Breast Cancer

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.

Hand-foot syndrome is a localized cutaneous side effect associatedwith the administration of several chemotherapeutic agents, includingthe oral fluoropyrimidine capecitabine (Xeloda). It is never life-threateningbut can develop into a painful and debilitating condition thatinterferes with patients' normal daily activities and quality of life. Severalsymptomatic/prophylactic treatments have been used to alleviatehand-foot syndrome, but as yet there is insufficient prospective clinicalevidence to support their use. The only proven method of managinghand-foot syndrome is treatment modification (interruption and/or dosereduction), and this strategy is recommended for patients receivingcapecitabine. Retrospective analysis of safety data from two largephase III trials investigating capecitabine as first-line therapy in patientswith colorectal cancer confirms that this strategy is effective inthe management of hand-foot syndrome and does not impair the efficacyof capecitabine. This finding is supported by studies evaluatingcapecitabine in metastatic breast cancer. Notably, the incidence andmanagement of hand-foot syndrome are similar when capecitabine isadministered in the metastatic and adjuvant settings, as monotherapy,or in combination with docetaxel (Taxotere). It is important that patientslearn to recognize the symptoms of hand-foot syndrome, so thatprompt symptomatic treatment and treatment modification strategiescan be implemented.

NEW ORLEANS-A German study has provided more support for a dose-dense chemotherapy approach as adjuvant therapy for high-risk breast cancer. The investigators found improvements in

The clinical development of trastuzumab(Herceptin) for thetreatment of HER2-overexpressingbreast cancer has been perhapsthe most important recentadvance in the management of metastaticbreast cancer. In their rigorousand comprehensive review, Emensand Davidson highlight the importanttrials that resulted in the US Food andDrug Administration (FDA) approvalof trastuzumab, discuss combinationchemotherapy options with trastuzumab,and preview promising futurestrategies for combining trastuzumabwith other targeted biologic agents.

There is little that can be done toimprove on this excellentreview by Emensand Davidson.In particular, the section on the preclinicalpharmacology of trastuzumab(Herceptin) provides a concise summaryof the multiplicity of mechanismsattributable to this fascinatingcompound. One of those mechanisms-its immunomodulatory effectthrough antibody-dependent cell-mediatedcytotoxicity-has led not onlyto clinical trials of interleukin-2 (Pro-leukin), as cited by the authors, but toother investigative approaches as well.

ASCO - Even after 8 years, elderly postmenopausal women who had osteoporosis treated with the selective estrogen-receptor modulator raloxifene (Evista) continued to realize a significant benefit in terms of reduced risk of invasive breast

ASCO - In a randomized phase III study from the Cancer and Leukemia Group B (CALGB), weekly paclitaxel proved superior to conventional every-3-week paclitaxel in women with metastatic breast cancer. The initial findings showed both

BETHESDA, Maryland-Convincing evidence indicates that physical activity can significantly reduce the risk of colon and breast cancer, according to a newly released National Cancer Institute (NCI) fact sheet. Moreover, studies also suggest a link between exercise and a reduced risk of cancers of the prostate, lung, and endometrium. However, despite the documented cancer and other health benefits of exercise, "recent studies have shown that more than 60% of Americans do not engage in enough regular physical activity," NCI said. The new publication summarizes the evidence supporting the role of exercise in cancer risk reduction and the possible underlying biological mechanisms

NEW YORK-The lack of fluid yield from cancer-containing breast ducts may pose a significant barrier to using ductal lavage as a cancer-detection tool in women with mammographic calcifications, Seema A. Khan, MD, reported at the 57th Annual Cancer Symposium of the Society of Surgical Oncology (abstract 29). In a study of 20 patients with mammographic calcifications, there were 10 cases of ductal carcinoma in situ (DCIS), of which only 3 (30%) yielded fluid. "This is not a technique that should be offered to women with the hope that we might detect occult cancer," said Dr. Khan, director, Bluhm Family Breast Cancer Early Detection and Prevention Program, Northwestern Memorial Hospital.

HAMBURG, Germany-Radiotherapy for breast cancer increases the risk of death from cardiovascular disease (CVD), compared with patients who did not receive such treatment, according to data from a large retrospective cohort study. Maartje Hooning, MD, a clinical epidemiologist from the Netherlands Cancer Institute, Amsterdam, and lead investigator of this study, presented the findings at the 4th European Breast Cancer Conference (abstract 291).

HAMBURG, Germany-The steroidal aromatase inactivator exemestane (Aromasin) is safe and provides superior progression-free survival, compared with tamoxifen, in the treatment of postmenopausal woman diagnosed with hormone-responsive metastatic breast cancer, according to the first head-to-head front-line phase III trial comparing the two agents. Robert Paridaens, MD, of the University Hospital Gasthuisberg, Leuven, Belgium, presented the findings at the 4th European Breast Cancer Conference (abstract 241).

HAMBURG, Germany-More than 90% of woman diagnosed with ductal carcinoma in situ (DCIS) will still be alive 10 years after diagnosis and treatment, regardless of how they were initially treated. Research data confirming these findings were presented at the 4th European Breast Cancer Conference (abstract 461).

Primary nonepithelial malignancies of the breast comprise an importantminority of breast neoplasms, including primary breast sarcomas,therapy-related breast sarcomas, the phyllodes tumors, and primarybreast lymphomas. With widespread mammographic detection ofbreast lesions, these tumors represent critical elements of the differentialdiagnosis of even benign-appearing lesions. Each has a distinctclinical profile, including presentation, available therapeutic options,and prognosis, further underscoring the importance of timely recognition.The increasing incidence of breast carcinomas and the subsequenttherapy thereof may be contributing to an increase in the numberof therapy-related breast tumors. This review discusses various featuresof these uncommon malignancies and their treatment, with thegoal of increasing understanding of their clinical behavior andmanagement.

SAN ANTONIO-The question of how much weight to give isolated bone marrow micrometastases in making breast cancer treatment decisions was the focus of three presentations at the 26th San Antonio Breast Cancer Symposium. Two of these studies confirmed that occult micrometastases are a warning sign of poor prognosis in many breast cancer patients. The third found that isolated tumor cells in the sentinel lymph node are not a major problem in patients with ductal carcinoma in situ (DCIS).

SAN ANTONIO-A new analysis of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial shows that the aromatase inhibitor anastrozole (Arimidex) was more effective in preventing relapses than tamoxifen in receptor-positive breast cancer patients (estrogen and/or progesterone positive [ER+ and/or PR+]), with the greatest effect seen in ER-positive/PR-negative (ER+/PR-) women, said Mitch Dowsett, PhD, professor of biochemical endocrinology, Royal Marsden Hospital, London, UK, on behalf of the ATAC Trialists’ Group.

SAN DIEGO-In a cohort of endometrial cancer patients at M.D. Anderson Cancer Center, those who had previously developed breast cancer and used tamoxifen did not have a higher incidence of high-risk histologic subtypes, compared with breast cancer patients not receiving tamoxifen, reported Brian M. Slomovitz, MD, at the Society of Gynecologic Oncologists 35th Annual Meeting (SGO abstract 24).

AN ANTONIO-Breast cancer patients with BRCA 1 or 2 mutations undergoing breast-conserving surgery plus radiotherapy do not have more in-breast recurrences or radiotherapy complications than their counterparts without the germ-line mutation, and they derive particular benefits from prophylactic bilateral oophorectomy, according to 10-year results from a large collaborative database reported at the 26th San Antonio Breast Cancer Symposium (abstract 5).

Locally advanced breast canceraccounts for up to 70% ofbreast cancer cases worldwide.[1] In the past decade, neoadjuvantsystemic therapy has emerged asa therapeutic option for early breastcancer. The main goal of neoadjuvanttreatment is to downstage breast tumors,rendering them operable or permittingbreast-conserving surgery.The therapy has been used increasinglyin patients who have large breasttumors and are candidates for mastectomy,but in whom tumor shrinkageallows for less extensive surgeryand better cosmetic results.[2] Thedegree of the tumor’s responsivenessto preoperative therapy could serveas a surrogate for the response ofmicrometastasis to therapy and theconsequent outcome.[3]

Breast cancer mortality has declinedin recent years due toadvances in screening and adjuvantsystemic therapy. Based on anoverall estimated risk of relapse foran individual woman, her age, comorbidities,and tumor characteristics,she may be offered adjuvant hormonetherapy, chemotherapy, or both.

For many oncologists, neoadjuvant treatment for breast cancer issynonymous with preoperative cytotoxic chemotherapy, regardless oftumor characteristics. Preoperative therapy with an endocrine agent isgenerally considered suitable only for the frail elderly or the medicallyunfit. However, favorable information regarding third-generationaromatase inhibitors in the treatment of all stages of breast cancerprompts a reconsideration of this bias. In light of the fact thatneoadjuvant therapy with aromatase inhibitors is restricted to postmenopausalwomen with strongly estrogen-receptor–positive tumors, the assumptionthat neoadjuvant combination chemotherapy is more efficaciousthan a third-generation aromatase inhibitor can be reasonablyquestioned. It is particularly remarkable that the outcome of a comparisonof adjuvant tamoxifen vs anastrozole (Arimidex)-the Arimidex,Tamoxifen Alone or in Combination (ATAC) trial-in more than 6,000patients was predicted by a neoadjuvant trial that showed an efficacyadvantage for a third-generation aromatase inhibitor (letrozole[Femara]) compared to tamoxifen in a sample of 337 patients afteronly 4 months of treatment. The potential of the neoadjuvant setting inefforts to identify new biologic agents that could build on the effectivenessof adjuvant aromatase inhibitors is therefore beginning to be appreciated.Finally, neoadjuvant therapy with an aromatase inhibitorcould be considered a sensitivity test of endocrine therapy that might beincorporated into strategies to individualize treatment according to response.For this possibility to be realized, however, a better understandingof the relationship between surrogates from the neoadjuvant settingand the long-term outcome of adjuvant aromatase inhibitor therapywill have to be established through practice-setting clinical trials.

SAN ANTONIO-Expression of a set of 21 genes can be analyzed from ordinary, paraffin-embedded tissue specimens and can predict which newly diagnosed, node-negative, tamoxifen-treated breast cancer patients are likely to have distant disease recurrence within 10 years, according to data reported at the 26th Annual San Antonio Breast Cancer Symposium (abstract 16). The assay is less useful in node-negative patients who have not been treated with tamoxifen.

This special "annual highlights" supplement to Oncology News International is a compilation of some of the major advances in the management of gastrointestinal cancers during 2003–2004, as reported in ONI. Guest editor Dr. James L. Abbruzzesecomments on the reports included herein and discusses advances in the clinical management of GI cancers, with a focus on developments in targeted therapy, newcombinations, adjuvant therapy, and what to watch for in 2004.

About 10% to 15% of patients who undergo breast-conservation surgeryand radiation therapy will subsequently develop ipsilateral breasttumor recurrence (IBTR). This paper reviews the biology, clinical management,and outcome of this entity. Risk factors for IBTR includeyoung age, positive microscopic margins, gross multifocality, an extensiveintraductal component, and lymphatic vessel invasion. The standardtherapy following IBTR has been mastectomy, but interest in furtherbreast-conservation approaches has recently arisen. Although theoutcome following salvage therapy is quite good, the risk of distantmetastases for patients with IBTR is three to five times greater than forthose without recurrence. The reason for this association has been controversial,but it now appears that IBTR is both a marker of the underlyingbiologic aggressiveness of the tumor and a source for furthertumor metastasis. Monitoring of patients following lumpectomy andradiation therapy, and aggressive therapy for IBTR when diagnosed,are clearly warranted. Prognostic factors at the time of IBTR and implicationsfor local and systemic therapy are discussed.

SAN ANTONIO-Docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide (TAC) improved overall survival by 30% and disease-free survival by 28% at 5 years, compared with the standard combination of flu-orouracil, doxorubicin, and cyclophosphamide (FAC) as adjuvant therapy for women with node-positive, early-stage breast cancer, John R. Mackey, MD, reported at the 26th Annual San Antonio Breast Cancer Symposium (abstract 43).