Breast Cancer

It is fair to say that combination chemotherapy is the standard of care inmetastatic breast cancer. In many ways, however, the burden of proof that it isthe standard of care remains with those who advocate combination therapy.Some of the push to consider combination therapy as the standard is provided by ameta-analysis of trials comparing single-agent and combination therapy in thissetting, which was reported by Fossati et al in 1998.[1] Although the vast majorityof individual trials included in the analysis did not show significant differences inhazard ratios for death, the meta-analysis showed a significant mortality advantagefor combination therapy. Yet the total population considered in this meta-analysis(990 patients in combination groups, 996 in single-agent groups) is not largecompared with some recent phase III trials in metastatic breast cancer, includingone reported by Sledge et al that showed that sequential doxorubicin and paclitaxelwas equivalent to the concurrent combination.[2] Further, no studies includingtaxanes are included in the meta-analysis, raising questions about the application ofits findings to contemporary oncology. In addition, the trials included did notexamine sequential single-agent treatment, an approach that clearly has merit andthat requires additional consideration and study.

Krag and Harlow believe thatsentinel lymph node biopsyfor breast cancer is still an experimentalprocedure because “longtermrandomized trials comparing thesurvival outcome of this procedurewith that of conventional axillary noderesection have not been completed.”Specifically, they are awaiting the resultsof the American College of SurgeonsOncology Group (ACOSOG)Z0011 trial and the National SurgicalAdjuvant Breast and Bowel Project(NSABP) B-32 trial before they makea determination about the “safety” ofthis procedure.[1] This is a commonmisconception, because these studieswill not prove whether sentinel nodebiopsy results in equivalent survivalcompared to standard level I/II axillarydissection in patients with clinicallynode-negative breast cancer. Thetime has come for clear thinking aboutthe design of these trials and precisereasoning about the interpretation oftheir ultimate results.

The biologic rationale for sentinellymph node biopsy, althoughit may ultimately stagethe axilla more accurately, is essentiallythat a positive lymph node representssystemic disease. Removal ofaxillary lymph nodes is of little, if any,therapeutic value, and most patients with tumors greater than 1 cm are offeredchemotherapy regardless ofnodal status. Thus, the risks of lymphedemaand neurologic deficit outweighany prognostic information derivedfrom an axillary node dissection whenthis same information can be accuratelyobtained in a less invasive, lessmorbid procedure.

Gemcitabine (Gemzar) and paclitaxel exhibit good activity and goodsafety profiles when used alone and together in the treatment of advancedbreast cancer. In a phase II trial, 45 patients with metastaticbreast cancer received gemcitabine at 1,200 mg/m2 on days 1 and 8 andpaclitaxel at 175 mg/m2 on day 1 every 21 days. Twenty-seven patients(60.0%) had prior adjuvant therapy. Objective response was observedin 30 patients (objective response rate 66.7%, 95% confidence interval[CI] = 52%–71%), including complete response in 10 (22.2%) and partialresponse in 20 (44.4%). Median duration of response was 18 months(95% CI = 11–26.7 months), median time to tumor progression for theentire population was 11 months (95% CI = 7.1–18.7 months), medianoverall survival was 19 months (95% CI = 17.3–21.7 months), and the1-year survival rate was 69%. Treatment was well tolerated, with grade3/4 toxicities being infrequent. Grade 3/4 leukopenia, neutropenia, andthrombocytopenia were each observed in six patients (13.3%). No patientwas discontinued from the study due to hematologic ornonhematologic toxicity. Thus, the gemcitabine/paclitaxel combinationshows promising activity and tolerability when used as first-line treatmentin advanced disease. The combination recently has been shownto be superior to paclitaxel alone as first-line treatment in anthracyclinepretreatedadvanced disease according to interim results of a phase IIItrial and it should be further evaluated in comparative trials in breastcancer.

Sentinel node surgery potentially increases the accuracy of identifyinglymph nodes that contain breast cancer and decreases morbiditycompared to conventional axillary lymph node resection. However, nolong-term comparisons of the two modalities have been carried out,and the survival benefit associated with one protocol vs the other remainsunknown. Although sentinel node surgery is not expected to increasethe cure rate of breast cancer patients, a significant reduction inthe incidence of permanent side effects associated with axillary noderesection will be a considerable advance. The completion of clinicaltrials establishing that no meaningful reduction in survival is associatedwith the decrease in side effects is important.

In patients with advanced breast cancer, treatment with paclitaxeland doxorubicin has been shown to produce impressive overall responserates (up to 94%) and to prolong overall survival significantly over acombination of fluorouracil (5-FU), doxorubicin, and cyclophosphamide(Cytoxan, Neosar) in one prospective phase III clinical study.

Gemcitabine has been evaluated in combination with paclitaxel,docetaxel, anthracyclines, vinorelbine, and cisplatin as first-line treatmentand after prior chemotherapy in patients with metastatic breastcancer. Results with gemcitabine/taxane combinations have been especiallyencouraging, with these combinations providing promising outcomeswith regard both to tumor response and tolerability. The combinationof gemcitabine and paclitaxel has garnered particular interestfor further phase III evaluation on the basis of high response rates anddurable responses in both treatment-naive and treatment-experiencedpatients, including anthracycline-pretreated patients.

Gemcitabine (Gemzar) and paclitaxel show good activity as singleagents and combined in metastatic breast cancer, and the combinationof paclitaxel/trastuzumab (Herceptin) has been shown to prolong timeto disease progression and survival significantly in this setting. Preclinicaldata indicate additive or synergistic effects of gemcitabine andtrastuzumab in HER2-positive human breast cancer cell lines. In aphase II trial, patients with HER2-overexpressing metastatic breastcancer who had received no prior chemotherapy for metastatic diseasereceived gemcitabine at 1,200 mg/m2 on days 1 and 8 and paclitaxel at175 mg/m2 on day 1 every 21 days for six cycles plus trastuzumab at aninitial loading dose of 4 mg/kg followed by 2 mg/kg weekly; patientswithout progressive disease after six cycles continued to receivetrastuzumab until disease progression. Overall, objective response wasobserved in 28 (67%) of 42 evaluable patients, including complete responsein 4 (10%) and partial response in 24 (57%); stable disease wasobserved in 7 (17%) and progressive disease was observed in 6 (14%).Median time to treatment failure was 9+ months. Median overall survivalhas not yet been reached, but is estimated at approximately 27months. Significant toxicities apart from neutropenia were uncommon.The triplet combination of gemcitabine, paclitaxel, and trastuzumab ishighly active and well tolerated in patients with HER2-overexpressingmetastatic breast cancer.

TORONTO-Postmenopausal women with early-stage breast cancer who took the aromatase inhibitor letrozole (Femara) after completing 5 years of tamoxifen therapy had a 43% lower risk of recurrence than those receiving placebo, an international phase III clinical trial has found.

COPENHAGEN, Denmark-In the first head-to-head comparison of the two taxanes, docetaxel (Taxotere) produced significantly longer survival in patients with metastatic breast cancer, compared with paclitaxel (Taxol), but at the cost of increased toxicity. Peter Ravdin, MD, PhD, clinical professor of medicine, The University of Texas Health Science Center, San Antonio, and principal investigator of the study, presented the phase III findings at ECCO 12, the European Cancer Conference (abstract 670). The study was sponsored by Aventis, manufacturer of Taxotere.

COPENHAGEN, Denmark-The risk and incidence of bone fractures associated with the use of the aromatase inhibitor anastrozole (Arimidex) for treatment of early breast cancer in postmenopausal women appears to stabilize after peaking at 2 years, easing some of the major concerns about the drug.

CHICAGO-A large body of epidemiological literature has identified a number of breast cancer risk factors that are not considered modifiable, Susan Gapstur, PhD, said at the Fifth Annual Lynn Sage Breast Cancer Symposium. These include family history of breast cancer, age, personal history of atypia, hormone levels and hormonally related factors such as dense breasts, age of first childbearing, and age at menopause.

Breast cancer is the most common noncutaneous malignancy inwomen in industrialized countries. Chemotherapy prolongs survival inpatients with early-stage breast cancer, and maintaining the chemotherapydose intensity is crucial for increasing overall survival. Manypatients are, however, treated with less than the standard dose intensitybecause of neutropenia and its complications. Prophylactic colonystimulatingfactor (CSF) reduces the incidence and duration of neutropenia,facilitating the delivery of the planned chemotherapy doses.Targeting CSF to only at-risk patients is cost-effective, and predictivemodels are being investigated and developed to make it possible forclinicians to identify patients who are at highest risk for neutropeniccomplications. Both conditional risk factors (eg, the depth of the firstcycleabsolute neutrophil count nadir) and unconditional risk factors(eg, patient age, treatment regimen, and pretreatment blood cell counts)are predictors of neutropenic complications in early-stage breast cancer.Colony-stimulating factor targeted toward high-risk patients startingin the first cycle of chemotherapy may make it possible for fulldoses of chemotherapy to be administered, thereby maximizing patientbenefit. Recent studies of dose-dense chemotherapy regimens with CSFsupport in early-stage breast cancer have shown improvements in disease-free and overall survival, with less hematologic toxicity than withconventional therapy. These findings could lead to changes in how earlystagebreast cancer is managed.

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.