BREAST CANCER

Exercise Reduces Risk Of Developing Invasive Breast Cancer (Yahoo News-01/03/2007) 

Significant findings have emerged from the California Teachers Study (CTS) that suggest long-term recreational physical activity plays a protective role against invasive and in situ breast cancer. "Previous studies have linked physical activity with a reduction in breast cancer, but few studies have examined risk separately for in situ and invasive breast cancers or have characterized risk by hormone receptor status," said Leslie Bernstein, professor of preventive medicine at the Keck School of Medicine of USC and primary investigator of the CTS. "This study is unique because it provides the first prospective study data documenting that a woman's long-term exercise habits are important in determining her future breast cancer risk." In a study to be published in the February 26 issue of the Archives of Internal Medicine, researchers analyzed data collected from a cohort of 110,599 women who were current or former California teachers and public school professionals with no prior history of breast cancer, and who were between the ages of 22 and 79 years at the start of the study. The study was initiated in 1995 with detailed collection of  information on women's exercise histories and current exercise habits. The study focused on the impact of strenuous activities, as well as moderate activities, collecting information on the amount each woman exercised per week from high school through age 54 years (or the woman's current age if she was younger than 54). Women were followed through the end of 2002 using information from California's statewide comprehensive cancer registry to identify which women developed breast cancer. During the 6.5 year follow-up period, 2,649 women were diagnosed with invasive breast cancer and 593 were diagnosed with in situ breast cancer, meaning the cancer was confined to the ducts or lobules of the breast. 

Invasive breast cancer risk was reduced among women participating in strenuous activity, such as swimming, jogging, or participating in aerobics activities for more than five hours per week annually, when compared to the least active women. Similar results were seen for in situ breast cancer risk. One unique finding in this study is that the benefit of long-term strenuous activity was only seen among invasive breast cancer patients with ER-negative tumors. Previous studies have suggested little to no difference in the effect of physical activity by hormone receptor status. "This finding was somewhat unexpected; however, if it is repeated in future studies of physical activity and breast cancer risk, in offers a promising complement to our current approaches to preventing breast cancer, namely the use of drugs that block estrogens, like tamoxifen or raloxifene. These drugs seem to be effective in reducing risk of ER-positive cancers, but do not impact the occurrence of ER-negative cancers," says Bernstein. "This study confirms that breast cancer risk is influenced by consistent participation in strenuous forms of exercise activity. However, it may require substantial commitment of time to achieve this lower risk," concludes Bernstein. "This study showed that risk was lower for women who exercised at least 5 hours per week and our prior studies of other groups of women have suggested a minimum of 3-4 hours per week." The research group included additional investigators from the Keck School of Medicine of USC and the USC/Norris Comprehensive Cancer Center, as well as the Northern California Cancer Center in Fremont, the California Department of Health Services Environmental Health Investigations Branch, the University of California, Irvine, and the California Department of Health Services Cancer Surveillance Section. 

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Raloxifene Cuts Risk of Certain Type of Breast Cancer  (HealthDay News-11/06/2008) 

A drug already approved to reduce the risk of breast cancer in high-risk women also seems to cut the risk for other women. A new analysis finds that those who took raloxifene (Evista) regularly over a number of years were less likely to develop invasive estrogen-receptor (ER) positive breast cancer, compared with women who did not take the drug. Raloxifene did not, however, cut the risk for noninvasive breast cancer or invasive ER-negative cancers. "This is a reaffirmation that the drug raloxifene is a very powerful SERM [selective estrogen receptor modulator] for reducing the risk of invasive breast cancer," said Dr. Jay Brooks, chief of hematology/oncology at Ochsner Health System in Baton Rouge, La. The study, published in the June 10 online issue of the Journal of the National Cancer Institute, was funded by Eli Lilly and Co., which makes Evista. SERMs block the female hormone estrogen by binding to estrogen receptors; estrogen helps fuel the growth of some breast cancers. Raloxifene and other hormonal therapies have an "estrogenic tickle" effect, explained V. Craig Jordan, author of an accompanying editorial in the journal and vice president and research director for medical science at Fox Chase Cancer Center in Philadelphia. Jordan did some of the early laboratory research on raloxifene. Raloxifene was originally developed to prevent and treat osteoporosis, and only later was found to help reduce the risk of invasive breast cancer in high-risk women. The new study expands on the original results of the RUTH (Raloxifene Use for the Heart) trial, originally designed to see if raloxifene, which has cholesterol-lowering properties, could reduce the risk of dying from coronary heart disease. The trial involved more than 10,000 postmenopausal women with coronary heart disease or at risk for the condition. Participants were randomly chosen to receive either daily raloxifene or a placebo and followed for a median of 5.6 years. 

Raloxifene turned out not to have any effect on heart disease mortality risk, but it did reduce the risk of invasive breast cancer by 44 percent, which translates into 1.2 women per 1,000 treated for one year who were spared the agony of a breast cancer diagnosis. The new analysis looked more specifically at raloxifene's effect on breast cancer and found a 55 percent lower incidence of invasive ER-positive tumors, but no effect on noninvasive breast cancer or invasive ER-negative breast cancer. According to the study authors, these findings are consistent with results from other trials involving women without heart disease. This trial and others found an increased risk of blood clots and fatal strokes among women taking raloxifene, indicating that women need to weigh the risks and benefits of the drug. Another question is how long to take raloxifene for breast cancer prevention, although the authors speculated that up to eight years might be safe and effective. "We're learning more about this class of drugs, what works and what doesn't work," Jordan said. "[Raloxifene] is good for osteoporosis, no good for coronary heart disease, but breast cancer is inhibited." 

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Zoledronic acid may inhibit breast cancer in bone; continued benefit of trastuzumab in HER2+ metastatic breast cancer (MedWire -03/06/2008)
 
Two poster presentations addressed two important questions being asked by multiple investigators: 
(1) Do bisphosphonates have anti-tumor activity, and if so, could they be used to help prevent breast cancer recurrence? 
(2) Should trastuzumab therapy be continued beyond progression in HER2+ women in the metastatic breast cancer setting, or is it time to stop and perhaps switch to another agent such as lapatinib?
Effects of zoledronic acid on bone micrometastases during neo-adjuvant chemotherapy Dr. Rebecca Aft, Siteman Cancer Center, Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO, USA. There is increasing evidence that the use of adjuvant bisphosphonates might have benefits in breast cancer beyond their ability to improve bone mineral density. Data presented by Dr. Aft lend further support to the hypothesis that bisphosphonates such as zoledronic acid may have anti-tumor activity. Dr. Aft presented the phase II study which involved 120 women with stage II-III breast cancer who were due to receive neo-adjuvant/adjuvant chemotherapy with epirubicin plus docetaxel before and after surgery between 2003 and 2006. The women were randomized to additional treatment or no additional treatment with zoledronic acid, which was administered at a dose of 4 mg every 3 weeks for 1 year. Women also received endocrine agents, radiation therapy, and trastuzumab when indicated. The aim was to look at the effects of the bisphosphonate on disseminated tumor cells (DTCs) in the bone marrow. Therefore, bone marrow aspirates were obtained at the start of the study before administration of zoledronic acid, 3 months later, and again at the end of 12 months’ treatment. DTCs in the bone marrow have been shown to correlate with an increased risk of distant recurrence in patients with early-stage breast cancer, especially if they are present in women who have been treated with adjuvant therapies. 

“We hypothesized that zoledronic acid induced changes in the bone microenvironment that would prevent the growth or survival of DTCs,” Dr. Aft and colleagues stated. At baseline, the percentage of bone marrow samples positive for DTCs was 48.3% in women randomized to no zoledronic acid and 43.3% in those randomized to receive the bisphosphonate. After 3 months, the percentage of samples with detectable DTCs was significantly lower if women had been treated with zoledronic acid than if they had not, at 30% and 47%, respectively (p=0.54). In addition, women who received the bisphosphonate were more likely to remain negative for DTCs at 3 months than those who did not receive the drug. However, at 12 months, there was no significant difference between the two groups. Commenting on these data, Dr. Julie Gralow of the Seattle Cancer Cancer Alliance in Washington State, USA, noted that there were several other studies showing that isphosphonates could decrease DTCs in bone marrow aspirates, including one by Dr. Lin et al (University of California, San Francisco, CA, USA) presented elsewhere at the ASCO 2008 meeting. [2] In the latter study, 45 patients with early-stage breast cancer with DTC already in the bone marrow were given a 4-mg intravenous injection of zoledronic acid every month for 2 years. Results showed significantly fewer DTCs in the bone marrow of women treated with the bisphosphonate at both 12 and 24 months compared with no bisphosphonate treatment. Dr. Gralow said that an outstanding question was whether zoledronic acid was treating established tumor cells in the bone marrow, or if it could be preventing tumor cells from becoming established in the bone marrow. 

The “big question”, however, is whether or not the effects on DTCs are actually a reflection of the ability of bisphosphonates to prevent metastases. She cited data on the use of clodronate and also referenced the late-breaking abstract presented earlier at the conference by Dr. Michael Gnant (Medical University of Vienna, Austria) on the Austrian Breast & Colorectal Cancer Study Group Trial 12 (ABCSG-12). [3] The latter showed improved disease-free survival in pre-menopausal patients treated with zoledronic acid every month for 6 months over those who did not receive the therapy. Dr. Gralow went on to note a recent analysis of the Z-FAST and ZO-FAST data [4] which also suggested that patients treated with zoledronic acid “upfront” every month for 6 months versus “delayed” treatment had fewer breast cancer recurrences, but these were interim results. The results of phase III studies, such as the National Surgical Adjuvant Breast and Bowel Project’s B-24 trial, the Breast International Group’s AZURE trial, and the Southwest Oncology Group’s SO307 trial - which are looking at the use of adjuvant bisphosphonates in breast cancer - are eagerly awaited, Dr. Gralow said. This is because these results could help determine if adjuvant bisphosphonate therapy does more than prevent bone loss. Trastuzumab Beyond Progression (TBP) phase III study Dr. Gunter von Minckwitz, German Breast Group, University Frankfurt, Germany.

Continuing trastuzumab beyond disease progression improves efficacy of second-line capecitabine treatment in HER2-positive (HER2+) metastatic breast cancer, according to the final efficacy analysis of the Trastuzumab Beyond Progression (TBP) study. [5] Dr. von Minckwitz presented the findings of the phase III trial on behalf of the German Breast Group (GBG). The TBP of GBG-26 study involved 156 women with HER2 positive metastatic breast cancer who had disease progression while taking trastuzumab and needed first- or second-line chemotherapy. The women were randomized to treatment with capecitabine with or without additional trastuzumab. Capecitabine was given at a dose of 2500 mg/m2 on days 1 to 14 of a 21-day treatment cycle. The key findings were that, compared with the chemotherapy alone, the combination of trastuzumab plus capecitabine:
Significantly improved the time to progression (5.6 vs. 8.2 months, respectively; p=0.03)
Was associated with a higher response rate (complete response plus partial response) as defined using standard RECIST criteria (27% vs. 48%, respectively; p=0.01) and a higher clinical benefit rate (54% vs. 75%; p=0.007)
Improved overall survival, although this was not significant (20.4 vs. 25.5 months)
Caused no increase in toxicity
Dr. Martin Piccart-Gebhart of the Jules Bordet Institute in Brussels, Belgium, was invited to comment on the study. She noted that the study had aimed to answer the second of four key questions surrounding the optimization of therapy for HER2+ metastatic breast cancer. These are: (1) Can we identify more patients who will benefit from trastuzumab? (2) Should trastuzumab be continued until progression? (3) Can trastuzumab resistance be overcome? (4) Can we improve patients’ response to trastuzumab?

Dr. Piccart-Gebhart noted that the TBP study had been closed prematurely when only 156 out of a planned 482 patients had been randomized. The study closed early because of positive findings from another study involving lapatinib in combination with capecitabine versus capecitabine alone, which showed that the principle of continuing anti-HER2 therapy after disease progression was better than using chemotherapy alone. [6,7] As a result of the early termination of the study, the patient population was rather small, she said. However, the results do provide evidence that it may be reasonable to continue to give women with HER2+ metastatic breast cancer further trastuzumab therapy despite disease progression during initial treatment. “The relative merits of trastuzumab continuation versus lapatinib continuation beyond first progression on trastuzumab remain unclear,” noted Dr. Piccart-Gebhart. She suggested that patient preference “should dictate the choice.”

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Treating advanced breast cancer (MedWire-02/06/2008)  

Treating advanced breast cancer in pre- and postmenopausal women was reviewed by several researchers during the general poster sessions at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO). In this report, we highlight data on the use of the novel estrogen receptor (ER) antagonist, fulvestrant, in postmenopausal women with advanced disease and on the use of the aromatase inhibitor (AI), anastrozole, in premenopausal women with ER+ advanced breast cancer rendered postmenopausal by treatment with the luteinising hormone-releasing receptor (LHRH) agonist, goserelin. Fulvestrant ‘effective therapy’ for heavily pretreated patients Dr. Guido Carillio, Humanitas Centro Catanese di Oncologia, Catania, Italy. “Fulvestrant represents an effective therapy for metastatic breast cancer and heavily pretreated patients who need a chemotherapy-rest for toxicity recovery,” reported Dr. Carillio and colleagues. They noted that fulvestrant is distinct and different from other endocrine therapies; it acts as an antagonist to the ER without any agonistic effects, “providing possible advantages over tamoxifen and other selective estrogen receptor modulators in the treatment of hormone-sensitive breast cancer.” Dr. Carillio and team reported their experience of using fulvestrant in 121 heavily pretreated patients with metastatic disease, all of whom had been treated between November 2005 and December 2007 and had received at least two prior endocrine therapies and a median of three chemotherapy regimens. Assessable data were available for 101 patients and this included three men with metastatic breast cancer. The median age of the patients was 59 years. Just under one fifth (16%) were HER2+ and three quarters (73%) had bone and visceral metastases.

Fulvestrant was given as an intramuscular injection at the usual approved dose of 250 mg every month. Patients received the drug for a median of 6 months, although this ranged from 3 to 26 months in the study. Half (50%) of the cohort achieved stable disease for at least 6 months and 14% exhibited partial responses to treatment. The clinical benefit rate was calculated to be 64%. Dr. Carillio and co-workers noted that several patients were able to overcome toxicities that they had experienced with chemotherapy and receive other antiblastic drugs after their disease had progressed. More often than not, these patients were aged 70 years and older. “Safety of fulvestrant was excellent,” noted the researchers. “Only a systemic intolerance reaction and unusual muscle pain in the injection site were recorded.” Pharmacokinetic profiles of high- and approved-dose fulvestrant Dr. Irene Kuter, Massachusetts GeneralHospital, Boston, MA, USA. Other data presented on fulvestrant looked at the pharmacokinetic profiles of a higher than currently approved dose of fulvestrant (500 mg) versus the usual 250 mg dose. “Fulvestrant at the approved dose (250 mg) is a well-established and efficacious treatment,” said Dr. Kuter and colleagues, “however, the question remains as to whether efficacy could be further improved with higher doses.” To find out, the Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors (NEWEST) study, is being conducted. 

The NEWEST study is a randomized, open-label, multicenter phase II trial that is looking at the effects of high dose (HD; 500 mg/month plus 500 mg on Day 14 of Month 1)) or approved dose (AD; 250 MG/month) of fulvestrant in postmenopausal women with ER+ locally advanced breast cancer who are treatment naive. Data from the primary efficacy analysis were presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2007 [3] and showed that fulvestrant HD reduced the mean Ki67 labeling index (LI) -measure of tumor activity - to a significantly greater extent than AD fulvestrant after only 4 weeks of treatment. The results of the pharmacokinetic analyses show that, in the neoadjuvant setting, increased fulvestrant exposure:
-Correlates with a reduction in Ki67 LI; 
-Is associated with reduced progesterone receptor expression; and
-Increases the chance of a tumor response. 
Studies with fulvestrant HD in the postmenopausal, hormone receptor-positive metastatic breast cancer setting are ongoing and include:
-FASLODEXTM fIRst line Study comparing endocrine Treatments (FIRST) -phase II trial of fulvestrant HD versus anastrozole as first-line therapy; and 
-COmparisoN of Fulvestrant In Recurrent of Metastatic breast cancer (CONFIRM) - a phase III study designed to “clarify the benefit of fulvestrant HD versus AD.” 
“The results of these studies will help to determine the potential role of fulvestrant HD in optimizing the use of fulvestrant in the clinic,” Dr. Kuter and co-workers concluded.

Goserelin plus anastrozole as first-line treatment for premenopausal advanced disease Dr. Amit Agrawal, University of Nottingham, Nottingham, UK.

Dr. Agrawal presented the findings of an exploratory trial looking at the first-line use of goserelin plus anastrozole in 36 premenopausal women with ER+ advanced breast cancer. The background for the trial is that AIs have “shown superiority” over tamoxifen in postmenopausal ER+ metastatic disease and that goserelin plus anastrozole has been shown to be an effective second-line treatment for premenopausal women with ER+ metastatic disease, he explained in an interview. 
To find out if the combination of the LHRH agonist and AI was also effective for the first-line treatment of premenopausal patients, Dr. Agrawal and colleagues looked at data collected from women with a median age of 44 years who were treated at the Nottingham Breast Institute between 2000 and 2007. Endocrine therapy was selected by the patients in conjunction with the multidisciplinary team for a variety of reasons, one of which was the wish to avoid chemotherapy. The women were treated with a 3.6 mg subcutaneous depot of goserelin every 4 weeks plus oral treatment with anastrozole (1 mg/day) as first-line therapy. Response rates and time to progression (TTP) were assessed. [4]The researchers noted that 24 (67%) patients derived a clinical benefit from the combination therapy, with two having complete responses, 11 partial responses, and 11 with stable disease of 6 months or more. The overall TTP was 7 months and ranged from 2 to 48 months. The median duration of therapy was at least 23 months in those who achieved a clinical benefit. At the time these data were analyzed, 13 patients had not yet progressed. “Combined therapy with goserelin plus anastrozole appeared to be effective and well tolerated as first-line therapy for premenopausal women with ER+ advanced breast cancer,” noted the team. They added that the combination was associated with decreased estradiol levels and that their findings “warrant further evaluation of dual estrogen blockade with goserelin and anastrozole in premenopausal women with HR+ advanced breast cancer.

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Cost-effectiveness of Aromatase Inhibitors; neo-adjuvant letrozole combined with lapatinib (MedWire-02/062008)

With aromatase inhibitors (AIs) replacing tamoxifen as the standard of care for many postmenopausal women requiring adjuvant endocrine therapy, the question of whether they are as cost-effective is increasingly being raised. Data presented during the general poster sessions at the 44th Annual Meeting of the American Society of Clinical Oncology showed that both anastrozole and letrozole are more cost-effective than tamoxifen when used for 5 years after surgery. Meanwhile, other data presented during the general poster sessions showed that the combination of an AI and letrozole, with an epidermal growth factor receptor (EGFR) inhibitor, lapatinib, given before surgery was not only reasonably tolerated by postmenopausal women with estrogen receptor (ER) and HER2-positive breast cancer but it also clearly induced tumor shrinkage. Cost-effectiveness of AIs versus tamoxifen: The US perspective
Dr. John Karnon, University of Adelaide, Adelaide, Australia. Dr. Karnon and colleagues used data from the Arimidex, Tamoxifen Alone or in Combination (ATAC) and Breast International Group (BIG) 1-98 trials to compare the cost-effectiveness of an AI (anastrozole or letrozole) versus tamoxifen for 5 years of adjuvant endocrine therapy in women with postmenopausal, hormone receptor-positive (HR+) early breast cancer. The analysis focused on costs in the USA. The ATAC and BIG 1-98 trials demonstrated the superiority of an AI over tamoxifen as an adjuvant endocrine therapy in terms of improved disease-free survival (and time-to-distant recurrence) and reduced incidence of certain side effects such as endometrial cancers and thrombotic events. “ More effective hormonal therapies that reduce the rate of recurrence in patients with early breast cancer may reduce downstream healthcare costs, improve quality of life, and increase survival,” Dr. Karnon and associates reported.

For their analysis, the team used the mathematical Markov model to look at the likely healthcare costs of 5 years of adjuvant endocrine treatment with anastrozole, letrozole or tamoxifen in terms of quality of life years (QALY) gained. They assumed a variety of factors such as the annual costs of treatment in the USA (e.g. annual drug costs), the costs of remaining disease-free, and the costs of of treating women who experienced disease recurrence (e.g. contralateral, loco-regional, distant), among others. Dr. Karnon and colleagues found that both anastrozole and letrozole are more cost effective than tamoxifen, and furthermore they suggested that letrozole is more cost effective than anastrozole. However, their calculations are based upon the 68-month follow-up data of the ATAC trial, and not the most recent analysis performed at a median of 100-months of follow-up. These 100-month data clearly showed continued benefits of using anastrozole over tamoxifen and that the risk of AI-induced bone fracture drops after 5 years of treatment to around the normal level expected for a postmenopausal woman, not treated for breast cancer.

Letrozole combined with lapatinib before surgery (LET-LOB study)
Dr. Antonio Frassoldati, Modena University Hospital, Modena, Italy. 
Explaining the rationale behind the ongoing phase IIbneo-adjuvant letrozole combined with lapatinib (LET-LOB) study in an interview with MedWire, Dr. Frassoldati commented that the main reason for conducting the investigation was “ to try to avoid the onset of resistance to hormone therapy by combining letrozole with a drug that inhibits both the HER1 and HER2 pathways that are up-regulated when there is a resistance to letrozole.” The LET-LOB trial is investigating the use of the AI plus lapatinib versus letrozole alone for 6 months before surgery in postmenopausal women with HR+ disease. For inclusion in the trial, women have to have histologically confirmed infiltrating primary breast cancers of at least 2 cm or greater in diameter. Before treatment and at the time of surgery, core biopsies are being taken and analyzed for EGFR (HER1), HER2, and a variety of other biomarkers. Surgery is performed within 2 weeks of the last dose of drug treatment. Dr. Frassoldati noted that the data he was presenting were preliminary. As of the end of April 2008, when the safety analysis was performed, around one third (n=37) of the required 91 patients needed for the trial had been randomized, and 25 of these had been enrolled for at least 6 months. Three of these 25 patients withdrew from the study, one withdrew consent, another experienced toxicity, and the third patient experienced disease progression. Dr. Frassoldati presented safety data on the remaining 22 patients all of whom had received pre-operative therapy, 16 of whom had undergone surgery.

The median age of the 25 evaluated patients was 66 years; 44% of women had stage IIA tumors, 44% had stage IIB tumors, and 12% had stage IIIA tumors. About half (52%) of the women had been recommended to have a mastectomy and the other half (48%) had been recommended for breast-conserving surgery. The majority (84%) of women had ductal carcinomas, with 8% having lobular tumors and 8% having other tumor types. Most (48%) tumors were grade 3, with about a quarter being grade 2. Most (68%) women had tumours that were HER2-negative, 68% were ER+ and progesterone receptor-positive (PR+), and 28% were ER+ but PR-.Adverse events (n=71) observed tended to be grade 1 or 2, with skin rash and diarrhea being the most frequently reported, affecting around 60% and 40% of patients, respectively. Cardiac safety was evaluated, and there were no episodes of congestive heart failure, although one patient did have a mild (grade 1) reduction in their left ventricular ejection fraction (LVEF). The mean LVEF for all patients was 60.7% at baseline and 61.7% after 24 weeks. Although clinical responses were observed, it is not currently possible to determine if these were due to the combination therapy or the AI alone, because the data remains blinded. At 3 months and 6 months, however, the respective values for complete response were 0% and 9%; values for partial response were 23% and 48%; values for stable disease were 73% and 43%; and values for progressive disease were 4% and 0%. There was an approximately 40% increase in the number of women able to undergo conservative surgery in comparison with mastectomy. Dr. Frassoldati noted that it is not expected that lapatinib will have activity by itself in this study, but that it might be able to moderate the expression of HER1/2 such that resistance to the AI therapy does not occur.

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Taxane versus non-taxane chemotherapy: Do taxanes matter? (MedWire-02/06/2008)

Improving survival in women with primary, node-positive breast cancer takes many approaches and one discussed during today’s poster sessions highlighted the benefits of using a taxane-based regimen. Dr. Dimitris Mavroudis from the University Hospital in Heraklion, Greece presented data from a randomized phase III trial comparing docetaxel with 5-fluorouracil, epirubicin and cyclophosphamide (FEC). Furthermore, Dr. Ulrike Nitz from the University of Düsseldorf in Germany presented the interim findings of the Intergroup EC-Doc Trial, which compared epirubicin plus cyclophosphamide (EC) followed by docetaxel against cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) or cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Both trials were initiated before the value of using taxane-based regimens was fully known. Commenting on these data, which are reported below, Dr. Linda Vahdat of Weill Cornell Medical College in New York, NY, USA, noted that they “ added to” and “ reflected” the “ existing body of literature” on the use of taxanes. She cited a recent meta-analysis by Dr. Laurentiis et al, which showed that adding a taxane to an anthracycline-based regimen clearly improved both disease-free and overall survival (DFS/OS) in high-risk women. Importantly, this meta-analysis showed that the benefits of taxane therapy appear to be independent of patients’ estrogen receptor status, degree of nodal involvement, the type of taxane used, the age and menopausal status of patients, and the administration schedule. Dr. Vahdat subsequently commented that taxanes are probably of benefit in most women with node-positive disease, and future research is likely to look at identifying women who are not likely to benefit from a taxane-based approach.

Docetaxel followed by anthracyclines improves relapse-free survival
Dr. Dimitris Mavroudis, University Hospital, Heraklion, Greece. 
The phase III trial presented by Dr. Mavroudis examined the role of adding docetaxel to an anthracycline-based regimen in the adjuvant treatment of node-positive, early breast cancer. “ At the time this study was initiated (1995), no data were available on the value of taxanes in the adjuvant setting,” the researchers explained. A total of 756 women with axillary node-positive operable breast cancer were recruited and randomized to treatment with four cycles of docetaxel followed by four cycles of EC or six cycles of FEC. Docetaxel was dosed at 100 mg/m2, epirubicin at 75 mg/m2, cyclophosphamide at 700 mg/m2, and 5-fluorouracil at 700 mg/m2. Treatment was given for 21 days with a 7-day rest period before the next cycle. The median age of the patients was 56 years in the docetaxel-EC arm and 57 years in the docetaxel-FEC arm. Approximately two thirds of patients in each arm were hormone receptor (HR)-positive, and approximately one-third had one to three positive nodes, around 45% had four to nine positive nodes, and 19-21% had 10 or more positive nodes. After a median follow-up of 62.5 months in the docetaxel-EC arm and 52.7 months in the docetaxel-FEC arm, more patients treated with the EC regimen than those treated with the FEC regimen met the primary endpoint of DFS (74.8% versus 68.9%, respectively; p=ns). The estimated 5-year OS rates were 83.3% and 82.4%, respectively. Granulocyte-colony stimulating factor was given to 90% of patients treated with docetaxel-EC and 74% of those receiving docetaxel-FEC (p=0.0001), but the rate of grade 3 and 4 febrile neutropenia and neutropenia was still higher in the patients who received the taxane-based regimen as compared with FEC (8% and 72% vs. 3% and 42%, respectively). Diarrhea was also more common in patients treated with docetaxel-EC versus docetaxel-FEC (3.7% vs. 0%, p=0.0001).

Dr. Mavroudis and co-workers concluded, “ Docetaxel followed by EC is more effective but also more toxic than FEC as adjuvant treatment for women with axillary node-positive early breast cancer.” Interim results of Intergroup EC-Doc Trial: Added taxane improves DFS. Dr. Ulrike Nitz, University of Dü sseldorf, Dü sseldorf, Germany. 
Dr. Nitz and colleagues presented interim data from the Intergroup EC-Doc Trial, which involved 2011 women with a median age of 52 years and one to three positive nodes. Similar to the study presented by Dr. Mavroudis and colleagues, the majority (78%) of women in this trial were HR-positive. In this trial patients were treated with either six cycles of CMF/CEF or four cycles of EC followed by four cycles of docetaxel (EC-Doc). Drug dosages were as follows: 

CMF 
o 5-flurouracil: 600 mg/m2
o Methotrexate: 40 mg/m2
o Cyclophosphamide: 600 mg/m2

CEF 
o 5-flurouracil: 500 mg/m2
o Epirubicin: 100 mg/m2
o Cyclophosphamide: 500 mg/m2

EC-Doc 
o Epirubicin: 90 mg/m2
o Cyclophosphamide: 600 mg/m2
o Docetaxel: 100 mg/m2


If indicated, patients were treated with endocrine therapy (tamoxifen and aromatase inhibitors), as well as post-surgical radiation therapy. After a median follow-up of 41 months, DFS was 91% in patients who received EC plus docetaxel compared with 85.5% in patients who received CEF or CMF. As expected, grade 3 and 4 toxicities (notably, febrile neutropenia) were more common in patients who received EC-Doc than in those who received CMF/CEF, although both treatments were considered well tolerated. The majority of grade 3 and 4 toxicities were reported during the first cycle of therapy, reducing with the subsequent three cycles. “ The results suggest the addition of a third-generation taxane based chemotherapy to conventional endocrine treatment in an otherwise intermediate risk group might be clinically relevant,” Dr. Nitz and team concluded. “ Further subgroup analyses are going.”

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European agency green-lights new breast cancer drug (YahooNews-13/06/2008)

GlaxoSmithKline announced today that the European Commission has granted a conditional marketing approval for lapatinib (Tyverb®), in combination with capecitabine for the treatment of certain types of advanced breast cancer. A unique, empowering, and often humorous story about the journey of a woman who has experienced breast cancer from many perspectives. The approval covers breast cancer tumors that over produce the HER2 protein, one of a small number of proteins known to be mutated in human breast and ovarian cancer. The approval is for lapatinib use in patients who have breast cancer that has spread to other parts of the body, and continues to progress despite prior treatment with combination chemotherapy and therapy with trastuzumab (Herceptin®). "Today's news will benefit women across Europe with HER2-positive advanced or metastatic breast cancer which needs further treatment after the previous standard treatments of anthracyclines, taxanes, and trastuzumab," said Dr. David Cameron, co-principle investigator of the Phase III trial that led to the drug's approval. "Lapatinib will play a valuable role in treating this especially aggressive form of advanced breast cancer, with the added benefit of convenience being a pill rather than needing intravenous administration." The approval was based on a Phase III large comparison trial in which women with locally advanced or metastatic HER2-positive breast cancer were given lapatinib plus capecitabine, compared to those given capecitabine alone. The data showed that the median time to progression was 5.5 months (23.9 weeks) in the lapatinib plus capecitabine group compared to 4.2 months (18.3 weeks) in the capecitabine alone group. 

The company is currently working with local regulatory authorities to ensure lapatinib is available to eligible patients as soon as possible. Lapatinib has a new mechanism of action that is different from current therapies that target the HER2 protein. It is administered orally and works by getting inside the cancer cell and blocking two receptor proteins involved in tumor growth and cell division. The most common adverse events during therapy with lapatinib plus capecitabine were gastrointestinal upset (diarrhea, nausea and vomiting) or skin disorders (rash and hand and foot syndrome). Diarrhea and rash were more common with the combination than with capecitabine alone. The majority of adverse events were mild to moderate in severity, and the incidence of serious to severe (grade 3 and 4) side effects was low and similar in both treatment groups. Lapatinib has also been associated with reports of adverse affects on heart, lung and liver function. Tykerb® is the brand name used for lapatinib in the United States and certain other countries. Tyverb® is the brand name used for lapatinib in Switzerland and in the European Union.

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Bone drug works for breast cancer survivors ( Reuters Health-18/06/2008)

Risedronate, better known by the brand name Actonel, is effective for maintaining or improving the bone strength of women who have had chemotherapy for breast cancer, researchers report. They explain in the Journal of Clinical Oncology that add-on chemotherapy has prolonged survival for women with breast cancer. However, chemotherapy brings on early menopause, which leads to the bone-thinning disease osteoporosis and to bone fractures. To investigate the usefulness of risedronate in combating these effects, Dr. Susan L. Greenspan of the University of Pittsburgh and colleagues assigned 87 women who had undergone chemotherapy to take risedronate or a placebo once a week. Many of the women in the study were also taking a so-called aromatase inhibitor such as letrozole to reduce the odds of a cancer relapse, and this made a difference to bone density. For example, by the end of the 24-month study, women in the placebo group had a significant reduction in bone density of 4.8 percent at the spine and 2.8 percent at the hip if they were on an aromatase inhibitor. Those in the placebo group who were not taking an aromatase inhibitor maintained bone density at the spine, but had a significant 1.2 percent loss at the hip. For women given risedronate, spine bone density fell by 2.4 percent and remained stable at the hip if they were also taking an aromatase inhibitor. The greatest improvement was seen in women on risedronate who were not taking an aromatase inhibitor: spine bone density rose by 2.1 percent and there was a 2.2 percent increase at the hip. Risedronate "proved to be effective with or without the use of an aromatase inhibitor," Greenspan and her colleagues conclude. Further studies, they add, are needed to see whether these improvements in bone density "translate to fracture reduction for these patients."

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Drug may become new breast cancer therapy (UPI-20/05/2008)

A U.S. study shows Gefitinib, a once-promising drug for treating lung cancer, can enhance hormonal therapy for treating some metastatic breast cancers. The finding concerning the drug, also known as Iressa, represents the first positive study involving breast cancer for the entire class of drugs known as epidermal growth factor receptor, or EGFR, tyrosine kinase inhibitors, said Dr. Massimo Cristofanilli, the study's principal investigator at the University of Texas M.D. Anderson Cancer Center. 
"We initiated this study in 2003 with hopes of reducing the resistance to hormonal therapy," said Cristofanilli. "There was a lot of preclinical work indicating that, in fact, resistance to hormonal therapy is strongly associated with an activated EGFR pathway. Also, EGFR over-expression has been associated with endocrine resistance. If there's a double blockage of the EGFR and the estrogen receptor, you may achieve better control of the disease." Cristofanilli will present the findings in Chicago June 1 during the annual meeting of the American Society for Clinical Oncology.

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