Breast Cancer

Our understanding of the biologyof breast cancer has undoubtedlyimproved in the pastdecade, and remarkable progress hasbeen achieved in its treatment. Thosecaring for these patients have longrealized that breast cancer is a diseasewith an extremely diverse natural history,and much remains to be learnedabout the interaction among knownpredictive and prognostic factors. Notlong ago, the “more is better” strategyexemplified by high-dose chemotherapy(often resulting in high-dose toxicity)dominated the research agendaand clinical practices of many institutions.Although a minimum chemotherapydose intensity is required[1]and increasing the frequency of specificregimens is advantageous,[2] furtherdose intensification with[3] orwithout stem cell rescue[4-6] offersno meaningful benefit in the adjuvantsetting.

Pemetrexed (Alimta) is a novel folate antimetabolite that primarilyinhibits the enzymes thymidylate synthase (TS), dihydrofolate reductase(DHFR), and glycinamide ribonucleotide formyl transferase(GARFT), all of which are involved in pyrimidine and purine synthesis.In a phase II trial of patients with T3/4, N0–2 breast cancer, expressionof thymidylate synthase (TS), dihydrofolate reductase (DHFR),glycinamide ribonucleotide formyltransferase (GARFT), p53, andc-erb-B2 (at the mRNA or protein level) was examined in tumor biopsyspecimens before and 24 hours after the first dose of pemetrexed andafter three cycles of single-agent treatment to establish correlations ofbiomarker levels and changes with clinical outcome and toxicity. Althoughfinal data are not available, initial indications are that clinicalresponse may correlate with decreased or low TS expression. The resultsobtained from clinical data are supported by laboratory results inthree cell lines (MDA-231, MCF-7, and ZR-75). These results suggestthat in vitro transcript profiling to identify which genes are importantpredictors of successful cytotoxic chemotherapy, followed by a focusedclinical trial to confirm the in vitro results, may be the best approachfor translational research.

Pemetrexed (Alimta) is a novel antimetabolite that inhibits the folatedependentenzymes thymidylate synthase, dihydrofolate reductase, andglycinamide ribonucleotide formyltransferase. Pemetrexed has demonstratedactivity in clinical trials in a variety of tumor types, includinglung, breast, colon, mesothelioma, pancreatic, gastric, bladder, headand neck, and cervix. Pemetrexed is rapidly metabolized into activepolyglutamate forms that are potent inhibitors of several tetrahydrofolatecofactor-requiring enzymes critical to the synthesis of purines and thymidine.Functionally, pemetrexed acts as a prodrug for its polyglutamateforms. Two different transporters are known to take extracellular folates,and some antifolates, into the cell. These are the reduced folate carrierand the folate receptor. One of the many attributes that make pemetrexedunique is that methodology has been developed to eliminate and controlmany of its associated clinical toxicities. Multivariate analyses demonstratedthat pretreatment total plasma homocysteine levels significantlypredicted severe thrombocytopenia and neutropenia, with orwithout associated grade 3/4 diarrhea, mucositis, or infection. Routinevitamin B12 and folic acid supplementation have resulted in decreasedfrequency/severity of toxicities associated with pemetrexed without affectingefficacy, making this novel antifolate a safe and efficaciousanticancer agent.

Pemetrexed (Alimta) is an antifolate that is effective in the inhibitionof multiple enzyme targets including thymidylate synthase,dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase.The compound has been evaluated in several phase I trials, bothas single agent and in combination with other cytotoxic agents. Theinitial schedule selected for further investigation in phase II trials waspemetrexed 600 mg/m2 as a 10-minute infusion on day 1 every 21 days.During the subsequent phase II development, the dose of pemetrexedwas adjusted to 500 mg/m2 due to bone marrow and gastrointestinaltoxicities. The adjusted dose of pemetrexed was well tolerated throughoutthe late-phase drug development program. Preclinical evidencesuggests that pemetrexed has additive or synergistic activity when combinedwith many other clinically important anticancer agents, includinggemcitabine (Gemzar), fluorouracil, carboplatin (Paraplatin),oxaliplatin (Eloxatin), paclitaxel, and vinorelbine (Navelbine). Doselimitingtoxicities in these studies were primarily hematologic, and therewas no evidence of cumulative hematologic toxicity. During the drugdevelopment program it was discovered that supplementation with folicacid and vitamin B12 profoundly increased the tolerability ofpemetrexed. The studies discussed in this review demonstrate thatpemetrexed is well tolerated as a single agent and will be an importantcontribution to combination chemotherapy regimens.

Pemetrexed (Alimta) is active in a variety of solid tumors, includingbreast and gynecologic cancers. Phase II trials of pemetrexed at a doseof 600 mg/m2 without vitamin B12 and folic acid supplementation inlargely pretreated metastatic breast cancer patients demonstrated objectiveresponse rates of 21% and 28%, with generally manageableneutropenia constituting the primary toxicity. In phase II trials using500 mg/m2 with or without vitamin supplementation in anthracyclineandtaxane-pretreated patients, response rates were lower (approximately9%) and treatment was generally well tolerated irrespective ofvitamin supplementation status. A phase II trial is currently comparingpemetrexed doses of 600 and 900 mg/m2 with vitamin B12 supplementationin patients with previously untreated advanced breast cancer. In aphase II trial in patients with advanced cervical cancer, pemetrexed at600 mg/m2 without vitamin supplementation and 500 mg/m2 with supplementationproduced similar response rates, with the frequency of neutropeniabeing somewhat lower among patients receiving the lower doseand vitamin supplementation. Preliminary results in an ongoing phaseII trial indicate activity of the regimen of gemcitabine (Gemzar) at1,000 mg/m2 plus pemetrexed at 500 mg/m2 with vitamin supplementationin patients with ovarian cancer. Ongoing and future studies willestablish optimal dosing regimens of pemetrexed and potential benefitsof vitamin supplementation in the settings of metastatic breastcancer and gynecologic malignancies.

NEW ORLEANS-Testing for a specific gene polymorphism may help to identify which patients are candidates for treatment with aromatase inhibitors, according to a presentation at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 507).

Six published randomized trials[1-6] and one meta-analysis[7] of published and unpublishedtrials have demonstrated thatbreast-conserving therapy (breast-conservingsurgery plus breast irradiation)is equivalent to mastectomy interms of survival. As a result, breastconservingtherapy is the option preferredby many women for thetreatment of early-stage breast cancer.[8] Breast irradiation followingbreast-conserving surgery is an integralpart of breast-conserving therapy.There are seven other publishedrandomized trials demonstrating thatbreast irradiation substantially reducesthe rate of local recurrence andprevents the need for subsequent mastectomy.[9-15] A recent meta-analysisalso supports the conclusion that breastcancer patients who receive breast irradiationhave improved survival.[16]

Dr. Arthur and colleagues havepresented a comprehensiveoverview of two of the mostnoteworthy radiotherapy (RT) advancesin the contemporary managementof breast cancer, ie, short-course hypofractionatedRT and intensity-modulatedradiotherapy (IMRT). Althoughboth challenge the conventional RTapproach to early-stage disease, theydiffer considerably in that hypofractionatedRT refers to treatment of eitherthe entire breast or a part of thebreast in a shorter time course thanwith standard fractionation, whereasIMRT refers to an alteration in themethod of treatment delivery. I willdiscuss each in turn.

Conventional radiotherapeutic treatment for early and advancedbreast cancer has been based on broad-field radiation treatment principlesthat date back several decades. Although these strategies havebeen successful, newer techniques now offer the ability to incorporateimproved target imaging, dosimetric planning, and treatment deliveryinto the treatment design. These newer techniques include acceleratedpartial-breast irradiation and hypofractionated whole-breast irradiationfor early-stage breast cancer, and intensity-modulated radiotherapy(IMRT) for both early and advanced breast cancer. Accelerated partial-breast irradiation and hypofractionated whole-breast radiotherapyare treatment approaches that promise both reduced overall treatmenttimes and the potential for increased use of breast-conservation therapy.IMRT offers unparalleled dose homogeneity and conformality thatenables dose reduction to normal structures with the potential to reducetreatment toxicity and improve cosmesis. Based on the publishedliterature, an increasing number of treatment facilities are offering treatmentwith these techniques. However, further clinical study remainsimportant to thoroughly define the appropriate clinical setting, patientselection criteria, and limitations for each of these innovative treatmentapproaches.

NEW ORLEANS-Addition of trastuzumab (Herceptin) to standard anthracycline-containing chemotherapy in the neoadjuvant setting led to a dramatic increase in the frequency of pathological complete remissions in patients with operable HER-2-positive breast cancer. Aman Buzdar, MD, professor of breast medical oncology, M.D. Anderson Cancer Center, presented the results of the phase III trial at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 520).

NEW ORLEANS-By monitoring the levels of circulating tumor cells (CTCs) in peripheral blood, it is possible to predict which patients with metastatic breast cancer will progress rapidly while on apparently futile therapy, Daniel F. Hayes, MD, of the University of Michigan Comprehensive Cancer Center, Ann Arbor, said at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 509).

This excellent and practical articleby Dr. Ravdin is worthwhilereading for every physician involvedin the long-term care of womenwith a previous diagnosis of breastcancer. Dr. Ravdin clearly outlinesthe theoretical rationale underlying theincreased risk of osteopenia and osteoporosisin women with a history ofbreast cancer. The fact that such womencommonly undergo prematuremenopause either deliberately, as partof treatment for breast cancer, or as asecondary effect of chemotherapy, andthat estrogen-replacement therapywith or without progesterone remainscontraindicated for fear of increasingthe risk of recurrence, clearly contributesto the increased possibility ofdeveloping osteopenia or osteoporosis.New data supporting the role ofaromatase inhibitors in adjuvant therapy[

The authors present a comprehensivereview of anthracycline-based adjuvant chemotherapyregimens, supporting the useof these regimens over CMF (cyclophosphamide[Cytoxan, Neosar],methotrexate, fluorouracil [5-FU]) inearly-stage breast cancer. They concludethat the addition of taxanes toanthracycline-containing regimens innode-positive disease may conferadditional benefit. Newer regimenscontaining taxanes and other agentsthat omit the use of anthracyclinesshow promise but are still underinvestigation.

NEW YORK-Computer-aided detection (CAD) of breast cancer using digitized mammograms could have detected malignancies at least 1 year earlier than film assessment by radiologists alone, according to findings from the Elizabeth Wende Breast Clinic, Rochester, New York.

Estrogen is known to play an important role in skeletal health. Femalebreast cancer patients who receive treatments that reduce estrogenlevels, such as aromatase inhibitors, may increase their risk of developingosteoporosis and their risk of fracture. Clinical guidelinesenable the physician to assess the risk of osteoporosis by patient historyand physical examination. For patients identified as being at risk, it isnecessary to test bone mineral density (BMD), using the result to determinewhich patients require treatment. Two groups can be identified asrequiring BMD assessment according to general guidelines: patients< 45 years old who become menopausal due to treatment, and breastcancer patients receiving aromatase inhibitors. Bisphosphonates appearto be the logical treatment of choice for breast cancer patients, asthey do not interact with the estrogen receptor. Although not all womenreceiving aromatase inhibitors will require additional treatment for bonehealth, postmenopausal women with a history of breast cancer at riskof osteoporosis should be identified, monitored, and managed accordingto practice guidelines.

The treatment of breast cancer has progressed substantially overthe past 15 years. Data from randomized adjuvant trials have shownthat the risk of disease recurrence and death is significantly reducedwhen adjuvant chemotherapy and/or hormonal therapy is added to treatment.As new strategies are incorporated, one of the continued controversiesin patient management is whether adjuvant anthracyclinesshould be the preferred treatment for all patients. Data from randomizedand translational clinical trials have become available and arehelping to elucidate the proper role of anthracyclines, as well as their acuteand long-term toxicities. In most situations, an anthracycline is currentlypreferred, but other single and combination chemotherapies arecurrently under evaluation and appear promising for use in the adjuvantsetting. Continued breast cancer research using molecular markers(such as topoisomerase II–alpha and gene clusters) as predictors oftreatment response, could help individualize decisions regardingwhether to incorporate anthracyclines into adjuvant therapy regimens.

NEW ORLEANS-The first results from a large international study presented at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 505) show that older node-negative breast cancer patients can avoid axillary clearance and have survival outcomes similar to those of women who undergo the invasive procedure. Stig Holmberg, MD, of Gothenberg, Sweden, principal investigator for the International Breast Cancer Study Group (IBCSG) Trial 10-93, said the study was performed to determine if sparing women the trauma and side effects associated with axillary clearance would improve their quality of life without compromising survival.

Multidisciplinary approachesto many human diseases areemerging as effective, patient-centered strategies in diverse areassuch as cancer, neurology, andcardiovascular disease. However, theyrequire significant organizational andfinancial resources. Dr. Rabinowitz articulatesthe key benefits of multidisciplinarycare for breast cancer, includingteam planning and coordination of care.There is not much objective informationto definitively prove that “centerbased”care leads to superior outcomesin terms of recurrence or survival. Thedata cited in this review include improvementsin measures of patient comfortand satisfaction with care, whichare important from an emotional standpointand even make business sense.This alone should motivate cancer careproviders to organize breast centers thatare designed appropriately given thesize of the population served and theresources available.

The 30 reports in this special supplement to Oncology News International represent highlights of ongoing major clinical trials and new research presented at ASCO 2004 regarding state-of-the-art chemotherapeutic management of gastrointestinal and other cancers. Important developments in capecitabine as adjuvant therapy, novel targeted agents, and new combinations are discussed.

The 30 reports in this special supplement to Oncology News International represent highlights of ongoing major clinical trials and new research presented at ASCO 2004 regarding state-of-the-art chemotherapeutic management of gastrointestinal and other cancers. Important developments in capecitabine as adjuvant therapy, novel targeted agents, and new combinations are discussed.

The Susan G. Komen BreastCancer Foundation joins authorDr. Barbara Rabinowitz in underscoringthe importance and valueof interdisciplinary/multidisciplinarybreast care. We agree, as well, thatthe multimodal approach that Dr.Rabinowitz carefully outlines in herarticle should be adopted more consistentlyand recognized as this nation’sstandard of breast care. Herarticle provides the perspective neededto understand why this is so.

The contemporary management of breast cancer is a complex endeavorthat requires a truly collaborative team approach, characterizedby ongoing communication and active information-sharing amongthe multiple disciplines involved. Programs designed to provide comprehensivebreast cancer management by a team of multidisciplinaryspecialists were introduced in the late 1970s and have been increasingslowly. Patients attending comprehensive breast centers receive carefrom a broad-based multidisciplinary team that most often includessurgeons, radiologists, pathologists, medical oncologists, radiationoncologists, plastic/reconstructive surgeons, primary care physicians,gynecologists, nurses, social workers, patient advocates, and geneticrisk counselors. At the heart of comprehensive, interdisciplinary breastcare is the consensus planning conference that brings together teammembers on a regular basis to discuss individual patient cases and developcomprehensive treatment plans. This interactive and dynamicforum has become integral to the interdisciplinary management of breastdiseases and results in an increased level of communication betweenthe participating health-care professionals and the patients they treat.Several professional organizations, most prominently the AmericanSociety of Breast Disease, promote and support an interdisciplinaryapproach to breast care.

NEW ORLEANS-A large study from the United Kingdom has provided some of the first data from a randomized population in support of sentinel node biopsy (SNB) in breast cancer patients. Robert E. Mansel, MD, of the University of

NEW ORLEANS-An international phase III study has found the combination of gemcitabine (Gemzar) plus paclitaxel to be superior to single-agent paclitaxel in the front-line treatment of metastatic breast cancer, producing a 22% reduction in risk of

Trastuzumab (Herceptin) is a therapeutic monoclonal antibody specificfor the human epidermal growth factor receptor type 2 (HER2), acell-surface tyrosine kinase receptor overexpressed by 25% to 30% ofbreast cancers. The drug is now regarded as one option for standardtherapy in HER2-overexpressing metastatic breast cancers. It is associatedwith a moderate response rate as a single agent, and in combinationwith standard chemotherapy, can produce greater response ratesand prolong the survival of women with advanced breast cancer. Itsactivity in metastatic breast cancer has led to active clinical trials examiningits potential role in the neoadjuvant and adjuvant settings.The successful clinical development of trastuzumab provides furtherproof of principle that biologically targeted therapies can have a profoundimpact on the management of breast cancer. Here we review theclinical development of this novel agent, emphasizing the potential fortherapeutic synergy when trastuzumab is combined with both standardchemotherapy and innovative molecularly targeted and biologic agents.