Estrogen Progesterone Receptor Research Articles

Coffee Intake Decreases Risk of Postmenopausal Breast Cancer: A Dose-Response Meta-Analysis on Prospective Cohort Studies.

Aim: A dose-response meta-analysis was conducted in order to summarize the evidence from prospective cohort studies regarding the association between coffee intake and breast cancer risk. Methods: A systematic search was performed in electronic databases up to March 2017 to identify relevant studies; risk estimates were retrieved from the studies and linear and non-linear dose-response analysis modelled by restricted cubic splines was conducted. A stratified and subgroup analysis by menopausal and estrogen/progesterone receptor (ER/PR) status, smoking status and body mass index (BMI) were performed in order to detect potential confounders. Results: A total of 21 prospective studies were selected either for dose-response, the highest versus lowest category of consumption or subgroup analysis. The dose-response analysis of 13 prospective studies showed no significant association between coffee consumption and breast cancer risk in the non-linear model. However, an inverse relationship has been found when the analysis was restricted to post-menopausal women. Consumption of four cups of coffee per day was associated with a 10% reduction in postmenopausal cancer risk (relative risk, RR 0.90; 95% confidence interval, CI 0.82 to 0.99). Subgroup analyses showed consistent results for all potential confounding factors examined. Conclusions: Findings from this meta-analysis may support the hypothesis that coffee consumption is associated with decreased risk of postmenopausal breast cancer.

Should molecular subtype be recommended as one of the selection criteria for accelerated partial breast irradiation? Preliminary results from an Asian cohort.

PurposeThe purpose of this study was to report clinical outcomes in patients treated with accelerated partial breast irradiation (APBI), stratified as per molecular subtype and American Society for Therapeutic Radiology and Oncology/Groupe Européen de Curiethérapie and European Society for Radiotherapy & Oncology (ASTRO/GEC-ESTRO) patient selection criteria in order to determine whether molecular subtype should be recommended as one of the selection criteria for APBI.Material and methods157 early-stage breast cancers patients, treated with APBI using multi-catheter interstitial brachytherapy with ≥ 6 months follow-up were included. Molecular subtype was assigned based on estrogen/progesterone receptor (ER/PR), Her2neu and tumor grade. Patients were stratified into ASTRO and GEC-ESTRO risk groups, as per updated ASTRO consensus statement (CS) and GEC-ESTRO recommendation, respectively. The Kaplan-Meier method was used to calculate the time to event data of clinical outcomes.ResultsWith a median follow-up of 35 months, local control (LC) and locoregional control (LRC) were not significantly different among the different molecular subtypes (p = 0.19, p = 0.41, respectively). None of the APBI guidelines predicted risk of local or locoregional recurrence. Re-analyzing the data by replacing ER status with molecular subtype in the ASTRO-CS did not show any significant difference in LC/LRC across the various categories. Her2neu subtype was associated with significantly lower disease-free survival, cause specific survival, and overall survival than the luminal subtypes.ConclusionsNone of the mentioned APBI guidelines predicted local or locoregional recurrence risk in our study population. Additional follow-up will be needed to recommend inclusion of molecular subtype (or at least HER2 receptor status) in the patient selection criteria for APBI.

Estrogen receptor and progesterone receptor status of breast cancer patients of eastern India: A multi-institutional study.

Context:There is a paucity of any significant data on the estrogen receptor (ER) and progesterone receptor (PR) status of breast cancer patients from the eastern part of India.Aims:This study aims to document the ER and PR status of breast cancer patients in the eastern Indian population, as catered by two premier tertiary care hospitals in Kolkata.Subjects and Methods:All breast cancer patients registered between January 1, 2013 and December 31, 2015, in the Departments of Oncology, of IPGMER and SSKM Hospitals and R. G. Kar Medical College and Hospital, Kolkata, who had at least undergone a core biopsy or surgery, were analyzed retrospectively for documentation of their ER and PR status, using the 2010 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) interpretation guidelines.Results:Over a period of 3 years, a total of 927 patients were included for the study. A total of 825 (89%) patients had their ER and PR data available for evaluation. ER and PR positive was seen in 312 (37.82%) patients, ER and PR negative in 399 (48.36%) patients, ER positive and PR negative in 71 (8.6%) patients, and ER negative and PR positive results was found in 43 (5.21%) patients.Conclusions:This is the first multi-institutional documentation of ER and PR status from eastern India, having a modest number of patients and one of the earliest documentations using the latest ASCO/CAP interpretation guidelines. These findings resemble the data from the south and also reiterate the fact that majority of the Indian breast cancer patients are still ER and PR negative in spite of the changes in the interpretation guidelines.

Unexpected pulmonary tumor: metastasis from a benign uterine leiomyoma in a post-menopausal woman: a case report

BackgroundThe occurrence of lung metastasis from benign uterine leiomyomas is rarely reported especially in post menopausal women. The pathogenesis of these metastatic benign tumors still remains a subject of various speculations.Case presentationA 57-year-old woman presented with a chronic cough and dyspnea. She had undergone 8 years previously, hysterectomy for benign leiomyomas. A chest computed tomography scan showed a 4 cm solitary nodular parenchymal tumor that increased in size after 12 months. The histological analysis of the biopsy from this nodule showed a benign tumor with regular spindle cells disposed in intersected fascicles. At immunohistochemical analysis, the tumor cells were positive for smooth muscle markers and oestrogen-progesterone receptors with a low mitotic index assessed by Ki-67. These features were consistent with a benign metastasizing uterine leiomyoma. At the multidisciplinary meeting, prescription of an aromatase inhibitor has been decided for the patient.ConclusionsBenign metastasizing uterine leiomyomas of the lung are very rare tumors. Although extremely rare in post menopausal women, their diagnosis should be considered in symptomatic patients with a history of hysterectomy for leiomyomas.

Tree nut, peanut, and peanut butter intake and risk of postmenopausal breast cancer: The Netherlands Cohort Study

PurposeNut intake has been associated with reduced mortality and risk of cardiovascular diseases, but there is only limited evidence on cancer. We investigated the relationship between nut intake and risk of postmenopausal breast cancer, and estrogen/progesterone receptor (ER/PR) subtypes.MethodsIn The Netherlands Cohort Study, 62,573 women aged 55–69 years provided information on dietary and lifestyle habits in 1986. After 20.3 years of follow-up, 2,321 incident breast cancer cases and 1,665 subcohort members were eligible for multivariate case-cohort analyses.ResultsTotal nut intake was significantly inversely related to ER negative (ER −) breast cancer risk, with HR 0.55 (95% CI 0.33–0.93) for those consuming at least 10 g nuts/day versus non-consumers (p trend = 0.025). There were no significant inverse associations with ER + or total breast cancer. While there was no variation between PR subtypes, the ER–PR- subtype was also significantly inversely associated with nut intake, with HR 0.53 (95% CI 0.29–0.99), p trend = 0.037. Intake of peanuts and tree nuts separately was also inversely related to ER − breast cancer subtypes, while no associations were found with peanut butter intake.ConclusionsOur findings suggest an inverse association between nut intake and ER − breast cancer, and no association with total or hormone receptor-positive subtypes.

Clinical value of radiotherapy in 78 patients with pT3N0M0 breast cancer after modified radical mastectomy

Objective To investigate the value of post-mastectomy radiotherapy (PMRT) in patients with T3N0 breast cancer (BC) who were treated with modified radical mastectomy (MRM). Methods A retrospective analysis was performed on the clinical data of BC patients treated with MRM from 1997 to 2014.The inclusion criteria were as follows: (1) female patients; (2) pathological diagnosis of invasive BC; (3) tumor volume greater than 5 cm without axillary lymph node metastasis; (4) the patients who received no neoadjuvant chemotherapy or endocrine therapy and had no distant metastasis or other second primary cancers. A total of 78 patients met the inclusion criteria. Forty patients (51%) received PMRT and sixty-seven patients (86%) received adjuvant chemotherapy. The Kaplan-Meier method was used to calculate overall survival (OS), disease-free survival (DFS)(DFS), and local-regional recurrence (LRR) rates, and survival differences between groups were analyzed by the log-rank test. Results The median follow-up time was 79 months (6-232 months). For all patients, the 5-year OS, DFS, and LRR rates were 89%, 87%, and 2%, respectively. The 5-year DFS, OS and LRR rates for radiotherapy group were 84%, 84% and 0%, respectively, versus 91%(P=0.641), 96%(P=0.126), and 5% for non-radiotherapy group. Only estrogen receptor/progesterone receptor (ER/PR) status and molecular type had significant impacts on DFS (P=0.002 and 0.031, respectively). One patient in non-radiotherapy group had chest wall recurrence. Conclusions MRM is effective in reducing LRR in T3N0M0 BC patients. Only ER/PR status and molecular type significantly influence DFS. Effective systemic therapy may be helpful for some T3N0 patients to avoid chest wall and supraclavicular radiotherapy after MRM, but large-sample studies are needed to further confirm this conclusion. Key words: Breast cancer/radiotherapy; Local regional recurrence

2261

OBJECTIVES/SPECIFIC AIMS: Evidence-based guideline-concordant care leads to better outcomes in patients with early stage breast cancer, including survival. However, previous studies of guideline compliance have been limited by small study sample sizes, localized geography, unknown causal factors, and lack of diverse population. We use a national database to assess socio-economic, clinical, and facility factors that impact treatment compliance with evidence-based guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN). METHODS/STUDY POPULATION: This is a retrospective cohort study of the National Cancer Data Base Participant User File Breast 2014, which captures ~70%–80% of all newly diagnosed cancer cases in the United States. Female patients who were diagnosed with early stage breast adenocarcinoma (T0, T1, T1A, T1B, 2, 2A, or T2N1) from 2004 to 2014 were eligible for this study. RESULTS/ANTICIPATED RESULTS: A total of 807,314 patients were included in this study. Evidence-based guidelines examined with associated compliance rates include surgery completion (79.3% overall compliance), breast conserving surgery Versus mastectomy (88.05% vs. 11.95%, respectively), radiation after breast conserving surgery (77.5% overall compliance), HER2 testing (88.6% overall compliance), estrogen/progesterone receptor (ER/PR) testing (96.3% overall compliance), hormone treatment for positive ER/PR breast cancer (80.2% overall compliance), and sentinel lymph node biopsy completion (67.5% overall compliance). Univariate association between these guidelines and covariates such as facility type, facility location, age, race, insurance status, median income quartiles, achievement of high school degree, urban Versus rural, Charlson-Deyo score, year of diagnosis, and overall survival were assessed. Logistic regression analysis will be used to determine multivariate relationships between these characteristics and the probability that a patient will be compliant to guideline regimen. DISCUSSION/SIGNIFICANCE OF IMPACT: The results of this study will help identify socio-economic, clinical, and facility factors that influence guideline-concordant care and subsequent critical outcomes for patients with early stage breast cancer. Lack of guideline concordant care for specific stages of cancer or treatment modalities will point to a need for tailored interventions to enhance compliance. A prediction model will help identify the most important predictors of noncompliance in breast cancer treatment so noncompliance can be prevented in at-risk populations.

Assessment of HER-2 status in invasive breast cancer in Brazil.

To characterize the frequency of HER-2-positive breast cancer in Brazil. In this prospective observational study, we first ascertained the HER-2 status of invasive breast cancer specimens by automated immunohistochemistry (IHC). For specimens classified as 2+ by IHC, we performed in situ hybridization (ISH). From February, 2011 to December, 2012, 1,495 breast specimens were registered, and 1,310 samples collected at 24 centers were analyzed. Median patient age was 54 years, and the majority of samples were obtained from segmental (46.9%) or radical mastectomy (34.4%). The predominant histological type was invasive breast carcinoma of no special type (85%), 64.3% had tubule formation (grade 3), and estrogen/progesterone receptors (ER/PR) were positive in 77.4/67.8% of the specimens analyzed, respectively. Using IHC, we found a negative HER-2 status (0 or 1+) in 72.2% of specimens, and 3+ in 18.5%; the 9.3% scored as 2+ were further analyzed by ISH, of which 15.7% were positive (thus, 20.0% of samples were HER-2- -positive by either method). We found no association between HER-2 scores and menopausal status or histological type. Tumors classified as 3+ came from younger patients, and had higher histological grade and less frequent expression of ER/PR. In the North region of Brazil, 34.7% of samples were 3+, with lower frequencies in the other four regions of the country. Our findings provide estimates for the frequency of HER-2 positivity in Brazil and raise the hypothesis that biological differences may underlie the different distribution of breast-cancer phenotypes among different Brazilian regions.

Abstract 1288: Telomere length genetic risk score is associated with breast cancer risk

Abstract Background: Genome-wide association studies (GWAS) have identified associations of telomere maintenance genes with breast cancer risk. This, coupled with the recognized role of telomere dysfunction as a cancer hallmark, has motivated the need for further study of telomeres and breast cancer. Further, the meta-GWAS discovery of seven single nucleotide polymorphisms (SNPs) associated with telomere length (TL) enables the use of an aggregated genetic risk score (GRS) for TL. We hypothesized that a higher GRS (representing shorter TL) would be associated with increased risk of breast cancer, and that a strengthened association may exist between higher TL GRS and aggressive breast cancer risk. Methods: In a race/ethnically diverse sample of invasive breast cancer cases (N=1,108) and non-cases (N=20,023) from the Women’s Health Initiative, we derived an unweighted TL GRS using seven previously identified TL-associated SNPs. Women were postmenopausal and the average age at enrollment was 63.9 years. We tested TL GRS associations with overall breast cancer risk and for estrogen receptor (ER), progesterone receptor (PR), and her2/neu (HER2) status-specific breast cancer risk using Cox proportional hazards models adjusted for age and race/ethnicity (in the entire sample) and age in strata of European American (EA; N=9,796), African American (AA; N=7,504), and Hispanic American (HA; N=3,229) women. We also considered reproductive risk factors, family history of breast cancer, hormone therapy, tumor characteristics, BMI, physical activity, smoking, alcohol, and US region as potential confounders. Results: We observed a small but statistically significant association between higher TL GRS (shorter TL) and reduced risk of overall breast cancer in the entire sample (HR=0.96, 95% CI: 0.93-1.00). Results of race/ethnicity-stratified analyses for TL GRS and overall breast cancer risk were not significant. The TL GRS was independently associated with decreased risk of ER-negative, PR-positive, and HER2-positive breast cancer risk in the entire sample (HR=0.82, 95% CI: 0.71-0.94, HR=0.94, 95% CI: 0.89-0.99, and HR=0.88, 95% CI: 0.79-0.99, respectively). Similarly, the TL GRS was associated with a reduced risk of ER-negative breast cancer in AA (HR=0.79, 95% CI: 0.64-0.97) and independently with PR-positive and HER2-positive breast cancer risk in HA (HR=0.85, 95% CI: 0.75-0.97 and HR=0.79, 95% CI: 0.58-0.99, respectively). Adjustment for other covariates did not influence hazards. Conclusions: Our results suggest that higher TL GRS is associated with reduced risk of overall breast cancer and with the development of specific breast cancer subtypes, such as ER negativity and/or PR and HER2 positivity. While our focus on GWAS-implicated SNPs may not encompass the full spectrum of genes involved in TL, further studies into the potential mechanism for shorter TL and reduced breast cancer risk are needed. Citation Format: Laurie Grieshober, Jean Wactawski-Wende, Rachael Hageman Blair, Lina Mu, Leah Preus, Jing Nie, Jiali Han, Jaymie R. Meliker, Thomas Rohan, Heather M. Ochs-Balcom. Telomere length genetic risk score is associated with breast cancer risk [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 1288. doi:10.1158/1538-7445.AM2017-1288

Adjuvant Capecitabine in Combination With Docetaxel, Epirubicin, and Cyclophosphamide for Early Breast Cancer

Capecitabine is not considered a standard agent in the adjuvant treatment of early breast cancer. The results of this study suggest that addition of adjuvant capecitabine to a regimen that contains docetaxel, epirubicin, and cyclophosphamide improves survival outcomes of patients with triple-negative breast cancer (TNBC). To investigate the effect of capecitabine on long-term survival outcomes of patients with early breast cancer, particularly in subgroups defined by cancer estrogen receptor (ER) and progesterone receptor (PR) content, and HER2 content (human epidermal growth factor receptor 2). This is an exploratory analysis of the multicenter FinXX randomized clinical trial that accrued 1500 women in Finland and Sweden between January 27, 2004, and May 29, 2007. About half received 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and fluorouracil (T+CEF), while the other half received 3 cycles of docetaxel plus capecitabine followed by 3 cycles of cyclophosphamide, epirubicin, and capecitabine (TX+CEX). Data analysis took place between January 27, 2004, and December 31, 2015. Recurrence-free survival (RFS). Following random allocation, 747 women received T+CEF, and 753 women received TX+CEX. Five patients were excluded from the intention-to-treat population (3 had overt distant metastases at the time of randomization; 2 withdrew consent). The median age of the remaining 1495 patients was 53 years at the time of study entry; 157 (11%) had axillary node-negative disease; 1142 (76%) had ER-positive cancer; and 282 (19%) had HER2-positive cancer. The median follow-up time after random allocation was 10.3 years. There was no significant difference in RFS or overall survival between the groups (hazard ratio [HR], 0.88; 95% CI, 0.71-1.08; P = .23; and HR, 0.84, 95% CI, 0.66-1.07; P = .15; respectively). Breast cancer-specific survival tended to favor the capecitabine group (HR, 0.79; 95% CI, 0.60-1.04; P = .10). When RFS and survival of the patients were compared within the subgroups defined by cancer steroid hormone receptor status (ER and/or PR positive vs ER and PR negative) and HER2 status (positive vs negative), TX+CEX was more effective than T+CEF in the subset of patients with TNBC (HR, 0.53; 95% CI, 0.31-0.92; P = .02; and HR, 0.55, 95% CI, 0.31-0.96; P = .03; respectively). Capecitabine administration with docetaxel, epirubicin, and cyclophosphamide did not prolong RFS or survival compared with a regimen that contained only standard agents. Patients with TNBC had favorable survival outcomes when treated with the capecitabine-containing regimen in an exploratory subgroup analysis. clinicaltrials.gov Identifier: NCT00114816.

Abstract S3-05: Integrated analysis of multidimensional genomic data on CALGB 40601 (Alliance), a randomized neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER2-positive breast cancer

Abstract Background: RNA profiling and mutational analyses in CALGB 40601 (NCT00770809) found significant impact on pathologic complete response (pCR) rates from tumor (intrinsic subtype, p53 mutation) and microenvironmental (immune cell) features. Integrated analysis across platforms is needed to better understand the roles of these different factors with respect to response to HER2-targeted therapies. Methods: We performed a comprehensive genomic analyses on pCR, defined as no invasive tumor in the breast, by integrating clinicopathological information with somatic mutation status, 422 segment-level DNA Copy Number Alterations (CNAs), and 510 gene expression signatures using mRNAseq and DNA exome sequencing from 213 pre-treatment tumors. Excluding 48 samples in the TL arm that was closed early due to futility, and 4 Normal-like tumors, the dataset consisted of 161 patients from TH and THL arms including 47 HER2-enriched (HER2E), 8 Basal-like, 54 Luminal A, and 52 Luminal B, all of whom received H. The main analysis was performed using the Elastic Net on multivariate logistic regression models for predicting pCR. The samples were divided into a training and a test set, then models were built to predict pCR by 10-fold cross-validation in the training set, then applying the best model onto the test set to construct ROC curves and evaluate prediction accuracy by calculating area under ROC (AUC). We also used the DawnRank, a network-based bioinformatics tool that integrates DNA and RNA data to identify driver genes, to find predictors of resistance to H-containing therapies. Results: Among clinicopathological factors, clinical estrogen/progesterone receptor (ER/PgR) status and intrinsic subtype by PAM50 were statistically associated with pCR, but treatment arm (TH vs THL) and stage were not. In the Elastic Net analysis, the models incorporating either gene signatures (AUC: 0.724) or CNAs (AUC: 0.777) were more predictive of response than mutation status model (AUC: 0.635). Gene signatures and CNAs were further combined with either mutation status (AUC: 0.773), clinical ER/PgR status (AUC: 0.787) or ER/PgR status plus intrinsic subtype (AUC: 0.784). The combination with the highest AUC comprised gene signatures, CNAs, and ER/PgR status, and demonstrated that CNAs at Chromosome (Chr.) 6p, 10q22, or 11q23, the signature of Correlation to HER2E, and a T-cell signature, positively predicted pCR and that Luminal and PgR gene signatures were negative predictors. The CN gain of Chr.6p, which contains the HLA genes, predicted for pCR and was associated with higher expression of HLA genes and B cell / IgG signatures. The CN loss of Chr.11q23 including CD3D, CD3E, and CD3G was also identified by DawnRank as a region associated with resistance. Conclusions: Tumor genetics (CNAs), tumor RNA subtype (HER2E, Luminal), and the microenvironment (immune cells) were independently predictive of response to H-containing therapies and biologically and clinically important for HER2-positive breast cancer, supporting integrated RNA- and DNA-based tumor assessments to clarify response to HER2-targeting. Support: U10CA031946/033601/180821/180882/180888. Citation Format: Tanioka M, Fan C, Carey LA, Hyslop T, Pitcher BN, Parker JA, Hoadley KA, Henry NL, Tolaney S, Dang C, Krop IE, Harris L, Berry DA, Mardis E, Perou CM, Winer EP, Hudis CA. Integrated analysis of multidimensional genomic data on CALGB 40601 (Alliance), a randomized neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER2-positive breast cancer [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 S3-05.

Clinical utility of interleukin-18 in breast cancer patients: A pilot study

Aim: The aim of this study is to analyze the protein expression of interleukin 18 (IL-18) in patients with untreated breast cancer and further to evaluate its clinical efficacy in predicting treatment outcome. Methods: In the present study, a total of 50 untreated patients with invasive ductal carcinoma of breast were included in the study. Expression of IL-18 was studied by immunohistochemistry method. Statistical analysis was carried out using Statistical Package for Social Sciences statistical software and P ≤ 0.05 was considered statistically significant. Results: Seventy-two percent of the breast cancer patients showed the presence of cytoplasmic and/or nuclear IL-18 immunoreactivity. IL-18 expression was significantly and positively correlated with the stromal response (χ2 = 3.97, r = 0.282, P = 0.044). Further, the IL-18 immunoreactivity was significantly higher in patients with HER2 amplification as compared to luminal B (χ2 = 2.82, r = −0.523, P = 0.047) breast cancer patients. Moreover, a trend of increased IL-18 expression was observed in estrogen/progesterone receptor (ER/PR) negative patients as compared to ER/PR positive patients (χ2 = 3.41, r = −0.282, P = 0.066). Conclusion: IL-18 could be used as a potential predictive marker and guide clinicians for recommendations to newer treatment. It might serve as a potential therapeutic target to establish novel treatment approaches along with the current treatment protocol used.

Utility of gene expression signature in treatment decision of breast cancer

Breast cancer is the most common cancer and a leading cause of cancer-related mortality in women worldwide. About 1.7 million women were diagnosed with breast cancer in 2012 and 6.3 million women were alive with breast cancer in the previous five years (1,2). Despite modern therapeutic interventions, the 5-year survival rate of breast cancer has improved only marginally and its recurrence is observed in more than 50% of the patients (3,4). Treatment failure and recurrence of breast cancer can be attributed to multiple factors which are difficult to predict for a particular patient (5). Genomic tests such as Oncotype DX, MammaPrint, miRNAs and other molecular and clinico-pathological markers are often employed for guiding therapeutic decisions (6-13) but it is difficult to say which test is reliable. Subtyping of breast cancer is largely based on estrogen/progesterone receptor (ER/PR), and human epidermal growth factor receptor 2 (HER2)/neu status and the most aggressive form is considered to be triple negative breast cancer (TNBC) (14), the drug resistance and recurrence rate of which is extremely high (15-17). Most alarmingly, TNBC has recently been found to be prevalent in as high as 74% of premenopausal women below 35 year of age (18). However, there exists no TNBC-specific therapeutic target yet.

Pattern of Local Recurrence and Distant Metastasis in Breast Cancer By Molecular Subtype.

Background and Purpose: No longer considered a single disease entity, breast cancer is being classified into several distinct molecular subtypes based on gene expression profiling. These subtypes appear to carry prognostic implications and have the potential to be incorporated into treatment decisions. In this study, we evaluated patterns of local recurrence (LR), distant metastasis (DM), and association of survival with molecular subtype in breast cancer patients in the post–adjuvant radiotherapy setting.Material and Methods: The medical records of 1,088 consecutive, non-metastatic breast cancer patients treated at a single institution between 2004 and 2012 were reviewed. Estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor-2 (HER2) enrichment were evaluated by immunohistochemistry. Patients were categorized into one of four subtypes: luminal-A (LA; ER/PR+, HER2-, Grade 1-2), luminal-B (LB; ER/PR+, HER2-, Grade > 2), HER2 over-expression (HER2; ER/PR-, HER2+), and triple negative (TN; ER/PR-, HER2-). Results: The median follow-up time was 6.9 years. During the follow-up, 16% (174/1,088) of patients failed initial treatment and developed either LR (48) or DM (126). The prevalence of LR was the highest in TN (12%) and the lowest in LA (2%). Breast or chest wall relapse was the most frequent site (≈80%) of recurrence in LA, LB, and HER2 subtypes, whereas the regional lymph nodes and chest wall were the common sites of relapse in the TN group (50.0%). DM rates were 6.4% in LA, 12.1% in LB, 19.2% in HER2, and 27.4% in TN subgroups. Five-year survival rates were 84%, 83%, 84%, and 77% in the LA, LB, HER2 and TN subgroups, respectively. There was a statistically significant association between survival and molecular subtypes in an univariate analysis. In the adjusted multivariate analysis, the following variables were independent prognostic factors for survival: T stage, N stage, and molecular subtype.Conclusions: Of the four subtypes, the LA subtype tends to have the best prognosis, fairly high survival, and low recurrent or metastases rates. The TN and HER2 subtypes of breast cancer were associated with significantly poorer overall survival and prone to earlier recurrence and metastases. Our results demonstrate a significant association between molecular subtype and survival. The risk of death and relapse/metastases increases fewfold in TN compared to LA. Future prospective studies are warranted and could ultimately lead to the tailoring of adjuvant radiotherapy treatment fields based on both molecular subtype and the more conventional clinicopathologic characteristics.

Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women.

BackgroundMost BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.MethodsFrom 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). “Cases” were defined as TH, and “controls” were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 “controls” carried a BRCA1 mutation found in the TH “case”. Matched SH2 “controls” carried a BRCA2 mutation found in the TH “case”. After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.ResultsThe majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC.ConclusionsOur observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0768-3) contains supplementary material, which is available to authorized users.

Clinicopathologic factors associated with de novo metastatic breast cancer

While breast cancers with distant metastasis at presentation (de novo metastasis) harbor significantly inferior clinical outcomes, there have been limited studies analyzing the clinicopathologic characteristics in this subset of patients. In this study, we analyzed 6126 breast cancers diagnosed between 1998 and 2013 to identify factors associated with de novo metastatic breast cancer. When compared to patients without metastasis at presentation, race, histologic grade, estrogen/progesterone receptor (ER/PR) and HER2 statuses were significantly associated with de novo metastasis in the entire cohort, whereas age, histologic grade, PR and HER2 status were the significant parameters in the subset of patients with locally advanced breast cancer (Stage IIB/III). The patients with de novo metastatic breast cancer had a significant older mean age and a lower proportion of HER2-positive tumors when compared to those with metastatic recurrence. Further, the HER2-rich subtype demonstrated a drastically higher incidence of de novo metastasis when compared to the luminal and triple-negative breast cancers in the entire cohort [odds ratio (OR)=5.68 and 2.27, respectively] and in the patients with locally advanced disease (OR=4.02 and 2.12, respectively), whereas no significant difference was seen between de novo metastatic cancers and those with metastatic recurrence. Moreover, the luminal and HER2-rich subtypes showed bone-seeking (OR=1.92) and liver-homing (OR=2.99) characteristics, respectively, for the sites of de novo metastasis, while the latter was not observed in those with metastatic recurrence. Our data suggest that an algorithm incorporating clinicopathologic factors, especially histologic grade and receptor profile, remains of significant benefit during decision making in newly diagnosed breast cancer in the pursuit of precision medicine.

Identification of novel susceptibility markers for the risk of overall breast cancer as well as subtypes defined by hormone receptor status in the Chinese population.

Genome-wide association studies (GWAS) have identified common variants associated with breast cancer (BC) risk at multiple genetic loci. Above all, accumulated evidence suggests that inherited risk variants may vary in BC subtypes defined by estrogen receptor (ER) or progesterone receptor (PR) status. However, the underlying susceptibility of some variants for BC subtypes has not been well investigated in the Chinese population. Our objective was to explore the association among 23 GWAS-identified single-nucleotide polymorphisms (SNPs) and overall BC incidence, as well as its subtypes, in Chinese women. An extensive association analysis using the Sequenom MassARRAY® platform was conducted in a case-control study, including 551 BC patients and 577 healthy controls. Using the chi-squared (χ2) test and genetic model analysis, we found an association with BC for four SNPs (rs616488 (1p36.22/PEX14), rs6678914 (1q32.1/LGR6), rs17530068 (6q14/unknown) and rs6001930 (22q13.1/MKL1)) at a 5% level. Stratified analyses under this genetic model determined that rs616488 and rs6001930 were specific to ER positive and PR positive, rs17530068 was specific to ER positive and PR negative, rs3817198 (11p15.5/LSP1) was specific to ER negative and rs4784227 (16q12.1/CASC16) was specific to PR positive. Our study provides powerful new evidence for the relationship between SNPs and BC susceptibility.

Abstract 4765: Impact of TP53 status and functional classification on molecular profiles in breast cancer subtypes

Abstract Breast cancer is a multifaceted disease with several clinical, pathological and molecular attributes contributing to disease prognosis or treatment outcome. Treatment measures in breast cancer are based on hormone/growth factor receptor -estrogen/progesterone receptor (ER/PR) or human epidermal growth factor receptor 2 (Her2) status. TP53 pathway inactivation in breast cancer is well-established. Although TP53's therapeutic relevance is well-recognized, it remains under-utilized in patient-management, since all TP53 mutants are treated equally in the diagnostic context. In reality, enormous heterogeneity exists in nature, type and functional impact of TP53 variants. Therefore, understanding the diversity of TP53 variants in breast cancer subtypes may enhance its diagnostic utility in this cancer. We utilized clinical NGS data, obtained using commercially available targeted panels, TruSeq Amplicon Cancer Panel (Illumina) and Ion AmpliSeq Cancer Hotspot Panel v2 (Thermofisher) to analyze tumor DNAs from cancer patients at the Advanced Molecular Diagnostic Laboratory (Princess Margaret Cancer Centre, Toronto, Canada). We focused on data from 105 advanced breast cancer patients. We consolidated several schemes proposed in the literature to classify TP53 variants, and evaluated patient molecular profiling and pathology data based on: (1) presence of TP53 variants; (b) coding effect; and (c) transcriptional activity. We further investigated whether TP53 variants were associated with reportable variant load, co-occurrence with other molecular changes and hormone/growth-factor receptor status. In our study group, 70.4% cases carried one or more variants. TP53 alterations were prevalent (40.9%) in our cohort, followed by PIK3CA variants (36.2%). 15/105 cases (14.3%) carried variants in both genes. Unlike in other cancer types, where missense TP53 variants predominate (e.g., colorectal, 72.6%), missense (49%) and nonsense/frameshift (42%) variants were similarly distributed in breast cancers. Gain-of-Function (GOF) and Loss-of-Function (LOF) TP53 variants were also equally distributed (32% vs. 33%). However, TP53mut PIK3CAmut breast cancer cases were more likely to carry missense and/or LOF variants (10/15 cases). TP53 variants were also associated with hormone/growth-factor receptor status. A greater proportion of ER- vs ER+, PR- vs PR+, and ER-PR-Her2- vs ER+PR+Her2- breast cancer cases carried missense GOF TP53 variants respectively when compared to missense LOF and variants of unknown significance taken together(80-85% vs 50-55%; p&amp;lt;0.0001). Finally, TP53mut cases were more likely to carry multiple variants in contrast to TP53wt cases (37.2% vs. 12.9%). Taken together, we define a stratification strategy for TP53 that takes into account the diversity of TP53 variants, and demonstrate its application to molecular profiling and clinico-pathological data in breast cancer. Citation Format: Swati Garg, Mahadeo A. Sukhai, Maksym Misyura, Mariam Thomas, Tong Zhang, Lillian L. Siu, Philippe L. Bedard, Tracy L. Stockley, Suzanne Kamel-Reid. Impact of TP53 status and functional classification on molecular profiles in breast cancer subtypes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4765.

Correlation of Ki67 Expression with Hormone Receptors, Human Epidermal Growth Factor Receptor-2 (HER-2) Status, P53 Mutation and Clinicopathological Characteristics in Pathologic Specimens of Breast Cancer Patients

Background: Breast cancer is the main cause of cancer in women and the second cause of ma­lignancy deaths. Ki-67 is one of the molecular markers used to evaluate cancer prognosis along with other factors such as age, tumor size, lymph node involvement, estrogen receptor (ER), progesterone receptor (PR), P53, human epidermal growth factor receptor-2 (HER-2), histolog­ical and nuclear grades. This study was aimed to evaluate the correlation of KI-67 expression with some biomarkers and clinico-pathological characteristics in breast cancer patients. Mate­rials and Methods: A total of 513 cases (all female) aged 40- 80 years, were randomly selected from patients who were admitted in two centers affiliated with Tehran University of Medical Sciences (Buo-alli and Kasra hospitals) over a 7-year period (2010-2015). Assessment of tumors for HER-2, P53, ER PR, pathological type and histologic grade was performed. Ki-67 labelling index (Ki-67LI) was defined as the percentage of MIB1-positive cells among a total number of 1,000 malignant cells at high-power magnification (×400). Results: Our study showed that age, ER and PR status were negatively correlated with Ki-67LI (P&lt;0.05). Moreover, number of lymph nodes involved, HER-2, P53 and nuclear grades had a positive correlation with Ki-67LI (P&lt;0.05), whereas, tumor size and histological grade showed no significant correlation with Ki-67LI (P =0.195 and P=0.721, respectively). Conclusion: Results of our study and other studies confirm that the expression of Ki-67 is significantly associated with ER, PR, HER-2 and P53 status. On the other hand, Ki-67 relationship with clinical characteristics such as age, tumor size and lymph node metastasis is not completely established and needs further research.[GMJ.2016;5(2):90-97]

MP57-18 EXPRESSION OF STEROID HORMONE RECEPTORS IN RESIDUAL CANCER AND STROMAL CELLS AFTER NEOADJUVANT CHEMOHORMONAL THERAPY WITH DOCETAXAL FOR HIGH-RISK LOCALIZED PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Localized: Surgical Therapy III1 Apr 2016MP57-18 EXPRESSION OF STEROID HORMONE RECEPTORS IN RESIDUAL CANCER AND STROMAL CELLS AFTER NEOADJUVANT CHEMOHORMONAL THERAPY WITH DOCETAXAL FOR HIGH-RISK LOCALIZED PROSTATE CANCER Shintaro Narita, Taketoshi Nara, Mingguo Huang, Koichiro Takayama, Kazuyuki Numakura, Hiroshi Tsuruta, Atsushi Maeno, Mitsuru Saito, Takamitsu Inoue, Norihiko Tsuchiya, Hiroshi Nanjo, Shigeru Satoh, and Tomonori Habuchi Shintaro NaritaShintaro Narita More articles by this author , Taketoshi NaraTaketoshi Nara More articles by this author , Mingguo HuangMingguo Huang More articles by this author , Koichiro TakayamaKoichiro Takayama More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Hiroshi TsurutaHiroshi Tsuruta More articles by this author , Atsushi MaenoAtsushi Maeno More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , Hiroshi NanjoHiroshi Nanjo More articles by this author , Shigeru SatohShigeru Satoh More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.672AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recent studies suggest that activation of steroid hormone receptors (SHRs) is associated with PCa progression and resistance to chemohormonal therapy. In this study, we investigated SHR expressions in human PCa tissues in patients who underwent radical prostatectomy (RP) with and without neoadjuvant chemohormonal therapy. METHODS A tissue microarray with 210 cores from 70 high-risk localized PCa patients who underwent RP without neoadjuvant therapy (NNA), with neoadjuvant hormonal therapy (NHT), or with neoadjuvant chemohormonal therapy with docetaxel (CHT) was used to assess the epithelial and stromal expressions of four SHRs including androgen receptor (AR), glucocorticoid receptor (GR), estrogen receptor (ER) alpha, and progesterone receptor (PR). Expression levels of SHRs between the three groups were statistically assessed. Multivariate analyses were performed to investigate the prognostic factors of BCR in patients who underwent surgery with CHT. RESULTS AR and GR were expressed in both residual cancer and stromal cells, whereas ER alpha and PR were mainly expressed in stromal cells. The mean nuclear AR immunoreactivity score in residual cancer cells was significantly higher in the NNA group than in the NHT and CHT groups. The mean nuclear GR immunoreactivity score in residual cancer cells and mean nuclear ER alpha and PR in stromal cells were significantly higher in the CHT group than in the NNA and NHT groups. The patients with a low PR immunoreactivity score in stromal cells had a significantly higher BCR rate than those with a high nuclear immunoreactivity score (p = 0.011). In multivariate analysis, the number of risk factors constituting the classification of high-risk, a preoperative PSA level, pathological chemotherapy effect, and low nuclear PR immunoreactivity score in stromal cells were independent prognostic factors for BCR. CONCLUSIONS Stromal PR expression may be a potential prognostic marker for BCR in high-risk PCa patients who underwent radical prostatectomy after neoadjuvant chemohormonal therapy. The expression of SHRs in both residual cancer and stromal cells may play an important role in PCa resistance to chemohormonal therapy. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e759-e760 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Shintaro Narita More articles by this author Taketoshi Nara More articles by this author Mingguo Huang More articles by this author Koichiro Takayama More articles by this author Kazuyuki Numakura More articles by this author Hiroshi Tsuruta More articles by this author Atsushi Maeno More articles by this author Mitsuru Saito More articles by this author Takamitsu Inoue More articles by this author Norihiko Tsuchiya More articles by this author Hiroshi Nanjo More articles by this author Shigeru Satoh More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...