Breast Neoplasms: Hortobágyi GN

Shyyan R, Sener SF, Anderson BO, Garrote LM, Hortobágyi GN, Ibarra JA, Ljung BM, Sancho-Garnier H, Stalsberg H, Anonymous00018. · Department of Surgery, Lviv Regional Cancer Center, Lviv, Ukraine. · Cancer. · Pubmed #18837018 No free full text.

Abstract: A key determinant of breast cancer outcome in any population is the degree to which newly detected cancers can be diagnosed correctly so that therapy can be selected properly and provided in a timely fashion. A multidisciplinary panel of experts reviewed diagnosis guideline tables and discussed core implementation issues and process indicators based on the resource stratification guidelines. Issues were then summarized in the context of 1) clinical assessment, 2) diagnostic breast imaging, 3) tissue sampling, 4) surgical pathology, 5) laboratory tests and metastatic imaging, and 6) the healthcare system. Patient history provides important information for the clinical assessment of breast and comorbid disease that may influence therapy choices. Focused clinical breast examination and complete physical examination provide guidance on the extent of disease, the presence of metastatic disease, and the ability to tolerate aggressive therapeutic regimens. Breast imaging improves preoperative diagnostic assessment and also permits image-guided needle sampling. Diagnostic mammography was not considered mandatory in low- and middle-income countries when resources are lacking. Needle biopsy is preferred to surgical excision for the initial diagnosis of suspicious breast lesions, unless resources are unavailable. Mastectomy should never be used as a method of tissue diagnosis. The availability of predictive tumor markers, especially estrogen receptor testing, is critical when endocrine therapies are available; quality assessment of immunohistochemistry testing is important to avoid false-negative results. Incremental allocation of resources can help address economic disparities and help ensure equity in access to timely diagnosis.

Eniu A, Carlson RW, Aziz Z, Bines J, Hortobágyi GN, Bese NS, Love RR, Vikram B, Kurkure A, Anderson BO, Anonymous00017. · Department of Breast Tumors, Oncology, Cancer Institute I. Chiricuta, Cluj-Napoca, Romania. · Breast J. · Pubmed #16430398 No free full text.

Abstract: Treating breast cancer under the constraints of significantly limited health care resources poses unique challenges that are not well addressed by existing guidelines. We present evidence-based guidelines for systematically prioritizing cancer therapies across the entire spectrum of resource levels. After consideration of factors affecting the value of a given breast cancer therapy (contribution to overall survival, disease-free survival, quality of life, and cost), we assigned each therapy to one of four incremental levels--basic, limited, enhanced, or maximal--that together map out a sequential and flexible approach for planning, establishing, and expanding breast cancer treatment services. For stage I disease, basic-level therapies are modified radical mastectomy and endocrine therapy with ovarian ablation or tamoxifen; therapies added at the limited level are breast-conserving therapy, radiation therapy, and standard-efficacy chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil [CMF], or doxorubicin and cyclophosphamide [AC], epirubicin and cyclophosphamide [EC], or 5-fluorouracil, doxorubicin, and cyclophosphamide [FAC]); at the enhanced level, taxane chemotherapy and endocrine therapy with aromatase inhibitors or luteinizing hormone-releasing hormone (LH-RH) agonists; and at the maximal level, reconstructive surgery, dose-dense chemotherapy, and growth factors. For stage II disease, the therapy allocation is the same, with the exception that standard-efficacy chemotherapy is a basic-level therapy. For locally advanced breast cancer, basic-level therapies are modified radical mastectomy, neoadjuvant chemotherapy (CMF, AC, or FAC), and endocrine therapy with ovarian ablation or tamoxifen; the therapy added at the limited level is postmastectomy radiation therapy; at the enhanced level, breast-conserving therapy, breast-conserving whole-breast radiation therapy, taxane chemotherapy, and endocrine therapy with aromatase inhibitors or LH-RH agonists; and at the maximal level, reconstructive surgery and dose-dense chemotherapy and growth factors. For metastatic or recurrent disease, basic-level therapies are total mastectomy for ipsilateral in-breast recurrence, endocrine therapy with ovarian ablation or tamoxifen, and analgesics; therapies added at the limited level are radiation therapy and CMF or anthracycline chemotherapy; at the enhanced level, chemotherapy with taxanes, capecitabine, or trastuzumab, endocrine therapy with aromatase inhibitors, and bisphosphonates; and at the maximal level, chemotherapy with vinorelbine, gemcitabine, or carboplatin, growth factors, and endocrine therapy with fulvestrant. Compared with the treatment of early breast cancer, the treatment of advanced breast cancer is more resource intensive and generally has poorer outcomes, highlighting the potential benefit of earlier detection and diagnosis, both in terms of conserving scarce resources and in terms of reducing morbidity and mortality. Use of the scheme outlined here should help ministers of health, policymakers, administrators, and institutions in limited-resource settings plan, establish, and gradually expand breast cancer treatment services for their populations.

Ross JS, Hatzis C, Symmans WF, Pusztai L, Hortobágyi GN. · Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208, USA. · Oncologist. · Pubmed #18515733 links to  free full text

Abstract: In the past 5 years, a number of commercialized multigene prognostic and predictive tests have entered the complex and expanding landscape of breast cancer companion diagnostics. These tests have used a variety of formats ranging from the familiar slide-based assays of immunohistochemistry and fluorescence in situ hybridization to the nonmorphology-driven molecular platforms of quantitative multiplex real-time polymerase chain reaction and genomic microarray profiling. In this review, 14 multigene assays are evaluated as to their scientific validation, current clinical utility, regulatory approval status, and estimated cost-benefit ratio. Emphasis is placed on two tests: oncotype DX and MammaPrint. Current evidence indicates that the oncotype DX test has the advantages of earlier commercial launch, wide acceptance for payment by third-party payors in the U.S., ease of use of formalin-fixed paraffin-embedded tissues, recent listing by the American Society of Clinical Oncology Breast Cancer Tumor Markers Update Committee as recommended for use, continuous scoring system algorithm, ability to serve as both a prognostic test and predictive test for certain hormonal and chemotherapeutic agents, demonstrated cost-effectiveness in one published study, and a high accrual rate for the prospective validation clinical trial (Trial Assigning Individualized Options for Treatment). The MammaPrint assay has the advantages of a 510(k) clearance by the U.S. Food and Drug Administration, a larger gene number, which may enhance further utility, and a potentially wider patient eligibility, including lymph node-positive, estrogen receptor (ER)-negative, and younger patients being accrued into the prospective trial (Microarray in Node-Negative Disease May Avoid Chemotherapy). A number of other assays have specific predictive goals that are most often focused on the efficacy of tamoxifen in ER-positive patients, such as the two-gene ratio test and the cytochrome P450 CYP2D6 genotyping assay.

Gonzalez-Angulo AM, Hortobágyi GN, Esteva FJ. · Department of Breast Medical Oncology, The University of Texas M. D. Ander-son Cancer Center, 1515 Holcombe Boulevard, Unit 1354, Houston, Texas 77030, USA. · Oncologist. · Pubmed #16951389 links to  free full text

Abstract: Breast cancer is the most common cancer in women in the U.S. and western Europe. Amplification of the her-2/neu gene occurs in approximately 25% of invasive ductal carcinomas of the breast. In experimental models, transfection of the her-2/neu gene results in transformation of mammary epithelial cells. In human breast cancer, amplification of the her-2/neu gene results in protein over expression and poor prognosis. Patients whose tumors have her-2/neu gene amplification have a shorter disease-free survival time than patients whose tumors exhibit a normal her-2/neu gene copy number. her-2/ neu gene amplification identifies a biologically unique subset of aggressive breast tumors that are sensitive to growth inhibition and apoptosis induced by anti-HER-2/neu-targeted therapies. The first HER-2/neu-targeted approach to reach the clinic was trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER-2/neu protein. Trastuzumab therapy prolongs the survival of patients with metastatic HER-2/neu-overexpressing breast cancer when combined with chemotherapy and has recently been demonstrated to lead to dramatic improvements in disease-free survival when used in the adjuvant therapy setting in combination with or following chemotherapy. However, potential cardiotoxicity requires careful patient selection. Here, we review the recently completed clinical trials of adjuvant trastuzumab in the adjuvant setting. HER-2/neu testing, patient selection, cardiotoxicity, duration of therapy, and directions for future research are discussed.

Pusztai L, Ayers M, Stec J, Hortobágyi GN. · Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. · Oncologist. · Pubmed #12773747 links to  free full text

Abstract: DNA microarrays represent an important new tool to analyze human tissues. The technology enables investigators to measure the expression of several thousand mRNA species simultaneously in a biological specimen. This process, called transcriptional profiling, represents a technological breakthrough in the analysis of biological specimens. It may be used to screen for individual genes that are differentially expressed between normal and diseased tissues in the hope of finding novel targets for drug development or finding new single-gene markers of clinical outcome. Microarrays are also applied to learn about the complex biology of cancer by simultaneously monitoring interactions between hundreds of genes during experimental conditions in vitro or during therapy in vivo. Analysis of gene expression patterns may also be used as a classification tool to sort cancer into various clinically relevant subgroups that is not currently possible with other methods. The first clinically important applications of this technology will likely be its use as a tool to refine diagnosis and improve the accuracy of predictions of prognosis and response to therapy. DNA microarrays in several "proof-of-principle" experiments have demonstrated that they can predict important clinical outcomes, including outcomes that cannot currently be predicted with other methods, but the true clinical utility and the limits of this exciting new technology are yet to be established. This paper reviews the current methodology and applications of this technique as they relate to clinical oncology.

Singletary SE, Walsh G, Vauthey JN, Curley S, Sawaya R, Weber KL, Meric F, Hortobágyi GN. · Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 444, Houston, Texas 77030-4095, USA. · Oncologist. · Pubmed #12773746 links to  free full text

Abstract: Although metastatic breast cancer is widely believed to carry a grim prognosis, treatment developments over the past 25 years have greatly improved survival outcomes in these patients. In selected cases, aggressive treatment approaches may occasionally result in long-term survival of 15 years or more. This review considers the role of surgery in the treatment of single or multiple metastatic lesions restricted to one site. For each site, available literature from 1992-2002 was assessed to determine the role of surgery on survival outcomes and to determine appropriate criteria for selecting the best candidates for surgery. For lung, liver, brain, and sternum metastases, the use of surgery with or without adjuvant therapy resulted in greater median survival times and 5-year survival rates. The best candidate for surgery had no evidence of additional metastatic disease, good performance status, and a long disease-free interval after treatment of the primary tumor. Current treatment standards for breast cancer follow-up do not include imaging studies other than mammography. The addition of chest x-rays as part of routine follow-up should be considered as a cost-effective approach for early assessment of metastases to the lung or sternum that may be appropriate for surgical excision.

Cristofanilli M, Buzdar AU, Hortobágyi GN. · Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. · Oncologist. · Pubmed #12697939 links to  free full text

Abstract: Inflammatory breast cancer (IBC) is the most aggressive manifestation of primary breast carcinoma, with the clinical and biological characteristics of a rapidly proliferating disease. The multidisciplinary management of IBC has changed in the past 3 decades and is presently clearly outlined in sequence, with preoperative or neoadjuvant chemotherapy representing the mainstay of treatment. Anthracyclines and taxanes are the most effective cytotoxic agents in the management of primary breast cancer and should be the standard of treatment for women with IBC. Locoregional treatment includes radiotherapy with or without surgery and continues to play a major role after appropriate medical treatment. The many investigations into the particular molecular determinants of IBC development have provided several interesting new therapeutic targets. Combination regimens that include angiogenic modulators, farnesyl transferase inhibitors, and p53 modulators hold great promise in the medical management of IBC. Future therapeutic approaches should focus on these discoveries so that we can improve the overall prognosis for women with IBC.

Nahta R, Hortobágyi GN, Esteva FJ. · Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. · Oncologist. · Pubmed #12604728 links to  free full text

Abstract: Increased expression and activation of receptor tyrosine kinases occurs frequently in human breast carcinomas. Several therapies targeting these receptors are currently in clinical trials. Therapeutic strategies include blockade of individual receptors with monoclonal antibodies and inhibition of tyrosine kinase function. Trastuzumab is the first of these biologic therapies to be approved for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. Novel trastuzumab-based combinations are being investigated in patients with advanced breast cancer. Large clinical trials have also been launched in the adjuvant setting. Small molecules that inhibit specific tyrosine kinases (e.g., epidermal growth factor receptor, HER2) are in phase I and phase II clinical trials. Other growth-factor-targeted drugs that have reached clinical development include STI571 and antibodies directed at the insulin-like growth factor pathway. Biologic therapies directed against these important receptors are promising. In this review we discuss challenges and opportunities for the development of growth-factor-targeted approaches for the treatment of breast cancer.

Hortobágyi GN. · Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. · Cancer. · Pubmed #18837030 No free full text.

This publication has no abstract.

Dawood S, Broglio K, Kau SW, Islam R, Symmans WF, Buchholz TA, McGuire SE, Meric-Bernstam F, Cristofanilli M, Hortobágyi GN, Gonzalez-Angulo AM. · Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, USA. · Oncologist. · Pubmed #18245008 links to  free full text

Abstract: The aim of this retrospective study was to determine the prognostic impact of initial clinical stage in patients who achieved a pathological complete response (pCR) after receiving primary systemic chemotherapy (PST). Between 1977 and 2006, 489 patients who had achieved a pCR after receiving an anthracycline-based PST regimen were identified. Recurrence-free survival (RFS) and overall survival (OS) were estimated with the Kaplan-Meier product limit method and the differences between groups were compared using the log-rank statistic. Cox proportional hazards models were fit to determine the association of initial clinical stage with survival outcomes after adjusting for patient and tumor characteristics. The median age was 47 years. Twenty (4.1%) patients had stage I disease, 243 (49.7%) had stage II disease, 189 (38.7%) had stage III disease, and 37 (7.5%) had inflammatory breast cancer (IBC). At a median follow-up of 45 months, 59 (12%) patients had experienced disease recurrence. The 5-year RFS and OS rates for the whole cohort were 87.8% and 89.3%, respectively. Lower clinical stage at diagnosis was associated with statistically significant higher RFS and OS rates. In a multivariate model, patients with clinical stage IIIB/C disease and those with IBC had lower RFS rates than patients with clinical stage I/II/IIIA disease. In addition, patients with clinical stage IIIB/C disease and those with IBC had a greater hazard of death than patients with clinical stage I/II/IIIA disease. Overall, patients who achieved a pCR had a low rate of recurrence. However, higher clinical stage and IBC were associated with worse outcomes in breast cancer patients who achieved a pCR after PST.

Gonzalez-Angulo AM, Hennessy BT, Broglio K, Meric-Bernstam F, Cristofanilli M, Giordano SH, Buchholz TA, Sahin A, Singletary SE, Buzdar AU, Hortobágyi GN. · Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, USA. · Oncologist. · Pubmed #17766649 links to  free full text

Abstract: The purpose of this study was to evaluate whether the survival of women with inflammatory breast cancer (IBC) treated at our institution has improved over the past 30 years. Three-hundred ninety-eight patients with IBC were treated between 1974 and 2005. Patient characteristics and outcomes were tabulated and compared among decades of diagnosis. Survival outcomes were estimated with the Kaplan-Meier product limit method and compared among groups with the log-rank statistic. Cox proportional hazards models were fit to determine the association between year of diagnosis and survival outcomes after adjustment for patient and disease characteristics and treatments received. The median follow-up was 5.8 years (range, 0.3-23.8 years). There were 238 recurrences and 236 deaths. The median recurrence-free survival (RFS) duration was 2.3 years and the median overall survival (OS) time was 4.2 years. In the models for RFS and OS, after adjustment for patient and disease characteristics, increasing year of diagnosis was not associated with a decrease in the risk for recurrence (hazard ratio, [HR], 1.00; 95% confidence interval [CI], 0.97-1.04) or death (HR, 0.97; 95% CI, 0.94-1.01). Our data show that there has not been an important change in the prognosis of patients with IBC in the last 30 years. Clinical trials focusing on the management of this aggressive disease are warranted. Disclosure of potential conflicts of interest is found at the end of this article.

Groot MT, Baltussen R, Uyl-de Groot CA, Anderson BO, Hortobágyi GN. · Institute for Medical Technology Assessment, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands. · Breast J. · Pubmed #16430401 No free full text.

Abstract: We estimated the costs and health effects of treating stage I, II, III, and IV breast cancer individually, of treating all stages, and of introducing an extensive cancer control program (treating all stages plus early stage diagnosis) in three epidemiologically different world regions--Africa, North America, and Asia. We developed a mathematical simulation model of breast cancer using the stage distribution and case fatality rates in the presence and absence of treatment as predictors of survival. Outcome measures were life-years adjusted for disability (DALYs), costs (in 2000 U.S. dollars) of treatment and follow-up, and cost-effectiveness ratios (CERs; in dollars per DALY averted). Sensitivity analyses were performed to determine the robustness of the results. Treating patients with stage I breast cancer resulted in 23.41, 12.25, and 19.25 DALYs averted per patient in Africa, North America, and Asia, respectively. The corresponding average CERs compared with no intervention were 78 U.S. dollars , 1,960 U.S. dollars, and 62 U.S. dollars per DALY averted. The number of DALYs averted per patient decreased with stage; the value was lowest for stage IV treatment (0.18-0.19), with average CERs of 4,986 U.S. dollars in Africa, 70,380 U.S. dollars in North America, and 3,510 U.S. dollars per DALY averted in Asia. An extensive breast cancer program resulted in 16.14, 12.91, and 12.58 DALYs averted per patient and average CERs of 75 U.S. dollars, 915 U.S. dollars, and 75 U.S. dollars per DALY averted. Outcomes were most sensitive to case fatality rates for untreated patients, but varying model assumptions did not change the conclusions. These findings suggest that treating stage I disease and introducing an extensive breast cancer program are the most cost-effective breast cancer interventions.

Cristofanilli M, Hortobágyi GN. · Department of Breast Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. · Oncologist. · Pubmed #15266101 links to  free full text

Abstract: The San Antonio Breast Cancer Symposium has become one of the leading forums for communication of important discoveries in breast cancer research. Over the past couple of years, seminal, practice-changing results have been presented at this meeting. The aromatase inhibitors represent the most effective endocrine interventions for postmenopausal women with hormone receptor-positive breast cancer. Their introduction into the adjuvant therapy of primary breast cancer was prompted by evidence from the ATAC trial. Progress in adjuvant chemotherapy included the introduction to taxanes, and more recently, the demonstration that the dose-dense administration of paclitaxel in association with doxorubicin and cyclophosphamide resulted in significant improvements in relapse-free and overall survival rates. Molecular targets have become accepted as rational targets, and targeted therapies are proceeding through clinical trials. The success of trastuzumab elicited much excitement, but a number of theoretical and practical hurdles must be overcome before other molecularly targeted agents are incorporated into standard therapy of primary and metastatic breast cancer.