bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-01-04: Early stage breast cancer prognostication using whole tumor or Ki67 heterogeneity-based digital imaging
Authors: Barnes M , Srinivas C , Xu C , Dean S , Singh S , Henricksen LA , Wik N , Morris D , Magliocco A , LaFleur B
Published: May 2016

Introduction:

Accurate prognosis of hormone-positive early stage breast cancer patients offers the opportunity to make more informed follow-up choices, for example the addition of adjuvant chemotherapy. More recently patient prognostication based on immunohistochemistry-scored protein expression (ER, PR, Her2 and Ki67) in the ATAC trial has been described as IHC4 (C-index of 0.78). However, IHC4 clinical translation has not occurred and may be hindered by the need for a clinically-validated standardized assay as well as pathologist scoring reproducibility. To address this idea, we employed a standardized assay system and automated scoring using digital image analysis to assess either whole tumor (WT) IHC expression values or Ki67 heterogeneity (Ki67H) quantification. The goals were to 1) establish a prognostic model based on and potentially improving the IHC4 concept and 2) improve pathologist scoring reproducibility.

Material and Methods:

A paraffin-embedded whole tissue cohort consisting of 120 cases of hormone-positive, HER2-negative, stage I and II, breast cancer patient samples were re-stained with standardized ER, PR, HER2, and Ki67 IHC assays. Three pathologists independently scored conventional glass slides microscopically (CM) and annotated WT on H&E and Ki67 heterogeneous regions on whole slide scanned images (WSI) for each case separately. The annotations were separately registered across serial stained slides and also scored via the digital pathology algorithm.

Results:

The mean patient age at the time of diagnosis is 63 years with a maximum follow-up of 18 years. Patients with regional and/or distal recurrence compose 26% of the cohort with a median recurrence free survival of 8.5 years. years. Clinical variables (CV) plus WT (C-index 0.74, r2 0.38) or Ki67H (C-index 0.77, r2 0.39) models improved on patient prognostication each as compared to the IHC4 plus CV (C-index 0.70, r2 0.19) in this cohort. High inter-pathologist reproducibility for the IHC score, as measured by concordance correlation coefficient was noted for Ki67H (0.90).

Conclusions:

Novel algorithmic scoring methodologies such as WT and Ki67H may improve on the IHC4 concept with high inter-pathology reproducibility. We are currently validating in a larger 600 patient cohort.

Citation Format: Barnes M, Srinivas C, Xu C, Dean S, Singh S, Henricksen LA, Wik N, Morris D, Magliocco A, LaFleur B. Early stage breast cancer prognostication using whole tumor or Ki67 heterogeneity-based digital imaging. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-01-04.
Abstract P1-03-02: Estrogens contribute to cytokine upregulation and cancer stem cell recruitment upon breast cancer contact with mature human mammary adipocytes: Effects of estrogen type and adipocyte donor weight
Authors: Slingerland J , Picon-Ruiz M , Jang K , Morata-Tarifa C , Pan C , Besser A , Kim M , Ince TA , Howard GA , El-Ashry D
Published: May 2016

Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. While obesity confers increased cancer risk and worse outcome, mechanisms thereof are not fully known. We show prolonged co-culture of fat cells (human adipocyte stem cells, differentiated adipocytes or mature adipocytes) from breast tissue together with breast cancer lines or cultured primary dissociated human breast tumor cells increases secretion of six different pro-inflammatory cytokines, each of which contributes to tumor progression through cancer stem cell recruitment. Prolonged exposure to fat cells or to each cytokine increases the proportion of cells that form mammosphere and express ALDH1 activity in vitro and that can initiate primary orthotopic tumors and metastasis in vivo. Adipocyte and cytokine exposures activate Src, and Src family kinase activity leads to induction of embryonic transcription factors that upregulate miR302b. miR302b induction is Sox2-dependent, promotes cytokine-driven sphere formation, and in turn, stimulates cMYC and SOX2 expression. Src is not only activated by adipocyte or cytokine exposures, it is also required to sustain cytokine induction, since Src inhibitors decrease cytokine production after co-culture. Cytokine upregulation was much greater after co-culture of ER+ breast cancer cells with mature, aromatase positive, adipocytes than with adipocyte stem cells. Cytokine induction was estrogen regulated. The mechanisms of cytokine induction, ER-coactivation and effects of different estrogenic ligands will be presented.

Present data illuminate the increased risk of breast cancer after menopause, particularly in obese women and the increased breast cancer mortality with obesity: cancer cell invasion into local fat, in the presence of high local aromatase and intracellular estrogen would establish feed-forward loops to activate Src, maintain pro-inflammatory cytokine production and increase tumor initiating cell abundance, tumor growth and metastasis. These data link obesity related pro-inflammatory cytokines to Src activation and cancer initiating cell abundance, and provide a novel rationale for Src inhibitors together with endocrine therapy for breast cancer.

Citation Format: Slingerland J, Picon-Ruiz M, Jang K, Morata-Tarifa C, Pan C, Besser A, Kim M, Ince TA, Howard GA, El-Ashry D. Estrogens contribute to cytokine upregulation and cancer stem cell recruitment upon breast cancer contact with mature human mammary adipocytes: Effects of estrogen type and adipocyte donor weight. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-03-02.
Abstract P1-03-04: Response to cyclooxygenase-2 inhibition is regulated by collagen dense stroma
Authors: Esbona K , Inman DR , Saha S , Wilke LG , Keely PJ
Published: May 2016

Women with dense breast have over four-fold risk for breast cancer and high breast density is correlated to increased collagen. In our previously characterized mouse model of MMTV-PyVT x Col1a1tm1jae, increased collagen levels in mammary tumors lead to enhanced tumor formation and progression. Additionally, high collagen density in vitro elevated expression of PTGS2, the gene for cyclooxygenase-2 (COX-2), by over four-fold. Because COX-2 over-expression is observed in 40% of invasive breast carcinoma cases and correlates with poor prognosis, we hypothesized that inhibition of COX-2 may be an effective target in the context of mammary tumors arising in dense tissue. Col1a1tm1jae (HD) or wild-type (wt) tumor mice were randomly assigned at 11 weeks of age to daily treatment with vehicle or celecoxib for 21 days. Tumors in HD mice were larger (p < 0.05) and expressed higher levels of COX-2 (p < 0.05) and PGE2 (p < 0.01). COX-2 and PGE2 expression levels were both decreased with COX-2 inhibition (wt and HD = p < 0.0001, for both markers). Cell proliferation decreased in both wt and HD tumors when COX-2 was inhibited (Epithelium wt and HD p < 0.0001; stroma wt = p < 0.05 and HD = p < 0.01). Notably, several cytokines, immune and stromal cell counts were elevated in HD tumors alone, and COX-2 inhibition reversed this effect. These findings indicate that COX-2 has a direct role in modulating tumor progression in dense matrices and it may be an effective therapeutic target for women with dense breast tissue.

Citation Format: Esbona K, Inman DR, Saha S, Wilke LG, Keely PJ. Response to cyclooxygenase-2 inhibition is regulated by collagen dense stroma. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-03-04.
Abstract P1-03-05: SPARC expression in primary metastatic breast cancer
Authors: Barinoff J , Brandi C , Thill M , Heinrichs C , Mensah J , Weikel W , Fisseler-Eckhoff A , Sinn P , Meyer A-S , Traut A , Schneeweiss A
Published: May 2016

Aim: To evaluate the prognostic value of the expression of secreted protein acidic and rich in cysteine (SPARC) in primary metastatic breast cancer (PMBC).

Patients and Methods: Fifty-two patients with PMBC diagnosed between 2005 and 2012 at x German centers were retrospectively analyzed for expression of SPARC in tumor cells using an immunoreactive score (IRS) integrating staining intensity and percentage of positive cells (IRS 0-12), and in stroma based on immunohistochemical (IHC) staining intensity only (IHC 0-3+). Association between SPARC expression, tumor characteristics and progression-free survival (PFS) and overall survival (OS) was analyzed.

Results: Only Her2 expression was associated with expression of SPARC in stroma (p 0.028, OR 13.9 95% 1.3-145.5) but not in tumor cells. SPARC expression in stroma was associated with shorter PFS (hazard ratio (HR) 2.6; 95% confidence interval (CI) 1.2-5.4; p 0.014), but not in tumor cells and shorter OS (HR 4.1; 95% CI 1.04-16; p 0.041) for SPARC expression in stroma of breast tumor. No clear association between expression of SPARC in tumor cells and outcome could be detected.

Conclusion: Only SPARC expression in stroma might be associated with shorter PFS and OS in patients with PMBC. This finding is in line with the known key role of expression of SPARC in the metastastatic process. Confirmation in prospective clinical trials is warranted.

Citation Format: Barinoff J, Brandi C, Thill M, Heinrichs C, Mensah J, Weikel W, Fisseler-Eckhoff A, Sinn P, Meyer A-S, Traut A, Schneeweiss A. SPARC expression in primary metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-03-05.
Abstract P1-05-04: A novel mechanism of epithelial-mesenchymal transition in breast cancer metastasis: Involvement of prostanoid receptor
Authors: Kwong A , Siu MT , Cheuk I , Ho JC , Chen J , Shin VY
Published: May 2016

Background: Triple-negative breast cancer is associated with higher metastatic rate and poor prognosis than other subtypes of breast cancer due to lack of targeted therapy. Epithelial-mesenchymal transition (EMT) is linked with metastasis with phenotypic conversion of epithelial cells. However, the regulation of EMT in breast cancer metastasis remains largely unstudied. Recent attention has focused on targeting the downstream of COX-2 pathway, understanding the role of prostanoid receptors in breast cancer metastasis may help the development of effective therapeutic interventions for patients with metastasis.

Methods: A stable EP2-expression cell line (MB-231-EP2) was used to study tumorigenesis and distant metastasis in human breast cancer metastatic model. Localization of EP2 and EMT markers were examined by immunostaining and immunofluorescence. Profiles of drug transporters genes were compared between siEP2 and siControl cells. Functional role of EP2 on cell proliferation, invasion and apoptosis were assessed. Alteration of EMT markers were examined by real-time PCR and Western blot analysis.

Results: Expression of EP2 receptor were higher in human primary tumors than non-tumor tissues. EP2 receptor was predominantly expressed in metastatic tumors than primary tumors in human breast cancer metastatic mice model. The metastatic tumors showed a higher Ki67 (cell proliferation) and CD31 (angiogenesis) than primary tumors in the xenograft tissues. Larger tumors and poor survival were seen in MD-231-EP2 bearing mice when compared with control. Silencing of EP2 by siRNA markedly reduced cell proliferation and invasion, but increased apoptosis and expression of solute carrier family 19 member A3 (SLC19A3) gene. Interestingly, SLC19A3 had a lower expression in primary tumors and was inversely correlated with EP2 expression. Ectopic expression of SLC19A3 suppressed cell proliferation and invasion through the restoration of E-cadherin and other EMT markers (Twist, Zeb1 and Snai2). Immunofluorescence staining showed that the localization of Twist and E-cadherin were altered in siEP2 cells.

Conclusion: Our results showed that EP2 promoted EMT and breast cancer metastasis through the downregulation of SLC19A3 expression. Taken together, targeting EP2/SLC19A3 signaling pathway maybe a potential treatment for metastasis and adjuvant chemotherapy to reduce the metastatic risk.

Citation Format: Kwong A, Siu MT, Cheuk I, Ho JC, Chen J, Shin VY. A novel mechanism of epithelial-mesenchymal transition in breast cancer metastasis: Involvement of prostanoid receptor. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-05-04.
Abstract P1-06-02: A force-sensitive organoid assay to quantify regenerative potential of single primary human mammary cells
Authors: Scheel CH , Linnemann JR , Miura H , Meixner LK , Irmler M , Kloos UJ , Hirschi B , Bartsch HS , Sass S , Beckers J , Theis FJ , Gabka C , Sotlar K
Published: May 2016

We have developed an organoid regeneration assay to quantify the ability of freshly isolated, single human mammary epithelial cells to generate complex branched ductal structures with basal and luminal features.

For this purpose, cells are cultured in adherent or floating collagen gels, corresponding to a rigid or compliant matrix. In both conditions, single luminal progenitors form spheres, whereas basal cells generate branched ductal structures. In compliant but not rigid collagen gels, branching ducts in multicellular structures generated by basal cells develop a lumen and alveoli at their tips. Importantly, branched structures generated by single basal cells express basal and luminal markers at correct positions, thereby demonstrating bi-potential. Functionally, basal cells in branched structures display cellular contractility, which we reveal to be required for alveologenesis. In conclusion, branched structures generated by single basal cells in compliant collagen gels resemble terminal ductal-lobular units (TDLU), the functional units of the mammary gland.

To prospectively isolate basal cells with regenerative potential, we added the membrane metallo-endopeptidase CD10 as a cell surface marker to existing sorting protocols, thereby enriching for TDLU-formation and enabling rigorous quantification of regenerative potential by extreme limiting dilution assay (ELDA). Moreover, the use of CD10 as a cell surface marker reveals the presence of stromal cells with endothelial qualities within the CD49fhi/EpCAM– population, previously labeled basal. In summary, we describe a defined in vitro assay system to quantify primary human mammary epithelial cells with regenerative potential and systematically investigate their interaction with the physical environment at distinct steps of morphogenesis.

Citation Format: Scheel CH, Linnemann JR, Miura H, Meixner LK, Irmler M, Kloos UJ, Hirschi B, Bartsch HS, Sass S, Beckers J, Theis FJ, Gabka C, Sotlar K. A force-sensitive organoid assay to quantify regenerative potential of single primary human mammary cells. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-06-02.
Abstract P1-06-08: Stem cell markers CD44+CD24- and ALDH1 in primary breast cancers and metastatic sentinel and non-sentinel lymph nodes
Authors: Kim W , Kim Y-M , Kim W , Lee J-S
Published: May 2016

Background and Aim

Studies of Aldehyde dehydrogenase 1 (ALDH-1) and CD44+/24- have suggested them as cancer stem cell (CSC) markers in breast cancers and the clinicopathologic and prognostic significance of these CSC markers have been widely investigated. However, expressions of CSC in metastatic axillary lymph nodes (ALN) of breast cancers have not yet been the center of interest. Therefore, the object of this study is to explore breast CSC markers CD44+CD24- and ALDH-1 in the primary breast tumor and metastatic ALNs by retrospectively analyzing the CSC expressions on metastatic tumor cells within ALN.

Method

180 surgically resected breast cancers were selected and among them 165 cases had undergone sentinel lymph node (SLN) with or without non-sentinel lymph node (NSLN) dissections. 50 SLNs (30.3%) and 43 NSLNs (30.9%) had metastatic tumor cells and total of 74 cases were involved with axillary lymph node metastasis. Double immunohistochemistry of CD44/CD24 and single immunohistochemical staining of ALDH-1 were applied on paraffin embedded breast tissue specimens and lymph node specimens to evaluate the CSC phenotypes of primary tumor and metastatic lymph nodes.

Results

The prevalence of CD44+/CD24- and ALDH-1(+) tumor cells in primary breast cancer was 76.7% and 45.0%. In triple negative breast cancers (TNBC) contained significantly higher percentage (49.2%) of ALDH-1 positive tumor cells (p=0.001). CD44+/CD24- phenotype was present in 65.2% and 40.0% in metastatic SLNs and NSLNs, respectively. The analysis of metastatic sentinel lymph nodes and breast cancers with CSCs indicated that there are significant relationships with ALDH-1(+) (p<0.001) and CD44+/CD24- (p<0.001) phenotypes. CSC expression in metastatic NSLNs and breast tumors also showed significant association (p=0.001). However, CSCs in metastatic SLNs and NSLNs did not show any significant relationships to the intrinsic molecular subtypes.

Conclusions

This study investigated the impact of the stem/progenitor phenotype defined by CD44 positivity/CD24 negativity and ALDH-1 positivity in sentinel lymph nodes (SLN) on non-sentinel lymph node (NSLN) metastases. CSC phenotypes expressed in metastatic SLNs and NSLNs, independently showed significant association with the primary breast tumors. However, in future, the authors recommend that the exploration of a much larger study including a vast amount of pool will provide a more reliable result.

Citation Format: Kim W, Kim Y-M, Kim W, Lee J-S. Stem cell markers CD44+CD24- and ALDH1 in primary breast cancers and metastatic sentinel and non-sentinel lymph nodes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-06-08.
Abstract P1-07-18: Breast cancer in young patients, twelve years of experience in a single institution
Authors: Morante ZD , Pacheco C , Limón RS , Neciosup S , Gomez HL
Published: May 2016

Breast cancer is very rare in young women and has a more aggressive biological behavior and a worse prognosis than in older premenopausal women. This study was designed to determine and evaluate the features of breast cancer in young patients less than 35 years old at the Instituto Nacional de Enfermedades Neoplásicas, Lima - Perú.

Medical records of 115 patients less than 35 years old with breast cancer, whom were diagnosed and received a kind of treatment, even surgery, chemotherapy, radiotherapy or all of them at the Instituto Nacional de Enfermedades Neoplásicas Lima-Perú, between January 2000 and December 2012, were reviewed.

Triple negative breast cancer (38.3%) is the most common subtype cancer and its presentation is in a lower age compared with the others subtypes (27.1 years vs 28.5 years p: 0.047). The high histological grade was more frequent in triple negative and HER2 subtypes (80% both vs 30% and 48% for luminal A and luminal B p: 0.001). The 2 yr and 5 yr overall survival was 75.0% and 59.3% for luminal A, 71.4% and 55.1% luminal B, 67.7% and 54.9% triple negative, 58.3% and 41.7% HER2 (p: 0.434). The 2 yr progression free survival was 81.6%, 72.6%, 61.5% and 59.4% for each group respectively (p: 0.522).

As conclusion, the breast cancer in 35 yr old or less women is uncommon; the triple negative subtype is more common, also in relation with high histological grade and in lower age. The overall survival and the progression free survival are worse in patients with lower age.

Citation Format: Morante ZD, Pacheco C, Limón RS, Neciosup S, Gomez HL. Breast cancer in young patients, twelve years of experience in a single institution. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-18.
Abstract P1-07-22: Infectious disease hospitalization in breast cancer patients: Risk and impact on prognosis
Authors: Brand JS , Colzani E , Johansson A , Giesecke J , Clements M , Bergh J , Hall P , Czene K
Published: May 2016

Background: Infection-related hospitalizations are a serious complication in breast cancer patients, resulting in treatment delay, prolonged hospitalization and future morbidity and mortality. Little, however, is known about the actual risk, clinical characteristics and outcomes of infection-related hospitalizations in this patient population.

Methods: We conducted a prospective population-based study including 7071 women diagnosed with primary invasive non-metastatic breast cancer between 2001 and 2008 in the Stockholm-Gotland region (Sweden), with complete follow-up until 2010. Standardized incidence ratios (SIRs) for infection-related hospitalizations (overall and by site) were estimated using background rates from the general female population, matched on age and calendar period. Associations with clinical characteristics and breast cancer outcomes (breast cancer death, distant metastasis and locoregional recurrence) were analysed using flexible parametric survival models.

Results: During a medium follow-up of 5.3 years, 657 hospital admissions with infections were observed and 1,2 and 5-year cumulative risks were 3.4, 4.7 and 8.1% respectively. Rates of infection-related hospitalizations were increased compared to the general female population (SIR = 2.12; 95% CI = 1.96-2.29) and site-specific SIRs were most pronounced for sepsis (SIR = 3.65; 95% CI = 3.13-4.26) and skin infections (SIR = 2.93; 95% CI = 2.35-3.64). The overall risk of infections was highest during the first year (SIR = 5.06; 95% CI, 4.46-5.74), and recurrent disease contributed to the long-term risk observed. Older age at diagnosis, chemotherapy, axillary radiotherapy, comorbidities and markers of tumor aggressiveness (large tumors, estrogen receptor negative tumors and lymph node positive tumors) were independent predictors of infectious disease risk. Analyses evaluating the prognostic impact of infections revealed an independent effect on breast cancer death and distant metastasis, associations that were mainly driven by sepsis (HR = 4.53; 95% CI, 3.25-6.33 and 1.69; 95% CI, 1.04-2.79 respectively). No association was found with future risk of locoregional recurrence.

Conclusions: Physicians and patients should be aware of the risk of serious infections which persists beyond the initial treatment period. Infection-related hospitalizations are an independent marker of poor prognosis. Further research is needed to elucidate the role of sepsis in breast cancer progression.

Citation Format: Brand JS, Colzani E, Johansson A, Giesecke J, Clements M, Bergh J, Hall P, Czene K. Infectious disease hospitalization in breast cancer patients: Risk and impact on prognosis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-22.
Abstract P1-07-26: Marital status and overall mortality in breast cancer patients: Differences by socioeconomic status and race/ethnicity
Authors: Martinez ME , Anderson K , Schwab R , Hurley S , Canchola AJ , Keegan THM , Cheng I , Clarke C , Glaser S , Gomez SL
Published: May 2016

Background: Results of several studies show that married cancer patients have lower mortality than unmarried patients. However, data on differences by race/ethnicity are lacking. We assessed the risk of overall mortality associated with marital status among patients with breast cancer according to neighborhood socioeconomic status (SES) and race/ethnicity.

Methods: We used data from the population-based California Cancer Registry to include breast cancer cases diagnosed between 2000 and 2009 with follow-up through December 31, 2012 and identified 175,154 women with invasive breast cancer. We estimated hazard rate ratios (HR) and 95% confidence intervals (CI) for overall mortality by neighborhood SES and race/ethnicity.

Results: Among all cases, 42.6% were unmarried at the time of diagnosis. In adjusted models, the HR for all-cause mortality (95% CI) for unmarried compared to married women was 1.20 (1.17-1.22). There was no significant difference by SES. However, significant variation was observed by race/ethnicity. The HRs (95% CI) were 1.23 (1.20-1.26), 1.20 (1.11-1.30), 1.12 (1.04-1.21), and 1.05 (0.99-1.11) for NH Whites, NH Asians/Pacific Islanders (API), NH Blacks, and Hispanics, respectively. Among API subgroups, Chinese (HR=1.35; 95% CI, 1.12-1.62) and Filipinas (HR=1.25; 95% CI, 1.09-1.44) were the only groups with significantly higher risk of total mortality associated with unmarried status.

Conclusions: Our results show that not being married at the time of breast cancer diagnosis is associated with worse overall survival compared to being married. Significant variation in risk of mortality was shown by race/ethnicity but not by neighborhood SES. Targeted, culturally-appropriate interventions to support unmarried breast cancer patients through their cancer treatment and survivorship need to be developed to improve their survival.

Citation Format: Martinez ME, Anderson K, Schwab R, Hurley S, Canchola AJ, Keegan THM, Cheng I, Clarke C, Glaser S, Gomez SL. Marital status and overall mortality in breast cancer patients: Differences by socioeconomic status and race/ethnicity. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-26.
Abstract P1-08-04: Sources of polycyclic aromatic hydrocarbons associated with gene-specific promoter methylation in women with breast cancer
Authors: White AJ , Chen J , McCullough LE , Xu X , Cho YH , Conway K , Beyea J , Stellman SD , Steck SE , Mordukhovich I , Eng SM , Terry MB , Engel LS , Hatch M , Neugut AI , Hibshoosh H , Santella RM , Gammon MD
Published: May 2016

Tobacco smoke, diet, and indoor and outdoor air pollution, all major sources of polycyclic aromatic hydrocarbons (PAHs), have been associated with breast cancer incidence. Aberrant methylation may be an early event in carcinogenesis, but whether PAHs influence the epigenome is unclear. Few studies have evaluated whether PAHs are associated with methylation, particularly in breast tumors where methylation changes are particularly relevant. In a population-based case-control study, we measured promoter methylation of 13 breast cancer-related genes in breast tumor tissue (n=765-851 cases) and global methylation in peripheral blood (1,055 cases/1,101 controls). PAH sources (current active smoking, residential environmental tobacco smoke (ETS), vehicular traffic, synthetic log burning, and grilled/smoked meat intake) were evaluated separately. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). When comparing methylated versus unmethylated genes, synthetic log use was associated with increased ORs for CDH1 (OR=2.28, 95%CI=1.07-4.83), HIN1 (OR=2.11, 95%CI=1.32-3.38) and RARβ methylation (OR=1.82, 95%CI=1.18-2.83) and decreased ORs for BRCA1 methylation (OR=0.44, 95%CI=0.30-0.65). Residential ETS was associated with decreased ORs for ESR1 (OR=0.74, 95%CI=0.56-0.99) and CCND2 methylation (OR=0.65, 95%CI=0.44-0.96). Current smoking and vehicular traffic were associated with decreased ORs for DAPK (OR=0.53, 95%CI=0.28-0.99) and increased ORs for TWIST1 methylation (OR=2.79, 95%CI=1.24-6.30), respectively. In controls, synthetic log use was inversely associated with LINE-1 methylation (OR=0.60, 95%CI=0.42-0.87). PAH sources were associated with hypo- and hypermethylation at multiple promoter regions in breast tumors and LINE-1 hypomethylation in blood of controls. Methylation may be a potential biologic mechanism for the association between PAHs and breast cancer incidence.

Citation Format: White AJ, Chen J, McCullough LE, Xu X, Cho YH, Conway K, Beyea J, Stellman SD, Steck SE, Mordukhovich I, Eng SM, Terry MB, Engel LS, Hatch M, Neugut AI, Hibshoosh H, Santella RM, Gammon MD. Sources of polycyclic aromatic hydrocarbons associated with gene-specific promoter methylation in women with breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-04.
Abstract P1-08-07: Predisposing germline mutations in a clinic based breast cancer (BC) population
Authors: Garber JE , Tung NM , Elkin EP , Allen BA , Singh NU , Wenstrup R , Hartman A-R , Winer EP , Lin NU
Published: May 2016

Background: Evaluation of women with BC for germline mutations associated with hereditary breast and ovarian cancer (HBOC) has become increasingly common due to its impact on management. Guidelines for genetic evaluation indicate testing for cases with early onset, triple negative disease or family cancer history. However, the majority of breast cancer occurs in patients without these high risk characteristics. The prevalence of mutations associated with HBOC has not been well characterized in this population.

Methods: We performed a cross sectional study using DNA from blood samples from consecutive new invasive BC patients seen at the Dana-Farber Cancer Institute (01/01/2010 to 07/31/2102) who consented to research. Subjects were otherwise unselected. Mutations in 25 cancer genes were identified using a next generation sequencing based panel. Germline sequence variations and large rearrangements were classified for pathogenicity.

Results: 456 samples from eligible subjects were included. The mean age of BC diagnosis was 50 years. Mutations were found in 51 women, 49 of which were associated with breast cancer (10.8%, 95% CI 8.1-14.0). BRCA1/2 mutations were found in 6.6% [95% CI 4.5-9.2%] while mutations in other BC-associated genes were found in 4.4% [95% CI 2.7-6.7%], particularly CHEK2 (2.2%, 95% CI 1.1, 4.0). Of the 49 women with BC-related mutations, 21 (43%) had BC diagnosed after age 45. In univariate analyses, age at diagnosis, Ashkenazi Jewish ancestry, triple negative histology and family BC/ovarian cancer (OC) history were associated with BRCA1/2 mutations, but no factors were significantly associated with mutations in other genes. Among 261 women with no FDR/SDR with BC/OC, 26 (10.0%) had a mutation. Nineteen mutations (10 BRCA1/2) were found in the 256 women (7.4%) who had not had previous genetic testing.

Conclusions: In a single academic institution, 11% of new breast cancer patients had a germline mutation in a breast cancer predisposition gene: 6.6% were in BRCA1/2. The elevated prevalence compared to population-based series may reflect the practice composition of academic centers, which often attract women younger at BC diagnosis. In an academic practice with an active cancer genetics program, 10 women with BRCA1/2 and 9 with other mutations had not had genetic testing. Expanded testing identifies additional predisposing mutations, the utility of which are being defined for the care of breast cancer patients and their families.

Citation Format: Garber JE, Tung NM, Elkin EP, Allen BA, Singh NU, Wenstrup R, Hartman A-R, Winer EP, Lin NU. Predisposing germline mutations in a clinic based breast cancer (BC) population. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-07.
Abstract P1-09-02: Higher incidence of second cancers in African American (AA) patients compared to Caucasian patients with a primary breast cancer
Authors: Diab N , Clark G , Hamlington B , Brzeskiewicz L , Langer L , Diab S
Published: May 2016

Background: AA women with breast cancer have lower survival rates compared to Caucasian women. Since this lower survival rate may be related to genetic mutations, and environmental/socioeconomically factors, we hypothesize that the same factors may lead to a higher risk of secondary cancers after an initial diagnosis of breast cancer.

Method: Analysis of the Surveillance, Epidemiology, and End Results (SEER) Program data using Multiple Primary - Standardized Incidence Ratio parameters. The incidence of second cancer diagnoses in AA and Caucasian women previously diagnosed with breast was compared to the incidence of cancer in the general population matched by age, race, and year of diagnosis. Results are reported as the observed risk divided by the expected risk (O/E).

Results: For the 43,688 AA pts, the overall O/E and excess risks were 1.48 and 51.2 compared to 1.11 and 14.7 for the 428,103 Caucasian patients. The mean ages of diagnoses of initial breast cancer diagnosis and second cancer were 57.2 and 65 years for AA patients compared to 61.8 and 70.2 years for Caucasian patients. The following is a summary of statically significant (p <0.05) selected O/E by the site of second cancer :

O/E for AA and white by site of second cancerSiteAAWhiteOral Cavity and Pharynx1.651.41Digestive System1.181Respiratory System1.271.13Skin excluding Basal and Squamous1.931.33Breast1.671.18Female Genital System1.110.95Urinary System1.561.18Endocrine System1.521.38All Lymphatic and Hematopoietic Diseases1.261.05

This higher risk of second cancers occurred despite the lower relative survival rate for AA compared to Caucasian patients with a 5-year relative survival rate of 68.6% for AA and 78.3% for Caucasian patients.

Conclusions: To our knowledge, this is the first report of the incidence of second cancers in AA patients with breast cancer compared to caucasian. More research to understand the biological, genetic, therapeutic, and environmental factors leading to this higher risk of second cancers is warranted.

Citation Format: Diab N, Clark G, Hamlington B, Brzeskiewicz L, Langer L, Diab S. Higher incidence of second cancers in African American (AA) patients compared to Caucasian patients with a primary breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-09-02.
Abstract P1-09-03: Socioeconomic characteristics of African American women with breast cancer
Authors: Winter A , Raska P , Ornstein M , Moore H , Montero A , Budd GT , Tullio K , Bailey J , Abraham J
Published: May 2016

Background: Breast cancer is the most common cancer among African American (AA) women. Despite having a lower incidence of breast cancer compared to white women (124.4 compared to 127.9 per 100,000), AAs have a higher death rate (30.2 compared to 21.3 per 100,000). One explanation for this discrepancy is that breast cancer in AAs is often detected at a later stage compared to white women. We conducted this retrospective study to examine socioeconomic characteristics among AA women with breast cancer to see if there were factors associated with stage of diagnosis which may contribute to the known disparities. Methods: We identified all AA women diagnosed with any stage breast cancer from 2006-2014 within the Cleveland Clinic Cancer Data Warehouse and classified them into either early or late stage disease at time of diagnosis. Stages 0-II were classified as early and stages III-IV as late. We examined several variables at diagnosis including age, marital status, tobacco use, alcohol use, Medicaid insurance status, and breast cancer subtype which included HER-2 positive (HER+), hormone receptor positive/HER2 negative (HR+/HER-), and triple negative(TN). AA median income was obtained from US census data according to the zip code at diagnosis. We conducted univariate logistic regression for individual estimates and confidence intervals and multiple logistic regression and model selection to determine significant predictors of stage of diagnosis. Results: Of the 771 AA women identified, 108 (14%) were diagnosed at a late stage of disease with a median age of 59 years. Receptor status distribution was 12.4%, 31%, and 16.6% for HER+, HR+/HER-, and TN respectively for early stage, and 15.7%, 27%, and 25% for late stage. Among early stage 50% were current or previous smokers and 2.6% had Medicaid insurance compared to late stage patients where 63% were current or previous smokers and 9.2% had Medicaid insurance. Multiplicative effect estimates and 95% confidence intervals from univariate logistic regressions identified the following significant factors: tobacco use 1.48 [1.11-1.96] and Medicaid 3.73 [1.56-8.51] (p-values<0.01), and TNBC 1.67 [1.02-2.68] (p-value<0.05). In a stepwise model selection, only tobacco use and Medicaid were retained in the model, as well as age at diagnosis. Conclusions: There are socioeconomic differences among AA women with breast cancer. Only tobacco use, Medicaid insurance, and age at diagnosis were predictive of late stage in this study.

Citation Format: Winter A, Raska P, Ornstein M, Moore H, Montero A, Budd GT, Tullio K, Bailey J, Abraham J. Socioeconomic characteristics of African American women with breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-09-03.
Abstract P1-10-23: Bladder symptoms in women with newly diagnosed breast cancer
Authors: Wong L , Chung C , Flores S , Mortimer J
Published: May 2016

Background: Changes in bladder function are recognized effects of aging and menopause but have not generally been reported in women treated for breast cancer. We initiated a prospective trial to assess the impact of (neo) adjuvant therapy on women with early stage breast cancer.

Methods: Women with newly diagnosed invasive breast cancer who were to initiate (neo) adjuvant chemotherapy or endocrine therapy were approached for study participation. At baseline a urinalysis, urine culture, and self assessment quality of life questionnaires were completed. The Urogenital Distress Inventory (UDI-6) assesses bladder symptoms and the Incontinence Impact Questionnaire (IIQ-7) assesses the impact of bladder symptoms on quality of life. Three months after initiation of (neo)adjuvant therapy, the quality of life questionnaires were repeated. We report the results of the pretreatment questionnaires.

Results: Between February and June, 2015, forty-nine women with newly diagnosed breast cancer were enrolled on study. The median age was 54 (Range 25-78); 21 were premenopausal and 28 postmenopausal. Twenty nine (59%) were treated in the adjuvant setting; 12 with chemotherapy and 17 with endocrine therapy. Twenty patients, (41%) were treated in the neoadjuvant setting with chemotherapy. Prior to initiation of therapy, " Frequent urination" was reported in 38 (65%), " Leakage related to urgency" in 5 ( 10%), " Leakage with physical activity" in 32 (55%) and "Small amounts of leakage" in 32 (55%). Bladder symptoms impacted the ability to perform household chores in 8 (16%), Physical recreation in 10 (20%), social activities in 9 (18%), and Emotional health in 5 (10%).

Conclusions: Symptoms of bladder dysfunction are common in women with newly diagnosed breast cancer even before therapy is initiated.

Citation Format: Wong L, Chung C, Flores S, Mortimer J. Bladder symptoms in women with newly diagnosed breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-23.
Abstract P1-11-03: Patient reporting pain intensity immediately after surgery can be associated with underlying depression in women with breast cancer
Authors: Kim YS , Lee JW , Kim J , Lee SB , Yu J , Ko BS , Kim HJ , Son BH , Ahn SH
Published: May 2016

Objective

The aims of this study were to determine the prevalence of severe, definite depression symptoms, as measured using the Center for Epidemiological Studies Depression Scale (CES-D), and the association between high CES-D scores (i.e., ≥25) and sociodemographic and perioperative factors during perioperative period.

Methods

Among 1690 consecutive breast cancer patients who were admitted for definitive breast surgery during the study period, 1499 patients were included in this study. Patients with a past medical history of psychiatric medication or support, a plan for elective surgery due to locoregional recurrence or any metastatic disease were excluded. The CES-D score was checked 1 day before definitive surgeries. The sociodemographic data and perioperative data were analyzed.

Results

The mean CES-D score was 18.5, with 24.1% (362/1499) and 56.7% (850/1499) having high CES-D scores of ≥25 and ≥16, respectively. Multivariate analysis revealed that the number of family members with any malignancy (≥2 vs 0), sedative medication (yes vs no) and postoperative numeric rating scale (NRS) scores (persistent, severe pain vs stably mild pain) were significant associated factors for severe, definite depression symptoms [CES-D score of ≥25: adjusted odds ratio (OR)=1.56, 95% confidence interval (CI)=1.10–2.21, P=0.013; adjusted OR=1.65, 95% CI=1.00–2.71, P=0.048; and adjusted OR=2.14, 95% CI=1.15–3.95, P=0.016, respectively].

Conclusion

Depression may increase the intensity of postoperative acute pain. Self-reporting of persistent postoperative pain intensity is potentially useful in detecting hidden depression symptoms in breast cancer patients during the perioperative period.

Citation Format: Kim YS, Lee JW, Kim J, Lee SB, Yu J, Ko BS, Kim HJ, Son BH, Ahn SH. Patient reporting pain intensity immediately after surgery can be associated with underlying depression in women with breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-11-03.
Abstract P1-12-07: Delayed initiation of adjuvant chemotherapy among breast cancer patients: A population-based study
Authors: Chavez-MacGregor M , Clark CA , Lichetensztajn DY , Giordano SH
Published: May 2016

BACKGROUND: Adjuvant chemotherapy improves outcomes of breast cancer patients; however the optimal timing to initiation of chemotherapy remains unknown. No study has evaluated the relationship between time to chemotherapy (TTC) and outcome in a population-based study of patients treated with contemporary regimens according to tumor subtype. In this large study we identified the determinants associated with a delay in the initiation of chemotherapy and determined whether TTC is related to outcome.

METHODS: Breast cancer patients diagnosed with stage I-III breast cancer between 2005-2010 and treated with adjuvant chemotherapy were identified in the California Cancer Registry. TTC was defined as number of days between surgery and the day the first dose of adjuvant chemotherapy was administered. Delayed TTC was defined as >91 days. Logistic regression and Cox-proportional hazard modeling were used.

RESULTS: A total of 24,843 patients were included. Factors associated with delays in TTC included low socioeconomic status, reconstructive surgical procedure, non-private insurance and Hispanic or non-Hispanic black race/ethnicity. Compared to patients receiving chemotherapy within 31 days from surgery, there was no evidence of adverse outcome among those with TTC of 31-60 or 60-90 days. To the contrary, patients treated >91 days from surgery experienced statistically significant worse overall survival (OS) (HR=1.34; 95%CI 1.15-1.57) and worse breast cancer specific survival (BCSS) (HR=1.27; 95%CI 1.05-1.53). In a subgroup analysis according to breast cancer subtype, TTC >91 days had a statistically significant detrimental impact among patients with triple negative breast cancer (TNBC) in terms of both OS (HR=1.53; 95%CI 1.17-2.00) and BCSS (HR=1.53; 95%CI 1.17-2.07).

CONCLUSIONS: In this large cohort of breast cancer patients treated with contemporary regimens, a delaying in the initiation of adjuvant chemotherapy >91 days was associated with adverse outcomes. A delay in TTC is particularly detrimental among patients with TNBC. The majority of the determinants of delays in chemotherapy initiation are socio-demographic in nature. As medical providers we must make every effort to provide timely care to all our patients so they can receive the full benefit of our current treatments.

Citation Format: Chavez-MacGregor M, Clark CA, Lichetensztajn DY, Giordano SH. Delayed initiation of adjuvant chemotherapy among breast cancer patients: A population-based study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-12-07.
Abstract P1-12-09: The oncologic effect of a gonadotropin releasing hormone (GnRH) agonist for ovarian protection during breast cancer chemotherapy
Authors: Kim HJ , Lee MH , Lee JE , Park SH , Lee ES , Kang Y-J , Lee JH , Shin HN , Kim SI , Im SA , Ahn SH , Lee KS , Sohn J , Han W , Nam SJ
Published: May 2016

Background: Recently, chemotherapy with a GnRH agonist was reported to protect against ovarian failure. This study was aimed at determining the oncologic effect of a GnRH agonist concurrent with chemotherapy for breast cancer patients.

Patients and Methods: A total of 1189 patients aged 20 to 40 years with stage I to III breast cancer who received (neo or adjuvant) chemotherapy from five hospitals in Korea from 2002 to 2012 were reviewed. A gonadotropin releasing hormone (GnRH) agonist was given to 410 patients for ovarian protection during chemotherapy (GnRH agonist group), and 779 patients received chemotherapy without ovarian protection (Chemotherapy alone group). A matching strategy was used to create matched sets of two groups by age, stage, hormone receptor status, Her2/neu status, neo or adjuvant chemotherapy, and institute.

Results: Survival analysis using Cox regression showed that the GnRH agonist group had better distant metastatic-free survival (HR=0.65, 95%CI 0.44-0.97) outcomes but similar disease free survival (HR=0.78, 95% CI 0.57-1.08) compared with the chemotherapy alone group. The survival benefit was significant for hormone receptor positive, Her2/neu negative breast cancer on distant metastasis (HR=0.44, 95% CI 0.20-0.99) and disease free survival (HR0.47 95% CI 0.23-0.93).

Conclusion: Ovarian protection using a GnRH agonist can be safely considered for premenopausal breast cancer patients for whom chemotherapy is planned.

Citation Format: Kim HJ, Lee MH, Lee JE, Park SH, Lee ES, Kang Y-J, Lee JH, Shin HN, Kim SI, Im SA, Ahn SH, Lee KS, Sohn J, Han W, Nam SJ. The oncologic effect of a gonadotropin releasing hormone (GnRH) agonist for ovarian protection during breast cancer chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-12-09.