Breast Cancer

Most men with breast cancer present with a mass in the breast, theevaluation of which should include a tissue diagnosis. If the presence ofinvasive cancer is established, adequate local therapy includes totalremoval of the breast. Most tumors are hormone-receptor positive. Inhigh-risk patients, the use of endocrine adjuvant therapy and/or combinedendocrine and chemotherapy should be considered. Patients withestrogen-receptor (ER)-negative disease should be offered chemotherapy.In patients with metastatic disease and ER-positive tumors, initialtreatment should be endocrine therapy; systemic chemotherapy shouldbe used in patients who are either hormone-receptor negative or resistantto available endocrine therapies.

Syed and Rowinsky present acomprehensive review of newtargeted therapies for breast cancer.This is an important review thatsummarizes new biologic targets andcurrent drugs in development for thetreatment of breast cancer-a rapidlyevolving field. Among the targets addressedin the article are epidermalgrowth factor receptor (EGFR), Ras/Raf/mitogen-activated protein (MAP)kinase, phosphatidylinositol 3-kinase(PI3K)/protein kinase B (AkT)/moleculartarget of rapamycin (mTOR), tumorangiogenesis, apoptosis, andhistone deacetylases. The list shouldalso be expanded to include differentiatingagents and inhibitors of invasionand metastasis. It is critical toemphasize the future of customizedtherapy and the use of biologic agentsalone, together, or in combination withchemotherapy for the treatment ofbreast cancer.

The review by Dr. Buzdar emphasizesa variety of clinicalfeatures observed in male breastcancer. Although this is an uncommondiagnosis even in a busy oncologypractice (representing less than 1%of all breast cancers), it is occasionallyseen.

As noted by Dr. Buzdar, breastcancer rarely affects men. Accordingto the most recent datafrom the National Cancer Institute’sSurveillance Epidemiology and EndResults program and the National Programof Cancer Registries, the incidenceof invasive breast cancer is 1.5cases per 100,000 men vs 134 casesper 100,000 women.[1] Breast cancerin women is a far greater public healthproblem and understandably has receivedthe lion’s share of researchfunding and public attention.

The article by Drs. Syed andRowinsky is well written andcomprehensive. They introduceseveral biologic pathways that are importantin breast cancer and focus onnew pharmaceutical agents designedto disrupt these pathways. Patients andphysicians hope that agents that targetthe tyrosine kinase signal transductionpathways, block tumor angiogenesis,modulate apoptosis, and inhibithistone deacetylation will be effective,nontoxic therapies for breastcancer. These molecularly targeted approacheshold promise, but deliveringon this promise requires that we movebeyond histologic characterization ofthe disease and rethink the design ofclinical trials.

CHICAGO-Adjuvant therapy with epirubicin (Ellence) followed by cyclophosphamide, methotrexate, and 5-fluorouracil (ECMF) prolongs relapse-free survival and overall survival with only modest toxicity in patients with early-stage breast cancer and should replace upfront CMF as standard therapy in that setting, Christopher J. Poole, MD, said at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 13).

In the current issue of ONCOLOGY,Drs. Emens and Jaffee haveprovided an excellent overview ofthe basic mechanisms involved in thetumor-specific immune response, aswell as a comprehensive update ofresearch on immune-based therapiesfor breast cancer.

Bisphosphonates have an established role in treating tumor-inducedhypercalcemia and decreasing the incidence of skeletal-related events.Recent data suggest that these agents may also prevent skeletal metastases.This review explains how cancer metastasizes to bone and howbisphosphonates may block this process, with a summary of clinicaltrials supporting the use of bisphosphonates to treat and prevent bonemetastases. For skeletal metastases in patients with breast cancer,multiple myeloma, or other solid tumors, bisphosphonates are importantadjuncts to systemic therapy. Despite promising results in metastaticprostate cancer, additional trials are needed before bisphosphonatesbecome part of standard treatment in this setting. Ongoing trials areevaluating the preventive role of the third-generation bisphosphonatesin breast cancer patients. Until the results of these trials are presented,bisphosphonates should only become a component of adjuvant treatmentin the context of a clinical trial. Bone loss, a common consequenceof cancer treatment, should be treated with the usual measures indicatedfor the management of osteoporosis, including bisphosphonates.

As outlined in the review byDrs. Emens and Jaffee entitled“Toward a Breast CancerVaccine: Work in Progress,” the developmentof anticancer vaccines hasclosely paralleled advances in the fieldof immunology. Basic immunologyhas provided and will continue toprovide important insights intohuman immunity that directly relateto the design and study of immunotherapeutics.To date, the mostimportant scientific observations applicableto immunotherapy include thefollowing:

Advances in biotechnology and basic immunology have convergedto create an unprecedented opportunity to use vaccines to harness thepower of the immune system in the fight against breast cancer. Cancervaccines have several therapeutic advantages over more traditionalbreast cancer treatment modalities. First, targeting the antitumorimmune response to critical tumor-specific antigens defines a therapywith exquisite specificity and minimal toxicity. Second, immune-mediatedtumor destruction occurs by mechanisms distinct from those underlyingthe efficacy of chemotherapy and hormone therapy. Thus, immunotherapyoffers an approach to circumventing the intrinsic drugresistance that currently underlies therapeutic failure. Third, thephenomenon of immunologic memory endows immunotherapy withthe potential for creating a durable therapeutic effect that is reactivatedat the onset of disease relapse. Moreover, immunologic memory alsounderlies the potential future use of vaccines for the prevention ofbreast cancer. Early clinical trials have highlighted the promise ofbreast cancer vaccines, and have further defined the challenges facingtranslational scientists and clinical investigators. The judicious applicationof laboratory advances to clinical trial design should facilitatethe development of immunotherapy as an additional major therapeuticmodality for breast cancer, with the potential for breast cancer preventionas well as treatment.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

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.