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Palbociclib is a cyclin-dependent kinase 4/6 inhibitor indicated for treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer in combination with endocrine therapy. We investigated the efficacy and safety of palbociclib in patients enrolled in North America during two-phase 3 trials: PALOMA-2 (n = 267, data cutoff: May 31, 2017) and PALOMA-3 (n = 240, data cutoffs: April 13, 2018, for overall survival, October 23, 2015, for all other outcomes). In PALOMA-2, treatment-naïve postmenopausal patients with advanced breast cancer were randomized 2:1 to palbociclib (125 mg/d; 3 weeks on/1 week off [3/1]) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. In PALOMA-3, patients who progressed on prior endocrine therapy were randomized 2:1 to palbociclib (125 mg/d; 3/1) plus fulvestrant (500 mg, per standard of care) or placebo plus fulvestrant; pre/perimenopausal patients received ovarian suppression with goserelin. Palbociclib plus endocrine therapy prolonged median progression-free survival vs placebo plus endocrine therapy in North American patients (PALOMA-2: 25.4 vs 13.7 months, hazard ratio, 0.54 [95% CI, 0.40-0.74], P < .0001; PALOMA-3: 9.9 vs 3.5 months, hazard ratio, 0.52 [95% CI, 0.38-0.72], P < .0001). Objective response and clinical benefit response rates were greater with palbociclib vs placebo in North American patients in both trials. While overall survival data are not yet mature for PALOMA-2, median overall survival was increased in PALOMA-3 (32.0 vs 24.7 months, hazard ratio, 0.75 [95% CI, 0.53-1.04]), though this did not reach statistical significance (P = .0869). Safety profiles in North American patients were similar to those of the overall populations; neutropenia was the most common treatment-emergent adverse event. No new safety signals were observed. In summary, palbociclib plus endocrine therapy is an effective treatment option for North American women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer., (© 2019 The Authors. The Breast Journal published by Wiley Periodicals, Inc.)

Estrogen receptor-positive (ER+) tumors represent the most common form of breast cancer. Although endocrine therapy (ET) results in benefit for the majority of these patients, disease progression invariably occurs. The discovery of the relation between cyclin-dependent kinases (CDKs) and the ER pathways is one of the major advances in unveiling mechanisms of resistance to ET. In this article we review the role of CDK4/6 inhibitors in ER + breast cancer patients., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Cancer is a risk factor for venous thromboembolism (VTE) and plasma d-dimer (DD) and tissue factor (TF) are established VTE associated markers. Circulating tumor cells (CTCs) are associated with the risk of VTE in metastatic breast cancer. This study aimed to correlate CTCs, blood coagulation and the urokinase plasminogen activator (uPA) system in primary breast cancer (PBC) patients. This prospective study included 116 PBC patients treated by primary surgery. CTCs were detected by quantitative RT-PCR assay for expression of epithelial (CK19) or epithelial-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, ZEB1, FOXC2). Plasma DD, TF, uPA system proteins were detected by enzyme-linked immunosorbent assays, while expressions of uPA system in surgical specimens were evaluated by immunohistochemistry. CTCs were detected in 27.6% patients. Patients with CTCs had a significantly higher mean plasma DD (ng/mL) than those of patients without CTCs (632.4 versus 365.4, p = 0.000004). There was no association between plasma TF and CTCs. Epithelial CTCs exhibit higher expression of uPA system genes compared to EMT&#95;CTCs. Patients with CTCs had higher plasma uPA proteins than those of patients without CTCs; there was no correlation between tissue expression of uPA system, CTCs, DD or TF levels. In multivariate analysis CTCs and patients age were independent factors associated with plasma DD. We found association between plasma DD and CTCs indicating a potential role for activation of the coagulation cascade in the early metastatic process. CTCs could be directly involved in coagulation activation or increased CTCs could be marker of aggressive disease and increased VTE risk., (© 2015 Wiley Periodicals, Inc.)

Background: The US Food and Drug Administration's (FDA's) recent decision to remove the indication of bevacizumab for metastatic breast cancer (MBC) has fueled a debate in the breast cancer community. We conducted a survey to assess the perception of health care workers involved in the management of women with MBC on the FDA's decision to ascertain how it will affect practice and to determine how bevacizumab is commonly used in the community for MBC., Methods: E-mails were sent out between September and November 2010 using a database of 3000 addresses maintained by the United Arab Emirates Cancer Congress. Individuals working for Roche or Genentech were excluded. The survey consisted of 22 questions that were divided into 3 parts addressing each participant's demographic profile, their opinion of the FDA's decision, and the typical use of bevacizumab in the community in the setting of MBC., Results: A total of 564 participants were included in the final analysis, contributing to an 18.8% response rate. Of these participants, 14.6% were from the United States, 7.8% were from Canada, 31.1% were from Europe, 2.0% were from the United Arab Emirates, 11.1% were from Asia, and 33.3% were from other countries. The majority of participants believed progression-free survival to be a surrogate for overall survival, that cost played a role in the FDA's decision, and that the decision would adversely affect the future of newer drugs currently being investigated for MBC. The majority of participants indicated that they would use bevacizumab for triple receptor-negative MBC (46.5%), would use it in a first-line setting (44.7%), and would use it in combination with paclitaxel (51.9%)., Conclusion: Our survey results highlight the discord between the opinion of community oncologists and the FDA's recent decision to withdraw the indication of bevacizumab for MBC., (Copyright © 2011 American Cancer Society.)

Background: Inhibition of mammalian target of rapamycin with everolimus may improve the efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction., Methods: Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40-75 mg/m(2) intravenously on day 1 of a 21-day cycle) in combination with everolimus (doses ranging from 20 to 50 mg orally on days 1 and 8 of a 21-day cycle) in a phase 1 trial using the continuous reassessment method to determine maximum tolerated dose. The first 2 patients developed a dose-limiting toxicity (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts., Results: Fifteen patients were treated. Dose-limiting toxicity included grade 3 mucositis (n = 1), prolonged grade 4 neutropenia (n = 1), and grade 3 infection/febrile neutropenia (n = 3). Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40 mg/m(2). Eleven patients underwent complete PK evaluation for everolimus, and 9 patients underwent complete PK evaluation for both everolimus and docetaxel. Widely variable changes in clearance were seen for both drugs, and the study was terminated because of lack of efficacy and concerns regarding toxicity seen with the combination., Conclusions: Weekly everolimus in combination with docetaxel every 3 weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs., (Copyright © 2011 American Cancer Society.)

Background: Enhancer of zeste homolog 2 (EZH2), a member of polycomb group proteins, is involved in the regulation of cell cycle progression and has been implicated in various human malignancies, including breast cancer, and also has been associated with aggressive tumor behavior. However, the clinical significance of EZH2 expression in inflammatory breast cancer (IBC), a rare but aggressive type of breast carcinoma, has not been explored. In this retrospective study, the authors examined EZH2 expression in IBC tumors and evaluated the relation between EZH2 expression and patient survival., Methods: Tissue microarrays of 88 surgically resected IBC tumors were stained immunohistochemically for EZH2, and the authors evaluated the association of EZH2 expression status with clinicopathologic factors and clinical outcome., Results: The median follow-up for the entire cohort was 45.7 months, and the 5-year overall survival (OS) rate was 45%. EZH2 was expressed frequently in IBC tumors (75.7%) and was associated significantly with unfavorable prognostic factors, such as higher tumor grade, negative estrogen receptor status, and triple-negative status (ie, negative for the estrogen, progesterone, and human epidermal growth factor 2 receptors). Univariate survival analysis indicated that patients who had EZH2-positive IBC had a significantly lower 5-year OS rate than patients who had EZH2-negative IBC (P = .01). In multivariate analysis, only positive EZH2 status remained an independent predictor of worse OS., Conclusions: EZH2 was expressed frequently in IBC tumors. The current results indicated that EZH2 expression status may be used to identify a subset of patients with IBC who have a relatively worse prognosis. Targeting EZH2 also may provide a novel strategy for improving the clinical outcome of patients with IBC., (Copyright © 2011 American Cancer Society.)

Background: Significant improvements in the survival of women with breast cancer have been observed and are attributed to a multidisciplinary approach and the introduction of polychemotherapy and endocrine regimens. The objective of this population-based study was to determine whether women with inflammatory breast cancer (IBC) who received treatment in a modern era had a poorer survival compared those with non-IBC locally advanced breast cancer (LABC)., Methods: The Surveillance, Epidemiology, and End Results program registry was searched to identify women with stage IIIB/C breast cancer diagnosed between 2004 and 2007 who had undergone surgery and radiotherapy. Patients were categorized as either having IBC or non-IBC LABC according the sixth edition of the American Joint Committee on Cancer (AJCC) criteria. Breast cancer-specific survival (BCS) was estimated using the Kaplan-Meier product limit method and compared across groups using the log-rank statistic. Cox models were then fitted to compare the association between breast cancer type and BCS after adjusting for patient and tumor characteristics., Results: A total of 828 (19.2%) women and 3476 (80.8%) women had stage IIIB/C IBC and non-IBC LABC, respectively. The median follow-up was 19 months. The 2-year BCS rate was 90% (95% confidence interval [95% CI], 88%-91%) for the entire cohort and 84% (95%CI, 80%-87%) and 91% (95%CI, 90%-91%) among women with IBC and non-IBC LABC, respectively. In the multivariable model, patients with IBC were found to have a 43% increased risk of death from breast cancer compared with patients with non-IBC LABC (hazard ratio, 1.43; 95%CI, 1.10-1.86 [P = .008])., Conclusions: In the era of multidisciplinary management and anthracycline-based and taxane-based polychemotherapy regimens, women with IBC continue to have worse survival outcomes compared with those with non-IBC LABC., (Copyright © 2010 American Cancer Society.)

Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, local and distant metastases, younger age of onset, and lower overall survival compared with other breast cancers. Historically, IBC is a lethal disease with less than a 5% survival rate beyond 5 years when treated with surgery or radiation therapy. Because of its rarity, IBC is often misdiagnosed as mastitis or generalized dermatitis. This review examines IBC's unique clinical presentation, pathology, epidemiology, imaging, and biology and details current multidisciplinary management of the disease, which comprises systemic therapy, surgery, and radiation therapy., (© 2010 American Cancer Society, Inc.)

Inflammatory breast cancer (IBC) represents a rare but aggressive and lethal form of locally advanced breast cancer (LABC) and frequently with HER-2 neu overexpressed or amplified. We retrospectively identified 16 newly diagnosed HER-2 ⁄ neu-positive IBC patients who were treated with preoperative trastuzumab. We determined the pathological complete response rate (pCR) when trastuzumab was added to preoperative chemotherapy in patients with HER2⁄ neupositive IBC. Furthermore, we assessed the expression of CXCR4 in metastatic recurrence sites. Ten patients (62.5%)achieved a pCR. Six patients (37.5%) achieved a partial response. Median follow-up of all patients was 24.2 months. Four(25%) patients have experienced a progression, of which three were in the brain. Two-year progression-free survival was 59.4% (95% CI 35–100). High expression of CXCR4 was detected in the brain metastases. We conclude that in spite of high pCR rates among women with HER-2 ⁄ neu-positive IBC treated with neoadjuvant trastuzumab-based regimens the outcome remains dismal and brain recurrences are frequent. CXCR4 may represent a novel therapeutic target.

Background: The significance of circulating tumor cells (CTCs) in blood and of disseminated tumor cells (DTCs) in bone marrow (BM) in patients with early stage breast cancer is unclear. In this study, the authors investigated the occurrence of CTCs and DTCs in women with early stage breast cancer and evaluated the correlation of their presence with other prognostic markers., Methods: Blood and BM aspirations were collected at the time of primary breast surgery. CTCs were detected by using the CellSearch assay, and DTCs were detected by immunostaining BM aspirates for pancytokeratin. The presence of CTCs and DTCs was correlated with tumor classification (T1 vs T2), tumor histologic grade, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, and lymph node (LN) status., Results: Of 92 patients who were included in the study, 49 had T1 tumors, and 43 had T2 tumors. CTCs were detected in 31% of patients, and DTCs were detected in 27% of patients. There was no correlation between the occurrence of CTCs and DTCs with the tumor classification (T1 vs T2) or histologic grade. CTCs were detected in 33% of patients with ER-positive disease versus 26% of patients with ER-negative disease, in 32% of patients with PR-positive disease versus 30% of patients with PR-negative disease, and in 25% of patients with HER2-positive disease versus 31% of patients with HER2-negative disease. DTCs were observed in 23% of patients with ER-positive disease versus 37% of patients with ER-negative disease, in 22% of patients with PR-positive disease versus 32% of patients with PR-negative disease, and in 0% of patients with HER2-positive disease versus 29% of patients with HER2-negative disease. CTCs and DTCs were nearly equally prevalent in both LN-positive women and LN-negative women. There was no significant correlation between the occurrence of CTCs or DTCs with tumor classification (T1 vs T2), tumor histologic grade, positive ER status, positive PR status, or positive HER2 status, and axillary LN status., Conclusions: CTCs and DTCs in women with early stage breast cancer did not correlate with the standard prognostic indicators that were considered. The implications of their occurrence in patients with early stage disease will require further large-scale studies., (Copyright (c) 2010 American Cancer Society.)

Inflammatory breast cancer (IBC) accounts for 1% to 5% of all breast cancer cases. Its aggressive biology is characterized by rapid disease progression and poor prognosis. To improve and standardize therapy for IBC, development of novel therapeutics to molecular targets of IBC is key. Trastuzumab treatment, an anti-HER2 humanized monoclonal antibody, has been demonstrated to improve the 3-year survival rate of patients with IBC (70.1% vs 53.3%; P = .0007). Another chemotherapeutic drug, lapatinib, a dual tyrosine inhibitor of epidermal growth factor (EGFR) and HER2 signaling, in combination with capecitabine demonstrated encouraging results, with a 51% decrease in disease progression. Further investigation is needed to confirm the efficacy of lapatinib., (Copyright 2010 American Cancer Society.)

Background: Although inflammatory breast cancer (IBC) is recognized as the most lethal variant of locally advanced breast cancer, few molecular signatures of IBC have been identified that can be used as targets to develop therapeutics that effectively inhibit the aggressive phenotype displayed by IBC tumors., Methods: Real-time polymerase chain reaction analysis, Western blot analysis, modified Boyden chamber invasion assays, vasculogenic mimicry (VM) assays, and gelatin zymography were used in the current studies. Agonists and antagonists of the prostanoid receptors EP3 and EP4 and of EP4 short-hairpin RNA (shRNA) knockdown approaches were used as tools to assess the role of prostanoid receptors EP3 and EP4 in the regulation of specific biologic activities of IBC cells., Results: The current studies revealed that the IBC breast cancer cell lines SUM149 and SUM190 express high levels of cyclooxygenase-2 messenger RNA and protein, produce abundant levels of prostaglandin E(2), and produce both EP3 and EP4 receptor proteins. Studies using the EP4 antagonist GW627368X and shRNA molecular knockdown approaches revealed a role for EP4 in regulating invasion of IBC cells. EP3, but not EP4, regulated the ability of SUM149 cells to undergo VM, which is the ability to form capillary-like structures, a characteristic exhibited by very aggressive tumor types. Inhibition of VM by sulprostone was associated with an inhibition of matrix metalloprotease-2 (MMP-2) enzyme activity., Conclusions: The prostanoid receptors EP3 and EP4 differentially regulate activities exhibited by IBC cells that have been associated with the aggressive phenotype of this lethal variant of breast cancer. Whereas EP4 regulates invasion, EP3 regulates VM and the associated increased MMP-2 enzyme activity., (Copyright 2010 American Cancer Society.)

Background: Inflammatory breast cancer (IBC) is the most aggressive form of locally advanced breast cancer (LABC). Patients with IBC commonly present with skin metastasis, which are observed microscopically as tumor emboli within dermal lymphatics. These metastatic tumor cells aberrantly overexpress E-cadherin and exhibit the ability to undergo self-renewal and are highly invasive. There are no therapeutics yet identified that target the structure and functions of IBC tumor emboli. The present studies evaluated the effects of the pan-histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) using IBC tumor spheroids derived from established IBC cell lines and tumor spheroids derived from pleural effusion (PE) aspirates of patients with IBC and LABC, designated as PE-IBC and PE-LABC., Methods: Methods used are as follows: culture of IBC cells from clonal density single cells in low adherence culture conditions that promote formation of IBC tumor spheroids; clonogenic assays; cell fractionation and Western blotting; confocal microscropy; and modified Boyden chamber invasion assays., Results: SAHA inhibited self-renewal of IBC tumor spheroids from established IBC cell lines and PE-IBC and PE-LABC, as assessed by decreased clonogenic growth. SAHA blocked homotypic aggregation of the cells that comprised the IBC tumor spheroids leading to loss of their 3-dimensional (3D) structure, which was associated with a change in location of E-cadherin protein from the plasma membrane in untreated IBC tumor spheroids to the cytoplasm of cells within IBC tumor spheroids with SAHA treatment. In addition, SAHA blocked the robust invasion exhibited by IBC tumor spheroids of established cell lines as well as by tumor spheroids derived from PE-IBC and PE-LABC., Conclusions: SAHA targets the integrity and biological activities of IBC tumor spheroids and may be a promising agent to evaluate for its effectiveness in treatment of IBC., (Copyright 2010 American Cancer Society.)

Background: This study was performed to evaluate the outcomes of patients with locally advanced breast cancer (LABC) who were treated with a multidisciplinary approach including primary systemic chemotherapy and noncross-resistant adjuvant chemotherapy., Methods: Patients with LABC received 4 or 6 cycles of doxorubicin and docetaxel (DT) as primary systemic chemotherapy (PST) every 21 days. Patients with adequate response underwent surgery followed by adjuvant chemotherapy according to pathologic response: complete (pCR), 2 more cycles of DT; partial (pPR), 2 more cycles of DT followed by 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF); and minor (pMR), 6 cycles of CMF. Patients then received radiation and tamoxifen (hormone receptor-positive patients only)., Results: Eighty-eight patients were evaluable. Seventy-four patients had an adequate response to DT and were considered operable, and 72 underwent surgery. Ten patients (13.9%) achieved a pCR, 22 (30.5%) achieved a pPR, and 40 achieved a pMR (55.5%). Fourteen patients were considered nonoperable after DT and underwent salvage CMF therapy. Five of these patients underwent surgery and 1 had achieved a pCR. The estimated 5-year recurrence-free survival (RFS) rates for patients with pCR, pPR, and pMR were 80%, 77%, and 59%, respectively, and the estimated 5-year overall survival (OS) rates were 90%, 91%, and 74%, respectively. The 5-year OS rates were 82% for initially operable and 21% for initially inoperable patients (P < or = .001), Conclusions: Multidisciplinary therapy that includes PST with DT and adjuvant therapy with CMF administered according to the clinical and pathologic response is associated with high long-term RFS and OS rates in patients with LABC. Clinical or pathologic PR or CR to DT predicts improved RFS and OS.

Metastasis to the breast from extramammary malignancies is rare. Nevertheless, its recognition is important because the prognosis and treatment differ from that of primary breast cancer. We report a unique case of primary peritoneal serous carcinoma that initially presented as inflammatory breast cancer. The patient received neoadjuvant chemotherapy for breast cancer and subsequently underwent bilateral total mastectomy and bilateral sentinel lymph node biopsy. She was found to have extensive intralymphatic carcinoma in both breasts, with only focal minimal breast parenchymal involvement, and residual metastatic carcinoma in bilateral sentinel lymph nodes. Further work-up revealed pelvic ascites and omental nodularities. The patient underwent laparoscopic bilateral salpingo-oophorectomy, which revealed high-grade serous carcinoma involving both ovaries and fallopian tubes. Molecular testing of tumor from the ovary and axillary lymph node showed an identical pattern of allelic loss, confirming a common origin for both tumors. To our knowledge, this is the first reported case of an extramammary primary malignancy that not only presented as inflammatory breast cancer but also was diagnosed and initially treated as such.

Background: The aim of the current study was to assess the prognostic value of baseline circulating tumor cells (CTCs) in a large cohort of patients with newly diagnosed metastatic breast cancer (MBC)., Methods: This retrospective study included 185 patients with newly diagnosed MBC evaluated between 2001 and 2007. CTCs were isolated and enumerated before patients started first-line treatment using the CellSearch system. Overall survival (OS) was calculated from the date of CTC measurement, estimated by the Kaplan-Meier product limit method, and compared between groups with the log-rank test. Cox proportional hazards models were fitted to determine the association between CTC levels and OS after controlling for other prognostic factors., Results: The median age of the patients at the time of MBC diagnosis was 49 years. Fifty-six (30.3%) patients presented with de novo metastatic disease, and 129 (69.7%) presented with newly recurrent breast cancer. A total of 114 patients (61.6%) had CTC<5, and 71 (38.4%) had CTC >or= 5. The median OS was 28.3 months and 15 months (P< .0001) for patients with CTC<5 and CTC >or= 5, respectively. Superior survival among patients with CTC<5 was observed regardless of hormone receptor and HER-2/neu status, site of first metastases, or whether the patient had recurrent or de novo metastatic disease. In the multivariate model, patients with CTC >or= 5 had a hazards ratio of death of 3.64 (95% confidence interval, 2.11-6.30) compared with patients with CTC <5., Conclusions: The results of this large retrospective study confirms that CTCs are a strong independent predictor of survival among women with either de novo or newly recurrent MBC. CTCs should be considered as a new stratification method for women with newly diagnosed MBC.

Background: The utility of sentinel lymph node (SNL) biopsy (SLNB) as a predictor of axillary lymph node status is similar in patients who receive neoadjuvant chemotherapy and patients who undergo surgery first. The authors of this study hypothesized that patients with positive SLNs after neoadjuvant therapy would have unique clinicopathologic factors that would be predictive of additional positive non-SLNs distinct from patients who underwent surgery first., Methods: One hundred four patients were identified who received neoadjuvant chemotherapy, had a positive SLN, and underwent axillary dissection between 1997 and 2005. At the time of presentation, 66 patients had clinically negative lymph nodes by ultrasonography, and 38 patients had positive lymph nodes confirmed by fine-needle aspiration. Eighteen factors were assessed for their ability to predict positive non-SLNs using chi-square and logistic regression analysis with a bootstrapped, backwards elimination procedure. The resulting nomogram was tested by using a patient cohort from another institution., Results: Patients with clinically negative lymph nodes at presentation were less likely than patients with positive lymph nodes to have positive non-SLNs (47% vs 71%; P=.017). On multivariate analysis, lymphovascular invasion, the method for detecting SLN metastasis, multicentricity, positive axillary lymph nodes at presentation, and pathologic tumor size retained grouped significance with a bootstrap-adjusted area under the curve (AUC) of 0.762. The resulting nomogram was validated in the external patient cohort (AUC, 0.78)., Conclusions: A significant proportion of patients with positive SLNs after neoadjuvant chemotherapy had no positive non-SLNs. The use of a nomogram based on 5 predictive variables that were identified in this study may be useful for predicting the risk of positive non-SLNs in patients who have positive SLNs after chemotherapy., (Copyright (c) 2008 American Cancer Society.)

Background: Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer with poorly understood prognostic variables. The purpose of this study was to define the prognostic impact of HER-2 status on survival outcomes of patients with IBC., Methods: In all, 179 patients with IBC, diagnosed between 1989 and 2005, with known HER-2 status, and treated with an anthracycline-based chemotherapy regimen without trastuzumab, were included in the analysis. Patients with HER-2-positive disease who received trastuzumab at the time of disease recurrence were included. Survival outcomes were estimated by the Kaplan-Meier product limit method and compared across groups using the log-rank statistic. A Cox proportional hazards model was fitted to determine the association of survival outcomes with HER-2 status after adjusting for patient and tumor characteristics., Results: A total of 111 patients (62%) had HER-2-negative disease and 68 (38%) had HER-2-positive disease. The median follow-up among all patients was 35 months. At the time of the analysis, 62 patients (55.9%) with HER-2-negative disease and 42 patients (61.8%) with HER-2-positive disease had a recurrence. Thirty-one patients (73.8%) with HER-2-positive disease who had a disease recurrence went on to receive trastuzumab. On univariate analysis, no statistically significant difference was observed for either recurrence-free survival (P = .75) or overall survival (P = .24) between patients who had HER-2-positive disease and those who had HER-2-negative disease. In a multivariate model, HER-2 status did not appear to significantly affect recurrence-free survival (hazards ratio [HR] of 0.75; 95% confidence interval [95% CI], 0.46-1.22 [P = .241]). In the multivariate model, patients with HER-2-positive disease had a decreased hazard of death (HR of 0.56; 95% CI, 0.34-0.93 [P = .024]) compared with patients with HER-2-negative disease., Conclusions: HER-2 status, in the absence of trastuzumab, did not appear to significantly affect recurrence-free survival. After adjusting for other characteristics, the addition of trastuzumab in the metastatic setting significantly improved survival in the HER-2-positive group above and beyond that of the HER-2-negative group. This gives us further insight into the biology of this aggressive disease and underlines the major effect of targeted intervention.

Background: Inflammatory breast cancer (IBC) is the most aggressive manifestation of primary breast cancer. The authors compared the prognostic features of IBC and non-IBC locally advanced breast cancer (LABC) to gain insight into the biology of this disease entity., Methods: This retrospective analysis consisted of 1071 patients, comprising 240 patients with IBC and 831 patients with non-IBC LABC who were enrolled in 10 consecutive clinical trials (5 from each disease group). All patients received similar multidisciplinary treatment. The authors measured time to disease recurrence for each individual site from the start of treatment to the date of disease recurrence or last follow-up (recurrence-free survival) and overall survival rates to the date of last follow-up or death., Results: The median follow-up period was 69 months (range, 1-367 months). Pathologically complete response rates were 13.9% and 11.7% in the IBC and non-IBC LABC groups, respectively (P = .42). The 5-year estimates of cumulative incidence of recurrence were 64.8 % and 43.4% (P < .0001), respectively, for IBC and non-IBC LABC. IBC had significantly higher cumulative incidence of locoregional recurrence and distant soft-tissue and bone disease. The 5-year overall survival (OS) rate was 40.5% for the IBC group (95% CI, 34.5%-47.4%) and 63.2% for the non-IBC LABC group (95% CI, 60.0%-66.6%; P < .0001)., Conclusions: IBC was associated with a worse prognosis and a distinctive pattern of early recurrence compared with LABC. These data suggested that investigating factors affecting "homing" of cancer cells may provide novel treatment strategies for IBC.

Chemokines are chemoattractant cytokines that regulate the trafficking and activation of leukocytes and other cell types under a variety of inflammatory and noninflammatory conditions. Over the past few years, studies have increasingly shown that chemokines play an important role in several aspects of tumor progression. Tumor cells express functional chemokine receptors, which can sustain proliferation, angiogenesis, and survival and promote organ-specific localization of distant metastases. Chemokine expression in human malignancies is associated with a leukocyte infiltration favoring the establishment of immune escape mechanisms. A literature review of relevant publications on preclinical testing of cancer therapies based on interference with the cancer chemokine network was performed. The feasibility, potential advantages, and limitations of the clinical translation of the results of such studies in treatment of different tumor types and settings are discussed. The chemokine network is a key player in the establishment of metastases. In the preclinical setting, blocking agents and antibodies directed against CXCR4 prevent metastasis of different cancers. In mouse models, overexpression of selected chemokines causes tumor infiltration by distinct leukocyte subsets, resulting in tumor regression and tumor-specific immunity generation. Researchers have also successfully used chemokines as carriers and/or adjuvants for cancer vaccines. The cancer chemokine network is a multifaceted therapeutic target., (Copyright 2007 American Cancer Society.)

Background: The purpose of the study was to determine the utility of quantitation of the extracellular domain (ECD) of the HER-2/neu receptor in the serum for predicting response to treatment in patients with primary breast cancer receiving neoadjuvant therapy., Methods: HER-2/neu ECD was measured in sera obtained from 39 patients with HER-2-amplified stage II-III primary breast cancer undergoing neoadjuvant chemotherapy. Patients were randomly assigned to either 4 cycles of paclitaxel followed by 4 cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) (n = 10) or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks (n = 29). Changes in HER-2 ECD were monitored with the Bayer HER-2/neu assay over 6 months and correlated with pathological response to treatment., Results: Before initiation of chemotherapy, 28.2% of patients had elevated concentration of the HER-2 ECD (>15 ng/mL). The median baseline serum HER-2 ECD concentration was 13.6 ng/mL (mean +/- SD, 20.3 +/- 35.5 ng/mL). A decrease in the median HER-2 ECD levels from baseline to Week 3 and from baseline to Week 6 of chemotherapy was seen regardless of treatment regimen. No significant difference in baseline HER-2 ECD levels was observed between the groups who achieved pathological complete response (pCR) and the group with residual disease (P = .41). However, a 9% drop from Week 3 to Week 6 after initial chemotherapy was predictive of pCR (P = .04)., Conclusion: A decrease in serum HER-2 ECD levels early during treatment was associated with pathological response in patients receiving primary chemotherapy, particularly trastuzumab-based regimens. Serum HER-2 ECD levels may serve to monitor neoadjuvant therapy in HER-2-positive primary breast cancer., ((c) 2007 American Cancer Society.)

Background: : Primary systemic therapy (PST) is the standard approach to the management of patients with locally advanced breast cancer (LABC). The authors hypothesized that the intratumoral administration of a nonreplicating adenoviral vector (Ad5) that contains the human wild-type p53, AdCMV-p53, combined with chemotherapy, could increase the efficacy of PST as measured by pathologic complete response., Methods: : In a prospective, open-label, Phase II trial, 13 patients with LABC were treated with 6 3-week cycles of PST, which consisted of intratumoral injections of Ad5CMV-p53 for 2 consecutive days plus docetaxel and doxorubicin followed by surgery. p53 status was determined at baseline and was assessed immediately after the first injection (up to 48 hours). Clinical response was assessed by clinical and radiologic methods., Results: : The trial was terminated early, because none of the patients achieved a pathologic complete response. The median age was 56 years (range, 39-71 years), and the median tumor size was 8 cm (range, 5-11 cm). Eight patients (73%) had a p53 mutation. Serial biopsies showed an increase in p53 messenger RNA (mRNA) and p21(WAF1/Cip1) mRNA. All 12 evaluable patients achieved an objective clinical response. The surgical specimens revealed scattered tumor cells with extensive tumor-infiltrate leukocytes (predominantly T-lymphocytes). At a median follow-up of 37 months (range, 30-41 months), 4 patients (30%) developed systemic recurrence, and 2 patients died. The estimate breast cancer-specific survival rate at 3 years was 84% (95% confidence interval, 65.7-100%). There was no increase in systemic toxicity., Conclusions: : Ad5CMV-p53 combined with PST is safe, active, and associated with local immunomodulatory effects. The promising clinical activity of this combination deserves further investigation in randomized studies.

Background: Breast carcinoma axillary lymph node (ALN) pathologic complete response (pCR) after primary chemotherapy is associated with significantly higher recurrence-free survival (RFS) and overall survival (OS) rates. The purpose of the current study was to determine long-term outcome in patients achieving a pCR of cytologically proven inflammatory breast carcinoma ALN metastases after primary chemotherapy., Methods: Patients with cytologically documented ALN metastases from inflammatory breast carcinoma were treated in three prospective primary chemotherapy trials. After surgery, patients were subdivided into those patients with and those patients without residual ALN carcinoma. Survival was calculated using the Kaplan-Meier method., Results: Of 175 patients treated, 61 had cytologically confirmed ALN metastases. Fourteen patients (23%) achieved a pCR of the ALNs after primary chemotherapy. The 5-year OS and RFS rates were found to be improved in those patients achieving a pCR of the ALNs (82.5% [95% confidence interval (95% CI), 62.8-100%] and 78.6% [95%CI, 59.8-100%], respectively, vs. 37.1% [95%CI, 25.4-54.2%] and 25.4% [95%CI, 15.5-41.5%], respectively) (P = 0.01 [for OS] and P = 0.001 [for RFS]). Combination anthracycline and taxane-based primary chemotherapy resulted in significantly more patients achieving an ALN pCR (45% vs. 16%; P = 0.01)., Conclusions: pCR of ALN metastases is associated with an excellent prognosis in patients with inflammatory breast carcinoma. The rates of ALN pCR are nearly 50% in patients with inflammatory breast carcinoma who are treated with anthracyclines and weekly paclitaxel before surgery. However, those patients with residual ALN disease at the time of surgery greatly require the introduction of novel therapeutic strategies.

Background: In three prospective, single-arm studies, the authors previously showed an improved outcome for anthracycline-naïve patients with isolated sites of recurrent breast carcinoma (BC) who were treated with doxorubicin-based chemotherapy after local therapy (surgery and/or radiotherapy). In the current report, the initial results are presented from a Phase II trial of docetaxel (100 mg/m(2) every 21 days for 6 cycles) given after local therapy for recurrent BC (Stage IV BC with no evidence of clinically measurable disease) in patients who received prior adjuvant anthracycline-based chemotherapy, and the authors provide an update of the 3 previous studies. An analysis of prognostic factors for these patients also is presented., Methods: Eligibility criteria for all studies included histologic proof of recurrent BC that had been resected and/or irradiated with curative intent. Survival was calculated using the Kaplan-Meier method. Univariate survival analyses were performed to test for associations between patient characteristics and outcome (log-rank test). Cox proportional hazards models were used to determine the multivariable correlations between patient characteristics and outcome., Results: The median follow-up for the docetaxel-based trial (n = 26 patients) was 45 months. Early outcomes for this study are promising. The median disease-free survival (DFS) was 44 months, and the 3-year DFS and overall survival (OS) rates were 58% and 87%, respectively. In the 3 doxorubicin-based studies, the median follow-up was 121.5 months for all living patients, and the estimated 20-year DFS and OS rates were both 26%. On multivariable analysis of patients from all 4 studies, the only significant prognostic factor for DFS and OS (P = 0.0006) was the number of involved axillary lymph nodes at initial diagnosis., Conclusions: A proportion of patients with isolated BC recurrences achieved prolonged DFS with combined-modality treatment. Patients who receive anthracycline-based chemotherapy at primary diagnosis may benefit from local treatment followed by docetaxel-based chemotherapy for isolated recurrences. The only significant independent prognostic factor was the number of involved axillary lymph nodes at initial diagnosis., (Copyright 2005 American Cancer Society.)

Background: To the authors' knowledge there are few data that correlate the expression of the epidermal growth factor receptor (EGFR) with the outcome of patients who have breast carcinoma and are treated with anthracycline chemotherapy., Methods: Pretreatment tumor tissue samples were available from 82 patients who had locally advanced breast carcinoma and were treated on 2 protocols investigating neoadjuvant 5-fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Immunohistochemical staining for EGFR (diluted 1:50) was performed, and the staining results were interpreted without knowledge of outcome., Results: Fourteen tumors (17%) were EGFR-positive, and 68 tumors (83%) were EGFR-negative. EGFR expression did not correlate with clinical stage (P = 0.361), HER-2/neu overexpression (P = 0.503), estrogen or progesterone receptor status (P = 0.631 and P = 0.838, respectively), nuclear grade (P = 0.448), or proliferative index (P = 0.769). Patients who had EGFR-positive tumors had a worse 5-year disease-free survival (DFS) rate (46% vs. 76%; P = 0.026) and overall survival (OS) rate (46% vs. 76%; P = 0.037) compared with patients who had EGFR-negative tumors. The pathologic complete response rate did not differ between the 2 groups (P = 0.389), although patients with EGFR-positive disease more commonly had > or = 4 positive lymph nodes after chemotherapy (64% vs. 29%; P = 0.028). EGFR expression continued to show a significant correlation with poorer DFS and OS in a Cox regression analysis model that included the presence or absence of four or more lymph nodes and EGFR status., Conclusions: EGFR expression may have prognostic significance in patients with locally advanced breast carcinoma who are treated with anthracycline chemotherapy. These data warrant further studies aimed at correlating EGFR expression and outcome in patients who have breast carcinoma treated with doxorubicin-based chemotherapy.

Background: In patients with breast carcinoma, ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) is an independent predictor of systemic recurrence and disease-specific survival (DSS). However, only a subgroup of patients with IBTR develop systemic recurrences. Therefore, the management of isolated IBTR remains controversial. The objective of the current study was to identify determinants of systemic recurrence and DSS after IBTR., Methods: The medical records of 120 women who underwent BCT for Stage 0-III breast carcinoma between 1971 and 1996 and who subsequently developed isolated IBTR were reviewed. Clinicopathologic factors were studied using univariate and multivariate analyses for their association with DSS and the development of systemic recurrence after IBTR., Results: The median time to IBTR was 59 months. At a median follow-up of 80 months after IBTR, 45 patients (37.5%) had a systemic recurrence. Initial lymph node status was the strongest predictor of systemic recurrence according to the a univariate analysis (P = 0.001). Other significant factors included lymphovascular invasion (LVI) in the primary tumor, time to IBTR < or = 48 months, clinical and pathologic IBTR tumor size > 1 cm, LVI in the recurrent tumor, and skin involvement at IBTR. In a multivariate logistic regression analysis, initially positive lymph node status (relative risk [RR], 5.3; 95% confidence interval [95% CI], 1.4-20.1; P = 0.015) and skin involvement at IBTR (RR, 15.1; 95% CI, 1.5-153.8; P = 0.022) remained independent predictors of systemic recurrence. The 5-year and 10-year DSS rates after IBTR were 78% and 68%, respectively. In a multivariate Cox proportional hazards model analysis, only LVI in the recurrent tumor was found to be an independent predictor of DSS (RR, 4.6; 95% CI, 1.5-14.1; P = 0.008)., Conclusions: Patients who initially had lymph node-positive disease or skin involvement or LVI at IBTR represented especially high-risk groups that warranted consideration for aggressive, systemic treatment and novel, targeted therapies after IBTR. Determinants of prognosis after IBTR should be taken into account when evaluating the need for further systemic therapy and designing risk-stratified clinical trials., ((c) 2005 American Cancer Society.)

Background: To investigate the role of primary hypothyroidism (HYPT) on breast carcinogenesis, the authors evaluated 1) the association between HYPT and a diagnosis of invasive breast carcinoma and 2) the clinicopathologic characteristics of breast carcinoma in patients with HYPT., Methods: For this retrospective chart review study, 1136 women with primary breast carcinoma (PBC) were identified from the authors' departmental data base. These women (cases) were frequency-matched for age (+/- 5 years) and ethnicity with 1088 healthy participants (controls) who attended a breast carcinona screening clinic. Women with HYPT who were receiving thyroid-replacement therapy before they were diagnosed with breast carcinoma or before the screening visit were identified., Results: The mean ages of cases and controls (51.6 years vs. 51.0 years, respectively; P = 0.30) and their menopausal status (65.4% premenopausal vs. 62% postmenopausal; P = 0.10) were comparable. Two hundred forty-two women in the case group (10.9%) with HYPT were identified. The prevalence of this condition was significantly greater the control group compared with the case group (14.9% vs. 7.0%, respectively; P < 0.001). PBC patients were 57% less likely to have HYPT compared with their healthy counterparts (odds ratio, 0.43l 95% confidence interval, 0.33-0.57). Seventy-eight white patients with PBC had HYPT and, compared with women who were euthyroid, they were older at the time of diagnosis (58.8 years vs. 51.1 years; P < 0.001), were more likely to have localized disease (95.0% vs. 85.9% clinical T1 or T2 disease, respectively; P = 0.025), and were more likely to have no pathologic lymph node involvement (62.8% vs. 54.4%; P = 0.15)., Conclusions: Primary HYPT was associated with a reduced risk for PBC and a more indolent invasive disease. These data suggest a possible biologic role for thyroid hormone in the etiology of breast carcinoma and indicate areas of research for the prevention and treatment of breast carcinoma.

Background: There is renewed interest in using the cytologic changes in the epithelial cells obtained from specimens such as nipple aspiration fluid (NAF) and ductal lavage for risk stratification of women at increased risk for developing breast carcinoma., Methods: Molecular tests such as fluorescence in situ hybridization (FISH) have the potential to be used as adjuncts to conventional cytology for more accurately categorizing cells in these types of specimens. The current study investigated the feasibility and utility of FISH analysis of aneusomy in chromosomes 1, 8, 11 and 17 as an adjunct to conventional cytology in the classification of NAF specimens., Results: The authors found chromosomal aneusomy for at least one chromosome in all three malignant and both markedly atypical cases. Of the five cases classified as being mildy atypical on cytology, four were disomic, and only one showed aneusomy in chromosomes 8 and 11., Conclusions: The current study established the possibilities, limitations, and feasibility of using FISH in conjunction with routine cytology for a more accurate classification of ductal epithelial cells in NAF specimens. FISH-based detection of chromosomal aneusomy helped to define mild atypia, thereby aiding in the selection of the truly atypical cases for appropriate therapeutic intervention. In addition, FISH-based detection of chromosomal aneusomy can also be a valuable adjunct to conventional cytology in selected cases for confirming a benign, suspicious, or malignant diagnosis.

Background: The current study was performed to determine the incidence of central nervous system (CNS) metastases and to examine associated disease characteristics in a group of patients with locally advanced breast carcinoma (LABC) or inflammatory breast carcinoma (IBC) treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX)., Methods: Seven hundred sixty-eight patients treated with multimodality therapy between 1982 and 2000 in any of 6 neoadjuvant trials were eligible for the current study. Five hundred ninety-two patients (77%) had LABC, and 176 (23%) had IBC. CNS disease was defined as the presence of brain metastases or leptomeningeal disease. Time to detection of CNS disease and overall survival were estimated using the Kaplan-Meier product-limit method, and differences were evaluated using log-rank tests., Results: The median patient age was 48 years. Most tumors were classified as T4 lesions (58%) and exhibited lymph node involvement (78%). Fifty-one percent of all tumors had positive hormone receptor status. At a median follow-up duration of 9.5 years, 61 patients (8%) had developed CNS metastases, with the CNS representing the first site of recurrence for 38 of these 61 (63%). Characteristics associated with the development of CNS metastases over time included negative hormone receptor status (P = 0.03), Grade 3 disease (P = 0.01), and larger tumor size (P = 0.02). The median time to detection of CNS metastases was 2.3 years. Ten patients (16%) remained alive after treatment for CNS metastases. The median survival from the time of diagnosis of CNS metastases was 8 months., Conclusions: CNS metastases from breast carcinoma were relatively uncommon and were strongly associated with more aggressive clinical presentation. Survival from the time of diagnosis of such metastases generally was short.

Background: Inflammatory breast carcinoma (IBC) is a rare and aggressive malignancy. Therapy for patients with IBC is multidisciplinary, and response to preoperative chemotherapy is considered an important predictor of outcome. Although only a limited number of molecular markers have been investigated in this setting, none has exhibited prognostic value for patients with IBC., Methods: Immunohistochemical assays for P53, MDM-2, and MUC-1 were performed retrospectively to evaluate potential correlations between these markers and pathologic response, time to progression (TTP), and overall survival (OS) in 19 patients with IBC., Results: After a median follow-up period of 46 months, patients with tumors that overexpressed P53 and did not express MUC-1 had a significantly shorter median TTP and median OS compared with other patients., Conclusions: Expression of P53 and MUC-1 may be predictive of treatment efficacy and outcome for patients with IBC. Furthermore, these two markers may represent novel therapeutic targets in such patients., (Copyright 2004 American Cancer Society.)

The proto-oncogene c-kit encodes a transmembrane tyrosine kinase growth factor receptor. Stem cell factor, the receptor ligand, plays an important role in the development of certain neoplasms. c-kit is selectively and competitively bound by STI-571, a newly developed tyrosine kinase inhibitor. Several investigators report conflicting results concerning its expression, especially in malignant breast lesions. The objective of this study was to better characterize the expression of c-kit within the spectrum of breast epithelium (normal breast epithelium, nonneoplastic lesions, and breast carcinoma). Seventy-seven randomly selected breast tissue samples, each containing normal breast epithelium (21), invasive breast carcinoma (41), in situ breast carcinoma (29), papilloma (8), fibroadenoma (5), fibrocystic change (11), and/or metastatic breast carcinoma (4), were immunostained with polyclonal rabbit antihuman c-kit (Dako, Carpenteria, CA) at a dilution of 1:200. The staining was interpreted as negative if no cells were immunoreactive, weak positive if 5% of the cells were immunoreactive, and positive if more than 5% of the cells were immunoreactive. Appropriate positive and negative controls were used. The observed staining was cytoplasmic, with highlighting of the nuclear membrane. Normal breast epithelium was positive in all cases. More than half of the cases of hyperplastic changes and benign neoplasms (fibroadenoma and papilloma) were positive. Only 10% of invasive and in situ carcinomas showed positivity for c-kit. c-kit is consistently expressed in normal breast epithelium, variably expressed in benign breast lesions, and poorly expressed in breast carcinoma. These data suggest that c-kit may play a role in breast tumor progression and may therefore have diagnostic, prognostic, and therapeutic implications.

Background: The objective of the current study was to determine the antitumor activity, safety, and pharmacokinetic (PK) profile of exatecan mesylate in patients with anthracycline-resistant and taxane-resistant, metastatic breast carcinoma., Methods: All patients had clinical evidence of metastatic breast carcinoma; disease resistance or progression after chemotherapy that included anthracyclines and taxanes; no prior chemotherapy with camptothecin derivatives; and bidimensionally measurable disease. The starting dose of exatecan mesylate was either 0.5 mg/m(2) per day or 0.3 mg/m(2) per day, depending on prior chemotherapy exposure. PK blood samples were collected from each patient during the first course of therapy., Results: Thirty-nine patients received a total of 172 courses of therapy (median, 4 courses; range, 1-16 courses). Three patients (7.7%) had a partial response, and 20 patients (51.3%) had either a minor response or stable disease. Approximately 20% of patients had stable disease for 6 months or longer. The median time to disease progression was 3 months, and the median survival was 14 months. The most frequent severe adverse event was neutropenia. The most frequent severe (Grade 3-4) nonhematologic toxicities were fatigue, nausea, headache, myalgia, constipation, emesis, and paresthesias in 28%, 10%, 10%, 8%, 8%, 5%, and 5% of patients, respectively. Exatecan mesylate displayed linear PK characteristics at the doses administered. The average plasma clearance, total volume of distribution, and terminal elimination half-life were approximately 1.4 L per hour per m(2), 12 L/m(2), and 8 hours, respectively., Conclusions: Exatecan mesylate had moderate activity in patients with anthracycline-refractory and taxane-refractory, metastatic breast carcinoma. The toxicity profile of exatecan mesylate was acceptable, and it appeared to have linear PK characteristics on the basis of multiple dose administration., (Copyright 2003 American Cancer Society.)

Background: Nipple aspirate fluid (NAF) cytology is a simple noninvasive method to study cells exfoliated into the ductal system of the breast. In the current study, the significance of cytologic findings in NAF was determined by correlating them with histopathologic findings from corresponding breast tissue. Cytologic-histologic correlations of NAF were performed in only a few studies., Methods: Nipple aspirate fluid was collected by breast massaging and by using a breast aspiration device from 74 women with biopsy confirmed intraductal or invasive carcinoma with or without a history of preoperative neoadjuvant chemotherapy. Cytospin preparations were Pap stained. The number of epithelial cells was quantitated and foamy macrophages were semiquantitatively scored. Cytologic findings were categorized as insufficient for diagnosis (less than 10 epithelial cells), benign, mild atypia, marked atypia or suspicious, and malignant. Finally, they were correlated with tissue findings., Results: Nipple aspirate fluid was obtained from 74 women, including 24 who had received preoperative neoadjuvant chemotherapy. The median age of patients was 54 years. A mean volume of 57 microL NAF and a mean of 149 epithelial cells were obtained. Foamy macrophages were present in 51 (70%) of the specimens. There was a significant correlation between the presence of epithelial cells and foamy macrophages (P < 0.001). Patients treated with chemotherapy had fewer epithelial cells in their NAF compared with patients who were not treated with chemotherapy. Thirty specimens (41%) were inadequate for diagnosis, 34 were (46%) benign, 5 (7%) were mildly atypical, 1 (1%) was markedly atypical, and 4 (5%) were malignant. Of the five cases with mildly atypical cytology, three were intraductal papilloma, one was low-grade papillary intraductal carcinoma, and one was low-grade intracystic papillary carcinoma with invasion in the corresponding tissue specimen. The single case with markedly atypical NAF cytology had extensive ductal carcinoma in situ (DCIS). Of the four cases with malignant NAF cytology, two were extensive DCIS and two had invasive carcinoma with extensive DCIS in the breast specimen. Overall, 3 (27%) of 11 cases of DCIS were detected in NAF and only 2 (4%) of 52 invasive carcinomas including the only two cases with extensive DCIS were detected in NAF., Conclusion: The probability of detecting malignant cells in NAF is dependent on the extent of DCIS and nipple involvement by DCIS. Nipple aspirate fluid is not a sensitive test for detecting invasive carcinoma of the breast. Atypical cytology in NAF is associated with papillary lesions in the underlying breast., (Copyright 2003 American Cancer Society.)

Purpose: The authors conducted a single-institution Phase I clinical trial to determine the maximum tolerated doses and to define the toxic effects of oral eniluracil and oral 5-fluorouracil (5-FU) combined with docetaxel in patients with metastatic breast carcinoma., Patients and Methods: Patients with metastatic breast carcinoma were eligible if they had disease progression after anthracycline-based therapy and had never been exposed to taxanes. The starting doses of oral eniluracil and oral 5-FU were 11.5 mg/m(2) and 1.15 mg/m(2), respectively, twice daily on Days 1-14. Docetaxel was given intravenously at a starting dose of 50 mg/m(2) on Day 1 only. The dose of docetaxel was escalated among cohorts until a maximum tolerated dose was reached. Courses were repeated every 21 days., Results: The authors treated 19 patients with Stage IV breast carcinoma, of whom 5 had received prior chemotherapy for their metastatic disease. Fifty-three percent had a performance status of 1, and 53% had bone or soft tissue involvement as the dominant site of disease. All patients had received prior therapy with doxorubicin. The dose-limiting toxicity was neutropenic fever. No episodes of sepsis were observed. Significant antitumor activity was observed with a total of two complete and nine partial responses. The recommended doses for Phase II studies are 72 mg/m(2) docetaxel on Day 1 and 10.0/1.0 mg/m(2) oral eniluracil/5-FU twice daily for a total of 14 days, with courses being repeated every 21 days., Conclusions: The combination of oral eniluracil/5-FU and intravenous docetaxel is a safe and well tolerated regimen. Significant antitumor activity is associated with this combination., (Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10488)

Background: Inflammatory breast carcinoma (IBC) is a rare but aggressive form of breast carcinoma. Anthracycline-based regimens represent the standard of treatment for IBC. Reports of significant clinical activity of paclitaxel in metastatic breast carcinoma led the authors to investigate the role of this drug in the management of IBC., Methods: Forty-four patients with IBC were enrolled between February 1994 and January 1998. The treatment plan consisted of induction chemotherapy (IC), mastectomy, adjuvant chemotherapy, and radiotherapy. Forty-two patients received IC with four cycles of fluorouracil, doxorubicin, and cyclophosphamide. If the clinical response was less than partial, patients were "crossed over" to paclitaxel before mastectomy. All patients received adjuvant paclitaxel. Patients unresectable after paclitaxel were offered high-dose chemotherapy with autologous peripheral blood progenitor cell support., Results: Thirty-four patients (81%) achieved an objective clinical remission; 3 patients (7%) achieved a clinical complete remission, 31 (74%) a partial remission. Six patients (14%) achieved pathologic complete remission. Sixteen patients were treated with paclitaxel, 7 of them (44%) were able to undergo mastectomy. Median time to progression (TTP) was 22 months. Median overall survival (OS) was 46 months. Concordance between clinical and pathologic response was documented in only 8 patients (24%). No differences in TTP and OS compared with a historical group of 178 IBC patients treated with anthracycline-based regimens., Conclusions: Paclitaxel improves tumor resectability in anthracycline-refractory IBC. The impact of paclitaxel on the prognosis of IBC needs to be better evaluated in future trials using more dose-intensive schedules of administration. New imaging modalities may contribute to improve assessment of response to IC., (Copyright 2001 American Cancer Society.)