Chemotherapy-treated Breast Cancer Patients Research Articles

Altered network efficiency of functional brain networks in patients with breast cancer after chemotherapy.

ObjectiveTo investigate the topological organization of functional brain networks in chemotherapy-treated breast cancer (BC) patients with source memory impairment.MethodsTwenty-eight patients with BCfollowingchemotherapyand40age-and education-matched healthy controls (HCs) were recruited in the current study. All participants underwent source memory tests and resting-state functional MRI scans. Individual whole-brain functional brain networks were constructed and analyzed using graph-based network approaches.ResultsCompared with the HCs, the BC patients showed lower scores in the source memory tests (P < 0.001).Graph-based analyses revealed that the patients showed higher absolute global and local efficiency (both P < 0.01) but lower normalized global and normalized local efficiency (both P< 0.001) compared with the HCs. Locally, several prefrontal, occipital, and parietal regions exhibited higher nodal efficiency and functional connectivity in the patients(P< 0.05, corrected). Finally, positive correlations were observed between normalized global efficiency and Mini-Mental State Examination scores (r = 0.398, P = 0.036) and between normalized local efficiency and the source memory scores (r = 0.497, P = 0.01) in the patients.ConclusionChemotherapy-treated BC is associated with abnormal organization of large-scale functional brain networks, which could account for source memory dysfunction in patients with BC.

ADIPOQ/adiponectin induces cytotoxic autophagy in breast cancer cells through STK11/LKB1-mediated activation of the AMPK-ULK1 axis

ABSTRACT ADIPOQ/adiponectin, an adipocytokine secreted by adipocytes in the breast tumor microenvironment, negatively regulates cancer cell growth hence increased levels of ADIPOQ/adiponectin are associated with decreased breast cancer growth. However, its mechanisms of action remain largely elusive. We report that ADIPOQ/adiponectin induces a robust accumulation of autophagosomes, increases MAP1LC3B-II/LC3B-II and decreases SQSTM1/p62 in breast cancer cells. ADIPOQ/adiponectin-treated cells and xenografts exhibit increased expression of autophagy-related proteins. LysoTracker Red-staining and tandem-mCherry-GFP-LC3B assay show that fusion of autophagosomes and lysosomes is augmented upon ADIPOQ/adiponectin treatment. ADIPOQ/adiponectin significantly inhibits breast cancer growth and induces apoptosis both in vitro and in vivo, and these events are preceded by macroautophagy/autophagy, which is integral for ADIPOQ/adiponectin-mediated cell death. Accordingly, blunting autophagosome formation, blocking autophagosome-lysosome fusion or genetic-knockout of BECN1/Beclin1 and ATG7 effectively impedes ADIPOQ/adiponectin induced growth-inhibition and apoptosis-induction. Mechanistic studies show that ADIPOQ/adiponectin reduces intracellular ATP levels and increases PRKAA1 phosphorylation leading to ULK1 activation. AMPK-inhibition abrogates ADIPOQ/adiponectin-induced ULK1-activation, LC3B-turnover and SQSTM1/p62-degradation while AMPK-activation potentiates ADIPOQ/adiponectin's effects. Further, ADIPOQ/adiponectin-mediated AMPK-activation and autophagy-induction are regulated by upstream master-kinase STK11/LKB1, which is a key node in antitumor function of ADIPOQ/adiponectin as STK11/LKB1-knockout abrogates ADIPOQ/adiponectin-mediated inhibition of breast tumorigenesis and molecular analyses of tumors corroborate in vitro mechanistic findings. ADIPOQ/adiponectin increases the efficacy of chemotherapeutic agents. Notably, high expression of ADIPOQ receptor ADIPOR2, ADIPOQ/adiponectin and BECN1 significantly correlates with increased overall survival in chemotherapy-treated breast cancer patients. Collectively, these data uncover that ADIPOQ/adiponectin induces autophagic cell death in breast cancer and provide in vitro and in vivo evidence for the integral role of STK11/LKB1-AMPK-ULK1 axis in ADIPOQ/adiponectin-mediated cytotoxic autophagy.

Abstract 3319: Elevating adipokine adiponectin level can induce cytotoxic autophagy in breast cancer cells and potentiate the efficacy of chemotherapeutic regimens: preclinical studies

Abstract Adiponectin, an adipocytokine secreted by adipocytes in the breast tumor microenvironment, negatively regulates cancer cell growth hence increased levels of adiponectin are associated with decreased breast cancer growth. However, its mechanisms of action remain largely elusive. We report that adiponectin induces a robust accumulation of autophagosomes, increases LC3II and decreases p62/SQSTM1 in breast cancer cells. Adiponectin-treated cells and xenografts exhibit increased expression of autophagy-related proteins. Lysotracker-Red-staining and tandem-mCherry-GFP-LC3 assay show that autophagosomes/lysosomes fusion is augmented upon adiponectin treatment. Adiponectin significantly inhibits breast cancer growth and induces apoptosis both in vitro and in vivo, and these events are preceded by autophagy, which is integral for adiponectin-mediated cell death. Accordingly, blunting autophagosomes-formation, blocking autophagosomes-autolysosome fusion or genetic-knockout of BECN1/Beclin1/ATG7 effectively impedes adiponectin induced growth-inhibition and apoptosis-induction. Mechanistic studies show that adiponectin reduces intracellular ATP levels and increases AMPK phosphorylation leading to ATG1 activation. AMPK-inhibition abrogates adiponectin-induced ATG1-activation, LC3II-turnover and p62-degradation while AMPK-activation potentiates adiponectin’s effects. Further, adiponectin-mediated AMPK-activation and autophagy-induction are regulated by upstream master-kinase LKB1, which is a key node in anti-tumor function of adiponectin as LKB1-knockout abrogates adiponectin-mediated inhibition of breast tumorigenesis and molecular analyses of tumors corroborate in vitro mechanistic findings. Adiponectin increases the efficacy of chemotherapeutic agents. Notably, high expression of adiponectin receptor, adiponectin and BECN1 significantly correlates with increased overall survival in chemotherapy-treated breast cancer patients. Collectively, these data uncover that adiponectin induces autophagic cell death in breast cancer and provide in vitroa and in vivo evidence for the integral role of LKB1-AMPK-ATG1 axis in adiponectin-mediated cytotoxic-autophagy. Citation Format: Seung J Chung, Ganji Purnachandra Nagaraju, Arumugam Nagalingam, Nethaji Muniraj, Panjamurthy Kuppusamy, Alyssa Walker, Juhyung woo, Balázs Győrffy, Edward Gabrielson, Neeraj K. Saxena, Dipali Sharma. Elevating adipokine adiponectin level can induce cytotoxic autophagy in breast cancer cells and potentiate the efficacy of chemotherapeutic regimens: preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3319. doi:10.1158/1538-7445.AM2017-3319

Abstract P4-07-08: Age-related microRNAs and their biomarker potential in chemotherapy-treated older breast cancer patients

Abstract BD and SH contributed equally to this study. Background MicroRNAs (miRNAs) are important regulators of cellular function and have been associated with both aging and cancer, while the impact of chemotherapy on miRNAs has barely been studied. Patients and Methods To examine whether chemotherapy accelerates the aging process, we have monitored age-related circulating miRNAs in 89 older breast cancer patients (≥70y), receiving adjuvant chemotherapy (N= 46; chemo group, ChG) or no chemotherapy (N= 43; control group, CoG). Patients and associated blood samples belonged to the cohort of our recently published study (Brouwers et al., Oncotarget. 2016.) All patients underwent geriatric assessment at inclusion (T0), after 3 months (T1) and 1 year (T2). At each timepoint we analysed the serum expression of nine age-related miRNAs (miR-20a, miR-30b, miR-34a, miR-106b, miR-191, miR-301a, miR320b, miR374a, miR-378a). Our primary aim was to assess miRNA changes during the study period, including differences between groups. Secondary endpoints included association of microRNAs with: chronological age, clinical geriatric assessment parameters and aging biomarkers assessed in the above-mentioned study. We then investigated the predictive role of miRNAs at T0 on: decline in functionality and quality of life, toxicity and unexpected hospitalization during or after chemotherapy. We also performed clustering of patients according to specific miRNA signatures. Results Except for miR-106b, which appeared to behave slightly different in ChG compared to CoG, all other miRNAs underwent moderate fluctuations during the study course with no significant differences between both groups. Also within the older cohort, several age-related miRNAs significantly (p&amp;lt;0.05) correlated with clinical aging/frailty (miR-106b, miR-191, miR-301a, miR-320b, miR-374a), as well as with other biomarkers of aging. In particular, miR-106b, miR-374a and miR-378a were associated with IL-6 (slope= -0.34, -0.30 and 0.30 respectively, p&amp;lt;0.05), whereas miR-301a and miR-378a showed a relevant correlation with MCP-1 (slope= -0.18 and 0.27 respectively, p&amp;lt; 0.05). Moreover, based on their 'aging miRNA' profiles, patients clustered into two distinct groups, cluster A (CA) and cluster B (CB), exhibiting significantly different results for several biological/clinical aging parameters. CA (N=43, miR-20a, miR-30b, miR-191, miR-301a and miR-374a underexpressed, miR-378a overexpressed) was characterized by older age, higher geriatric risk profile, as well as elevated IL-6, TNFα and MCP-1 levels compared to CB (N=45, inverse expression pattern). Moreover, 31.9% of CA patients but only 7.4% of CB patients experienced decline in quality of life after chemotherapy (p=0.051). Conclusions These results further corroborate our recent findings, stating that adjuvant chemotherapy does not significantly boost aging progression in elderly breast cancer patients. Our data also endorsed specific age-related miRNAs as promising aging/frailty biomarkers in oncogeriatric populations. Citation Format: Dalmasso B, Hatse S, Brouwers B, Laenen A, Berben L, Kenis C, Smeets A, Neven P, Schöffski P, Wildiers H. Age-related microRNAs and their biomarker potential in chemotherapy-treated older breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-07-08.

An Emerging Role of Pharmacist in Pre-chemotherapy Counseling Among Breast Cancer Patients

The understanding of adult patients receiving cancer chemotherapy of their regimen is important for better control of chemotherapy-related side effects. Often, patients forget, misunderstand or unsatisfied with the information received. The purpose of this study is to investigate the effectiveness of pharmacist-led pre-chemotherapy counseling on the knowledge of chemotherapy treated breast cancer patients. It is a randomized and prospective study where patients were randomly distributed into intervention group who received pharmacist-led pre-chemotherapy counseling and control group who did not receive pharmacist-led pre-chemotherapy counseling. Knowledge assessments and perception of the patients were carried out after pharmacist-led pre-chemotherapy counseling in both intervention and control group using a structured validated questionnaire. Overall, 38 out of 40 patients completed the study with a 97% response rate. Significant improvement in the understanding of chemotherapy regimen and its side-effects was observed in the intervention group as compared to the control group. Besides, patients counseled by pharmacists were able to recall back the information even at the sixth cycle of the chemotherapy regimen compared to the control group. Majority of the breast cancer patients agreed that pharmacist-led pre-chemotherapy counseling was effective. This study suggests that pharmacist-led pre-chemotherapy counseling improves patient knowledge and understanding of the chemotherapy regimen received.

The effects of erythropoiesis-stimulating agents on the short-term and long-term survivals in metastatic breast cancer patients receiving chemotherapy: a SEER population-based study.

Current clinical guidelines state that the use of erythropoiesis-stimulating agents (ESAs) may be considered to treat chemotherapy-induced anemia in the non-curative setting to alleviate anemia-related symptoms. However, no convincing survival benefit has been demonstrated to support the use of ESAs in these patients. Using the comprehensive data collected in the National Cancer Institute (NCI)-surveillance epidemiology and end results (SEER) and Medicare-linked database, we analyzed the effect of ESA use on the short-term (18-month) and long-term (60-month) survival rates of chemotherapy-treated metastatic breast cancer patients. Confounding variables were adjusted using a propensity score approach. We also analyzed the effects of ESA on the survival of patients receiving trastuzumab, a commonly prescribed targeted therapy agent in treating HER2-positive tumors. Metastatic breast cancer patients who received ESA treatment exhibited similar 60-month survival rate to those without ESA treatment (22.8 vs. 24.9%, p = 0.8). ESA-treated patients had a trend toward better 18-month survival [crude hazard ratio (HR) 0.86, 95% confidence intervals (CI) 0.68-1.09, p = 0.21]. This protective effect during the first 18 months of chemotherapy became marginally significant after adjusting for the propensity of receiving ESAs (HR 0.80, 95% CI 0.63-1.01, p = 0.070). An interaction effect between ESA and trastuzumab on patient survival was noticeable but not statistically significant. ESAs did not negatively affect the long-term survival of metastatic breast cancer patients. Moreover, ESAs improved patients' survival during the first 18 months of chemotherapy treatment. These findings endorse the current clinical guideline. Given the short survival of these patients, the potential short-term beneficial effects of ESAs are clinically meaningful.

Erythropoiesis stimulating agents and clinical outcomes of invasive breast cancer patients receiving cytotoxic chemotherapy

The use of erythropoiesis stimulating agents (ESAs) to treat anemia in breast cancer patients who are treated with chemotherapy is a matter of ongoing debate. Several recent randomized trials challenged conventional wisdom, which holds that ESAs are contraindicated for breast cancer patients undergoing curative treatment. We aimed to perform the first large national population-based study to analyze the association between ESA use and breast cancer patient outcomes. Cytotoxic chemotherapy-treated invasive breast cancer patients were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Non-ESA users were sequentially 1:1 matched to 2,000 randomly sampled ESA users on demographics (age, diagnosis year, race, marital status, and socioeconomic status), tumor presentation (stage, grade, and status of hormone receptors), and treatments (surgery, radiation, and sub-types of chemotherapy) using a minimum distant strategy. Breast cancer-specific survival of ESA and matched non-ESA users was compared using Fine and Gray competing risk model. Compared to ESA users, non-ESA users exhibited dramatically different baseline characteristics such as less advanced tumor, and fewer co-morbidities. Non-ESA users had a significantly more favorable breast cancer-specific survival (subdistribution hazard ratio [sHR]=0.75, p<0.0001). This survival disparity was progressively diminished in the sequential matching of demographics (sHR=0.74, p=0.0004), presentation (sHR=0.86, p=0.06), and treatment (sHR=0.89, p=0.17) variables. Stratified analyses identified subgroups of patients whose breast cancer-specific survival were not different between ESA and non-ESA users. In the SEER-Medicare database, ESA usage does not seem to be associated with unfavorable breast cancer-specific survival in breast cancer patients receiving cytotoxic chemotherapy. The ESA-breast cancer prognosis association is complex and requires more intensive investigations.

A prospective study of grey matter and cognitive function alterations in chemotherapy-treated breast cancer patients.

PurposeSubsequent to chemotherapy treatment, breast cancer patients often report a decline in cognitive functioning that can adversely impact many aspects of their lives. Evidence has mounted in recent years indicating that a portion of breast cancer survivors who have undergone chemotherapy display reduced performance on objective measures of cognitive functioning relative to comparison groups. Neurophysiological support for chemotherapy-related cognitive impairment has been accumulating due to an increase in neuroimaging studies in this field; however, longitudinal studies are limited and have not examined the relationship between structural grey matter alterations and neuropsychological performance. The aim of this study was to extend the cancer-cognition literature by investigating the association between grey matter attenuation and objectively measured cognitive functioning in chemotherapy-treated breast cancer patients.MethodsFemale breast cancer patients (n = 19) underwent magnetic resonance imaging after surgery but before commencing chemotherapy, one month following treatment, and one year after treatment completion. Individually matched controls (n = 19) underwent imaging at similar intervals. All participants underwent a comprehensive neuropsychological battery comprising four cognitive domains at these same time points. Longitudinal grey matter changes were investigated using voxel-based morphometry.ResultsOne month following chemotherapy, patients had distributed grey matter volume reductions. One year after treatment, a partial recovery was observed with alterations persisting predominantly in frontal and temporal regions. This course was not observed in the healthy comparison group. Processing speed followed a similar trajectory within the patient group, with poorest scores obtained one month following treatment and some improvement evident one year post-treatment.ConclusionThis study provides further credence to patient claims of altered cognitive functioning subsequent to chemotherapy treatment.

Cognitive Deficits in Korean Women Treated With Chemotherapy for Breast Cancer

Cognitive deficits have been reported as detrimental side effects in chemotherapy-treated breast cancer patients and survivors. Korean women treated for breast cancer may experience unrecognized cognitive deficits related to their treatment. However, no research has examined cognitive test performance in chemotherapy-treated Korean breast cancer survivors. The objectives of this study were 2-fold: (1) to examine differences in occurrence and severity of cognitive deficits in Korean women treated with adjuvant chemotherapy for breast cancer as compared with a control group of women without breast cancer and (2) to examine the relationship of selected demographic and cultural factors with cognitive test performance. Sixty-four Korean women, 32 women treated for localized breast cancer and 32 healthy controls, were enrolled. Breast cancer participants were assessed with established cognitive measures within 4 months after chemotherapy, and healthy controls, within 6 months after negative screening mammography. The breast cancer group showed a significantly higher occurrence and greater severity of cognitive deficits than controls did. Importantly, older age, less education, greater collectivist tendency, and greater childrearing burden were reliably associated with poorer attention and working memory test performance. Cognitive deficits were found in chemotherapy-treated Korean women with moderate to large effect sizes compared with controls. Cultural characteristics contributed to worse cognitive performance. Healthcare providers should recognize that Korean women may be highly vulnerable to cognitive deficits. Cultural factors also need to be considered when assessing cognitive function and designing therapeutic interventions to counteract negative cognitive outcomes.

Selective impairment of attention networks in breast cancer patients receiving chemotherapy treatment.

Complaints about attention disorders are common among breast cancer survivors who have undergone chemotherapy treatment. However, it is not known whether these complaints indicate a global attention deficit or the selective impairment of attention networks. This study sought to investigate the attentional abilities of breast cancer patients after chemotherapy treatment using the attention network test (ANT). The participants included breast cancer patients who had undergone chemotherapy (CT, N = 58), patients who had not undergone chemotherapy (non-CT, N = 53), and matched healthy controls (HC, N = 55). All participants completed the ANT, which provides measures of three independent attention networks (alerting, orienting, and executive control) and neuropsychological background tests. Our results indicated that the chemotherapy-treated breast cancer patients had significant deficits in the alerting and executive control networks but not in the orienting network. The CT group scored significantly lower in several cognitive tasks, including attention, memory, and information processing tasks, relative to the other two groups. Additionally, significant correlations were found between information processing and the efficiency of the executive control network within the CT group. These results suggest that the three attention networks were selectively impaired following chemotherapy treatment, which affected different brain areas in the breast cancer survivors.

A genome-wide association study of chemotherapy-induced alopecia in breast cancer patients.

IntroductionChemotherapy-induced alopecia is one of the most common adverse events caused by conventional cytotoxic chemotherapy, yet there has been very little progress in the prevention or treatment of this side effect. Although this is not a life-threatening event, alopecia is very psychologically difficult for many women to manage. In order to improve the quality of life for these women, it is important to elucidate the molecular mechanisms of chemotherapy-induced alopecia and develop ways to effectively prevent and/or treat it. To identify the genetic risk factors associated with chemotherapy-induced alopecia, we conducted a genome-wide association study (GWAS) using DNA samples from breast cancer patients who were treated with chemotherapy.MethodsWe performed a case-control association study of 303 individuals who developed grade 2 alopecia, and compared them with 880 breast cancer patients who did not show hair loss after being treated with conventional chemotherapy. In addition, we separately analyzed a subset of patients who received specific combination therapies by GWASs and applied the weighted genetic risk scoring (wGRS) system to investigate the cumulative effects of the associated SNPs.ResultsWe identified an SNP significantly associated with drug-induced grade 2 alopecia (rs3820706 in CACNB4 (calcium channel voltage-dependent subunit beta 4) on 2q23, P = 8.13 × 10-9, OR = 3.71) and detected several SNPs that showed some suggestive associations by subgroup analyses. We also classified patients into four groups on the basis of wGRS analysis and found that patients who classified in the highest risk group showed 443 times higher risk of antimicrotubule agents-induced alopecia than the lowest risk group.ConclusionsOur study suggests several associated genes and should shed some light on the molecular mechanism of alopecia in chemotherapy-treated breast cancer patients and hopefully will contribute to development of interventions that will improve the quality of life (QOL) of cancer patients.

Dissociation of decision making under ambiguity and decision making under risk in breast cancer patients receiving adjuvant chemotherapy: A neuropsychological study

There is evidence that women with breast cancer show a cognitive impairment after having undergone chemotherapy treatment; this cognitive impairment may result in behavioral deficits. However, the neural mechanism of this cognitive impairment remains unclear. The present study investigated the neural basis of the cognitive impairment caused by chemotherapy treatment by exploring the decision-making function of the executive subcomponents under ambiguity and risk in breast cancer survivors. Participants included breast cancer patients who had undergone chemotherapy (CT, N=63) or patients who did not undergo chemotherapy (non-CT, N=62), as well as matched healthy controls (HC, N=61). All participants were examined using the Iowa Gambling Task (IGT) to assess their decision-making under ambiguity, the Game of Dice Task (GDT) to assess their decision-making under risk and neuropsychological background tests. Our results indicated that during the IGT test, the chemotherapy-treated breast cancer patients selected from the disadvantageous decks with a higher frequency than the non-treated breast cancer patients or healthy controls, whereas all three groups performed at the same level when performing the GDT. The CT group demonstrated significantly lower scores in several cognitive tasks, including attention, memory, executive functions and cognitive processing, when compared with the other two groups. In addition, within the CT group, significant correlations were found between the IGT performance and information processing, as well as with working memory. This study demonstrated that breast cancer survivors treated with chemotherapy may have selective reductions in IGT performance but unimpaired GDT performance and that these deficits may result from dysfunctions in the limbic loop rather than in the dorsolateral prefrontal loop.

Androgen receptor expression is a predictive marker in chemotherapy-treated patients with endocrine receptor-positive primary breast cancers

The androgen receptor (AR) is intensively discussed as a prognostic and/or predictive marker in breast cancer patients. We evaluated the value of AR mRNA expression with the Affymetrix HG-U 133A array in 3 different cohorts: a cohort of breast cancer patients who received adjuvant treatment (cohort A; n = 165), a cohort of untreated breast cancer patients (cohort B; n = 200) and a cohort of chemotherapy-treated breast cancer patients with estrogen receptor (ER)-positive tumors (cohort C; n = 223). AR mRNA expression was associated with lower grading (Grades 1 and 2) as well as ER and progesterone receptor (PgR) positivity in all cohorts. In the treated cohort (cohort A), low androgen receptor expression was associated with shorter event-free survival (OR 2,34, 95 % CI 1.01-5.43, p = 0.047) which was not seen in the untreated cohort B. Subgroup analysis revealed that shorter survival of patients with low AR mRNA expression was observed mainly in the ER-positive subgroup of patients treated with adjuvant chemotherapy. In the validation cohort C we could confirm a benefit of chemotherapy for the group of tumors with high AR mRNA expression (5-year event-free survival (EFS) 74 % versus 57 %, p = 0.013). In this cohort, low AR mRNA expression was associated with shorter event-free survival also in multivariate analysis (OR 2.86, 95 % CI 1.29-6.35, p = 0.010) adjusted for HER2, ki-67, tumor size, age and tumor grade. We provide evidence that AR expression is associated with chemotherapy responsiveness in ER-positive patients.

The role of bimatoprost eyelash gel in chemotherapy-induced madarosis: An analysis of efficacy and safety

Objectives:Breast cancer patients suffer from madarosis (loss of eyelashes) due to chemotherapy side effects. An effective treatment or prevention for alopecia or madarosis induced by chemotherapy is not available. Potential drug side effects of bimatoprost solution include increased eyelash length, darkness, and number. A formulation of bimatoprost which maximizes eyelash enhancement and minimizes intraocular and systemic side effects has not been reported.Materials and Methods:An Institutional Review Board (IRB) and Investigational New Drug (IND) approved, randomized, single-blinded, prospective, internally controlled trial compared bimatoprost eyelash gel in relation to eyelash enhancement of madarosis patients. Forty eyelids of 20 chemotherapy-treated breast cancer patients were randomized to treatment or control (fellow eyelid). Both patient and surgeon (blindly) evaluated bimatoprost gel's effectiveness in improving eyelash appearance at baseline and at monthly intervals.Results:The median follow-up time was 3 months (range 1-4). There was a significant difference between treated and fellow eyelash length during month 2 [1.00 mm (P=0.004)] and month 3 [1.00 mm, P=0.02)], in eyelash pigment [month 1 (2.5, P=0.04); month 2 (2, P=0.0009); month 3 (3, P=0.06)] and thickness [month 2 (2, P=0.002); month 3 (3, P=0.01)]. There was an improvement in the patient satisfaction scale from baseline 16 (median, range 7-21) to 26 (median, range 17-33, P=0.002) at last follow-up.Conclusions:Bimatoprost eyelash gel appears promising for chemotherapy-induced madarosis. Patients may find the effects restorative and cosmetically enhancing.

LOH at 1p31 (ARHI) and Proliferation in Lymph Node-Negative Breast Cancer

Background: The mitotic activity index (MAI) is a strong prognosticator in node-negative invasive breast cancer patients. Recently, a correlation between the MAI and specific chromosomal aberrations at chromosome 1p was described.Methods: Analysis of MAI, immunohistochemical staining patterns for proliferation-associated phosphohistone H3 (PPH3), phosphorylated ERK1/2, p21, cyclin E, Ki67 and cyclin D1 proteins; and prognosis in 158 adjuvant chemotherapy-treated T1-2N0M0 invasive breast cancer patients, analysis of LOH at 1p31 (including ARHI) using the dinucleotide repeats D1S207, D1S430 and D1S464 in 76 patients. Single and multivariate survival analysis was used to evaluate the importance of the various markers tested.Results: LOH at 1p31 did not correlate with MAI nor provide prognostic information. Phosphohistone H3 was the best prognosticator for patients in all age groups with 20 year distant metastasis free survival of distant metastases 93% vs. 72% respectively (p = 0.004, HR = 4.5). In multivariate analysis, phosphohistone H3 &lt; 13 vs. ≥13 exceeded the prognostic value of the mitotic activity index.Conclusions: LOH at 1p31 is common in breast cancer, and correlates with loss of proliferation-associated proteins, but not with MAI, PPH3 or prognosis. PPH3 is the best prognosticator in this study group of adjuvant chemotherapy-treated lymph node-negative breast cancer patients.

Comparing the Prognostic Value of PTEN and Akt Expression with the Mitotic Activity Index in Adjuvant Chemotherapy-Treated Node-Negative Breast Cancer patients aged &lt;55 years

Background: The prognostic value of the PI3K/Akt/mTOR pathway and PTEN in invasive breast cancer (IBC) is controversial. Cell proliferation, especially the Mitotic Activity Index (MAI), is strongly prognostic in lymph node-negative (LNneg) invasive breast cancer. However, its prognostic value has not been compared with the value of Akt and PTEN expression. Material and Methods: Prognostic comparison of Her2Neu, p110alpha (PIK3CA), Akt, mTOR, PTEN, MAI and cell-cycle regulators in 125 LNneg patients aged <55 years with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)-based adjuvant systemic chemotherapy. Results: Twenty-one (17%) patients developed distant metastases = DMs (median follow-up: 134 months). p110alpha correlated (p = 0.01) with pAkt but only in PTEN-negatives; pAkt correlated (p = 0.02) with mTOR. PTEN-negativity correlated with high MAI, high grade and ER-negativity (p = 0.009). The MAI was the strongest prognosticator (Hazard Ratio = HR = 2.9, p = 0.01). Her2Neu/p110α/Akt/mTOR features have no additional prognostic value to the MAI. PTEN had additional value but only in MAI < 3 (39/125 = 31%; 8% DMs). 19/39 = 49% of the MAI < 3 patients have combined MAI < 3 / PTEN+ with 0% DMs, contrasting 15% DMs in MAI < 3 / PTEN− (p = 0.03). Conclusions: In T1−3N0M0 adjuvant CMF-treated breast cancer patients aged <55 years, MAI was the strongest survival predictor. The PI3K/Akt/mTOR pathway and cell-cycle regulator characteristics had no additional prognostic value, but PTEN has. Patients with combined MAI < 3 & PTEN-positivity had 100% survival. The small subgroup of MAI < 3 patients that died were PTEN-negative.

SNPs associated with the genetic predisposition to develop therapy-related acute myelogenous leukemia after chemotherapy for breast cancer

8536 Background: t-AML is a syndrome occurring after exposure to chemo or radiotherapy. Since for similar treatments only some patients ends developing a secondary leukemia, it has been proposed a genetic predisposition associated to this syndrome. Methods: To analyse single nucleotide polymorphisms (SNPs) on genes that could be involved on risk of developing t-AML by means of RFLP and SNP genome screening using high density microarrays .Two groups of individuals were genotyped: Group A, composed by patients that develop t-AML after chemotherapy for breast cancer (BC) and Group B (control), formed by chemotherapy treated BC patients that after a period of more than 10 years have not developed t-AML. We have studied 12 polymorphisms on genes from drug detoxification pathways (NOQ1, GSTP1), DNA repair (XPC[3 ], XRCC1[2 ], NBS1, ERCC5 and XRCC3) and DNA synthesis (MTHFR[2 ]), in which the nucleotide change implies a change in the protein sequence (nA=16, nB=18) . Alternatively, for each patient, more than 10.000 SNPs were genotyped by means of of high density microarrays (Affymetrix) (nA=12, nB=18). The alele frequencies for each SNP between two groups were compared. Results: In RFLP study, we observe two SNPs on MTHFR gene displaying remarkably different allele frequencies between BC patients (Table). In microarray study, we found 12 SNPs with differences of allele frequency higher that 45% between A and B groups, located 6 on chromosome 8. Conclusions: The results suggest that the MHFTR gene is a candidate for being studied by its possible relation with the genetic predisposition to develop t-AML after BC treatment although its functional implication with the disease must still be elucidated. Moreover, data from SNP arrays suggest that the genome regions marked by those 12 SNPs, specially those on chromosome 8, are candidate for being studied by its possible relation with the genetic predisposition to develop t-AML after BC treatment. Financed by FIS G03/008. [Table: see text] No significant financial relationships to disclose.

Chemotherapy-related adverse events among breast cancer patients: A retrospective analysis of the SEER-Medicare database

10634 Background: Systemic chemotherapy is a common treatment option for female breast cancer (BC) patients. Chemotherapeutic agents often cause myelosuppression events (MEs), which may be costly and severe. Methods: Women ≥ 65 years of age diagnosed with stage I - III breast cancer from 1/1/92–12/31/99 within The Surveillance, Epidemiology and End Results (SEER)-Medicare database were analyzed. Using our extensive previous work with this BC cohort, a retrospective cohort study was conducted to assess the incidence and costs of MEs in chemotherapy-treated BC patients. Chemotherapies were captured using HCPCS codes; hospitalizations related to ME events (identified with ICD-9 diagnosis codes for anemia, thrombocytopenia, or leukopenia) were detected anytime after index date (date of first BC diagnosis). Total inpatient charges after index date were calculated. Results: 31,748 female BC patients were identified, 17.6% of whom received chemotherapy during follow-up. The mean age for these patients was 75.6 years (SD = 6.6, Range: 66–107). ME-related hospitalizations were significantly more likely in chemotherapy than non-chemotherapy patients, with 12.1% and 1.8%, respectively [OR = 2.3 (2.0–2.5)]; anemia in 8.6% and 5.1%, respectively [OR = 1.8 (1.6–1.0)], thrombocytopenia in 2.0% and 0.7%, respectively [OR = 2.9 (2.3–3.7)], and leukopenia in 4.4% and 0.5%, respectively [OR = 9.7 (7.8–12.1)]. Chemotherapy patients had significantly higher inpatient charges than patients without chemotherapy. Among chemotherapy patients, significantly higher inpatient charges were found in those with MEs than without ($15,297 vs. $4,211, p &lt; 0.0001). Conclusion: Chemotherapy-related MEs were common among Medicare BC patients and led to substantial hospital charge increases. No significant financial relationships to disclose.

Effects of Epoetin Alfa on Cognitive Function, Mood, Asthenia, and Quality of Life in Women with Breast Cancer Undergoing Adjuvant Chemotherapy

Several recently published studies describe moderate to severe cognitive dysfunction in breast cancer survivors who were treated with adjuvant chemotherapy 1-5 years before undergoing extensive neuropsychological testing. While these studies are hypothesis-generating and preliminary given their small size and retrospective nature, they consistently suggest that between approximately 15% and 25% of chemotherapytreated breast cancer patients will have evidence of cognitive dysfunction some years after chemotherapy, compared to about 10% of breast cancer survivors who did not receive chemotherapy. Recent preclinical data strongly suggest that erythropoetin is a potent, endogenous neuroprotective agent that prevents neuronal apoptosis from a variety of insults including hypoxia, trauma, subarachnoidal hemorrhage, and encephalitis. Erythropoietin also appears to enhance learning in a mouse spatial learning maze model. We have conducted a pilot study of epoetin alfa versus placebo in early-stage breast cancer patients who received standard adjuvant anthracycline-based chemotherapy to determine the feasibility of administering standardized neurocognitive assessment tests in the oncology practice setting in order to understand whether the Executive Interview 25 test can detect the subtle cognitive impairment in verbal fluency, attention, and short-term memory observed with chemotherapy, and to assess whether epoetin alfa—treated patients have less evidence of cognitive dysfunction during and 6 months after chemotherapy compared with control-treated patients. We report here the preliminary results of this pilot clinical trial.