Breast Cancer

Over the past 2 decades, breast-conservation therapy with lumpectomyand whole-breast radiotherapy has become a standard option for themajority of women with newly diagnosed breast cancer. Long-term localcontrol is achieved in approximately 85% of patients, and the therapy isgenerally well tolerated. There can, however, be long-term effects on thebreast and other nearby tissues that may range from asymptomaticfindings on examination to severe, debilitating problems. Infection, fatnecrosis, and severe musculoskeletal problems such as osteoradionecrosisor soft-tissue necrosis are uncommon, affecting less than 5% ofpatients. However, changes in range of motion, mild-to-moderate musculoskeletalpain, and arm and breast edema are much more common.As more women choose breast-conservation therapy for management oftheir breast cancer, physicians will encounter these problems, as well asin-breast tumor recurrence, with greater frequency. This review willfocus on the incidence, contributing factors, and management of thelate problems of infection, fat necrosis, musculoskeletal complications,and local recurrence following breast-conservation therapy.

Breast-conserving therapy maywell be the best-studied therapyin all of medicine, with dataavailable from seven mature prospectiverandomized trials that comparedoutcomes with the “gold standard” ofablative mastectomy, as well as datafrom specific programs across thecountry and globe, reflecting a broadrange of clinical and technical skillsand philosophic and technical variationson the theme of breast-conservingtherapy. However, relatively littlehas been published on the late effectsof this therapy. Frassica et al havedone an excellent job of producing adescriptive catalog of the majority ofpotential late effects in patients whosurvive breast-conserving therapy,complete with suggestions regardingmanagement.

Sequelae that affect quality of lifein women following breastconservationtherapy can begrouped into three categories: (1) thosethat affect cosmesis such as skinchanges, distortion, and asymmetry ofthe breasts; (2) those that cause physicalsymptoms such as local pain, decreasedmobility of the ipsilateralshoulder, and in extreme cases, respiratoryand cardiovascular impairments;and (3) those that require furthertreatment such as breast infection andabscess, arm edema, soft-tissue andbone necrosis, rib fractures, in-breasttumor recurrence, and second malignancieswithin the treated area.

The adverse effects of cancertreatment can be divided intothree groups: those that aresignificant and life-threatening, thosethat are not life-threatening but resultin lifestyle changes, and those that areof minor severity and limited duration.The potential significant and lifethreateningeffects of radiation in thetreatment of breast cancer includecardiac toxicity and carcinogenesis.Two prospective randomized trials ofbreast-conserving surgery and radiationhave demonstrated no increase inthe risk of non–breast cancer death at20 and 25 years among patients whoreceived radiation compared to thosetreated by mastectomy.[1,2]

ASCO—Three studies of MRI screening for women at high risk of breast cancer, presented at the 39th Annual meeting of the American Society of Clinical Oncology, show high sensitivity and the ability to detect cancers missed on mammography or ultrasound, but in two of the studies, the technique had lower specificity than mammography, resulting in unnecessary biopsies. The better specificity seen in the study from Germany may stem from the greater experience of the physicians involved in that study. The researchers agreed that MRI is not recommended for breast cancer screening in the general population, but should be considered in high-risk women as a complement to mammography, in an attempt to find breast cancers early in these women and reduce the need for prophylactic mastectomies. The German researchers, however, suggested that MRI could replace mammography screening in women at high risk of developing the disease. German Study

ASCO—Although evidence-based medicine tends to support the use of single-agent chemotherapy for metastatic breast cancer, trials are beginning to document a benefit from combination chemotherapy. One study, reported at the 39th Annual Meeting of the American Society of Clinical Oncology (abstract 25), showed a statistically significant improvement in time to disease progression and objective response when the combination of gemcitabine (Gem-zar) and paclitaxel was compared with paclitaxel alone. "Because of the favorable risk benefit profile reported in this clinical trial, gemcitabine/paclitaxel is a new treatment option for metastatic breast cancer patients who may benefit from combi-nation chemotherapy," said Joyce O’Shaughnessy, MD, codirector of the Breast Cancer Prevention Program, Baylor-Sammons Cancer Center, Dallas.

HOUSTON—Ablation of thyroid hormone function may help prevent the development of breast cancer, according to a study by Massimo Cristo-fanilli, MD, and his colleagues at M.D. Anderson Cancer Center. This work, a retrospective analysis of the incidence of hypothyroidism in breast cancer patients, was published in the Proceedings for the 94th Annual Meeting of the American Association for Cancer Research, scheduled for April 2003 in Toronto; owing to the outbreak of severe acute respiratory syndrome (SARS), the meeting was postponed until July in Washington, DC. The study (abstract 2903) was prompted by reports showing the ability of thyroid hormones to sustain serum-free proliferation of breast cancer cell lines, as well as work that correlated the presence of antithyroid autoantibodies with a better breast cancer prognosis. Thus it seemed reasonable to expect that primary hypothyroidism, which itself is usually an autoimmune syndrome, might reduce the risk of primary breast cancer, as well as ameliorate the course of disease.

The hereditary breast/ovarian cancer syndrome is responsible forapproximately 5% of all breast cancers and 10% of all ovarian cancers.Although this accounts for a small portion of these diseases, muchattention has been focused on this syndrome because of the abundanceof research in this area. The majority of the hereditary breast/ovariansyndrome can be attributed to germ-line mutations in the BRCA1 andBRCA2 genes. Reliable screening techniques for these mutations havebeen developed and are readily available in clinical practice. Forpatients who are thought to have the hereditary breast/ovarian cancersyndrome based on family history or genetic testing, options exist foreither intensive screening or prophylactic surgery. This review willdiscuss the mechanisms by which mutations in the BRCA genes lead tothe development of cancer, the limitations of currently available screeningtechniques, and the efficacy of prophylactic surgery. In general,prophylactic oophorectomy can be performed laparoscopically as anoutpatient procedure, carrying as its main drawback the associatedconsequence of surgical menopause. Prophylactic mastectomy is quiteeffective in reducing the risk of breast cancer but is a more extensivesurgical procedure and results in disfigurement. For any given patient,the best estimates of individual risk of breast or ovarian cancer shouldbe weighed against the benefits of prophylactic surgery and the patient’spersonal wishes.

The "Update on Breast CancerPrevention" by Rastogi andVogel provides a comprehensiveand balanced review of the currentstatus of breast cancer chemoprevention.Several areas that the authorsaddress warrant further attention.

Four randomized prospective trials have evaluated tamoxifen forchemoprevention of breast cancer. The National Surgical AdjuvantBreast and Bowel Project P-1 trial reported that tamoxifen reduced therisk of invasive breast cancer by 49%. Two smaller European trials, theRoyal Marsden Hospital Chemoprevention Trial and the Italian TamoxifenPrevention Study, demonstrated no decrease in the incidence ofbreast cancer among women using tamoxifen. The International BreastCancer Intervention Study confirmed that tamoxifen can reduce therisk of breast cancer in healthy women. The Multiple Outcomes ofRaloxifene Evaluation trial, which evaluated the use of raloxifene(Evista) to prevent osteoporosis, found that the risk of invasive breastcancer decreased by 76%. A uniform theme in these trials is thattamoxifen reduces the risk of breast cancer among women at high riskfor the disease. Tamoxifen is currently approved for breast cancer riskreduction. However, because of the side effects associated with its use(ie, endometrial cancer and thromboembolism), other agents are beinginvestigated. The Study of Tamoxifen and Raloxifene is designed tocompare the efficacy of tamoxifen and raloxifene in reducing breastcancer risk. Aromatase inhibitors will also be studied in the setting ofchemoprevention for breast cancer.

Breast cancer is the most commonmalignancy diagnosed inAmerican women today. Giventhe frequency of the diagnosis, approachesthat reduce breast cancerincidence also have the potential toprovide a major impact on morbidityof the disease and its treatment, costto the individual and to society, andoverall cancer mortality. In their paper,Rastogi and Vogel present a conciseand comprehensive review of thefour prospective randomized clinicaltrials of tamoxifen for chemopreventionof breast cancer, as well as ongoingand future studies examininghormonal alternatives to tamoxifen.

CHICAGO-The use of surgical resection of local disease in women presenting with metastatic breast cancer results in a statistically significant survival advantage, Seema Khan, MD, said at the Lynn Sage Breast Cancer Symposium.

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.