bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-09-17: Frequency of large rearrangements in BRCA1, BRCA2, ATM, CHEK2, and PALB2 in hereditary cancer testing
Authors: Bissonnette J , Doonanco K , Xu Z , Klein RT , Hruska KS
Published: May 2016

Objectives

Large deletions and duplications are recognized as a cause of many inherited cancer syndromes; however, few studies have examined the frequency. In one study, large rearrangements accounted for 11-14% of pathogenic variants in BRCA1 and 1-3% of pathogenic variants in BRCA2 (Judkins 2012). Additionally, in a study of invasive ovarian cancer patients, large deletions and duplications accounted for 6% of BRCA1 and 3% of BRCA2 pathogenic variants (Zhang 2011). The frequency of large deletions and duplications in moderate penetrance genes, such as ATM, CHEK2, and PALB2, has not been carefully studied. We therefore sought to determine the frequency of pathogenic and likely pathogenic (P/LP) large deletions and duplications in BRCA1, BRCA2, ATM, CHEK2, and PALB2.

Methods

We analyzed a consecutive case series of patients who had BRCA1/2 and cancer panel testing. The data were analyzed to determine the percentage of deletions or duplications of greater than 250 bp identified on array comparative genome hybridization as a percentage of all pathogenic variants (PVs)/likely pathogenic variants (LPVs) in each of BRCA1, BRCA2, ATM, CHEK2, and PALB2.

Results

Large deletions/duplications accounted for 10.1% (55/545) of cases with a BRCA1 PV/LPV and 1.8% (10/556) of cases with a BRCA2 PV/LPV. By ethnicity, BRCA1/2 large deletions/duplications accounted for a higher fraction of PV/LPVs in Asians (11.3%) and Hispanics (8.1%). In Hispanic individuals, all of the large deletions/duplications were identified in BRCA1, accounting for 14.6% of all BRCA1 PV/LPV in this group. In the moderate penetrance genes, large deletions/duplications accounted for 4.6% (9/195), 5.1% (22/436), and 9.9% (13/132) of cases with a PV/LPV in ATM, CHEK2, and PALB2, respectively. There were two recurrent deletions in our cohort: the CHEK2 founder Slavic deletion of exons 9-10 observed in 16 of our cases, and a deletion of exon 11 in PALB2 observed in 6 cases.

Conclusions

Large deletions/duplications account for a substantial proportion of clinically significant variants in hereditary cancer genes. The proportion of large deletions/duplications in BRCA1 and BRCA2 reported here is similar to previous data. However, our cohort suggests that Asian individuals may have a higher proportion of mutations due to large deletions/duplications than previously reported. Among moderate risk cancer genes, PALB2 has the highest proportion of large deletions/duplications.

Citation Format: Bissonnette J, Doonanco K, Xu Z, Klein RT, Hruska KS. Frequency of large rearrangements in BRCA1, BRCA2, ATM, CHEK2, and PALB2 in hereditary cancer testing. [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 P2-09-17.
Abstract P2-09-18: Exploration of the diagnostic utility of next generation sequencing with TruSight cancer panel for BRCA negative hereditary breast and ovarian cancer patients
Authors: Dacheva D , Dodova R , Mitkova A , Kamenarova K , Tzveova R , Popov I , Vlahova A , Taushanova – Hadjieva M , Valev S , Dikov T , Timcheva K , Christova S , Mitev V , Kaneva R
Published: May 2016

Background. Breast cancer is the most commonly diagnosed malignancy and the most frequent cause of death in women due to cancer. About 5% to 10% of breast cancers are thought to be hereditary. Pathogenic mutations in BRCA1/2 genes across Hereditary Breast and Ovarian Cancer (HBOC) patients estimates are at around 15-20%. Other less common genes have also been associated with an increased risk of developing breast cancer, such as mutations in the TP53, PTEN, RAD51C, CDH1, ATM, CHEK2 or PALB2 tumor suppression genes. NGS based sequencing panels allow fast and simultaneous screening of large number of high- and low-penetrance susceptibility genes in these patients.

Methods. In the current study we included a group of 31 Bulgarian female breast cancer patients, selected following the strict BCLC and NCCN criteria for hereditary cancer. All of them were prescreened by direct sequencing and MLPA analysis, and tested negative for pathogenic mutations in BRCA1 and BRCA2 genes. Next generation target resequencing using a panel of 94 cancer related genes (Illumina TruSight cancer panel) was performed to explore the hereditary component beyond BRCA1/2 genes in these patients. All detected mutations and variants of unknown clinical significance (VUSs) were confirmed by Sanger sequencing method.

Results. Pathogenic and likely pathogenic mutations were found in 14 out of 31 BRCA1/2 negative patients: 1 new frameshift mutation in ATM gene; 6 new likely pathogenic missense mutations in PTCH1, RAD51C, MET, MUTYH, ATM and CHEK2; 7 previously reported pathogenic missense variants in WRN, ERCC4, PALB2, PRF1, RET, SDHB and AIP genes. In addition 27 VUSs (one new splice donor variant in ALK gene and 26 missense variants) were found.

Conclusions. The use of next generation target resequencing with TruSight Cancer panel lead to identification of clinically relevant pathogenic variants in 45% of the investigated patients. This could be the preferred diagnostic method in HBOC patients, carefully selected according the strict BCLC and NCCN criteria.

Citation Format: Dacheva D, Dodova R, Mitkova A, Kamenarova K, Tzveova R, Popov I, Vlahova A, Taushanova – Hadjieva M, Valev S, Dikov T, Timcheva K, Christova S, Mitev V, Kaneva R. Exploration of the diagnostic utility of next generation sequencing with TruSight cancer panel for BRCA negative hereditary breast and ovarian 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 P2-09-18.
Abstract P2-11-07: Mutually exclusive expression pattern of the immune co-inhibitory molecules B7-H4 and PD-L1 in triple negative breast cancer
Authors: Shaffer DR , Nagashima K , Cortez-Retamozo V , Feldman I , Smith J , Zafari M , Larson R , Mabry R , Novorantseva T , Briskin M , Sathyanaryananan S
Published: May 2016

B7-H4 (VTCN1, B7x, B7S1) is a transmembrane protein belonging to the B7 family of costimulatory proteins and has been shown to inhibit T cell proliferation, cytokine secretion, and cytotoxic lymphocyte (CTL) induction. B7-H4 expressed on tumor cells or macrophages has been associated with poor prognosis and impaired T cell function in renal cell and ovarian cancers. Here we show B7-H4 is abundantly expressed in human breast cancer with triple negative breast cancer (TNBC) having the highest overall B7-H4 mRNA expression. We developed a specific and sensitive immunohistochemistry (IHC) assay for evaluation of B7-H4 protein and quantified B7-H4 expression in 156 breast tumor samples. Approximately 70% of the breast tumor samples had detectable B7-H4 expression whereas none of the normal or benign breast tissues stained positive for B7-H4. Multiplex IHC and flow cytometry studies showed that the majority of B7-H4 expression was restricted to the tumor epithelial cells, the CD45+ immune cells were negative for B7-H4 expression. Interestingly none of the TNBC samples that were positive for B7-H4 showed detectable expression of PD-L1 suggesting that B7-H4 and PD-L1 checkpoint proteins may act in a mutually exclusive manner.

To evaluate the role of B7-H4 on tumor immune evasion, we overexpressed murine or human B7-H4 on the mouse colon-26 (CT26) tumor cell line and injected these cells intravenously into Balb/c mice. By day 14 we observed significantly more tumors as well as larger percent tumor area in the lungs of mice given CT26 cells transduced with human or mouse B7-H4 as compared to vector control transduced cells. These data suggest B7-H4 expression in tumors can accelerate tumor growth in immune competent mice and that targeting B7-H4 may provide therapeutic benefit. Given the mutually exclusive expression patterns of B7-H4 and PD-L1 a B7-H4 targeting agent may provide particular benefit in those patients where current anti-PD-1/PD-L1 therapies are not effective.

Citation Format: Shaffer DR, Nagashima K, Cortez-Retamozo V, Feldman I, Smith J, Zafari M, Larson R, Mabry R, Novorantseva T, Briskin M, Sathyanaryananan S. Mutually exclusive expression pattern of the immune co-inhibitory molecules B7-H4 and PD-L1 in 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 P2-11-07.
Abstract P2-12-21: The “penny farthing” incision for mastectomy: A novel technique to reduce “dog ear” deformity and improve access to the axilla
Authors: Poole G , Sheikh L
Published: May 2016

Introduction:

Medial and lateral “dog ear” deformities are a common problem with mastectomy incisions. The challenges include different skin tensions superiorly and inferiorly and variable BMI. Also, the standard mastectomy incision is also not in the optimal place for sentinel node biopsy access.

No published technique is universally applicable and some advanced techniques require excess dissection and operative time.

Aims:

1) To perform a literature search for all published techniques

2) To pilot test a new, simple incision

Methods:

A literature search using PubMed was performed that revealed eight previous techniques (1).

A new, simple technique was developed to incorporate most of the historical principles. Circles of different sizes are marked out medially (small) and laterally (large). The lateral circle incorporates the optimal position for access to the axilla for sentinel node biopsy or axillary clearance. These circles are joined by asymmetrical superior and inferior lines to encourage rotation during closure. Tumour size and position are taken into consideration. Wound closure begins from the centre which allows the wound to "choose" its own corners and tuck them inwards therefore minimising "dog ear" formation.

Results:

Seventy- five consecutive patients had the procedure by a single surgeon over an 18 month period.

At the conclusion of each procedure there was no residual "dog ear" deformity at either wound end.

Of the 36 patients seen for 12 month follow up only one (BMI 42) has required revision of the wound.

Conclusion:

The "Penny Farthing" incision is a novel, simple and promising technique to deal with "dog ear" deformity in mastectomy.

Reference:

1. Thomas R, Mouat C, King B. Mastectomy flap design: the ‘waisted teardrop’ and a method to reduce the lateral fold. ANZ Journal of Surgery. 2012; 82: 329-333.

Citation Format: Poole G, Sheikh L. The “penny farthing” incision for mastectomy: A novel technique to reduce “dog ear” deformity and improve access to the axilla. [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 P2-12-21.
Abstract P2-12-22: Atypical ductal hyperplasia and breast cancers - A ten year clinical and pathological review on core biopsy, lumpectomy and mastectomy specimens
Authors: Co M , Kwong A
Published: May 2016

Introduction

Atypical ductal hyperplasia (ADH) is known to be associated with underlying pre-malignant or malignant breast conditions. Here we report our 10-year data on ADH found in core biopsy, lumpectomy and mastectomy specimens

Methods

From 1st January 2005 to 31st December 2014, a total of 104 core needle biopsy specimens and 218 lumpectomy / mastectomy specimens were found to contain ADH. Clinical, radiological and pathology data were retrieved and analysed from a prospectively-maintained database.

Results

Out of the 104 patients with core biopsy showing ADH, 101 patients received excision and 3 refused operation. 34 patients turned out to have ductal carcinoma in-situ (DCIS) on excision, while 6 had invasive ductal carcinoma (IDC), 1 had lobular carcinoma in-situ (LCIS) and 1 had angiosarcoma resulting in an upstaging rate of 40.4% (42/104). The remaining patients had benign lesions including papillary lesions, fibrocystic disease, or ADH alone. Multivariate analysis found that the only correlating factor for the presence of DCIS or IDC was suspicious mammographic features (BIRADS 4 or above) (P = 0.008 and 0.02 respectively) but not other parameters such as extent of micro-calcifications (P = 0.12) or age (P = 0.11).

Histopathological diagnosis after excision of lesions containing ADH on core biopsyExcisional Biopsy ResultNumber (%)DCIS34 (32.7%)ADH32 (30.8%)Benign27 (26%)IDC6 (5.8%)LCIS1 (0.9%)Angiosarcoma1 (0.9%)Refuse operation3 (2.9%)

218 lumpectomy or mastectomy specimens were found to harbor ADH. 62 (28.4%) had co-existing pre-malignant or malignant breast diseases. The only determining factor for the presence of malignant or pre-malignant condition was suspicious breast imaging features (BIRADS 4 or above) after multivariate analysis (P = 0.0003).

Co-existing conditions in the lumpectomy / mastectomy specimens with ADHCo-existing Patholog(ies)Number (%)Atypical Ductal Hyperplasia alone97 (44.4%)Fibroadenoma / Fibrocystic disease31 (14.2%)Intraductal papilloma22 (10%)Phyllodes tumor6 (2.8%)Ductal carcinoma in-situ36 (16.5%)Invasive ductal carcinoma23 (10.6%)Lobular carcinoma in-situ1 (0.5%)Invasive lobular carcinoma1 (0.5%)Malignant phyllodes tumor1 (0.5%)

Conclusion

ADH is closely related to the presence of invasive cancer or DCIS especially when suspicious breast imaging features are present. The upstaging rate is still high in patients where initial biopsy was ADH.

Citation Format: Co M, Kwong A. Atypical ductal hyperplasia and breast cancers - A ten year clinical and pathological review on core biopsy, lumpectomy and mastectomy specimens. [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 P2-12-22.
Abstract P2-13-05: A head to head comparison between SurgiMend® - Fetal bovine acellular dermal matrix and Epiflex® - Decellularized human skin tissue in breast reconstruction in 127 cases
Authors: Eichler C , Vogt N , Brunnert K , Sauerwald A , Puppe J , Warm M
Published: May 2016

Introduction: The use of acellular dermal matrices (ADM) has become a widely used option in breast reconstruction. A great deal of literature is available, totaling over 2400 ADM reconstructions. Nonetheless, head to head comparisons between SurgiMend® and Epiflex® are not yet reported. In fact, this is the first clinical data report on the use of Epiflex®. This work will therefore compare postoperative complication rates and costs for these ADMs.

Methods: This analysis is a retrospective review of a single surgeon's 6-year experience with both SurgiMend® – an acellular bovine dermal collagen matrix for soft-tissue reconstruction and Epiflex® – a decellularized human skin tissue from 2008 to 2013.

Results: One hundred patients had a total of 127 implant based reconstructions using SurgiMend® (64 cases; 50.4 %) or Epiflex® (63 cases; 49.6%). Gross complication rates were 11.1 % for SurgiMend® and 40.6 % for Epiflex® including hematoma, postoperative skin irritation, infection, necrosis and revision surgery. The most common complication was postoperative red breast syndrome . Severe complications requiring revision surgery were significantly increased in patients treated with Epiflex® (12.5 %) compared to SurgiMend® (4.8 %). Conclusions: This retrospective analysis favors the use of SurgiMend® over Epiflex® due to significantly lower gross complication rates. Severe complication rates are comparable to those reported in literature for both products. Although results promote the use of SurgiMend®, the single surgeon, retrospective nature of this work limits its clinical impact.

Citation Format: Eichler C, Vogt N, Brunnert K, Sauerwald A, Puppe J, Warm M. A head to head comparison between SurgiMend® - Fetal bovine acellular dermal matrix and Epiflex® - Decellularized human skin tissue in breast reconstruction in 127 cases. [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 P2-13-05.
Abstract P2-13-11: Assessing the impact of post-surgery areola repigmentation and 3-dimensional nipple tattoo procedures on body image and quality of life among medically underserved breast cancer survivors
Authors: Burke NJ , Orenstein F , Napoles T , Chaumette S , Luce J
Published: May 2016

Background: The benefits of 3D nipple tattooing include restoration of a natural looking breast as well as the avoidance of additional surgeries to create a breast that more closely resembles its pre-surgical appearance. 3D nipple tattooing forms part of completion of the physical reconstruction process, offers women opportunity for a greater sense of closure around the loss of their breast, and plays an important role in helping a woman feel "whole again" physically, sexually and emotionally. The project's aim was to evaluate the experience of 3D-nipple/areola tattooing for medically underserved women who have undergone breast reconstruction and remain without a nipple or areola.

Methods: In-depth interviews were conducted with 20 women who had undergone 3D-nipple/areola tattooing. Interviews were conducted in English and Spanish, recorded, translated and transcribed into English for analysis. Two research team members coded all interview transcripts and the research team met monthly to discuss emergent themes.

Results: Interview narratives addressed the often unexpected impact 3D nipple-tattooing had on body image, self-esteem, emotional well-being, intimacy, and inter-personal relationships. Women described their decision-making processes as weighing concern about the needle, the pain, and the uncertainty of the outcome with the opportunity for returning to a more 'normal' appearance. Women also discussed the impact of the experience on their survivorship and sexuality in positive ways.

Conclusions: 3-D nipple and/or areola tattooing is an acceptable and meaningful reconstruction process for medically underserved public hospital patients. The decision to undergo 3-D nipple and /or areola tattooing can be complex and is impacted by a women's surgical history and outcomes. The emotional response and positive impacts of the tattooing on body image and self-esteem illustrate the value of the procedure in the context of women's lives.

Citation Format: Burke NJ, Orenstein F, Napoles T, Chaumette S, Luce J. Assessing the impact of post-surgery areola repigmentation and 3-dimensional nipple tattoo procedures on body image and quality of life among medically underserved breast cancer survivors. [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 P2-13-11.
Abstract P3-01-11: Sentinel lymph node (SLN) localization is highly successful after neoadjuvant chemotherapy (NCT) for breast cancer
Authors: Sugg S , Hayes R , Gbenon A , Lizarraga I , Erdahl L , Weigel R , Liao J , Menda Y , Scott-Conner C
Published: May 2016

Background: Recent multi-center trial results are concerning for the ability to identify SLNs after NCT. SLN localization was shown to be less successful (80%) after NCT when compared with no NCT (99%) (SENTINA), and the SLN identification rate in Z1071 in which all patients received NCT was 93%.

Purpose: To examine the effect of NCT, patient and disease characteristics, imaging and surgical technique on SLN localization rates in breast cancer patients undergoing chemotherapy.

Methods: Retrospective, single institution study was performed on patients who underwent surgery for breast cancer from January 2008 to December 2013. All patients who underwent SLN biopsy and either adjuvant chemotherapy (ACT) or NCT, were included. All patients underwent lymphoscintigraphy, and SLN biopsy was performed with the definitive breast surgery.

Results: 68 patients underwent NCT, and 133 underwent ACT. Our SLN localization rate was 198/201 (98.5%) overall; 98.6% (67 of 68) with NCT and 97.7% (130/133) with ACT (p=1.0). Compared with the NCT group, the ACT patients were significantly older, white, with more ER/PR positive tumors. The NCT group had more positive nodes on preop imaging (64% v. 20%, p<0.001), FNA (82% v. 22%, p<0.001), and a lower use of blue dye (37% v. 61%, p=0.05) but there were no differences in the number of SLN removed (1.43 v. 1.33 p=0.32), or nodes that were positive on intraoperative evaluation (30 v. 33%, p=0.75). Comparing the patients who had successful and failed SLN localization, there were no differences in demographics, tumor type, Stage, prior breast surgery, preoperative node positivity on imaging or FNA or timing of chemotherapy.

Conclusion: In this single institution series, SLN non-localization was a rare event and not associated with NCT. We were unable to identify any patient or disease characteristics, imaging or surgical techniques associated with SLN non-localization. The etiology of the lower SLN identification rates with NCT in multi-institutional trials remains to be elucidated.

Citation Format: Sugg S, Hayes R, Gbenon A, Lizarraga I, Erdahl L, Weigel R, Liao J, Menda Y, Scott-Conner C. Sentinel lymph node (SLN) localization is highly successful after neoadjuvant chemotherapy (NCT) for 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 P3-01-11.
Abstract P3-01-14: A nomogram to predict the likelihood of axillary non-sentinel lymph node metastases in sentinel lymph node positive primary breast cancer patients
Authors: Hartkopf AD , Brucker SY , Helms G , Henzel M , Hahn M , Wallwiener M , Schoenfisch B , Taran F-A , Fehm TN
Published: May 2016

Background:

Completion of axillary lymph node dissection (ALND) was long lasting standard in patients with non-metastatic primary breast cancer (PBC) and axillary sentinel lymph node (SLN) involvement. However, this approach is currently questioned since recent prospective trials have found that some SLN-positive women with PBC might not benefit from subsequent ALND. Nomograms that estimate the probability of further non-sentinel lymph node (NSLN) metastases could guide clinical decisions.

Methods:

We compared the predictability of three different nomograms (MSKCC, Stanford University, Cambridge) on the NSLN status with an own logistic regression model in a training and validation set. SLN-positive women who underwent primary surgery including ALND at Tuebingen University, Germany, between 06/2005 - 12/2009 (training set) and 01/2010 - 02/2012 (validation set) were available for this analysis. The area under the receiver operating characteristics (ROC) curve was calculated for each nomogram.

Results:

295 and 175 patients were included into the training and validation set, respectively. Of these 118 (40%) and 57 (33%) patients were NSLN-positive. Variables within our model were tumor size, proportion of positive SLNs, size of SLN metastases, lymphangiosis carcinomatosa, multicentricity and extracapsular invasion. The respective area under the ROC curve values for the MSKCC / Stanford University / Cambridge / own regression model were 0.73 / 0.70 / 0.63 / 0.75 in the training set and 0.73 / 0.66 / 0.52 / 0.73 in the validation set.

Conclusion:

The predictability of our logistic regression model was comparable to the MSKCC nomogram and superior to the Stanford University and Cambridge nomogram. Although a training and a validation set was used, further testing on an independent patient population is warranted.

Citation Format: Hartkopf AD, Brucker SY, Helms G, Henzel M, Hahn M, Wallwiener M, Schoenfisch B, Taran F-A, Fehm TN. A nomogram to predict the likelihood of axillary non-sentinel lymph node metastases in sentinel lymph node positive primary 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 P3-01-14.
Abstract P3-01-21: Is lymph node ratio (LNR) having additional contribution for predict prognosis on pathologic lymph node staging in node-positive breast cancer patients?
Authors: Kaplan MA , Odabasi H , Ozdemir N , Harputluoglu H , Aliustaoglu M , Berk V , Gunaydin Y , Uncu D , Elkiran T , Aydin D , Isikdogan A
Published: May 2016

PURPOSE:

The aim of the study was to determine whether LNR have additional contribution on pathologic lymph node staging.

METHODS:

To examine the prognostic value of LNR examined the original histopathological reports of 2049 node-positive breast cancer patients treated in the references centers of the Turkey. The LNR was defined as the number of positive lymph nodes (LNs) over the total number of LNs removed. The LNR cutoffs were defined as low-risk, 0.01-0.20; intermediate-risk, 0.21- 0.65; and high-risk, LNR >0.65.

RESULTS:

The median follow-up was 11.8 years. Median Disease free survival (DFS) was 191.8, 110.6 and 78.2 months in patients with pN1, pN2 and pN3 tumor, respectively (p<0.001). Median DFS was 191.9, 106.4 and 78.1 months in patients with LNR low, intermediate and high risk tumor, respectively (p<0.001). Median DFS was not reached and 200.1 months in patients with pN2 and LNR low risk patients, pN1 and LNR high risk patients, respectively (p=0.254).

CONCLUSIONS:

LNR is an important prognostic parameter for DFS and might provide potentially more information than pN-stage in patients with pN1/LNR high risk and pN2/LNR low risk.

Citation Format: Kaplan MA, Odabasi H, Ozdemir N, Harputluoglu H, Aliustaoglu M, Berk V, Gunaydin Y, Uncu D, Elkiran T, Aydin D, Isikdogan A. Is lymph node ratio (LNR) having additional contribution for predict prognosis on pathologic lymph node staging in node-positive 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 P3-01-21.
Abstract P3-03-04: Establishment and characterization of ESR1-mutant breast cancer PDX models
Authors: Wick MJ , Helman E , Meade J , Clark MJ , Vaught T , Tolcher AW , Rasco D , Patnaik A , Lang A , Beeram M , Papadopoulos KP
Published: May 2016

The estrogen receptor (ER or ESR1) drives proliferation and growth of luminal type breast cancers. Endocrine therapies are highly effective in a majority of these cancers types; however, disease progression eventually occurs due to acquired resistance resulting in hormone-independent breast cancer. One mechanism of resistance is acquired mutations at codons 537 and 538 in the ligand binding domain of the receptor which are found in ∼12% of pretreated, ER+ patients. These mutations result in constitutive ER activation and hormone-independent progressive disease.

Although ESR1 mutated breast cancers are insensitive to endocrine therapy, novel agents targeting these mutations may be effective; however few preclinical models of ESR1-mutant breast cancer are available for preclinical analysis. To this end we have established two patient derived xenograft (PDX) models harboring mutations at codon 537; ST941 with ESR1Y537S and ST1799 with ESR1Y537C. We have characterized these models using genomic analysis and compared with analysis from paired or serially collected clinical tissue and blood. Dependence on estradiol for model growth and sensitivity to endocrine therapies were also evaluated and compared with a hormone-dependent breast cancer models.

The ESR1 mutations were not present in primary clinical tissue while several additional mutations were identified including in TP53 and PIK3CA genes. In vivo the ESR1 mutant models grew in the presence or absence of exogenous estradiol and demonstrated reduced sensitivity to endocrine therapies compared with hormone-dependent breast cancer models. ST941 treated with tamoxifen, letrozole or fulvestrant reported moderate tumor growth inhibition versus control while tumor stasis or regressions were reported in MCF-7 and hormone-dependent PDX breast models.

Overall we have established and characterized two models of ESR1 mutant breast cancer which can be utilized for development of targeted therapies.

Citation Format: Wick MJ, Helman E, Meade J, Clark MJ, Vaught T, Tolcher AW, Rasco D, Patnaik A, Lang A, Beeram M, Papadopoulos KP. Establishment and characterization of ESR1-mutant breast cancer PDX 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 P3-03-04.
Abstract P3-03-05: Establishment and evaluation of ER+ breast cancer models using an optimized methodology for exogenous hormone delivery
Authors: Wick MJ , Vaught T , Meade J , Gamez L , Farley M , Tolcher AW , Rasco D , Patnaik A , Drengler RL , Rosenthal A , Papadopoulos KP
Published: May 2016

Preclinical in vivo models of estrogen receptor positive (ER+) breast cancer rely on exogenous supplementation of hormones for growth. This requirement leads to animal toxicity and mortality over time, limiting development and drug testing in these types of models. Efficacy of test agents, particularly endocrine therapies, may also be altered in these models due to excessive hormone exposure, highlighting the need to improve methods for the establishment and testing of ER+ breast models.

We have developed an alternative method of hormone supplementation in ER+ breast cancer models and optimized this method for testing of endocrine therapies. Using two cell-based breast models, we demonstrated improved breast tumor take and time to tumor volume endpoint while reducing animal toxicity and mortality associated with standard hormone supplementation. Subsequent studies identified the lowest effective dose (LED) of supplement for hormone dependent model growth with a preclinically relevant time to tumor volume endpoint. Activity of endocrine therapies including tamoxifen, letrozole, fulvestrant and exemestane were compared at the standard and LED hormone concentrations. In these studies tamoxifen treatment resulted in tumor regressions which was not appreciably improved using the LED dose of supplement. However letrozole activity was improved in the LED study suggesting hormone supplementation can impact activity of some agents. Using this process we also generated a panel of ER+ patient-derived xenograft (PDX) models, including two novel hormone therapy responsive models from chemo-naïve or hormone therapy pretreated patients, designated ST986 and ST2177, respectively.

This improved method of hormone supplementation diminishes the adverse effects of standard hormone supplementation and provides utility for development of anticancer therapies in ER+ breast models.

Citation Format: Wick MJ, Vaught T, Meade J, Gamez L, Farley M, Tolcher AW, Rasco D, Patnaik A, Drengler RL, Rosenthal A, Papadopoulos KP. Establishment and evaluation of ER+ breast cancer models using an optimized methodology for exogenous hormone delivery. [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 P3-03-05.
Abstract P3-05-09: Exploring bazedoxifene and palbociclib as potential therapeutic strategies for overcoming ESR1-mediated endocrine resistance
Authors: Nguyen M , Buchwalter G , Luo F , Garraway L , Brown M , Jeselsohn R
Published: May 2016

INTRODUCTION

Despite effective endocrine treatments, endocrine resistance remains a major clinical challenge. We and other groups have recently detected ligand-binding domain ESR1 mutations in metastatic estrogen receptor positive ( ER+) breast cancers. Our preclinical studies showed that these mutations confer constitutive activity and relative resistance to tamoxifen and fulvestrant. In this study we sought to investigate therapeutic strategies to overcome resistance rendered by the ESR1 mutations. Since our previous studies showed relative resistance to tamoxifen or fulvestrant, we hypothesized that bazedoxifene, a high affinity third generation SERM/SERD could overcome resistance driven by the ER mutant resistance. Additionally, we hypothesized that inhibiting cyclin D1, a key ER transcriptional target gene and cell cycle regulator, is a second potential therapeutic strategy to circumvent resistance rendered by mutant ER. Therefore in this study we tested the effects of bazedoxifene, palbciclib and their combination on cell proliferation in the presence and absence of the ESR1 mutations.

METHODS

For this study we established doxycycline inducible MCF7 cell lines expressing the ER-LBD mutations (Y537S, Y537N and D538G) and WT-ER as control. Cell proliferation response to bazedoxifene, tamoxifen, fulvestrant, palbociclib and the bazedoxifene-palbociclib combination was evaluated.

RESULTS

Cells harboring mutant ER were relatively resistant to tamoxifen and fulvestrant, as expected, and remained sensitive to single agent bazedoxifene and palbociclib. The combination of bazedoxifene and palbociclib was found to be superior to the single agents and exhibits synergistic activity.

CONCLUSION

The combination of bazedoxifene and palbociclib inhibits mutant ER cell growth and other cell models of endocrine resistance and is a potential therapeutic combination.

Citation Format: Nguyen M, Buchwalter G, Luo F, Garraway L, Brown M, Jeselsohn R. Exploring bazedoxifene and palbociclib as potential therapeutic strategies for overcoming ESR1-mediated endocrine resistance. [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 P3-05-09.
Abstract P3-05-10: Non-coding RNAs derived from near the ESR1 gene acts as a transcriptional regulator during estrogen deprivation adaptation of ER positive breast cancer cells
Authors: Fujiwara S , Saitoh N , Tomita S , Abdalla MO , Iwase H , Nakao M
Published: May 2016

Endocrine therapies that blocks estrogen production are effective for estrogen receptor (ER)-positive breast cancer. However, endocrine therapy treated patients eventually experience relapse after a long period of estrogen deprivation. The mechanism underlying acquisition of estrogen independent growth by ER positive breast cancer cells remains unclear.

To understand such molecular mechanism, we used a cell model LTED (long term estrogen deprivation) which MCF7 cells were cultured under estrogen deprivation for 4-10 months. In LTED cells, we found that ER encoded gene ESR1 was up-regulated and ER overproduction was essential for estrogen-independent cell growth. We also revealed that RNA transcriptions of the ESR1 and several neighbor genes were co-induced from both coding and non-coding regions in LTED cells, using RNA-sequence. These highly transcribed regions were corresponded to active histone modifications and transcription factor bindings according to publically available genome-wide analyses data. Fluorescence in situ hybridization (FISH) analyses indicated that RNA from the chromatin domain region nearby ESR1 were co-localized and made foci in nucleus.

We found non-coding regions that are particularly highly transcribed. FISH analyses indicated that RNAs from these regions might interact with the parental ESR1 gene locus. Recent studies have shown that non-coding RNAs are involved in transcriptional regulation and chromatin regulation. To understand the role of the non-coding RNA, we have generated MCF7 cells lines that lack the non-coding site, using CRISPR/CAS9 system. We found that mRNA transcription of multiple genes including ESR1 were impaired by the deletion. These findings suggested that these non-coding RNAs may be involved in chromatin regulation of the chromatin domain nearby ESR1.

In this study, we found non-coding RNAs that control transcription of chromatin domain genes in ER positive breast cancer cells. Such non-coding RNA mediated transcriptional regulation might be critical for endocrine therapy resistance adaptation.

Citation Format: Fujiwara S, Saitoh N, Tomita S, Abdalla MO, Iwase H, Nakao M. Non-coding RNAs derived from near the ESR1 gene acts as a transcriptional regulator during estrogen deprivation adaptation of ER positive breast cancer cells. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-10.
Abstract P3-05-15: Spatial and temporal genomic heterogeneity of estrogen receptor and clinical impact in a patient with advanced breast cancer
Authors: Rizel S , Dvir A , Soussan-Gutman L
Published: May 2016

Endocrine therapy targeting Estrogen receptor alpha (ERα) is a key therapeutic strategy for hormone-driven breast cancer. Resistance to endocrine therapy may be intrinsic, arising from different clones or acquired by evolution influenced by selective pressure conditioned by therapy. Emerging evidence points to the role of acquired ERα mutations in driving resistance, when detected in the metastases but were absent from primary tumor.

Here we studied tumor genomic evolution in a patient who developed two distinct recurrent consequences. The first recurrence was located at the lung and developed 14 years from diagnosis. In the adjuvant setting, the patient was treated with chemotherapy and had no endocrine therapy incorporated. On initial recurrence, the patient was treated with aromatase-inhibitor which resulted in complete response and the site is free of tumor now for 5.7 years. However, 2 years into endocrine therapy with aromatase-inhibitor the patient developed a single hepatic metastasis and treatment was changed to fulvestrant for 8 months with slow ongoing progression. The patient had partial hepatectomy, cholecystectomy and metastatectomy 3 months after fulvestrant was stopped. Histology and immunohistochemical stains confirmed breast origin, ER +2, 100%, PR +3, 100%.

The endocrine therapy resistant hepatic lesion was sequenced by hybrid capture Next Generation Sequencing (NGS) and ERα (D538G) mutation was detected along with PIK3CA and GATA3 typical for hormone+ breast cancer. We have studied the primary tumor by same NGS method and detected only the PIK3CA and GATA3 mutations. In the lung lesions, responsive for endocrine therapy when sequenced by NGS the ERα (D538G) resistant mutation was absent.

Clinical data for treatment of ERα (D538G) mutation driving endocrine resistance is lacking. The patient could not tolerate tamoxifen and failed treatments with aromatase-inhibitor and chemotherapy, losing 14 kg in weight. Treatment with megestrol acetate 160 mg was initiated and patient achieved partial response confirmed by hepatic MRI and an improved performance status which is now ongoing for 8 months.

This case represents the first evidence of heterogeneous response to endocrine therapy explained by presence/absence of ERα (D538G) resistant mutation along with evidence for an active treatment in not an uncommon scenario.

Citation Format: Rizel S, Dvir A, Soussan-Gutman L. Spatial and temporal genomic heterogeneity of estrogen receptor and clinical impact in a patient with advanced 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 P3-05-15.
Abstract P3-06-14: DSS1 depletion is a promising strategy increasing chemosensitivity possibly independent of BRCA2 expression
Authors: Gondo N , Rezano A , Kuzushima K , Iwata H , Kuwahara K
Published: May 2016

Background

DSS1 (deleted in split-hand/split-foot malformation 1) was originally identified as a BRCA2-associated protein, and its downregulation results in the degradation of BRCA2. Some reports demonstrated that BRCA2 overexpression was correlated with histopathological grade III in sporadic breast cancers, implicating the involvement of BRCA2 overexpression in the proliferation rate of breast cancer cells. Because DSS1 is a stabilizer of BRCA2, we investigated whether altered expression of DSS1 was associated with malignant advancement of sporadic breast cancers. By comparison of DSS1 mRNA level, we reported that the high DSS1 expression groups in breast cancer patients showed worse prognosis in relapse-free survival; however, DSS1 expression per se was not correlated with other clinical parameters including cellular proliferation or tumor grade. Therefore, we hypothesized that breast cancer cells highly expressing DSS1 might be resistant to anti-cancer drugs, and compared chemosensitivity in overexpression or underexpression of DSS1 in breast cancer cells.

Methods

We established MCF7 overexpressing DSS1 (MCF7/DSS1) by retroviral transfection. DSS1 or BRCA2 knockdown in MCF7 was performed using siRNA transfection. The susceptibility to the cytotoxic chemotherapy such as doxorubicin and paclitaxel in breast cancer cells was analyzed by flow cytometry to detect apoptosis.

Results

MCF7/DSS1 showed more resistant to cytotoxic drugs compared with GFP-control MCF7 transfectants (MCF7/GFP). The percentages of apoptotic cells in MCF7/DSS1 and MCF7/GFP treated by doxorubicin were 40.2% and 12.0%, respectively. Conversely, depletion of DSS1 in breast cancer cells resulted in enhanced chemosensitivity compared to control cells. Although DSS1 knockdown induced the downregulation of BRCA2, BRCA2 depletion itself did not show such enhancement of chemosensitivity.

Conclusion

Consistent with the cohort study of sporadic breast cancers, we demonstrated that high expression of DSS1 increased resistance of breast cancer cells to cytotoxic chemotherapy in vitro. Conversely, DSS1 knockdown increased the susceptibility to these drugs in spite that BRCA2 depletion did not affect chemosensitivity. These results indicate that DSS1 could be a molecular target to increase chemosensitivity, which is independent of BRCA2 expression.

Citation Format: Gondo N, Rezano A, Kuzushima K, Iwata H, Kuwahara K. DSS1 depletion is a promising strategy increasing chemosensitivity possibly independent of BRCA2 expression. [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 P3-06-14.
Abstract P3-07-19: Progesterone receptor positivity is an independent predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer
Authors: Fohlin H , Nordenskjöld A , Fornander T , Löfdahl B , Skoog L , Stål O
Published: May 2016

Introduction:The expression of estrogen receptor (ER) and progesterone receptor (PgR) predicts the response to endocrine therapy of breast cancer. Nearly all PgR positive tumors are also ER positive. The independent predictive information of PgR has been questioned after an overview by the EBCTCG. However, the studies in the overview were performed before modern PgR immunohistochemistry (IHC) was developed.

Purpose: We aim to investigate the independent predictive value of PgR determined by IHC in ER positive tumors.

Materials and methods: Between 1976 and 1990 the Stockholm Breast Cancer Study Group conducted a randomized trial comparing adjuvant tamoxifen versus control. We evaluated 618 patients with ER-positive "low-risk" breast cancer ( tumor size≤ 30 mm and lymph node-negative) for whom PgR was determined by immunohistochemistry. The median follow-up was 17 years. Hazard ratios (HRs) and 95 % confidence intervals (CIs) were estimated using the Cox's proportional hazards model.

Results: Patients with ER+/PgR+ tumors receiving tamoxifen had a reduced recurrence risk compared with those who were not treated with tamoxifen (HR= 0.40, 95% CI 0.27 – 0.59, p< 0.001). For patients with ER+/PgR- tumors the difference between tamoxifen vs. no tamoxifen treatment was not statistically significant (HR= 0.88, 95% CI 0.51 – 1.52, p= 0.65). P for interaction between the groups was 0.02.

Tam vs. controlPgR (IHC)HR (95% CI)P valueP for interactionRecurrence-free survival≥ 10 %0.40 (0.27 - 0.59)< 0.0010.02 < 10 %0.88 (0.51 - 1.52)0.65 Distant recurrence-free survival≥ 10 %0.41 (0.25 - 0.65)< 0.0010.08 < 10 %0.80 (0.44 - 1.47)0.47 Breast-cancer specific survival≥ 10 %0.35 (0.21 - 0.60)< 0.0010.11 < 10 %0.70 (0.37 - 1.33)0.28 

Conclusion: Our results indicate that the PgR expression adds predictive value to the ER expression regarding benefit from tamoxifen treatment.

Citation Format: Fohlin H, Nordenskjöld A, Fornander T, Löfdahl B, Skoog L, Stål O. Progesterone receptor positivity is an independent predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive 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 P3-07-19.
Abstract P3-07-22: RS1008805 polymorphism in CYP19A1 gene is related to the efficacy of hormone therapy in early breast cancer
Authors: Wang X , Shao X , Zheng Y , Shi L , Huang Y
Published: May 2016

Purpose It has been suggested that genetic polymorphisms in CYP19A1 gene were related to aromatase activity as well as circulating steroid hormone levels in postmenopausal women. Therefore, it is biologically reasonable that CYP19A1 rs1008805 (A/G) polymorphism may be associated with clinical outcome for hormone therapy.

Methods Genotyping for CYP19A1 polymorphism rs1008805 was performed on 287 women with HR-positive early breast cancer. Associations were evaluated between CYP19A1 rs1008805 genotypes and disease-free survival (DFS).

Results Based on the analysis of the whole cohort, no significant differences were observed between rs1008805 genotypes and DFS, 5-year DFS rate. However, in postmenopausal women, rs1008805 genotypes were significantly associated with DFS and 5-years DFS rate (AA versus AG versus GG: 89.2 months versus 58.2 versus 32.7 months; 55.9% versus 47.8% versus 0%; P = 0.019). In addition, when the population was subgrouped into two cohorts, women carrying GG variant have a poorer DFS, 5-years DFS rate (GG versus AA or AG: 32.7 months versus 70.6 months; 0% versus 52.1%; HR, 3.613; 95% CI,1.380-9.457; P = 0.005). Furthermore, being adjusted by patients features in multivariate analyses, GG genotype remained an independent prognostic factor for DFS (HR, 3.439; 95% CI, 1.251-9.456; P = 0.017). However, there was no significant differences in DFS and 5-years DFS rate between women harbor the minor allele and those with the homozygous common allele (AG or GG versus AA: 52.4 months versus 89.2 months; 41.0% versus 52.9%; HR, 1.288; 95% CI, 0.705-2.353; P = 0.408). In addition, there were no differences between rs1008805 polymorphisms and DFS among premenopausal women.

Conclusions The homozygous minor allele (GG) of CYP19A1 rs1008805 is significantly associated with worse clinical outcome of hormone therapy in postmenopausal HR-positive early breast cancer patients. If confirmed, genotyping for CYP19A1 polymorphisms rs1008805 may provide predictive information for better selection of endocrine treatment.

Citation Format: Wang X, Shao X, Zheng Y, Shi L, Huang Y. RS1008805 polymorphism in CYP19A1 gene is related to the efficacy of hormone therapy in early 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 P3-07-22.