bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-07-01: IRS1 expression is required for estrogen stimulated growth in breast cancer cells
Authors: Zhang X , Varma S , Yee D 
Published: February 2018

Abstract
Insulin receptor substrate (IRS) proteins are adaptor proteins phosphorylated by activated type I insulin-like growth factor receptor (IGF-1R) and insulin receptor (IR). In addition to their roles in normal cell physiology, we have shown IRS expression is required for breast cancer cell growth and motility. IRS1 plays a more important role in mitogenesis and survival while IRS2 in cancer cell metastasis. Moreover, this family of adaptor proteins is also involved in the signal transduction of many other transmembrane receptors. Thus, IRS proteins could be potential cancer therapeutic targets. We have previously shown that reduced IRS1 impairs IGF and insuliln stimulated cancer cell growth and tumorigenicity even when signaling is not affected due to possible compensation of IRS2 and other adaptor proteins. To further study the role of IRS-1 function in breast cancer, we created doxycycline inducible IRS-1 shRNA cells. We also found that IRS1 knockdown significantly reduced estradiol stimulated growth. To investigate if reduced IRS1 regulated E2 stimulated binding of ERa ChIP assay was performed using the pS2 promoter. Compared to parental MCF-7L cells, inducible IRS1 knock down clone 3G5 demonstrated significantly reduced promoter binding. Degradation of IRS-1 with a pharmacologic antagonist (NT-157) also diminished ERa binding to pS2 promoter. Further qRT-PCR analysis for mRNA levels of estrogen regulated genes, such as PGR, TFF1, etc. showed those genes were significantly down regulated. To evaluate effects of IRS-1 levels on estrogen stimulated growth, we evaluated 3G5-B12 (a subclone of 3G5) cell growth in a xenograft model. 3G5-B12 cells have similar levels of IGFIR and ERa expression compared to their parent cells. Estrogen dependent xenograft growth was similar to those of parent MCF-7L cells. After doxycycline was administered in the diet, 3G5-B12 tumor growth was significantly inhibited compared to those fed with normal mouse diet, and this inhibition was prolonged at least 2 and a half months. Parental MCF-7L tumor growth was not affected by the doxycycline diet. Doxycycline inducible IRS1 knock down significantly prolonged the time before tumors reached 1000mm3 compared with those tumors on a normal diet. In conclusion, IRS-1 is required for optimal estrogen receptor function as measured by promoter binding and xenograft growth. Our data suggested suppression of IRS-1 function may target several growth pathways in breast cancer cells and represents a new drug target.
Citation Format: Zhang X, Varma S, Yee D. IRS1 expression is required for estrogen stimulated growth in breast cancer cells [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-07-01.
Abstract P3-08-11: The prognostic impact of retinoic acid-induced 2 (RAI2) expression in ERα-positive breast cancer patients
Authors: Nishikawa S , Kondo N , Endo Y , Hato Y , Hisada T , Nishimoto M , Dong Y , Okuda K , Kato H , Takahashi S , Nakanishi R , Toyama T 
Published: February 2018

Abstract
Background: Breast cancer cells disseminate to the bone marrow and form bone metastases in a large majority of late-stage patients. Retinoic Acid-Induced 2 (RAI2) was reported as a putative suppressor of early hematogenous dissemination of tumor cells to the bone marrow in breast cancer, particularly in estrogen receptor α (ERα)-positive breast cancer. Here, we investigated mRNA expression of RAI-2 in breast cancer patients during long-term follow-up.
Materials and methods: A total of 451 invasive breast cancer tissues was available for analysis of RAI2 mRNA using a TaqMan PCR system. We also sought correlations between clinicopathological factors and levels of RAI2 expression in these samples. The expression of markers associated with tumor-initiating capacity, such as SNAI1, SNAI2 and VIM was also analyzed. The median follow-up period was 9.0 years. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional hazards regression analysis was used for univariate and multivariate analyses of prognostic values.
Results: We found positive correlations between low expression of RAI2 mRNA and shorter disease-free survival and overall survival in breast cancer patients (P=0.003, P&lt;0.0001, respectively), which was limited to ERα-positive patients (P=0.04, P=0.0009, respectively), and not seen in ERα-negative patients (P=0.52, P=0.27, respectively). Low RAI2 mRNA levels were positively correlated with high grade, ERα-negativity and PgR negativity. Multivariate analysis indicated that low level RAI2 mRNA expression was an independent factor for survival both overall in breast cancer and in ERα-positive breast cancer patients
Multivariate analysis (ERα-positive breast cancer patients) OS Multivariate patientsp valueHR(95%CI)Tumor size≤2cm1390.83691 (Reference) &gt;2cm207 1.08(0.54-2.28)Node statusNegative176&lt;0.00011 (Reference) Positive144 4.72(2.33-10.34)Grade11240.95921 (Reference) 2•3218 0.98(0.50-2.14)RAI2 mRNA expressionhigh140&lt;0.00011 (Reference) middle•low206 4.79(2.14-12.78)
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Conclusion:We show that low expression of RAI2 is an independent factor predictive of a poor prognosis in ERα-positive breast cancer patients. RAI2 could be a promising candidate biomarker and therapeutic target in ERα-positive breast cancer to prevent dissemination to the bone marrow.
Citation Format: Nishikawa S, Kondo N, Endo Y, Hato Y, Hisada T, Nishimoto M, Dong Y, Okuda K, Kato H, Takahashi S, Nakanishi R, Toyama T. The prognostic impact of retinoic acid-induced 2 (RAI2) expression in ERα-positive breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-08-11.
Abstract P3-09-10: Withdrawn
Authors: Pollán M , Lope V , Pérez-Gómez B , Molina AJ , Tardón A , Díaz-Santos M , Ardanaz E , O'Callhagan C , Altzibar JM , Gómez-Acebo I , Moreno V , Peiró R , Marcos-Grajera R , Kogevinas M , Aragonés N , López-Abente G , García-Pérez J 
Published: February 2018

Abstract
This abstract was withdrawn by the authors.
Abstract P3-10-04: Obesity and adipose inflammation in men with breast cancer
Authors: Williams S , Parrish JC , Zhou XK , Wang H , Dierickx A , Gucalp A , Dannenberg AJ , Iyengar NM 
Published: February 2018

Abstract
Background: Elevated body mass index (BMI) is associated with increased risk of hormone receptor (HR)-positive breast cancer in postmenopausal women and worsened outcomes after breast cancer diagnosis. These observations may be partly attributable to adipose inflammation, which is prevalent in the breasts of obese women and is associated with worsened breast cancer survival. In men, some studies have reported obesity to be a risk factor for breast cancer, however the biologic links are not well characterized. Whether adipose inflammation occurs in male breast tissue has not been previously reported. Here we examined the relationships among pre-diagnosis BMI, adipose inflammation, and breast cancer features in men.
Methods: Males diagnosed with stage 0 – III breast cancer who underwent mastectomy at Memorial Sloan Kettering (MSK) between August 1991 – November 2011 were included in this retrospective cohort study. Pre-operative BMI was categorized as normal or underweight (&lt;25), overweight (25 – 29.9), obese (≥30), or morbidly obese (≥40 or ≥35 + co-morbidity). Archived breast tissue was subjected to CD68 immunohistochemistry to detect adipose inflammation, defined by the presence of dead or dying adipocytes surrounded by macrophages – known as crown-like structures of the breast (CLS-B). Clinicopathologic associations with BMI and CLS-B were analyzed by logistic regression and Fisher's exact test.
Results: A total of 141 men were included; median age 63 (range 23 – 96). By BMI category, 25 were normal or underweight, 65 overweight, and 51 obese – of which 19 were morbidly obese. Only 11 men had known BRCA1/2 mutations. Median age at diagnosis was 69 in normal/underweight men versus 63 in obese men and 51 in morbidly obese men (P≤0.05). Among those with invasive tumors, average tumor size was 1.50 cm (± 0.84) in normal/underweight men versus 2.04 (±0.81) in morbidly obese men (P≤0.05). Archived breast tissue was available from 92 (65%) men. Breast adipose inflammation was present in 55 (60%) men, and average BMI was 31 (±8) versus 28 (±5) in men with versus without inflammation, respectively (P=0.07).
Conclusions: Obesity is associated with early onset breast cancer in men. Morbidly obese men were diagnosed with breast cancer at an even younger age and had larger tumors than normal weight individuals. These findings support further studies to investigate mechanisms, such as adipose inflammation, through which obesity may promote breast cancer in men.
Citation Format: Williams S, Parrish JC, Zhou XK, Wang H, Dierickx A, Gucalp A, Dannenberg AJ, Iyengar NM. Obesity and adipose inflammation in men with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-04.
Abstract P3-10-15: Stellate cells and mesenchymal stem cells in benign mammary stroma are associated with risk factors for breast cancer
Authors: Olsson HL , Isfoss BL , Holmqvist B , Jernstrom H 
Published: February 2018

Abstract
Background: It is not known whether stromal cells in benign breast tissue can mediate risk of breast cancer. We recently described aldehyde dehydrogenase 1 A1 (ALDH1) positive (+) cells in morphologically normal breast stroma of premenopausal women, and the data indicated that their distribution is associated with clinical risk factors for breast cancer. The aim of the present study was to define the identities of these cells using histological and immunohistological methods, and to investigate associations between those cells and hormonal and genetic risk factors in pre- and postmenopausal women.
Methods: Stroma of morphologically normal tissue was analyzed in samples from 101 well-characterized women whose breasts had been operated. Morphology and immunolabeling were applied to determine cell identities based on the putative stem cell markers ALDH1 and stage-specific embryonic antigen-3 (SSEA3), and immunophenotypes indicating mast cells or stellate cells. The results were compared with the patients' risk factors using regression analysis (two-tailed).
Results: ALDH1+ round/oval cells were associated with low parity in BRCA1/2 carriers (p = 0.022), while in non-BRCA1/2-carriers they were negatively associated with nulliparity (p = 0.057). In premenopausal women ALDH1+ round/oval cells were associated with family history (p = 0.058). SSEA3+ round/oval cells were morphologically and immunohistologically consistent with multilineage stress-enduring (Muse) cells, and these cells were independently associated with the breast cancer risk factors low parity (p = 0.015), family history (p = 0.021), and hormone use after menopause (p = 0.032). ALDH1+ spindle-shaped/polygonal cells were immunohistologically consistent with stellate cells, and were negatively associated with family history of breast cancer (p = 0.001).
Conclusion: This study identified novel stromal cell types in benign breast tissue that have a potential for stratifying women for breast cancer risk.
Citation Format: Olsson HL, Isfoss BL, Holmqvist B, Jernstrom H. Stellate cells and mesenchymal stem cells in benign mammary stroma are associated with risk factors for breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-15.
Abstract P3-12-12: Serum estrogen-levels in women 48-56yrs with hormone receptor-positive breast cancer. Cross-Sectional study using an ultra-sensitive LC-MS/MS-method
Authors: Van Houdt M , Neven P , Anneleen L , Ivo J , Dirk V , Jaak B , Annouschka L , Hans W 
Published: February 2018

Abstract
Background and Purpose: Randomized clinical trials in early stage hormone receptor positive breast cancer (HR+BC), have shown that total estrogen suppression (TES) for 5 yrs or after 2-3 yrs of tamoxifen treatment improved outcome over 5 yrs of TAM monotherapy. This relative improvement is in absolute figures most visible in patients with a high relapse risk. To achieve TES, women need to be (rendered) menopausal and treated with an oral aromatase inhibitor (AI). We measured serum estrogens in women of peri-menopausal age with HR+BC starting or on anti-hormonal agents.
Methods: Serum estradiol (E2) and estrone (E1) were quantified using a sensitive liquid chromatography-tandem mass spectrometry method (LC-MS/MS; Pauwels et al. JCO 2013) in women 48-56 yrs old with HR+BC starting or on anti-hormonal therapy in a cross sectional observational monocentric study. We report the frequency that (and explore why) AI-users had estrogens above the lower limit of quantification (LLOQ). We measured estrogen levels in TAM users with &gt; 3 months' amenorrhea by previous use of (neo)adjuvant chemotherapy. Finally, we studied the frequency of both estrogens or either alone were &lt; LLOQ in non-users. Statistics are descriptive; biomarkers for estrogen levels were analyzed using linear mixed models. [amendment on study NCT01223833]
Results: Estrogen levels were assessed in 566 samples from 401 women; 96 (126 samples) were on AI, 128 (182 samples) on TAM and 217 (258 samples) non-users. Some patients had more than one blood sample in different groups. 13,5% of AI users were above LLOQ for E2 and E1; 7,5% for E1 alone. Some were due to ovarian reactivation. An important proportion (18%) of 83 non-hysterectomized TAM users with amenorrhea had E2 levels &gt;40ng/L; 9,1% and 28.2% respectively in patients who had and didn't have (neo)adjuvant chemotherapy. None of non-users were below LLOQ for E1, while 20.7% were below LLOQ for E2.
Conclusions:TES is not always achieved in AI-users; reasons why were multiple. Amenorrhea is no guarantee for TES in TAM users, as a significant proportion had high E2 levels even when previously exposed to (neo)adjuvant chemotherapy. Using LC-MS/MS, undetectable levels for E1 better reflect TES than below LLOQ for E2.
Citation Format: Van Houdt M, Neven P, Anneleen L, Ivo J, Dirk V, Jaak B, Annouschka L, Hans W. Serum estrogen-levels in women 48-56yrs with hormone receptor-positive breast cancer. Cross-Sectional study using an ultra-sensitive LC-MS/MS-method [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-12.
Abstract P3-14-08: The impact of a structured surveillance protocol using bioimpedance spectroscopy (BIS) on preventing breast cancer related lymphedema (BCRL) in high-Risk patients
Authors: Whitworth P , Cooper A , Shah C , Vicini F 
Published: February 2018

Abstract
Background: We evaluated the impact of structured surveillance using bioimpedance spectroscopy (BIS) to prevent clinical BCRL in a group of high-risk (axillary lymph node dissection) patients.
Methods: From April 2010 through November 2016, 93 patients who were treated with axillary lymph node dissection (ALND) were prospectively monitored with BIS using L-Dex (Impedimed). Patients received a pre-operative baseline L-Dex measurement followed by post-operative assessments at regular intervals. An elevated L-Dex score was defined as an increase of ≥10 points above baseline (considered subclinical BCRL). Intervention consisted of applying an over the counter (OTC) sleeve for 4 weeks followed by re-evaluation. The need for complete decongestive physiotherapy (CDP) represented a surrogate for the development of clinically significant, chronic BCRL.
Results: Median follow-up was 24 months (range: 0.3-206.4 months). The median number of nodes removed was 19 (range: 5-41) and the median number of positive nodes was 3. Median age was 53 years old. Eighty five percent of patients underwent mastectomy and the remainder breast conserving therapy. 55% of patients received taxane based chemotherapy, 24% received some form of axillary RT (15% high tangents and 9% comprehensive regional nodal RT) and 74% had an elevated body mass index (BMI, &gt; 25). Overall, 75% of these patients had at least one additional high-risk feature, 48% had at least two, and 6% had 3 (either taxane chemotherapy, axillary RT or elevated BMI). Thirty-three patients (35.4%) developed an elevated L-Dex score at some point during follow up. Overall, 10 patients (11%) required CDP at any point after treatment.
Conclusions: The results of this analysis support previously published data on the efficacy of prospective BCRL surveillance and early intervention using BIS. Of the 93 high-risk patients prospectively followed and managed in this structured BCRL protocol, 11% required CDP. These results compare favorably to all contemporary studies reporting BCRL rates in high-risk patients.
Citation Format: Whitworth P, Cooper A, Shah C, Vicini F. The impact of a structured surveillance protocol using bioimpedance spectroscopy (BIS) on preventing breast cancer related lymphedema (BCRL) in high-Risk patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-08.
Abstract P4-04-01: Loss of mismatch repair predicts resistance to endocrine therapy and sensitivity to CDK4/6 inhibitors in ER+ breast cancer
Authors: Haricharan S , Punturi N , Singh P , Holloway KR , Anurag M , Schmelz J , Schmidt C , Lei JT , Suman V , Hunt K , Olson JA , Hoog J , Li S , Huang S , Edwards DP , Kavuri SM , Bainbridge MN , Ma CX , Ellis MJ 
Published: February 2018

Abstract
Estrogen receptor positive (ER+) breast cancer is treated with endocrine therapy but intrinsic resistance occurs in ˜1/3 of patients and acquired resistance in ˜1/5 of the remainder. While many resistance mechanisms have been explored, clinical trials testing associated therapeutics have had mixed outcomes. Understanding mechanisms of resistance and finding therapeutic strategies to target them, therefore, remain important challenges.
In this study we discover an intriguing link between mismatch repair (MMR) deficiency, specifically of the MutL complex (MLH1/3, PMS1/2), and endocrine therapy resistance in ER+ disease. We find a direct role for MutL loss in inducing endocrine therapy resistance in vitro and in vivo by knocking down multiple MutL genes using CRISPR and stable shRNA approaches validated using standard rescue experiments. We identify the underlying mechanism: MutL deficiency in ER+ breast cancer abrogates Chk2-mediated feedback inhibition of CDK4/6 that appears necessary for endocrine therapy responsiveness. Consequently, pharmacological targeting of CDK4/6 in vitro and in vivo significantly inhibits growth of endocrine therapy resistant MutL-deficient ER+ breast cancer cells. These results are corroborated by data from a neoadjuvant clinical trial demonstrating that cell cycle regulation of MutL-mutant tumors is estrogen-independent but CDK4/6 dependent.
The results of this study provide important biological and clinically relevant insights. 1) a novel role for MMR in endocrine therapy resistance 2) A mechanism underlying the effectiveness of CDK4/6 inhibitors in some de novo endocrine therapy resistant tumors. While there are currently no biomarkers to guide the use of CDK4/6 inhibitors for ER+ breast cancer, markers of MMR dysregulation could identify patients in whom CDK4/6 inhibition may, most effectively, prevent disease recurrence.
Citation Format: Haricharan S, Punturi N, Singh P, Holloway KR, Anurag M, Schmelz J, Schmidt C, Lei JT, Suman V, Hunt K, Olson Jr JA, Hoog J, Li S, Huang S, Edwards DP, Kavuri SM, Bainbridge MN, Ma CX, Ellis MJ. Loss of mismatch repair predicts resistance to endocrine therapy and sensitivity to CDK4/6 inhibitors in ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-01.
Abstract P4-04-17: Elacestrant (RAD1901) demonstrates anti-tumor activity in a fulvestrant-resistant PDX model
Authors: Arlt H , Garner F , Bihani T 
Published: February 2018

Abstract
Background: Breast cancer is subdivided into categories based on tumor receptor status, with estrogen-receptor positive (ER+) breast cancer making up approximately two-thirds of all breast cancers diagnosed. In advanced or metastatic disease, dependence on ER signaling is often retained even after multiple rounds of endocrine therapy, supporting the use of ER targeting agents for several lines of treatment prior to chemotherapy. Selective estrogen receptor degraders (SERDs) have gained recent attention as ER antagonists given their ability to target and degrade ER. Fulvestrant, the only approved SERD on the market, is currently used as a second-line therapy in the metastatic setting, however, the intramuscular route of administration and pharmacokinetic properties of fulvestrant have fueled the development of more potent and orally bioavailable SERDs. We have previously described elacestrant (RAD1901), a novel and orally bioavailable SERD, as an inhibitor of ER+ breast cancer growth in preclinical patient-derived xenograft (PDX) models, including those that are insensitive to fulvestrant. Here, we describe elacestrant activity in an ER+ PDX model that had been treated with multiple rounds of fulvestrant treatment.
Methods: An ER+/PR+ PDX model, MAXF-713, derived from a treatment-naïve patient, was passaged multiple times in the presence of fulvestrant over the course of a year. After each round of fulvestrant treatment, elacestrant or fulvestrant were evaluated for anti-tumor activity. Pharmacodynamic endpoints including changes in ER and ER target gene expression were also evaluated.
Results: Despite repeated exposure to fulvestrant, the PDX model retained sensitivity to elacestrant. In fact, regardless of the number of prior rounds of fulvestrant treatment, elacestrant produced consistent tumor growth inhibition within every passage, while the effects produced by fulvestrant exhibited a high degree of variability.
Conclusions: Our data demonstrate that elacestrant is a SERD that can inhibit tumor growth in a fulvestrant-resistant preclinical setting and provides rationale for examining elacestrant in the clinical setting in patients that have progressed on fulvestrant treatment.
Citation Format: Arlt H, Garner F, Bihani T. Elacestrant (RAD1901) demonstrates anti-tumor activity in a fulvestrant-resistant PDX model [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-17.