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Gene expression assays (GEAs) can guide treatment for early-stage breast cancer. Several large prospective randomized clinical trials, and numerous additional studies, now provide new information for selecting an appropriate GEA. This systematic review builds upon prior reviews, with a focus on five widely commercialized GEAs (Breast Cancer Index®, EndoPredict®, MammaPrint®, Oncotype DX®, and Prosigna®). The comprehensive dataset available provides a contemporary opportunity to assess each GEA's utility as a prognosticator and/or predictor of adjuvant therapy benefit.
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Neoplasias de la Mama , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Femenino , Quimioterapia Adyuvante , Perfilación de la Expresión Génica , Biomarcadores de Tumor/genética , Estadificación de Neoplasias , PronósticoRESUMEN
Although the incidence of cutaneous melanoma (CM) has been increasing annually, the mortality rate has been decreasing, likely due to better prevention, earlier detection, improved surveillance, and the development of new therapies. Current clinical management guidelines by the National Comprehensive Cancer Network (NCCN) are based on patient risk assignment using staging criteria established by the American Joint Committee on Cancer (AJCC). However, some patients with localized disease (stage I-II), generally considered to have a good prognosis, will develop metastatic disease and die, whereas some patients with later stage disease (stage III-IV) will be cured by surgery, adjuvant therapy, and/or systemic therapy. These results emphasize the importance of identifying patients whose risk may be over or underestimated with standard staging. Gene expression profile (GEP) tests are noninvasive molecular tests that assess the expression levels of a panel of validated genes, providing information about tumor prognosis, including the risk of recurrence, metastasis, and cancer-specific death. GEP tests can provide prognostic information beyond standard staging that may aid clinicians and patients in treatment and surveillance management decisions. This review describes how combining clinicopathologic staging with a robust assessment of tumor biology may provide information that will allow more refined intervention and long-term management.
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National guidelines recommend sentinel lymph node biopsy (SLNB) be offered to patients with > 10% likelihood of sentinel lymph node (SLN) positivity. On the other hand, guidelines do not recommend SLNB for patients with T1a tumors without high-risk features who have < 5% likelihood of a positive SLN. However, the decision to perform SLNB is less certain for patients with higher-risk T1 melanomas in which a positive node is expected 5%-10% of the time. We hypothesized that integrating clinicopathologic features with the 31-gene expression profile (31-GEP) score using advanced artificial intelligence techniques would provide more precise SLN risk prediction. METHODS: An integrated 31-GEP (i31-GEP) neural network algorithm incorporating clinicopathologic features with the continuous 31-GEP score was developed using a previously reported patient cohort (n = 1,398) and validated using an independent cohort (n = 1,674). RESULTS: Compared with other covariates in the i31-GEP, the continuous 31-GEP score had the largest likelihood ratio (G2 = 91.3, P < .001) for predicting SLN positivity. The i31-GEP demonstrated high concordance between predicted and observed SLN positivity rates (linear regression slope = 0.999). The i31-GEP increased the percentage of patients with T1-T4 tumors predicted to have < 5% SLN-positive likelihood from 8.5% to 27.7% with a negative predictive value of 98%. Importantly, for patients with T1 tumors originally classified with a likelihood of SLN positivity of 5%-10%, the i31-GEP reclassified 63% of cases as having < 5% or > 10% likelihood of positive SLN, for a more precise, personalized, and clinically actionable SLN-positive likelihood estimate. CONCLUSION: These data suggest the i31-GEP could reduce the number of SLNBs performed by identifying patients with likelihood under the 5% threshold for performance of SLNB and improve the yield of positive SLNBs by identifying patients more likely to have a positive SLNB.
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Perfilación de la Expresión Génica/normas , Melanoma/diagnóstico , Perfilación de la Expresión Génica/métodos , Perfilación de la Expresión Génica/estadística & datos numéricos , Humanos , Metástasis Linfática/diagnóstico , Metástasis Linfática/prevención & control , Melanoma/cirugía , Ganglio Linfático Centinela/patología , Ganglio Linfático Centinela/fisiopatología , Biopsia del Ganglio Linfático Centinela/métodos , Biopsia del Ganglio Linfático Centinela/normas , Biopsia del Ganglio Linfático Centinela/estadística & datos numéricosRESUMEN
Gene expression profile (GEP) testing is now commercially available for metastatic risk prediction in patients with cutaneous squamous cell carcinoma (CSCC) and one or more high-risk factors. The purpose of this article is to provide an early framework for healthcare providers looking to integrate patient-specific tumor biology into their clinical practice using GEP testing. To develop a framework for clinical use, an expert panel was convened to identify CSCC management decision points where GEP testing may be immediately incorporated into practice until the definitive results of prospective trials become available. Based on their discussion, the expert panel focused on the areas of nodal evaluation, adjuvant radiation therapy, and follow-up and surveillance. The panel emphasized that GEP prognostic test results should not currently be used as a surrogate for standard of care treatment but as an additional data point when determining individualized management for patients with high-risk CSCC. Whenever possible, decisions on management plans for these patients should be developed with multidisciplinary input. J Drugs Dermatol. 2021;20:6(Suppl):s5-11. doi:10.36849/JDD.6068.
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Carcinoma de Células Escamosas , Neoplasias Cutáneas , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Perfilación de la Expresión Génica , Humanos , Estadificación de Neoplasias , Estudios Prospectivos , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/terapiaRESUMEN
Aim: Define changes in clinical management resulting from the use of the prognostic 31-gene expression profile (31-GEP) test for cutaneous melanoma in a surgical oncology practice. Patients & methods: Management plans for 112 consecutively tested patients with stage I-III melanoma were evaluated for duration and number of clinical visits, blood work and imaging. Results: 31-GEP high-risk (class 2; n = 46) patients received increased management compared with low-risk (class 1; n = 66) patients. Test results were most closely associated with follow-up and imaging. Of class 1 patients, 65% received surveillance intensity within guidelines for stage I-IIA patients; 98% of class 2 patients received surveillance intensity equal to stage IIB-IV patients. Conclusion: We suggest clinical follow-up and metastatic screening be adjusted according to 31-GEP test results.
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Biomarcadores de Tumor/genética , Melanoma/diagnóstico , Guías de Práctica Clínica como Asunto , Neoplasias Cutáneas/diagnóstico , Oncología Quirúrgica/normas , Adulto , Anciano , Anciano de 80 o más Años , Toma de Decisiones Clínicas , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Masculino , Melanoma/genética , Melanoma/secundario , Melanoma/terapia , Persona de Mediana Edad , Estadificación de Neoplasias/normas , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Estados Unidos , Espera Vigilante/normasRESUMEN
The American Journal of Managed Care® and Exact Sciences Corporation hosted a roundtable meeting to discuss the impact of colorectal cancer (CRC) screening modalities on improving patient outcomes. The roundtable participants were a diverse panel of experts, including primary care, gastroenterology, and oncology providers; experts in health outcomes research and health policy; and managed care executives with commercial and public payer experience. Participants discussed CRC prevention and treatment strategies, screening modalities and adherence, molecular diagnostics, patient navigation, evaluation of large data sets, managed care, outcomes research, quality improvement, and reimbursement policies. They focused on developing better value-based medical policies and payment procedures, identifying knowledge, practice, and access deficits related to CRC screening. Participants also provided suggestions on how to improve care quality and patient outcomes through effective evidence-based approaches. They also discussed costeffectiveness modeling for CRC screening, specifically the advantages and the real-world limitations of these models.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Navegación de Pacientes , Neoplasias Colorrectales/diagnóstico , Análisis Costo-Beneficio , HumanosRESUMEN
Merkel cell carcinoma (MCC) usually arises in sun-exposed areas of older patients and might be more aggressive in the immunocompromised. We performed a retrospective chart review of 40 consecutive MCC patients treated at our institution between the years 2006-2017. Clinical and epidemiologic data were utilized and therapy and survival were analyzed. Compared to Surveillance, Epidemiology, and End Results (SEER) data, our population was entirely Caucasian (100% versus 95%; P=0.11) and male predominant (75% versus 63%; P=0.11). The median age was 76. The patients more often had Tumor-Node-Metastasis (TNM) stage I disease (50% versus 39%; P=0.00003) and a primary tumor size <2cm (57.5% versus 34%; P<0.01). They received more frequently lymph node dissection (70% versus 63%, P=0.002) compared with the SEER findings. We identified a subset of immunocompromised patients (n=10) who presented with more stage III disease (40% versus 33%; P=0.021). Time to death averaged 290.1 days in this subset versus 618.2 days (P<0.001) in immunocompetent patients and their likelihood of death was 5 times higher. As clinical outcomes in MCC patients vary by immunological status, a multidisciplinary tumor-board approach may better optimize individual patient management.
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Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/patología , Huésped Inmunocomprometido , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Anciano , Anciano de 80 o más Años , Carcinoma de Células de Merkel/terapia , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Humanos , Escisión del Ganglio Linfático , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Radioterapia Adyuvante , Estudios Retrospectivos , Programa de VERF , Factores Sexuales , Neoplasias Cutáneas/terapia , Tasa de Supervivencia , Factores de Tiempo , Carga TumoralRESUMEN
New therapeutic modalities for melanoma promise benefit in selected individuals. Efficacy appears greater in patients with lower tumor burden, suggesting an important role for risk-stratified surveillance. Robust predictive markers might permit optimization of agent to patient, while low-risk prognostic markers might guide more conservative management. This review evaluates protein, gene, and multiplexed marker panels that may contribute to better risk assessment and improved management of patients with cutaneous melanoma.
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Biomarcadores de Tumor/metabolismo , Melanoma/patología , Medición de Riesgo/métodos , Neoplasias Cutáneas/patología , Biomarcadores de Tumor/genética , Humanos , Melanoma/genética , Melanoma/metabolismo , Pronóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Melanoma Cutáneo MalignoRESUMEN
Cases of Merkel cell carcinoma have become increasingly more common in the last two decades, and its incidence has been predicted to climb further. Immunosenescence might explain in part the higher Merkel cell carcinoma prevalence in seniors aged 70 and older. This cancer might also be more aggressive in immunocompromised patients. In a subset of immunocompromised Merkel cell carcinoma patients, we identified significant lymphopenia and a more advanced disease stage compared with their immunocompetent counterparts. Time to death in this cohort was much shorter than in immunocompetent subjects, and their likelihood of death from Merkel cell carcinoma was five times higher. Avelumab approval in 2017 represents an important step forward in the therapy of Merkel cell carcinoma. Hopefully, PD1/PDL1 inhibitors will improve survival in immunocompromised Merkel cell carcinoma hosts, traditionally linked with inferior clinical outcomes.
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Antineoplásicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Células de Merkel/tratamiento farmacológico , Huésped Inmunocomprometido/efectos de los fármacos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/farmacología , Azatioprina/farmacología , Azatioprina/uso terapéutico , Carcinoma de Células de Merkel/inmunología , Femenino , Humanos , Huésped Inmunocomprometido/inmunología , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Cutáneas/inmunología , Resultado del TratamientoRESUMEN
Paclitaxel has been linked with a number of immunosuppressive effects such as decreased numbers and activity of dendritic cells, NK-cells and monocytes, which may in turn lead to defective T-cell activation. In addition, this agent was shown to cause mitotic arrest resembling high-grade dysplasia throughout the gastrointestinal tract, including the appendix. We have previously documented a series of lung cancer patients who developed pre-malignant colonic polyps and/or colon cancer either during or weeks following chemotherapy with paclitaxel, suggesting a potential role of this agent in their pathogenesis. We describe herein a patient who developed adenocarcinoma of the appendix five months after paclitaxel therapy for a locally advanced lower esophageal cancer. Although the cancer of the appendix was in early stage, it was poorly differentiated and showed lymphovascular invasion. The context, timeline and existing experience suggest that this second cancer was triggered by a pre-existing insult, conceivably delivered by paclitaxel.
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Adenocarcinoma/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Apéndice/diagnóstico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Primarias Secundarias/diagnóstico , Adenocarcinoma/patología , Anciano de 80 o más Años , Neoplasias del Apéndice/patología , Humanos , Masculino , Neoplasias Primarias Secundarias/patología , Paclitaxel/administración & dosificaciónRESUMEN
Risk stratification of patients with early stage breast cancer may support adjuvant chemotherapy decision-making. This review details the development and validation of six multi-gene classifiers, each of which claims to provide useful prognostic and possibly predictive information for early stage breast cancer patients. A careful assessment is presented of each test's analytical validity, clinical validity, and clinical utility, as well as the quality of evidence supporting its use.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica/métodos , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Femenino , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Reproducibilidad de los ResultadosRESUMEN
Hormone receptor-positive breast cancer is treated with estrogen inhibitors. Fulvestrant (FASLODEX™), an estrogen receptor (ER) antagonist with no known agonist effects, competitively binds, blocks and degrades the ER. Vascular endothelial growth factor (VEGF) may mediate resistance to ER antagonists. Cediranib is a highly potent VEGF signaling inhibitor with activity against all three VEGF receptors. This randomized Phase II study evaluated cediranib plus fulvestrant. Postmenopausal women with hormone-sensitive metastatic breast cancer were eligible. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response, clinical benefit rate (CBR), safety/tolerability and pharmacokinetics (PK). Patients received cediranib 45 mg/day (n=31) or placebo (n=31) both plus fulvestrant. Demographic/baseline characteristics were well balanced. Patients treated with cediranib had a numerical advantage in PFS (hazard ratio=0.867, P=0.669; median 223 vs. 112 days, respectively) and ORR (22 vs. 8 %, respectively) vs. placebo, although not statistically significant. CBR was 42 % in both arms. The most common adverse events (AEs) in the cediranib arm were diarrhea (68 %), fatigue (61 %) and hypertension (55 %). The incidence of grade ≥ 3 AEs (68 % vs. 32 %), serious AEs (48 % vs. 13 %), discontinuation AEs (39 % vs. 10 %), and cediranib dose reductions/interruptions (74 % vs. 32 %) were higher in the cediranib arm. There was no evidence of a clinically relevant effect of cediranib on fulvestrant PK. Cediranib plus fulvestrant may demonstrate clinical activity in this population, but cediranib 45 mg was not sufficiently well tolerated. Investigation of lower doses of cediranib plus hormonal/chemotherapy could be considered.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Estradiol/administración & dosificación , Estradiol/efectos adversos , Estradiol/análogos & derivados , Estradiol/farmacocinética , Antagonistas de Estrógenos/administración & dosificación , Antagonistas de Estrógenos/efectos adversos , Antagonistas de Estrógenos/farmacocinética , Femenino , Factor 2 de Crecimiento de Fibroblastos/sangre , Fulvestrant , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Adulto JovenRESUMEN
BACKGROUND: Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab. METHODS: In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated. RESULTS: Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma. CONCLUSIONS: Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.
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Anticuerpos Monoclonales/uso terapéutico , Biomarcadores de Tumor/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Microambiente Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Ipilimumab , Masculino , Melanoma/genética , Persona de Mediana Edad , Estadificación de Neoplasias , Polimorfismo Genético , Estudios Prospectivos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias Cutáneas/genética , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Adulto JovenAsunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/terapia , Técnicas y Procedimientos Diagnósticos/tendencias , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias del Colon/epidemiología , Neoplasias del Colon/genética , Femenino , Humanos , Masculino , Enfermería Oncológica , Guías de Práctica Clínica como Asunto , PronósticoRESUMEN
Gene expression profiling allows us to look into a tumor cell to see how genetic information is communicated and affects cell behavior. Data gathered during the development of the 70-gene assay (MammaPrint) set the stage for future assay development. Recently, a 21-gene assay (Oncotype DX) was recommended by ASCO and NCCN as a standard of care for newly diagnosed, stage 1 or 2, node-negative, estrogen-receptor-positive breast cancer patients.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Perfilación de la Expresión Génica , Genómica/tendencias , Oncología Médica/tendencias , Biomarcadores de Tumor , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Femenino , Humanos , Estadificación de Neoplasias , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
PURPOSE: Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer. EXPERIMENTAL DESIGN: In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers. RESULTS: In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry. CONCLUSION: Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.