bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P4-10-02: Cancer team approach for implementing survivorship care plans in the breast cancer survivorship clinic
Authors: Danciu OC , Bharadwaj SN , Hoskins K
Published: May 2016

Background: Recommendations from the Institute of Medicine are that cancer patients receive individualized survivorship care plan (SCP) and treatment summary. SCP includes guidelines for monitoring and maintaining health and is a communication tool shared with families and health care providers. Offering SCP and treatment summary to cancer survivors remains challenging due to time and resource limitations, inadequate reimbursement and survivor access.

Methods: Survivorship starts when completing the initial treatment (surgery, chemotherapy or radiation therapy). A team of medical oncologists, nurse practitioner and patient navigator created a process of pre-screening and identifying breast cancer (BC) survivors. SCP and treatment summary were pre-populated, individualized for each patient, then finalized and discussed with the patients during their medical oncology clinic visit. Pre intervention data was retrospectively collected, including all BC cases from March 2014 to March 2015. Post intervention data was prospectively collected over eight weeks. Pre and post intervention SCP completion rates were compared with chi square analysis.

Results: A baseline one year review of 1124 encounters noted 23 of 90 (25%) BC survivors received SCP. Ninety-six encounters occurred during the 8 week pilot period. Sixteen (16.6%) cases met the definition of BC survivor. During the pilot period, 15 out of 16 (93.7%) survivors received the SCP and treatment summary (p <0.0001). After the pilot period, 96.4% of BC survivors were seen in the BC survivorship clinic.

Conclusions: We successfully piloted the implementation of SCP for BC survivors. Our team found that using clinic visit screening and pre-identifying patients that transition into the survivorship program resulted in improvement of compliance with survivorship measures. In BC survivorship clinic we address specific survivorship issues and review SCP and treatment summary.

Citation Format: Danciu OC, Bharadwaj SN, Hoskins K. Cancer team approach for implementing survivorship care plans in the breast cancer survivorship clinic. [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 P4-10-02.
Abstract P5-01-10: Correlation of apparent diffusion coefficient with standardized uptake value in invasive lobular carcinoma of breast using in hybrid 18F-FDG PET/MR
Authors: Choi JE , Kang SH , Lee SJ , Kong EJ
Published: May 2016

Purpose: To compare the apparent diffusion coefficient (ADC) with maximum standardized uptake values (SUV) derived from combined 18F-FDG PET/MRI in invasive lobular carcinoma (ILC) patients.

Methods: From 2012 Aug to 2015 Feb, 53 women with histologically proven ILC (mean age, 50.3 ± 7.7 y-o) underwent hybrid 18F-FDG PET/MR (Siemens Biograph mMR) scan for preoperative assessment. During PET acquisition, simultaneous diffusion-weighted imaging (DWI, b values: 0, 400, 800 s/mm2) was performed using breast coil. ILC over than 2 Cm in size were analyzed. Regions of interest (ROI) were drawn covering the entire ILC on the attenuation-corrected PET-image and the monoexponential ADC-map on PET/MR workstation. All the patients were received surgical treatment within 3 weeks after scan. Spearman rank correlation coefficient (ρ) was calculated to examine the correlation between SUVmax and ADC value.

Results: Total 25 ILC (5.4±1.3 cm; 2.1-6.3 cm) of 22 women were enrolled. 24 ILC showed ER (+)/PR (+) and all ILC showed HER2 (-). 15 patients were confirmed metastatic axillary lymph nodes. The mean of SUVmax was 2.14 ± 2.2 (0.91-11.9) and mean of ADC was 1.02 ×10-3 (0.82 -1.31 ×10-3) mm2/s. Higher histologic grade was correlated with higher SUV (ρ = -0.6, p=0.001). And SUV showed inverse correlation with ADC (ρ = -0.48, p=0.016).

Conclusion: The present data show inverse correlation between increased glucose-metabolism and cellularity in ILC patients. 18F-FDG PET and DWI thus may offer complementary information for the evaluation of treatment response in ILC.

Citation Format: Choi JE, Kang SH, Lee SJ, Kong EJ. Correlation of apparent diffusion coefficient with standardized uptake value in invasive lobular carcinoma of breast using in hybrid 18F-FDG PET/MR. [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 P5-01-10.
Abstract P5-02-04: Plasma autoantibodies associated with basal-like breast cancers
Authors: Wang (Student) J , Figueroa JD , Wallstrom G , Barker K , Park JG , Demirkan G , Lissowska J , Anderson K , Qiu J , LaBaer J
Published: May 2016

Background: Basal-like breast cancer (BLBC) is a rare aggressive subtype that is less likely to be detected through mammographic screening. Identification of circulating markers associated with BLBC could have promise in detecting and managing this deadly disease.

Methods: Using samples from the Polish Breast Cancer study, a high-quality population-based case-control study of breast cancer, we screened 10,000 antigens on protein arrays using 45 BLBC patients and 45 controls, and identified 748 promising plasma autoantibodies (AAbs) associated with BLBC. ELISA assays of promising markers were performed on a total of 145 BLBC cases and 145 age-matched controls. Sensitivities at 98% specificity were calculated and a BLBC classifier was constructed.

Results: We identified a 13-AAbs (CTAG1B, CTAG2, TP53, RNF216, PPHLN1, PIP4K2C, ZBTB16, TAS2R8, WBP2NL, DOK2, PSRC1, MN1, TRIM21) that distinguished BLBC from controls with 33% sensitivity and 98% specificity. We also discovered a strong association of TP53 AAb with its protein expression (p=0.009) in BLBC patients. In addition, MN1 and TP53 AAbs were associated with worse survival (MN1 AAb marker HR=2.25 95%CI= 1.03-4.91 p=0.04; TP53, HR=2.02, 95%CI 1.06-3.85, p=0.03). We found limited evidence that AAb levels differed by demographic characteristics.

Conclusions: These AAbs warrant further investigation in clinical studies to determine their value for further understanding the biology of BLBC and possible detection. Currently, they are also being tested in a large national blind validation trial using a well characterized independent sample set.

Citation Format: Wang (Student) J, Figueroa JD, Wallstrom G, Barker K, Park JG, Demirkan G, Lissowska J, Anderson K, Qiu J, LaBaer J. Plasma autoantibodies associated with basal-like breast cancers. [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 P5-02-04.
Abstract P5-02-07: Effect of multidisciplinary case conferences on physician decision making: Breast diagnostic rounds
Authors: Foster T , Bouchard-Fortier A , Olivotto I , Quan ML
Published: May 2016

Background: Participation in multidisciplinary case conferences (MCCs) continues to be highly variable, in spite of proven benefits. One contention is the lack of perceived utility on patient management.

Purpose: To evaluate the utility of MCCs on physician decision making in benign and malignant breast disease management.

Methods: At the Foothills Medical Centre, diagnostic breast MCCs occur biweekly. Patients with interesting or challenging diagnostic or management issues were discussed by attending surgeons, radiologists, pathologists, nurse coordinators and oncologists. Prior to case discussion, the presenting physician was asked to specify his/her management plan. Their response was recorded and compared to the management plan consensus after the MCC discussion. For each case a clinical summary and question was provided by the presenting physician, followed by a review of diagnostic images and/or pathology. After group discussion, a management consensus was achieved and documented. A management change was defined as a difference compared to the pre-MCC plan or if there was no definite management plan prior to MCC.

Results: From November 5th, 2014 to May 6th, 2015, 52 patients were discussed in 11 MCCs (1 to 8 patients per MCC). No MCCs were cancelled due to insufficient patients. Of these, 23 (44%) had a change in the management plan compared to the pre-MCC intent including 7 cases where there was no clear plan prior to MCC. Among the 23 cases with a management change, 12 (52%) were due to new or clarified information from radiology review, 6 (26%) were due to new or clarified details from pathology review and 5 (22%) changes occurred from both radiology and pathology review. All cases presented resulted in a consensus management recommendation.

Conclusion: The MCCs had a substantial impact on physician decision making. Nearly half of cases presented resulted in a change in clinical recommendation, the majority of which were based on new/clarified diagnostic imaging or pathology information. Presentation of cases at MCCs should be encouraged given their clinical impact on patient care, especially for challenging diagnostic or management issues.

Citation Format: Foster T, Bouchard-Fortier A, Olivotto I, Quan ML. Effect of multidisciplinary case conferences on physician decision making: Breast diagnostic rounds. [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 P5-02-07.
Abstract P5-03-05: Genomic analysis and efficacy of entinostat in basal-like and HER2-overexpressing models
Authors: Tanioka M , Usary J , Darr DB , Harrell CJ , Perou CM
Published: May 2016

Background. The histone deacetylase inhibitor Entinostat has been under development for patients with metastatic estrogen receptor-positive breast cancer, and its use in Basal-like and HER2-overexpressing breast cancer has been limited. Here we provide results of a study using cell-lines and genetically engineered mouse (GEM) models of breast cancer to examine the effects of Entinostat and combination therapies on multiple in vitro and in vivo models.

Methods. Breast cancer cell lines SKBR3, BT474 and MCF-7 were treated with or without Entinostat at their IC50 doses and their gene expression profiles determined. Two breast cancer GEM models (MMTV-neu and C3-Tag) were used to test the efficacy of Entinostat alone, or in combination with cyclophosphamide, or a murine version of an anti-mouse PD1 immune checkpoint inhibitor.

Results: Entinostat was an effective in vitro drug with IC50 ranging from 700 to 1500 nM. Supervised analysis of gene expression data coming from treated cell lines showed induction of multiple major histocompatibility complex (MHC) class I/II genes on 6p21. In addition, several MHC genes were also upregulated in C3-Tag treated by Entinostat; because of these findings, the GEM models are currently being treated with the combination of Entinostat and the anti-mouse PD-1 inhibitor. In vivo, GEM tumors treated only with Entinostat were observed to have high objective response rates of 88% and 33% in MMTV-Neu and C3-Tag, respectively. The combination with cyclophosphamide provided significant improvements in the C3-Tag mice over either agent alone, with 11 of 17 mice achieving a CR or PR, and an extension of overall survival (98 days vs 33 days); Entinostat (42d, p=0.002) and Cytoxan (47d, p=0.001).

Conclusions. Entinostat showed anti-tumor activity in vitro and in vivo, and was synergistic with cyclophosphamide in the Basal-like C3-Tag mouse model. The upregulation of MHC genes induced by Entinostat at RNA level suggested the interaction with immune response, which is currently under study and will be presented.

Citation Format: Tanioka M, Usary J, Darr DB, Harrell CJ, Perou CM. Genomic analysis and efficacy of entinostat in basal-like and HER2-overexpressing models. [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 P5-03-05.
Abstract P5-03-12: Selenocystine inhibits triple-negative breast cancer cell proliferation by inducing cell apoptosis and S-phase arrest
Authors: Long M , Qiu W , Wu J , Liu R , Su H
Published: May 2016

Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited effective treatment options. New therapeutic approaches are urgently needed to improve the prognosis of TNBC. Reactive oxygen species (ROS) are inherent byproducts of oxidative metabolism, and forced stimulation of glucose oxidation in cancer cells raises oxidative stress and sensitizes cells to different stresses. Therefore, targeting the antioxidant capacity of cancer cells has become a promising anticancer strategy. As a redox modulator, selenocystine (SeC) has received a great deal of attention and has been shown effective against human melanoma, hormone receptor-positive breast cancer, and cancers of liver, lung and cervical in vitro. However, whether SeC exerts an anticancer effect on TNBC cells has never been explored.

Methods: The dose-response effects and time course of effects of SeC on three different TNBC cell lines, MDA-MB-231, MDA-MB-436 and MDA-MB-468, were investigated in this study. Cellular viability was determined by the CCK-8 assay and cell morphology were recorded under a light microscope. Cellular apoptosis was detected using Annexin V/PI staining assay and cell cycle distribution was analyzed by flow cytometry.

Results: SeC induced cell growth inhibition in all three TNBC cell lines. For 24, 48 and 72 hours of SeC treatments, the IC50 values were 40.8, 12.8 and 9.2 μM for MDA-MB-231 cells; 14.6, 5.4 and 3.0 μM for MDA-MB-436 cells; and 69.6, 29.3 and 19.9 μM for MDA-MB-468 cells. The changes of cellular morphology of TNBC cells in response to SeC treatment were similar to those cells undergoing apoptotic pathway. This result was confirmed by Annexin V/PI staining assays (Table 1). Cell cycle analysis further revealed that SeC also induced S-phase arrest in a dose-dependent manner (Table 2).

Conclusion: In summary, SeC inhibited TNBC cell viability in a dose- and time-dependent manner which was attributed to the induction of apoptosis and S-phase arrest. Our finding indicates that SeC is a potential therapeutic agent for TNBC.

Table 1. Apoptotic rate of TNBC cells after SeC treatment.Conc.(μM)MDA-MB-231MDA-MB-436MDA-MB-46805.8 %18.1 %26.7 %1025.5 %45.8 %60.7 %2040.1 %67.1 %70.9 %4054.7 %70.7 %74.5 %

Table 2. SeC induces S-phase arrest in TNBC cells in a dose-dependent manner. Conc.(μM)G0/G1 (%)S (%)G2/M (%)MDA-MB-231016.655.927.5 1050.139.310.6 2045.548.16.4 4041.753.05.3MDA-MB-436042.127.630.3 1036.335.028.7 2034.340.725.0 4032.445.422.2MDA-MB-468059.123.717.2 1054.929.315.8 2050.135.714.2 4043.843.113.1

Citation Format: Long M, Qiu W, Wu J, Liu R, Su H. Selenocystine inhibits triple-negative breast cancer cell proliferation by inducing cell apoptosis and S-phase arrest. [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 P5-03-12.
Abstract P5-04-06: Analysis of STEAP1 expression as a therapeutic target in breast cancer
Authors: Aft R , Mudalagiriyappa C , Pillai S , Watson M
Published: May 2016

Objective: The six transmembrane epithelial antigen of the prostate (STEAP1) is predominantly overexpressed in human prostate cancer. STEAP1 was first identified as a prostate-specific cell-surface antigen and found to be up-regulated in various cancers including lung, bladder, colon, and ovarian with little expression in normal tissue. An anti-STEAP1 monoclonal antibody linked to an antimitotic agent is currently in Phase I clinical trials for prostate cancer patients. Microarray data from our lab suggested that STEAP1 is also highly expressed in human breast cancers and bone marrow disseminated tumor cells. In this study we evaluate expression STEAP1 in primary tumors, and bone marrow (BM) from breast cancer patients.

Experimental procedures: RNA was isolated from primary tumor, non-malignant breast tissue and bone marrow (BM) from stage II and III breast cancer patients, healthy volunteers, breast cancer cell lines and BM from patient derived xenographs (PDX). Disseminated tumor cells (DTCs) from patient BM were enriched by microfiltration and analyzed by RNA-in situ hybridization (ISH). STEAP1 RNA expression was analyzed by Nanostring nCounter and qRT-PCR using human specific probes. STEAP1 immunohistochemical (IHC) staining of human tissue was performed using standard protocols. Knockdown of steap1 expression was accomplished using a lentiviral system.

Results: STEAP1 mRNA was up-regulated in 77% of tumors (28/36) compared to the corresponding normal tissue. STEAP1 protein was expressed in 100% of tumors (8/8) and was absent in non-malignant breast tissue (7/7) by IHC staining. STEAP1 mRNA was not expressed normal BM, but was detected in 8% (6/74) of BM from patients with early stage breast cancer. STEAP1 expression in the BM was associated with triple negative disease (3/6) and recurrent disease development (4/6, p=.028). STEAP1 expression was observed in individual DTCs isolated from patients BM, while no expression was observed in normal BM. In a PDX model of breast cancer, STEAP1 expression in BM was only observed in mouse who developed metastatic disease associated (7/10, p=.004). Knockdown of STEAP1 in the breast cancer cell line MDA-MB231 cells inhibited cell growth by 80-90%.

Conclusion: STEAP1 is expressed in human breast tumors and disseminated tumor cells found in the bone marrow of breast cancer patients. Expression of STEAP1 in the BM is significantly associated with the development of metastatic disease in patients as well as in a mouse model of breast cancer. Our data indicate that STEAP1 could serve as a therapeutic target for the treatment of minimal residual disease in breast cancer.

Citation Format: Aft R, Mudalagiriyappa C, Pillai S, Watson M. Analysis of STEAP1 expression as a therapeutic target in 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 P5-04-06.
Abstract P5-04-14: The covalent JNK inhibitor, JNK-IN-8, synergizes with lapatinib to cause cell death in basal-like breast cancer cell lines
Authors: Ebelt ND , Van Den Berg CL
Published: May 2016

Basal-like and claudin-low breast cancers have the worst prognosis and represent 15-20% of breast cancers diagnosed each year. Endocrine and molecularly targeted therapies, such as trastuzumab, are ineffective due to lack of ER expression or HER2 amplification in the tumors. They also have a high frequency of p53 mutations, low BRCA1 expression and high EGFR expression. Our lab has shown that high expression of JNK2 in human basal-like breast cancers leads to significantly decreased disease-free survival. JNK2 also promotes basal-like tumor progression in mice by increasing EGFR-mediated migration through facilitating internalization of EGFR, upregulating EMT gene expression and promoting metastasis.

The ATP-competitive JNK inhibitor SP600125 has been commonly used by researchers to elucidate JNK-specific mechanisms, but this inhibitor was found to have high affinity to many other intracellular kinases. A new JNK inhibitor, JNK-IN-8, has been developed that binds covalently to all three JNK gene products and is more selective than the SP600125 compound (Zhang, et al. 2012). Using this inhibitor, we have found that basal-like breast cancer cell lines can become sensitized to lapatinib. This combination is synergistic and causes apoptotic cell death, while as single agents at these concentrations, these drugs have little effect on cell viability. Treatment with either lapatinib or JNK-IN-8 decreases transcriptional activity of NF-κB significantly, but combination of the two drugs reduces NF-κB activity to an almost negligible amount compared to vehicle treatment. Combination treatment also led to a 6-fold increase in ROS production that may be activating apoptosis.

We hypothesize that inhibition by both JNK-IN-8 and lapatinib cause independent decreases in NF-κB activation that, when combined, cause a synergistic decrease in NF-κB-mediated survival mechanisms. Use of the JNK-IN-8 inhibitor with lapatinib in humans may increase survival in patients with basal-like or claudin-low breast cancers.

Zhang, T. et al. "Discovery of potent and selective covalent inhibitors of JNK". Chem Biol. 2012 Jan 27;19(1):140-54.

Citation Format: Ebelt ND, Van Den Berg CL. The covalent JNK inhibitor, JNK-IN-8, synergizes with lapatinib to cause cell death in basal-like breast cancer cell lines. [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 P5-04-14.
Abstract P5-04-20: TLE1 protein expression in HER2-positive and triple-negative breast cancer
Authors: Lee HJ , Oh M-H , Lee J-H , Cho HD , Jang S-H , Jung HY , Kim K-J
Published: May 2016

Purpose

Transducin-like enhancer protein 1 (TLE1) is a member of the Groucho (Gro)/TLE family of transcriptional co-repressors that regulate the transcriptional activity of a wide range of genes. TLE1 has been shown to be a specific and diagnostically useful immunohistochemical marker for synovial sarcoma. However, there have been few reports of the status of TLE1 in breast cancers. The purpose of this study was to clarify the nuclear expression of TLE1 in 511 Korean breast cancers by immunohistochemistry (IHC) and to correlate the findings to clinicopathologic variables including prognostic significance.

Methods

IHC was performed on tissue microarrays (TMAs) in 511 cases of breast cancer. Associations between the TLE1 expression and the clinicopathologic characteristics were retrospectively analyzed. Progression-free survival and disease-specific survival was assessed by the Kaplan–Meier method and Cox regression model.

Results

Of 511 cases of breast cancer, high expression of the TLE1 was detected in 63 (12.3%) cases. TLE1-high expression was strongly associated with HER2-positive breast cancer phenotype (p < 0.001) and triple-negative breast cancer phenotype (p < 0.001). Furthermore, high TLE1was significantly associated with high histologic grade (p < 0.001), node-negative (p =0.011), estrogen receptor negativity (p < 0.001), progesterone receptor negativity (p < 0.001), CK5/6 positivity (p < 0.001), epidermal growth factor receptor positivity (p < 0.001), high ki-67 proliferative index (p < 0.001) and high p53 expression (p < 0.001). Survival analysis demonstrated no significant association between TLE1 expression and disease progression and cancer-related death (p =0.112 and p =0.068, respectively).

Conclusion

Our results show that high TLE1expression is significantly associated with HER2-positive and triple-negative breast cancer. TLE1 may represent a potential therapeutic target for this aggressive disease, which warrants further investigation.

Citation Format: Lee HJ, Oh M-H, Lee J-H, Cho HD, Jang S-H, Jung HY, Kim K-J. TLE1 protein expression in HER2-positive and triple-negative 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 P5-04-20.
Abstract P5-06-05: MED12 exon 2 mutations in phyllodes tumors of the breast
Authors: Nagasawa S , Ohta T , Tsugawa K
Published: May 2016

Exon 2 of MED12, a subunit of the transcriptional mediator complex, has been frequently mutated in uterine leiomyomas and breast fibroadenomas; however, it has been rarely mutated in other tumors. Although the mutations were also found in uterine leiomyosarcomas, the frequency was significantly lower than in uterine leiomyomas.

Here, we examined the MED12 mutation in phyllodes tumors, another biphasic tumor with epithelial and stromal components related to breast fibroadenomas. Mutations in

MED12 exon 2 were analyzed in nine fibroadenomas and eleven phyllodes tumors via

Sanger sequencing. A panel of cancer- and sarcoma-related genes was also analyzed using Ion Torrent next-generation sequencing. Six mutations in fibroadenomas, including those previously reported (6/9, 67%), and five mutations in phyllodes tumors (5/11, 45%) were observed. Three mutations in the phyllodes tumors were missense mutations at

Gly44, which is common in uterine leiomyomas and breast fibroadenomas. In addition, two deletion mutations (in-frame c.133_144del12 and loss of splice acceptor

c.100-68_137del106) were observed in the phyllodes tumors. No other recurrent mutation was observed with next-generation sequencing. Frequent mutations in MED12 exon 2 in the phyllodes tumors suggest that it may share genetic etiology with uterine leiomyoma, a subgroup of uterine leiomyosarcomas and breast fibroadenoma.

Citation Format: Nagasawa S, Ohta T, Tsugawa K. MED12 exon 2 mutations in phyllodes tumors of the breast. [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 P5-06-05.
Abstract P5-07-06: A competing risks analysis of the association between prediagnostic serum glucose and lipids and breast cancer survival
Authors: Wulaningsih W , Vahdaninia M , Rowley M , Holmberg L , Garmo H , Malmstrom H , Lambe M , Hammar N , Walldius G , Jungner I , Coolen A , Van Hemelrijck M
Published: May 2016

Background: Abnormal levels of glucose and lipids may be linked to survival after breast cancer (BC) diagnosis, but their association to other causes of mortality such as cardiovascular (CV) disease may result in a competing risk problem and invalidate conventional analyses.

Methods: We assessed serum glucose, triglycerides (TG) and total cholesterol (TC) measured prospectively three months to three years before diagnosis in 1,798 women with BC in the Swedish Apolipoprotein Mortality Risk Study (AMORIS). In addition to using multivariable Cox proportional hazards regression, we employed latent class proportional hazards models to capture any heterogeneity of associations between these markers and BC death. The latter method was extended to include the primary outcome (BC death) and competing outcomes (CV death and death from other causes), allowing latent class-specific hazard estimation for cause-specific deaths.

Results: No association between prediagnostic glucose, TG or TC with BC death was observed with Cox regression. With latent class proportional hazards model, two latent classes (Class I and II) were identified in the cohort. Class I, comprising the majority (81.5%) of BC patients, had an increased risk of BC death following higher TG levels (HR: 1.87, 95% CI: 1.01-3.45 for every log TG increase). Lower overall survival was observed in Class II, but no association for BC death was found. On the other hand, TC positively corresponded to CV death in Class II, and similarly, glucose to death from other causes.

Conclusion: Higher TG was associated with an increased risk of BC death in the majority of BC patients. Our study also identified a subgroup of BC patients at higher risk of early death likely driven by other metabolic-related diseases, which adds to our understanding into BC survival in presence of competing outcomes.

Citation Format: Wulaningsih W, Vahdaninia M, Rowley M, Holmberg L, Garmo H, Malmstrom H, Lambe M, Hammar N, Walldius G, Jungner I, Coolen A, Van Hemelrijck M. A competing risks analysis of the association between prediagnostic serum glucose and lipids and breast cancer survival. [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 P5-07-06.
Abstract P5-07-15: Breast cancer estrogen receptor scoring in tissue microarrays: Specialist breast pathologist versus automation
Authors: Jordan LB , Akbar S , Purdie CA , Thompson AM , McKenna SJ
Published: May 2016

Rationale: Tissue microarrays (TMAs) have become a valuable resource for biomarker expression in translational research. Immunohistochemical (IHC) assessment of TMAs is the principal method for analyzing protein expression in large numbers of patient samples efficient with conservation of tissue. However, manual IHC assessment of TMAs remains a challenging and laborious task. With advances in image analysis, computer generated analyses of TMAs have the potential to lessen the burden of expert pathologist review. Computerized ER scoring relies on tumor localization.

Aim: The objective of this study was to compare the effectiveness of a locally developed automated invasive tumor location system with the skills of specialist breast pathologists.

Methods: In this study, tumor localization for estrogen receptor (ER) scoring was evaluated comparing computer- generated segmentation masks with those of two specialist breast pathologists. Automated tumor localization was achieved using a novel image analysis algorithm, which labeled compact groups of pixels called superpixels. Machine learning techniques were adopted to model color, shape and textural properties of superpixels in a rotation invariant manner, suitable for histopathology images. The resulting automatically and manually-obtained segmentation masks were used to obtain IHC scores for thirty-two ER stained invasive breast cancer TMA samples using FDA-approved IHC scoring software.

Results: Pixel-level comparisons showed lower agreement between automated and manual segmentation masks (κ = 0.84) than between pathologists' masks (κ = 0.91). However, this had little impact on computed IHC scores (Allred method; κ = 0.91, Quickscore method; κ = 0.92).

Conclusion: The automated system provides sufficiently consistent measurements for standardized IHC analysis of nuclear staining in TMAs from large clinical trials.

Citation Format: Jordan LB, Akbar S, Purdie CA, Thompson AM, McKenna SJ. Breast cancer estrogen receptor scoring in tissue microarrays: Specialist breast pathologist versus automation. [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 P5-07-15.
Abstract P5-08-16: Local immunologic environment related with tumor infiltrating lymphocytes (TIL) and PD-1/PD-L1 expression in early stage breast cancer
Authors: Okabe M , Toh U , Iwakuma N , Mishima M , Kawahara A , Kage M , Itoh K , Akagi Y
Published: May 2016

Purpose:

Recent studies have shown that local immune environment revealed with programmed death 1(PD-1)/programmed death ligand 1(PD-L1) and tumor infiltrating lymphocytes(TIL) affects the tumor-growth and prognosis. In this study, we evaluated the tumor local immune environments using immunohistological staining for analysis of PD-1/PD-L1 expression and TIL of tumor local in operable early-stage breast cancer.

Method:

A total of 100 surgical specimens of stageI-III invasive breast carcinoma paraffinembedded between 1995 and 2005 were analyzed. Immunohistological staining for PD-1, PD-L1, PTEN, CD3, CD8, and CD163 were performed by the conventional PAP method. In addition, intratumoral and intrastromal TILs and macrophages were simultaneously stained by anti-CD3, CD8, CD163 antibodies and measured by 'Win ROOF' computer software (version 5.7, Mitani Corporation, Japan).

Results:

Intratumoral PD-1 expressed significantly higher in triple negative breast cancer (TNBC) compared to other subtype BC (p=0.0094), intratumoral and intrastromal CD3+ lymphocytes and CD163+ macrophages were also significantly higher in TNBC, respectively (CD3: p=0.0002; 0.0139 and CD163: p=0.0043; 0.0270). PTEN loss was also more frequently observed in TNBC (p=0.0475). In addition, after a median 5-year follow-up, patients of luminal A subtype with lower PD-L1 and PTEN expression showed better disease free survival (DFS) with a significant difference (p=0.0148, p=0.0475).

Conclusion:

Local expression of PD-1/PD-L1 antigens on tumor cells, CD3+ lymphocytes, CD163+ macrophages infiltration singnificantly increased in early-stage TNBC. PTEN expression on tumor local might be associated with DFS in patients with early-stage BC.

Citation Format: Okabe M, Toh U, Iwakuma N, Mishima M, Kawahara A, Kage M, Itoh K, Akagi Y. Local immunologic environment related with tumor infiltrating lymphocytes (TIL) and PD-1/PD-L1 expression in early stage 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 P5-08-16.
Abstract P5-08-26: CYP1A2– A novel genetic marker for aromatase inhibitor response in the treatment of breast cancer patients
Authors: Simonsson M , Veerla S , Markkula A , Rose C , Ingvar C , Jernström H
Published: May 2016

Background: Endocrine resistance is a major obstacle for optimal endocrine treatment in breast cancer (BC). Several genetic markers for tamoxifen response have been proposed. Although some genetic markers have been proposed for response to aromatase inhibitors (AI), data is insufficient. The aim of this study was 1) to perform an exploratory analysis of genes involved in Absorption, Distribution, Metabolism, and Elimination (ADME) to find new predictive markers in a subset of the cohort and 2) examine these potential markers in relation to risk for events in the extended cohort.

Materials and methods: In Lund, Sweden, 190 AI-treated primary breast cancer patients with estrogen receptor positive tumors, who underwent breast cancer surgery between 2002 and 2008, were followed until December 31st 2012. Clinical data were obtained from medical records and population registries. The impact of single nucleotide polymorphisms (SNPs) on risk for breast cancer events was conducted on a subset of the cohort followed until December 31st 2011 (13 cases, 11 controls) and analyzed with data from a DMET (TM) chip including 1931 SNPs in 225 ADME-related genes. Secondly, four SNPs in CYP19A1 and the significant SNPs from the first analysis were reanalyzed concerning disease-free survival in the extended cohort of 190 patients.

Results: A CYP1A2 SNP was significantly associated with risk for early events among the 24 AI-treated BC patients both in the subset of the cohort, (P=0.0007) and in the extended cohort, adjusted HR 3.83 (95% CI 1.40-10.42). SNPs in CYP19A1 alone were not significantly associated with disease-free survival in any of the analyses. The impact of the CYP1A2 SNP was modified by a SNP in CYP19A1, where patients with both SNPs had increased risk for early events, adjusted HR 5.21 (95% CI 2.05-13.23) compared to other patients.

Conclusion: This study identified a potential and new predictive marker in BC patients: CYP1A2 alone and CYP1A2 in combination with CYP19A1. If confirmed, these results may provide a way to more personalized medicine.

Citation Format: Simonsson M, Veerla S, Markkula A, Rose C, Ingvar C, Jernström H. CYP1A2– A novel genetic marker for aromatase inhibitor response in the treatment of breast cancer patients. [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 P5-08-26.
Abstract P5-08-41: Prognostic contribution of mammographic breast density and HER-2 overexpression to the Nottingham prognostic index in patients with invasive breast cancer
Authors: Masarwah A , Sudah M , Sutela A , Päivi A , Ritva V
Published: May 2016

Purpose: To examine the associations between very low mammographic breast density (VLD), HER2, ER and PR status in a more homogenized patient group within matched NPI categories. We also aimed to investigate whether those variables could be added to the NPI to enhance its prognostic and predictive values and better categorize which patients are at higher risk.

Materials and methods: A total of 270 patients with invasive breast cancer were included in the final analysis. Patients with mammographic breast density of <10% were considered as VLD. We compared the performance of NPI with and without ER, PR , VLD and/or HER2. Factors first underwent univariate and then multivariate analysis to assess the factors combined until the best fit was obtained. Cox multivariate analysis, time-dependent receiver operating characteristic curve (tdROC), concordance index (c-index) and prediction error (i.e. 0.632+ bootstrap estimator) were used to derive an updated version of NPI. Patients' survival was assessed by the Kaplan-Meier method using a log rank (Mantel-Cox) test.

Results: The average NPI value was 4.66 (range 2.12-7.40), the percentage of HER2 positive patients progressively increased from the low to the high prognostic groups of NPI (p<0.001). While MBD, ER and PR status showed no such difference in distribution. Patients showed survival differences in the intermediate and high risk groups of NPI according to VLD and HER2 status (p<0.001 and p=0.02, respectively). Outcome analysis showed that the addition of both factors combined provides improved patient outcome stratification superior to the traditional NPI helping to significantly decrease the percentage of patients in the intermediate patient groups.

Conclusion: VLD breasts and HER2 positivity are prognostic factors for breast cancer independent of the NPI. Moreover, their addition to the NPI helps increase its prognostic accuracy and reduces the percentage of patients in the intermediate prognostic group.

Citation Format: Masarwah A, Sudah M, Sutela A, Päivi A, Ritva V. Prognostic contribution of mammographic breast density and HER-2 overexpression to the Nottingham prognostic index in patients with invasive 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 P5-08-41.
Abstract P5-09-12: The importance of education for adherence to mammographic screening in the Brazilian public health services
Authors: Blanco EC , Ribeiro IM , Nascimento CCP , da Silva CA , Abrah㯀 CF , Borges MM
Published: May 2016

Introduction: A third of the registration of new cases of breast cancer in Brazil corresponds to locally advanced or late diagnosed disease. The benefits of screening in this sense become evident and measurable in terms of their temporal extent and adherence of the target population to its recommendations. Unlike the organized mammographic screening where there is call, breast health education, monitoring and enforcement of the intervals between examinations, in the opportunistic model, individuals are subject to the recommendations from the spontaneous demand by health services. Objective: To determine the influence of education in breast cancer for adherence to mammographic screening in brazilian public health services. Methods: This is a cross-sectional, descriptive and comparative study between two groups of women with (group A, n=136) and without (group B, n=128) knowledge about breast cancer, who appeared in the Center of Detection, Diagnosis and Monitoring (CDDM) for organized screening. For this were interviewed 264 women in relation to the realization of previous mammograms in the last three years. The repetition of examinations, respecting the range of 24 months was defined as criteria to classify participants in adherent or not to screening. Results: Both groups of women had a similar mean age (50.2 ± 9.2 and 49.5 ± 9.5 years; p>0.05). Of the respondents, 77.2% (n=204) reported mammographic screening before joining the CDDS, however highest proportion was registered in group A (64.8%). Sixty women denied conducting prior mammography with predominance in the Group B (93.4% vs 6.6%, p<0.05). One hundred forty-four women were adherent to screening, 90.2% (n=130) of these belonged to group A. The remaining variables (education, occupation, family income, distance between place of residence and mammography center and personal / family history of breast cancer) were not associated with adherence to screening (p>0.05). Conclusion: The decrease in the adherence to conducting periodic mammography observed in group B reflects the opportunistic character of the screening in the country, where it loses the chance to sensitize women through education to improve their effective adhesion. Acknowledgements to the Brazilian Ministry of Health for their support to the study.

Citation Format: Blanco EC, Ribeiro IM, Nascimento CCP, da Silva CA, Abrah㯀 CF, Borges MM. The importance of education for adherence to mammographic screening in the Brazilian public health services. [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 P5-09-12.
Abstract P5-12-08: Time course of changes in serum FSH, serum estradiol, and menstruation in premenopausal patients with breast cancer taking tamoxifen after completing chemotherapy: A report from the ASTRRA study
Authors: Kim HJ , Ahn SH , Nam SJ , Park SH , Ro JS , Im SA , Jung YS , Noh WC
Published: May 2016

BACKGROUND

Ovarian suppression with tamoxifen after chemotherapy is a promising therapeutic approach, particularly in young, high-risk breast cancer patients. Assessment of restoration of ovarian function is important with respect to the initiation of ovarian suppression.

METHODS

In total, 1289 women who remained or resumed premenopausal status after chemotherapy were randomized to receive 5 years of tamoxifen or 5 years of tamoxifen plus 2 years of ovarian suppression. Prospectively collected hormone data were available for 24 months after completing chemotherapy for 267 breast cancer patients without ovarian suppression.

RESULTS

At 6 months, a premenopausal status was identified in 56.6%, 36%, and 16.2% of patients using serum FSH, E2, and with menstruation bleeding, respectively, and about 30% more women achieved ovarian restoration using all three parameters during the 24-month follow-up. Ovarian function restoration differed significantly according to age group (log-rank, P<0.001 for all definitions). At 6 months, the distribution of patients according to hormone levels was as follows: group 1 (FSH <30 mIU/ml, E2 >20 pg/ml), 28.0%; group 2 (FSH <30 mIU/ml, E2 ≤20 pg/ml), 28.4%; group 3 (FSH ≥30 mIU/ml, E2 >20 pg/ml), 8.0%; and group 4 (FSH ≥30 mIU/ml, E2 ≤20 pg/ml), 35.6%. During the 24-month follow-up, the prevalence of menstruation restoration was higher in group 1 (71.6%) than in the other three groups. Restoration of serum E2 and menstrual bleeding occurred in 44% and 33% of patients in group 2, respectively; the corresponding percentages in group 4 were 40.6% and 28.7% (P<0.001).

CONCLUSIONS

Ovarian function should be monitored using serum FSH, serum E2, and menstruation history for at least 24 months after completing chemotherapy during tamoxifen treatment to establish eligibility for ovarian suppression.

Citation Format: Kim HJ, Ahn SH, Nam SJ, Park SH, Ro JS, Im SA, Jung YS, Noh WC. Time course of changes in serum FSH, serum estradiol, and menstruation in premenopausal patients with breast cancer taking tamoxifen after completing chemotherapy: A report from the ASTRRA 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 P5-12-08.
Abstract P5-12-11: Duration of ovarian function suppression for premenopausal women with hormone receptor-positive breast cancer: Retrospective study
Authors: Ozaki Y , Tamura N , Utiyama M , Masuda J , Koganemaru S , Miura Y , Tanabe Y , Ogura T , Kadowaki M , Miura D , Kawabata H , Takano T
Published: May 2016

Background: Although tamoxifen (TAM) plus ovarian function suppression (OFS) is one of standard adjuvant treatments in premenopausal women with hormone receptor-positive breast cancer, the optimal duration of OFS has not been clearly established.

Patients and Methods: We retrospectively reviewed data of premenopausal patients with breast cancer, who received TAM and OFS (goserelin or leuprorelin) as adjuvant therapy between February 2004 and April 2015. The primary analysis was to compare disease-free survival (DFS) between patients who received OFS shorter than 3 years and those who received OFS longer than 3 years. The analyses were performed with Cox proportional hazards models and propensity score matching models.

Results: We analyzed 206 premenopausal patients with hormone receptor-positive breast cancer. Median follow-up time was 56 months. Median age was 42 years (range, 24-52 years). Twenty six per cent of the patients had positive axillary nodes and 30% had received neo-adjuvant or adjuvant chemotherapy. Median duration of OFS was 26 months. Duration of OFS was shorter than three years (OFS < 3y) in 74% patients, and longer than three years (OFS > 3y) in 26% patients. Patients with node-positive disease were more in OFS > 3y group than in OFS < 3y group, and more patients received chemotherapy in OFS > 3y group than in OFS < 3y group. 5-year disease-free survival (DFS) was 96.1%. DFS in patients aged ≤ 40 years and aged > 40 years were 91.8% and 99.0%, respectively (p=0.0223). Propensity score matching model showed that DFS was not significantly different between patients in OFS < 3y group and those in OFS > 3y group (97.4%, 91.6%; p=0.2406). In patients aged ≤ 40 years and/or those who received chemotherapy, 5-year DFS was 96.7% in OFS < 3y group, 90.1% in OFS > 3y group (p=0.3011).

Conclusions: Our data suggest that OFS < 3y is not inferior to OFS > 3y for premenopausal women with hormone receptor-positive breast cancer as adjuvant endocrine therapy. A randomized trial is needed to establish the optimal OFS duration for these patients.

Citation Format: Ozaki Y, Tamura N, Utiyama M, Masuda J, Koganemaru S, Miura Y, Tanabe Y, Ogura T, Kadowaki M, Miura D, Kawabata H, Takano T. Duration of ovarian function suppression for premenopausal women with hormone receptor-positive breast cancer: Retrospective 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 P5-12-11.