Localized Breast Cancer Patients Research Articles

227P - Baseline quality of life (QoL) and chemotherapy related toxicities (CRT) in localized breast cancer (BC) patients (pts): The French multicentric prospective CANTO cohort study

BackgroundIn this study we aimed to examine the independent effect of baseline QoL and persistent CRT among pts with early BC. MethodsWe included data stage I-III BC pts treated with chemotherapy who were included in the CANTO prospective cohort study (NCT-01993498) from 03/2012 to 12/2014. The primary outcome was CRT defined as the presence at 3-6 months after the end of treatment, of any of the following toxicities (NCI-CTC-AE): infection, venous or arterial thrombosis, neurological G2-4, digestive G3-4 or pulmonary toxicities G3-4). Treatment deliver including chemotherapy dose reductions were also examined. The independent variable of this study was baseline Qol defined by the EORTC QLQ-C30 subscales of general global health status (GHS) (< or≥70) and physical functioning PF (< or≥90). The defined cutoffs correspond to the average values in the French general population. Clinical relevant adjustment covariates included stage, age, performance status (PS), body mass index (BMI), HR and HER2 status, baseline lymphopenia, albumin, creatinine clearance, alcohol consumption, and smoking status. Multivariable logistic models were performed. ResultsAmong 3079 BC pts included in this analysis, 33% received neoadjuvant and 77% adjuvant treatment. Median age at diagnosis was 53 years, median BMI= 25kg/m2, 94% of patients had a PS=0 and 83% stage I-II disease. Pts reported on average a good GHS = 68 (±19) and PF=90 (±14). GHS and PF were higher in women with better performance status PS=0 vs 1+, (68 vs 60 p<0.001) and 91 vs 78 p<0.001) respectively. 952 (31%) BC pts developed ≥1 CRT: 23% had an infection, 7% thrombosis, 0.3% G3-4 diarrhea, nausea or vomiting, 4% G2-4 neurological and 0.2% G3-4 pulmonary toxicities. 16% had chemotherapy dose reduction. Pts with a baseline GHS <70 had 19 % higher odds of CRT vs to those with GHS≥70, OR=1.19 [95% CI 1.02-1.41] and similarly those with a PF<90 had a 23% higher odds of CRT when compared to those with PF≥90 (OR=1.23 [95% CI 1.03-1.49]). ConclusionsGlobal and physical QoL before BC treatments are independently associated with CRT. QoL should be assessed before any treatment to identify patients at risk CRT. Clinical trial identificationNCT01993498. Legal entity responsible for the studyUNICANCER/Villejuif, France, 94805 Principal Investigator: Fabrice André Gustave Roussy – Villejuif. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Effect of Radiotherapy Variables on Circulating Effectors of Immune Response and Local Microbiome

Effective radiation (RT) induced immunogenicity requires sufficient numbers of effector and memory T-cells in order to generate anti-tumor immune response. Standard RT regimens, with daily exposure of active hematopoietic tissue and circulating lymphocytes over 4-8 weeks result in treatment-induced lymphopenia. Improvements in RT technology allow for hypofractionated regimens, potentially mitigating the risk of lymphopenia. In this study, we hypothesize that differences in RT fractionation (short versus protracted) and field size (whole breast vs partial breast) may result in different effects on circulating immune mediators. To test this hypothesis, we are prospectively studying patients with breast or prostate cancer undergoing standard protracted vs short-course hypofractionated RT. This is an ongoing prospective non-randomized study assessing 4 distinct cohorts of cancer patients: localized prostate cancer undergoing standard fractionation RT to at least 70 Gy (cohort 1A) vs stereotactic body RT in 5 fxs (cohort 1B); or localized breast cancer patients undergoing standard fractionation RT (cohort 2A) vs partial breast RT in 5 fxs (cohort 2B). Blood samples are collected at baseline, at midpoint during RT, at completion of treatment and at 3-6 months after completion of RT. Lymphocyte counts are obtained and characterization of T-cell subsets is performed using multi-parameter flow cytometry. Inflammatory cytokines in the plasma are measured using bead-based multi-analyte immunoassay. The study has thus far accrued 33/60 planned patients, 13 of whom have completed all 4 blood draws (Cohorts 1A n=3, 1B n=4, 2A n=0, 2B n=6). A significant (P=0.023) decline in absolute lymphocyte count (ALC) for protracted RT patients (n=3) was detected, which persists at 3 month follow up (mean decline 0.93, SD 0.25), with both CD4 and CD8 populations impacted. Conversely, patients undergoing short course radiation (n=10) do not have depletion of ALC, with 8/10 patients maintaining stable ALC during RT. A more detailed characterization of immune subsets, including NK cells, dendritic cells and myeloid cells is ongoing, as well as analysis of inflammatory cytokines. An increase of IL-2 was noted during protracted, but not short, RT in one patient; additional datasets will be acquired. Elucidating the impact of different regimens of RT on circulating immune cells provides valuable information on how RT can best be harnessed to potentiate its immunogenic effects. These preliminary results confirm that shorter radiation courses result in less, or no lymphopenia, whereas protracted radiation courses result in persistent lymphopenia, sustained 3 months after RT is completed. Variables of RT techniques such as fractionation and field size likely impact the availability of key effectors of immune rejection, and warrant further ongoing study.

Health-related quality of life and physical fitness in breast cancer patients: the impact of a supervised physical exercise program in women with no exercise experience

ABSTRACTAfter breast cancer diagnosis (BCD), localized breast cancer (BC) patients are treated with curative intent by several therapeutic modalities. Despite the benefit of those therapies, the induction of side effects is acommon consequence affecting psychosocial and physiological outcomes. This quasi-experimental study compared physical fitness in recent-term (14–30 months; n= 11) and later-term (74–92 months; n= 8) BCD patients. After inclusion, recent-term BCD patients were engaged in asupervised exercise program and was explored its impact on physical fitness, health-related quality of life (HR-QOL) and fatigue. At baseline (M1) and after 8 (M2) and 16 weeks (M3) of this period, HR-QOL and fatigue were evaluated by the EORTC QLQ-C30 questionnaire and physical fitness through the estimation of maximum oxygen consumption (VO2max,ml.kg.min–1), handgrip force (kg) and sit-stand test. At baseline, women with later-term BCD have revealed better VO2max (p < 0.05) than recent-term BCD patients. There was asignificant time*group interaction for physical fitness outcomes and only the patients who have participated in the exercise program reported significant changes between baseline and at 16 weeks. The observed results demonstrated that performing regular exercise is associated with effective psychosocial and physiological recovery after BCD.

Circular RNA expression in exosomes derived from breast cancer cells and patients.

We aimed to explore the roles of circular RNAs (circRNAs) in breast cancer (BCa). RNA was extracted from exosomes and BCa cells and analyzed using the RNA sequencing technique or microarray. Compared with controls, 1147 and 1195 circRNAs were dysregulated in exosomes from metastatic and localized BCa patients, respectively. A total of 480 dysregulated circRNAs were found in metastatic patients compared with localized patients, and these dysregulated circRNAs were enriched in eight pathways. Compared with MCF-7 cells and their exosomes, there were 5842 and 1137 dysregulated circRNAs in MDA-MB-231 cells and exosomes, respectively, and 5 circRNAs were confirmed using real-time quantitative PCR. We identified a number of dysregulated circRNAs in exosomes from BCa cells and patients.

Abstract P2-14-19: Surgical and long-term outcomes of patients receiving neoadjuvant pertuzumab-containing regimens for HER2-positive localized breast cancer

Abstract Background: The addition of pertuzumab to trastuzumab and chemotherapy significantly improves the pathologic complete response (pCR) rate in HER2+ localized breast cancer in the preoperative setting. Although many patients are converted to breast conserving therapy (BCT) candidates by neoadjuvant HER2-directed therapy, a significant proportion opt for a mastectomy for various reasons. Among mastectomy procedures, nipple sparing mastectomy (NSM) is frequently chosen instead of non-nipple sparing mastectomy (NNSM). In this study, we evaluated the surgical and long-term outcomes of HER2+ patients receiving neoadjuvant pertuzumab-containing regimens. Methods: We performed a retrospective review of localized breast cancer patients treated with neoadjuvant pertuzumab-containing regimens from 2011 to 2016, who underwent BCT or mastectomy at an academic institution and two community-based practices. Disease characteristics, treatment regimens, surgical outcomes, and recurrence data were extracted from the electronic medical records. Results: Among 90 patients with stage II-III HER2+ breast cancer, 45 received AC-THP (50.0%), 26 received THP (with adjuvant AC) (29.0%), and 19 received TCHP (21.0%). The majority of patients had grade 3 tumors (61.1%), clinical stage II disease (80.0%), invasive ductal carcinoma (86.7%), and ER+ disease (65.6%). Thirty-seven (41.0%) patients underwent BCT and 53 (59.0%) patients underwent mastectomy. Among the mastectomy patients, 38 (71.7%) patients underwent bilateral mastectomies, specifically 33 (62.0%) patients underwent a NSM and 20 (38.0%) patients underwent a NNSM. The type of surgery that patients underwent stratified by type of neoadjuvant regimen is outlined in the Table 1 below. Most patients who underwent BCT and mastectomy received radiation, including 36 (97.3%) BCT, 24 (72.7%) NSM, and 18 (95.0%) NNSM. Over a median follow-up period of 33 months, 6 patients (6.7%) had recurrences with 2 (2.2%) local recurrences and 4 (4.4%) distant recurrences. The 2 local recurrences occurred in one patient who underwent BCT and one patient who underwent NNSM followed by post-mastectomy radiation. Conclusions: Among mastectomy patients, NSM was more commonly pursued than NNSM. Rates of local recurrence following pertuzumab-containing regimens for HER2-positive localized breast cancer were low overall, regardless of the type of surgery. Data on plastic surgery approaches and complication rates will be presented at the meeting. Table 1.Type of surgery in patients receiving neoadjuvant HER2-directed therapy. AC-THP (N = 45)TCHP (N = 19)THP (N = 26)BCT46.7%47.4%26.9%NNSM26.7%10.5%23.1%NSM26.7%42.1%50.0% Citation Format: Haddad SA, Spring LM, Jimenez RB, Vidula N, Comander A, Shin JA, Coopey SB, Gadd MA, Hughes KS, Taghian A, Smith BL, Isakoff SJ, Moy B, Bardia A, Specht MC. Surgical and long-term outcomes of patients receiving neoadjuvant pertuzumab-containing regimens for HER2-positive localized breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-19.

Characterization of Somatic Mutations in Malaysian Luminal Breast Cancer

Luminal breast cancer subtype (ER/PR+, HER2+/-) represents about two-thirds of all breast cancers, and better understanding of the genetic alterations underpinning the disease pathogenesis is desirable to develop improved treatment plans and to increase patients’ survival. To date, other than hormonal and anti-HER2 therapies (e.g. tamoxifen, aromatase inhibitor, trastuzumab), no other targeted therapies have been approved by FDA for luminal breast cancer. Despite thousands of breast tumour samples have been sequenced, there is no data yet on Malaysian patients. Therefore, it is clinically important to identify actionable mutated genes or pathways implicated in our local breast cancer patients to establish a more defined framework for precision medicine and clinical trials. In this discovery study, a total of nine pairs of newly diagnosed luminal breast cancer cases (>80% tumour content) and their matched normal samples were subjected to exome sequencing. We detected a total of 491 somatic from nine pairs of breast tumour-normal samples. PIK3CA is the most frequently mutated gene in our discovery cohort of patients (n=4/9). Kinases and phosphatases were found as the most significantly enriched mutated genes (enrichment score = 3.12), with all nine luminal breast cancer samples harboring at least one non-synonymous mutation in this cluster of genes. This profile suggested that alteration in protein phosphorylation processes is among the key drivers in luminal breast cancer pathogenesis. Interestingly, genes involved in four key druggable cancer pathways, i.e. PI3K/AKT/mTOR, MAPK/ERK, NF-kβ and VEGF signalling pathways were found commonly mutated and require validation in a larger cohort. In conclusion, we have successfully profiled the somatic mutations in Malaysian luminal breast cancer and this is the first study conducted in Malaysian patients. These findings revealed the role of multiple gene testing in discovering luminal breast cancer mutational landscape.

Metabolomics research on potential role for 9-cis-retinoic acid in breast cancer progression.

Deciphering the molecular networks that discriminate organ‐confined breast cancer from metastatic breast cancer may lead to the identification of critical biomarkers for breast cancer invasion and aggressiveness. Here metabolomics, a global study of metabolites, has been applied to explore the metabolic alterations that characterize breast cancer progression. We profiled a total of 693 metabolites across 87 serum samples related to breast cancer (46 clinically localized and 41 metastatic breast cancer) and 49 normal samples. These unbiased metabolomic profiles were able to distinguish normal individuals, clinically localized and metastatic breast cancer patients. 9‐cis‐Retinoic acid, an isomer of all‐trans retinoic acid, was identified as a differential metabolite that significantly decreased during breast cancer progression to metastasis, and its levels were also reduced in urine samples from biopsy‐positive breast cancer patients relative to biopsy‐negative individuals and in invasive breast cancer cells relative to benign MCF‐10A cells. The addition of exogenous 9‐cis‐retinoic acid to MDA‐MB‐231 cells and knockdown of aldehyde dehydrogenase 1 family member A1, a regulatory enzyme for 9‐cis‐retinoic acid, remarkably impaired cell invasion and migration, presumably through preventing the key regulator cofilin from activation and inhibiting MMP2 and MMP9 expression. Taken together, our study showed the potential inhibitory role for 9‐cis‐retinoic acid in breast cancer progression by attenuating cell invasion and migration.

Advantages of intraoperative implant for interstitial brachytherapy for accelerated partial breast irradiation either frail patients with early-stage disease or in locally recurrent breast cancer.

PurposeTo describe the intraoperative multicatheter implantation technique for accelerated partial breast irradiation (APBI) delivered with high-dose-rate brachytherapy (HDR-BT). Secondarily, to evaluate outcomes and toxicity in a series of 83 patients treated with this technique at our institution.Material and methodsRetrospective analysis of a series of patients treated with HDR-BT APBI after intraoperative multicatheter interstitial implant between November 2006 and June 2017 at our institution. We assessed cosmesis, toxicity, overall survival (OS), and disease-free survival (DFS).ResultsEighty-three patients were included: 59 patients (71.1%) with primary early-stage breast cancer and 24 (28.9%) with locally recurrent breast cancer. Tumorectomy was performed in all cases, with intraoperative tumor margin assessment and sentinel node biopsy. Median age was 82 years (range, 44-92). The total prescribed dose was 32 Gy (8 treatment fractions) in 60 patients (72.3%), and 34 Gy (10 fractions) in 23 patients (27.7%). Median follow-up was 40 months (range, 1-136 months). Three-year OS and DFS in the recurrent and primary cancer groups were 87% vs. 89%, and 96 % vs. 97.8%, respectively. Five patients died from non-cancer related causes. No local relapses were observed. Rates of acute and late toxicity were low in both groups. The cosmesis was good or excellent in most of patients treated for primary disease; in patients who underwent salvage brachytherapy for local recurrence, cosmesis was good in 49 patients and fair in 6.ConclusionsThis technique, although time-consuming, achieves good local disease control with a satisfactory toxicity profile in both early-stage and local recurrent breast cancer patients. It may be especially suitable for frail patients.

Monitoring deep inspiration breath hold for left-sided localized breast cancer radiotherapy with an in-house developed laser distance meter system.

Deep inspiration breath hold (DIBH) in left‐sided breast cancer radiotherapy is a technique to reduce cardiac and pulmonary doses while maintaining target coverage. This study aims at evaluating an in‐house developed DIBH system. Free‐breathing (FB) and DIBH plans were generated for 22 left‐sided localized breast cancer patients who had radiation therapy (RT) after breast‐conserving surgery. All patients were treated utilizing an in‐house laser distance measuring system. 50 Gy was prescribed, and parameters of interest were target coverage, left anterior descending coronary artery, (LAD) and heart doses. Portal images were acquired and the reproducibility and stability of DIBH treatment were compared to FB. The comparing result shows there is a significant reduction in all LAD and heart dose statistics for DIBH compared to FB plans without compromising the target coverage. The maximum LAD dose was reduced from 43.7 Gy to 29.0 Gy and the volume of the heart receiving >25 Gy was reduced from 3.3% to 1.0% using the in‐house system, both statistically significant. The in‐house system gave a reproducible and stable DIBH treatment where the systematic error ∑, and random error σ, were less than 2.2 mm in all directions, but were not significantly better than at FB. The system was well tolerated and all patients completed their treatment sessions with DIBH.

Innovation in Action – Breast Care Nurse Specialists in the pursuit of excellence have actively instigated innovative solutions for the introduction of a recovery package for their local breast cancer patients following completion of treatment

Innovation in Action – Breast Care Nurse Specialists in the pursuit of excellence have actively instigated innovative solutions for the introduction of a recovery package for their local breast cancer patients following completion of treatment

Abstract P2-05-10: UCBG 2-14: A prospective multicenter non-randomized trial evaluating the effect of EndoPredict® (EPclin®) clinico-genomic test on treatment decision making among patients with intermediate clinical risk

Abstract Background: Genomic tests can identify ER-positive Her2-negative localized breast cancer (BC) patients (pts) who may not drive any benefit from adjuvant chemotherapy (CT). Several genomic tests have reached a high level of analytical and clinical validity, as well as clinical utility in such situation. Recent results suggest that the safe de–escalation of adjuvant chemotherapy may be most beneficial in pts with clinical high or indetermediate risk, as assessed by classical variables or online tools, through the use of a genomic test. The clinical risk though remains quite uncertain with variable definition and grey zones. The present study aimed at determining if EPclin clinico-genomic test had a significant impact on treatment decision making among pts with predefined intermediate /borderline clinical risk. Patients and methods: Women were eligible for the present study if they had complete surgical removal of a localized ER+ Her2- pN0 or pN1mi BC, and were considered by the multidisciplinary team meeting (MTM) of the center as being in a "grey zone" of uncertain CT benefit based on classical clinic-pathological assessment. The MTM1 proposed a decision (chemo/no chemo). After informed consent, an EPclin signature classified the tumor as low risk (EPclin Score &amp;lt; 3.3, no chemo advised) or high risk (&amp;gt; 3.3, a theoretical indication for adjuvant chemo). Primary end point was the proportion of change between initial adjuvant CT decision at MTM1 and final administration of CT (yes/no). A 5 steps Fleming design was planned, considering that a change rate of 15% or less was not acceptable (low clinical utility). A one-step design was used (unilateral α = 2.5% and β = 1%). Results: 203 pts were included, of whom 198 are evaluable for the main end point. 74% of the tumors were grade 2, 72% T1 , 25% T2, 3% T3; 16% were pN1mi and 84% pN0. Median age was 57. EpClin® was low risk in 67% and high risk in 33% of the cases. The global rate of decision change between MTM1 and final administration of CT was 70/198 (35.4% IC-95% = [28.7-42.1]), with 55 (27.7%) decreases and 15 (7.6%) increases in CT indication. 27% instead of 47% of all pts finally received CT (43% decrease in CT prescription). In the multivariate analysis, the factors associated to decrease for less CT were EPclin score (OR 0.11 [0.03-0.35]), proliferation (OR 1.08 [1.03-1.13]) and higher grades (OR 5.22 [1.04-26.08]); while EPclin score was positively (OR 76.6 [7.11-824.8]), but higher grades inversely (OR 0.06 [0-0.86]) associated to an increase in CT administration. Of note, the change in final decision occurred after the MTM2 and after report of the results and discussion with the patient in 9 of the 70 cases (12% of changes; 4.5% of the whole population)(8 decreases and 1 increase in CT administration). Conclusion: Adendom met its primary objective, with 35% of intermediate clinico-pathological risk pts getting significant therapeutic changes upon the receipt of an EPclin gene expression profile. 43% of these "intermediate risk" pts planned for CT avoided it. 12% of the changes were discrepant with the test's results and occurred after discussion with the patient. Citation Format: Penault-Llorca F, Kwiatkovski F, Grenier J, Levy C, Leheurteur M, Uwer L, Derbel O, Le Rol A, Jacquin J-P, Jouannaud C, Quenel-Tueux N, Girre V, Foa C, Guardiola E, Lortholary A, Catala S, Lemonnier J, Delaloge S. UCBG 2-14: A prospective multicenter non-randomized trial evaluating the effect of EndoPredict® (EPclin®) clinico-genomic test on treatment decision making among patients with intermediate clinical risk [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 P2-05-10.

English

We consider the problem of outlier detection in bivariate exponential data fitted using the generalized linear model via Bayesian approach. We follow closely the work outlined by Unnikrishnan (2010) and present every step of the detection procedure in details. Due to the complexity of the resulting joint posterior distribution, we obtain the information on the posterior distribution from samples generated by Markov Chain Monte Carlo sampling, in particular, using either the Gibbs sampler or the Metropolis-Hastings algorithm. We use local breast cancer patients’ data to illustrate the implementation of the method.

Patterns of Care for Localized Breast Cancer in Oklahoma, 2003–2006

Despite well-established clinical guidelines for breast cancer treatment, Standard of Care (SOC) is not universal in the U.S. The purpose of this study was to describe the extent to which patients receive guideline-based, stage-specific treatments for localized female breast cancer in Oklahoma. Data were obtained from the Oklahoma Central Cancer Registry for the period 2003–2006. We included localized, invasive female breast cancers and analyzed both treatment and demographic factors. We used the National Comprehensive Cancer Network (NCCN) treatment guidelines to determine SOC. Among women who received breast conserving surgery (BCS), we used logistic regression to evaluate factors related to SOC. In Oklahoma, 92 percent of the 4,177 localized breast cancer patients were treated with recognized SOC. In women aged ≥65 years with BCS, those ≥75 years had a lower adjusted odds of meeting SOC than did those without insurance, with comorbid conditions, or whose comorbid status was unknown. Among women aged <65 years, those with Medicare/Medicaid, Medicare only, or without insurance, along with comorbid conditions, had a lower adjusted odds of meeting SOC. Overall, 92 percent of women met SOC. Factors such as age, insurance type, and comorbid conditions were associated with meeting SOC.

Can a homeopathic medicine complex reduce hot flashes induced by adjuvant endocrine therapy in localized breast cancer patients? Results of a randomized placebo-controlled phase III trial.

9627 Background: Homeopathy is already used for the management of menopausal hot flashes (HF) and could reduce this frequent endocrine therapy’s (ET) side effect. Methods: Localized breast cancer p...

Taxane-based regimens as adjuvant treatment for breast cancer: a retrospective study in egyptian cancer patients.

To evaluate the impact of adding taxanes to anthracycline-based regimens in the adjuvant setting in localized young female breast cancer patients on the overall survival (OS) and the disease free survival (DFS). This retrospective study included all female breast cancer patients who were candidates for adjuvant chemotherapy presenting to Kasr Al Ainy centre of clinical oncology and Cairo oncology centre (Cairo Cure) in the period from January 2005 till December 2010. Our study included 865 patients, 732 of whom received anthracycline based regimens and 133 taxane based regimens. The mean age of patients was 39 years. After a median follow up of 50 months the median DFS was 48.4 months. Survival analysis indicated that the tumor size (>5cm vs. <5cm) p=0.001), nodal involvement (Yes vs. No) p=0.0001) and pathology (invasive lobular vs. ductal) p=0.048) affected DFS. As regards hormonal status, ER, PR and HER 2neu positive patients had longer DFS (p=0.001, 0.003, 0.106). On multivariate analysis DFS was affected by tumor size and lymph node involvement (p=0.014, 0.007). Subgroup analysis showed improvement in arms treated with taxanes in terms of DFS with positive Her2neu, ER and PR, but this was not statistically significant. Adding adjuvant taxanes to anthracyclines is beneficial for treatment of localized breast cancer among all subgroups, especially higher risk groups .The type of adjuvant chemotherapy regimens and tumor characteristics have direct effects on DFS.

Abstract C69: Investigating correlations of DARC underexpression (Duffy Null phenotypes) with increased breast cancer lymph node metastasis

Abstract DARC (aka Duffy), a chemokine receptor, is expressed on erythrocytes and endothelial cells in blood vessels. It has been linked to inhibition of tumor metastasis, through blockade of tumor cell invasion into vessels, and to regulation of plasma levels of some cytokines which influence leukocyte egress from blood into tissues. The Duffy null (Fy-) phenotype, in which DARC is not expressed on red blood cells, is especially prevalent among people of West African descent. These populations are also highly susceptible to aggressive subtypes of breast and prostate cancers with higher rates of metastases. There is limited evidence, from a Chinese study, that the Fy- phenotype may be associated with increased breast cancer (BrCa) invasiveness and lower rates of survival. However, little is known about how the presence or absence of DARC expression may affect breast cancer metastases and overall survival among African-American and European- American women. Our lab is investigating whether Fy- phenotypes could be associated with increased BrCa metastasis by genotyping the Fy- (null and weak) alleles and assessing DARC gene expression in breast and lymphoblast cells using qPCR and Immunofluorescence (IF). Because there are two isoforms of DARC and the Fy- SNP is located in the promoter of one and the 5′UTR of the other, it is plausible that the alternate isoform is specific to these cell types and may still be expressed. Here we present data from the preliminary stages of this project; including characterizing Duffy alleles in our cell line models. We have genotyped the 3 known DARC polymorphisms that result in Fy- (and weak) erythrocyte phenotypes in breast cancer and lymphoblast cell lines. Specifically, we validated that HAPMAP Yoruba lines are homozygous for the -541T&amp;gt;C point mutation Fy- allele (rs2814778) and half of the African-American lines are heterozygous while the remaining are homozygous for the Fy- allele and the CEPH-European lines do not have the Fy- allele. Our breast cancer (BrCa) lines are derived from tumors of varying molecular subtypes, isolated from African-American women. We show that these BrCa lines are homozygous for the Fy- allele and yet still express the DARC protein. The specific isoform expressed in these cells (DARC-2) may not be the same as used to phenotype the Fy- status in erythrocytes (DARC-1). This suggests that a Fy- genotype may still have some tissue specific expression of DARC-2 in epithelial cells. Therefore, we will also show whether these SNPs correspond with expression of the DARC gene in HAPMAP lymphoblasts and delineate which isoform is being expressed in both cell types. In conclusion, we hypothesize that Fy- status as determined in endothelial and erythrocytes, in people of African descent may remove the metastatic protection of DARC and alternate expression of DARC-2 on epithelial cells may increase the rate of metastases in these populations. Currently, we are analyzing clinical samples (blood and breast tissues) from local breast cancer patients for Fy- status and will determine if this correlates with metastatic disease. In addition, biochemical experiments will be conducted to determine whether DARC-related chemokines are in higher prevalence in the Fy- patients, how the isoforms differ in their affinity to the chemokine ligands and whether this is associated with specific breast cancer subtypes. Citation Format: Melissa Davis, Rupa Hire, Jonathan Swanson, Kauthar Mumin, Michele Monteil, Michele Lou. Investigating correlations of DARC underexpression (Duffy Null phenotypes) with increased breast cancer lymph node metastasis. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C69. doi:10.1158/1538-7755.DISP13-C69

Abstract LB-278: Metformin exposure on survival in localized breast cancer patients with type II diabetes mellitus using electronic health records

Abstract Background: Literature addressing metformin exposure post diagnosis of breast cancer hints at a potential protective association on mortality outcomes, although findings have been inconclusive. In this research, we contribute to this body of evidence by using robust clinical indicators to focus on subgroups of breast cancer patients that might be most appropriate for potential metformin treatment. Methods: Robust breast cancer staging, treatment, and medication exposure attributes were compiled from Mayo Clinic Electronic Health Records and Breast Cancer Registry using a combination of structured queries and natural language processing of clinical notes. A cohort of female Breast Cancer Registry patients having type II diabetes mellitus (T2DM) at breast cancer diagnosis with a median follow-up period of 79.0 months after breast cancer diagnosis was identified (N=350). Univariate and multivariate cox proportional hazard regression analysis were used to model characteristics of BMI at diagnosis, age at diagnosis, metformin, insulin, thiazolidinedione, and sulfonylurea exposure after diagnosis, cancer grade, cancer stage, chemotherapy, hormone therapy, radiotherapy, lumpectomy, and mastectomy. Patients presenting with metastatic breast cancer at diagnosis, receiving immunotherapy for breast cancer treatment, and concurrent metformin and insulin exposure for T2DM treatments were excluded from the analysis cohort. Results: Univariate analysis independently identified metformin exposure (HR=0.243,p=0.0016), insulin exposure (HR=3.481,p=0.0210), age at breast cancer diagnosis (HR=1.075,p=0.0001), and targeted radiotherapy (HR=0.337,p=0.0082) as having a significant association with all-cause mortality. The multivariate model of metformin exposure (HR=0.274,p=0.0123), insulin exposure (HR=2.502,p=0.1160), age at breast cancer diagnosis (HR=1.043,p=0.0480), and targeted radiotherapy (HR=0.303,p=0.0044) on all-cause mortality demonstrated significant associations for all variables (Wald Chi-Square=25.2916,p&amp;lt;0.0001). A parallel multivariate model demonstrated metformin exposure (HR=0.101,p=0.0323), insulin exposure (HR=5.241,p=0.0265), and targeted radiotherapy (HR=0.292,p=0.0520) as having significant associations with breast cancer-specific mortality. Discussion: These findings suggest a protective association for metformin and a potential detrimental association for insulin therapy on all-cause and breast cancer-specific mortality amongst non-metastatic breast cancer patients with T2DM. The findings presented include robust clinical indicators for BMI, stage, and grade at diagnosis, post-diagnosis diabetes medication exposure, and endpoints of all cause and breast cancer specific mortality that have not been available in larger population studies. Our findings have potential pharmacogenetic implications for inhibition of localized breast cancer cell growth by targeting downstream components of the adenosine monophosphate-activated protein kinase pathway, the insulin/insulin-like growth factor-1 signaling pathway, and directly and indirectly via additional metabolic pathways with specific drug therapy combinations. Citation Format: Matthew K. Breitenstein, Leiwei Wang, Richard M. Weinshilboum, Jyotishman Pathak. Metformin exposure on survival in localized breast cancer patients with type II diabetes mellitus using electronic health records. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-278. doi:10.1158/1538-7445.AM2014-LB-278

Abstract 132: Investigating correlations of DARC under-expression (Duffy null phenotypes) with increased breast cancer lymph node metastasis

Abstract DARC (aka Duffy), a chemokine receptor, is expressed on erythrocytes and endothelial cells in blood vessels. It has been linked to inhibition of tumor metastasis, and to regulation of plasma levels of some cytokines. The Duffy null (Fy-) phenotype, in which DARC is not expressed on red blood cells, is especially prevalent among people of West African descent. Little is known about how the presence or absence of DARC expression may affect breast cancer metastases and overall survival among African-American and European- American women. Our lab is investigating whether Fy- phenotypes could be associated with increased BrCa metastasis by genotyping the Fy- (null and weak) alleles and assessing DARC gene expression in breast and lymphoblast cells using qPCR and Immunofluorescence (IF). There are two isoforms of DARC, each with the Fy- SNP located in the promoter of one and the 5’UTR of the other. Due to this SNP, it is plausible that the alternate isoform is specific to these cell types and may still be expressed. Here we present data from the preliminary stages of this project; including characterizing Duffy alleles in our cell line models. We have genotyped the 3 known DARC polymorphisms that result in Fy- (and weak) erythrocyte phenotypes in breast cancer and lymphoblast cell lines. Specifically, we validated the genotype of HAPMAP lines from Yoruba, African-American, and CEPH-European descent for the -541T&amp;gt;C point mutation Fy- allele (rs2814778). Our breast cancer (BrCa) lines are derived from tumors of varying molecular subtypes, isolated from African-American women. We show that these BrCa lines are homozygous for the Fy- allele and yet still express the DARC protein. The specific isoform expressed in these cells (DARC-2) may not be the same as used to phenotype the Fy- status in erythrocytes (DARC-1). This suggests that a Fy- genotype may have some tissue specific expression of DARC-2 in epithelial cells. As well, we show that the levels of expression of the two DARC isoforms vary and are distinct among ancestral groups. We also show expression on the RNA level for individuals who have the duffy null genotype, which will be further validated. In conclusion, we hypothesize that Fy- status, as determined in endothelial and erythrocytes in people of African descent, may remove the metastatic protection of DARC. Also, alternate expression of DARC-2 on epithelial cells may increase the rate of metastases in the African population. Currently, we are analyzing clinical samples (blood and breast tissues) from local breast cancer patients for Fy- status and will determine if this correlates with metastatic disease. In addition, biochemical experiments will be conducted to determine whether DARC-related chemokines are in higher prevalence in the Fy- patients, how the isoforms differ in their affinity to the chemokine ligands, and whether this is associated with specific breast cancer subtypes. Citation Format: Andrea Walens, Brianna Bennett, Kauthar Mumin, Michael Lou, Rupali Hire, Michele Monteil, Melissa Davis. Investigating correlations of DARC under-expression (Duffy null phenotypes) with increased breast cancer lymph node metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 132. doi:10.1158/1538-7445.AM2014-132

Decline of cognitive functions among elderly localized breast cancer patients after adjuvant treatment: COG-AGE study.

9509 Background: Cognitive deficits (CD) have been reported among patients receiving chemotherapy (CT) for cancer.Despite their increased propensity for age-related CD that may worsen during CT, el...

Association of Fatigue with Perceived Stress in Chinese Women with Early Stage Breast Cancer Awaiting Adjuvant Radiotherapy.

Cancer-related fatigue (CRF) is common in women with breast cancer, but little is known of its relationship with perceived stress. We conducted a cross-sectional study to explore the associations of CRF with perceived stress, anxiety, depression, pain and sleep quality in 133 Chinese women (aged 25-68 years) with early stage breast cancer. The majority of women had completed surgery and chemotherapy and were awaiting radiotherapy. Self-administered questionnaires consisting of the Brief Fatigue Inventory, Perceived Stress Scale-10, Hospital Anxiety and Depression Scale, Brief Pain Inventory, and Pittsburgh Sleep Quality Index were used to collect data. Forty-five per cent of the women were severely fatigued. Compared with local healthy women and US breast cancer patients, the group's mean perceived stress score was significantly higher (both p < 0.01). Higher perceived stress (β = 0.18, p = 0.032), higher anxiety (β = 0.30, p < 0.001) and higher pain severity (β = 0.38, p < 0.001) were associated with increased severity of CRF. The association of CRF with perceived stress was partially mediated by anxiety, suggesting a possible pathway from cancer and cancer treatment to CRF via stress appraisals and emotional distress. The findings indicate the importance of monitoring the psychological status of patients during treatment.