for us to recommend this drug for all premenopausal women undergoing chemotherapy for breast cancer, because we don't yet have all the information we need on dosing, cost effectiveness, and whether this drug actually prevents bone fractures," Hershman said. "However, this research does show we need to be more vigilant about monitoring patients' bone densities before and during treatment, so we can protect bone health and offset bone fracture or osteoporosis risk." Previous research found that similar drugs prevent bone loss in breast cancer patients during and after chemotherapy. Recent findings have suggested that zoledronic acid prevents bone loss in postmenopausal women and may reduce the risk of breast cancer recurrence.

[Back]

Happiness may affect breast cancer risk (UPI-25/08/2008)

Happiness and optimism may help guard against breast cancer, while adverse life events may increase breast cancer risk, Israeli researchers said. Ronit Peled of Ben-Gurion University of the Negev in Israel questioned women about their life experiences and evaluated their levels of happiness, optimism, anxiety and depression prior to diagnosis. Researchers used this information to examine the relationship between breast cancer and life events or psychological distress. A total of 622 women ages 25 to 45 were interviewed: 255 breast cancer patients and 367 healthy women. The study, published in the British journal BMC Cancer, showed a clear link between outlook and risk of breast cancer, with optimists 25 percent less likely to have developed the disease. Conversely, women who suffered two or more traumatic events had a 62 percent greater risk. "Young women who have been exposed to a number of negative life events should be considered an 'at-risk' group for breast cancer and should be treated accordingly," Peled said in a statement. 

[Back]

Dense breasts may increase cancer risk (Yahoo News-25/08/2008) 

Women with denser breasts have an increased risk for developing breast cancer and having breast cancers with invasive characteristics, U.S. researchers said. Vanderbilt-Ingram Cancer Center researchers said breast cancer cells grown in dense, rigid surroundings step up their invasive activities. Lead author Dr. Alissa Weaver said the findings suggest a cellular mechanism for the correlation between human breast tissue density and tumor aggressiveness. Weaver and colleagues were interested in invadopodia -- the finger-like protrusions that a cancer cell uses to make holes in the extracellular matrix -- matrix-degrading enzymes are associated with invadopodia. These structures are believed to be important for cancer invasion. The study, published in the journal Current Biology, found that breast cancer cells cultured on a denser -- and thus, more rigid -- matrix had a greater number of active invadopodia than breast cancer cells cultured on a less dense matrix. "If you have enough invadopodia, over time they'll make large holes that cells can move through to invade and metastasize," Weaver said in a statement. "We thought that more 'stuff' for the cells to get through was going to make it harder, so we expected to see less matrix degradation but instead we found cells actually sense the rigidity and degrade more." 

[Back]

Arm swelling after breast cancer surgery common  (Reuters Health-07/08/2008) 

Following surgery for breast cancer, many women will experience arm swelling - a bothersome condition doctors refer to as lymphedema. Lymphedema is a public health issue "deserving greater attention," doctors from Australia wrote in a recently published paper. Among 287 women with breast cancer, 190 took part in all assessments during 18 months of follow-up after surgery and arm swelling developed in 62 (33 percent) of them during that time, Dr. Sandra C. Hayes and colleagues from Queensland University of Technology in Kelvin Grove found. Roughly 60 percent of these women had fleeting symptoms, whereby the lymphedema dissipated with or without treatment. However, 40 percent of women experienced long-term arm swelling lasting more than 3 months, with or without intermittent periods of relief. Women with lymphedema, Hayes told Reuters Health, "were twice as likely to have poorer upper-body function when compared with women who had not developed arm swelling. Poor upper body function is associated with reduced quality of life," she noted. More extensive breast surgery increased the odds of lymphedema six-fold and having more than 20 cancerous lymph nodes removed increased odds four-fold. Hayes noted that two identified risk factors for arm swelling post-surgery -- insufficient physical activity and not using the affected arm -- "are amenable to interventions and should be investigated for their preventive and therapeutic effects among women after treatment for breast cancer." "It was found that use of the treated side likely decreases risk of developing lymphedema," Hayes said.

[Back]

Estrogen receptor modification is marker of treatment response (MedWire News-6/08/2008)

Scientists have found that endocrine therapy for breast cancer reduces the level of phosphorylation at serine 118 of the estrogen receptor (ER) protein and that the magnitude of this reduction is related to treatment outcome. Study co-author Fabrice Andre (Institut Gustave Roussy, Villejuif, France) and colleagues say that "modulation of ER phosphorylation by endocrine therapy could be used as [a] surrogate marker to evaluate both the bioactivity and efficacy of endocrine therapy." Andre and colleagues explain in the Annals of Oncology that endogenous estradiol activates the ER by inducing a conformation change in its structure and phosphorylation at serine 118. Following activation by estradiol, ER induces transcription of genes that, amongst other activities, stimulate the proliferation of breast tissue. By inhibiting various steps in this estrogen pathway, endocrine therapies have proved useful in treating women with breast cancer. Nevertheless, many women relapse after treatment and there is a need to develop biologic parameters to identify tumors that are refractory. For the present study, the researchers obtained tumor samples from 80 breast cancer patients treated with endocrine therapy and performed tissue microarray analysis for various biomarkers before and after treatment, including ER phosphorylated serine 118 (Pser18ER). Analysis revealed that the level of Pser18ER in breast tumors fell by 51% on average after treatment with endocrine therapy. Notably the magnitude of Pser118ER decrease was higher in tumors that responded to endocrine therapy as compared with refractory tumors. Andre and colleagues comment: "Overall, our study suggests that Pser118ER immunostaining could be used as [a] surrogate marker to monitor the efficacy of endocrine therapy."

[Back]

21-gene assay predicts breast cancer relapse better than Adjuvant! (MedWire News-7/08/2008)

The 21-gene assay is a more accurate predictor of relapse than standard clinical features for breast cancer patients with hormone receptor-positive operable tumors treated with chemohormonal therapy, research shows. Based on their finding, Joseph Sparano, (Albert Einstein Cancer Center, New York, USA) and colleagues say that the tool could be used to "select low-risk patients for abbreviated chemotherapy regimens or high-risk patients for more aggressive regimens or clinical trials evaluating novel treatments." Sparano and colleagues explain that it can be difficult to evaluate new therapeutic strategies which combine taxane, anthracyline, and endocrine therapy in hormone receptor-positive regimens, as the relapse rates are generally quite low. "Extremely large trials that must include thousands of patients are now required to detect improved outcomes for new treatment strategies," they comment in the Journal of Clinical Oncology. In the present study, the researchers assessed 465 patients with hormone receptor-positive breast cancer with zero to three positive axillary nodes and followed them up for recurrence. Patients were evaluated using the 21-gene assay (Oncotype DX, Genomic Health, Inc, Redwood City, CA) and Adjuvant! - a standardized validated instrument that projects patient outcomes based on classical clinicopathologic features. In all, 99 women experienced a recurrence of disease after 5 years of follow-up. The researchers found that risk scores generated by the 21-gene assay significantly predicted recurrence overall and for both the node-negative and node-positive patients better than Adjuvant! criteria. For patients with a risk score of less than 18, approximately 3.3% of patients experienced recurrence within 5 years if there were zero to one positive nodes, and 7.9% experienced recurrence if there were two to three positive nodes. Plotting risk scores as a linear, continuous variable, they found that a higher score predicted recurrence with a hazard ratio of 2.64 compared with 1.34 for Adjuvant! criteria. Summarizing their findings, the researchers comment: "Greater use of selection and enrichment strategies that include molecular markers offers potential for providing more informed treatment recommendations, improving the efficiency of clinical trials, and conserving resources."

[Back]

Family breast cancer may not mean early screening (Reuters Health-07/08/2008)

New research suggests that just because a woman has family members with breast cancer, it does not mean that she should undergo early screening for the cancer. According to the report, there are certain factors doctors can look for to determine whether early screening is advisable. "Breast cancer is very common. Familial clustering is also rather common," Dr. Geertruida H. de Bock, the study's first author, told Reuters Health. "About 25 to 30 percent of breast cancer is family clustered, but the (rate) of breast cancer in the family is not very useful in predicting if you will get breast cancer yourself." At present, having a first-degree relative (mother, sister, or daughter) diagnosed with breast cancer before age 40 is considered to be an indication for starting breast cancer screening before age 50, de Bock and her team note in the journal BMC Cancer. However, this practice is based on estimates from families with risky gene mutations or who are otherwise cancer-prone. To better understand the risk in the general population, the researchers looked at 1,987 women, all of whom had sisters who had been diagnosed with breast cancer. Some of the study participants had breast cancer while others didn't. 
The researchers identified four familial factors that were related to developing breast cancer at a younger age: 
--at least two cases of breast cancer in a first-degree relative; 
--at least two cases of breast cancer in first or second-degree (grandparent, grandchild, uncle, aunt, nephew, niece, half-sibling) relatives younger than 50; 
--at least one case of breast cancer in a first or second-degree relative younger than 40; 
--or any case of cancer affecting both breasts 
Women who had at least two of these risk factors were roughly eleven times more likely than those with no risk factors to develop breast cancer by age 30. For cancers occurring before ages 40 and 50, the presence of two or more factors raised the risks by five-fold and two-fold, respectively.

However, because breast cancer is so uncommon in younger women, even with two or more of the above factors, the odds of breast cancer by age 30 is just 1 percent. By ages 50 and 70, the risks of breast cancer increased to 13 and 11 percent, respectively. Given that these risks are already pretty low, women with just one factor are likely to have a very low risk and may not require early screening at all.  The authors believe that by looking for the factors they identified, doctors can better inform patients of their true risk of breast cancer and whether early screening is warranted. "There is a tendency to screen everyone and I think screening has disadvantages as well as advantages," de Bock said. Doctors "should be critical about it and really think about it if there isn't really an increased risk."

[Back]

Male breast cancer treatment often delayed (Reuters Health-07/07/2008)

Yes, men can and do get breast cancer -- and the disease is often treated at a late stage, according to research presented Sunday in Lugano, Switzerland. Dr. Marina Garassino of the University of Study of Milan, Italy and colleagues reviewed the medical records of 146 men, about 62 years old on average, who were diagnosed with breast cancer. The researcher reported the findings at a conference organized by the European Society for Medical Oncology. One third of the men had advanced breast cancer by the time they were seen by a doctor, Garassino noted in a telephone interview with Reuters Health that. "This is not the same as in females, in which the presentation is advanced in less than 10 percent." Doctors and patients may both play a part in delayed diagnosis of male breast cancer, Garassino surmises. "Physicians may not recognize the tumor in men; they see a lump but don't think that it may be breast cancer. Also men might not suspect that they have a tumor and they arrive to the physician later than females." "Male breast cancer is a very hormonal-dependent disease," Garrasino said, and there is some evidence that, if treated early, "prognosis may be better" than in women. All of the men underwent surgery to remove their cancer, 48 men then received radiation treatment, and 100 received add-on chemotherapy or hormonal therapy. "Of note," the investigators say, is the finding that 42 men (30 percent) received no further treatment after surgery. Overall 10-year survival rates were 47 percent for men with earlier-stage disease, and 44 percent for men with more advanced disease. "The message for men," Garassino said, "is this: if you have a lump in your breast, go immediately to the physician. Don't wait, because you may have a tumor."

[Back]

2 Breast Cancer Screening Strategies Prove Effective (Yahoo News-29/07/2008)

The typical U.S. breast cancer screening strategy results in women being tested twice as often as a different approach use in Norway, but both are equally good at detecting disease, a new report says. A study in the July 29 online issue of the Journal of the National Cancer Institute finds that a traditional physician- and self-referral screening strategy held up well against the Norway approach, in which the government sends letters to all women in a specific age range inviting them to have a screening mammogram. The Norway program aims for women to be screened every two years, while the U.S.-based "opportunistic screening" strategies advise women to have annual screening mammograms. In comparing the strategies as applied to 45,050 women in Vermont and 194,430 women in Norway from 1997 to 2003, the researchers found that the age-adjusted screening detection rate of cancers was similar between the two populations (2.77 per 1,000 woman-years in Vermont versus 2.57 in Norway). However, more than three times as many women in Vermont were recalled for further examination than in Norway (9.8 percent versus 2.7 percent). When all cancers detected during regular screening and between screening mammograms were combined, no substantial differences were found in the prognostic features of invasive cancers detected in the two populations. Given the shorter interval between screenings, the report's authors hypothesized that "Vermont women and/or their health care providers may more readily pursue evaluation of symptoms and clinical findings than their Norwegian counterparts." "Our results demonstrate that despite its longer screening interval, the organized population-based screening program in Norway achieved similar outcomes as the opportunistic screening in Vermont," the team wrote. 

[Back]

Bone Density Predicts Chances of Breast Cancer (HealthDay News-28/07/2008) 

Calculating a woman's bone mineral density appears to shed light on her risk for breast cancer.A new study has found that high bone mineral density (BMD) predicts a greater likelihood of developing breast cancer, independent of how high her risk is on the often-used Gail model.The two measurements together might be used in tandem to better predict breast cancer risk, the researchers said. The findings, which were expected to be published in the Sept. 1 issue of Cancer, follow closely on the heels of other research linking different aspects of bone health with breast cancer risk. One study presented at the American Society of Clinical Oncology annual meeting in May found that Zometa (zoledronic acid), a drug used to treat osteoporosis, lowered the risk of breast cancer recurrence in premenopausal women. And another study released this spring found that women with breast cancer who have a vitamin D deficiency at the time of their diagnosis were more likely to have a recurrence or to die from their disease. Vitamin D is also critical to bone health. The Gail model incorporates information on family history, age and other factors to estimate a woman's risk of breast cancer over five years and over her lifetime. The model does not, however, include data on bone mineral density, which is known to be a risk factor for breast cancer. This study, led by researchers at the University of Arizona, Tucson, incorporated Gail scores and hip BMD information on almost 10,000 postmenopausal women participating in the Women's Health Initiative.

After an average of almost nine years of follow-up, women with a high Gail score were, overall, 35 percent more likely to develop breast cancer. And for each unit of increase in total hip BMD, a woman's risk rose 25 percent. There was a particularly high increase in risk for women with the highest BMD and Gail scores. Women with high bone density often are overweight or obese, a condition which elevates their risk of breast cancer and which may well be the common denominator, said Dr. Jay Brooks, chairman of hematology/oncology at Ochsner Health System in Baton Rouge, La. "This is more information that shows a link in my opinion, between increasing weight, obesity and the development of breast cancer," he added. But the picture for women remains a complicated one, another expert said. "Even with these additional findings, however, it's still not clear what the precise relationships are between estrogen, bone density and breast cancer," said Dr. Mary Daly, director of the Cancer Prevention and Control Program at the Fox Chase Cancer Center in Philadelphia.

[Back]

Breast cancer mortality increases with body mass index (Reuters Health-25/09/2008)

 A higher body mass index (BMI) is associated with lower survival rates in women with breast cancer, according to a report in the July 10th issue of the Journal of Clinical Oncology. "We have found strong evidence that high BMI and a recent pregnancy are associated with a poorer prognosis after a diagnosis of breast cancer," Dr. Gillian C. Barnett told Reuters Health. "Our study suggests that advice on weight loss should be given to all obese patients with breast cancer." Dr. Barnett from Addenbrooke's Hospital, Cambridge, UK and colleagues investigated the impact of established risk factors for incident breast cancer on overall survival after a diagnosis of breast cancer, using data from the Studies of Epidemiology and Risk Factors in Cancer Heredity. Women with the highest BMIs were 52 percent more likely to die than women with the lowest BMIs, the investigators report. BMI is the ratio of weight to height, which is often used to see if a patient's weight is outside normal parameters. "The Women's Interventional Nutritional Study reported improved event-free survival in women randomly assigned to a reduced fat diet (associated with weight loss)," Barnett pointed out. "Further definitive clinical weight loss intervention trials in breast cancer populations are required to further clarify the relationship between breast cancer mortality and BMI." Survival was also significantly worse in women who had four or more full-term pregnancies and in women whose last pregnancy was more recent, the report indicates. In contrast, the team found that prognosis improved with recent alcohol consumption, with light to moderate drinking reducing the risk of dying by 22 percent. "The association between alcohol consumption and improved survival is surprising," Barnett commented. "The results of several other studies have not shown such an association."

[Back]

No need for gene screens in breast cancer families (Yahoo News-22/07/2008)

Research reported today should provide relief to women who are worried after a relative's breast cancer diagnosis. The study in the open access journal BMC Cancer shows that a family history of breast cancer does not give a useful indication of the likelihood that a woman will develop it herself at an early age. An increased risk of breast cancer for relatives of breast cancer patients has been demonstrated in many studies. As physicians and the general population have become more aware of this increased risk, the demand for referring healthy women with a family history of breast cancer for intensive screening or genetic testing has risen. Geertruida H. de Bock led a team from Leiden University Medical Centre in the Netherlands who investigated whether the increased risk was significant enough to accurately predict breast cancer. According to de Bock, "Due to the low prevalence of early breast cancer in the population, the predictive value of a family history of breast cancer was 13% before the age of 70, 11% before the age of 50, and 1% before the age of 30." These numbers are much lower than most women would probably expect. As the authors explain, "Applying family history related criteria results in the screening of many women who will not develop breast cancer at an early age." Given the psychological harm that screening visits can cause, more stringent criteria should be applied to early screening. The researchers recommend that these results be used to "reassure a large number of women regarding their personal breast cancer risk." 

[Back]

Cancer researchers call for ethnicity to be taken into account (Yahoo News-17/07/2008)

Breast cancer research needs to investigate how a person's ethnicity influences their response to treatment and its outcome, according to a new Comment piece in today's Lancet (18 July) by researchers from Imperial College London. Emerging evidence suggests that particular drugs may benefit people from one ethnic group more than others, because of differences in their genetic makeup. However, most key trials looking at treatments for breast cancer have been carried out in predominantly white populations in Europe, North America and Australasia. Other populations might not respond to a drug in the same way as the white populations in these trials, argue the researchers writing today. They suggest that clinical trials should record participants' ethnicity and analyse whether there are differences in how patients from particular ethnic groups respond to a particular therapy. The researchers highlight the example of a drug called trasztuzumab, which is commonly used to treat people with breast cancer that is HER-2 positive. Most studies of trasztuzumab have not reported the ethnicity of participants. However, a recent study showed that people with a particular genotype responded better than others to treatment with this drug. The genotype in question is more common in some ethnic groups than in others, so the researchers argue that an individual's ethnicity could be a key factor in determining which treatments are most likely to benefit them. 

Dr Carlo Palmieri, from the Division of Surgery, Oncology, Reproductive Biology and Anaesthetics at Imperial College London and one of the authors of the piece, said: "Everyone responds differently to treatment and it's often very difficult to predict how well someone will respond to a particular drug. However, evidence is now emerging that shows how your genes might influence whether or not a particular treatment can help you. "There are small genetic differences between people from different ethnic backgrounds and it is really important that we find out whether these genetic differences mean that certain drugs perform well in people from certain ethnic groups but not in others. It's only by doing this that we can make sure each individual receives the best possible care," added Dr Palmieri. Breast cancer is predominantly a disease of the economically developed world, but rates are rising rapidly in Asian and economically developing countries. Different ethnic groups have different incidences of certain kinds of breast cancer regardless of where they live. For example, there is a greater incidence of basal type breast cancer within African-American and West African populations. People's outcomes from breast cancer also vary between ethnic groups for reasons which are still not entirely clear. 

[Back]

Costly cancer drug offers hope, but also a dilemma (Yahoo News-6/07/2008)

It took only an instant for 58-year-old Gailanne Reeh to go from the picture of health to death's door. By chance, her doctor noticed a lump under her arm during a routine exam. It turned out to be advanced breast cancer.Soon she was having tests to reveal the extent of the cancer and hearing the grim results.The surgeon, she recalled, "looked at me and said: 'This is not a conversation I like to have. But I can't do anything for you. You can't be cured. You can't be treated. All we can do is manage your cancer. On scans to detect tumors, the doctor told Reeh, "you light up like a Christmas tree." And so, like many others in that situation, Reeh, the vivacious owner of a staffing agency in Boston, was given bevacizumab, also known as Avastin, a drug that signifies both the hopes and dilemmas of modern medicine. Looked at one way, Avastin, made by Genentech, is a wonder drug. Approved for patients with advanced lung, colon or breast cancer, it cuts off tumors' blood supply, an idea that has tantalized science for decades. And despite its price, which can reach $100,000 a year, Avastin has become one of the most popular cancer drugs in the world, with sales last year of about $3.5 billion, $2.3 billion of that in the United States. But there is another side to Avastin. Studies show the drug prolongs life by only a few months, if that. And some newer studies suggest the drug might be less effective against cancer than the Food and Drug Administration had understood when the agency approved its uses. While many patients and their doctors say the drug can improve the quality of life — like a sense of well-being and an ability to carry out daily tasks without exhaustion or pain — such effects can be hard to document. Meanwhile, many patients with cancers other than those of the colon, lung or breast are taking the drug, even in cases where there is no compelling evidence that it can help.

Avastin also has serious, if infrequent, side effects, some of which can be lethal. And because it is almost always used with standard chemotherapy — it did not work as well when researchers tried it alone — patients on Avastin do not escape chemotherapy's side effects."I still use Avastin routinely, but it's sobering," Dr. Leonard Saltz, a colon cancer specialist at Memorial Sloan-Kettering Cancer Center in New York, said of the new data. "It's not a slam dunk and, in fact, the incremental benefit may be more modest than we want to admit." If Avastin were inexpensive or if it cured cancer or even held it at bay, as the drug Gleevec does for blood cancer, few might care. But like a half-dozen or so new biotechnology drugs with a similar combination — alluring promise, high price and only arguable benefits — Avastin raises troubling questions:
What does it mean to say an expensive drug works? Is slowing the growth of tumors enough if life is not significantly prolonged or improved? How much evidence must there be before billions of dollars are spent on a drug? Who decides? When, if ever, should cost come into the equation? For a patient like Reeh, fighting for her life, the cost is not the main concern. If her insurer did not pay, she said, she would go into debt, find a way to raise the money. But some in the pharmaceutical industry worry that such prices will raise concerns about whether the drugs are worth it, leading to a backlash like price controls or restrictions on use. Roy Vagelos, a former chief executive of Merck who is considered an elder statesman of the industry, said in a recent speech that he was troubled by a drug, which he would not name but which was a clear reference to Avastin, that costs $50,000 a year and adds four months of life. "There is a shocking disparity between value and price," he said, "and it's not sustainable." Some patient advocates are also troubled by very expensive treatments like Avastin coming into routine use on what they see as little more than a hope and an expensive prayer. "It's absolutely critical that we start having a public discussion," said Barbara Brenner, executive director of Breast Cancer Action, an advocacy group. "I think of Avastin as a model that is showing us where the problem is."

The Rising Cost
The problem is largely one of cost.
Cancer drugs constitute the second biggest category of drugs in the United States behind cholesterol-lowering medicines, and accounted for $17.8 billion of total prescription drug sales of $286.5 billion in 2007, according to IMS Health, a health care information company. Spending on drugs for cancer grew 14 percent last year, faster than for all but three other diseases. About 100,000 Americans take Avastin, according to Genentech's data. The drug is being formally tested in as many as 450 clinical trials for about 30 types of cancer. And Genentech, its partner Roche and the National Cancer Institute are now starting studies that will include more than 26,000 people with lung, colon or breast cancer at earlier stages of the disease than were studied initially. If Avastin is approved for those earlier-stage patient groups, it could have a major impact in delaying the return of their cancer, but hundreds of thousands of additional people could end up taking it, possibly for years.And that, insurers and patient advocates say, could impose a considerable financial burden. The drug's price, as charged by Genentech, can be $4,000 to more than $9,000 a month, depending on a patient's weight and the type of cancer. Avastin's cost to patients and insurers can be much higher, though, because doctors and hospitals buy the drug and then sell it to patients or their insurers, often marking up the price. So the $2.3 billion that Genentech recorded in sales of Avastin represents only part of what Americans spent on the drug last year. And while doctors typically want the best for their patients, there also are other factors that may push them to prescribe Avastin. "Think about where the interests are aligned," said Dr. Deborah Schrag, a colon cancer specialist at the Dana-Farber Cancer Institute in Boston. "Patients who seek out cancer care are often quite willing to try all kinds of things. Doctors want to help them and may be financially incentivized. And it is often quite hard for insurance companies to intervene."

Medicare requires that the doctor or hospital buying Avastin be paid an amount equal to Genentech's average selling price plus a markup of 5 to 6 percent. Of that amount, Medicare pays 80 percent and the patient pays 20 percent. Doctors and hospitals typically do not make much money on Avastin for Medicare patients, and can even lose money if they buy the drug at a price that is higher than average. But patients can end up paying thousands of dollars a month. Some have supplemental insurance to take care of it; others do not. But private insurers sometimes pay several times as much as Medicare pays for Avastin. Doctors and hospitals have at times charged as much as $35,000 a month for the drug, said Dr. Peter Dumich, who reviews claims for cancer patients for AWAC, a company that helps employers contain health care costs. The insurers have little choice, Dr. Dumich says, when their contracts say they must pay a portion, like 80 percent of the charge, whatever the charge actually is. "Providers have them over a barrel," he said. And, like Medicare, private insurers may in turn require patients to pay a percentage of what can be hefty bills. That has happened to Jim Lemieux, a colon cancer patient at Dana-Farber. His private insurance requires that he pay 25 percent of the cost of his treatment, which includes Avastin. His insurer, he said, is charged $6,000 a month for the drug, making his share $1,500. Lemieux, who was a sales manager at a car dealership, says he cannot bear to look at his medical bills. They include bills for hospitalizations and surgery and co-payments for standard chemotherapy, as well as Avastin. To try to make ends meet, he and his wife just sold their house and are moving into their son's basement. Even so, he says, he expects he will have to file for bankruptcy. "You figure you've got insurance," Lemieux said. "I paid 30 years and never got sick. I should have just paid the money to myself." But he is not planning to give up Avastin. "I'm trying to stay alive," Lemieux said. "I decided I'm not going to die from Stage 4 colon cancer."

A Promising Dream 
When Napoleone Ferrara was hired by Genentech in 1988, he was assigned to work on a drug to ease labor during childbirth. But he could not get cow pituitary glands out of his mind. Dr. Ferrara had noticed in his previous academic job that when he mixed extracts from the glands with cells from blood vessels, the vessel cells started to grow rapidly. Something made by those glands, he reasoned, could spur vessel growth. He found that substance in 1989 and called it vascular endothelial growth factor, or VEGF (pronounced VEJ-eff). He even isolated its gene. And that led to a new idea for a cancer drug. It drew from a hypothesis for a sort of universal cancer treatment, advanced by the late Dr. Judah Folkman of Harvard. Dr. Folkman had argued, starting in 1971, that tumors must grow their own blood vessels to bring them nourishment and oxygen. If you could choke off those vessels, Dr. Folkman said, you could halt cancers. Dr. Ferrara and his colleagues realized that if they could block VEGF, cancer cells might not be able to grow blood vessels. So Genentech developed a monoclonal antibody, a type of protein, that would bind to VEGF and disable it. In 1997, the company began testing its antibody, which became Avastin, in cancer patients. There were some setbacks. Avastin failed in its first big clinical trial, against very advanced breast cancer. Genentech's stock dropped 10 percent in one day, and some analysts questioned whether the company's investment would ever pay off. Meanwhile, the company was well into a trial of Avastin for colorectal cancer. Patients got chemotherapy plus either Avastin or a placebo. The Avastin patients lived more than four months longer, a median of 20.3 months, compared with 15.6 months for the other group. "We were excited," Dr. Schrag said. "Four months is big." In February 2004, 15 years after Dr. Ferrara's initial discovery, the Food and Drug Administration approved Avastin for patients with advanced colon cancer. A blockbuster was born. But now there is a question mark over that evidence. That first exciting result compared Avastin with a type of chemotherapy that has since been widely replaced by a more effective regimen.

In a later, larger study comparing Avastin with current chemotherapy, Avastin slowed the growth of tumors but did not extend life by an amount considered statistically significant. Dr. Schrag said she would continue to give the drug to her colon cancer patients. But when she talks to patients about Avastin now, she said, she will add a few more caveats. She believes that some patients are helped — that they may feel better and, she hopes, may even, in some cases, live longer. She says a few of her Avastin patients lived several years and some are still alive. Of course, she acknowledges, there is no proof that Avastin was responsible, but it is stories like those that give her, and patients, hope. "All patients want to be the tail end of the survival curve," Dr. Schrag said. When Avastin was approved for colon cancer, Genentech decided to charge $2,200 for an average dose, taken every two weeks. That was a reflection of the research and development it had put into the drug as well as continuing research, said Walter Moore, the company's director of government relations. Genentech, which has never before revealed what it spent to develop Avastin, now says that it and its partner Roche have spent more than $2.25 billion starting with Dr. Ferrara's original work. The figure includes research, clinical trials and filing for regulatory approval and is well beyond what was spent by the federal government, which conducted important clinical trials of Avastin. Through May 2006, the government had spent $44.6 million on Avastin trials and related laboratory work, according to figures obtained from the National Cancer Institute by Consumer Watchdog, an advocacy group. While it is impossible to compare directly the company's investment to the costs of developing other cancer drugs, the amount Genentech says it spent is "on the high side" of the industry average, said Henry Grabowski, a professor of economics at Duke University who has analyzed drug development costs. Genentech says it and Roche — which owns a majority of Genentech and markets Avastin outside the United States — will spend an additional $1 billion testing Avastin as a treatment for early-stage cancers. The price also reflected Genentech's perceived value of the drug compared with other cancer treatments. The price was half that of Erbitux, a colon cancer drug from ImClone Systems and Bristol-Myers Squibb that was approved the same month as Avastin and had not been shown to prolong life. But Avastin is typically used for a longer time and by more patients than Erbitux. And the Avastin dose for lung and breast cancer is twice that for colon cancer, doubling the price.

Eric Schmidt, an analyst at Cowen and Company, said pharmaceutical companies typically based drug prices on what the market could bear. "It's high because Genentech can price it high," he said, noting that Avastin's price was in line with that of some other cancer drugs. Despite the company's research and development costs, Schmidt said, Genentech is one of the most profitable of pharmaceutical and biotechnology companies. Other countries have different views about whether Avastin is worth its price. An institute that advises the British government on which drugs to pay for recommended against it, saying that the drug was not cost effective based on its cost per year of life extended. In the United States, Genentech argues that it puts patients first, with free drugs for those who have no way to pay for them and donations to charities that can help with payments. It also capped the price for a year's supply of Avastin at $55,000 (not counting markups by doctors and hospitals) for patients with incomes of less than $100,000 a year. But progress against cancer has a price, the company says. "The quest is to eliminate the disease," Arthur Levinson, Genentech's chief executive, said at an annual investor meeting. "And, yes, there is going to be a cost to that."

Of Dubious Benefit
After colon cancer, the next target was lung cancer. 
Dr. Bruce Johnson of Dana-Farber knew the difficulties well. He had been at the National Cancer Institute, where he reviewed 25 years' worth of clinical trials, 30 studies that started with high hopes and ended with little progress. He used to give talks quoting a World War I general: "Ground gain minimal. Casualties huge. Conclusion — press on." Avastin, in that context, looked like something of a triumph. Patients who took it along with standard chemotherapy survived for a median of 12.3 months, compared with 10.3 months for those getting only chemotherapy. The results were announced in 2005. "Finally," Dr. Johnson said, "something worked." But as with colon cancer, a newer study adding Avastin to a different chemotherapy regimen has raised questions about its effectiveness against lung cancer. The study's Avastin patients lived no longer than those who got the chemotherapy plus placebo. Although the drug did slow the median time until progression of tumors, the difference was less than a month. The third approval for Avastin, for advanced breast cancer, came in February of this year. The clinical trial found it significantly slowed the progression of cancer but did not significantly extend life. The FDA went against its own panel of outside experts, who had voted 5 to 4 against approval. The agency's action has not sat well. Senator Charles Grassley, Republican of Iowa, asked the Government Accountability Office to look into the FDA's approval of Avastin and some other drugs that "appear to have little to no effect in protecting lives and increasing health." Dr. Lee Newcomer, an oncologist and executive at the insurer United HealthCare, said patients were not well served, and neither were insurers, nor the public, which ultimately foots the bill. If a drug just stops tumor progression, without the woman's living longer or feeling better, without her noticing anything different, Dr. Newcomer said, "you're treating an X-ray." 

Patient advocacy groups were split.
"Even when these drugs 'work,' what kind of impact are you talking about?" said Fran Visco, president of the National Breast Cancer Coalition, which opposed approval. "But we market them and give them to everybody." Yet other doctors and advocates for patients say that when tumors grow, patients can notice new or worsening symptoms. And they certainly experience greater anxiety. Dr. Kathy Albain, a breast cancer specialist at Loyola University Medical Center in Maywood, Illinois, polled colleagues and patients and found overwhelming support for approving drugs based on delaying tumor progression. It would be ideal to show that a drug also prolongs life, but that may not be realistic, she said. The reason is that when a woman's cancer progresses, doctors change the drugs they use, hoping to slow the cancer. That dilutes any impact of the first drug — in this case Avastin. Kay Wissmann, director for government relations at the Breast Cancer Network of Strength, a patient advocacy group, said women should have a choice to use Avastin. "We've got some good evidence about this particular drug," she said, "so maybe we should let the people with metastatic disease have the option of using it."

Unapproved Uses
Then there are patients who cannot wait for evidence that a drug works for their cancer. One patient's husband had no medical training. But he determined through his own literature search that his wife's form of brain cancer produced a lot of VEGF, the very substance Avastin neutralized. So the couple wanted to try Avastin, even though it had never been tested for brain cancer. It was 2004, when the only Avastin approval was for colon cancer. They asked the woman's doctor, Dr. Virginia Stark-Vance, to give them the drug. Dr. Stark-Vance, a solo practitioner in Dallas and Fort Worth, was reluctant, worried that Avastin could cause bleeding in the brain. That had happened in one of the earliest clinical trials, when a 29-year-old woman whose liver cancer had spread to her brain collapsed from a hemorrhage while riding her bicycle. Finally, Dr. Stark-Vance agreed on the condition that the woman be hospitalized to receive Avastin, in case there was a brain hemorrhage. Had there been one, Dr. Stark-Vance "could have lost her license," said Dr. Henry Friedman, a brain cancer specialist at Duke. Like many others taking Avastin, this woman plunged into the unknown, without the assurance of a clinical trial studying whether the drug worked for her type of cancer. Doctors are free to prescribe Avastin, or any other drug on the market, for unapproved uses, at their discretion. As much as 75 percent of cancer drug use is of this "off label" variety, according to an estimate by the National Comprehensive Cancer Network, a group of big cancer centers. And some doctors say that with patients dying, they simply cannot wait for airtight evidence. "Of course we want everything to be evidence-based," said Dr. Yashar Hirshaut, an oncologist in New York. "I also like the American flag and apple pie. But, he explained, "You say, 'This person is dying right here and I need something that will help, and there's a logical construct that I can see how it will help.' "One of his patients, Alice Lichter, has had gastric cancer since 2006. Dr. Hirshaut is throwing the whole arsenal at it, giving her gemcitabine, a drug used for pancreatic cancer, plus virtually every drug approved for colon cancer: Avastin, Erbitux, Eloxatin, irinotecan, 5-FU and leucovorin. Most are not approved for gastric cancer. Once every two to four weeks, Lichter, 72, flies from her home in Miami and checks into Lenox Hill Hospital in New York, where she undergoes four days of intravenous infusions. "I call Lenox Hill my second home," she said. 

'You Name It, It Got Tried' 
Lichter, whose cancer appears to have receded, said she never questioned Dr. Hirshaut's judgment. And she has no idea how much her drugs cost because Medicare is paying for them and her supplemental insurance covers her co-payment. Insurers say they are often forced by state laws to pay for cancer drugs not approved by the Food and Drug Administration, and Medicare must pay if the drug's use is listed in a compendium, a reference compiled by cancer specialists, whose standards are looser than the FDA's. Such requirements are one reason about 12 percent of United HealthCare's Avastin patients have cancers other than colon, breast and lung. "Brain, stomach, pancreas, primary cancers of the liver, bladder, small bowel, larynx, prostate — you name it, it got tried," Dr. Newcomer said. But the anecdotes and evidence from small trials that may seem to justify off-label use sometimes turn out to be misleading. That happened with pancreatic cancer. After patients and doctors decided Avastin had to be helping, cancer researchers themselves conducted a large study. So did Roche. Avastin, both studies concluded, did not prolong life for people with cancer of the pancreas. For brain cancer, doctors are encouraged, although they do not really know for sure whether Avastin helps. The brain tumor in Dr. Stark-Vance's patient shrank so much after two infusions of Avastin that the radiologist who performed the brain scans called Dr. Stark-Vance in wonderment. Dr. Stark-Vance began treating more patients. Some insurers paid for the drug. Others, including Medicare and Medicaid, did not. But Dr. Stark-Vance said Genentech agreed to provide the drug free for her patients who could not otherwise pay.

As word spread, Dr. Friedman at Duke and Genentech organized studies of a type generally considered less than definitive. There was no control group that took another drug or got a placebo. Everyone got Avastin. Otherwise, no one would enroll in the study, doctors argued. Then the investigators compared the results with what they thought would have happened without Avastin. The patients lived a median of about nine months, about three months longer than the researchers estimate would have been expected. But such comparisons have led scientists seriously astray in the past because the people being treated with a new drug often are very different from previous patients who did not take it and because overall medical care steadily improves. Nonetheless, Genentech has said it planned to apply this year to the FDA for approval for Avastin to treat glioblastoma, the deadliest form of brain cancer. Dr. Stark-Vance said her initial Avastin brain cancer patient broke her hip and had to be taken off the drug because it interfered with wound healing. She eventually died. But by now, even without an FDA approval, "the whole country" is using Avastin for glioblastoma, Dr. Friedman said.

Better Than Nothing?
Gailanne Reeh remembers what life was like within a few months of those initial scans, when her cancer began causing terrible symptoms. Her abdomen grew so full of fluid that it was hard to bend to tie her shoes. Bowel movements were difficult, and even lying down was uncomfortable with that huge mass in her abdomen. She says she was chilled by what she recalls her doctor saying: "There was so much growing so fast in my abdomen and so much in my bowel, it was not a matter of maybe I would get a bowel obstruction. It was when I would get a bowel obstruction," Reeh said. "And when I got it, there would be nothing anyone could do. I would die." To try to stave off such a horrible outcome, her oncologist, Dr. Eric Winer of Dana-Farber, offered to enroll her in a clinical trial comparing Avastin with another new biotech drug. Reeh was assigned to the group that got Avastin in combination with the chemotherapy drug paclitaxel, also known as Taxol. The study closed after six months, but Reeh continued with her drug regimen, and her insurer is paying. After six months of treatment the fluid in her abdomen was down to just a trace, her tumors were stable or smaller and she felt like her former self again.

"I'm really, really excited," she said.
Was it the Avastin?
Dr. Winer said he did not know, since Taxol can also shrink tumors. It is impossible to draw conclusions from individual patients, he said. Still, he said, "I think it is quite likely that the combination of Taxol and Avastin improved her odds of having a better quality of life." Dr. Winer says that when he is not sitting in front of a patient, he thinks about whether drugs like Avastin are worth it to society. But when facing a seriously ill patient, who, based on clinical trial results, might benefit — even if only a little — from Avastin along with chemotherapy, he has to think about his patient's needs. "I can't say, 'Let's not use Avastin; it's a very expensive drug and I am worried about the cost to society,' " Dr. Winer said. And so, Dr. Winer said, the answer you get when you ask whether drugs like Avastin are worth it very much depends on whom you ask. "A person who hasn't been affected by cancer will say, 'Gee, why should we pay for an expensive treatment that doesn't extend life when we have other needs?' " Dr. Winer said. A person like Reeh will have a different response. She does not want to give up Avastin. Last month, she reluctantly stopped taking her drugs for a while because Taxol was injuring the nerves in her feet. But later this month she hopes to resume taking both drugs, or at least Avastin. Reeh says she knows her cancer may very well kill her eventually. But what is it worth to feel better again? "It's really about living and not waiting to die," she said. And what if 5 percent of Avastin patients live a lot longer than they would have without the drug? "I might be in that 5 percent," she said.

[Back]

Plastic surgeons' discarded breast tissue aids cancer research (Yahoo News)

To learn about what triggers breast cancer and how to create better treatments, scientists first have to know more about the composition and functioning of cells in normal breast tissue. So, using discarded breast tissue, donated by patients and provided by four Vancouver plastic surgeons following breast reduction surgery, B.C. cancer researchers have been able to create a catalogue of genes present in healthy breast tissue. In a study published Thursday in the journal Cell Stem Cell, 13 scientists from Vancouver, Britain and Ontario report on their highly technical analysis of normal human breast stem cells. Doctors conduct cosmetic surgery on a patient. To learn about what triggers breast cancer and how to create better treatments, scientists first have to know more about the composition and functioning of cells in normal breast tissue. We know a lot about how to kill the bulk of the tumour, but what we don't know is how to shut down the factory that is producing the parts that make the cancer in the first place" said lead author Afshin Raouf, a researcher in the Terry Fox laboratory at the B.C. Cancer Agency. His collaborators include other researchers at the cancer agency, the Ontario Cancer Institute, the University of B.C. and the United Kingdom Cambridge Research Institute. Raouf said in an interview the research lays the groundwork for learning how to eliminate the stem cells that fuel breast cancer. "We need to get smarter in drug design so that instead of killing every single molecule, we can spare healthy tissue with less toxic chemotherapy and be more specific about our biological targets. That's the ultimate goal," he said. Researchers are focused on stem cells in breast tissue because they now realize that stem cells can be like "the bad seeds (that) produce cancer." However, stem cells also play a good and necessary role in breast tissue: they help the mammary glands grow rapidly at puberty and they facilitate the expansion of breast cells during the menstrual cycle and especially during pregnancy when the breasts enlarge with cells to produce, store and secrete milk for breast-feeding infants. "Stem cells are there to create the spare parts, but we now understand that when something goes wrong with the molecules in normal stem cells, it can lead to cancer. So, before we can understand how genes get hijacked, we need to understand all the molecules present in healthy breast tissue, then compare them to those present in breast tumours," Raouf said. "If you think of tumours as a sack of coloured marbles, and imagine that we are looking for the one red-coloured marble causing the cancer, you can understand that we are trying to isolate something specific so that we can create drugs that can find those specific targets."

[Back]

Insulin resistance ups breast cancer risk (Yahoo News)

Overweight, insulin resistant women are at greater risk of advanced breast cancer diagnosis, University of Melbourne researchers said. Insulin resistance is most commonly caused by being overweight and inactive and is often a precursor to type 2 diabetes. University of Melbourne researcher Dr. Anne Cust, a key collaborator on an international study, tracked more than 60,000 Swedish women over a 20-year-period from 1985 to 2005. All were cancer free when recruited. The researchers found that women who were overweight or had signs of insulin resistance -- such as elevated blood glucose or insulin levels -- were about 50 percent more likely to be diagnosed with an advanced breast cancer tumor. "Women with insulin resistance or who were overweight were less likely to be diagnosed with stage 1 breast cancers but at greater risk of being diagnosed with stage 2 to 4 tumors -- larger more advanced cancers," Cust said. "We know that being overweight and having insulin resistance is a risk factor for getting cancer but -- in the case of breast cancer -- our study indicates that the cancer will be more advanced." The findings were presented at the Population Health Conference in Brisbane. 

[Back]

Breast Cancer Test Rates Drug Therapy Candidates (HealthDay News-8/07/2008)

The U.S. Food and Drug Administration has approved a genetic test designed to evaluate whether a person with breast cancer is a good candidate for treatment with the drug Herceptin (trastuzumab). The SPOT-Light HER2 CISH test measures how many copies of the HER2 gene are in breast tumor cells. People with breast cancer may have more than the normal two copies of this gene in each breast cell, which can cause overactive cell growth and division. Breast cancer patients with too many copies of the HER2 gene and overproduction of a corresponding protein are typically treated with Herceptin. The test was evaluated during clinical trials in the United States and Finland, using tumor samples from breast cancer patients. It's produced by Invitrogen Corp. of Carlsbad, Calif.

[Back]

Researchers Identify Breast Cancer Preventive Properties in Common Vitamin Supplement (Yahoo News)

Early laboratory research has shown that resveratrol, a common dietary supplement, suppresses the abnormal cell formation that leads to most types of breast cancer, suggesting a potential role for the agent in breast cancer prevention. Resveratrol is a natural substance found in red wine and red grapes. It is sold in extract form as a dietary supplement at most major drug stores. “Resveratrol has the ability to prevent the first step that occurs when estrogen starts the process that leads to cancer by blocking the formation of the estrogen DNA adducts. We believe that this could stop the whole progression that leads to breast cancer down the road,” said Eleanor G. Rogan, Ph.D., a professor in the Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center. Rogan was the lead author of the report that was published in the July 2008 issue of Cancer Prevention Research, a journal of the American Association for Cancer Research. For the current study, Rogan and colleagues measured the effect of resveratrol on cellular functions known to contribute to breast cancer. The formation of breast cancer is a multi-step process which differs depending on type of disease, a patient’s genetic makeup and other factors. However, scientists know that many breast cancers are fueled by increased estrogen, which collects and reacts with DNA molecules to form adducts. Rogan and colleagues found that resveratrol was able to suppress the formation of these DNA adducts. “This is dramatic because it was able to be done with fairly low concentrations of resveratrol to stop the formation of these DNA adducts in the cells we studied,” said Rogan. Although researchers experimented with up to 100 µmol/L of resveratrol, the suppression of DNA adducts was seen with 10 µmol/L. A glass of red wine contains between 9 and 28 µmol/L of resveratrol. The researchers also found that resveratrol suppressed the expression of CYP1B1 and the formation of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, two known risk factors for breast cancer. Rogan said resveratrol works by inducing an enzyme called quinone reductase, which reduces the estrogen metabolite back to inactive form. By making estrogen inactive, resveratrol decreases the associated risk. The current study was conducted in laboratory cultures, and will need to be confirmed in larger human trials, Rogan said.

[Back]

High serum estrogen linked to breast cancer recurrence (MedWire News-10/03/2008)

Women whose breast cancer recurs after treatment for a primary tumor have almost twice as much circulating estrogen as their peers who remain disease free, study findings demonstrate. Lead researcher Cheryl Rock and colleagues were somewhat surprised by the results since the majority of women in the study were treated with anti-estrogen therapy, but say their results confirm the role of estrogen in increasing the risk for initial development of breast cancer and its later recurrence. "Taking anti-estrogen drugs... may not completely wipe out the hormone's effect in women who have high levels of estrogen," Rock commented. "What the results mean for women who have already been treated for breast cancer is that they should do as much as they can to reduce estrogen in their blood, such as exercising frequently and keeping weight down," she added. Participants in the current study were drawn from the larger Women's Healthy Eating and Living Trial (WHEL) that analyzed blood samples from 3088 women who had been treated for early-stage breast cancer but who were cancer-free at the time they enrolled. Rock and colleagues selected 153 women whose cancer had recurred after a median of 7 years and compared them with 153 women who remained disease-free and were matched for clinical site, cancer stage, age at cancer diagnosis, date of cancer diagnosis, and date of randomization into the WHEL Study. The researchers found that higher serum concentrations of total estradiol, bioavailable estradiol, and free estradiol were each associated with risk for recurrence.

Indeed, women whose cancer recurred had an average total estradiol concentration that was double the average for the women whose cancer did not recur, at 22.7 pg/ml versus 10.8 pg/ml. The researchers concede that the study only investigated serum estrogen at a single time point and that numerous genetic and other factors, including diurnal variation, may influence serum hormone concentrations and their effect on risk for recurrence. Nevertheless, Rock and colleagues assert that their findings provide evidence that higher serum estrogen concentrations contribute to risk for recurrence in women who have been diagnosed and treated for early-stage breast cancer.

[Back]

Tumor grade should be routinely incorporated into breast cancer staging (MedWire News-21/05/2008)

Tumor histologic grade is an independent prognostic indicator in breast cancer and predicts survival in women with tumors of different sizes and varying lymph node involvement, UK researchers say. "We believe the treatment of [breast cancer] patients should be based on both grade and stage in addition to tumor size and not restricted to information on size and lymph node stage (TNM system)," Emad Rakha (University of Nottingham) and colleagues assert. Although histologic grade of breast cancer has long been recognized as a valuable prognostic factor, there are still some concerns regarding the incorporation of grade into routine breast cancer staging systems. Indeed, the latest Breast Task Force of the American Joint Committee on Cancer did not include histologic tumor grade in its staging criteria. One of the main reasons for omitting grade was the perceived interaction between tumor size and histologic grade and lack of clear evidence for the role of grade in small tumors (TNM stage pT1 and pT2). Rakha and colleagues investigated outcomes in 2219 breast cancer patients who were treated based on assessment with the Nottingham Prognostic Index, which incorporates tumor size, lymph node stage, and tumor grade based on degree of tubule formation, nuclear pleomorphism, and level of mitosis. Of these cases, 412 (18.6%) were grade 1, 790 were grade 2 (35.6%), and 1017 (45.6%) were grade 3. Multivariate analysis revealed that tumor grade was a significant independent predictor of breast cancer specific survival, with a hazard ratio of 3.9 for grade 3 relative to grade 1 after a median of 9 years. Crucially, tumor grade was also a significant predictor in each of the tumor subgroups when considered individually ie, tumor sizes pT1a, pT1b, pT1c, and pT2 and lymph node stages pN0, pN1, and pN2. "We recommend routine assessment of histologic grade of breast cancer using the Nottingham consensus criteria linked with good practice in tumor tissue handling and preparation," say Rakha and colleagues in the Journal of Clinical Oncology.

[Back]

HER2-positive breast cancer: from trastuzumab to innovatory anti-HER2 strategies.(Yahoo News-1/08/2008)

Overexpression of HER2 is encountered in approximately 20% of invasive breast cancers. It is an independent adverse prognostic factor and, more importantly, it is currently the best predictive factor for the activity of trastuzumab, an anti-HER2 monoclonal antibody (MoAb), which has revolutionized the treatment of this breast cancer subgroup. Increasing knowledge of molecular pathways involving the HER family of growth factor receptors has paved the way toward new efficient targeted therapies. In this report the authors review the targeted therapies of clinical importance for HER2-positive breast cancer, which include anti-HER2 MoAbs and tyrosine kinase inhibitors that directly interfere at the receptor level. 
Clinicians are still facing many uncertainties concerning the optimal use of these new agents, and scientists are working on dissecting the mechanisms of resistance developed by HER2-positive cancer cells. 
Interesting perspectives in the treatment of HER2-positive breast cancer will be discussed. They consist of designing HER2 peptide-based vaccines, targeting downstream pathway molecules beyond the membrane receptor, and exploring synergistic antineoplasic strategies. 

[Back]

Breast conservation therapy for stage I or stage II breast cancer: a meta-analysis of randomized controlled trials. (Yahoo News-19/6/2008)

In this study the authors carried out a meta-analysis to determine the effectiveness of breast conservation therapy (BCT) or mastectomy (MT) for stage I or stage II breast cancer. A fully recursive literature search was conducted in the Cochrane Controlled Trials Register Databases, Medline, EMBASE and Chinese Biomedical Literature Database in any language. Randomized controlled trials (RCTs) were considered for inclusion. Analyses were carried out using RevMan software. In all, 18 RCTs including a total of 9388 patients were included. The meta-analysis showed that the overall survival in 3, 5, 10, 15 and 20 years and the locoregional recurrence rate in 3, 5, 15 and 20 years were not statistically significantly different between group BCT and group MT, but 10-year locoregional recurrence rate increased in group BCT. The sensitivity analysis indicated that both overall survival and locoregional recurrence rate were not statistically significantly difference between group BCT and group MT. In the subgroup analysis, there was no significant difference in OS and locoregional recurrence rate between group BCT and group MT, but 20-year locoregional recurrence rate was statistically significantly higher in group BCT than group MT for women with tumors 2cm or smaller. On the basis of the results from this study it was concluded that BCT was a better choice than MT for women with stage I or stage II breast cancer. 

[Back]

European oncologists' preferences for the management of breast cancer: case presentations and expert commentary. (Yahoo News) 

The development of new cytotoxic and biological agents has brought a welcome extension in the range of therapeutic options available to women with both early-stage and advanced breast cancer. Among the most significant recent developments has been the recognition of HER2 as a prognostic factor and target for treatment. In a series of meetings across Europe, 230 experienced oncologists and an expert faculty discussed and voted on how best to treat five women whose cases were chosen to bring out important issues in treatment. In most cases, a range of options were considered appropriate, and intriguing differences emerged between countries in the choices preferred. The following represents a very abbreviated outline of the cases and the management decisions made:
Case 1, symptomatic, visceral, metastatic disease overexpressing HER2: most favoured option, trastuzumab plus docetaxel. Case 2, adjuvant chemotherapy in high-risk, hormone-negative, HER2-positive disease: favoured option, FEC-100 for three cycles, followed by three cycles of docetaxel (trastuzumab also given).
Case 3, adjuvant endocrine therapy in a postmenopausal woman with hormone-positive, HER2-negative disease: favoured option, tamoxifen for two years followed by aromatase inhibitor (either exemestane or anastrozole).
Case 4, inflammatory HER2-positive breast cancer progressing on FEC-100: favoured option, switch to a taxane plus trastuzumab. Case 5, a young woman with hormone-negative, HER2-positive disease who develops symptomatic visceral metastases a year after adjuvant FEC-100 and trastuzumab:
favoured option, enrollment in a clinical trial of the HER2 tyrosine kinase inhibitor lapatinib alone or in combination with trastuzumab or chemotherapy. 
Together, the expression of these preferences and the discussions that followed provide a valuable insight into current practice at a time of exceptionally rapid change in the management of breast cancer. 

[Back]

Risks and benefits of bisphosphonates. (Yahoo News)

Bone is the most common site for metastasis in cancer and is of particular clinical importance in breast and prostate cancers due to the prevalence of these diseases. Bone metastases result in considerable morbidity and complex demands on health care resources, affecting quality of life and independence over years rather than months. The bisphosphonates have been shown to reduce skeletal morbidity in multiple myeloma as well as a wide range of solid tumours affecting bone by 30-50%. Quite appropriately, these agents are increasingly used alongside anticancer treatments to prevent skeletal complications and relieve bone pain. 
The use of bisphosphonates in early cancer is also increasingly important to prevent the adverse effects of cancer treatments on bone health. These include ovarian suppression and the use of aromatase inhibitors in breast cancer patients and androgen deprivation therapy in those with prostate cancer. Bisphosphonate strategies, similar to those used to treat postmenopausal osteoporosis, have suggested that bisphosphonates are a safe and effective treatment for the prevention of treatment-induced bone loss. 
When compared to other cancer therapies, the frequency and severity of adverse events related to bisphosphonate therapy are generally mild and infrequent; thus, the benefits of treatment with any bisphosphonate almost always outweigh the risks. However, renal dysfunction may occasionally occur and over recent years, a new entity, bisphosphonate-associated osteonecrosis of the jaw (ONJ), has been described. The incidence, clinical importance and prevention strategies to minimise the impact of this problem on patients requiring bisphosphonates is discussed.

[Back]

Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer (Yahoo News)

Background We compared the efficacy of two different taxanes, docetaxel and paclitaxel, given either weekly or every 3 weeks, in the adjuvant treatment of breast cancer. Methods We enrolled 4950 women with axillary lymph node–positive or high-risk, lymph node–negative breast cancer. After randomization, all patients first received 4 cycles of intravenous doxorubicin and cyclophosphamide at 3-week intervals and were then assigned to intravenous paclitaxel or docetaxel given at 3-week intervals for 4 cycles or at 1-week intervals for 12 cycles. The primary end point was disease-free survival. Results As compared with patients receiving standard therapy (paclitaxel every 3 weeks), the hazard ratio for disease-free survival was 1.27 among those receiving weekly paclitaxel (P=0.006), 1.23 among those receiving docetaxel every 3 weeks (P=0.02), and 1.09 among those receiving weekly docetaxel (P=0.29) (with an hazard ratio >1 favoring the groups receiving experimental therapy). As compared with standard therapy, weekly paclitaxel was also associated with improved survival (hazard ratio, 1.32; P=0.01). An exploratory analysis of a subgroup of patients whose tumors expressed no human epidermal growth factor receptor type 2 protein found similar improvements in disease-free and overall survival with weekly paclitaxel treatment, regardless of hormone-receptor expression. Grade 2, 3, or 4 neuropathy was more frequent with weekly paclitaxel than with paclitaxel every 3 weeks (27% vs. 20%). Conclusions Weekly paclitaxel after standard adjuvant chemotherapy with doxorubicin and cyclophosphamide improves disease-free and overall survival in women with breast cancer. (ClinicalTrials.gov number, NCT00004125 [ClinicalTrials.gov] .) 

[Back]

U.K. woman conceives breast cancer gene-free baby (Yahoo News-30/06/2008)

A British woman is 14 weeks pregnant after conceiving the country's first baby guaranteed to be free of a hereditary breast cancer, doctors have revealed. The unidentified woman and her husband underwent in vitro fertilization to screen 11 embryos for the presence of one gene, BRCA-1. The woman is now 14 weeks pregnant with her first child. Women who carry either the BRCA-1 or BRCA-2 gene have a 50 to 80 percent chance of developing breast cancer. The 27-year-old woman and her 28-year-old husband, who remain anonymous, decided to go through the invasive in vitro fertilization procedure in order to produce embryos that could be genetically screened. The couple, who are fertile, decided to screen embryos using the technique called preimplantation diagnosis because the husband had tested positive for the gene, and his grandmother, mother, sister and cousin had all suffered breast cancer. "For the past three generations, every single woman in my husband's family has had breast cancer, as early as 27 and 29," the woman told British media. "I thought this was something I had to try because, if we had a daughter with the gene and she was ill, I couldn't look her in the face and say I didn't try." Five of the 11 embryos conceived in the lab were free of the gene. One of the two implanted in the woman became a viable fetus. Two healthy embryos have also been frozen for future use. "Women now have the option of having this treatment to avoid the potentially guilty feeling of passing on this genetic abnormality to a child. This gives us the chance to eradicate this problem in families," said the couple's doctor, Paul Serhal, medical director of the Assisted Conception Unit at University College London Hospital. "Women now have the option of having this treatment to avoid the potentially guilty feeling of passing on this genetic abnormality to a child. This gives us the chance to eradicate this problem in families," he said. Only one other woman, an Israeli mother-to-be, is believed to have conceived after undergoing the screening process. But critics are saying it's not morally acceptable to destroy viable embryos because they carry a gene that may cause cancer. And some ethicists are expressing concern that screening embryos for undesirable genes may lead to "designer babies" who are created for their looks or smarts. 

"What we are saying is that we don't just accept any children we happen to conceive, we want to choose them," said McGill University Professor and medical ethicist Margaret Somerville. The technique itself was actually developed 15 years ago and several clinics have been doing it for years in Canada. But doctors normally screen for genetic diseases like cystic fibrosis. Not for the potential of developing illnesses such as breast cancer. Doctors point that there are no guarantees. Despite the high incidence of cancer among women who carry the BRCA-1 and BRCA-2 genes, they account for only five per cent of all breast cancers. "You are testing for a disease which may or may not occur in a child," Dr. Simon Phillips said. Having a certain gene just means an increased risk of having cancer. Laurence Shaw, deputy medical director of the Bridge Fertility Centre in London, described the technique as "an exciting development." "It opens the door to a lot of questions about screening of diseases that might happen in the future," he told the Press Association. "However we should be aware that this does not mean that the baby born will be immune from breast cancer - it means that the baby with that gene has a decreased likelihood of having that cancer." 

[Back]

Breast Cancer Vaccines Look Promising (HealthDay- 26/06/2008)

Women with metastatic breast cancer who developed an immune response to an investigational vaccine lived twice as long as those who didn't have an immune response, new research shows. "If you were an immune responder, you had double the survival of a non-responder," said study author Dr. Susan Domchek, an associate professor of medicine at the University of Pennsylvania. Her report is one of several focusing on breast cancer vaccines expected to be discussed this week at the Department of Defense Era of Hope breast cancer research meeting, in Baltimore. "Metastatic breast cancer is treatable but not curable," Domchek said. While the ultimate hope is to cure the cancer, breast cancer vaccines are one possible way to try to control the disease's spread. Although most people think of vaccines as shots given to healthy people to prevent infectious diseases such as measles and the flu, various cancer vaccines that have been studied for decades use cancer cells, parts of cells or substances called antigens to trigger an immune response against cancer cells already in the body. In her study, Domchek used pieces of a protein called human telomerase reverse transcriptase (hTERT) peptide to vaccinate 19 women with breast cancer that had spread. The peptide is nearly universally overexpressed in human cancers and is recognized by certain T-cells in the body's immune system. At the start of the study, the women had no measurable T-cell response to hTERT. After up to eight vaccinations with the hTERT peptide, however, 13 of the 19 women made T-cells that reacted to the peptide. We biopsied the patients' breast cancer and saw that we could see these T-cells in the tumors themselves," she said. "And, in some cases, we could see evidence of tumor cells' death."

"Those who responded lived significantly longer," she said. "People who responded lived 32 months versus a median of 17 [for those who did not respond]. Three of the women who were responders have lived more than three years." Among the questions that remain, however, said Domchek, is this: "Were those women going to do well no matter what we did? Is immune response just a marker for a healthier patient?" Other research on breast cancer vaccines expected to be presented at the meeting include:
A study that focused on breast cancer patients with HER-2-positive tumors (for whom relapse is common after treatment) treated with a combination of vaccine plus an anti-cancer drug. Dr. Lupe Salazar, an assistant professor of medicine at the University of Washington, in Seattle, and her team sequenced the HER-2 protein and put pieces of it into a vaccine. They gave it to patients, along with the anti-cancer drug Herceptin. The combination helped to generate significant levels of T-cell immunity specific to the HER-2 cells, she said. As of now, "all eight [women] have done this," she said. The study will eventually include 52 women. A study that uses immunostimulatory peptides as a vaccine looked at the best way to deliver them. Dr. Davorka Messmer, an assistant project scientist at the Moores Cancer Center at the University of California San Diego, and her team tested a vaccine using nanoparticles loaded with the HER2 peptide that carry an immune system-stimulating peptide, called Hp91, on the outside or the inside. "We found it more potent if the immunostimulatory peptide was put on the surface of the nanoparticle," she said. The study was conducted in animals. While breast cancer vaccines have been studied for at least 30 years, they have yet to make a real difference in the lives of patients, said Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society. That's not to say they won't someday, he added. "When you look at the theory, it makes sense," he said. "The bottom line is, we are getting there, but [we're] not there yet." Many questions remain, he said, such as "why some patients have immune responses, and others don't." It is likely, he said, that some of the vaccines will be specific to one cancer, and others may work on more than one type of cancer.

[Back]

Genetic test will identify those most at risk of breast cancer (Yahoo News-26/06/2008)

The chances of getting breast cancer vary more than sixfold among women because of their genetic inheritance but the breast screening programme fails to target those at highest risk, scientists have found. Researchers at the University of Cambridge say it may soon be possible to offer women a genetic test based on the seven common gene sites that determine cancer risk and to focus prevention efforts accordingly. Currently doctors only test women with a very strong family history of breast cancer for the high-risk genes such as BRCA1 and BRCA2. These gene faults increase the chances of a woman developing cancer from around 9 per cent to 80 per cent. But they are rare and few women benefit from such testing. There are other common genetic variations that modestly increase the risk – but when they occur together they have a substantial effect. Around 3,300 women in the UK carry the low risk genes for each of the seven gene sites identified, who have less than half the risk of breast cancer of the general population – a 4.2 per cent lifetime risk compared with a 9.4 per cent risk. At the other end of the scale, around 400 women have high risk genes for each of the seven sites, giving them a 23 per cent risk of developing breast cancer – two and a half times that of the population as a whole. The remainder of the female population is distributed between these extremes and the researchers say genetic testing could provide each woman with an assessment of her risk of breast cancer, which could be used to target the screening programme. Currently all women over 50 are invited for breast screening every three years and they have a 2.3 per cent risk of developing breast cancer over 10 years, averaged over the whole population. With genetic testing it would be possible to offer breast screening to all women with at least the same risk (2.3 per cent) but regardless of age. A woman of 40 with a 3 per cent risk would be offered screening while a woman of 55 with a 1 per cent risk would not. 

Paul Pharaoh from the University of Cambridge, who led the study, published in The New England Journal of Medicine, said: "It is about tuning the screening programme to make it more efficient. You would screen the same number of women but pick up more cancers by targeting it on those at highest risk. "We are a few years away from a new and powerful range of genetic tests for breast cancer. Genetic testing has the potential to identify women [under 50] at increased risk who would benefit from mammography at an early age... and also to identify women [over 50] with a low risk of breast cancer who may not need such regular checks." Dr Lesley Walker, director of cancer information at Cancer Research UK, which funded the research, said: "This study marks the potential for a tailor-made approach to screening for breast cancer which could radically change who we target and how we detect early signs of the disease. Great progress has been made in our understanding of the ways in which certain genes affect the risk of breast cancer. But there is still some way to go before this kind of genetic profiling becomes a reality."

[Back]