bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-14-11: Gene-expression analyses identify altered transcription factors and supports the antitumor activity of novel bromodomain inhibitors in triple negative breast cancer
Authors: Ocana A , Perez-Peña J , Serrano-Heras G , Corrales-Sanchez V , Montero JC , Gascón-Escribano MJ , Picazo MG , García-Olmo DC , Martin M , Pandiella A
Published: May 2016

Introduction: Identification of novel therapeutic targets in triple negative breast cancer (TNBC) is a main goal. In silico evaluation of human tumors by gene expression analyses can identify functions that could be pharmacologically inhibited. BET bromodomain inhibitors are a new family of compounds that reduce activity of oncogenic transcription factors through the inhibition of bromodomains.

Material and methods: We performed gene expression and functional analyses comparing triple negative tumors with normal breast samples. RT-PCR was used to evaluate genes down-regulated by treatment with the BET bromodomain inhibitors JQ1 and OTOX15 at different time points in MDA-MB231 cells. Cell proliferation and colony growth was measured by MTT uptake and 3D growth in matrigel in a panel of cell lines including HS578T, BT549, MDA-MB231 and HCC3153 treated with JQ1 and OTOX15. Evaluation of apoptosis and cell cycle was performed by flow cytometry using Annexin V and propidium iodide, respectively. Western-blot was used for evaluation of protein expression. Xenografted animals were used for the assessment of the in vivo activity of JQ1.

Results: Gene expression analyses identified upregulated genes including a number of transcription factors. These genes were more expressed in MDA-MB231 compared with MCF-10A. Treatment with JQ1 reduced the expression of some transcription factors at different time points. JQ1 and OTX015 reduced proliferation and cell growth in a panel of triple negative cell lines. They also led to arrest at the G0/G1 phase in HS578T and MDA-MB231 at 12 and 24 hours; that was confirmed by the biochemical evaluation of cell cycle mediators. An induction of apoptosis was observed at 48 hours in HS578T. JQ1 at 50 mg/kg daily reduced tumor growth in MDA-MB231 xenografted in nude mice.

Conclusion: Gene-expression profiling identified upregulated transcription factors in triple negative tumors compared with normal breast human samples. BET bromodomain inhibitors reduced the expression of some of these genes in cellular models. JQ1 shows clear antitumor activity in vitro and in vivo.

Citation Format: Ocana A, Perez-Peña J, Serrano-Heras G, Corrales-Sanchez V, Montero JC, Gascón-Escribano MJ, Picazo MG, García-Olmo DC, Martin M, Pandiella A. Gene-expression analyses identify altered transcription factors and supports the antitumor activity of novel bromodomain inhibitors 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 P3-14-11.
Abstract P4-01-04: Immunohistochemical and histological features of mammographic dense and non-dense tissue in breast cancer patients
Authors: dos Santos CC , Marshall P , Torresan R , Tinóis E , Duarte G , Teixeira S
Published: May 2016

Objective: We investigated immunohistochemical and histological composition of dense and non-dense breast tissue in 18 women undergoing mastectomy as the initial treatment for breast cancer. Materials and Methods: In each mammogram, we localized the dense and the non-dense areas. We used a localization technique based on a linear approximation method with interpolation of mammogram images and breast pictures. The selected areas were retrieved during mastectomy and analyzed. Results: Estrogen and progesterone receptors, Ki-67 and CD-34, were equally expressed in both tissues, as well as the percentage composition of fat. The percentage compositions of brownish spots among dense and non-dense tissues were significantly different (p = 0.0226). The number of terminal ductal lobular units was higher for dense than for non-dense breast tissues (p = 0.0019). In the non-dense breast tissue, there were no proliferative lesions with atypia, while we found flat epithelial atypia in 3 of the dense areas evaluated. Proliferative lesions without atypia and non-proliferative lesions were found in both tissues, but they were more frequent in dense than in non-dense breast tissues (23.5% vs 11.8%, p = 0.0455, and 17.6% vs 2.9%, p = 0.0253, respectively). Fibrosis was more frequently extensive or moderate in dense tissue, while it was predominantly mild in non-dense tissue (p = 0.03). Conclusion: There was no difference in the expression of the estrogen and progesterone receptors, Ki-67 and CD-34, in the dense and non-dense tissue areas in breast-cancer women. In addition, both stroma fibrosis and epithelial proliferation were responsible for higher mammographic density.

Citation Format: dos Santos CC, Marshall P, Torresan R, Tinóis E, Duarte G, Teixeira S. Immunohistochemical and histological features of mammographic dense and non-dense tissue in 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 P4-01-04.
Abstract P4-01-06: Microcalcifications as imaging biomarker in breast cancer: High-throughput radiogenomic analysis using microarrya data
Authors: Shin SU , Kim W , Song SE , Chu A , Han W , Moon WK
Published: May 2016

Purpose: To investigate relationships between microcalcifications and gene expression pattern using microarray analysis in breast cancer.

Materials and methods: The institutional review board approved this retrospective study and waived the informed consent. Clinicopathologic finding, mammographic features, and gene expression data were evaluated in 133 women (mean age, 50.1 years; range, 21-79 years) with stage I-III breast cancer. Women with microcalcifications (n=33) and without microcalcifications (n=100) were compared. Immunohistochemical analysis of estrogen receptor, progesterone receptor, HER-2, and Ki-67 expression was performed. Differentially expressed genes (DEGs) using Affymetrix GeneChip® Human Gene 2.0 ST arrays (53,427 probes) were identified in tissue with microcalcifications versus without microcalcifications. In addition, genes included in the prediction analysis of PAM50, MammaPrint® and OncotypeDX® were also compared between two groups (microcalcifications versus no calcification). To further investigate the functions and underlying biology of DEGs, we performed enrichment analysis using the Gene Ontology database and pathway anlyais using the Kyoto Encyclopedia of Genes and Genomes database and Ingenuity Pathway Analysis.

Results: Among clinicopathologic varibales, HER2 positivity (p<0.001) and presence of comedo necrosis (p=0.024) are significantly higher in the calcification group. About 128 genes had differential expression (> 1.5 fold difference, adjusted p value<0.05). Among known gene signatures, GRB7 (fold change=2.26, p=0.006) and ERBB2 (fold change=2.13, p=0.001) which are known as associated with recurrence, cell invasion and poor survival were highly expressed. In contrast, ZNF385B which is associated with p53-mediated apoptosis and good prognosis was underexpressed (fold change=0.39, p=0.001) in calcification group. Significant gene ontology terms included response to wounding, coagulation, wound healing, and response to hypoxia. Network and canonical pathway analysis indicated that increased cellular movement, cellular growth and proliferation, cellular develoment, coagulation and atherosclerosis signaling in breast cancer with microcalcifications, suggesting biological aggressiveness.

Conclusion: Gene expression patterns are different according to microcalcifications status in breast cancer. Breast cancers with mammographic microcalcifications are associated with metabolic aggressiveness and poor prognosis.

Citation Format: Shin SU, Kim W, Song SE, Chu A, Han W, Moon WK. Microcalcifications as imaging biomarker in breast cancer: High-throughput radiogenomic analysis using microarrya data. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-01-06.
Abstract P4-03-02: Up-classification of suspicious breast masses using opto-acoustic imaging
Authors: Lavin PT , Stavros AT , Ulissey MJ
Published: May 2016

Purpose: Breast cancer diagnostic methodologies have been optimized to achieve increased sensitivity at the expense of relatively low specificity. Seno Medical's opto-acoustic (OA) imaging fuses real time co-registered, temporally interleaved laser optic and ultrasound imaging showing dual functional (hemoglobin de-oxygenation) and morphology findings for breast masses using a hand-held probe. We present data from the PIONEER Pilot study (n=100). We have shown improved specificity for OA relative to the ultrasound component (IUS) and the site determination by conventional diagnostic ultrasound (CDU). We now examine the BI-RADS upgrades for 36 malignant masses achieved by OA versus IUS and the site determinations using CDU.

Materials and Methods: A total of 7 independent registration readers (IRRs) blindly assessed all 36 malignant masses using IUS first and OA second without any knowledge of clinical data or outcome. Among the cancers, there were 2 BI-RADS 4b, 12 BI-RADS 4c, and 22 BI-RADS 5 according to participating site radiologists' CDU evaluations. IRRs trained to identify and score three OA internal features and two OA external features for all masses were immediately offered the results of two nomograms based on their OA feature scores to predict the Probability of Malignancy (POM), which was then used to assign a BI-RADS category.

Results: Combining data from all 7 readers, OA findings enabled upgrades of site CDU-determined BI-RADS categories 43% of the time for BI-RADS 4b and 29% for BI-RADS 4c; in contrast, the overall percentages of IUS upgrades versus site CDU were 21% for BI-RADS 4b and 10% for BI-RADS 4c. Overall, 12% of all OA reads resulted in upgrades in contrast to 4.4% for IUS compared to site CDU BI-RADS classifications. Relative to IUS, the overall percentages of OA upgrades were 58% for BI-RADS 4b and 34% for BI-RADS 4c. OA has comparable sensitivity to IUS.

Conclusions: OA was more likely than IUS to result in a BI-RADS upgrade of a malignant mass. If subsequently confirmed, OA findings may help identify more cancers prior to biopsy. The 2,095 PIONEER Pivotal Study will allow for confirmation.

Clinical Relevance: The ability to upgrade BI-RADS 4b and 4c for cancer masses is an unmet need. If verified, these findings could provide additional evidence to confirm a malignant mass earlier and spare subsequent diagnostic evaluations. This may help plan the efficient identification and excision of malignant masses.

Citation Format: Lavin PT, Stavros AT, Ulissey MJ. Up-classification of suspicious breast masses using opto-acoustic imaging. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-03-02.
Abstract P4-03-09: Malignant hyperechoic lesions in breast ultrasound - Frequency and characteristics
Authors: Camacho J , Horvath E , Pizzolon MF , Pinochet MA , Gallegos M , Galleguillos C , Uchida M , Cadiz F , Silva C
Published: May 2016

PURPOSE

Challenge current axiom regarding hyperechogenic lesions in breast US categorized as mainly benign lesions. 2) Present frequency of malignant hyperechoic lesions, describe their sonographic and histological characteristics.

METHOD AND MATERIALS

IRB approved retrospective review of 2369 consecutive US-guided Core biopsies between 2006 and 2014. Lesions were considered hyperechogenic when more than 90% of its volume had higher echogenicity than surrounding subcutaneous tissue. Variables assessed were: age, size, histology, mass or non-mass, margins, echogenicity, acoustic effect, orientation, location, presence of a hypoechoic center, vascularization and BI-RADS category. Qualitative variables were described by percentage distribution, mean and SD.

RESULTS

Thirty one (1,3%) lesions biopsied were hyperechoic: only 17 (54.8%) were benign. We found 14 patients (range, 39-81 years, mean 57,5 years) with hyperechoic cancers, accounting for 1,77% of all cancers. 12 (85,7%) were ductal and 2 (14,3%) lobular histology (mean 17,5 mm range 8-40mm). All of them exhibited a small central hypoechoic area and were partially or completely surrounded by fatty tissue. Shape, margins, orientation and vascular architecture were highly suggestive of malignancy at US, mammography and in MRI (BI-RADS 4B and 5). On histology, all lesions were surrounded by fatty tissue, with a low–cell count collagenous center with a higher peripheral cellularity, mixing and interweaving with adipose tissue.

CONCLUSION

Hyperechogenic breast cancers are rare (1.77%), and we challenge the current concept of high rate of benignity with a 45,2% of chances for malignancy. We propose that hyperechogenicity is given by interweaving bundles with adipose tissue, which provide higher amount of acoustic reflective surfaces, thus explaining its sonographic pattern.

CLINICAL RELEVANCE/APPLICATION

Hyperechogenic breast lesions should not be considered as always benign. Malignancy thresholds should not be influenced by this sonographic characteristic.

We propose histopathological explanation of this sonographic pattern.

Citation Format: Camacho J, Horvath E, Pizzolon MF, Pinochet MA, Gallegos M, Galleguillos C, Uchida M, Cadiz F, Silva C. Malignant hyperechoic lesions in breast ultrasound - Frequency and characteristics. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-03-09.
Abstract P4-07-08: The prognostic significance of ataxia-telangiectasia-mutated (ATM) and p53 expression in breast cancer
Authors: Suh KJ , Ryu HS , Lee K-H , Im S-A , Kim T-Y , Kim H , Yang Y , Moon H-G , Han S-W , Oh D-Y , Han W , Kim T-Y , Park IA , Noh D-Y , Bang Y-J
Published: May 2016

The purpose of this study was to investigate the correlation of ataxia-telangiectasia-mutated (ATM) protein and p53 expression with clinicopathological features and prognosis in patients with sporadic breast cancers. The expression of ATM and p53 was determined by immunohistochemistry in 420 surgically resected breast cancers. Loss of ATM was observed in 126 out of 407 evaluable cases (31.0%), and was significantly associated with aggressive features with large tumor size, lymph node metastasis, higher tumor grade, and negativity of ER and/or PR. ATM loss was associated with a significantly shorter disease-free survival (DFS) (p = 0.019). Abnormal p53 expression was found in 39.3% of tumors (157 out of 400), conferring a worse DFS as well (p = 0.002). When investigated together, combined ATM and p53 expression status were associated with a worse DFS (p = 0.002). On multivariate analysis, ATM loss and abnormal p53 expression status was an independent predictor of poorer DFS (intact ATM and normal p53 vs. ATM loss and abnormal p53, HR 3.350; 95% CI 1.496 - 7.502; p = 0.003). Furthermore, in patients treated with adjuvant anthracyclines, either p53 alone or p53 combined with ATM significantly influenced DFS (p = 0.004, p = 0.015, respectively). The present study demonstrates that expression of ATM and p53 is an independent prognostic marker in breast cancers, and might be a practical tool for predicting benefits from anthracycline-based adjuvant therapy.

Citation Format: Suh KJ, Ryu HS, Lee K-H, Im S-A, Kim T-Y, Kim H, Yang Y, Moon H-G, Han S-W, Oh D-Y, Han W, Kim T-Y, Park IA, Noh D-Y, Bang Y-J. The prognostic significance of ataxia-telangiectasia-mutated (ATM) and p53 expression in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-07-08.
Abstract P4-09-04: Robust 7-gene signature for recurrence prognosis of breast cancer validated in formalin-fixed paraffin-embedded samples
Authors: Chacolla RJ , Trevino VM , Scott SP , Guzman EA , Cardona S
Published: May 2016

BACKGROUND: Breast cancer (BC) is a heterogeneous disease with diverse biological-molecular characteristics and clinical behaviors. Traditionally, prediction of recurrence in patients recently diagnosed is a big challenge for oncologists. In the last decade, advances in gene expression profiling technologies have improved the genetic knowledge of breast cancer by reporting several prognostic gene-signatures. However, there is still a need for covering the molecular heterogeneity of this cancer. Integration of public microarray data could be used to identify better and robust predictive gene-signatures. The aim of this study was to investigate prognostic genes that might function as biomarkers to differentiate among all heterogeneous BC patients, into those with high, medium or low recurrence risk.

METHODS: We collected nine public datasets, 1574 BC patients with median follow-up time of 10 years. The data were split into train-test, 50% each. Train was subject to univariate and multivariate analysis to generate a signature, which was validated in the test data. Seven genes were identified with high accuracy for recurrence prediction. This signature was validated in 40 formalin-fixed paraffin-embedded (FFPE) Mexican BC tissues with clinical follow up of 3 to 13 years by quantitative RT-PCR assays.

RESULTS: We identified a 7-gene signature which showed an accuracy prediction measured by concordance index of 65.62% and Log-rank test p-value: 1 x 10-15. The validation of the gene-signature level expression in 40 FFPE samples in Kaplan Meier analysis showed prediction significance by concordance index of 65.25% and Log-Rank p-value: 0.0005.

CONCLUSIONS: This 7-gene signature may provide a powerful tool to guide the adequate treatment protocols in early-diagnosed breast cancer patients.

Citation Format: Chacolla RJ, Trevino VM, Scott SP, Guzman EA, Cardona S. Robust 7-gene signature for recurrence prognosis of breast cancer validated in formalin-fixed paraffin-embedded samples. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-04.
Abstract P4-09-05: Expression of breast cancer stem cell marker as a predictor of prognosis and response to trastuzumab in HER2-positive breast cancer
Authors: Seo AN , Lee HJ , Kim EJ , Jang MH , Kim YJ , Kim JH , Kim S-W , Ryu HS , Park IA , Im S-A , Gong G , Jung KH , Park SY
Published: May 2016

BACKGROUND: Breast cancer stem cells (BCSCs) have been suggested to have clinical implications for cancer therapeutics because of its proposed role in chemoresistance. The aim of this study was to investigate the impact of BCSC marker expression in clinical outcome and trastuzumab response HER2-postive breast cancer.

METHODS: We analyzed the clinical significance of BCSC marker (ALDH1 and CD44+/CD24-) expression in 242 HER2-positive primary breast cancers using immunohistochemistry. In addition, we examined the relationship between BCSC marker expression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab.

RESULTS: In the first set, ALDH1 positivity and CD44+/CD24- phenotype were detected in 10.0% and 29.9%, respectively. ALDH1 positivity and CD44+/CD24- phenotype correlated with hormone receptor negativity. In survival analyses, CD44+/CD24- phenotype, but not ALDH-1 expression, was found to be an independent prognostic factor for poor disease-free and overall survival of patients in entire group, and in subgroup not receiving trastuzumab. In HER2-positive primary breast cancer patients treated by adjuvant trastuzumab, CD44+/CD24- phenotype was also an independent poor prognostic factor for disease-free survival. However, ALDH1 positivity and CD44+/CD24- phenotype had no effect on trastuzumab response and survival in patients with metastatic HER2 positive breast cancer.

CONCLUSION: These results suggest that CD44+/CD24- phenotype can be used as a prognostic factor for clinical outcome and a predictive factor of trastuzumab response in patients with HER2-positive primary breast cancer.

Citation Format: Seo AN, Lee HJ, Kim EJ, Jang MH, Kim YJ, Kim JH, Kim S-W, Ryu HS, Park IA, Im S-A, Gong G, Jung KH, Park SY. Expression of breast cancer stem cell marker as a predictor of prognosis and response to trastuzumab in HER2-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 P4-09-05.
Abstract P4-09-19: Comprehensive multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast
Authors: Gatalica Z , Vranic S , Ghazalpour A , Xiu J , Ocal I , McGill J , Bender R , Discianno E , Sanati S , Reddy S , Pockaj B
Published: May 2016

Introduction: Malignant phyllodes tumors are rare breast malignancies (0.1% of all breast tumors) with limited effective treatment options for recurrent and metastatic disease. Recent trials indicated a potential for anti-angiogenic therapy in soft tissue sarcomas, which led us to investigate these pathways.

Materials and Methods: Thirty-five malignant phyllodes tumors (including two cases with matched primary and metastatic tumors) were profiled using gene sequencing (Next-generation and Sanger), gene copy number analysis (in-situ hybridization), whole genome RNA expression, and protein expression (immunohistochemical assay).

Results: RNA microarray assay showed consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin2, VCAM1, PDGFRA, PTTG1, and CYP3A5 in all cases analyzed (n=5). No mutations in KDR (VEGFR2) were detected (0/26). EGFR protein overexpression was observed in 25/26 (96%) of cases with amplification of the EGFR gene in 8 cases (33%). EGFR gene mutations were identified in 2 cases (8%) including one case with presumed pathogenic V774M mutation and one case with EGFRvIII mutation. The most common mutations included those of TP53 (50%) and PIK3CA (15%) while other mutations (BRCA1, BRCA2, RET, CDH1, MLH1, ATM) were rare affecting single phyllodes cases. Two cases with matched primary and metastatic cancers harbored the same mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively).

Conclusions: Comprehensive multiplatform profiling approach to phyllodes tumors identifies various molecular alterations of which some are potentially actionable. Our data suggests that anti-angiogenic therapy may also be effective in patients with malignant phyllodes tumor. Evaluation of EGFR pathway discovered consistent protein over-expression but rare activating mutations, which necessitates refinement in patient selection targeting these pathways.

Citation Format: Gatalica Z, Vranic S, Ghazalpour A, Xiu J, Ocal I, McGill J, Bender R, Discianno E, Sanati S, Reddy S, Pockaj B. Comprehensive multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-19.
Abstract P4-11-05: Safety of fertility preservation indicated by a diagnosis of breast cancer: A Swedish registry-matched cohort study
Authors: Rodriguez-Wallberg KA , Eloranta S , Krawiec K , Lissmats A , Liljegren A
Published: May 2016

Purpose

The number of women that perform fertility preservation (FP) before initiating chemotherapy for treatment of breast cancer is increasing. Our purpose was to investigate the safety of performance of fertility preservation with and without hormonal stimulation in the incidence rate of breast cancer relapse.

Patients and methods

The study was designed as a matched cohort study. Women who had undergone FP at the Reproductive Medicine clinic of Karolinska University Hospital (N=187), irrespective of whether hormonal stimulation was required or not, were considered exposed. For all exposed women, two age-matched women who had not undergone fertility preservation were identified in the Regional Breast Cancer Registry Stockholm-Gotland and the Swedish National Quality Registry for Breast Cancer (N=319). The proportional hazards assumption was evaluated by applying the Grambsch-Therneau test on the Schoenfeld residuals obtained from each model, respectively. When interpreting the test results, a significance level of 5% was used to determine statistical significance.

Results

In the exposed cohort, a higher proportion of women underwent FP with hormonal stimulation aiming at freezing eggs or embryos (81%, N=142), whereas only 19% underwent freezing of ovarian tissue or attempted egg retrieval without hormonal stimulation (N=35). The mean follow up time was 6.3 years (range: 1.5-17.8 years), and median follow-up: 5.7 years.

There was no evidence of non-proportional hazards with respect to the effects of fertility preservation on the risk of relapse in the whole FP cohort, irrespective if the women underwent hormonal stimulation or not for FP, or of receptor status or tumour size at diagnosis. A stratified Cox regression model that allowed separate baseline hazard functions for each level for the investigation of the effect of number of involved lymph nodes was performed. In this model, the effect of fertility preservation on the risk of relapse was virtually unchanged (IRR: 1.02, 95% CI:0.56-1.84).

Conclusion

Fertility preservation either using hormone stimulation or not is unlikely to cause substantially increase recurrence risk of breast cancer, and irrespective of the receptor status, tumorur size of lymph node compromise. The incidence of breast cancer relapse after hormonal or non-hormonal fertility preservation was not different from that of matched controls from the Regional Breast Cancer Registry in this large cohort study.

Citation Format: Rodriguez-Wallberg KA, Eloranta S, Krawiec K, Lissmats A, Liljegren A. Safety of fertility preservation indicated by a diagnosis of breast cancer: A Swedish registry-matched cohort study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-05.
Abstract P4-13-20: Activity of HP-based therapies as third and later lines for the treatment of HER2-positive metastatic breast cancer: A retrospective study from a single institution
Authors: Argolo D , Friedman M , Smyth L , Iyengar N , Singh J , Patil S , Norton L , Baselga J , Hudis C , Dang C
Published: May 2016

Background: Dual anti-HER2 blockade with trastuzumab and pertuzumab (HP) plus chemotherapy is an effective therapy (Rx) in the 1st-line setting for HER2-positive metastatic breast cancer (MBC). Our single arm phase II study included patients (pts) treated with HP plus paclitaxel in the 2nd-line setting with progression-free survival (PFS) benefit. Recently, we reported results from a retrospective study of pts treated at our institution, suggesting a longer PFS for those who received HP-based Rxs when compared to any other anti-HER2 based Rxs in the 2nd-line setting. To further assess the activity of this combination in later Rx lines, we conducted a retrospective analysis of pts with HER2-positive MBC who had progressive disease after 2nd-line and were treated with HP-based Rxs in the 3rd and later lines at MSKCC. Historically, the median (med) PFS in this setting with trastuzumab-based Rx is about 3-4 months.

Methods: Pts diagnosed with HER2-positive MBC and treated with HP-based Rxs at MSKCC between 1-1-2011 and 03-30-2015 and who progressed on 2nd-line Rx were identified through an institutional database. Primary endpoint was PFS in 3rd and later treatment lines.

Results: 70 pts who received any HP-based Rx in the 3rd or later lines of treatment were eligible. The med number of prior anti-HER2 Rx was 3. The baseline characteristics and Rxs are summarized in Table 1. The med PFS for the entire cohort was 5.7 months (95% CI, 4.8-6.5).

Conclusions: In this retrospective analysis involving heavly pretreated patients, HP-based Rx appears to be an active regimen and compares favorably to historical data. This supports the NCCN endorsement of HP-based Rx in later lines if HP has not been delivered previously.

Baseline Characteristics and treatments (n=70)Characteristic(n)(%)Age  Median56 Range27-83 Gender  Female70100.0Male00.0Race  Black1014.3White5477.1Other68.6Ethnicity  Non Hispanic6694.3Hispanic45.7ER/PR status  ER and PR negative2738.6ER and/or PR positive4361.4Type of disease  Non visceral1622.9Visceral5477.1Visceral CNS2130.0Anti-HER2 in early stage  Yes2941.4No4158.6Line of therapy  3rd line1927.14th line1521.45th line912.96th line912.97th line811.48th line and beyond1014.3HP-based regimens  Chemotherapy + HP5477.1Endocrine therapy + HP57.1HP alone912.9Other22.9

Citation Format: Argolo D, Friedman M, Smyth L, Iyengar N, Singh J, Patil S, Norton L, Baselga J, Hudis C, Dang C. Activity of HP-based therapies as third and later lines for the treatment of HER2-positive metastatic breast cancer: A retrospective study from a single institution. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-20.
Abstract P4-14-09: Cardiac safety of trastuzumab without an anthracycline in patients with HER2-positive early stage breast cancer: A single center experience
Authors: Mukku RB , Verma S , Liu J , Steingart R , Hudis C , Yu AF , Dang C
Published: May 2016

Background: Trastuzumab (H) improves disease-free survival and overall survival in HER2+ early breast cancer (EBC) but is associated with risk of treatment-induced cardiotoxicity especially when administered after an anthracycline. We performed a single center retrospective study to assess the cardiac safety of adjuvant trastuzumab therapy without anthracyclines in a real-world clinical setting.

Methods: Patients (pts) with HER2+ early breast cancer (EBC) who received H without anthracycline-based chemotherapy between January 2010 and June 2014 were studied. Patients enrolled in a clinical trial were excluded. Tumor characteristics, chemotherapy regimen, cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. A cardiac event (C.E.) was defined as New York Heart Association class III or IV heart failure with LVEF decline of > 10% to < 55% or possible/probable cardiac death, as previously defined by the NSABP B-31 trial.

Results: In total, 174 pts with HER2+ EBC treated with H-based therapy without anthracyclines were identified. Median age was 59 years (range, 32 to 85 years), 72 (41%) had hypertension, 55 (32%) had hyperlipidemia, 29 (16%) had diabetes, and 5 (3%) had coronary artery disease. At baseline, all pts had a LVEF > 50% (median, 66%; range, 50% to 81%). Two (1.1%) pts developed a C.E. Both pts had risks factors for C.E. (1 - age > 60 years, hypertension, and prior history of anthracycline exposure; 1- age > 60 years, hypertension, hyperlipidemia, and baseline LVEF of 50-55%). After discontinuation of H, both patients had recovery of LVEF to > 50% and resolution of heart failure symptoms. Twelve (6.9%) pts developed asymptomatic LVEF decline of > 10% points to < 55% during H therapy. Of the 14 patients who developed cardiotoxicity, H was prematurely interrupted or discontinued in 8 patients.

Conclusion: In our single center experience of patients being treated off study, the incidence of C.E.s and asymptomatic LVEF decline during H therapy without an anthracycline was 1.1% and 6.9%, respectively. These appeared higher than events reported in clinical trials possibly due to the inclusion of an older group of women with a higher prevalence of cardiovascular risk factors. Overall, the incidence of symptomatic heart failure is low for H without an anthracycline even in this older group.

Citation Format: Mukku RB, Verma S, Liu J, Steingart R, Hudis C, Yu AF, Dang C. Cardiac safety of trastuzumab without an anthracycline in patients with HER2-positive early stage breast cancer: A single center experience. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-09.
Abstract P4-14-13: Pertuzumab (P) use in first-line HER2-positive metastatic breast cancer (mBC) in US community oncology practices: Treatment patterns and outcomes
Authors: Robert N , Goertz H-P , Asmar L , Tseng W-Y , Jiao X , Portera C , Yoo B , Patt D , Antao V
Published: May 2016

Background: Pertuzumab was FDA-approved in 6/2012 for use in first-line in combination with trastuzumab (H) and docetaxel for patients (pts) with HER2-positive mBC. This retrospective study investigated the clinical characteristics, treatment patterns, safety, and outcomes for pts with HER2-positive mBC who received a P-containing regimen in first-line in US community oncology practices.

Methods: This study utilized iKnowMed electronic health records, Claims Data Warehouse, and Social Security Death Index. Pts with HER2-positive mBC, who received a P-containing regimen between 6/2012 and 6/2014 and were followed through 12/2014, had ≥2 visits within the McKesson Specialty Health/US Oncology Network, and were not on clinical trials during the study period, were eligible.

Results: Of the 322 pts who received a P-containing regimen in the first-line setting, 25% were ≥65 years of age, 63% were post-menopausal, 61% had hormone receptor-positive mBC, 84% had a performance status of 0 or 1, and 76% had a Charlson Comorbidities Index of 0. Twenty-one percent of pts had 1 site of metastasis noted, 32% had 2 sites, and 47% had 3 or more sites. Pts with de novo mBC made up 40% of this cohort. Of the pts with recurrent mBC, over 60% received H in the early-stage BC setting. In the first-line mBC setting, 93% of the 322 pts received H+P+taxane, and 7% received H+P with other chemotherapy agent(s). Common adverse events reported included: fatigue (49%), diarrhea (44%), nausea (33%), peripheral neuropathy (33%), neutropenia (24%), and rash (22%). Further analyses including outcomes of these 322 pts will be presented.

Conclusions: First-line P was given in combination with H and chemotherapy agent(s) (93% taxane). No new safety signals were observed. More details on the clinical characteristics, specific treatment patterns, and safety will be presented, along with the progression-free survival of these pts receiving first-line P-containing therapy in a real-world setting.

Citation Format: Robert N, Goertz H-P, Asmar L, Tseng W-Y, Jiao X, Portera C, Yoo B, Patt D, Antao V. Pertuzumab (P) use in first-line HER2-positive metastatic breast cancer (mBC) in US community oncology practices: Treatment patterns and outcomes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-13.
Abstract P4-14-26: Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including HER2-positive breast cancer patients with brain metastases
Authors: Baird RD , Arkenau H-T , Deva S , Cresti N , Garcia-Corbacho J , Hogarth L , Frenkel E , Kawaguchi K , Arimura A , Donaldson K , Posner J , Sarker D , Jodrell D , Plummer R , Spicer J , Italiano A
Published: May 2016

BACKGROUND

S-222611 is an oral, reversible ErbB tyrosine kinase inhibitor of EGFR and HER2 with potent pre-clinical activity. MTD was not reached during the dose-escalation phase, (maximum dose 1600 mg QD). PK and efficacy data supported a daily dose of 800 mg. An expansion cohort of patients has been treated to further explore safety and efficacy.

METHODS

Subjects with advanced solid tumors expressing EGFR and/or overexpressing HER2 were enrolled. S-222611 800 mg daily was administered until disease progression or unacceptable toxicity.

RESULTS

76 patients were included in this phase 1 expansion cohort with a variety of tumor types. Dose reduction was required because of adverse events in 15 patients; the most frequent of which being diarrhea and elevated bilirubin. Two patients discontinued treatment due to drug- related adverse events. Of the 25 patients with HER2-positive metastatic breast cancer (MBC), 4 partial responses were observed, and prolonged stable disease (≥ 6 months) was observed in 3 additional patients. These 25 patients had received prior HER2-directed therapy as shown in Table 1.

Table 1. Prior therapies received by patients with HER2-positive MBCPrior therapyn (%)Trastuzumab22 (88)T-DM13 (12)Lapatinib16 (64)Chemotherapy23 (92)

Six of these patients had brain metastases, in whom 1 intracranial response and 2 prolonged stable disease (≥ 6 months) were observed (Table 2).

Table 2. HER2-positive MBC patients with brain metastases - best overall response to S-222611Pts #HER2 IHCBrain metastasesBest overall response (RECIST 1.1)Patient 13+Target lesionPRPatient 23+Target lesionSD (≥12 M)Patient 33+Target lesionSD (6.0 M)Patient 43+Non-target lesionSD (4.7 M)Patient 53+Non-target lesionSD (3.3 M)Patient 63+Non-target lesionNE

The patient showing intracranial response was previously treated with lapatinib and capecitabine after diagnosis of BM.

CONCLUSIONS

S-222611 was well tolerated at a dose of 800 mg once daily. Anti-tumour activity, including shrinkage of brain metastases, was evident in a heavily pre-treated population of patients with HER2-positive breast cancer.

Citation Format: Baird RD, Arkenau H-T, Deva S, Cresti N, Garcia-Corbacho J, Hogarth L, Frenkel E, Kawaguchi K, Arimura A, Donaldson K, Posner J, Sarker D, Jodrell D, Plummer R, Spicer J, Italiano A. Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including HER2-positive breast cancer patients with brain metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-26.
Abstract P5-03-01: Therapeutic targeting of Rac GTPases in ER+ and HER2+ breast cancer
Authors: Hampsch RA , Shee K , Miller TW
Published: May 2016

As crucial regulators of cell motility, survival, and proliferation, Rac GTPases (Rac1/2/3) have been implicated in cancer. We previously found that P-REX1, a guanine nucleotide exchange factor that activates Rac GTPases, forms a PI3K-driven positive feedback loop to promote activation of Rac enzymes, receptor tyrosine kinases, PI3K/AKT/mTOR, and MEK/ERK in ER+ breast cancer cells. Importantly, inhibition of Rac GTPases with a small molecule (EHT1864) simultaneously suppressed activation of both the PI3K/AKT/mTOR and MEK/ERK pathways. While co-targeting of the PI3K/AKT/mTOR and MEK/ERK pathways with drug combinations has anti-tumor activity in preclinical models and is being tested in ongoing clinical trials, targeting Rac as a common upstream signaling node may be a more efficient means of simultaneously targeting these two oncogenic pathways.

In breast cancer cell lines, treatment with EHT1864 decreased activation of AKT, mTOR, p70S6K, and S6 in a dose-dependent manner. Pulldown of activated Rac from cell lysates revealed that GTP-bound Rac1 and/or Rac3 bind MEK1/2, ERK1/2, p70S6K, S6, Raptor, Rictor, and mTOR. Temporal analysis indicated that EHT1864 inhibits phosphorylation of p70S6K (an mTORC1 substrate) before AKT is inhibited, suggesting that Rac may directly activate p70S6K and/or mTORC1. Mining of sensitivity data from ∼700 cell lines to a panel of 138 drugs (COSMIC/GDSC database) revealed that the growth-suppressive effects of EHT1864 correlate most strongly with growth-suppressive patterns induced by a p70S6K inhibitor, supporting the notion that Rac directly activates p70S6K. Additionally, EHT1864 treatment dose-dependently decreased phosphorylation of ERK1/2 and MEK1/2, and induced apoptosis in breast cancer cell lines. In a panel of 16 breast cancer lines, cells with activating mutations in PIK3CA (encodes the p110-alpha subunit of PI3K) exhibit increased EHT1864 sensitivity. Pharmacokinetic analysis of EHT1864 (100 mg/kg, i.p.) in plasma in NSG mice revealed that drug was present at >50 uM for 1 h after administration. In mice bearing s.c. ER+/HER2+ BT-474 breast cancer xenografts, EHT1864 (100 mg/kg BID) significantly slowed tumor growth compared to vehicle control. Thus, therapeutically targeting Rac could be an effective means of reducing cancer cell proliferation and survival by simultaneously suppressing both the PI3K/AKT/mTOR and MEK/ERK signaling pathways in ER+ and HER2+ breast cancers.

Citation Format: Hampsch RA, Shee K, Miller TW. Therapeutic targeting of Rac GTPases in ER+ and HER2+ breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-03-01.
Abstract P5-03-13: The anticancer effects of Supinoxin® (RX-5902) in triple-negative breast cancer MDA-MB-231 through phosphorylated p68 on Tyr593
Authors: Kim DJ , Yang MY , Lee YB , Remenyi J , Fuller-Pace F
Published: May 2016

Several studies have indicated that the DEAD box RNA helicase DDX5/p68 plays several important roles in cancer (1, 2). In particular, p68 that is phosphorylated on Tyr593 has been shown to be associated with cell transformaton, epithelial mesenchymal transition (EMT) and cell migration (3). Therefore, phosphorylated p68 may be a promising target for novel anti-cancer therapeutics. We previously reported that 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] piperazine (RX-5902, Supinoxin®) inhibits the growth of cancer cells at low nanomolar concentrations by interacting with phosphorylated p68 on Tyr593, interfering with the phosphorylated p68-β-catenin signaling pathway (4). In this study, we sought to determine whether phosphorylated p68 on Tyr593 plays a key role in RX-5902's ability to inhibit cancer cell growth by knocking down p68. p68-siRNA efficiently down-regulated the expression of phosphorylated p68 on Tyr593 as well as p68 in the triple-negative (TN) breast cancer cell line, MDA-MB-231. Exposure of p68-siRNA-transfected cells to the IC50 concentration of RX-5902 protected MDA-MB-231 cells from the cytotoxic effects of RX-5902, indicating the phosphorylated p68 on Tyr593 is a key molecule for RX-5902 cytotoxic effects. We also examined the tumor growth inhibition (TGI) of RX-5902 in the human TN-breast tumor (MDA-MB-231) xenograft mouse model. Not only did RX-5902 demonstrate potent efficacy in this model but also oral administration with RX-5902 resulted in dose-dependent TGI and extended the overall survival of these animals. Oral administration of 160, 320 and 600 mg/kg of RX-5902 showed 54.4%, 84.4% and 100% TGI, respectively whereas 5 mg/kg of Abraxane (iv) showed only 48.2% TGI at day 29. Further studies demonstrated the inhibitory effects of RX-5902 on cellular motility in MDA-MB-231 in wound healing assays, suggesting the potential function of phosphorylated p68 on Tyr593 in cell migration (5). These data support the potential therapeutic activity of RX-5902 in triple negative breast cancers. A Phase 1 study of RX-5902 on relapse/refractory solid tumors is ongoing.

References

1. Fuller-Pace, FV, RNA Biology 10, 121–132 (2013)

2. Dai et al. Journal of Experimental & Clinical Cancer Research, 33, 64-71 (2014

3. Yang et al., Cell, 127, 139–155 (2006)

4. Kost et al., Journal of Cellular Biochemistry ;online: 3 FEB 2015 05:14PM EST | DOI: 10.1002/jcb.25113) (2015).

5. Remenyi et al, presented at 2015 AACR (2015).

Citation Format: Kim DJ, Yang MY, Lee YB, Remenyi J, Fuller-Pace F. The anticancer effects of Supinoxin® (RX-5902) in triple-negative breast cancer MDA-MB-231 through phosphorylated p68 on Tyr593. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-03-13.
Abstract P5-04-17: From transcriptome meta-analysis to targeted therapies in triple negative breast cancer
Authors: Rozali E , Al-Ejeh F
Published: May 2016

Triple-Negative Breast Cancer (TNBC) is a subtype of breast cancer that urgently requires the identification and approval of novel targeted therapies. Even for breast cancer subtypes that have approved targeted therapies such as tamoxifen in ER+ and herceptin in HER2+ patients, there are a proportion of patients that do not respond to these therapies or develop resistance and succumb to metastatic recurrence. Thus, there is a clinical need to identify patients who do not benefit from current standard therapies and developing new strategies for therapy for non-responsive patients across all breast cancer subtypes.

We hypothesised a potential prognostic and drug discovery approach by meta-analysis of multiple global gene expression profiles of breast cancer studies to identify significantly over- and under-expressed genes that associate with clinical outcomes (metastatic and/or death events within five years). These genes were filtered through 3 methods to annotate their predicted functions (1). The third and most generalised method identified a 133-gene signature set that was prognostic in all subtypes of breast cancer. These signatures, particularly with the devised score calculated as the ratio of the average expression of the over-expressed genes to the under-expressed genes, were patented (2). Of the 133 genes, we selected a 21-gene list representing novel and new targets in breast cancer drug development. The 21 genes were selected through an unbiased ranking of least-published cancer and non-cancer studies in PubMed.

This poster reports the characterisation of these 21 genes as drug targets in TNBC. A siRNA screen measuring proliferation and viability (xCELLigence RTCA) was performed (2 siRNAs per gene) on 3 TNBC cell lines (MDAMB231, SUM159PT and BT549) and MCF10A. The top gene hits that show a dependence on cancer proliferation and viability were followed up with clonogenic assays, cell cycle profiles and apoptosis assays. Parallel to these experiments, a negative-selection clustered regularly interspaced short palindromic repeats (CRISPR) screen involving the 21 genes (6 constructs per gene) is currently underway on MDAMB231 cell line in vitro and in vivo to identify cancer dependence on these genes for survival and metastasis.

References

1. Al-Ejeh, F., Simpson, P.T., Saunus, J.M., Klein, K., Kalimutho, M., Shi, W., Miranda, M., Kutasovic, J., Raghavendra, A., Madore, J., et al. 2014. Meta-analysis of the global gene expression profile of triple-negative breast cancer identifies genes for the prognostication and treatment of aggressive breast cancer. Oncogenesis 3:e124.

2. Al-Ejeh, F. 2015. PCT/AU2015/050096 (SUBMITTED).

Citation Format: Rozali E, Al-Ejeh F. From transcriptome meta-analysis to targeted therapies 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 P5-04-17.