Breast Cancer

BETHESDA, Maryland—Newly released data show that the nation’s mortality rate for all cancers combined, which declined between 1994 and 1998, remained stable from 1998 through 2000. However, the mortality rate for the four leading malignancies in the United States—lung, female breast, prostate, and colorectal—continued to decline in the late 1990s, according to the "Annual Report to the Nation on the Status of Cancer, 1975-2000."

WASHINGTON-Common over-the-counter pain relievers such as ibuprofen and aspirin, taken two or more times per week, may cause a significant reduction in the risk of breast cancer, according to a presentation at the 94th Annual Meeting of the American Association for Cancer Research (AACR abstract 4893).

In this issue of ONCOLOGY, Dr.Aman Buzdar provides a timelysynopsis of current perspectiveson breast cancer in men. I would onlyadd or expand upon a few points.

This is a period of rapid developments in radiotherapy for malignantdisease. New methods of targeting tumors with computed tomography(CT) virtual simulation, magnetic resonance imaging (MRI), andpositron-emission tomography (PET) fusion provide the clinician withinformation heretofore unknown. Linear accelerators (linacs) withmultileaf collimation (MLC) have replaced lead-alloy blocks. Indeed,new attachments to the linacs allow small, pencil beams of radiation tobe emitted as the linac gantry rotates around the patient, conforming tothree-dimensional (3D) targets as never before. Planning for these deliverysystems now takes the form of "inverse planning," with CT informationused to map targets and the structures to be avoided. In thearea of brachytherapy, techniques utilizing the 3D information providedby the new imaging modalities have been perfected. Permanentseed prostate implants and high-dose-rate (HDR) irradiation techniquestargeting bronchial, head and neck, biliary, gynecologic, and otheranatomic targets are now commonplace radiotherapy tools. CT-guidedpermanent seed implants are being investigated, and a new method oftreating early breast cancer with HDR brachytherapy via a ballooncatheter placed in the lumpectomized cavity is coming to the forefront.Newer modalities for the treatment of malignant and benign diseaseusing stereotactic systems and body radiosurgery are being developed.Targeted radionuclides using microspheres that contain radioemittersand other monoclonal antibody systems tagged with radioemitters havebeen recently approved for use by the Food and Drug Administration.

Traditional therapies for breast cancer have generally relied uponthe targeting of rapidly proliferating cells by inhibiting DNA replicationor cell division. Although this strategy has been effective, its innate lackof selectivity for tumor cells has resulted in diminishing returns, approachingthe limits of acceptable toxicity. A growing understanding ofthe molecular events that mediate tumor growth and metastases has ledto the development of rationally designed targeted therapeutics thatoffer the dual hope of maximizing efficacy and minimizing toxicity tonormal tissue. Promising strategies include the inhibition of growthfactor receptor and signal transduction pathways, prevention of tumorangiogenesis, modulation of apoptosis, and inhibition of histone deacetylation.This article reviews the development of several novel targetedtherapies that may be efficacious in the treatment of patients with breastcancer and highlights the challenges and opportunities associated withthese agents.

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.