Breast Cancer

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.

ORLANDO - Oncotype DX was prognostic and predicted estrogen-receptor (ER)-positive, node-negative breast cancer patients’ response to adjuvant tamoxifen in a study presented by Soonmyung Paik, MD, at the American Society of Clinical Oncology 41st Annual Meeting (abstract 510). "The advantage of Oncotype DX is that it is quantitative in nature," Dr. Paik said.

TORONTO, Ontario-When performing lymphoscintigraphy in breast cancer patients, sentinel nodes are seen most clearly if patients stand and hold their arm out, Sunhee Kim, MD, a resident in radiology at Mt. Sinai Hospital, New York, reported at the 52nd Annual Meeting of the Society for Nuclear Medicine (abstracts 1314, 1315). The standing position is superior to supine, and arm out is better than arm up, she told ONI in an interview at the conference. "The arm out position produces better spatial delineation between the nodes," while standing helps separate the breast lesion from the nodes, Dr. Kim said.

NOTTINGHAM, UNITEDK I N G D O M - G e m c i t a b i n e(Gemzar)/docetaxel (Taxotere) andcapecitabine (Xeloda)/docetaxelshowed similar efficacy against metastaticbreast cancer, according to

TYLER, TEXAS-A 5-daycourse of oral irinotecan (Camptosar)given every 3 weeks is active in patientswith metastatic breast cancerafter the failure of prior anthracycline,

MILAN, ITALY-In a dosefindingand pharmacokinetic phase Istudy, a team of French and Italianresearchers has found combinationtherapy with oral vinorelbine (Navelbine)and capecitabine (Xeloda) to be

PHILADELPHIA, PENNSYLVANIA-Adjuvant treatment withAdriamycin/Taxotere (AT) did not improveoutcome over standard treatmentwith doxorubicin/cyclophosphamide(AC) for women with early-stage

ORLANDO-Interim findingsfrom two large randomized phaseIII studies-a North American jointanalysis and an international trial-have changed the standard of care for

ORLANDO - Initial adjuvant therapy with the aromatase inhibitor letrozole (Femara) offered significantly better protection against further breast cancer, any cancer, or death, compared with tamoxifen, in patients with hormone-sensitive early-breast cancer, according to results from the large-scale BIG 1-98 trial. Letrozole also had different side effects than tamoxifen, but none nearly as consequential for patients as the benefits, said lead investigator Beat Thürlimann, MD, University of Basel, Switzerland.

ASCO - Interim findings from two phase III studies, one a North American joint analysis and the other a large international trial, have changed the standard of care for women with early invasive HER2-positive breast cancer. Trastuzumab

Overweight and obesity increase the risk of developing several cancers.Once cancer develops, individuals may be at increased risk of recurrenceand poorer survival if they are overweight or obese. A statisticallysignificant association between overweight or obesity and breast cancerrecurrence or survival has been observed in the majority of populationbasedcase series; however, adiposity has been shown to have less of aneffect on prognosis in the clinical trial setting. Weight gain after breastcancer diagnosis may also be associated with decreased prognosis. Newevidence suggests that overweight/obesity vs normal weight may increasethe risk of poor prognosis among resected colon cancer patients and therisk of chemical recurrence in prostate cancer patients. Furthermore, obesecancer patients are at increased risk for developing problems followingsurgery, including wound complication, lymphedema, second cancers,and the chronic diseases affecting obese individuals without cancer suchas cardiovascular disease and diabetes. Mechanisms proposed to explainthe association between obesity and reduced prognosis include adiposetissue-induced increased concentrations of estrogens and testosterone,insulin, bioavailable insulin-like growth factors, leptin, and cytokines.Additional proposed mechanisms include reduced immune functioning,chemotherapy dosing, and differences in diet and physical activityin obese and nonobese patients. There have been no randomized clinicaltrials testing the effect of weight loss on recurrence or survival inoverweight or obese cancer patients, however. In the absence of clinicaltrial data, normal weight, overweight, and obese patients should beadvised to avoid weight gain through the cancer treatment process. Inaddition, weight loss is probably safe, and perhaps helpful, for overweightand obese cancer survivors who are otherwise healthy.

PHOENIX-Between 17.5% and 29.8% of 57 nonmetastatic breast cancer patients had cognitive impairment prior to starting chemotherapy in an ongoing study exploring the effects of chemotherapy on cognitive functioning among breast

SAN ANTONIO-Long-term disease-free survival in node-positive, estrogen-receptor (ER)-positive postmenopausal breast cancer patients is improved when hormonal therapy follows chemotherapy, according to a 10-year analysis of the

Drs. Partridge and Schapira areto be complimented on a conciseand comprehensive reviewof pregnancy before, during, andafter a diagnosis of breast cancer. Aswomen are able and willing to deferpregnancy until later in life, the issuesaddressed in this article will be encounteredwith increasing frequencyin oncology.

Drs. Patridge and Schapira setout to review breast cancerand pregnancy, discuss treatmentoptions for breast cancer duringpregnancy, and summarize the availableevidence regarding safety of pregnancyafter breast cancer. This is asubstantial undertaking. They beginby reviewing the epidemiologic dataindicating an early increase in risk ofbreast cancer development after pregnancyand the likely long-term protectiveeffect of pregnancy on breastcancer risks. The subsequent focus oftheir review is on breast cancer duringpregnancy, a relatively rare occurrence.In a study from California,Smith et al indicated that the frequencyof breast cancer concurrent withpregnancy was 1.3 per 10,000 livesingleton births.[1] The authors notea frequently quoted figure of 1 in 3,000pregnancies.

The relationship between pregnancy and breast cancer is complex,and a paucity of available data further complicates decision-makingfor many women diagnosed with breast cancer during pregnancy ordesiring to become pregnant after such a diagnosis. Treatment of breastcancer during pregnancy requires a multidisciplinary care team andcareful consideration of the risk of the disease and gestational age ofthe fetus, in conjunction with the patient’s preferences. Chemotherapyshould be deferred beyond the first trimester. There is no evidence thatpregnancy in a breast cancer survivor will decrease long-term survival;in fact, studies suggest a potential protective effect of pregnancy afterbreast cancer in terms of the risk of recurrence. However, the availablestudies are limited by substantial potential biases, and concerns remainfor some women and their doctors about the risks of pregnancy afterbreast cancer. This article reviews what is known about the associationbetween pregnancy and breast cancer, discusses treatment options forwomen diagnosed with the disease during pregnancy, and summarizesevidence regarding the safety of pregnancy after breast cancer.

Targeted therapies offer a new approach to breast cancer treatment.Rather than eliminating both malignant and normal cellsnonspecifically, these so-called “rational” therapies exploit second messengerproteins, ligands, and receptors that are known to be upregulatedin neoplastic cells, or are implicated in cancer metastasis. This reviewwill highlight a number of these targets and the mechanisms that havebeen targeted in drug design. We will also describe recently completedand currently ongoing clinical trials investigating targeted therapiesand their potential to augment standard breast cancer therapy.

Recent advances in treatment modalities for breast and prostate cancerhave resulted in an increasing number of patients that are cured orthat, despite residual disease, live long enough to start experiencingcomplications from cancer treatment. Osteoporosis is one such problemthat has been increasingly identified in cancer patients. Hypogonadismand glucocorticoid use are the two major causes of bone loss inthese patients. Osteoporosis is characterized by low bone mass and abnormalbone microarchitecture, which results in an increased risk offractures. Vertebral body and hip fractures commonly result in a drasticchange of quality of life as they can result in disabling chronic pain,loss of mobility, and loss of independence in performing routine dailyactivities, as well as in increased mortality. In patients with prostatecarcinoma, androgen-deprivation therapy by either treatment with agonadotropin-releasing hormone (GnRH) or bilateral orchiectomy resultsin increased bone turnover, significant bone loss, and increasedrisk of fractures. Patients with breast cancer are at increased risk forestrogen deficiency due to age-related menopause, ovarian failure fromsystemic chemotherapy, or from the use of drugs such as aromataseinhibitors and GnRH analogs. Several studies have indicated that theprevalence of fractures is higher in breast and prostate cancer patientscompared to the general population. Therefore, patients at risk for boneloss should have an assessment of their bone mineral density so thatprevention or therapeutic interventions are instituted at an early enoughstage to prevent fractures. This article will address the characteristicsof bone loss observed in breast and prostate cancer patients and potentialtreatments.

The improved survival associated with adding the anti-vascular endothelialgrowth factor (VEGF) monoclonal antibody bevacizumab(Avastin) to chemotherapy for the treatment of patients with metastaticcolorectal cancer demonstrates the importance of targeting collateralcells involved in tumor growth, progression, and metastatic spread.Based on the Gompertzian model of tumor growth, adding anti-VEGFagents to standard chemotherapy may be especially effective in earlystages of cancer. By improving chemotherapy delivery to the tumor andinhibiting regrowth between treatment cycles, anti-VEGF agents mayalter the growth pattern of a tumor such that it is more susceptible toeradication. These concepts also suggest that anti-VEGF agents couldenhance the effectiveness of chemotherapy given conventionally or ina dose-dense fashion. As such, it is possible that the effectiveness ofchemotherapy could be maintained or improved, even at lower cumulativedoses, which may improve its tolerability. Additionally, the effectsof anti-VEGF agents on metronomic chemotherapy, which is reportedto have antiangiogenic properties on its own, warrant further evaluation.Preclinical data demonstrate that cytostatic angiogenesis inhibitorsare potent complementary agents to metronomic chemotherapy,producing sustained complete regressions in some models of humancancer. Dose-dense and metronomic chemotherapy have in common ashortened dosing interval and resultant increased and/or prolongedexposure of tumor cells to chemotherapy in vivo. Optimizing the use ofanti-VEGF agents in the clinic demands further investigation of themost appropriate way to combine them with chemotherapy, particularlyregimens designed to exploit known tumor growth patterns andthose designed to target the endothelial cells involved inneovascularization with multiple agents.

Granulocyte-macrophage colony-stimulating factor (GM-CSF,sargramostim [Leukine]) is a powerful cytokine that is able to stimulatethe generation of dendritic cells. Adjuvant treatment with continuous lowdoseGM-CSF has been shown to prolong survival of stage III/IV melanomapatients. Data on continuous low-dose GM-CSF therapy in tumorsother than prostate cancer are still lacking.

SAN ANTONIO-Updated results from the Intergroup Exemestane Study of 4,740 breast cancer patients show adjuvant therapy with the aromatase inhibitor exemestane (Aromasin) after 2 to 3 years of tamoxifen can cut risk of recurrence by