Breast Cancer

Hormonal therapies have longplayed an important role inthe treatment of metastaticand early-stage breast cancer. Afterdemonstrating equivalent efficacy andless toxicity than high-dose estrogen,tamoxifen-a selective estrogen-receptormodulator (SERM)-has beenwidely used for the treatment of metastaticbreast cancer.[1] Multiple randomizedadjuvant trials subsequently demonstrated that patients treated withtamoxifen experienced fewer breastcancer recurrences, leading to its widespreaduse in the adjuvant setting.[2]

Published literature indicates that the selective estrogen-receptormodulators (SERMs) tamoxifen and raloxifene (Evista) have favorableeffects on bone density, lipid profiles, and the incidence of secondbreast cancers, and unfavorable effects on the incidence of venousthrombosis and hot flushes. Tamoxifen increases the risk of endometrialcancer, but raloxifene does not. The effects of SERMs on sexualfunction and cognition are unclear. Because the selective antiaromataseagents are relatively new, the long-term effects of these agentson normal tissues are less well established. It appears that the nonsteroidalagents (anastrozole [Arimidex], letrozole [Femara]) and steroidal(exemestane [Aromasin]) antiaromatase agents may have differenteffects on normal tissues. Preliminary data demonstrate that anastrozoleincreases the risk of arthralgias and produces a decrease in bonedensity. In contrast, exemestane appears to favorably affect bonedensity and lipid profile, similar to tamoxifen and raloxifene. Theincidence of contralateral breast cancer is decreased in women onadjuvant anastrozole, but data for the other antiaromatase agents arenot yet available. Hot flushes have been reported with the use ofselective aromatase inhibitors, but their incidence seems to be comparableto what is reported with SERMs. Antiaromatase agents do notappear to cause venous thrombosis. More information about the effectsof the antiaromatase agents on normal tissue will become available asdata from ongoing adjuvant and chemoprevention trials are reported.Clinically, we should be conscious of the differences between antiaromataseagents and SERMs and their impact on women’s health.

With the advent of aromataseinhibitor use in the adjuvantsetting,[1] and the inceptionof trials examining their usefor breast cancer prevention, it seemsprudent to evaluate what we know todate about the long-term effects of these agents. Unfortunately, unlike selectiveestrogen-receptor modulators(SERMs)-in particular tamoxifen,[2]which has been used for over 15 yearsin patients with early-stage breast cancer-long-term data on the use of aromataseinhibitors are minimal.

SAN ANTONIO-Ductal lavage was associated with a high false-negative rate in a recent study, according to Seema A. Khan, MD, associate professor of surgical oncology, Lynn Sage Breast Center at Northwestern University. Moreover, about half of the non-fluid-yielding ducts examined in the study contained cancer, she said at the 25th Annual San Antonio Breast Cancer symposium (abstract 25).

SAN ANTONIO-Once-weekly treatment with recombinant human erythropoietin (epoetin alfa, Epogen, Procrit), given concurrently with adjuvant chemotherapy for breast cancer, maintains or improves hemoglobin levels while attenuating decreases in quality of life (QOL), interim trial results show.

SAN ANTONIO-Adding the epidermal growth factor receptor (EGFR) inhibitor gefitinib mesylate (Iressa, also known as ZD1839) to tamoxifen (Nol-vadex) has improved initial antitumor response and delayed the development of acquired tamoxifen resistance in a xenograft model of human breast cancer, according to Rachel Schiff, PhD, of Baylor College of Medicine’s Breast Center. Dr. Schiff reported her group’s results at the 25th Annual San Antonio Breast Cancer Symposium (abstract 18).

SAN ANTONIO-Elderly women are less likely to receive radiotherapy (RT) after breast-conserving surgery, an omission that has a negative impact on survival in this group, Pauline T. Truong, MD, said at the 25th Annual San Antonio Breast Cancer Symposium (abstract 29). The researchers, from the Breast Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver Island, BC, examined the impact of omitting radiation therapy among 5,557 women, age 50 to 89, with T1-2, M0 invasive breast cancer who were treated with breast-conserving surgery between 1989 and 1998. The women were stratified by age (50 to 64, 65 to 74, and 75 to 89) and by type of treatment (postsurgery radiation or no radiation). Multivariate analysis took into account patient age, tumor factors, and treatment factors. The median follow-up was 6.4 years.

BETHESDA, Maryland-Well-established epidemiological evidence shows that neither an induced nor a recognized spontaneous abortion increases a woman’s risk of breast cancer, a workshop convened by the National Cancer Institute (NCI) concluded after an extensive review of the available scientific data. However, important gaps exist in the understanding of how events prior to and during pregnancy may affect a woman’s risk of malignant breast tumors, and those gaps need to be filled, the workshop’s report added (see Table).

SAN ANTONIO-Treatment with a bisphosphonate can counteract bone mineral density (BMD) deterioration in hormone-receptor-positive premenopausal breast cancer patients undergoing combined endocrine treatment, according to preliminary study results of a large, prospective, controlled multicen-ter trial presented at the 25th Annual San Antonio Breast Cancer Symposium (abstract 12).

SAN ANTONIO-A large Swedish cohort study of hormone replacement therapy (HRT) use and breast cancer suggests that women on progestin-containing regimens are three times more likely to develop breast cancer than are women who have never used HRT. Estrogen-only preparations, in contrast, did not appreciably increase the risk, said Hakan Olsson, MD, professor of oncology, University Hospital, Lund, at the 25th Annual San Antonio Breast Cancer Symposium (abstract 34).

SAN ANTONIO-Results of two randomized International Breast Cancer Study Group (IBCSG) trials of chemoendocrine therapy for node-negative breast cancer suggest that adjuvant chemotherapy may provide additional benefit over endocrine therapy alone for patients with estrogen-receptor (ER)-negative, but not ER-positive, tumors.

PITTSBURGH-Long-term follow-up data from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials of tamoxifen plus chemotherapy in node-negative, estrogen receptor (ER)-positive breast cancer patients suggest that chemotherapy does not add to the benefits of tamoxifen among women aged 60 or older. Bernard Fisher, MD, distinguished service professor at the University of Pittsburgh and past chairman and scientific director of the NSABP, reviewed the results of several trials, beginning with NSABP B-20. That trial established the value of combining cyclophosphamide (Cytoxan, Neosar), methotrexate, and fluorouracil (CMF) with tamoxifen in node-negative, estrogen receptor-positive women.

NORFOLK, Virginia-Using an innovative technique called protein chip mass spectrometry, researchers at Eastern Virginia Medical School in Norfolk have identified specific serum protein profiles that may enhance the detection of breast cancer. Lori Wilson, MD, previously research associate at Eastern Virginia Medical School and now surgical oncology fellow at John Wayne Cancer Institute in Santa Monica, California, reported that in early testing, the biomarker profiles have shown a specificity and sensitivity that approaches that of mammography.

EDINBURGH-Idarubicin (Idamycin) paired with capecitabine (Xeloda) and administered orally is well tolerated and active as a first-line treatment for older women with breast cancer, according to results of a recent dose-finding study. The oral idarubicin/capecitabine regimen was associated with 8 responses among 16 postmenopausal women who had chemotherapy-naive locally advanced or metastatic breast cancer, according to David Cameron, MD, senior lecturer in oncology at Western General Hospital, University of Edinburgh.

FAIRFAX, Virginia-In women with HER2/neu-positive advanced breast cancer, augmenting trastuzu-mab (Herceptin)/paclitaxel with carboplatin (Paraplatin) provides superior response and time to progression, results of a randomized phase III trial suggest. The response rate was 52% for patients who received trastuzu-mab/paclitaxel/carboplatin (TPC), significantly higher (P = .04) than the 36% response rate for trastuzumab/paclitaxel (TP). Time to progression was 11.2 months for TPC, vs 6.9 months for TP (P = .007). Investigator Nicholas J. Robert, MD, chairman of the US Oncology Breast Committee, Fairfax, Virginia, presented the results.

CHICAGO-The novel biologic agent ZD1839 (gefitinib; Iressa) provided some clinical benefit, and may have relieved bone pain, in heavily pretreated patients with advanced breast cancer, according to results of a recent phase II trial. Of 63 patients treated, 9 or 14.3% had a partial response or stable disease, and 15% of patients remained on treatment for 4 to 8 months or longer

MIAMI-As neoadjuvant therapy for breast cancer, docetaxel (Taxotere) plus cisplatin delivers pathologic complete response rates as good or better than standard anthracycline-containing regimens, results of a nonrandomized study suggest. The study involved 57 patients with locally advanced and inflammatory breast cancer.

CHICAGO-A capecitabine (Xeloda) plus paclitaxel regimen is effective and safe as first-line treatment of metastatic breast cancer, according to 3-year results of a multicenter, phase II study. Toxicity was manageable, with a relatively low incidence of grade 3/4 adverse events, including hand-foot syndrome. The study, which is among the latest to evaluate the potential for synergy between capecitabine and taxanes, was described by William J. Gradishar, MD, associate professor of medicine at Northwestern University Medical School, Chicago.

SAN ANTONIO, Texas-The genetic signature of breast tumors seems to be a powerful predictor of aggressiveness and metastatic potential, outperforming the individual clinical parameters that have traditionally been used, according to several presentations at the San Antonio Breast Cancer Symposium.

SYDNEY, Australia-Capecitabine (Xeloda) plus docetaxel (Taxotere) is a cost-saving treatment for patients with advanced breast cancer previously treated with an anthracycline-containing regimen, results of an economic analysis suggest. The combination, shown in a pivotal randomized trial to provide a significant survival benefit over docetaxel alone in advanced breast cancer, is also associated with a decrease in total treatment costs, according to Carlene Todd, health economist with Roche Products Pty. Ltd., Sydney, Australia.

HEIDELBERG, Germany-Breast cancer patients who have received prior hormone-replacement therapy (HRT) have a significantly reduced risk of metastasis to bone, lung, and liver, according to a study reported by Ingo J. Diel, MD, of the Institute for Gynecological Oncology in Mannheim Germany. Dr. Diel was previously affiliated with the Department of Obstetrics and Gynecology at University Hospital in Heidelberg, Germany. The German study supports previous reports of improved outcome for breast cancer patients who have used HRT.

SAN ANTONIO-A 10-year update of Canada’s MA.5 trial has found a continuing survival advantage for node-positive premenopausal breast cancer patients treated with adjuvant cyclophosphamide/epirubicin (Ellence)/fluorouracil (5-FU) (CEF) vs those given classic cyclophosphamide/methotrexate/5-FU (CMF).

SAN ANTONIO, Texas-In women with node-positive breast cancer, shortening the time between adjuvant chemotherapy cycles significantly reduces mortality and risk of recurrence, with no significant increase in toxicity, according to results of a large, randomized cooperative group trial. Interim analysis from Cancer and Leukemia Group B (CALGB) 9741 showed that dose-dense chemotherapy reduced mortality by 31% and risk of recurrence by 26% vs conventional administration.

SAN ANTONIO-In women with primary breast cancer, the tumor invasion factors urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) can predict benefit from adjuvant chemotherapy and should support clinical decision making, according to European investigators who for years have been studying the role of these two molecules in breast cancer. Nadia Harbeck, MD, of Technical University, Munich, Germany, described their most recent findings at the 25th Annual San Antonio Breast Cancer Symposium (abstract 7).

PITTSBURGH-Women with benign breast disease were 54% more likely to develop invasive breast cancer than were women without a diagnosis of benign breast disease, according to an analysis of data from Breast Cancer Prevention Trial (BCPT) of the National Surgical Adjuvant Breast and Bowel Project (NSABP). Lead investigator Jiping Wang, MD, a research associate in biostatistics at the University of Pittsburgh and a statistician for the NSABP, reported that the risk associated with benign breast disease was higher among women age 50 and older.

The use of aromatase inhibitorshas increased dramatically inthe past few years as a resultof the emergence of new, more specificagents, such as anastrozole(Arimidex), exemestane (Aromasin),and letrozole (Femara). This class ofagents effectively blocks the peripheralformation of estradiol, decreasingits concentration to less than 10%,while maintaining selectivity.[1]Evaluation of these selective aromataseinhibitors as adjuvant therapyfor early-stage breast cancer wasbased on the findings of trials inmetastatic breast cancer, summarizedby Visvanathan and Davidson, thatdemonstrated the equivalence and,in some cases, superiority of thearomatase inhibitors comparedwith megestrol and tamoxifen,including their superior side-effectprofile.[2-4]

Breast cancer oncologists makechoices between agents withinthe same therapeutic classevery day-eg, paclitaxel vs docetaxel(Taxotere), doxorubicin vs epirubicin(Ellence), tamoxifen vs anaromatase inhibitor. In the case ofchemotherapeutic agents, we do notyet have results from adequately powereddirect comparisons, and so, decisionsare based on indirectcomparisons between trials, safetyconsiderations, side-effect profiles,cost considerations, and clinical experience.In the case of adjuvantaromatase inhibitor therapy vs tamoxifen,the results of a huge trial areavailable to consider and, indeed, reconsider.In the years to come, theArimidex, Tamoxifen Alone or inCombination (ATAC) trial experiencewill be augmented with resultsfrom multiple other trials that addressalmost all the worthwhile clinicalquestions (except 5 vs 10 yearsof an aromatase inhibitor).

BEIRUT, Lebanon-Vinorelbine (Navelbine) plus capecitabine (Xeloda) is a highly effective and well tolerated first-line chemotherapy regimen for metastatic breast cancer, according to results of a recent 30-patient multicenter phase II trial. Investigators reported a response rate of 67%, with the main toxicity being grade 3/4 neutropenia in 13% of patients.

The aromatase inhibitors are regarded as standard approaches tofirst- or second-line endocrine therapy in women with hormoneresponsivemetastatic breast cancer. Their efficacy and apparent lackof toxicity have led to their evaluation as adjuvant therapy. Althoughinitial results with these agents in early breast cancer are promising,our collective long-term experience documenting tamoxifen’s benefitsand our uncertainty about the long-term effects of aromatase inhibitorssuggest that it is too early to recommend their routine use in theadjuvant setting. However, anastrozole is also a reasonable therapeuticoption in the adjuvant setting, particularly in individuals with acontraindication to tamoxifen such as those with thromboembolicdisease or those who develop breast cancer while receiving tamoxifenor raloxifene (Evista) therapy. Anastrozole (Arimidex) was recentlyapproved by the Food and Drug Administration for the adjuvanttreatment of postmenopausal women with hormone-receptor–positiveearly breast cancer. Ongoing trials are assessing the potential role ofaromatase inhibitors in the adjuvant, neoadjuvant, and preventivesettings.

SAN ANTONIO-In the first phase II trial of gefitinib (Iressa, also known as ZD1839) in breast cancer, the agent showed limited activity in patients with heavily pretreated metastatic breast cancer, according to a report presented at the 25th Annual San Antonio Breast Cancer Symposium (abstract 20).