bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-08-03: The association between primary breast cancer and thyroid cancer: A meta-analysis
Authors: Joseph Kyle R , Edirimanne Senarath , Eslick Guy
Published: May 2015

Background: Previous studies have suggested an aetiological link between breast cancer and thyroid cancer, however, there has never been a formal meta-analysis which collates the existing evidence supporting the hypothesis that breast cancer or thyroid cancer predispose an individual to developing the other.

Method: A systematic search was carried out using the electronic databases Pubmed and Medline. We searched for articles containing epidemiological evidence of breast cancer following thyroid cancer and vice versa. Additionally, we searched for articles that included epidemiological data involving the incidence of all second primary malignancies following both breast cancer and thyroid cancer, and compared the data sets.

Results: The meta-analysis performed in a total of 18 studies, showed that there is a significantly increased risk of developing thyroid cancer as a second primary malignancy of breast cancer (RR=1.59, 95% CI: 1.28-1.99; I2=79.99, p<0.001). Additionally, there was marginally increased risk of developing breast cancer as a second primary malignancy of thyroid cancer (RR=1.24, 95% CI: 1.18-1.30; I2=24.67, p=0.18), compared to the general risk of developing a second primary malignancy following thyroid cancer.

Conclusion: The findings of this meta-analysis suggest that there is less likely to be a common aetiological factor of the two cancers, but rather a specific aspect of the pathophysiology of breast cancer which pre-disposes individuals to develop thyroid cancer. Elucidation of the common mechanisms between breast cancer and thyroid cancer will have important implications in both diagnostic and therapeutic management of these cancers. Benefit of thyroid ultrasound screening after breast cancer surgery needs to be assessed.

Citation Format: Kyle R Joseph, Senarath Edirimanne, Guy Eslick. The association between primary breast cancer and thyroid cancer: A meta-analysis [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 P2-08-03.
Abstract P2-13-11: Multimodality perioperative analgesia with paravertebral nerve block and gabapentin reduces narcotic use and hospital length of stay in mastectomy patients
Authors: Cheng Zandra H , Frenk Vlad , Bishop Jennifer D , Bowling Theresa , Pass Helen A
Published: May 2015

Postoperative pain control is the major determinant in hospital length of stay (LOS) in patients undergoing mastectomy. Using a multimodality approach for peri-operative analgesia (PA) with paravertebral nerve block (PVB)(regional anesthesia) as well as including pre- and postoperative oral gabapentin, we significantly reduced both LOS and narcotic usage (NU) when compared to PVB alone or conventional postoperative management (CPM) with on demand postoperative pain medications. A single institution, retrospective chart review of patients undergoing mastectomy from 2009 to 2014 was performed (n = 129; 84 bilateral, 45 unilateral) with a subset analysis performed on patients undergoing tissue expander (TE) reconstruction (n=86) or bilateral mastectomies (n=84). Patients were grouped by PA type (CPM, PVB by catheter infusion, and PVB with gabapentin (PVB+G)). Data were analyzed via using Student t-test and significance was defined as p<0.05. As seen in the table below, LOS and NU decreased with increasing multimodal PA approach. LOS was significantly decreased by PVB+G compared to CPM and PVB for all mastectomies, bilateral mastectomies, and mastectomies with tissue expander (TE) reconstruction. NU was significantly decreased by PVB+G compared to CPM and PVB for all mastectomies and bilateral mastectomies, and trended toward decreasing NU in TE reconstruction.

All (n = 129)(1) CPM (n=51)(2) PVB (n=35)(3) PVB+G (n=53)p 1 vs 3; p 2 vs 3LOS (days)2.3 (0.84)2.1 (0.71)1.61 (0.54)<0.0001; <0.0005NU (mg)73 (42.9)52 (32.3)39 (25.3)<0.001; 0.04TE reconstruction (n=86)(1) CPM (n=25)(2) PVB (n=21)(3) PVB+G (n=40) LOS (days)2.2 (0.50)2.3 (0.63)1.61 (0.44)<0.001;<0.001NU (mg)86 (32.6)55 (34.4)43 (36.3)<0.001; 0.10Bilateral (n=84)(1) CPM (n=20)(2) PVB (n=24)(3) PVB+G (n=40) LOS (days)2.4 (0.7)2.2 (0.72)1.65 (0.52)<0.009;<0.001NU (mg)84 (37.4)58 (32.4)38 (24.5)<0.001;0.0066NU = narcotic use normalized to morphine sulfate

We have found employing a multimodality approach to PA with the addition of the GABA analogue, gabapentin, to regional anesthesia via PVB catheter infusion significantly improves the postoperative course of patients undergoing mastectomy procedures by decreasing LOS and NU.

Citation Format: Zandra H Cheng, Vlad Frenk, Jennifer D Bishop, Theresa Bowling, Helen A Pass. Multimodality perioperative analgesia with paravertebral nerve block and gabapentin reduces narcotic use and hospital length of stay in mastectomy 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 P2-13-11.
Abstract P2-13-18: Oncologic outcome of 2,217 patients with breast cancer after negative sentinel lymph node biopsy without axillary lymph node dissection
Authors: Park Jong Tae , Lee Hak Min , Ahn Sung Gwe , Lee Seung Ah , Jeong Joon
Published: May 2015

Background

Sentinel lymph node biopsy (SLNB) is a standard method for nodal staging and enables to omit axillary lymph node dissection after negative sentinel lymph node (SLN). False-negative rate of SLNB has been reported as 5-7%. To dissolve the concerns regarding the axillary recurrence due to false-negative cases after negative SLNB, we investigated oncologic outcomes of a large number of breast cancer patients with negative SLN after SLNB.

Methods

A total of 2,475 patients with clinically node-negative breast cancer underwent SLNB at Severance hospitals between December 1998 and December 2013. 99-m Tc radiocolloid or blue dye was used in SLNB with periareolar intradermal injection technique. Intraoperative frozen examination of SLN was performed. If frozen test for SLN showed negative result, further axillary node dissection was omitted. Survival rates were estimated by the Kaplan-Meier method. Multivariate survival analysis was performed using the Cox-regression hazard model.

Results

Among 2,475 patients, 2,217 patients had no metastatic focus on SLN. A mean of 2.4 sentinel lymph nodes was dissected in all of the patients. At a median follow-up of 36 months, only 13 patients (0.6%) had axillary recurrence, and a median time to the recurrence was 20 months (range 7-45 months). During the follow-up period, 22 local, 16 regional, and 44 distant recurrences were observed. In multivariate analysis for axillary recurrence, tumor size and refusal of systemic therapy were demonstrated to be independent risk factors for axillary recurrence (hazard ratio (HR) 1.77, 95% confidence interval (CI), 1.08-2.89, P=0.024; HR 0.15, 95% CI, 0.03-0.75, P=0.021). Disease-free survival and axillary recurrence-free survival rates at 3 years were 96.5% (95% CI, 0.960-0.970) and 99.2% (95% CI, 0.990-0.994), respectively.

Conclusions

The axillary recurrence rate was very low in patients with negative SLN. Our findings supported that SLNB is a reliable procedure and its oncologic safety is not affected by the chance of axillary recurrence after negative SLNB.

Citation Format: Jong Tae Park, Hak Min Lee, Sung Gwe Ahn, Seung Ah Lee, Joon Jeong. Oncologic outcome of 2,217 patients with breast cancer after negative sentinel lymph node biopsy without axillary lymph node dissection [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 P2-13-18.
Abstract P2-14-07: A systematic review of the clinical evidence regarding PIP breast implants
Authors: Wazir Umar , Kasem Abdul , Mokbel Kefah
Published: May 2015

Background: Mammary implants marketed by Poly Implant Prothèse (PIP) were found to contain industrial grade silicone and this caused heightened anxiety and extensive publicity regarding their safety in humans. These implants were used in a large number of patients worldwide for augmentation or breast reconstruction.

Methods: Articles were identified by searches of Medline, PubMed, Embase and Google Scholar databases up to March 2014 using the terms: "PIP", "Poly Implant Prothèse","breast implants" and "augmentation mammoplasty" or "silicone" In addition the websites of regulating bodies in Europe, USA and Australia were searched for reports related to PIP mammary implants.

Results: PIP mammary implants are more likely to rupture than other implants and can cause adverse effects in the short to the medium term related to the symptoms of rupture such as pain, lumps in the breast and axilla and anxiety. Based on peer-reviewed published studies we have calculated an overall rupture rate of 14.5% (383/2635) for PIP implants.

Conclusions: There is no evidence that PIP implant rupture causes long-term adverse health effects in humans so far. The long-term adverse effects usually arise from inappropriate extensive surgery, such as axillary lymph node dissection or extensive resection of breast tissue due to silicone leakage.

Citation Format: Umar Wazir, Abdul Kasem, Kefah Mokbel. A systematic review of the clinical evidence regarding PIP breast implants [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 P2-14-07.
Abstract P2-16-01: Discovery of fully human monoclonal antibodies as therapeutic candidates for the treatment of HER2-negative breast cancer
Authors: Boozer Christy , Algate Paul , Bonavia Aurelio , Branum Mark , Chan-Hui Po-Ying , Fitch Alison , Greenfield Brad , Sutherland Claire , Swiderek Kristine
Published: May 2015

Unlike HER2-positive breast cancer, there are limited treatment options for patients diagnosed with triple negative and endocrine resistant HER2-negative breast cancer, and as such HER2-negative breast cancer represents a significant unmet medical need. The goal of this work is to use Theraclone’s proprietary I-STAR platform to mine the memory B cell immune repertoire of breast cancer patients for the discovery of therapeutically relevant monoclonal antibodies (mAbs) and targets that may be exploited as candidates for treatment of HER2-negative breast cancer.

Matched serum and PBMC samples were collected from breast cancer patients at multiple clinical sites. The selected patient populations included, but were not limited to, patients who were treatment naïve, those who had received immunotherapy or adjuvant chemotherapy, and patients who had an exceptional clinical response to treatment and/or disease. Serum antibody binding to a diverse panel of 5 well characterized breast cancer-derived cell lines of luminal and basal sub-types was determined. Utilizing this approach, patients with a robust serological profile across multiple breast cancer cell lines were identified and prioritized for memory B cell repertoire analysis via the I-STAR platform. Using a high throughput and miniaturized, multiplex flow cytometry assay, the secreted IgG antibodies from over 85,000 individually enriched and expanded B cell clones were screened for binding to the tumor cell line panel and a large number of positive B cell clones were identified. The screening hits can be binned into several unique binding profiles, many of which were confirmed to be shared across multiple patient samples. Deep sequence analysis of the variable regions of the antibodies produced by the B cell clones demonstrated that several of the screening hits were derived from clonally related B cells; the majority of the screening hits represented antibodies derived from unique B cell clones. A representative set of these antibodies was expressed recombinantly for further in vitro characterization.

Citation Format: Christy Boozer, Paul Algate, Aurelio Bonavia, Mark Branum, Po-Ying Chan-Hui, Alison Fitch, Brad Greenfield, Claire Sutherland, Kristine Swiderek. Discovery of fully human monoclonal antibodies as therapeutic candidates for the treatment of HER2-negative 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 P2-16-01.
Abstract P2-16-02: Bi-specific antibodies targeting signaling pathway crosstalk are a new breast cancer immunotherapeutic strategy
Authors: Zhang Yanliang , Gros Edwige , Chagar Sarabjit , Cao Jian , Zhou Heyue , Motamed Kouros , Kaufmann Gunnar F , Fu Yanwen
Published: May 2015

All of the currently approved therapeutic anti-cancer antibodies are monospecific and therefore only capable of interfering with the biological function of a single molecular target. However, breast cancers mostly involve crosstalk of often synergistic signal transduction pathways, and thus, isolated blockade of a single signal transduction pathway is frequently met by escape mechanisms, such as upregulation of redundant pathways, rendering the monospecific immunotherapy less effective. Using chemical biology and molecular biology, Sorrento has developed new approaches to generate IgG-like bi-specific antibodies (BsAbs) targeting either two compensating signal transduction pathways, such as HER family members or a breast cancer specific antigen and an immuno-regulatory molecule such as PDL1 or PD1. The chemical biology method involves specific hetero-dimerization of two half antibody molecules using bio-orthogonal chemistry. The molecular biology approach utilizes phage display by either discovering common light chains for the two relevant antigens in combination with two distinct heavy chains or by selecting dual specific antibodies, namely a single antibody that can recognize two distinct antigens. Progress will be presented on bi-specific as well as dual specific antibodies against Her3 and Her4 as well as immunomodulatory BsAbs with data on in vitro characterization, cell-based functional assays, and in vivo models.

Citation Format: Yanliang Zhang, Edwige Gros, Sarabjit Chagar, Jian Cao, Heyue Zhou, Kouros Motamed, Gunnar F Kaufmann, Yanwen Fu. Bi-specific antibodies targeting signaling pathway crosstalk are a new breast cancer immunotherapeutic strategy [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 P2-16-02.
Abstract P2-18-06: Low dose capecitabine is effective and relatively nontoxic in breast cancer treatment
Authors: Carpenter John
Published: May 2015

Capecitabine has been widely used in treatment of both early and advanced breast cancer in the United States since 1998. The dose limiting toxicity is diarrhea, which is dose limiting and can be severe. Lower doses are widely used without any apparent compromise in efficacy and are consistently less toxic (see Naughton, Clinical Breast Cancer 2010). Here a continuous dose regimen of capecitabine 1000 mg. daily was used in 24 patients with breast cancer, both early and advanced, from March 2012-September 2013. Four received the drug as adjuvant treatment, 8 as preoperative therapy, and 12 for advanced disease. Duration of treatment ranged from 0.5 to 15 months. Toxicity was modest: 1 had moderate nausea, none experienced vomiting, 2 mild anemia (one with marrow replacement by tumor), 2 mild palmar irritation, and 1 grade 1 thrombopenia. No diarrhea was seen. One patient died of hepatic necrosis and portal vein thrombosis; the relationship to treatment was uncertain. 12/20 with measurable disease experienced a response to treatment (1 complete and 11 partial responses by RECIST criteria), 1 had stable metastatic disease for 9 months, and 7 had progression of disease. The median duration of response was 5 months (range 2-15 months). Use of capecitabine in this dose and schedule for treatment of breast cancer appears comparably effective to higher conventional doses and dramatically less toxic.

Citation Format: John Carpenter. Low dose capecitabine is effective and relatively nontoxic in 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 P2-18-06.
Abstract P3-02-04: The contribution of the national health system to mammographic screening in Brazil
Authors: Freitas-Junior Ruffo , Rodrigues Danielle CN , Correa Rosangela S , Peixoto João-Emilio , Rahal Rosemar MS
Published: May 2015

INTRODUCTION: In Brazil, access to mammography is provided through the National Health System (SUS), the Supplemental Health System, or is paid for directly by the patient. SUS is the official government system and was established to conform to the constitutional requirement that health is a right of all Brazilian citizens and a duty of the state. In recent years SUS breast cancer control policies have advanced and government strategies for early detection have strengthened. However, evaluations are needed to monitor the effectiveness of these actions. OBJECTIVE: To describe the coverage of mammography in breast cancer screening conducted by the National Health System in Brazilian macro-regions and states in 2012. METHODS: An ecological study, where the estimate of coverage was the number of exams performed expressed as a percentage of the number of exams expected in the target population of women 50-69 years old. The exams performed refer to target population mammography production data from the Outpatient Information System (CIS) of DATASUS. To calculate the expected number of exams for this population, the biennial screening recommendations of the National Cancer Institute (NCI) and an estimate of the female population based on the census of the Brazilian Institute of Geography and Statistics (IBGE) were used. RESULTS: The coverage estimate for SUS-performed mammography in Brazil in 2012 was 26.6%. Stratified by macro region, the lowest coverage was in the northern region (12.1%) and highest in the South (34.6%).

National coverage of screening mammography in Brazil, performed by the National Health System (SUS), according to the geographical regions.Macro-regionsCoverageMinimumMaximump*North Region12.10.227.2Northeast Region23.910.337.20.001Southeast Region28.515.532.5South Region34.630.341.0Midwest Region14.810.319.7* Chi-square test

Units of the Federation an estimated coverage ranged from 0.2% to 41%, the lowest in the state of Amapa and the largest in Santa Catarina. 48% of states were in the range of 10.1% to 20% coverage. CONCLUSION: The results imply that the contribution of SUS to mammography screening in Brazil is higher in both macro-regions and states with higher income and better organised health system.

Citation Format: Ruffo Freitas-Junior, Danielle CN Rodrigues, Rosangela S Correa, João-Emilio Peixoto, Rosemar MS Rahal. The contribution of the national health system to mammographic screening in Brazil [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 P3-02-04.
Abstract P3-04-14: Prognostic impact of Her2 and hormone receptor expression in inflammatory breast cancer: A SEER database analysis
Authors: Affan Anna Maria , Mohan Babu P , Iruku Kali Praveena , Ravakhah Keyvan
Published: May 2015

INTRODUCTION: Inflammatory breast cancer (IBC) is known to be one of the most aggressive forms of breast cancer. Patients with IBC generally present with early metastases and are frequently resistant to conventional chemotherapies. By using the SEER database, we explored the clinical relevance of Her2 and hormone receptor (HR) expression in IBC tumors and the possible impact it may have on management.

METHODS: Data for patients with IBC was extracted from the Surveillance, Epidemiology, and End Results (SEER 18) database from 2010 to 2011. A sub-analysis with the available receptor status data for the same period was analyzed using CanSurv survival software. The Actuarial method was used to construct survival curves according to the following receptor variables; Her2+/HR+, Her2+/HR-, Her2-/HR+, and triple negative IBC groups. Demographic data including race and age was also extracted.

RESULTS: Of 354 cases of IBC reported, 5% (n=18) of the tumors were Her2+/HR+, 7.9% (n=28) Her2+/HR-, 15.3% (n=54) Her2-/HR+, and 12.4% (n=44) triple negative. Highest 1 year survival rates were seen in those patients with Her2-/HR+ tumors at >95% while Her2+/HR+ had the lowest 1 yr survival rates at 65%.

Caucasian patients above 30 years represented the highest racial group at approximately 70% (n=105). Analysis of this subgroup showed 38% (n=40) of these patients having HER2-/HR+. Despite more than 75% (n=33) of these patients presenting with advanced disease, the 1 year survival remained highest among all the receptor combinations analyzed. This observation held true across all racial groups even with those population numbers for IBC being less.

CONCLUSION: The Her2-/HR+ receptor combination group showed the greatest 1 year relative survival when compared to the other groups. These results suggest that HR expression in the absence of Her2 is associated with an increased survival. This can play in a role in the management of IBC by incorporating hormonal therapy into the treatment protocols for patients with IBC to possibly improve survival.

Citation Format: Anna Maria Affan, Babu P Mohan, Kali Praveena Iruku, Keyvan Ravakhah. Prognostic impact of Her2 and hormone receptor expression in inflammatory breast cancer: A SEER database analysis [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 P3-04-14.
Abstract P3-05-10: Glucocorticoid and aldosterone mimic progestin-induction of a therapy-resistant cytokeratin-5 positive cell population in estrogen receptor-positive breast cancer through a Bcl6-dependent mechanism
Authors: Rui Hallgeir , Sato Takahiro , Peck Amy , Girondo Melanie A , Liu Chengbao , Kovatich Albert J , Hooke Jeffery A , Shriver Craig D , Mitchell Edith , Hyslop Terry , Goodman Chelain
Published: May 2015

Resistance to anti-estrogen therapy remains a significant problem in patients diagnosed with estrogen receptor-α (ERα) positive breast cancer. Recent progress has defined a "lumino-basal" subclass of ERα-positive breast cancer characterized by mosaic presence of a minor population of ERα-negative cells expressing the basal cytokeratin-5 (CK5). The CK5-positive cells are therapy-resistant and have increased tumorigenic potential. Initial studies have suggested that progestins but not other steroids expand this CK5+ cell population. Unexpectedly, we discovered that at least two 3-ketosteroids other than progestins, glucocorticoids and mineralocorticoids, are capable of inducing the CK5+/ERα- cell population. CK5+ cells induced by glucocorticoid or aldosterone showed increased clonogenicity in soft agar, expressed the stem cell marker CD44, showed loss of ERα and PR expression, and demonstrated therapy-resistance with reduced apoptosis in response to chemotherapy, and were further enriched following adjuvant antiestrogen or chemotherapies. Induction of CK5+ cells by 3-ketosteroids was consistently preceded by induction of Bcl6, a transcriptional repressor implicated in breast cancer progression. Suppression of Bcl6 by shRNA or the Bcl6 suppressor, prolactin, abolished 3-ketosteroid-induction of CK5+ cells. Prolactin also blocked 3-ketosteroid-induced colony formation in vitro and suppressed progestin-induction of the CK5+ cell population in T47D xenograft tumors in vivo. Survival analyses with recursive partitioning revealed that CK5 and Bcl6 transcripts or protein levels in ERα+ breast cancer identify patients at high or low risk for tumor in two independent cohorts. The observations provide a mechanism by which stress-related or pharmacologic elevation of glucocorticoids may adversely affect patients with ERα+/CK5+ breast cancer, and may justify further exploring of inhibitors to 3-ketosteroid receptors or Bcl6 for therapeutic benefit.

Citation Format: Hallgeir Rui, Takahiro Sato, Amy Peck, Melanie A Girondo, Chengbao Liu, Albert J Kovatich, Jeffery A Hooke, Craig D Shriver, Edith Mitchell, Terry Hyslop, Chelain Goodman. Glucocorticoid and aldosterone mimic progestin-induction of a therapy-resistant cytokeratin-5 positive cell population in estrogen receptor-positive breast cancer through a Bcl6-dependent mechanism [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 P3-05-10.
Abstract P3-05-15: Divergent activation of AKT1 and AKT2 isoforms downstream of PI3K mutation impacts response of breast cancer cells to estradiol and PI3K inhibitors
Authors: Nakshatri Harikrishna , Goswami Chirayu , Badve Sunil , Magnani Luca , Lupien Mathieu , Bhat-Nakshatri Poornima
Published: May 2015

Background: PI3K mutations are observed in 30% of breast cancers, which are more common in estrogen receptor (ERα) positive breast cancers compared to ERα-negative breast cancers. AKT, a the major kinase downstream of PI3K, modulates ERα activity. It is unknown whether PI3K mutation leads to preferential activation of specific AKT isoform with ability to modulate ERα function.

Results: We report elevated AKT1 but not AKT2 mRNA in breast cancers with PI3K mutation. Breast epithelial cells with targeted substitution of PI3K with PI3K-E545K or PI3K-H1047R demonstrated elevated AKT1_pS473 compared to AKT2_pS474, distinct AKT substrate phosphorylation, and enhanced Estrogen Receptor (ERα) activity. AKT1 had a dominant role in ERα:estradiol (E2)-dependent gene expression and proliferation. We have identified an unique gene expression signature in ERα-positive breast cancers that is dependent on ERα, estradiol (E2), AKT1, and the pioneer factor FOXA1. Elevated expression of this signature in ERα-positive tumor was associated with better response to endocrine therapy and outcome. In addition, AKT1 determined the sensitivity to PI3α-specific inhibitor BYL719 and pan-PI3K inhibitor BKM120. In contrast, AKT2 controlled global gene expression and elevated levels of an AKT2-directed protein signature predicted poor outcome in breast cancer patients.

Conclusions: PI3K mutation favors AKT1 activation leading to imbalance in AKT isoform-specific kinome/proteome and an effect on specific signaling pathways, particularly ERα:E2 signaling network. Knowledge gained from this functional dissection of AKT isoform activity downstream of PI3K mutation can be exploited for therapeutic stratification, particularly for anti-estrogen and PI3K inhibitor-based therapies.

Citation Format: Harikrishna Nakshatri, Chirayu Goswami, Sunil Badve, Luca Magnani, Mathieu Lupien, Poornima Bhat-Nakshatri. Divergent activation of AKT1 and AKT2 isoforms downstream of PI3K mutation impacts response of breast cancer cells to estradiol and PI3K inhibitors [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 P3-05-15.
Abstract P3-13-09: Personalized therapy in breast cancer: Brazilian experience
Authors: Moreira Raphael Brandao , Alessandretti Matheus Bongers , Buzaid Antonio Carlos , Cruz Marcelo Rocha
Published: May 2015

INTRODUCTION

Cancer biology is characterised by genomic alterations. There is an ongoing revolution in cancer research due to the emergence of novel technologies based on next generation sequencing (NGS).

OBJECTIVES

To identify abnormalities in individual patients with the aim of providing targeted therapy matched to individuals genomic alterations.

METHODS

From April 2013, to February 2014, we included patients who had metastatic breast cancer with lesion accessible for biopsy. The tumor tissue stored in paraffin was evaluated by the method of next-generation sequencing (NGS) where 236 cancer-related genes were sequenced.

ResultsPatientsTarget TherapyObjective ResponseMutations1EverolimusNOERBB2, PIK3CA2EverolimusYesPI3KCA, FGFR, AKT3EverolimusYesPI3KCA, FGFR4EverolimusYesAKT1, PI3KCA5EverolimusYesAKT16EverolimusYesAKT1, FGFR7EverolimusYesAKT1. FGFR8EverolimusNoERBB2, PI3KTable1

Mutations PrevalenceMutationPrevalenceTP5383,30%PIK3CA60,60%FGFR33%CCND125%PTEN25%BRCA216%AKT50%Table2

RESULTS

Fourteen patients were included and NGS was feasible. An actionable genomic alteration was identified in 12 (85,7%) patients, most frequently in TP53 (10 [83,3%], PIK3CA (8 [66,6%]), AKT (5 [50%]), FGFR1 (4 [33%]), CCND1 (3 [25%]), PTEN (3[25%]) and BRCA2 (2[16%]). Therapy could be personalized in 12 of 14 patients. Of the 8 patients who received targeted therapy, 5 presented objective response.

CONCLUSION

. NGS was able to find genomic alterations in the majority of breast cancer tissues;

. Most patients did not have "actionable" mutations for which a specific therapy could be offered;

. We are just at the dawn of exploring this strategy and NGS can effectively contribute for increasing the understanding of the disease.

REFERENCES

1. Jeffrey. Ross, Massimo Cristofanilli et al, JClin Oncol 3, 2013 (suppl; abster 1009).

Citation Format: Raphael Brandao Moreira, Matheus Bongers Alessandretti, Antonio Carlos Buzaid, Marcelo Rocha Cruz. Personalized therapy in breast cancer: Brazilian experience [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 P3-13-09.
Abstract P4-06-03: Targeting the insulin receptor with a small peptide (S961) in cancer
Authors: LaPara Kelly , Yee Douglas
Published: May 2015

The insulin-like growth factor (IGF)/insulin receptors are members of the superfamily of growth factor receptor tyrosine kinases. The insulin and type I IGF-I receptors (IGF-1R) have very similar structure and share high homology (∼84%) in the kinase domain. Their dimeric structure allows for the formation of either holo or hybrid receptors. Thus, targeting of any individual receptor has been a challenge. We have previously shown that the insulin receptor is expressed in tamoxifen resistant breast cancer cell lines. Therefore, specific targeting might be a useful strategy to block this pathway. The antagonist S961 is a single chain peptide that binds insulin receptor and has been reported to have partial antagonist activity. The affinity of S961 for the insulin receptor is comparable to that of insulin and the selectivity of the insulin receptor versus IGF1 is higher than that of insulin itself (Sturis et al). To determine if S961 has activity in breast cancer cells, we tested its ability to disrupt insulin and IGF-I signaling and growth in a panel of cancer cell lines (MCF-7L, MCF-7L TamR, MDA-231, and HepG2 cells). MCF-7L cells express high levels of IGF1, while HepG2 express mostly insulin receptor. Pre-incubation with S961 significantly suppressed p-Akt and p-MAPK after insulin stimulation in the HepG2, but not in MCF-7L. In contrast, insulin receptor stimulation in MCF-7L TamR cells, which do not express IGF1R, was inhibited by S961. Even a 1000-fold increase in S961 was unable to suppress insulin receptor activation in cells expressing both insulin receptor and IGF1R. S961 inhibits insulin-stimulate cell cycle progression in MCF7L TamR cells. In these TamR cells, S961 also suppresses colony formation in anchorage independent growth assays. These data suggest S961 is an effective inhibitor of insulin receptor activation but only when little IGF1R is expressed. Thus, insulin receptor targeting might be useful in the management of endocrine resistant breast cancer.

Citation Format: Kelly LaPara, Douglas Yee. Targeting the insulin receptor with a small peptide (S961) in 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 P4-06-03.
Abstract P4-11-32: Routine histopathological variables predict oncotype DX risk categories
Authors: Kawabata Hidetaka , Kinowaki Keiichi , Tamura Nobuko , Kobayashi Yoko , Kadowaki Masami , Miura Daishu , Takano Toshimi , Shimomura Akihiko , Iwatani Tsuguo , Kitawaki Yuko , Fujii Takeshi
Published: May 2015

Background: Oncotype DX(ODX) is a clinically validated, commercially available multi-gene assay that provides prognostic and predictive information in estrogen receptor(ER)-positive, Her2-negative breast cancer. Because health care system does not cover this expensive assay in many countries, physicians and researchers try to use routine histopathological variables predict ODX Recurrence Score (RS). Hyunseok Kim et.al presented at ASCO that Estimated Recurrence Score (ERS) model could identify those patients most likely to benefit from including ODX RS results in therapeutic decision-making (J Clin Oncol 32:5s, 2014 suppl; abstr 559).

Methods: We retrospectively reviewed histopathological slides between July 2007 and April 2014 from Toranomon Hospital patients (n=149) with early stage ER-positive, Her2-negative breast cancer, for whom ODX was ordered. We developed an original linear regression model using routine histopathological markers (Allred Score for progesterone receptor (PR), nuclear grade(NG), and Ki67) to calculate an Estimated Recurrence Score (ERS), and correlated it with the observed ODX RS assay result. ERS=20.46+0.298xKi67–1.48xPR+1.41xNG predicts the ODX RS with an R2 of 0.48. In order to internally validate this model in the Toranomon Hospital cohort in Japan, we adapted Hyunseok’s algorithm.

Results: 132 patients had an observed RS ≤ 25 (89%) and 17 patients had an observed RS above 25 (11%). When the ERS was < 21 (n=124), we accurately classified 97% of them (120) who were found to have a low risk (observed RS ≤ 25). Similarly, 83% of those (5/6) with an ERS > 30 fell into a high risk category with observed RS > 25.

Table1 (TAILORx risk categories)Toranomon cohortODX ≤25ODX RS>25TotalERS < 211204124ERS(21-30)11819ERS(> 30)156Total13217149

We also presented the comparison of ERS and observed RS based on original risk categories.

Table2 (Original risk categories )Toranomon cohortODX RS<18ODX RS 18-30ODX RS>30TotalERS(<18)6633099ERS(18-30)1725244ERS(>30)0156Total83597149

Conclusions: We developed an ERS model to find those patients most likely to benefit from ODX RS results in clinical practice setting. Although further external and prospective validation is mandatory, preliminary result supports the usefulness of this ERS model.

Citation Format: Hidetaka Kawabata, Keiichi Kinowaki, Nobuko Tamura, Yoko Kobayashi, Masami Kadowaki, Daishu Miura, Toshimi Takano, Akihiko Shimomura, Tsuguo Iwatani, Yuko Kitawaki, Takeshi Fujii. Routine histopathological variables predict oncotype DX risk categories [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 P4-11-32.
Abstract P4-11-39: Epithelial-mesenchymal transition phenotype in triple negative breast cancer: ZEB1 as a potential biomarker for poor clinical outcome
Authors: Jang Min Hye , Kim Hyun Jeong , Kim Eun Joo , Lee Hee Jin , Park So Yeon
Published: May 2015

Background: Triple negative breast cancer (TNBC) is a heterogeneous group of disease. TNBC is closely related to epithelial-mesenchymal transition (EMT) and breast cancer stem cell (BCSC) phenotype. Recent studies have shown that TNBC can be classified into six subtypes including basal-like, mesenchymal–like and mesenchymal stem-like. However, clinical significance of EMT phenotype in TNBC is not clear.

Methods: We performed immunohistochemical analyses of EMT markers (expression of vimentin, smooth muscle actin, osteonectin and N-cadherin; loss of E-cadherin), BCSC markers (CD44+/CD24- and ALDH1) and EMT inducers (CD146 and ZEB1) in 173 TNBCs using tissue microarrays, and correlated their expressions with clinicopathologic features of the tumor.

Results: Expression of vimentin, CD44+/CD24- and CD146 was significantly higher in basal-like TNBCs (TNBC with expression of CK5/6 and/or EGFR) than in non-basal-like TNBCs. Expression of EMT markers was commonly correlated with high histologic grade, CD44+/CD24- phenotype and metaplastic carcinoma. CD146 expression was related to the expression of EMT markers and CD44+/CD24- phenotype. ZEB1 expression showed an association with the expression of smooth muscle actin, but not with BCSC markers. And it was closely correlated with high histologic grade and metaplastic carcinoma. In survival analyses, although expression of EMT and BCSC makers was not associated with the survival of the patients, ZEB1 expression was found to be an independent prognostic factor for poor disease-free survival of the patients.

Conclusion: EMT phenotype can be a signature of certain subgroup of TNBC. Especially, ZEB1 expression can be used as a potential biomarker to define a subgroup of TNBC associated with poor clinical outcome.

Citation Format: Min Hye Jang, Hyun Jeong Kim, Eun Joo Kim, Hee Jin Lee, So Yeon Park. Epithelial-mesenchymal transition phenotype in triple negative breast cancer: ZEB1 as a potential biomarker for poor clinical outcome [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 P4-11-39.
Abstract P5-05-05: Low molecular weight cyclin E regulates response to aromatase inhibitors in post-menopausal breast cancer patients
Authors: Doostan Iman , Moulder Stacy L , Hunt Kelly K , Keyomarsi Khandan
Published: May 2015

Almost seventy percent of all breast cancer patients have estrogen receptor (ER) positive tumors requiring hormonal therapy. Aromatase inhibitors (AIs) are considered as the first line hormonal therapy for ER+ post-menopausal patients. However, resistance to these drugs remains a major challenge in clinic and the biology of such resistance is not clear.

Previous studies have shown that cyclin E pathway, a key regulator in the G1 to S transition of cell cycle, is deregulated in breast cancer. Full-length cyclin E is abnormally cleaved into low molecular weight isoforms (LMW-E) that renders patients to poor survival. Here we hypothesize that cyclin E deregulation can confer resistance to AIs. To address this, we engineered aromatase overexpressing MCF7 cells to overexpress LMW-E under doxycycline inducible promoter. Full-length cyclin E, GFP and empty vector transfected cells were also generated and used as controls. Our results indicated that AIs inhibited proliferation by arresting the cells at G1 phase of the cell cycle. However, LMW-E expression significantly enhanced proliferation of the cells when treated with AIs. In addition, LMW-E bypassed G1 arrest following AI treatment. At the molecular level, AIs decreased CDK2, pCDK2, and Rb levels and attenuated Rb phosphorylation. However, these effects were completely rescued only when LMW-E was expressed. Moreover, using an in vitro kinase assay we indicated that AIs decreased CDK2 kinase activity while LMW-E expression reversed this effect by increasing CDK2 enzymatic activity. Taken together, these results suggest that LMW-E inactivates Rb protein as a tumor suppressor and renders the cells to bypass G1 checkpoint following AI treatment. In addition, this study provides early evidence that CDK2 inhibitors could be beneficial in combination with AIs for LMW-E expressing tumors. Currently we are investigating whether LMW-E can bypass the activity of AIs using inducible breast cancer cell line xenograft. We are also examining the correlation between cyclin E status and response to treatment in a cohort of patients who received AIs in the neo-adjuvant setting.

Citation Format: Iman Doostan, Stacy L Moulder, Kelly K Hunt, Khandan Keyomarsi. Low molecular weight cyclin E regulates response to aromatase inhibitors in post-menopausal 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 P5-05-05.
Abstract P5-06-04: The PARP inhibitor niraparib demonstrated activity in patient-derived triple-negative breast cancer xenograft models with high homologous recombination deficiency (HRD) score
Authors: Wang Yan , Cairo Stefano , Deas Olivier , Hartman Anne-Renee , Jones Joshua , Gutin Alexander , Lanchbury Jerry , Sangale Zaina , Solimeno Cara , Judde Jean-Gabriel , Timms Kirsten , Wilcoxen Keith
Published: May 2015

Triple negative breast cancer (TNBC), which comprises 15% of all breast cancers, has a poor prognosis and currently lacks effective treatment. TNBCs are highly proliferative, genomically unstable and share molecular characteristics with that of BRCA1/2 mutation driven breast cancer. Poly(ADP-ribose) polymerase-1 (PARP) is a key DNA repair enzyme that mediates single strand break (SSB) repair through the base excision repair (BER) pathway. PARP inhibitors have been demonstrated to selectively kill tumor cells that harbor BRCA1 and BRCA2 mutations. In addition, pre-clinical and preliminary clinical data suggest that PARP inhibitors are selectively cytotoxic for tumors with homologous recombination repair deficiency caused by dysfunction of genes other than BRCA1 or BRCA2.

Niraparib is a potent, orally active PARP inhibitor that is being evaluated in Phase 3 clinical studies for ovarian cancer and BRCA related breast cancer. Previously, we demonstrated that a subset of basal breast cancer (BBC) patient-derived xenograft (PDX) models responded robustly to single agent niraparib treatment. To understand the selectivity observed, the samples from a collection of 37 BBC PDX models have been subjected to homologous recombination deficiency (HRD) analysis. HRD analysis is a DNA-based assay that is capable of detecting homologous recombination deficiency independent of its etiology. Genome-wide SNP data was generated from a custom Agilent SureSelect XT capture followed by sequencing on an Illumina HiSeq2500. SNP data was analyzed using three algorithms (LOH, TAI and LST scores), and the final HRD score is the sum of the LOH+TAI+LAST scores.

Niraparib’s antitumor activity was investigated in patient derived BBC models with various HRD scores. The correlation between niraparib efficacy, HRD score and BRCA deficiency will be discussed.

Citation Format: Yan Wang, Stefano Cairo, Olivier Deas, Anne-Renee Hartman, Joshua Jones, Alexander Gutin, Jerry Lanchbury, Zaina Sangale, Cara Solimeno, Jean-Gabriel Judde, Kirsten Timms, Keith Wilcoxen. The PARP inhibitor niraparib demonstrated activity in patient-derived triple-negative breast cancer xenograft models with high homologous recombination deficiency (HRD) score [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 P5-06-04.
Abstract P5-07-06: Exploring the involvement of TTK kinase in centrosome amplification and Her2+ breast cancer
Authors: King Jamie L , Saavedra Harold I
Published: May 2015

The centrosome is the cellular organelle responsible for accurate chromosome segregation. In normal cellular function, regulation of the centrosome duplication cycle in concert with the cell cycle is necessary for accurate passage of genetic information. However, when modulators of the cell and/or centrosome duplication cycles are deregulated, this process can result in centrosome amplification (CA, the acquisition of more than two centrosomes), leading to improper segregation of chromosomes and genomic instability. CA generates low-level aneuploidy (which is tolerated) and polyploidy (selected against when checkpoints are present). An integral goal in the field of centrosome biology is to characterize how alterations in modulators of CA influence disease development. In cancer, CA is associated with aggressive tumor types and metastasis and is likely to affect response to treatment. However, the full role of CA in tumorigenesis is poorly understood. Specifically in breast cancer, CA is observed in pre-cancerous lesions, which suggests CA in conjunction with genomic instability is an early contributor to tumorigenesis. In an effort to study mechanisms associated with CA, we are investigating the function of CA in in vitro and in vivo breast cancer models. Our lab and others have detected that TTK (MPS1) kinase, a proposed modulator of centrosome duplication, is overexpressed in Her2+ breast cancer cell lines at the mRNA and protein level compared to non-transformed mammary epithelial cells. We hypothesize that overexpression of TTK leads to CA and that inhibiting TTK expression in cancer cells will prevent active generation of CA and CIN (chromosome instability), leading to suppressed tumorigenic properties and further cancer evolution. Preliminary data shows that transient knockdown of TTK via siRNA attenuates the degree of CA in Her2+ breast cancer cells. Additional preliminary data shows that stable abrogation of TTK via shRNA can inhibit the proliferation of Her2+ breast cancer cells but does not alter expression of some members in the intrinsic apoptotic pathway. Ongoing studies will address the impact of altering TTK expression on CA, CIN, downstream centrosomal duplication signaling and tumorigenic properties of breast cancer cells. The results of these studies will address the mechanistic complexities, such as what centrosomal signaling pathways associated with TTK are underlying CA in breast cancer. We believe this work will help discern how deregulated centrosome regulatory molecules influence mammary tumorigenesis and/or responses to treatment.

Citation Format: Jamie L King, Harold I Saavedra. Exploring the involvement of TTK kinase in centrosome amplification and Her2+ 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 P5-07-06.