Breast Cancer

The first interim results from the BCIRG 006 phase III trial showed that trastuzumab (Herceptin) combined with docetaxel (Taxotere)-based regimens significantly improved disease-free survival (DFS) in early HER2-positive breast cancer. Genetic studies further delineated a subgroup of patients for whom truly targeted therapy may be applied in the future.

Docetaxel (Taxotere) and paclitaxel (Taxol) produced similar outcomes in the adjuvant treatment of breast cancer in the North American Breast Cancer Intergroup Trial E1199. Joseph Sparano, MD, profesor of medicine, Albert Einstein Cancer Center, Montefiore Medical Center, New York, presented the results as a late-breaking abstract at the 28th Annual San Antonio Breast Cancer Symposium (abstract 48).

Accumulating clinical experience with MammoSite breast brachytherapy is supporting its safety, efficacy, and good cosmetic outcomes, while also providing lessons to improve its use, according to a pair of studies presented at the 47th Annual Meeting of the American Society for Therapeutic Radiology and Oncology

SAN ANTONIO—GlaxoSmithKline has announced the initiation of a global multicenter phase II trial (known as EGF 105084) to evaluate Tykerb (lapatinib) for the treatment of ErbB2 (HER2)-overexpressing breast cancer that has metastasized to the brain. Tykerb is an orally bioavailable small molecule that potently inhibits two receptors, ErbB2 and ErbB1. It is currently in development as a first-line treatment for ErbB2-overexpressing breast cancer.

Recent clinical studies from the National Cancer Institute (NCI) show that the macrolide analog ixabepilone (BMS-247550) is effective in treating metastatic breast cancer, is less susceptible to resistance than paclitaxel, and is associated with much lower rates of peripheral neuropathy than the taxanes.

Radiation therapy (RT) reduces the risk of breast cancer recurrence even in women with favorable early disease, researchers reported at the 47th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (abstract 3). Although recurrence was uncommon with combined breast-conserving surgery and hormonal therapy, it was one-half less common when whole-breast radiation therapy was further added to treatment.

The past 2 decades of systemic therapy for breast cancer have beena period of monumental change, in terms of both theory and technology.Adjuvant therapy developed from two strands of research-one insystemic chemotherapy and one in hormonal therapy-both of whichwere aided by the application of higher statistical methodology to clinicaltrials. The agent with the single greatest public health impact inoncology has been tamoxifen, but problems with tamoxifen therapy ledto the development of the aromatase inhibitors, and further researchled to the use of hormonal therapy in a chemopreventive capacity. Theevolution of systemic chemotherapy for breast cancer has been an interplaybetween theory-driven approaches and new agents. By the late1980s, accumulating data revealed that overexpression of HER2 (erbB2)played an important role in a substantial portion of breast cancers,which prompted the development of trastuzumab (Herceptin), an agenttargeting HER2-positive disease. Determining HER2 status proved essentialto assessing patient eligibility for trastuzumab therapy. Decodingof the human genome and application of bioinformatics furtherrevolutionized the possibilities in breast cancer treatment.

After peaking in 1990, the absolutenumber of deaths peryear attributed to breast cancerhas fallen steadily.[1] This declineoccurred despite trends thatwould seem to increase breast cancermortality (population growth, aging,increased obesity) and was mirroredeven in countries lacking routine supportfor mammography. Systemictherapy is at least partly responsiblefor this mortality decline, and in supportof this conclusion the predictedbenefits (based on trials and metaanalyses)have been seen in population-based studies.[2] In this issue ofONCOLOGY, Mina and Sledge providea timely and inspiring review of2 decades of progress in systemic therapyfor breast cancer. This leads toseveral questions, including: How didwe get here and what is next?

Based on their initial experience with 3D digital breast tomosynthesis, radiologists at Dartmouth Hitchcock Medical Center and Dartmouth Medical School believe the investigational technique "is closer to the truth than standard mammography," Steven Poplack, MD, associate professor of diagnostic radiology and obstetrics and gynecology, said at the 2005 meeting of the Radiological Society of North America (abstract SSG01-05).

Over a 30-year period in the20th century, human flightevolved from the propeller tothe jet engine and then managed tosend us to the moon and back. Thechanges over the past 30 years in ourunderstanding of the biology of breastcancer and its application to treatmentare no less startling. Since 1975, wehave witnessed an astounding evolutionin our strategies to prevent,[1]diagnose,[2] and manage[3] a diseasethat affects the lives of so many in theUnited States[4] and around theworld.[5] These efforts have generatedmany headlines and an occasionalstumble. Nonetheless, they have hada dramatic impact on the lives of millionsof people, and it is hoped thatthe rate of improvement will furtheraccelerate in years to come.

DENVER-Accelerated intensity-modulated radiation therapy (IMRT) of the breast in the prone position is feasible and has only modest acute toxicity in patients who have undergone breast-conserving surgery for breast cancer, according to a report presented at the 47th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (abstract 1062).

Drs. Perez and Muss provide acomprehensive review of therole of adjuvant chemotherapyin the management of breast cancerpatients. The benefits of anthracyclinevs nonanthracycline regimens are discussed,the taxanes are reviewed indetail, and data regarding dose intensity,dose density, and optimal numberof chemotherapy cycles areexplored. Data on newer agents andbiologic agents also are presented.Debate continues regarding the subsetsof patients who will derive thegreatest benefit from chemotherapyand which regimen is most appropriate.While the review indicates theefficacy of several regimens as definedby randomized clinical trials, itdoes not emphasize patient-specificfactors in determining the optimaltherapy for a given patient.

Improvements in early diagnosisand treatment of breast cancer overthe past few decades have clearlyreduced disease-related mortality. The2000 Oxford Overview published recentlyby the Early Breast Cancer Trialists’Cooperative Group (EBCTCG)highlights some of the widely practicableadjuvant drug treatments thatwere under investigation in the 1980s,and have substantially reduced 5-yearrecurrence rates as well as 15-yearmortality rates.[1] Optimal adjuvanthormone therapy is associated with asubstantial improvement of diseaseoutcomes in hormone receptor–positivewomen. Chemotherapy is alsoassociated with considerable benefitsin women with breast cancer, regardlessof age, stage, or hormone receptorstatus. However, chemotherapy isnot without risks. The treatment isassociated with many adverse eventsthat may significantly affect a patient’squality of life while she is receivingtreatment. Other effects may be longstanding,permanent, and, rarely, lifethreatening.

This review of adjuvant chemotherapyby Perez and Muss isconcise and complete. For themost part, the authors present the datain a balanced way. The role of adjuvantchemotherapy has been establishedin breast cancer. Appropriateutilization of adjuvant chemotherapycan significantly reduce the risk ofdisease recurrence and improve survival.These benefits are associatedwith adjuvant chemotherapy regardlessof the age of the patient, nodalstatus, or hormonal status of cancer.

Mortality in breast cancer has declined in the past decade, owing toadvances in diagnosis, surgery, radiotherapy, and systemic treatments.Adjuvant chemotherapy has had a major effect on increasing survivalin women with locoregional breast cancer. Like all treatments, adjuvantchemotherapy is a work in progress, and it has evolved from singleoral agents to complex multidrug regimens. The choice of regimens isnot without controversy, however, and several have been shown to bemore effective than others, especially in patients who are at high riskfor recurrence. The taxanes paclitaxel and docetaxel (Taxotere) havebeen shown to be effective in the adjuvant setting, and they have alsobeen shown to improve the outcomes in node-positive disease. Bothdisease-free and overall survival are greater with doxorubicin,paclitaxel, and cyclophosphamide given in a dose-dense, every-2-weekschedule with growth factor support than with the same agents givenin an every-3-week schedule. Disease-free and overall survival in patientswith node-positive disease are greater with docetaxel, doxorubicin(Adriamycin), and cyclophosphamide (TAC) than with fluorouracil,doxorubicin, and cyclophosphamide (FAC). Febrile neutropenia iscommon with the TAC regimen, but it can be minimized with growthfactor support. Based on these findings, dose-dense therapy and TAC arethe current adjuvant treatments of choice in patients with node-positivedisease; other, less-intense regimens may be appropriate in patientswith lower-risk disease. Ongoing trials are investigating the efficacy ofcommonly used regimens, new chemotherapeutic and biologic agents,and novel doses and schedules of currently available agents.

ORLANDO-Decreasing breast cancer survivors’ dietary fat reduced the rate of disease recurrence by 24%, according to a study presented by Rowan T. Chlebowski, MD, PhD, at the American Society of Clinical Oncology 41st Annual Meeting (abstract 10). "A lifestyle intervention resulting in dietary fat reduction may increase relapse-free survival in a population of mostly postmenopausal breast cancer patients," said Dr. Chlebowski, chief, Division of Medical Oncology and Hematology, Harbor-UCLA Medical Center.

In this review of hepatic resectionfor metastatic breast cancer, theauthors argue that a small groupof women with isolated liver metastasesmay be appropriate candidates forsurgical resection. Although some datahave been reported, the few publishedstudies represent small, retrospectivesingle-institutional series with no standardizedcriteria for resection. Nevertheless,the potential prospect ofimproved patient outcome in the settingof liver metastases from breastcancer deserves further consideration.

The selective activity and demonstratedsafety of targetedtherapies has generated newhope for improving the treatment ofpatients with cancer.

The epidermal growth factor (EGF) receptor HER2 is a transmembranereceptor tyrosine kinase that plays a crucial role in the regulationof cell proliferation and survival. The overexpression of HER2correlates strongly with prognosis in breast cancer. The targeted blockadeof HER2 activity with monoclonal antibodies (eg, trastuzumab[Herceptin]) and small-molecule tyrosine kinase inhibitors (eg,lapatinib) results in the inhibition of tumor growth in HER2-positivecancers. Anti-HER2 therapies have also shown efficacy in combinationwith chemotherapy in clinical trials in patients with HER2-positive breast cancer. Their efficacy may, however, be limited bymolecular mechanisms that compensate for HER2 suppression (eg,activity of EGF receptor) or mechanisms of resistance (eg, loss ofPTEN). HER2 continues, however, to be overexpressed by the cancercells, and the continued suppression of HER2 may be required formaximum antitumor effect. It should be noted that in the absence ofdefinitive data from randomized trials showing an absence or presenceof benefit, the use of anti-HER2 agents such as trastuzumab in multiplesequential regimens has become the standard of care. CombiningHER2 blockers with agents that overcome the compensatory or resistancemechanisms may increase the efficacy of anti-HER2 therapies.In addition, anti-HER2 therapies can have synergy with common chemotherapyregimens and remain effective through multiple lines oftherapy. Optimizing the use of therapies that target HER2 signalingwill lead to further advances in the treatment of breast cancer.

Podnos and Wagman provide acomprehensive review of surgicalresection for hepatic breastcancer metastases. The authors presentthe disparate data accrued by variouscenters in the United States, Europe,and Asia, and then attempt to consolidatethese experiences to draw conclusionsand provide guidelines. Thisreview is well-written, thorough, andinteresting; however, as with anyreview of a topic devoid of level 1evidence, the authors raise more questionsthan answers.

In general, surgery has no role inthe curative treatment of metastaticbreast cancer. Metastatic breastcancer is considered incurable, associatedwith an average survival of 18 to24 months. Certain factors such as hormone-receptor negativity, HER2/neupositivedisease, and a short disease-freeinterval portend a poor prognosis. Theliver is not usually a site of initialfailure-less than 15% of patients fitthis pattern.[1] Even fewer are candidatesfor surgical resection due toextrahepatic disease. Eventually, overhalf of all patients with metastatic diseasewill have liver metastasis duringtheir clinical course.

Tremendous gains have been made regarding the treatment of breastcancer. The combination of chemotherapy, radiation therapy, and surgeryhave vastly improved patient course. Hepatic manifestations ofmetastatic breast cancer are extremely difficult to treat. Traditionally,chemotherapy and hormonal treatment of hepatic metastases of breastcarcinoma have not significantly improved survival. For patients withbreast cancer metastases isolated to the liver, operative treatment isincreasingly being used to prolong life and disease-free intervals. Thisarticle reviews the use of surgery for treatment of isolated breast cancermetastases to the liver.

ARLINGTON, Virginia-Data from more than 40,000 women who underwent both digital and film mammography at 33 sites in the US and Canada show that, while the techniques have similar overall diagnostic accuracy in breast cancer screening, digital mammography is more accurate in women under the age of 50 years, women with radiographically dense breasts, and pre- or perimenopausal women.

EDMONTON, Canada-Two docetaxel (Taxotere)-based chemotherapy regimens in combination with the monoclonal antibody trastuzumab (Herceptin) given after surgery significantly improved disease-free survival (DFS) in women with early-stage HER2-positive breast cancer, according to interim results of a phase III trial announced by the Breast Cancer International Research Group (BCIRG) and Sanofi-Aventis. The BCIRG 006 trial compared a standard treatment arm of four cycles of doxorubicin (Adriamycin) and cyclophosphamide followed by docetaxel (AC-T) with two trastuzumab-containing regimens: AC-T plus trastuzumab (AC-TH) and docetaxel plus carboplatin plus 1 year of trastuzumab (TCH) given concomitantly with chemotherapy.

In their article entitled “AdjuvantHormonal Therapy in Early BreastCancer,” Kumar and Leonard summarizemuch of the available datafrom trials of hormonal therapy in preandpostmenopausal women. They concludethat the use of aromatase inhibitorshas led to an improvement indisease-free survival in postmenopausalpatients with early-stage breast cancer,but that the optimal timing ofaromatase inhibitor therapy and thelong-term side effects of the drugsremain uncertain. The authors alsohighlight the benefits associated withtamoxifen in premenopausal womenand discuss the unresolved role of ovarianablation in this population.

Breast cancer is a systemic diseasewith 10-year relapse risksafter surgery alone ranging between30% and 50%.[1] About 60%to 75% of breast cancers are hormonereceptor–positive[2] and are potentiallyresponsive to endocrine therapy,which remains a cornerstone in the adjuvanttherapy of such tumors in thisera of targeted therapy and genomics.

For many years, tamoxifen has been the gold standard adjuvanthormonal therapy with the greatest impact in early breast cancer forboth pre- and postmenopausal women. Tamoxifen-based adjuvant endocrinetherapy and chemotherapy have together contributed substantiallyto the reduction in breast cancer mortality that has occurred inrecent years. Over the past few years, the role of aromatase inhibitorshas grown in prominence and they are now on the threshold of supplantingtamoxifen as the new gold standard adjuvant therapy for postmenopausalwomen with estrogen-receptor–positive disease. With extendeduse of oral antihormones such as tamoxifen, the role of ovariansuppression on the other hand has become less clear in the adjuvantsetting. This article reviews the most important data regarding the variousadjuvant hormonal treatments in the management of early breastcancer and will also give a brief overview of the role of these agents inthe neoadjuvant setting.

The use of adjuvant endocrinetherapy in early-stage breastcancer is thought to eradicatemicrometastatic disease that may leadto systemic recurrences. Until relativelyrecently, the standard adjuvantendocrine therapy option was tamoxifen.Data from the Early Breast CancerTrialists’ Collaborative Group(EBCTCG) overview analysis reporteda 50% reduction in the risk of relapseand a 28% reduction in the riskof death in estrogen receptor (ER)-positive patients treated with 5 yearsof tamoxifen.[1] This benefit was observedregardless of menopausal orlymph node status and whether or notpatients were receiving chemotherapy.There was no such benefit documentedin ER-negative cancersreceiving tamoxifen. Tamoxifen hasalso been associated with a 47% reductionin the risk of developing contralateralbreast cancer.[1]

Genetic counseling and testing for susceptibility to breast and ovariancancer is often an integral component of management for womenwith a personal and/or family history of these malignancies. In thisarticle, we will briefly review the function and genetic epidemiology ofthe two major susceptibility genes, BRCA1 and BRCA2. We will thenaddress approaches to risk assessment for women at high risk with respectto the probability that they harbor a deleterious mutation in oneof these genes, and the likelihood that they will develop cancer if sucha mutation is identified. The process of genetic counseling and testingis discussed, including a summary of the potential benefits, limitations,and risks of testing as well as a summary of test result interpretation.We conclude with a review and appraisal of the various options forbreast and ovarian cancer risk reduction and screening options forwomen with a BRCA1 or BRCA2 mutation.

ORLANDO-Results from the European Cooperative Trial in Operable Breast Cancer (ECTO) show that the addition of paclitaxel to a commonly used breast cancer chemotherapy regimen improved time to progression without increasing toxicities, Luca Gianni, MD, reported at the American Society of Clinical Oncology 41st Annual Meeting (abstract 513). "ECTO is the first study to show therapeutic benefit from adjuvant paclitaxel by directly comparing two regimens of identical duration and similar tolerability," said Dr. Gianni, Istituto Nazionale Tumori, Milan, Italy.