bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-07-19: Effects of JAK pathway inhibition in pre-clinical models of breast cancer bone marrow metastases
Authors: Bottos Alessia , Gill Jason , Radimerski Thomas , Tzankov Alexandar , Wodnar-Filipowicz Aleksandra , Hynes Nancy E
Published: May 2015

Bone marrow (BM) metastases are an important problem in metastatic breast cancer. Metastatic-relapse occurs even decades after the first diagnosis and can show different clinical features compared to the primary disease. The cross-talk between cancer cells and the microenvironment influences tumor behaviour and impinges on therapeutic efficiency.

To uncover new targets for the inhibition of BM metastases, we performed a transcriptional analysis of BM stromal cells using in-vivo models of breast cancer bone metastases. We identified IL6, and its downstream JAK kinases pathway, as major up-regulated signals in the bone stroma of tumor-bearing mice. Moreover, we found that a significant proportion of BM metastases from breast cancer patient biopsies are positive for pSTAT3 staining, attesting to activation of JAK-STAT signaling. These results provide a rational to investigate the therapeutic potential of a JAK inhibition in bone metastases. We evaluated the effect of two JAK inhibitors: the BSK805, a JAK2 inhibitor, and ruxolitinib a JAK1-JAK2 inhibitor currently in clinical trials for metastatic breast cancer. In pre-clinical models of breast cancer metastases (the triple negative MDA-MB231 SCP1833 and the ER+ EO771), treatment with the JAK inhibitors decreased pSTAT3 signaling in the bone, but surprisingly increased metastastic tumor burden.

Considering the importance of the JAK-STAT pathway as a therapeutic target, we are investigating the possible bystander effects of blocking JAK kinases. Analysis of the BM stoma showed that JAK inhibition decreased TRAP+ osteoclasts and affected the mesenchymal compartment, with a significant increase in the BM fat compartment in tumor-bearing animals. The reasons for and the consequences of these changes in the bone stroma are under investigation. As the JAK-STAT signaling pathway is also a key regulator of the hematopoietic compartment, we are studying how JAK inhibitors influence the immune response in tumor bearing mice. Further dissection of the immunomodulatory effect of JAK inhibition and how this influences tumor dissemination and expansion is warranted.

Citation Format: Alessia Bottos, Jason Gill, Thomas Radimerski, Alexandar Tzankov, Aleksandra Wodnar-Filipowicz, Nancy E Hynes. Effects of JAK pathway inhibition in pre-clinical models of breast cancer bone marrow metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-19.
Abstract P1-09-31: Crowdsourcing the collateral damage from breast cancer treatment
Authors: Love Susan M , Obidegwu Amaka , Fischetti Christine A
Published: May 2015

INTRODUCTION: Although survivorship research focuses on quality of life after breast cancer treatments, it is usually initiated by providers and focused on previously reported side effects and consequences of treatment. Patients are often reluctant to report side effects they may experience during and after cancer treatment and providers are often reticent to ask. In an effort to explore the patient perspective, the Dr. Susan Love Research Foundation convened a collaboration of advocacy groups to "crowdsource" women’s questions regarding collateral damage from treatment. These concerns will then be incorporated into the Health of Women [HOW] Study, an ongoing, online cohort study of breast cancer open to anyone aged 18 or older.

METHODS: Emails to current HOW participants were sent out July 2013 to solicit questions about collateral damage. In October 2013, we undertook the design of a new website landing page for the submission of questions, partnered with other breast cancer advocacy organizations, and began collecting responses. Responses were then categorized to guide questionnaire development.

RESULTS: Sixteen breast cancer and other advocacy organizations came together to support this project. Emails to current HOW participants resulted in 1191 responses. The website landing page resulted in an additional 3000 responses. Overall, 16.8% of respondents complained of fatigue, 16.3% of memory problems, 15.7% of anxiety and/or depression, and 14.0% of numbness/neuropathy. Other less frequently reported problems included problems with nail growth, vision, hearing, urinary tract infections, and allergy-like symptoms.

CONCLUSION: Through this approach, we received an overwhelming number of responses about collateral damage from treatment. Many of the issues are known side effects, while others are less commonly reported, but debilitating nonetheless. We will next compare responses to previously validated questionnaires, develop a comprehensive collateral damage questionnaire for inclusion in the HOW Study, and generate a report for publication to be distributed to the participants.

Citation Format: Susan M Love, Amaka Obidegwu, Christine A Fischetti. Crowdsourcing the collateral damage from breast cancer treatment [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-09-31.
Abstract P1-15-16: The utilization of hypofractionated breast radiotherapy in the United States between 2003 and 2011
Authors: Huo Dezheng , Hasan Yasmin , Yao Katharine
Published: May 2015

Background: Recently, several randomized trials have found that accelerated hypofractionated whole breast irradiation (HF-WBI) had equivalent local recurrence rates and disease-free survival, compared to conventional fractionated whole breast irradiation (CF-WBI). It is unknown if the pattern of care regarding HF-WBI has changed in the United States after the publication of these trials, given its administrative advantage.

Methods: Using data from the National Cancer Database, this study included 559,362 non-metastasic female breast cancer patients who received post-lumpectomy external beam radiotherapy to their breast or regional nodes. We examined the trend of HF-WBI use in the U.S. and factors related to its use using logistic regression models.

Results: Of patients receiving external beam radiotherapy, about 5% underwent HF-WBI. The most common HF-WBI dose schedule is 42.4-42.6 Gy in 16 fractions without or with boost radiation. There was a 20-fold increased trend in the use of HF-WBI, increasing from about 0.6% in 2003 to 13% in 2011 (p<0.0001). Among patients with pT1-2N0-1 disease, a subgroup for whom previous clinical trials of HF-WBI are mainly applicable, HF-WBI use increased from 0.6% in 2003 to 14% in 2011. Although not included in previous clinical trials, patients with ductal carcinoma in situ also experienced an increased use of HF-WBI, from 0.5% in 2003 to 12% in 2011. We found age was strongly correlated with HF-WBI use; the older a patient, the more likely she received HF-WBI. African Americans were less likely to use HF-WBI. Patients with low grade were more likely to receive HF-WBI than those with high grade and patients with negative nodes are more likely to received HF-WBI. Large volume, academic cancer centers are more likely to adopt HF-WBI than community cancer programs. Interestingly, patients who live at least 50 miles away from a cancer center are about 58% more likely to receive HF-WBI than patients living within 50 miles of a cancer center.

Conclusions: The utilization of hypofractionated radiotherapy significantly increased from 2003 to 2011 in the United States, which is presumably influenced by publication of several randomized trials. In 2011, HF-WBI accounted for more than 10% of all external beam radiotherapy for early breast cancer patients. Patient and facility factors impacted the patterns of HF-WBI use.

Citation Format: Dezheng Huo, Yasmin Hasan, Katharine Yao. The utilization of hypofractionated breast radiotherapy in the United States between 2003 and 2011 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-16.
Abstract P2-05-09: Functional mapping of the oncogenic kinome activity of triple-negative breast cancer cells
Authors: Pan Bo , Mori Miki , Lee Pei Rong Evelyn , Hartog Marij , Sun Qiang , van 't Veer Laura , Coppe Jean-Philippe
Published: May 2015

Background: Triple-negative breast cancer (TNBC) accounts for approximately 10 to 15% of all breast cancer cases. The management of TNBC cases will significantly improve once molecular mechanisms specific to TNBC cells will be identified and treated accordingly. Evidence suggests that TNBC cells display deregulated kinase-dependent signaling cascades that differ from non-triple-negative breast cancer cells. We hypothesized that uniquely divergent phospho-circuits could be distinguished between TNBC and non-TNBC cell lines. By revealing such unique, dysfunctional phospho-signaling network, our long-term objective is to identify kinases that underpin triple-negative breast cancer development, and can be inhibited using targeted therapy.

Methods: The kinome activity of TNBC and non-TNBC cell lines was identified (HCC70, MDA-MB-231, MDA-MB-436 compared to AU565, MCF-7, T47D). The functional phospho-signature of each breast cancer cell was analyzed using a high throughput experimental platform that monitors the level of activity of myriad kinases at once. This technique uses 242 phospho-sensing probes and 78 controls in an aqueous-based assay to simultaneously and directly measure the phospho-catalytic activity of phosphorylating enzymes in cell lysates. We mapped the most significantly deranged phospho-signaling cascades and the related kinases.

Results: Using 6 cell lines tested under various conditions, we generated 72 phospho-signatures, out of a total of 23,040 data points. After validating the repeatability and robustness of the assay, the kinase activity signature of each breast cancer cell line was analyzed and compared to each other using unsupervised hierarchical clustering. The phospho-sensing assay revealed the heterogeneity of kinase activity networks among breast cancer cells. These data also established that phospho-signaling cascades related to AKT, ERK, and SRC kinases were differentially altered in TNBC and non-TNBC cell lines.

Conclusions: We successfully identified unique phospho-circuits of TNBC and non-TNBC cell lines. Our goal is now to test whether specific kinase inhibitors can efficiently kill or prevent the growth of TNBC cell lines in culture and animal models. We will expand our approach into a high-content, functional kinome-screening platform to characterize the phospho-fingerprint of breast cancer cells and tissues, and explore the druggable, kinase-dependent mechanisms critical to triple-negative breast tumors.

Citation Format: Bo Pan, Miki Mori, Pei Rong Evelyn Lee, Marij Hartog, Qiang Sun, Laura van 't Veer, Jean-Philippe Coppe. Functional mapping of the oncogenic kinome activity of triple-negative breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-05-09.
Abstract P2-06-03: Prostaglandin E receptor EP4 is a therapeutic target in breast cancer stem cells
Authors: Fulton Amy , Kundu Namita , Kochel Tyler , Ma Xinrong , Reader Jocelyn
Published: May 2015

There is an urgent need to identify mechanisms underlying the survival of cells expressing cancer stem cell or tumor-initiating properties. The cyclooxygenase-2 (COX-2) pathway is highly expressed in many breast tumors and contributes to poor outcomes. The COX-2 product prostaglandin E2 (PGE2) promotes tumor growth and metastasis by acting on the G-protein-coupled receptor EP4. We compared the expression and function of COX-2 and EP4 in mammosphere-forming and bulk populations derived from a panel of human and murine luminal and basal type tumor cells with different metastatic capacities. Expression of both EP4 and COX-2 were markedly increased in mammosphere-forming cells derived from basal and/or metastatic cells relative to the bulk population, but neither COX-2 or EP4 levels were elevated in mammospheres derived from luminal or non-metastatic cells. Breast cancer stem cells, expressing elevated EP4 are correspondingly more sensitive to inhibition with EP4 antagonists both in vitro and in limiting-dilution assays in vivo. Somewhat to our surprise, cancer stem cells remain relatively sensitive to lysis by Natural Killer cells. We have also shown that EP4 blockade protects NK cells from tumor-induced immune suppression. These studies identify EP4 as a potential therapeutic target in the general tumor cell population and show that EP4 targeting may selectively inhibit cells with tumor-initiating or stem cell properties. EP4 antagonists can directly inhibit cancer stem cells and tumor metastasis and indirectly support NK-mediated mechanisms of tumor control. We are delineating the mechanisms by which EP4 and COX-2 are upregulated in cells with stem-like properties. In addition to EP4 and COX-2, STAT3 is upregulated in stem cells. Inhibition of STAT3 reduces mammosphere-forming capacity. Our studies support a mechanism whereby COX-2/EP4 signaling induces STAT3 to support breast cancer stem cell survival by a feed-forward mechanism.

Citation Format: Amy Fulton, Namita Kundu, Tyler Kochel, Xinrong Ma, Jocelyn Reader. Prostaglandin E receptor EP4 is a therapeutic target in breast cancer stem cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-06-03.
Abstract P2-06-06: Mammospheres derived from circulating epithelial tumor cells are an indicator for presence of metastasis in patient with breast cancer
Authors: Pizon Monika , Zimon Dorothea , Pachmann Ulrich , Pachmann Katharina
Published: May 2015

Background:

A major obstacle in the successful treatment of cancer is the occurrence of metastasis. The presence of CETCs is closely related to tumor recurrence, but the mechanisms through which CETCs promote metastasis are still unclear. The aim of this study was to determine the proliferative capacity of CETCs by analyzing the frequency of mammosphere formation with subsequent phenotypic characterization of the spheres arising in breast cancer patients.

Methods:

CETCs were cultured under condition favoring growth of mammospheres from 38 patients with breast cancer, including a subpopulation of 13 patients with metastatic disease. Cell viability, stem cell marker expression and ALDH 1 activity was evaluated by fluorescence scanning microscope (Olympus Scan®R).

Results:

Sphere formation was observed in 74 % of patients with breast cancer. Patients with distant metastasis had higher numbers of mammospheres (median 13,0 vs 1,0; p≤0,001) compared to patients without metastasis. In multivariate analysis, a high number of mammospheres was associated with the presence of metastasis. The mammospheres area under the ROC curve was 0,99. Six or more spheres classified metastatic disease with a sensitivity and specificity of 96 % and 100 %, respectively. These results suggest that above cut-off six in the number of mammospheres is statistically highly indicator for disease progression. Analysis of surface marker expression profile of mammospheres showed that spheres cultured from CETCs had typical phenotype of cancer stem cells with a high enzymatic activity for ALDH 1 with the ALDEFLUOR assay. There was no sphere formation in a control group with 50 healthy donors.

Conclusion

This study demonstrates that a small fraction of CETCs has proliferative activity.

Identifying the CETC subset with cancer stem cells properties may provide more clinically useful prognostic information and may be a new indicator for the presence of metastases.

Citation Format: Monika Pizon, Dorothea Zimon, Ulrich Pachmann, Katharina Pachmann. Mammospheres derived from circulating epithelial tumor cells are an indicator for presence of metastasis in patient with breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-06-06.
Abstract P2-07-02: IGF1R/FAK crosstalk is essential for epithelial-to-mesenchymal transition (EMT), migration, and invasion of TNBC cells
Authors: Taliaferro-Smith LaTonia D , Oberlick Elaine , Liu Tongrui , McGlothen Tanisha Z , O'Regan Ruth
Published: May 2015

Triple negative breast cancers (TNBCs) are highly metastatic and deadly tumors that currently lack effective prevention and treatment options. Insulin-like growth factor 1 receptor (IGF1R) and focal adhesion kinase (FAK) both play a role in several developmental processes, and both IGF1R and FAK signaling pathways have been linked to a number of common pathological diseases, including breast cancers. In particular, overexpression of IGF1R and FAK are closely associated with metastatic breast tumors. However, the relationship between the IGF1R and FAK signaling cascades in metastatic TNBCs remain largely unknown. The present study aimed to investigate the interrelationship between IGF1R and FAK crosstalk in regulating the malignant properties of TNBC cells. Using stable small hairpin RNA (shRNA)-mediated IGF1R silencing and stable full-length IGF1R plasmid over-expression methods, we demonstrated that IGF1R was essential for maintaining mesenchymal morphologies of TNBC and regulating the expression of EMT markers, including vimentin, ZEB-1, Snail-1, E-cadherin, ZO-1, and claudin-1. Using colony formation, spheroid migration, and Matrigel invasion assays, we further showed that IGF1R promoted migratory and invasive TNBC phenotypes, including increased colony formation, cell migration, and invasion. Most importantly, IGF1R-mediated migration and invasion required FAK activation and could be augmented using pharmacological inhibitors of FAK. Our findings in TNBC cells demonstrate a novel role of the IGF1R/FAK signaling pathway in regulating critical processes involved in the metastatic cascade. These results may improve the current understanding of the basic molecular mechanisms of TNBC metastasis and provide a strong rationale for co-targeting of IGF1R and FAK as therapy for mesenchymal TNBCs.

Citation Format: LaTonia D Taliaferro-Smith, Elaine Oberlick, Tongrui Liu, Tanisha Z McGlothen, Ruth O'Regan. IGF1R/FAK crosstalk is essential for epithelial-to-mesenchymal transition (EMT), migration, and invasion of TNBC cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-07-02.
Abstract P2-07-06: Niclosamid overcomes epithelial-mesenchymal transition of lapatinib resistance through inhibiting Src activation in HER2 positive breast cancer
Authors: Liu Junjun , Chen Xiaosong , Mao Yan , Shen Kunwei
Published: May 2015

Background: The Src pathway is known to regulate tumor matastasis and plays a role in epithelial-mesenchymal transition(EMT). Lapatinib, although, has improved clinical outcome for HER2 positive breast cancer patients, acquired resistance to lapatinib remains an important reason influencing its clinical efficacy. Our previous research shows lapatinib acquired resistance HER2 positive breast cancer cell lines, SKBR3-R and BT474-R have EMT phenomenon and multiple pathway activated. Niclosamide is an FDA-approved antihelminthic agent, which is found has cytotoxicity effect on tumor stem cells recently. We wished to determine the effect of niclosamide on EMT and lapatinib resistance cells and investigate niclosamide as a potential therapeutic agent for HER2 positive breast cancer.

Methods: SKBR3 and BT474, two HER2 positive breast cancer cell lines, were continuously exposed to increasing doses of lapatinib to establish two stable cell lines resistant to lapatinib, SKBR3-R and BT474-R. Cell proliferation was determined by CCK8 assay. Protein expression was determined by western-blotting. Invasion ability was analyzed by transwell assay. FITC staining flow cytometry (FCM) was conducted to observe the percentage of apoptosis.

Results: Both two HER2 positive lapatinib resistant cell lines, SKBR3-R and BT474-R had EMT phenomenon. Niclosamide had a stronger inhibition effect on lapatinib resistant cell lines than parental cell lines, and induced more apoptosis by FCM. Western-blot showed niclosamide could reverse the EMT phenomenon of SKBR3-R and BT474-R with E-cadherin up-regulated and snail,vimentin down-regulated at the concentration of 0.5-1μM. A significant reduction of Src signaling was also confirmed, as well as the downstream Akt and Erk pathway. After adding niclosimide for 48 hours, SKBR3-R and BT474-R’s capability of invasion were inhibited.

Conclusion: Our results suggested that niclosamide had a strong cytotoxic effect on HER2 positive lapatinib resistant breast cancer cell lines. The EMT induced by lapatinib resistance could be reversed by niclosamide, associated with the inhibition of Src pathway activation, as well as the downstream pathways. Niclosamide treatment produced reduced levels of invasion, serving as a novel therapeutic way for lapatinib-resistant breast cancer patients.

Citation Format: Junjun Liu, Xiaosong Chen, Yan Mao, Kunwei Shen. Niclosamid overcomes epithelial-mesenchymal transition of lapatinib resistance through inhibiting Src activation in HER2 positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-07-06.
Abstract P2-13-13: Predictors of bilateral mastectomy in breast cancer patients
Authors: Fu Yun , Zhuang Zhigang , Dewing Michelle , Sophia Apple , Helena Chang R
Published: May 2015

Background: Breast cancer surgery has experienced an evolutional change from radical mastectomy to conservative techniques due to the migration of stage of disease at diagnosis and adjuvant use of multimodality treatment. While breast conservation is preferred by most, the trend of bilateral mastectomy has been on the rise in the United States. The aim of this study is to determine factors that may affect patients’ choice of bilateral mastectomy.

Methods: This is a retrospective study of 376 patients diagnosed with primary invasive breast cancer who were treated by bilateral or unilateral mastectomy (BM or UM) at the Revlon/UCLA Breast Center between Jan. 2002 and Dec. 2010. Patients in the bilateral mastectomy (BM) group were further divided into groups of bilateral mastectomy for bilateral breast cancer and for unilateral breast cancer and contralateral prophylactic mastectomy.

Results: When compared with the UM group, the following factors were found to be associated with the BM: younger age (p<0.001), pre-menopause (p<0.001), having a family history of breast cancer (p<0.001) or ovarian cancer (p=0.017), BRCA 1 and 2 mutations (p<0.001, p=0.011, respectively), more breast biopsies (p=0.007), history of breast augmentation (p=0.014), more MRI study within 6 months before the surgery (p=0.029), more likely to have reconstruction surgery (p<0.001) and sentinel lymph node biopsy (SLNB) (p<0.001). Multivariate analysis indicated that patients with smaller tumor size (p<0.001, OR 0.087), negative nodes (p<0.001), sentinel lymph node biopsy as nodal surgery (p<0.001, OR 0.259), BRCA mutation (p=0.020, OR 6.537) and positive family history (p=0.001, OR 2.732) were more likely to choose bilateral mastectomy with reconstruction using tissue expanders or implants (p<0.001, OR 4.546).

Conclusion: Bilateral mastectomy is associated with lower TN stage, requiring only SNLB, presence of BRCA mutation and/or high risk family history. Tissue expanders or implants based reconstructions were more frequently chosen by patients with bilateral mastectomy.

Citation Format: Yun Fu, Zhigang Zhuang, Michelle Dewing, Apple Sophia, Chang R Helena. Predictors of bilateral mastectomy in breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-13-13.
Abstract P2-13-20: Randomized clinical trial comparing 2-octylcyanoacrylate versus intradermic suture with nylon: Similar cosmetic results with different safety profile
Authors: Freitas-Junior Ruffo , Becker Thiago S , Rahal Rosemar MS , Paulinelli Regis R
Published: May 2015

Introduction: There are multiple options available for closing surgical incisions. This study compared the cosmetic results between the use of 2-octylcyanoacrylate and nylon sutures in elective breast surgery. Objectives: To compare the efficacy and cosmetic outcome between the adhesive and conventional suturing with nylon on the cutaneous synthesis mammary surgeries. Methods: we performed a prospective, randomized, controlled trial with 79 patients, 37 in group 2-octylcyanoacrilate and 42 in the group with nylon suture. We evaluated the surgical aspect of the scar in 40 and 180 days, the occurrence of complications (such as dehiscence, hematoma, infection and allergic reactions), the size of the wound and breast lesions, surgical time and skin closure time, hemoglobin and preoperative WBC, age, height and weight of patients. Statistical analysis was performed by t test and chi-square. Results and discussion: the study was stopped before the end of the recruitment of patients for the presence of a greater number of dehiscence in the adhesive group (OR: 11.42, 95% CI 1.36 - 96.02, p=0.007). There were no significant differences between the groups regarding other complications, not in relation to surgical time and the aesthetic appearance of scars after 40 and 180 days. The average size of the wound was greater in the adhesive group than in the suture, being respectively 32.97 (+ 10.54) mm and 27.64 (+ 9.56) mm, no correlation of size with the largest number of dehiscence. Conclusion: The results showed that the cosmetic scar appearance of 2-octylcyanoacrilate is equivalent to those obtained with the intradermal nylon suture, but the risk of dehiscence is higher.

Citation Format: Ruffo Freitas-Junior, Thiago S Becker, Rosemar MS Rahal, Regis R Paulinelli. Randomized clinical trial comparing 2-octylcyanoacrylate versus intradermic suture with nylon: Similar cosmetic results with different safety profile [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-13-20.
Abstract P2-13-23: The oncologic safety of nipple-areolar complex skin sparing mastectomy compared with skin sparing mastectomy: 8 years follow up results
Authors: Yeu Kyung Jun , Park Jeong Yeong , Choi Jung Eun , Kang Su Hwan , Bae Young Kyung , Lee Soo Jung
Published: May 2015

Background: Skin sparing mastectomy (SSM) has been conducted in breast cancer patient because of both oncologic safety and cosmetic satisfaction. Preservation of nipple-areolar complex (NAC) is helpful to keep more natural breast shape, but, can cause anxiety about local recurrence. This study reviewed long term follow-up result of SSM and nipple-areolar skin sparing mastectomy (NASSM), retrospectively.

Patients and methods: This study included 272 primary breast cancer patients who received SSM (94 patients) or NASSM (178 patients) except bilateral breast cancer from September 1996 to December 2008. Frozen section was conducted for analysis of NAC resection margin status. In case of positive resection margin, NAC was sacrificed. Local recurrence and overall survival of SSM and NASSM group was analyzed.

Results: The mean follow-up was 94.9 months. 81 NAC resection margins (29.8%) were invaded by tumor cells. The positive resection margin of NAC was associated with presence of ductal carcinoma in situ (p=0.005), especially extensive intraductal component (p=0.005) and invasive carcinoma with multiplicity (p=0.048). The patients in NASSM group tended to have more worse disease free survival than those in SSM group (75.3% vs 86.2%, P=0.087). But, in analysis of only local recurrence including NAC, there were 25 cases (14.0%, 7 in skin flap and 18 in NAC) of local recurrence in NASSM group and 8 (8.5%) in SSM group. Local recurrence free survival of the NASSM group was 86.0% and that of the SSM group was 91.5% (P=0.278). Distant recurrence after surgical treatment for local relapse occurred in only one SSM case. There was no significant difference for the overall survival between NASSM and SSM group (97.8% vs 96.8%, p=0.556).

Conclusion: In this study, result of long term follow up showed that patients in NASSM group tend to have more local recurrence than patients in SSM group, even if there is no statistically significance. However, surgically well-controlled local recurrence of skin flap and/or NAC did not affect on overall survival. NASSM is alternative method for SSM with oncological safety and better cosmetic outcome.

Citation Format: Kyung Jun Yeu, Jeong Yeong Park, Jung Eun Choi, Su Hwan Kang, Young Kyung Bae, Soo Jung Lee. The oncologic safety of nipple-areolar complex skin sparing mastectomy compared with skin sparing mastectomy: 8 years follow up results [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-13-23.
Abstract P2-16-03: C-Met is a potential therapeutic target for antibody-drug conjugates in breast cancer
Authors: Fu Yanwen , Gros Edwige , Lee Alice , Johnson Kimberly , Zhang Hong , Yalamanchili Silpa , Motamed Kouros , Chen Gary , Jones Bryan , Miao David , Kaufmann Gunnar F
Published: May 2015

C-Met, a transmembrane receptor tyrosine kinase, plays a key role in malignant transformation of epithelial cells by activating signal transduction pathways essential for cellular proliferation, survival, migration and invasion. C-Met overexpression, with or without gene amplification, has been reported in primary breast cancers and correlate with poor prognosis. C-Met signaling inhibition, such as tyrosine kinase inhibitors (TKIs), usually not sufficient for sustained treatment efficacy, we believe that antibody drug conjugates (ADCs) offer the promise and potential of delivering potent anti tumor activity with the advantage of reduced side effects. We generated antibody drug conjugates containing a proprietary human anti-c-Met antibody (STI-D0606) with either a tubulin inhibitor or DNA damaging agent, such as doxorubicin analogs. STI-D0606, a fully human antibody (IgG1) selected from phage library was conjugated with the cytotoxin via site specific bioconjugation. The conjugates retained binding affinity and showed potent cell killing in a variety of c-Met positive cell lines. Progress will be reported in terms of in vivo efficacy in c-Met-positive human breast tumor xenograft in preclinical models.

Citation Format: Yanwen Fu, Edwige Gros, Alice Lee, Kimberly Johnson, Hong Zhang, Silpa Yalamanchili, Kouros Motamed, Gary Chen, Bryan Jones, David Miao, Gunnar F Kaufmann. C-Met is a potential therapeutic target for antibody-drug conjugates in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-16-03.
Abstract P3-05-14: Modeling chemoendocrine therapy for ER+/p53wt luminal breast cancer
Authors: Cao Shiliang A , Lim Elgene , Brown Myles , Bailey Shannon T
Published: May 2015

Background

ER+ breast cancers are predominantly p53 wildtype (wt). Despite this genotype, these cancers are relatively resistant to chemotherapy-induced apoptosis in the presence of estrogen. Thus, current clinical practice is to administer hormonal therapy and chemotherapy sequentially rather than concurrently. Using the ER+/p53wt cell line MCF-7, we previously demonstrated that ER bound by either the ER agonist estradiol or partial antagonist tamoxifen inhibits the expression of a set of proapoptotic p53 target genes, whereas the full ER antagonist fulvestrant, a selective ER downregulator (SERD), removes the ER-mediated suppression of these genes, sensitizing breast cancer cells to p53-mediated cell death .We hypothesize that effective chemoendocrine therapy requires complete ER antagonism resulting in ER downregulation, increased p53 activity, and ultimately apoptosis.

Methods:

To model mechanisms of tumor sensitivity and resistance to therapy in vivo, therapeutic experiments were performed in immunodeficient mice bearing ER+/p53wt tumor xenografts derived from a 61-year-old African-American female with grade 2 invasive ductal carcinoma. The mice were randomly assigned to the following treatment groups: A) fulvestrant B) tamoxifen, C) doxorubicin, D) fulvestrant plus doxorubicin, E) tamoxifen plus doxorubicin, and F) control. Tumors were measured weekly for 42 days to determine treatment effects on growth. In addition, RNA was harvested from tumors at an early time point for RNA sequencing to determine genes regulated by the treatments.

Results:

Combination therapy comprising doxorubicin plus fulvestrant resulted in tumor regression compared with single-agent or doxorubicin plus tamoxifen treatment, which inhibited the growth of tumors but did not lead to their regression.

Conclusions:

Current paradigms for the treatment of ER+ breast cancer either in the adjuvant or advanced setting have involved the sequential use of endocrine therapy and chemotherapy. This protocol is partially based on evidence of potential antagonism between tamoxifen and chemotherapy as observed in early studies. Our published work in vitro and the preclinical study presented here suggest that complete ER antagonism with SERDs such as fulvestrant is required to overcome the ability of ER to block p53-mediated apoptosis. Our results suggest treatments involving fulvestrant concurrent with chemotherapies involving p53 activation should be considered for the treatment of patients with ER+/p53wt breast cancer.

Citation Format: Shiliang A Cao, Elgene Lim, Myles Brown, Shannon T Bailey. Modeling chemoendocrine therapy for ER+/p53wt luminal breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-14.
Abstract P3-07-27: Patterns of chemotherapy (CT) use by molecularly-defined subtype among a population-based cohort of breast cancer (BC) patients (pts) from California
Authors: Clarke Christina A , Chu Laura , Wang Lisa , Song Chunyan , Green Marjorie , Moy Lisa , Yang Juan , Tao Li , Gomez Scarlett Lin
Published: May 2015

Background: Guidelines describe recommended BC treatments (tx) according to tumor subtype; however, population-based data regarding tx utilization are limited.

Objective: To describe tx utilization by tumor HER2, hormone receptor (HR) status, and stage among representative pts from California.

Methods: We examined patterns of CT (including biologic tx) reported as received for all 131,450 female BC pts diagnosed with primary invasive BC in California between 1/1/2005 and 12/31/2011 in the California Cancer Registry, including n=19,918 HER2+ [65% HR+, 33% HR-]; n=91,919 HER2- [84% HR+, 15% HR-]; and n=19,613 HER2 unknown. Neoadjuvant & adjuvant CT data was only available for a subset of 35,040 pts diagnosed 2010-2011 (4,609 HER+; 27, 604 HER2-). Descriptive statistics were used for comparisons.

Results: CT was reported as highest among pts with metastatic breast cancer (MBC) and HER2+ status (Table 1). The proportion of pts with early BC (EBC) receiving CT increased from 58% in 2005 to 69% in 2010, but was generally steady for MBC pts (74.2% in 2005 to 79.6% in 2011). 20.7% of HER2+ pts received neoadjuvant CT vs 8.6% for HER2- pts. Similarly, adjuvant CT was more common in HER2+ (55.5%) than HER2- (28.5%) pts. As expected the proportion of pts receiving CT was lower in HR+ vs HR- pts for EBC and MBC [eg. all stages HER2+ (62% vs 71%); HER2- (33% vs 68%)].

Conclusion: In this population-based cohort, ∼20-40% of MBC pts may not have received any CT or biologics. CT was more commonly received by HER2+ patients compared to HER2- patients for both EBC and MBC.

Table 1. Patterns of chemotherapy (including biologics) use among California female BC pts by stage and HER2 status, 2005-2011EBCMBCHER2+HER2-HER2+HER2-Any chemotherapyNo5898 (33.4%)52467 (61.0%)317 (22.6%)1519 (43.7%)Yes11463 (64.8%)32403 (37.7%)1063 (75.9%)1894 (54.5%)Unknown322 (1.8%)1128 (1.3%)20 (1.4%)60 (1.7%)Any neoadjuvant therapy (2010-2011 data only)No3546 (76.9%)24794 (89.8%)**Yes953 (20.7%)2381 (8.6%)**Unknown110 (2.4%)429 (1.6%)**Any adjuvant therapy (2010-2011 data only)No1943 (42.2%)19296 (69.9%)**Yes2556 (55.5%)7879 (28.5%)**Unknown110 (2.4%)429 (1.6%)*** not applicable

Citation Format: Christina A Clarke, Laura Chu, Lisa Wang, Chunyan Song, Marjorie Green, Lisa Moy, Juan Yang, Li Tao, Scarlett Lin Gomez. Patterns of chemotherapy (CT) use by molecularly-defined subtype among a population-based cohort of breast cancer (BC) patients (pts) from California [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-27.
Abstract P3-07-34: Breast cancer pathologic subtype and fetal microchimerism
Authors: Mahoney David A , Winget Veronica L , Gadi VK , Li Christopher I , Porter Peggy L , McDougall Jean A
Published: May 2015

Background: Stably persistent offspring-origin cells in a woman’s circulation and tissues decades after pregnancy, also known as fetal microchimerism, is deficient in women with biologically unselected breast cancer and suggests a protective role. Although the finding is in harmony with the well-known association of parity with protection against future breast cancer, it has recently emerged that certain tumor types such as triple negative breast cancer are positively associated with parity. Here we tested the hypothesis that fetal microchimerism is positively associated with triple negative breast cancer in young women.

Methods: Buffy coat specimens were obtained from a subset (n=450) of pathologically confirmed low-risk luminal and high-risk triple negative breast cancer patients and control participants from a population-based cohort study of all women aged 20-44 diagnosed with invasive breast cancer in the three county Seattle-Puget Sound metropolitan area from 2004-2010. Using quantitative PCR, DNA extracts from these specimens were tested for the presence and concentration of Y chromosome sequence DYS14, a marker of male fetal microchimerism.

Results: At this interim analysis of 405 specimens, 29.3% (56/191) of the healthy controls tested positive. Using controls as a reference group, 37.8% (34/90; OR .68; 95% CI .39-1.2) of women who developed luminal breast cancer tested positive for the presence of DYS14, while 26.6% (33/124; OR 1.14; 95% CI .67-1.96) of women who developed triple negative breast cancer tested positive.

Discussion: A preliminary analysis does not suggest an association between fetal microchimerism and breast cancer pathologic subtype in young women. Additional analyses are pending and will be presented at the meeting. Young women may regulate fetal microchimerism differently and surprisingly our data may suggest that as fetal microchimerism emerges later in life in the circulation, so does the protection against breast cancer – a finding consistent with population based studies of parity as a risk factor for breast cancer.

Citation Format: David A Mahoney, Veronica L Winget, VK Gadi, Christopher I Li, Peggy L Porter, Jean A McDougall. Breast cancer pathologic subtype and fetal microchimerism [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-34.
Abstract P3-11-10: Response to subsequent therapies after failure to achieve pathologic complete response (pCR) after neo-adjuvant chemotherapy (NAC) in patients (pts) with triple negative breast cancer (TNBC)
Authors: Pahuja Shalu , McGuire Kandace , Davidson Nancy , Brufsky Adam , Rastogi Priya , Jankowitz Rachel , Lembersky Barry , Puhalla Shannon
Published: May 2015

Background: More than half of pts with TNBC do not achieve a pCR after NAC, which carries a poor prognosis. It is unclear whether these patients respond to subsequent therapies on relapse. We sought to determine the time to progression (TTP) on subsequent therapies for recurrent disease in TNBC patients who did not achieve pCR to neo-adjuvant therapy.

Methods: We retrospectively identified 117 TNBC pts who received NAC from 2009 through 2012 using an electronic database at the Magee Women’s Breast Cancer Program at the University of Pittsburgh. Patient records were then assessed for pts who did not achieve a pCR for time to local or distant recurrence (TTR) and time to progression (TTP) on susbequent therapies.

Results: 86 of 117 TNBC pts did not achieve pCR to NAC defined as residual disease present in either the breast and/or axilla. Median follow up was 2 yrs (range 1-4yrs). Out of these 86 pts, 21 pts(25%) had recurrence in form of distant metastasis or local recurrence. Nearly all pts(95%) received anthracycline and taxane based NAC. Median TTR was 19 months (4-29 months). Therapies received in the metastatic setting most commonly included single agent capecitabine, paclitaxel, nab-paclitaxel, and eribulin. The most commonly received doublets included carboplatin with paclitaxel or gemcitabine. Median TTP on systemic chemotherapy was 15 weeks (3 -39 weeks), 6 weeks (1-24 weeks) and 6 weeks (2-9 weeks) in first, second and third line setting, respectively. Greater than 80% pts were able to receive two lines of systemic chemotherapy but <50% received third line treatment. Two pts died before initiating any systemic treatment.

Conclusions: Response to subsequent chemotherapeutic regimens in metastatic setting in TNBC pts who do not achieve pCR to anthracycline and taxane based NAC is limited. This highlights the importance of identifying new agents and targeted therapies for this poor prognosis sub-type.

Citation Format: Shalu Pahuja, Kandace McGuire, Nancy Davidson, Adam Brufsky, Priya Rastogi, Rachel Jankowitz, Barry Lembersky, Shannon Puhalla. Response to subsequent therapies after failure to achieve pathologic complete response (pCR) after neo-adjuvant chemotherapy (NAC) in patients (pts) with triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-10.
Abstract P3-11-15: Different clinical usefulness of AJCC response criteria according to the subtypes in stage II/III breast cancer patients after neoadjuvant chemotherapy
Authors: Yang Yaewon , Im Seock-Ah , Kim Tae-Yong , Lee Kyung-Hun , Keam Bhumsuk , Han Sae-Won , Oh Do-Youn , Kim Tae-You , Han Wonshik , Moon Hyeong-Gon , Park In Ae , Noh Dong-Young
Published: May 2015

Background: Response to neoadjuvant chemotherapy (NAC) is a useful prognostic marker for relapse and overall survival but their prognostic role is distinct in different breast cancer subtypes. Pathologic complete response (pCR) is a current gold standard for evaluating response to NAC. Despite its clinical usefulness, discrimination into pCR and non-pCR is too simple because non-pCR includes broad range of actual responses from very good partial response to even progressive disease. American Joint Committee on Cancer (AJCC) 7th edition proposed response criteria for NAC based on precise clinical stage before NAC and pathologic staging after NAC. The purpose of this study is to evaluate the clinical usefulness of AJCC response criteria in each breast cancer subtypes.

Patients and Methods: Patients with clinical stage II or III breast cancer treated with NAC at Seoul National University Hospital were enrolled and reviewed retrospectively. AJCC response criteria for NAC were adopted from the AJCC 7th edition: complete response (CR), absence of invasive carcinoma in both breast and lymph node; partial response (PR), decrease in either or both T or N stage; no response (NR), no change or increase in either or both T or N stage. The definition of each breast cancer subtypes were adopted from 2011 St Gallen Consensus Panel for current study.

Results: From January 2009 to December 2010, 183 patients were enrolled in the study with median follow up period of 38.0 months. AJCC response was significantly associated with relapse free survival (RFS) (P<0.001), whereas pCR was not (P=0.120). In subgroup analysis, AJCC response was a significant prognostic factor for RFS in luminal B (P<0.001), HER-2 enriched (P=0.035) and triple negative breast cancer (P=0.037) groups, but not in luminal A group patients (P=0.101). On the contrary, pCR was not significantly associated with RFS in any groups.

Conclusion : AJCC criteria is an easily reproducible tool for response evaluation for breast cancer patients in NAC setting compared with classically used pCR in all breast cancer subgroups except luminal A.

Citation Format: Yaewon Yang, Seock-Ah Im, Tae-Yong Kim, Kyung-Hun Lee, Bhumsuk Keam, Sae-Won Han, Do-Youn Oh, Tae-You Kim, Wonshik Han, Hyeong-Gon Moon, In Ae Park, Dong-Young Noh. Different clinical usefulness of AJCC response criteria according to the subtypes in stage II/III breast cancer patients after neoadjuvant chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-15.