bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P4-08-26: Validation of different prognostic scores in breast cancer patients with brain metastases of the BMBC registry (GBG-79)
Authors: Witzel ID , Riecke K , Laakmann E , Weide R , Neunhoeffer T , Park-Simon T-W , Schmidt M , Fasching PA , Hesse T , Polasik A , Mohrmann S , Würschmidt F , Schem C , Bechtner C , Würstlein R , Fehm T , Möbus V , Burchardi N , Loibl S , Müller V
Published: May 2019

Background

The incidence of brain metastases from breast cancer is increasing and treatment is a major challenge. Different scores were developed to estimate the prognosis of patients with brain metastases by objective criteria. Sperduto et al. established the disease-specific breast-graded prognostic assessment (GPA) score in 400 breast cancer patients which includes age, performance status and tumor subtype. It has been described that the Breast- GPA best identifies patients with bad prognosis (Laakmann et al. 2016). Aim of this analysis was to validate the Breast-GPA in a large cohort of breast cancer patients with brain metastases.

Materials and methods

Data of 613 breast cancer patients from the Brain Metastases in Breast Cancer (BMBC) registry treated in 80 different clinical German institutions between 2000 and 2016 was analyzed.

Results

135 patients (22%) had a triple-negative, 199 (32%) a luminal-like und 279 (46%) a HER2-positive primary breast cancer. At diagnosis of brain metastases most patients had a good Karnofsky performance status (100%: 14.4%, 80-90%: 44.7%, 60-70%: 28.9%, 40-50%: 9.0%, 10-30%: 3.1%). Median age of patients was 56 years (22-90 years).

Median survival in the overall cohort was 7.1 months (95% CI 6.2-7.8 months).

Distribution of GPA scores was: 0-1: 11.9% (n=73), 1,5-2: 22.3% (n=137), 2,5-3: 47.8% (n=293), 3,5-4: 18% (n=110).

Median overall survival within the GPA-subgroups varied between 2.4 (CI95% 2.0 - 3.4); 4.8 (3.6 - 6.9); 9.2 (7.2 - 11.3) and 12.3 (8.9 - 18.0) months and, thus, was significantly shorter compared with the times published by Sperduto et al. (3.4; 7.7; 15.1 und 25.3 months).

Conclusions

The breast-GPA is easy to calculate in clinical routine, allows to assess patients` prognosis objectively and can facilitate making therapeutic decisions. However, absolute survival may differ from the originally published cohort in other settings.

Citation Format: Witzel ID, Riecke K, Laakmann E, Weide R, Neunhoeffer T, Park-Simon T-W, Schmidt M, Fasching PA, Hesse T, Polasik A, Mohrmann S, Würschmidt F, Schem C, Bechtner C, Würstlein R, Fehm T, Möbus V, Burchardi N, Loibl S, Müller V. Validation of different prognostic scores in breast cancer patients with brain metastases of the BMBC registry (GBG-79) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-26.
Abstract P4-08-35: Young age at diagnosis is associated with worse prognosis in the luminal A breast cancer subtype. A retrospective institutional cohort study
Authors: Liu Z , Sahli Z , Wang Y , Wolff AC , Cope L , Umbricht CB
Published: May 2019

Background: Breast cancer (BCA) presents with distinct molecular subtypes, each associated with different patterns of relapse, drug sensitivity, and prognosis. Although age at diagnosis is a recognized independent prognostic risk factor, its relative importance among molecular subtypes is not well documented. The aim of this study was to evaluate the prognostic role of age at diagnosis among BCA patients of different immunohistochemical subtypes (LuminalA, LuminalB, Her2, Triple-negative).

Methods: We conducted a retrospective study of women with invasive BCA undergoing surgery at the Johns Hopkins Hospital from January 2000 - December 2016, excluding patients presenting with stage IV breast cancer. Patients were stratified into three age groups: ≤ 40, 41-60, and > 60 years, and multivariable analysis was performed using Cox regression. To explore age-related differences in gene expression, we identified differentially expressed genes (DEG) between age groups among BCA subtypes in the TCGA dataset. Finally, we identified key driver genes within DEG using a weighted gene co-expression network analysis.

Results: Our cohort included 3,524 patients with a median follow-up of 85.1 months. LuminalA breast cancer patients had significantly lower 5-year Disease Free Survival (DFS) and Distant Metastasis-Free Survival (DMFS) in the ≤ 40 year age group compared to the 40-60 year age group (HR=2.69, 95%CI: 1.72 - 4.23 and HR=2.95, 95%CI: 1.78 - 4.90, respectively), while the other molecular subtypes showed no significant association of DFS or DMFS with age. Age was a stronger predictor of 5- year DFS and 5-year DMFS than tumor grade or proliferative index (Ki67) in LuminalA BCA patients, but not other subtypes.

Gene expression data were obtained from 1097 BCA TCGA patients, divided into two groups (≤40y, n=36; >40y, n=455). We identified 374 DEG between ≤40y and >40y LuminalA BCA subsets. The DEG were enriched in 7 pathways, and the WGCNA analysis identified two modules of co-expressed genes. No age group-specific DEG were identified in non-LuminalA subtypes.

Conclusion: Age at diagnosis may be an important prognostic factor in LuminalA BCA and may improve risk stratification and personalized therapy. Prospective studies are needed to further evaluate the prognostic value of age in this subset of BCA patients.

Citation Format: Liu Z, Sahli Z, Wang Y, Wolff AC, Cope L, Umbricht CB. Young age at diagnosis is associated with worse prognosis in the luminal A breast cancer subtype. A retrospective institutional cohort study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-35.
Abstract P4-09-02: Validation of iPrevent using the prospective family study cohort (ProF-SC)
Authors: Phillips K-A , Liao Y , Collins IM , Buchsbaum R , Weideman P , Bickerstaffe A , MacInnis RJ ,   kConFab Investigators, Cuzick J , Antoniou A , Andrulis IL , John EM , Daly MB , Buys SS , Hopper JL , Terry MB
Published: May 2019

Background: iPrevent (https://www.petermac.org/iprevent) provides women with highly-tailored risk management information after first estimating their breast cancer (BC) risk using the established risk prediction models, IBIS and BOADICEA. iPrevent has an internal switching algorithm that governs which model is used for each woman, depending on her risk factor data (i.e. LCIS/atypical hyperplasia status, BRCA status, and cancer family history). This study assessed the calibration and discriminatory accuracy of the 10-year BC risk estimates provided by iPrevent. Methods: Subjects were 16,574 women in the ProF-SC, aged 18-70 years and without BC or bilateral mastectomy at recruitment. After 10 years follow-up, 655 women (4%) were diagnosed with invasive BC. A “batch mode” for iPrevent is not available, so the iPrevent-assigned cumulative 10-year invasive BC risks were calculated by entering self-reported risk factors at cohort entry into either the IBIS (10,169 women) or BOADICEA (6,405 women) software packages (according to the iPrevent switching algorithm). To assess calibration, the mean iPrevent-assigned risk was compared with the mean 10-year observed invasive BC incidence, using a chi-squared goodness-of-fit statistic for the whole cohort, and by quartiles of risk. To evaluate discriminatory accuracy, the overall area under the receiver operating characteristic curve (AUC) for the development of invasive BC within 10 years was computed. Data were censored at date of invasive or in situ BC diagnosis, bilateral mastectomy, death, loss to follow-up, or at 10 years of follow-up. Results: For the whole cohort, iPrevent assigned risk was well-calibrated – 690 expected BCs (E) 655 observed (O) (E/O=1.05, 95% CI: 0.98-1.14), although for women in the highest risk quartile, i.e. >6% 10-year risk, E/O=1.19, 95% CI: 1.07-1.32. The AUC was 0.70, 95% CI: 0.68-0.72. Conclusions: iPrevent is well calibrated overall and has good discriminatory accuracy for predicting 10-year BC risk, thus justifying its clinical use.

Citation Format: Phillips K-A, Liao Y, Collins IM, Buchsbaum R, Weideman P, Bickerstaffe A, MacInnis RJ, kConFab Investigators, Cuzick J, Antoniou A, Andrulis IL, John EM, Daly MB, Buys SS, Hopper JL, Terry MB. Validation of iPrevent using the prospective family study cohort (ProF-SC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-09-02.
Abstract P4-10-15: Obesity influences the character of the breast cancer in postmenopausal women in Japan
Authors: Suzuki M , Takei H
Published: May 2019

Background: We know Estrogen Receptor (ER) positive and/or Progesterone Receptor (PgR) positive tumors tend to develop more frequently in obese individuals in postmenopausal women. However, the average body size of a Japanese woman is relatively smaller than that of a Caucasian woman. There are few reports about the influence of the obesity to the character of the Japanese breast cancer women and the tendency is not clear. The aim of this study is to clarify whether the tendency is the same even in Japanese breast cancer women. Furthermore, we investigate whether HER2 expression (HER2) and Ki-67 index (Ki-67) have some relations with the height (HT), the weight (WT) and the body mass index (BMI) in Japanese breast cancer women.

Methods: HT and WT of 279 Japanese women with breast cancer in Kitamurayama hospital were evaluated. The mean HT and WT of them are 153.6cm and 54.9kg. Subsequently, the women's BMI (WT/(HT)2) was calculated. The mean BMI was 23.3. The ER and PgR were stained for immunohistochemical (IHC) analysis. Regardless of the intensity, stained cases were defined as positive. HER2 was divided into HER2 negative (IHC score 0, +1 and/or FISH negative) or positive (IHC score +3 and/or FISH positive). Ki-67 was determined by staining with MIB-1 antibody, and the cutoff value was decided on 20%, and divided into two groups of more than 20% (Higher) and less than 20% (Lower). Then, we examined the relationship of HT, WT and BMI with ER, PgR, HER2 and Ki-67 in postmenopausal and premenopausal women.

Result: In postmenopausal women, WT and BMI were significantly higher in ER positive (p=0.0230, p=0.0129). WT and BMI were also significantly higher in PgR positive (p=0.0049, p=0.0294,). There was no significant difference between HER2 positive and Her2 negative, and between Ki-67 Higher and Ki-67 Lower either. In premenopausal women, no significant association was observed in all items.

Conclusion: In postmenopausal women, HT did not have the significant difference between ER (and PgR) positive and ER (and PgR) negative. However, ER (and PgR) positive were significantly higher in WT and BMI. It was thought that the obesity influences the character of the breast cancer in postmenopausal women. Compared to less obese postmenopausal Japanese women with breast cancer, more obese postmenopausal Japanese women have a propensity for developing hormone sensitive tumors.

Citation Format: Suzuki M, Takei H. Obesity influences the character of the breast cancer in postmenopausal women in Japan [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-15.
Abstract P4-10-16: Neoadjuvant chemotherapy infusion in the arm ipsilateral to breast cancer increases the risk of lymphedema
Authors: Bergmann A , Bello MA , Thuker LC , Andrade MF , Bevilacqua JI
Published: May 2019

Background: Neoadjuvant chemotherapy (NAC) has been administered to clinically axillary positive breast cancer (BC) patients. Current guidelines still recommend axillary lymphadenectomy (AL) in patients with persistent positive axillary lymph node disease. We aimed to evaluate the association of NAC and/or adjuvant chemotherapy (CT) infusion in the ipsilateral upper limb (IA) with AL and the occurrence of lymphedema (LE) secondary to BC treatment. Methods: A prospective cohort study of 683 women subjected to AL and treated with NAC and/or adjuvant CT for BC. The patients were evaluated before treatment, immediate and every 6 months after surgery. Cumulative incidence and population attributable risks of LE were calculated. Results: 8-year cumulative incidence of LE was 33.1%. NAC and CT infusion and infusion of >2 cycles into the IA respectively increased by 1.68, 1.67 and 1.78 times the risk of LE respectively (all P<0.01). LE could be avoided in 9.4% of cases if the CT infusion had not been administered in the IA. Conclusions: 33.1% of women developed LE. The risk of LE was increased among women who received CT in the IA. Avoidance of NAC or adjuvant CT in the IA could prevent 9% of the LE cases observed in this population.

Citation Format: Bergmann A, Bello MA, Thuker LC, Andrade MF, Bevilacqua JI. Neoadjuvant chemotherapy infusion in the arm ipsilateral to breast cancer increases the risk of lymphedema [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-16.
Abstract P4-11-03: Withdrawn
Authors: Kim EY , Park YL , Park CH , Suh BC
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Kim EY, Park YL, Park CH, Suh BC. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-11-03.
Abstract P4-14-13: Tamoxifen induced ovarian hyperstimulation during hormonal therapy for breast cancer
Authors: Kim MK , Shin H-c
Published: May 2019

Introduction

Adjuvant endocrine therapy is an integral compo-nent of care for endocrine-dependent breast cancer.

To date, international consensus statements recommend tamoxifen (20 mg/day) for five years as the standard adjuvant endocrine therapy for premenopausal women. Tamoxifen is a potent inducer of ovarian function and consequent hyper-estrogenism in premenopausal women. However, the incidence rate and risk factors associated this phenomenone were not clarified.

Methods

Among consecutive patients who were operated under diagnosis of breast cancer from March 2012 to December 2016 in Chung-Ang university hospital, patients who received post-operative tamoxifen therapy for endocrine-dependent breast cancer (stage 0-III) at age under 60 were selected and retrospectively analysed. Serial data on serum estradiol and follicular stimulating hormone(FSH) were collected. When the serum concentration of estradiol was higher than 400 pg/mL, which exceeds the normal estradiol production by a single preovulatory follicle, we classified them as tamoxifen induced ovarian hyperstimulation group. Clinicopathologic factors were analyzed between ovarian hyperstimulation group and non-hyperstimulation group by x2 and student t-test.

Results

Among 205 patients, 19 patients(9.3%) showed high values of serum estradiol during tamoxifen therapy. They showed 44 times of high estradiol level during follow up period. The serum concentrations of estradiol and FSH were 1047.97638.8pg/mL and 11.57.3 mIu/mL, respectively. The mean duration from the start of the single administration of tamoxifen to the initial detection of a high concentration of estradiol was 666.4+433.1 days.

Univariate and multivariate analysis between ovarian hyperstimulation and non-hyperstimulation groups showed younger age(<40years) and only endocrine therapy without chemotherapy were related to higher prevalence of ovarian hyperstimulation significantly. (p <0.001, =0.031 each) Pathologic stages and progesterone receptor expressions on breast tumor were not related to manifestation of ovarian hyperstimulation.

Conclusions

The Incidence rate and occurrence time of ovarian hyperstimulation associated with adjuvant tamoxifen treatment in breast cancer patients under age 60 were 9.3% and around 2-year after treatment with tamoxifen. Young age under 40 years old and endocrine treatment without chemotherapy were risk factors predicting occurrence of ovarian hyperstimulation during tamoxifen treatment. It should be noted that tamoxifen is a potent inducer of ovarian function and close monitoring of the endocrine parameters during treatment with tamoxifen would be essential.

Citation Format: Kim MK, Shin H-c. Tamoxifen induced ovarian hyperstimulation during hormonal therapy for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-13.
Abstract P5-02-03: Testing machine learning algorithms' performance for non-invasively identifying breast cancer molecular subtypes using BI-RADS evaluations
Authors: Ozcan A , Aksoy Ozcan U , Ekemen S , Ulus S , Oyan B
Published: May 2019

Purpose: Inter- and intra-observer variability adversely affects interpretation of highly advantageous MRI data in breast cancer diagnosis, prognosis and therapeutic decisions. Machine learning (ML) might potentially provide support to the physicians for objective decision strategies. In this work, ML methods using BI-RADS features were tested for non-invasively determining molecular subtypes of breast cancer.

Methods: In this IRB approved study, Out of 126 consecutive patients' retrospective data with written consent, 69 patients (mean±std age 48.24±11.62 and range [27-82]) with full histopathological and MRI data were selected. In surgical histopathological data ER+PR+HER2- was classified as luminal HER2(-), ER+PR+HER+ was classified as luminal HER2(+), ER-PR-HER2+ was classified as HER2(enriched) and ER-PR-HER2- was classified as triple negative. The cohort revealed 51 luminal HER2(-), 11 luminal HER2(+), 7 triple negative cases without any HER2(enriched) occurrence. DCE, DW, T2W MRI data were obtained on a 1.5T Magnetom Espree (Siemens, Erlangen, Germany) scanner which were subsequently interpreted in consensus by 2 radiologists of 15 and 10 years of experience.

Age, mass and non-mass properties, non-enhancing BI-RADS findings, ADC values obtained from radiologist drawn ROIS and kinetic curve properties were fed to 22 standard ML algorithms provided in Matlab® (Mathworks, Natick, MA, USA) as predictors for 3 categories. The algorithms were run by cross validating on 50 folds whereby reported classifier accuracy was obtained from each of the observations when in held-out fold.

Results: Out of 22 ML algorithms tested Support Vector Machine's Fine Gaussian variant, Ensemble Boosted Trees and Fine K-Nearest Neighbor resulted in 76.8%,71.0% and 53.6% accuracy with (100%, 18%, 0%), (92%, 9%, 14%) and (67%, 18%, 14%) true positive rates for predicting each histopathological category respectively. Furthermore, PCA based dimension reduction worsened the outcomes indicating high sensitivity to the feature set.

Conclusion: ML algorithms demonstrated potential as a decision support system increasing assessment objectivity with an added non-invasiveness advantage. However, overall algorithm performance indicates further studies with larger cohorts and broader feature are necessary for refinements and improving ML methodology in breast cancer imaging.

Citation Format: Ozcan A, Aksoy Ozcan U, Ekemen S, Ulus S, Oyan B. Testing machine learning algorithms' performance for non-invasively identifying breast cancer molecular subtypes using BI-RADS evaluations [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-02-03.
Abstract P5-02-04: Not presented
Authors: Sheth D , Pineda F , Karczmar G , Abe H
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Sheth D, Pineda F, Karczmar G, Abe H. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-02-04.
Abstract P5-03-10: Circulating exosomal microRNA profiling to depict mechanisms of chemotherapy resistance among triple negative breast cancer
Authors: He Y , Tang J
Published: May 2019

Background: Chemotherapeutic resistance leads to high mortality among triple negative breast cancer (TNBC) and underlying mechanisms are poorly understood. Exosomes have been new member of liquid biophsy. MicroRNAs (miRNAs), as the most important inclusions in exosomes, making them ideal candidate biomarkers and therapeutical targets.

Methods: We isolated exosomes and analyzed exosome-carried miRNAs signatures in several TNBC cells lines sensitive or resistant to adariamycin, docetaxel or cisplatin. The resistance transfer capacity was determined by flow cytometry after sensitive cells incubated 48 hours with exosomes from drug resistant cells. Locked nucleic acid probes and enzyme-labeled fluorescence (LNA-ELF-FISH) was performed to detect exosomal miRNA molecules transfer. Animal mode was constructed to evaluate treatment feasibility using miRNA modified exosomes. Serum exosomes from 40 TNBC stage IV patients underwent chemotherapy before or after progress disease (PD) status were isolated to analyze miRNA profiling for potential biomarkers identification.

Results: We successfully isolated and identified exosomes from several drug sensitive and resistant TNBC cell lines and patients. Exosomal miR-222, miR-4443, miR-100, miR-17, miR-210 were found significantly upregulated from chemotherapy resistance cells. Incubation of exosomes from the resistant cells with the sensitive cells resulted in increasing resistant capacity among sensitive cells. Exosomal miRNA molecules transfer were detected using LNA-ELF-FISH. Transfection of synthesized miRNAs competitors into exosomes increased drug sensitivity in vivo. Exosomal miR-222, miR-4443, miR-100, miR-17, miR-210 were also found upregulated significantly from serums of patients after PD status. These five miRNAs were able to differentiate patients with PD status from those with CR or PR status with at least 89% accuracy.

Conclusion: Exosomes from chemotherapy resistant TNBC cells could transfer drug resistance to sensitive cells via exosomal miRNAs. A circulating exosomal microRNA profiling was estabilished for potential biomarkers and therapeutical targets identification.

Citation Format: He Y, Tang J. Circulating exosomal microRNA profiling to depict mechanisms of chemotherapy resistance among triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-10.
Abstract P5-03-14: Not presented
Authors: Xu Z , Tang J
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Xu Z, Tang J. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-14.
Abstract P5-04-04: Withdrawn
Authors: Das GM , Kulkarni S , Oturkar C , Edge SB , Wilton JH , Wang J , Swetzig WM , Adjei AA , Bies R , Hutson AD , Morrison CD , Kaipparettu BA , Groman A , Kumar S , Capuccino H
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Das GM, Kulkarni S, Oturkar C, Edge SB, Wilton JH, Wang J, Swetzig WM, Adjei AA, Bies R, Hutson AD, Morrison CD, Kaipparettu BA, Groman A, Kumar S, Capuccino H. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-04.
Abstract P5-04-06: Withdrawn
Authors: Katzenellenbogen JA , Min J , Kim SH , Laws MJ , Zhao Y , Ziegler Y , Nelson ER , Shahoei SH , Chu D , Park BH , Katzenellenbogen BS
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Katzenellenbogen JA, Min J, Kim SH, Laws MJ, Zhao Y, Ziegler Y, Nelson ER, Shahoei SH, Chu D, Park BH, Katzenellenbogen BS. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-06.
Abstract P5-04-12: Withdrawn
Authors: Charmsaz S , Doherty B , Cocchiglia S , Bolger J , Vareslija D , McCartan D , Hill A , Young L
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Charmsaz S, Doherty B, Cocchiglia S, Bolger J, Vareslija D, McCartan D, Hill A, Young L. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-12.
Abstract P5-04-22: Withdrawn
Authors: Treuner K , Hayes M , Schnabel CA , Heinz S
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Treuner K, Hayes M, Schnabel CA, Heinz S. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-22.
Abstract P5-04-27: Investigating the incidence of ESR1 gene amplification in breast cancers resistant to multiple endocrine agents
Authors: Turnbull AK , Martinez-Perez C , Mok S , Tanioka M , Fernando A , Renshaw L , Keys J , Wheless A , Garrett A , Parker J , He X , Sims AH , Carey LA , Perou CM , Dixon JM
Published: May 2019

Background: Around 70% of all breast cancers (BCs) are estrogen receptor positive (ER+), but some do not respond to endocrine therapy (ET) and many eventually develop resistance. ESR amplification (ESRA) linked to an increase in ESR1 gene expression is known to occur in some cancers that are endocrine resistant. However, the incidence of ESRA has been the object of debate and its clinical significance remains unclear. This study aimed to investigate the incidence of ESRA in BCs resistant to multiple sequential ETs and optimise a fluorescence in-situ hybridisation (FISH) methodology to robustly detect ESRA.

Methods: Two unique cohorts have been studied:

(A) 20 post-menopausal women with ER+ BC with acquired resistance to letrozole, subsequently treated with up to 4 different lines of ET. Serial RNA and DNA from 3-5 cancer samples per patient (58 samples from 20 patients) were analysed by Ribo0-RNAseq and DNA exome sequencing;

(B) 18 post-menopausal women who developed ER+ BC recurrences on 1st line adjuvant letrozole, then on 2nd line tamoxifen and subsequently on 3rd line exemestane. Tissues were collected at the time of each surgery.

We have optimised a FISH method to assess ESRA in these tissues.

Results: In cohort A, 6/20 patients developed ESR1 gene amplification (ESRA) at some point during treatment. In 5 of these cases, ESRA was only found while on 2nd or 3rd line exemestane but was not present on acquired resistance to previous letrozole or tamoxifen. 1 patient had ESRA at the time of first recurrence on letrozole.

The FISH method showed concordance with the genomic analysis. This suggests that ESRA may be associated with BCs that are treated with and then become resistant to exemestane.

ESRA is also evident in samples from Cohort B, which includes 18 exemestane resistant cases. The complete analysis is ongoing.

Conclusions:

· ESRA can be seen in ER+ recurrent BCs.

· ESRA may be associated with BCs treated with 2nd or 3rd line exemestane.

· The frequency of ESRA in endocrine and exemestane resistance can now be ascertained using an optimised FISH-based method, which is more cost-effective than alternative genomic and biochemical methods.

Citation Format: Turnbull AK, Martinez-Perez C, Mok S, Tanioka M, Fernando A, Renshaw L, Keys J, Wheless A, Garrett A, Parker J, He X, Sims AH, Carey LA, Perou CM, Dixon JM. Investigating the incidence of ESR1 gene amplification in breast cancers resistant to multiple endocrine agents [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-27.
Abstract P5-05-13: Quantitative combinatory indexed ChIP-seq reveals distinct transcriptional complexes containing estrogen receptor and GREB1 at chromatin in breast cancer cells
Authors: Sun J , Lippman ME
Published: May 2019

GREB1 is an estrogen-activated gene in estrogen receptor a (ER)-positive breast cancer cells. GREB1 is also required for estrogen-stimulated breast cancer cell growth and its level is highly correlated to ER level in breast cancer cells and tumor samples. In endocrine resistant diseases, GREB1 is often dysregulated. GREB1 has been shown to interact with ER and bind to the same ER binding sites throughout the genome. There is no identified functional domain in GREB1 and it is not completely known how GREB1 exerts its function to regulate the transcription of ER target genes. In order to demonstrate whether GREB1 is present in the ER-containing transcriptional complex at chromatin, we have adapted and developed a quantitative combinatory indexed ChIP-seq assay suitable for dissecting components in a transcriptional cofactor complex in a genome-wide scale. In ER-positive MCF-7 breast cancer cells, we found that almost all GREB1 binding sites are the same sites bound by ER or its bona fide coactivator SRC-3. We further found that GREB1 and SRC-3 are both present in the same ER-containing complex at chromatin. Thus, both GREB1 and SRC-3 are integral members of the ER transcriptional complex at chromatin. Moreover, we discovered that only a portion of GREB1 at chromatin is present in the ER complex while the other portion of GREB1 is present in a different complex lacking ER or SRC-3 at the same genomic loci. Thus, two distinct GREB1-containing complexes are identified in equilibrium at chromatin: one contains ER/SRC-3 and the other one lacks ER/SRC-3. Our results suggest a non-traditional role of GREB1 in transcriptional regulation of ER target genes. The method used in our study can be widely applied for probing components of transcriptional complexes at chromatin.

Citation Format: Sun J, Lippman ME. Quantitative combinatory indexed ChIP-seq reveals distinct transcriptional complexes containing estrogen receptor and GREB1 at chromatin in breast cancer cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-13.
Abstract P5-07-02: Not presented
Authors: Chatterjee S , Berdnikov A , Buchel E , Safneck J , Marshall AJ , Murphy LC , Raouf A
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Chatterjee S, Berdnikov A, Buchel E, Safneck J, Marshall AJ, Murphy LC, Raouf A. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-02.
Abstract P5-07-07: The immune microenvironment of ductal carcinoma in situ of the breast
Authors: Yamashita N , Hisamatsu Y , Shigechi T , Tokunaga E , Saeki H , Oki E , Maehara Y
Published: May 2019

Background: The importance of tumor-infiltrating lymphocytes (TIL) in invasive breast carcinoma for tumor development and therapeutic response is widely accepted. However, the immune microenvironment of breast ductal carcinoma in situ (DCIS) has not been fully elucidated. Evasion of immune surveillance is a necessary step in tumor evolution. In DCIS, the tumor cells are relatively protected from the immune system due to an myoepithelial cell layer and basement membrane, and intraductal immune cells are rarely detected. In contrast, in invasive disease, cancer cells and immune cells are often intermingled. Thus, understanding the immune microenviroment of in situ to invasive carcinoma transition might be particularly important to identify novel targets for early stage of tumor invasion.

Aims: The aim of this study is to evaluate the clinical importance of TILs in DCIS.

Methods: TILs were assessed in 133 DCIS samples with or without microinvasive disease according to the proposed method from the International Immuno-Oncology Working Group on Breast Cancer. In addition, the relationship between TILs in DCIS and clinicopathological features was evaluated.

Results: TILs are present in most DCIS in varying levels. The median proportion of TILs in DCIS was 14%. Only a minority of DCIS showed >50% TILs, which represented only 12.8% of all cases. High TILs in DCIS was significantly associated with comedo necrosis (p<0.0001), high nuclear grade (p=0.0030), ER negativity (p<0.0001), PR negativity (p<0.0001), HER2 positivity (p=0.0030). Triple negative DCIS and HER2 positive DCIS had significantly higher level of TILs (p=0.0008). No correlation was demonstrated between TILs and recurrence risk.

Conclusions: High TILs in DCIS was significantly associated with adverse histopathologic features. Further characterization of immune environment of DCIS may be essential for immunotherapy and breast cancer prevention.

Citation Format: Yamashita N, Hisamatsu Y, Shigechi T, Tokunaga E, Saeki H, Oki E, Maehara Y. The immune microenvironment of ductal carcinoma in situ of the breast [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-07.
Abstract P5-07-08: Withdrawn
Authors: Persson E , Gregersson P , Fitzpatrick P , Ståhlberg A , Landberg G
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Persson E, Gregersson P, Fitzpatrick P, Ståhlberg A, Landberg G. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-08.
Abstract P5-07-11: Transcriptome alteration of breast cancer cells in the process of tumor-associated macrophages-promoted metastasis
Authors: Long M , Yang M , An J , Su H , Liu R
Published: May 2019

Introduction: Tumor-associated macrophages (TAMs) play an important role in the process of tumor metastasis. Previous studies have shown that TAMs induce breast cancer cells undergo epithelial-mesenchymal transition (EMT) by secreting CCL18. Reciprocally, the induced mesenchymal-like breast cancer cells activate macrophages into a TAM-like phenotype via secreting the cytokine granulocyte-macrophage colony stimulating factor (GM-CSF), forming a positive feedback loop that is essential to breast cancer metastasis.

Methods: To better understand the underlying mechanism that links this positive feedback loop to breast cancer metastasis, a TAMs-induced EMT cell model (MCF-7) was used. RNA-seq was used to compare the transcriptome of MCF-7 cells which were cocultured with TAMs and those with or without monocyte-derived macrophages (MDMs). Results were further verified by qRT-PCR.

Results: Among 811 known protein-coding genes with reliable readouts, 42 were significantly changed between groups (P<0.001). Further analysis using KEGG, Reactome and Wikipathways databases found that these 42 genes were enriched in 15 signal pathways (P<0.01). According to their biological function, these pathways can be divided into 5 functional groups: SUMOylation related, virus related, immune related, interferon related and cytokine related. The last 3 groups demonstrated that our model were representative and able to provide some real and useful information, while SUMOylation and virus related signal pathways have never been reported to be involved in TAMs induced breast cancer metastasis.

Conclusion: We investigated the transcriptome alteration of MCF-7 cells in the process of TAMs-promoted metastasis. Results from bioinformatic analysis indicated SUMOylation and virus related signal pathways in the process of TAMs induced breast cancer metastasis, which are yet to be confirmed.

Citation Format: Long M, Yang M, An J, Su H, Liu R. Transcriptome alteration of breast cancer cells in the process of tumor-associated macrophages-promoted metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-11.
Abstract P5-07-14: CCL18 signaling from breast tumor-associated macrophages fosters the activation of fibroblasts into a chemoresistance-inducing phenotype
Authors: Song E , Su S , Chen J
Published: May 2019

Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment critically involved in cancer progression. Our recent study identified a specific CAFs subset by two cell-surface molecules, CD10 and GPR77. We proved that CD10+GPR77+ CAFs could promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). However, their origin and underlying activating initiation mechanism are unclear. Tumor-associated macrophages (TAMs) are the most abundant immune-related stromal cells and the important source of inflammatory cytokine. Here, we demonstrated that CCL18 secreted by TAMs could induces the activation of normal breast fibroblasts into a CD10+GPR77+ CAFs phenotype, which are not only resistant to chemotherapy themselves, but also can induce chemoresistance in cancer cells by abundantly producing IL-8 and IL-6 and enriching the population of cancer stem cells. In conclusion, our studies have identified an inflammatory signaling network in the interaction of different kind of stroma cells in tumor microenvironment and highlighted its potential values as predictive markers and therapeutic targets to abrogate tumor formation and improve chemotherapeutic efficacy.

Citation Format: Song E, Su S, Chen J. CCL18 signaling from breast tumor-associated macrophages fosters the activation of fibroblasts into a chemoresistance-inducing phenotype [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-14.
Abstract P5-08-06: Differential effects of eribulin on key transcription factors snail and slug
Authors: Kaul R , Risinger AL , Mooberry SL
Published: May 2019

Microtubule targeting agents (MTAs) are a mainstay in the treatment of breast cancer and a growing body of evidence demonstrates that they have non-mitotic effects that contribute to their anticancer actions. Even after decades of clinical use, there is much to still be learned about the mechanisms of action these drugs, and differences among them, for optimal utility. MTAs rapidly alter microtubule dynamics, often within minutes, leading to significant changes in oncogenic cellular signaling. We evaluated the early effects of eribulin on key oncogenic signaling pathways following a 2 h incubation using clinically relevant concentrations and compared the effects to those initiated by other MTAs. These studies led to the identification of novel mechanisms by which MTAs disrupt oncogenic signaling and contribute to the reversal of epithelial to mesenchymal transition (EMT), including unanticipated differences among drugs.

The TGF-β-mediated expression of the Snail transcription factor is a key driver pathway of EMT in breast cancer. The effects of eribulin and other MTAs on TGF-β-induced, Smad-dependent expression of Snail were evaluated. Our results show that eribulin and vinorelbine, but not paclitaxel or ixabepilone, inhibit the ability of TGF-β to promote the transcriptional induction of Snail by impeding the nuclear transport of Smad2/3 proteins in 4 triple-negative breast cancer cell lines. This study begins to explain how microtubule disruption might contribute to the eribulin-mediated EMT reversal observed in vitro, in vivo, and in patients.

Slug is another member of the Snail family of transcription factors that plays a central role in breast cancer EMT. Although Snail and Slug are often grouped together due to functional similarities, it is becoming increasingly clear that Slug has an independent role in regulating stemness and cancer cell survival during partial EMT. In contrast to our findings with Snail, eribulin and vinorelbine, but not paclitaxel or ixabepilone, induced Slug expression independent of TGF-β stimulation in a subset of triple-negative breast cancer cell lines. Studies are ongoing to identify the molecular pathways and consequences of eribulin and vinorelbine-induced Slug induction, which might begin to identify biomarkers of patient response to different MTAs. This work highlights the multifaceted nature of MTA-mediated effects on EMT-associated signaling pathways in breast cancer cells and prompts a reevaluation of their differential efficacy in tumors with distinct molecular profiles. These studies are supported by Eisai Inc.

Citation Format: Kaul R, Risinger AL, Mooberry SL. Differential effects of eribulin on key transcription factors snail and slug [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-08-06.
Abstract P5-08-08: Not presented
Authors: Zhao Y , Sun H , Jin W
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Zhao Y, Sun H, Jin W. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-08-08.
Abstract P5-09-16: Multiple mutations in a single lineage: is it time for a shift in predictive testing?
Authors: Scalia Wilbur J , Laprise J , Beaston M , Legare RD
Published: May 2019

Germline cancer genetic testing is a critical part of patient care influencing cancer risk reduction, prevention and now treatment decision-making. Single syndrome and mutation testing has been available for twenty years, however massively parallel sequencing technology has made multigene panel tests more readily available and at lower costs. Currently, it remains unclear if there is benefit related to panel testing in cancer families and patients already harboring a pathogenic mutation. We report 5 families found to harbor additional pathogenic mutations identified with multigene panel testing.

One Ashkenazi family was found to harbor both a founder and non-founder BRCA mutation in a single lineage. Four additional families were found to harbor a second mutation in either a novel breast/ovary cancer gene or in a gene related to an established cancer syndrome. All patients were either initially BRCA2 or PALB2 positive and were subsequently found to have a second mutation in either CHEK2, RAD51D, ATM, MUTYH or PMS2. In 2 cases, the secondary mutation either increased frequency and/or decreased start age of colonoscopy screening. Interestingly, 2 of the additional mutations were first reported as variants of uncertain significance later reclassified as likely pathogenic.

In all cases the traditional approach of single site/syndrome analysis for predictive testing would have failed to identify the second pathogenic mutation resulting in an underestimate of cancer risk in negative family members. Notably, the majority of secondary mutations were present within the same lineage as the known familial mutation. In 3 of 5 cases, the finding of a second mutation in already identified mutation carriers led to additional changes in medical management. As multigene panel testing becomes more accessible in both cost and provider acceptance, this case series illustrates the need to strongly consider use of multigene panel testing for relatives undergoing testing for known familial mutations regardless of family history, and ultimately indicating a role for re-testing established mutation carriers.

Citation Format: Scalia Wilbur J, Laprise J, Beaston M, Legare RD. Multiple mutations in a single lineage: is it time for a shift in predictive testing? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-16.
Abstract P5-09-18: Multiple cancer susceptible genes sequencing in BRCA-negative breast cancers with high hereditary risk
Authors: Lang G-T , Hu X , Shi J-X , Huang W , Shao Z-M
Published: May 2019

Background Breast cancer susceptibility is strongly associated with a patient's hereditary background. Comprehensive BRCA mutation screening in our cancer center shows a lower BRCA mutation prevalence (9.1%) in Chinese breast cancer patients with hereditary risk. Multiple cancer susceptible genes sequencing can assist in discovering detrimental germline mutation in BRCA-negative breast cancers.

Methods From 2005-2014, BRCA-negative breast cancer patients with any two of the following risk factors were recruited: (1) pathological diagnosis of triple-negative breast cancer, (2) male breast cancer, (3) primary bilateral breast cancers in one individual, regardless of synchrony or asynchrony, (4) early-age onset breast cancer (less than or equal to 40 years of age at diagnosis), or (5) patients with a family history of breast and/or ovarian cancer (at least one first- and/or second-degree relative with breast cancer or ovarian cancer). A total of 384 Chinese subjects were screened by next-generation sequencing for 32 breast cancer associated susceptibility genes (APC, ATM, BARD1, BMPR1A, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MEN1, MET, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PALLD, PMS2, PTCH1, PTEN, RAD50, RAD51C, RAD51D, RET, SMAD4, STK11, TP53, VHL). Mutations were classified as pathogenic/likely-pathogenic if they had a truncating, initiation codon or splice donor/acceptor effect, or if pathogenicity was demonstrated in published literature.

Results In total, we acquired 39 patients (10.2%) with pathogenic/likely-pathogenic germline mutations, including one carrying two distinct mutations. Major mutant non-BRCA genes were MUTYH (n=11), PTCH1 (n=7), RET (n=6) and PALB2 (n=5). Other mutant genes included TP53 (n=3), RAD51D (n=2), CHEK2 (n=1), BRIP1 (n=1), CDH1 (n=1), MRE11 (n=1), RAD50 (n=1) and PALLD (n=1). In addition, PTCH1 mutation carriers were found to be associated with the clinical features of triple-negative and early-age onset breast cancer.

Conclusions Among BRCA-negative breast cancer patients with high hereditary risk in China, 10.2% carried mutations in breast cancer associated susceptibility genes. MUTYH and PTCH1 had relatively high mutation rates (2.9% and 1.8%). Some clinical features might be associated with germline mutations of particular genes in breast cancer.

Key words germline mutation, BRCA-negative, hereditary breast cancer, multiple-gene sequencing

Citation Format: Lang G-T, Hu X, Shi J-X, Huang W, Shao Z-M. Multiple cancer susceptible genes sequencing in BRCA-negative breast cancers with high hereditary risk [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-18.
Abstract P5-10-05: Not presented
Authors: Semetei Kyzy A , Makimbetov E , Kudaibergenova I , Isakova J
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Semetei Kyzy A, Makimbetov E, Kudaibergenova I, Isakova J. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-10-05.