Breast Cancer

Carcinoma of the breast is the most common cancer in women in the United States and is second only to lung cancer as a cause of cancer death in women. The incidence of breast cancer has risen steadily over the past decade, with the most dramatic increase seen in smaller primary breast tumors, partly because widespread use of screening mammography permits earlier detection [1].

This section will examine several controversial or uncommon topics in breast cancer: use of dose-intensive therapy, estrogen replacement therapy, male breast cancer, and breast cancer in pregnancy. The section on dose-intensive therapy will trace the development and clinical rationale for the use of this therapy. For additional information, refer to the section on autologous bone marrow transplantation. Estrogen replacement therapy in patients previously treated for breast cancer is an area of active investigation and controversy.

Combined-modality positronemissiontomography (PET)–computed tomography (CT) isbecoming the imaging method ofchoice for an increasing number ofoncology indications. The goal of thispaper is to review the evidence-basedliterature justifying PET-CT fusion.The best evidence comes from prospectivestudies of integrated PETCTscans compared to other methodsof acquiring images, with histopathologicconfirmation of disease presenceor absence. Unfortunately, veryfew studies provide this kind of data.Retrospective studies with similarcomparisons can be used to provideevidence favoring the use of integratedPET-CT scans in specific clinicalsituations. Also, inferential conclusionscan be drawn from studies whereclinical rather than pathologic dataare used to establish disease presenceor absence.

SAN ANTONIO-Anastrozole (Arimidex) is the initial treatment of choice for postmenopausal women with hormone-receptor-positive (HR+) early breast cancer, Anthony Howell, MD, University of Manchester, UK, said at the 27th Annual San Antonio Breast Cancer Symposium (abstract 1). Final results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial showed the aromatase inhibitor to have superior efficacy and a better side effect profile than tamoxifen.

SAN ANTONIO-The bisphosphonate zoledronic acid (Zometa) effectively counteracts bone loss associated with combination endocrine treatment in premenopausal women with hormone-responsive breast cancer, Michael Gnant, MD, University of Vienna, said at the 27th Annual San Antonio Breast Cancer Symposium (abstract 6) on behalf of the Austrian Breast and Colorectal Cancer Study Group (ABCSG).

SAN ANTONIO-For postmenopausal women with hormone-receptor-positive early-stage breast cancer, switching to anastrozole (Arimidex) after 2 years of tamoxifen is more effective than continuing on tamoxifen, according to Raimund Jakesz, MD, Vienna Medical School, Vienna, Austria. The conclusion arose out of analysis of combined results of two trials enrolling a total of 3,224 women: the Viennese ABCSG (Austrian Breast and Colorectal Cancer Study Group) Trial 8, and the German ARNO 95 Trial (by the German Adjuvant Breast Cancer Group).

ROCKVILLE, Maryland-Abraxane (paclitaxel protein-bound particles for injectable suspension, American Bioscience) has received Food and Drug Administration approval for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Previous therapy should include an anthracycline unless clinically contraindicated.

SAN ANTONIO-Sequential therapy with three cycles of fluorouracil, epirubicin (Ellence) 100 mg/m2, and cyclophosphamide (FEC-100) followed by three cycles of docetaxel (Taxotere) improved outcomes over six cycles of FEC alone, in node-positive breast cancer patients over the age of 50. Professor Henri Roche, Institut Claudius Regaud, Tou-louse, France, reported the results of the multicenter study from France and Belgium at the 27th Annual San Antonio Breast Cancer Symposium (abstract 27). While the study also included younger women, the significant improvements in disease-free and overall survival were limited to women aged 50 and older.

SAN ANTONIO-A randomized, multicenter trial from the United Kingdom has demonstrated what clinicians have instinctively felt: that sentinel node biopsy (SNB) is associated with less morbidity and better quality of life than standard axillary node surgery. Professor Robert E. Mansel, University of Cardiff, Wales, presented the results of the Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC) trial at the 27th Annual San Antonio Breast Cancer Symposium (abstract 18).

SAN ANTONIO-A 70-gene profile developed in Amsterdam to distinguish low-risk from high-risk women with node-negative breast cancer has been shown to be predictive for disease recurrence after surgery. Martine Piccart, MD, chair of the Breast International Group and head of the Medical Oncology Department, Institut Jules Bordet, Brussels, presented the results at the 27th Annual San Antonio Breast Cancer Symposium (abstract 38)

Dr Gundry comprehensivelydiscusses the role of breastmagnetic resonance imaging(MRI) in staging and screening breastcancer. I will emphasize and expandon some of the author’s key points.

Contrast-enhanced breast magnetic resonance imaging (MRI) is arelatively new but increasingly used modality for the detection of breastcancer. MRI has demonstrated utility in identifying additional tumorfoci and extent of disease in patients with known breast cancer. This isespecially useful with invasive lobular carcinoma, which is difficult toevaluate on mammography. MRI has been found to identify the primarytumor in 70% to 86% of cases of occult breast cancer. Contrastenhancedbreast MRI has shown some usefulness in the detection ofresidual cancer following surgery but is limited by postoperative changes.In patients who have undergone neoadjuvant chemotherapy, breast MRIis most accurate in those patients in whom there is little or no responseto chemotherapy. The use of contrast-enhanced breast MRI for breastcancer screening is controversial. It has only been used in a few smallstudies of high-risk patients. The limitations of breast MRI includeuptake in benign lesions and normal tissue, sensitivity for ductal carcinomain situ, cost, and availability. This paper will discuss the uses,benefits, and limitations of contrast-enhanced breast MRI in the stagingand screening of breast cancer.

In this excellent review of breastmagnetic resonance imaging (MRI),Gundry discusses the potential advantagesand disadvantages of magneticresonance in breast cancerscreening and management and givesrecommendations for how it shouldbe applied.

ATLANTA-A randomized trial finds that most women aged 50 or older who underwent breast-conserving surgery for early-stage breast cancer need radiation therapy (RT) in addition to tamoxifen to minimize the risk of a breast relapse. However, the data also suggest that selected women aged 60 or older may be able to safely skip radiation therapy. Lead author Anthony W. Fyles, MD, a radiation oncologist at the Princess Margaret Hospital, Toronto, Canada, presented findings of the trial at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (abstract 2). (For a full report, see N Engl J Med 351:963-970, 2004).

Several key areas must be considered in the diagnosis and managementof spinal cord compression. Because the outcome can be devastating,a diagnosis must be made early and treatment initiated promptly.Although any malignancy can metastasize to the spine, clinicians shouldbe aware that this occurs more commonly in certain diseases, ie, lungcancer, breast cancer, prostate cancer, and myeloma. The current algorithmfor early diagnosis of spinal cord compression involves neurologicassessment and magnetic resonance imaging of the entire spine.Treatment generally consists of intravenous dexamethasone followedby oral dosing. Depending on the extent of the metastases, symptomsmay also be managed with nonnarcotic pain medicines, anti-inflammatorymedications, and/or bisphosphonates, with local radiation administeredas needed. Surgery has often led to destabilization of the spine.

This study was designed to evaluate the cardiac safety of the combined treatment of HER2-positive metastaticbreast cancer patients with trastuzumab (Herceptin) plus epirubicin and cyclophosphamide (EC) incomparison with EC alone in HER2-negative metastatic breast cancer patients. Patients included those withmetastatic breast cancer without any prior anti-HER2 treatment, anthracycline therapy, or any other chemotherapyfor metastatic disease. This was a nonrandomized, prospective, dose-escalating, multicenter, openlabel,phase II study in Germany. A control group of 23 patients received EC 90/600 mg/m2 3-weekly for sixcycles (EC90 alone). A total of 26 HER2-positive patients were treated with trastuzumab, or H (2 mg/kg weeklyafter an initial loading dose of 4 mg/kg), and EC 60/600 mg/m2 3-weekly for six cycles (EC60+H); another 25HER2-positive patients received H and EC 90/600 mg/m2 3-weekly for six cycles. Asymptomatic reductions inleft ventricular ejection fraction (LVEF) of more than 10% points were detected in 12 patients (48%) treatedwith EC60 + H and in 14 patients (56%) treated with EC90 + H vs 6 patients (26%) in the EC90 alone cohort.LVEF decreases to < 50% occurred in one patient in the EC60+H cohort and in two patients in the EC90+Hcohort during the H monotherapy. No cardiac event occurred in the cohort with EC90 alone. The overallresponse rates for EC60+H and EC90+H were >60%, vs 26% for EC90 alone. The interim results of this studysuggest the cardiac safety of the combination of H with EC may be greater than that of H with AC (doxorubicin[Adriamycin]/cyclophosphamide); however, studies in larger numbers of patients are warranted. The combinationregimen revealed promising efficacy.

Adjuvant chemotherapy has been shown to be beneficial in patientswith breast cancer, and anthracycline-containing regimens are more effectivethan non–anthracycline-containing ones. The French AdjuvantStudy Group (FASG) compared FEC100 and FEC50 (fluorouracil[5-FU]/epirubicin [Ellence]/cyclophosphamide [Cytoxan, Neosar])in patients with node-positive breast cancer, with an end point of overallsurvival. After a median follow-up of 10 years, the benefit/risk ratio of theFEC100 regimen in patients with positive axillary nodes is strongly positive.Furthermore, a medicoeconomic study showed that the cost per yearof life saved was very low-approximately 1,000 euros.

The 6th University of Texas M. D. Anderson Cancer Center Investigators’Workshop was held on July 16–20, 2003, in Amelia Island, Florida.The purpose of these annual workshops has been to review the latest data onnew agents, with a particular emphasis on the broadly used agent irinotecan(Camptosar), and also novel regimens or agents.

Primary systemic therapy (ie, preoperative or neoadjuvant) increasesthe possibility for breast-conserving surgery in patients with primarybreast cancer. Patients with pathologic complete response to primarysystemic therapy have improved survival compared with those with persistenttumors. Several phase II trials have evaluated gemcitabine-containingdoublet or triplet regimens as primary systemic therapy for breastcancer, results of which have shown promising clinical and pathologicresponse rates with manageable toxicity. Results of a phase I/II studyof gemcitabine (Gemzar)/epirubicin (Ellence)/docetaxel (Taxotere), orGEDoc, with prophylactic filgrastim (Neupogen), as primary systemictherapy in 77 evaluable patients with primary breast cancer are reportedherein. Dose-limiting toxicities were grade 3 febrile neutropenia(n = 1) and grade 3 diarrhea (n = 2) at the fourth dose level ofGEDoc tested (gemcitabine at 800 mg/m2 days 1 and 8, epirubicin at90 mg/ m2 day 1, and docetaxel at 75 mg/m2 day 1). As assessed byultrasound, 92% of patients responded overall (22% complete response),and 79% of patients could undergo breast-conserving surgery. Thepathologic complete response rate in resected breast tissue was 26%.

Use of the gemcitabine (Gemzar) plus docetaxel (Taxotere) combinationin metastatic breast cancer is motivated by the different mechanismsof action of the drugs, partially nonoverlapping toxicity profiles,and good single-agent activities of both drugs in treatment-naive andanthracycline-pretreated patients. In phase II trials, combinations ofgemcitabine at 900 or 1,000 mg/m2 on days 1 and 8 and docetaxel at 75to 100 mg/m2 on either day 1 or day 8 every 3 weeks, or gemcitabine at800 mg/m2 on days 1, 8, and 15 and docetaxel at 35 mg/m2 on days 1, 8,and 15 or 100 mg/m2 on day 1 every 4 weeks, have produced responserates of 36% to 79% in patients receiving primarily second-line treatment;response rates were greater than 50% in five of six studies. Inphase II trials using every-2-week regimens of gemcitabine at 1,500 or2,000 mg/m2 on day 1 and docetaxel at 50 or 65 mg/m2 on day 1 or 55mg/m2 on day 8, response rates were 50% in pretreated patients and66% in treatment-naive patients. Neutropenia is the primary toxicity ofthe combination; in phase II studies performed with or without growthfactor support, rates of grade 3/4 neutropenia ranged from 29% to 79%and rates of febrile neutropenia ranged from 0% to 18%. An ongoingphase III trial is comparing gemcitabine at 1,000 mg/m2 on days 1 and8 plus docetaxel at 75 mg/m2 on day 1 every 21 days, vs capecitabine at1,000 mg/m2 twice daily for 14 days plus docetaxel at 75 mg/m2 on day1 every 21 days in patients with metastatic breast cancer. Results of thistrial will help to determine optimal use of taxane-based combinationsin patients with advanced disease.

Although anthracyclines and the taxanes comprise the most activefirst-line cytotoxic treatments in patients with hormone-insensitive orlife-threatening metastatic breast cancer, many patients progress andrequire other chemotherapeutic agents. Development of new combinationsand/or agents is thus needed. Gemcitabine (Gemzar) and platinumcompounds have been employed as single agents, and the additionof gemcitabine to the platinums results in significant clinical benefitand response rates. Correlative biologic studies are expected fromseveral already-reported trials and may help elucidate predictive factorsfor both response and toxicity when combining gemcitabine andthe platinums. Trials incorporating these doublets in earlier stages ofbreast cancer or in the neoadjuvant setting may further elucidate theirrole in breast cancer treatment.

The rapid emergence of gemcitabine (Gemzar) as a viable component inchemotherapy for breast cancer is indeed an encouraging development.Specifically, until relatively recently, the focus of research and treatmentwith gemcitabine was primarily on lung cancer. Growing opinion amongmany experts in breast cancer held that studies of gemcitabine in breast cancer werenoticeably lacking and that such research was warranted. Fortunately, these voiceswere heard, and the manufacturers of gemcitabine responded with an acceleratedinitiative to explore further the role of gemcitabine in breast cancer. Rapid progresswas made.

Gemcitabine (Gemzar) possesses meaningful antitumor activity inthe treatment of breast cancer, repeatedly demonstrating superior outcomeswithout the price of excessive toxicity in most patients. In combinationwith other agents, it has a potential for nonoverlapping toxicities,a novel mechanism of action, as well as a potential lack of completecross-resistance. Randomized phase III trials with gemcitabinehave yielded response rates that have translated into time to diseaseprogression and survival benefits. Thus, enthusiasm continues forgemcitabine, especially in combination with other cytotoxic agents. Theaugmentation of efficacy (ie, response rates, time to disease progression,overall survival) by the addition of gemcitabine to paclitaxel hasestablished this regimen as a first-line treatment option for patientswho might benefit from combination therapy. Gemcitabine now remainsunder active investigation for the treatment of early-stage breastcancer, with ongoing trials characterizing its role in the neoadjuvantsetting.

The tAnGo trial is a randomized, open-label, multicenter phase IIItrial examining adjuvant treatment with epirubicin (Ellence)/cyclophosphamide(Cytoxan, Neosar) for four cycles followed by paclitaxel aloneor combined with gemcitabine (Gemzar) for four cycles in patients withearly-stage breast cancer. In the Cancer and Leukemia Group B(CALGB) 9344 trial, addition of paclitaxel to anthracycline/cyclophosphamideadjuvant therapy resulted in increased time to recurrence andimproved survival. Because an unplanned subgroup analysis in CALGB9344 indicated a significant benefit of paclitaxel in patients with estrogenreceptor (ER)-negative disease but not ER-positive disease, the initialtAnGo trial design called for enrollment of patients with ER-negativedisease. The tAnGo trial entry criteria were recently amended toallow any ER status, given experience suggesting that clinical benefitof taxane-containing regimens in ER-positive disease may emerge overa time frame longer than that required to detect benefit in ER-negativedisease. Gemcitabine has been included as a partner for paclitaxel inthe tAnGo trial based on high response rates, including high completeresponse rates, observed in phase II trials of the combination in moreadvanced disease and based on the tolerability and safety of the combinationcompared with those of other taxane-containing two-drug combinations.The tAnGo trial is currently accruing patients and has atarget population of 3,000. Trial results should provide important informationon the role of gemcitabine in adjuvant therapy for breastcancer.

Trastuzumab (Herceptin) is an effective treatment in patients withHER2-overexpressing metastatic breast cancer. Risk of trastuzumabinducedcardiotoxicity raises concerns regarding combined use withanthracyclines or other potentially cardiotoxic agents followinganthracycline treatment. We characterized interactions betweentrastuzumab and gemcitabine (Gemzar) and the combination ofgemcitabine and cisplatin or carboplatin (Paraplatin) as such combinationsmight help reduce the risk of cardiotoxicity. Multiple drugeffect/combination index isobologram analysis was used to study theefficacy of chemotherapeutic drug plus trastuzumab combinations inHER2-overexpressing breast cancer cell lines. Combination index valueswere derived from parameters of the median effect plots, and statisticaltests were used to determine whether the mean combinationindex at multiple effect levels significantly differed from a combinationindex value of 1.0 (values < 1.0 indicate synergy; values > 1.0,antagonism; values equal to 1.0, additivity). At a wide range of clinicallyachievable drug concentrations, interactions between trastuzumaband gemcitabine were synergistic at low concentrations of gemcitabineand antagonistic at high concentrations. A consistent synergistic interactionwas observed with the three-drug combination of trastuzumabplus gemcitabine plus carboplatin or cisplatin. Available clinical dataon the use of trastuzumab plus gemcitabine, and trastuzumab plusgemcitabine/paclitaxel, as well as clinical data on the use ofgemcitabine/cisplatin in breast cancer, are discussed. These findingsindicate that trastuzumab plus gemcitabine and trastuzumab plusgemcitabine plus cisplatin or carboplatin are rational combinations toevaluate in clinical trials.

Gemcitabine (Gemzar) and paclitaxel are active drugs in the treatmentof metastatic breast cancer. Phase I clinical trials data have suggestedthat the gemcitabine plus paclitaxel combination is safe in breastcancer patients. Two doses/administration schedules have been preferredin subsequent phase II and III trials: gemcitabine on days 1 and8 plus a taxane on day 1, every 3 weeks; or gemcitabine plus a taxaneon days 1 and 14, every 4 weeks. In phase II trials, 114 of 221 patients(52%) responded to gemcitabine/paclitaxel therapy. Response rates werelower among patients who received previous chemotherapy for metastaticdisease (response rates: 45%, second line and 70%, first line).Toxicity of gemcitabine/paclitaxel regimens has generally been low, withfew cases of neutropenia or nonhematologic toxicity. Results of therandomized phase III registration trial show a clear advantage forgemcitabine plus paclitaxel over paclitaxel alone in time to disease progression,objective response, and overall survival. Triplet combinations,in which an anthracycline is added to gemcitabine/paclitaxel, are beingexplored in the metastatic and neoadjuvant settings.

MILAN, Italy-In women with fibroglandular or dense breasts, magnetic resonance imaging (MRI) is more sensitive than mammography for detection of multiple malignant foci, suggesting that a dynamic MRI examination is warranted before treatment planning in this group of patients, a team of Italian radiologists and surgeons has concluded. Yet in breasts with an almost completely fatty pattern, both techniques had comparable sensitivity, their multicenter, prospective, nonrandomized study showed. Further, while MRI achieved a 17% gain in sensitivity over mammography in detection of invasive foci, the two techniques had similar sensitivity in detection of in situ foci, and neither had a strong positive predictive value (PPV), the researchers found.

ROCKVILLE, Maryland-The FDA has approved a new indication for Eloxatin (oxaliplatin for injection, Sanofi-Synthelabo)-as a treatment combined with conventional chemotherapy for the postsurgical treatment of patients with stage III colon cancer after complete tumor resection. The drug, as with its previous two US approvals, is to be used in combination with infusional fluorouracil/leucovorin (5-FU/LV). The company noted that the supplemental approval provides the first new adjuvant treatment for colon cancer in more than a decade.

ROCKVILLE, Maryland-Femara (letrozole tablets, Novartis) has received marketing approval from the US Food and Drug Administration (FDA) for the extended adjuvant treatment of postmenopausal women with early breast cancer who have received 5 years of adjuvant therapy with tamoxifen. The FDA based its approval on data from the MA-17 trial, an international, independent study supported by Novartis.

This year alone, more than 215,000 women in the United States will bediagnosed with, and over 40,000 will die from, invasive breast cancer.Recently, mortality from female breast cancer has declined despite anincrease in its incidence. This decline corresponds with improved screeningfor prompt tumor detection, and advances in the treatment of earlydisease. Of these, endocrine therapy has played a prominent role. Forwomen with estrogen receptor (ER)-positive and/or progesterone receptor(PR)-positive breast cancers, endocrine therapy has proven to be amajor component of adjuvant therapy, but it is not effective in womenwhose breast cancers lack ERs and PRs. The selective estrogen-receptormodulator (SERM) tamoxifen has been well established as safe and effectivein the adjuvant care of both pre- and postmenopausal women withhormone-receptor–positive early breast cancer. For premenopausalwomen, ovarian suppression is an important option to be considered.Additionally, the aromatase inhibitors have recently demonstrated utilityin postmenopausal women. The ideal sequencing of treatment withtamoxifen and/or an aromatase inhibitor is the subject of several ongoingstudies. Factors involved in selecting an appropriate endocrine regimenhave grown considerably over the past decade. It is becoming more importantfor those caring for women with breast cancer to fully understandthe available endocrine treatment options and the prognostic and predictivefactors available to help select the most appropriate treatment. Thegoal of this article is to assist clinicians in making decisions regardingadjuvant hormonal therapy and to provide information regarding availableclinical trials. To achieve this, the therapeutic options for hormonaltherapy will be reviewed, as will prognostic and predictive factors used inmaking decisions. Finally, four cases illustrating these difficult decisionswill be discussed, with recommendations for treatment.