bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-02-13: EpCAM-independent enrichment approach for isolation of circulating tumor cells (CTCs) in breast cancer - What can be found in the EpCAM-depleted fraction?
Authors: Fehm T , Schneck H , Gierke B , Pawlak M , Templin M , Niederacher D , Neubauer H
Published: May 2016

Circulating tumor cells (CTCs) are the potential precursors of metastatic disease. Many assays have been established for the enumeration of CTCs. However, major limitations include the reliance on the expression of the cell surface marker epithelial cell adhesion molecule (EpCAM). These approaches may not detect CTCs that either express no/low levels of EpCAM or undergo epithelial-to-mesenchymal transition (EMT). We present an enrichment strategy combining different antibodies specific for surface proteins and extracellular matrix (ECM) components to capture EpCAMneg cell lines and EpCAMneg CTCs from EpCAM-depleted breast cancer blood samples. Expression of proteins (Trop2, CD49f, cMet, CK8, CD44, ADAM8, CD146, TEM8, CD47) was verified by immunofluorescence on EpCAM-positive (e.g. MCF7, SKBR3) and -negative (MDA-MB-231) breast cancer cell lines; antibodies and ECM proteins (e.g. hyaluronic acid (HA), collagen I, laminin) were further spotted in a single- and multi-arrayed format onto glass slides (Schott, NEXTERION® AL) and coupled to immunomagnetic beads (Dynabeads/Adembeads). Tumor cell adhesion of EpCAMpos/neg cell lines was visualized by Coomassie/MitoTracker; EpCAMneg CTCs enriched via functionalized Adem-/Dynabeads were identified by immunofluorescence staining for anti-pan-Cytokeratin(CK)-FITC/anti-CD45 AF647/DAPI and quantified manually by microscopy. Regarding cell lines, marginal binding of EpCAMneg MDA-MB-231 cells to EpCAM-antibodies could be observed. Efficient adhesion/capturing of EpCAMneg cells could be achieved via HA and immobilized antibodies against CD49f and Trop2. By analyzing 29 EpCAM-depleted fractions from 25 metastatic breast cancer patients, we were able to identify EpCAMneg CTCs in 69% of the samples [range 1-24] applying Trop2, CD49f, cMet, CK8 and/or HA magnetic enrichment. Accessorily, EpCAMneg dual-positive (CKpos/CD45pos) cells could be traced in 28 out of 29 samples [range 1-480]. Herein, we demonstrate an enhanced enrichment strategy to optimize capturing of EpCAMneg CTCs by targeting various cell surface antigens with antibody mixtures and ECM components. Thereby, potential relevant CTCs can be gathered and subjected to subsequent molecular analysis.

Citation Format: Fehm T, Schneck H, Gierke B, Pawlak M, Templin M, Niederacher D, Neubauer H. EpCAM-independent enrichment approach for isolation of circulating tumor cells (CTCs) in breast cancer - What can be found in the EpCAM-depleted fraction?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-13.
Abstract P2-05-04: The development of the metastatic site pattern during time in different subtypes of breast cancer
Authors: Lindman H , Haji A
Published: May 2016

Introduction:

The most common metastatic sites in breast cancer (BC) are bone, lung and liver, but metastases to CNS, other visceral organs, skin and lymph nodes are often seen. Depending on the BC subtypes there are data on different patterns of the metastatic sites. However, little is known about the risk for development of new metastatic sites during the course of the disease. Possibly, the development of new sites of the disease is signs of novel intrinsic capabilities of the metastases that might be explained by new mutations. Primary aim of this study was to examine the metastatic pattern and development of new metastatic sites in different BC subgroups.

Materials and Methods:

This is a population based cohort study covering patients in the Uppsala County treated for metastatic BC (MBC) from 2009 to 2014. The information was collected from the real-time treatment registry and medical records. The distant sites were classified as bone, lung/pleura, soft tissue, other visceral and CNS and the timing was defined in steps starting with M1 when patient first was defined as having MBC. The BC subtypes were defined as luminal A, luminal B, HER2-positive (HER2) and triple negative (TN) based on immunohistochemical analyses. The metastatic patterns at death were compared with the patterns at M1.

Results:

Totally 391 patients with MBC with a median age of 65 years were included. Median disease-free survival was 51 months. The development of metastases in new sites occurred in up to three distinguished steps, with median lag times of 22, 13 and 14 months, respectively. The median survival from M1 was 69, 37, 64 and 17 months for the luminal A, luminal B, HER2 and TN subtypes.

The frequencies of metastases in in first (M1) and subsequent sites (next) in each subtypeM1%/next%BoneLung/pleuraSoft tissueLiverOther visceralCNSLuminal A74/431/2122/1020/2816/151/4Luminal B66/1144/1438/327/3216/54/10HER246/1536/2042/1719/2810/1319/31TN27/746/1751/629/017/1117/17The sums of the figures represent the risk for metastases in a certain site at death.

Conclusion:

The pattern of metastatic sites at M1 in different BC subtypes does not represent the pattern for development of new metastatic sites during the course of the disease. We observed a significantly different risk for developing new metastatic sites depending on subtypes, most obvious regarding liver metastases. TNBC seemed to have less ability to develop new metastatic sites.

Citation Format: Lindman H, Haji A. The development of the metastatic site pattern during time in different subtypes of breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-04.
Abstract P2-11-04: Serum IgG response against prostate-related antigen revealed by personalized peptide vaccination in patients with metastatic recurrent breast cancer
Authors: Toh U , Okabe M , Iwakuma N , Mishima M , Shichijo S , Yamada A , Noguchi M , Itoh K , Akagi Y
Published: May 2016

Purpose: We have indicated that IgG and CTL boosting response could be a potential prognostic factor for overall survival (OS) and progression free survival (PFS) in metastatic recurrent breast cancer (mrBC) patients, who had received personalized selected peptide vaccine (PPV) therapy in our previously reported clinical phase II study. The aim of this study is to identify the prognostic role of serum value of IgG antibody against prostate related-antigen (PRA), including prostate-specific antigen (PSA), prostate specific membrane antigen (PSMA) and prostate acid phosphatase (PAP) in mrBC patients

Methods: Peripheral blood samples of 77 patients with mrBC were analyzed for serum anti-PRA IgG levels before and after 6th and 12th PPV therapy prospectively. Most of the peptides using for PPV are derived from cancer associated antigens expressing in various types of advanced cancers, but the peptides derived from PRAs were not used in this study.

Results: After PPV therapy, total serum levels of anti-PRA IgG were significantly increased in 31 mrBC patients (Group 1) whereas in remaining 46 rmBC patients (Group 2). Either serum anti-PSA, anti-PAP and/or anti-PMSA IgGs showed a significant increase in patients of Group 1 after 6th (p=0.045) and 12th PPV treatment (p < 0.001), irrespective of their intrinsic subtypes. The median PFS and median OS of Group 1 patients were 8.1 and 14.3 months, while those of Group 2 patients were 5.1 and 10.8 months, respectively. Anti-PRA IgG levels were significantly associated with PFS (p=0.0073; HR: 0.37) and OS (p=0.025; HR: 0.43) between these two groups, whereas no significant relation was found with age, clinical response rate and recurrent metastatic status.

Conclusions: The Group 1 patients with elevated anti-PRA IgG may have better prognosis compared to Group 2 patients who showed no IgG elevation after PPV treatment for rmBC. These results indicated a clinical significance between pre-and post- treatment measurement of serum anti-PRA IgGs in mrBC patients receiving PPV therapy, and may be a useful prognostic marker for monitoring the outcome to PPV treatment of breast cancer.

Citation Format: Toh U, Okabe M, Iwakuma N, Mishima M, Shichijo S, Yamada A, Noguchi M, Itoh K, Akagi Y. Serum IgG response against prostate-related antigen revealed by personalized peptide vaccination in patients with metastatic recurrent breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-04.
Abstract P2-13-08: Breast lipofilling: A systematic review of current practice and oncological safety
Authors: Wazir U , Kasem A , Headon H , Mokbel K
Published: May 2016

Background: Lipofilling is a reconstructive and aesthetic technique that has recently grown in popularity and is increasingly being used in breast surgery. Concerns had been raised regarding its safety when used for remodelling and reconstruction of the breast.

Methods: We reviewed the current literature by systematically searching PubMed and Google Scholar databases regarding the current evidence regarding the oncological safety of the procedure in patients seeking aesthetic breast enhancement and in patients requiring oncoplastic reconstruction.

Results: Among the 864 patients included in the currently available studies on breast cancer patients who underwent lipofilling, only 14 (1.6%) recurrences were identified. However, evidence has emerged suggestive that the use of lipofilling in the background of ductal carcinoma in situ (DCIS) may be associated with an increased risk of neoplasia.

Conclusions: Over the subsequent two decades, little evidence has been found to support these early theoretical concerns, and growing numbers of proponents of the procedure are confident in its safety. Further study is required to better delineate the effect of lipofilling on DCIS.

Citation Format: Wazir U, Kasem A, Headon H, Mokbel K. Breast lipofilling: A systematic review of current practice and oncological safety. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-13-08.
Abstract P3-05-07: RAD1901, a novel oral, selective estrogen receptor degrader (SERD) with single agent efficacy in an ER+ primary patent derived ESR1 mutant xenograft model
Authors: Garner F , Brown J , Katzenellenbogen J , Lyttle CR , Hattersley G
Published: May 2016

Despite advances in the treatment of metastatic breast cancer, many women eventually relapse with more aggressive forms of endocrine-resistant disease. Mutations in the ESR1 gene encoding the estrogen receptor (ER) have recently emerged as a potential mechanism for the development of clinical resistance to conventional anti-estrogen therapies, such as fulvestrant. To overcome some of the pharmacokinetic limitations and intramuscular administration challenges associated with fulvestrant endocrine therapy and to combat the development of resistance, there is a significant need for the development of more durable and more effective ER-targeted therapies. Here, we begin to describe and characterize the preclinical efficacy of RAD1901, a novel, orally bioavailable small-molecule SERD, with significant therapeutic potential for treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 demonstrated profound tumor growth inhibition in MCF-7 xenograft models when compared to fulvestrant and tamoxifen. Importantly, RAD1901 also demonstrated marked single agent efficacy in a primary patient-derived xenograft (PDx) model harboring the ESR1 Y537S mutation indicating the utility of this SERD against clinically relevant ER mutants. Further biochemical binding studies and co-crystallization experiments of RAD1901 bound to the ER further confirms the ability of RAD1901 to bind to both mutant and wild type forms of the ER. RAD1901 is currently undergoing clinical testing in postmenopausal women with ER-positive advanced breast cancer.

Citation Format: Garner F, Brown J, Katzenellenbogen J, Lyttle CR, Hattersley G. RAD1901, a novel oral, selective estrogen receptor degrader (SERD) with single agent efficacy in an ER+ primary patent derived ESR1 mutant xenograft model. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-07.
Abstract P3-05-12: Combination of anti-progranulin (GP88/PGRN) antibody and letrozole inhibits tumor formation of letrozole resistant breast cancer cell lines
Authors: Serrero G , Dong J , Yue B , Hicks D , Hayashi J
Published: May 2016

The 88 kDa glycoprotein GP88 (Progranulin, PCDGF, acrogranin) is the largest member of the granulin/epithelin family of growth modulators identified as a driver of tumorigenesis. GP88 (PGRN) was also shown to be overexpressed in invasive ductal carcinoma (IDC)whereas it was negative in benign tumors and normal mammry epithelial tissue, thereby establishing GP88 as a therapeutic and diagnostic target in breast cancer (BC). Our laboratory has developed validated tools to measure GP88 in tumor biopsies and biological fluids as well as blocking its action. WE showed that GP88 was secreted and detected in the serum of BC patients at an increased level when compared to healthy subjects. Pathological studies with 530 cases of ER+ IDC with clinical outcomes showed that GP88 tumor expression was an independent prognostic indicator of recurrence in early stage BC patients. Training study followed by an independent validation study demonstrated that high GP88 tissue expression (GP88 3+) was associated with a 4-fold increase in risk of recurrence at 5 years. A neutralizing anti-GP88 antibody AG1 was expressed in a high yield CHO cell line was developed. The present study examined the effect of AG1 in letrozole resistant cell line AGLetR developed by long term selection in letrozole supplemented medium. This cell line showed decreased letrozole responsiveness in vivo and therefore constituted an excellent model for investigating letrozole resistance in vitro as well as in vivo. Here we report the results of studies investigating the effect of various doses of AG1 on LetR tumor development in combination with letrozole for AGLetR. We show that treatment with AG1 (10 mg/kg i.p.) in combination with letrozole was efficient to maintain long term responsiveness and inhibit tumor growth. Letrozole alone (5mg/kg) was unable to inhibit tumor growth and showed a doubling of tumor volume. Interestingly, long term combination treatment lead to tumor regression and inhibited tumor growth.

These data suggest that inhibiting GP88 could provide a novel and alternative therapeutic strategy for patients with resistance to anti-estrogen therapy, being tamoxifen or letrozole.

This works is supported by 2R44CA124179, HHSN 261201200060C, and HHSN2612014400C from NCI.

Citation Format: Serrero G, Dong J, Yue B, Hicks D, Hayashi J. Combination of anti-progranulin (GP88/PGRN) antibody and letrozole inhibits tumor formation of letrozole resistant breast cancer cell lines. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-12.
Abstract P3-05-13: Estrogen-independent growth of ESR1-mutant breast cancer cells requires CDK4/6
Authors: Luo F , Le X , Jeselsohn R , Brown M , Garraway L
Published: May 2016

A recent breakthrough in cancer treatment has been the development of highly specific cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. CDK4/6 inhibitors, such as palbociclib, prevent cell cycle progression from growth phase (G1) to the DNA synthesis (S) phase of the cell cycle. Palbociclib, however, is only approved for first-line treatment of patients with estrogen receptor positive (ER+) breast cancer in combination with an aromatase inhibitor, letrozole. Approximately 20% of metastatic breast cancer patients, harbor an activating mutation in the ligand-binding domain (LBD) of the estrogen receptor gene, ESR1, which confers resistance to estrogen deprivation. It is unclear whether tumors harboring these endocrine treatment-associated mutations will also respond to CDK4/6 inhibition. We have found that estrogen-independent growth of ESR1 -mutant breast cancer cells requires CDK4/6. Thus, ESR1-mutant breast cancer cells are sensitive to CDK4/6 inhibition. Mechanistically, ERS1 LBD-mutant cells upregulate key mediators of the G1-S cell cycle transition. Furthermore, the sensitivity of ESR1-mutant breast cancer cells to CDK4/6 inhibition requires RB1. While cells expressing RB1 respond to CDK4/6 inhibition, knockout of RB1 via CRISPRs enables ESR1-mutant breast cancer cells to resist combined estrogen depletion and CDK4/6 inhibition. Our studies suggest that tumors harboring ESR1 LBD mutations and an intact RB1 will respond to combined CDK4/6 inhibition and estrogen deprivation.

Citation Format: Luo F, Le X, Jeselsohn R, Brown M, Garraway L. Estrogen-independent growth of ESR1-mutant breast cancer cells requires CDK4/6. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-13.
Abstract P3-11-04: Metabolic profiles in female Sprague-Dawley rats receiving either a standard (4% fat) or Western (20% fat) diet and changes in rats bearing mammary cancers
Authors: Thompson MD , Grubbs CJ , Moeinpour F , Steele VE , Miller MS , Lubet RA
Published: May 2016

The methylnitrosourea(MNU)-induced model of ER+ mammary cancers in female Sprague-Dawley rats has been routinely used in our laboratories for screening chemopreventive agents. We recently reported that metformin was ineffective in preventing mammary cancers in this model when given to rats on a standard diet (Thompson, et al, Cancer Prev Res. 2015;8:231-9). In this study, we evaluated metformin in rats placed on either standard diet (4% fat) or a Western diet (20% fat, low calcium). As fat calories, these diets were 8% and 42%, respectively. The rats were placed on standard diet or Western diet at 43 days of age, given MNU (via the jugular vein) once at 50 days of age, and administered metformin or vehicle at 57 days of age for the remainder of the study. Serum of the rats in the various groups was obtained at 78 days of age, and at the end of the study (when mammary tumors were present). The levels of approximately 500 metabolites were compared in the serum based on data obtained by Metabolon (Research Triangle Park, NC). These studies showed that each of the four groups [(standard diet (early and late) or Western diet (early and late)] yielded four clearly distinct patterns based on an unsupervised principal component analysis. Certain of the metabolites which were differentially expressed in serum from standard vs Western diets at the early time point were alpha-10-undecanoate, 13-methylmyristic acid, 4-hydroxy-benzoate, 2-amino-heptanpate, tocopherol, and nicotinamide. Certain of these were fatty acids and lipid soluble vitamins that one would expect to be altered. Comparing serum from standard vs Western diets at the late time point confirmed many of these metabolic differences. We also compared serum from the early and late time points since the latter serums were typically from animals with a significant number of mammary cancers. We observed a number of metabolite changes including 4-hydroxy-butyrate, acetyl-carnitine, oxalate, and threonate. These cancer- related profiles will be discussed at greater lengths. Altered profiles caused by the administration of metformin and other chemopreventive agents will also be discussed. Of interest, metformin was consistently ineffective in preventing mammary cancers in rats given either standard or Western diet. Supported by NCI contract HHSN261201200021I.

Citation Format: Thompson MD, Grubbs CJ, Moeinpour F, Steele VE, Miller MS, Lubet RA. Metabolic profiles in female Sprague-Dawley rats receiving either a standard (4% fat) or Western (20% fat) diet and changes in rats bearing mammary cancers. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-11-04.
Abstract P3-12-06: Active breathing control in the management of left-sided breast cancer with irradiation: A dosimetric analysis of cardiac and lung dose
Authors: Gogineni ES , Kehrer JD , Jones GC , Premo C , Stinson S
Published: May 2016

Purpose: Deep inspiratory breath hold (DIBH) is a technique that has been increasingly utilized over the past several years for the purpose of reducing the radiation dose received by the heart and ipsilateral lung during radiotherapy (RT) for breast cancer. The purpose of this study was to provide a comparative analysis of cardiac and lung dose in patients treated with and without moderate DIBH with an active breathing control (ABC) device during RT for left-sided breast cancer at a community radiation oncology center.

Methods: From June 2013 to December 2014, 83 patients with stages 0-III left-sided breast cancer were treated with RT. Of these, 45 patients underwent CT simulation with an ABC device and the remaining 38 patients underwent standard free-breathing CT simulation for RT planning. Twenty-eight patients in the ABC cohort were treated with standard tangent fields and 18 were treated with locoregional RT. The non-ABC cohort included 26 patients treated with standard tangents and 12 treated with locoregional RT. A 4- or 5-field technique was utilized in all locally advanced patients to allow for coverage of the supraclavicular fossa and internal mammary lymph nodes with inclusion of low axillary coverage based on individual risk factors. All patients were treated with 3D-conformal techniques utilizing multi-leaf collimators to block the heart. Comparisons were made between mean heart dose, heart V5, mean lung dose, and lung V5 with and without the use of ABC. Kruskal-Wallis tests were used to determine significance between groups with α for significance set at p ≤0.05.

Results: On combined analysis, the use of DIBH with ABC resulted in a reduction in heart V5 (1.5 versus 5.4%; p=0.018). Mean heart dose, mean lung dose, and lung V5 were not significantly improved with the use of ABC. On subgroup analysis, patients treated with locoregional RT had reduced mean heart dose (161 cGy versus 309 cGy; p=0.014) and heart V5 (2.3% versus 14.8%; p<0.001) compared to patients treated with a standard free-breathing technique.

Conclusions: The use of ABC provided a significant reduction in heart V5 in all patients with left-sided breast cancer and in mean heart dose and heart V5 in patients treated with locoregional RT. This retrospective, single-institution analysis demonstrates the feasibility of implementing moderate DIBH with ABC technology in the treatment of left-sided breast cancer in a community radiation oncology center.

Citation Format: Gogineni ES, Kehrer JD, Jones GC, Premo C, Stinson S. Active breathing control in the management of left-sided breast cancer with irradiation: A dosimetric analysis of cardiac and lung dose. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-06.
Abstract P3-12-16: Hydrosorb® versus control (water based spray) in the management of radio-induced skin toxicity: Results of multicentre controlled randomized trial
Authors: Bazire L , Fromentin I , Diallo A , de Lalande B , Pernin V , Dendale R , Fourquet A , Savignoni A , Kirova Y
Published: May 2016

Purpose: To report the results of a randomised study comparing the efficacy of Hydrosorb® versus control (water based spray) in the topical treatment of grade 1 and 2 radiation dermatitis in population of patients treated for early stage breast cancer (BC) with normo fractionated radiotherapy (RT).

Patients and Methods: Breast cancer patients with grade 1-2 radio-induced dermatitis during normo fractionated postoperative radiotherapy were eligible (according to the CTCAE v3 scale). They were randomised to receive either Hydrosorb® (A) or water based spray (B). The primary endpoint was local treatment failure defined as interruption of radiotherapy because of skin radiotoxicity or and/or change of local cares for skin alteration. Secondary endpoints were the evaluation of skin colorimetry, pain, and quality of life. Pain was assessed according to two classes with a VAS cut-off of 2.

Results: Two-hundred seventy eight patients were enrolled (A = 142, B = 136). There were 186 successfully treated patients (82 in Hydrosorb® arm, and 74 in the control arm). There were 60 "failures" in the Hydrosorb® arm, and 62 in the control arm (p = 0.72), but mostly without interruption of the radiotherapy. Twenty-four patients stopped the radiotherapy treatment for local cares (16 in Hydrosorb®, arm and 8 in control arm). No risk factors were associated with failure to local treatment. The average absolute reduction of colorimetric levels between day 28 and day 0 was 4 in the Hydrosorb®, and 4.2 in the water spray groups, respectively (p = 0.36). Forty-eight patients in the Hydrosorb® arm had a VAS > 2 versus 51 patients in the placebo arm, i.e. 34% and 38%, respectively (p = 0.45). A significant reduction of pain was observed on D7 (p = 0.04) and D21 (p = 0.01) in the Hydrosorb® arm. Sixty patients in the Hydrosorb® arm and 55 patients in the placebo arm had moderately to severely altered quality of life (p = 0.76).

Conclusions: The present study showed no significant difference between Hydrosorb® and simple water spray in the treatment of acute radio-induced dermatitis even if there was a trend to an improvement in pain at the first weeks after the treatment. Systematic prevention measures and modern breast cancer radiotherapy techniques now allow excellent tolerability, but the place of topical treatment to optimize this tolerability has yet to be defined.

Citation Format: Bazire L, Fromentin I, Diallo A, de Lalande B, Pernin V, Dendale R, Fourquet A, Savignoni A, Kirova Y. Hydrosorb® versus control (water based spray) in the management of radio-induced skin toxicity: Results of multicentre controlled randomized trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-16.
Abstract P3-12-21: Post-mastectomy radiotherapy for T3N0 breast cancers: A retrospective, multi-institution review
Authors: Frandsen JE , Cannon G , Poppe M
Published: May 2016

Purpose

The role of post-mastectomy radiotherapy (PMRT) for node-negative breast cancers that are larger than five centimeters remains undefined. The purpose of this study was to report outcomes for women with T3N0 breast cancers treated with and without PMRT.

Methods

T3N0 breast cancers diagnosed between 1985 and 2014 were collected from the tumor registries of two large healthcare systems. For the purpose of our analysis, patients were divided into two groups: (1) women who received PMRT and (2) those who did not receive PMRT. Chi-square and students t-tests were used to compare baseline characteristics. Kaplan Meier estimates were used to analyze freedom from locoregional recurrence (FFLR), relapse free survival (RFS), and overall survival (OS).

Results

This analysis identified 93 women with T3N0 breast cancers. Of these, 53 received PMRT and 40 did not. Median follow up was 6.2 years and 5.3 years in the non-PMRT and PMRT cohorts, respectively. Women not undergoing PMRT were more likely to be diagnosed in the 1980s and 1990s than women receiving PMRT (p< 0.05). Adjuvant chemotherapy and endocrine therapy were less frequently given in patients not receiving PMRT (p<0.05), again associated with an earlier treatment era. There was a trend toward increased FFLR in the women receiving PMRT (p=0.15). FFLR in the PMRT cohort was 97.9% and 97.9% at five and ten years, respectively. For women not receiving PMRT, FFLR was 88.4% and 88.4% at five and ten years, respectively. RFS (p=0.66) and OS (p=0.48) were similar.

Conclusions

Women not receiving PMRT in our study had a locoregional failure rate of only 11.6% at ten years despite receiving inferior systemic treatment by current standards. Locoregional control after PMRT for T3N0 breast cancers was excellent with a 2.1% failure rate at ten years. Further research is needed to define PMRT indications for this patient population when receiving chemotherapy and endocrine therapy in line with current guidelines.

Citation Format: Frandsen JE, Cannon G, Poppe M. Post-mastectomy radiotherapy for T3N0 breast cancers: A retrospective, multi-institution review. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-21.
Abstract P3-13-07: Radiofrequency ablation (RFA) is a promising treatment option for primary breast cancer: Experience in 386 Japanese breast cancer patients
Authors: Takahashi M , Ito T , Oura S , Nagamine S , Yamamoto N , Yamamichi N , Earashi M , Doihara H , Imoto S , Mitsuyama S , Akazawa K
Published: May 2016

Background. Radiofrequency ablation (RFA) is used for the treatment of various solid tumors. Several small experiences have reported as a primary treatment for breast cancer using RFA. However, the clinical benefits remain uncertain. We retrospectively studied 386 patients and analyzed their RFA-related complications and outcomes.

Methods. A clinical database was constructed from 10 institutions. RFA was performed using an electrical generator connected to a single cooled-tip electrode or multiple electrodes. Adjuvant systemic therapy and whole breast radiation were administered according to the clinicopathological background of each patient. Follow-up periods ranged from 1 to 90 months (mean 45.4 months). RFA-related complications and risk factors for in-breast recurrence after RFA were evaluated. Variables evaluated included patient characteristics, pre- and post-operative imaging modalities, tissue sampling modalities, and RFA-related factors.

Results. Skin burns were observed in 7 patients (1.8 %) and RFA-induced damage to the nipple-areolar complex in 7 patients (1.8 %). Persistent induration of the breast after RFA was observed in 137 patients (35.5 %). Eleven patients (2.8 %) developed in-breast recurrence. In-breast recurrence was more frequent in patients with tumor size >2.0 cm, ER-negative tumor, HER2-positive tumor, positive nodes, no breast irradiation and adjuvant chemotherapy.

Conclusions. Skin burns were a major problem after RFA, but the frequency of burns was relatively low. Breast induration was also developed, but it did not bring harmful effect to the patients with this complication. We conclude that RFA is a promising treatment option for solid T1 breast cancer without malignant potential.

Citation Format: Takahashi M, Ito T, Oura S, Nagamine S, Yamamoto N, Yamamichi N, Earashi M, Doihara H, Imoto S, Mitsuyama S, Akazawa K. Radiofrequency ablation (RFA) is a promising treatment option for primary breast cancer: Experience in 386 Japanese breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-13-07.
Abstract P4-02-12: Breast MRI: Enhancing pre-operative planning in women with newly diagnosed breast cancer
Authors: Carr B , Lamb LC , Zarfos K , Weigert J , Singh R
Published: May 2016

Hypothesis:

Preoperative breast MRIs in newly diagnosed breast cancer patients may lead to additional findings, including larger disease involvement, thus leading to a change in the operative plan. This information can led to better surgical planning and decreased rates of surgical re-excisions.

Methods:

This was a single surgeon, single institution, retrospective analysis of women with newly-diagnosed breast cancer who had surgery between December 2013 and December 2014. A total of ninety-six patients underwent preoperative breast MRI. Exclusion criteria were patient's refusal of MRI or surgery, contraindication to MRI based on implants or body habitus, and male patients.

Results:

Overall, breast MRI most closely correlated to pathological tumor size (gold standard). MRI had a 64% correlation with pathology size, whereas mammography and ultrasound correlation were 44% and 43% respectively. As breast density increased, MRI correlation to pathologic tumor size improved. For breast density between 25-50%, tumor size by MRI correlated with pathology size in 27% of patients, mammogram correlation was 33% and ultrasound was 12%. When breast density increased to 51-75%, MRI correlation improved to 92%, whereas mammogram correlation was 56% and ultrasound was 68%. The majority of patients fell within these two density categories; correlation for breast density <25% and >75% were not statistically significant. Of the breast biopsies preformed for MRI abnormalities not otherwise identified by mammography or ultrasound, 42% were positive for invasive cancer or DCIS. Thirty-eight percent of patients had a change in operative plan based on their MRI findings. Of the ninety-six patients, nine were changed from breast conserving surgery to mastectomy, and 29 underwent a larger area of resection than planned prior to MRI, due to findings of more extensive disease on MRI not otherwise appreciated by mammography or ultrasound.

Conclusion:

Pre-operative MRI played a significant role in the pre-surgical evaluation of patients with newly diagnosed breast cancer. In our series, breast MRI demonstrated better correlation with extent of disease compared to other imaging modalities. This is turn enhanced patient and surgeon decision making and led to more precise pre-operative surgical planning.

Citation Format: Carr B, Lamb LC, Zarfos K, Weigert J, Singh R. Breast MRI: Enhancing pre-operative planning in women with newly diagnosed breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-02-12.
Abstract P4-02-14: Incidentally detected enhancing lesions found on preoperative breast MRI: Analysis of T2 signal intensity and apparent diffusion coefficient significantly improve classification
Authors: Arponen O , Sudah M , Masarwah A , Sutela A , Vanninen R
Published: May 2016

Purpose and Background− Reportedly, magnetic resonance imaging (MRI) detects mammographically and sonographically (US) occult incidental lesions in 10-29% of patients with a malignant primary breast lesion. We evaluated diagnostic performance of the BI-RADS reporting system and utility of T2- and diffusion weighted imaging (DWI) for MRI detected additional lesions.

Methods− This prospective study protocol included 3.0T structural breast MRI with T2-weighted imaging and DWI performed according to EUSOMA guidelines in 112 consecutive patients with primary breast lesions (mean age 57.0±12.7 years, range 38-80 years). Breast lesions with one or more suspective feature according to the BI-RADS lexigon were biopsied. T2 signal intensity (SI) and DWI findings were assessed.

Results− Altogether 33 (29.5%) patients had 36 primarily MRI detected incidental additional lesions. In addition, 36 sographically or mammographically detected lesions were histopathologically confirmed and a total of 8 lesions were followed up. Of incidental lesions, 16 (44.4%) proved to be malignant. Mean size was 0.82±0.29 cm (range 0.5 cm to 1.5 cm) and 1.5±1.61 cm (range 0.5 cm to 5.0 cm) for 29 mass lesions and 7 NMLE lesions, respectively.

In mass lesions, traditional morphological or kinetic features were not correlated to malignancy except for fast initial enhancement (P=0.003). The BI-RADS classification produced 100% sensitivity, 40% specificity, 53.3% PPV, 100% NPV and 51.7% overall accuracy. Both the low T2 SI (P=0.05) and low ADC values (P<0.001) significantly correlated with malignancy yeilding improved 86.7%/90.5% specificity and 65.0%/90.5% negative predictive value, respectively (McNemar's test, P<0.01). Combining low T2 SI, ADC values or morphologic or kinetic features did not improve the results.

Conclusion− A single suspective morphologic or kinetic MRI feature is the most sensitive parameter to discover an incidental breast malignancy, as some incidental lesions present with only a few suspicious MRI feature. Specificity of MRI is improved when T2 SI or DWI are addressed.

Citation Format: Arponen O, Sudah M, Masarwah A, Sutela A, Vanninen R. Incidentally detected enhancing lesions found on preoperative breast MRI: Analysis of T2 signal intensity and apparent diffusion coefficient significantly improve classification. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-02-14.
Abstract P4-03-07: Contribution of high-resolution ultrasonography in the diagnosis of non-palpable breast cancer with calcification
Authors: Arai T , Takebe K
Published: May 2016

Background: In diagnosis of non-palpable calcificated breast cancer (NPCBC), stereo-guided mammotome (ST-MMT) serves as the standard. However, ultrasound resolution has improved dramatically recently. We hypothesized that through ultrasonography, it will become possible to diagnose NPCBC by US guided examination such as fine needle aspiration cytology (FNAC) and core needle biopsy (CNB) with much less invasion than ST-MMT.

Method: (Study1) The results of ultrasonic detection ability and US guided examination were studied among the benign lesions of 35 cases and 90 NPCBC patients histologically diagnosed in our facilities from 2010 to 2012. Of the 90 histological types, 74 (82%) were DCIS, and 16 (18%) were invasive carcinoma. (Study 2) The results of 193 progress observation cases from 2008 to 2012 with Birads Category 3 and 4a calcification were examined.

Result: (Study1) Using ultrasonography (Toshiba Aprio XG), calcification was detected in 88 of the 90 NPCBC lesions as echogenic foci. Two non-detectable lesions were DCIS of Van Nuys 1 and Van Nuys 2. The results of the FNAC were 80% positive and 20% indeterminate (there were no negative cases). In the 88 cases of possible calcified substance extracted through FNAC, 99% were confirmed under microscopic observation. (Study 2) 163 of 193 cases were able to be followed-up every six months for two to four years. An increase in calcification was observed in nine cases. Five of these cases were diagnosed with DCIS: Four were Van Nuys 1; one was Van Nuys 2. All five cases were of low-grade-malignancy.

Conclusion: The diagnostic method using FNAC to visualize calcification using high-resolution ultrasonography is an effective method to reduce the non-efficient, invasive breast cancer detecting method of ST-MMT. The diagnostic method is particularly useful in women of small breast size in Asian countries. The few low-grade DCIS cases included were not detected with ultrasound. However, we believe it is not a diagnostic error. As a result, we stopped using the ST-MMT from 2010. In spite of this, in the MMG screening performed in our facilities from 2010 to 2012, the detection rate of NPCBC without mass on MMG was 0.17 %. This detection rate is excellent in our country.

Citation Format: Arai T, Takebe K. Contribution of high-resolution ultrasonography in the diagnosis of non-palpable breast cancer with calcification. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-03-07.
Abstract P4-04-19: Primary breast cancer culture in a perfusion-based bioreactor suitable for in vitro testing of immune blockade therapy
Authors: Muraro MG , Muenst S , Mele V , Spagnoli GC , Oertli D , Weber WP , Soysal SD
Published: May 2016

Introduction: Interaction between cancer cells and immune system critically affects development, progression and treatment of human malignancies. Two-dimensional (2D) in vitro culture systems and in vivo animal models are the primary tools used to test cancer cell response to drugs but they are not suited for the development of immune-mediated therapies. Here we present an innovative method to culture breast cancer tissue in porous 3D scaffolds by using a perfusion-based bioreactor system that allows the maintenance and expansion of tumor microenvironment.

Experimental procedures: Freshly excised breast cancer specimens were fragmented and cultured in a 3D "sandwich-like format" between two layers of porous collagen scaffold under perfusion flow (U-CUP). DMEM/F12, supplemented with 10% autologous human serum, was used as a culture medium. We assessed the ability of tumor and non-malignant cells to survive and expand into the scaffold in perfusion culture, as well as their capacity to recapitulate features of the original breast cancer tissue. The maintenance of immune-infiltrating cells allowed testing of immune blockade therapy in vitro using anti-PD-L1 and anti-CTLA4 antibodies alone or in combination.

Results: The U-CUP culture system preserved tissue viability better compared to a static culture and promoted the expansion of breast cancer cells from surgical specimens together with accompanying stromal and immune cells into the porous scaffold. Tumor tissues were viable after 21 days and mostly recapitulating the initial histology with formation of glands. Administration of anti-PDL1 antibody, alone or in combination with anti-CTLA4, to the culture medium was associated with increased expression of markers of immune-activation (i.e. IFNg) and decreased expression of immunosuppressive cytokine IL10.

Conclusions: Our results show that culture of breast cancer tissue in a 3D perfusion-based bioreactor might represent a promising system for the pre-clinical evaluation of immune-mediated therapies. Preserving malignant, interstitial and immunocompetent cells comprised in surgically excised breast cancer samples might allow a direct evaluation of the effects of various treatments on the complex tumor microenvironment. This engineered in vitro model could be extended as a platform allowing the testing of innovative approaches for the treatment of human malignancies, possibly in the direction of personalized medicine.

Citation Format: Muraro MG, Muenst S, Mele V, Spagnoli GC, Oertli D, Weber WP, Soysal SD. Primary breast cancer culture in a perfusion-based bioreactor suitable for in vitro testing of immune blockade therapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-19.
Abstract P4-04-22: Upregulation of the interleukin 17/granulocyte-colony stimulating factor/fibroblast growth factor axis in breast cancer and its negative association with treatment outcome
Authors: Kawaguchi K , Suzuki E , Yamamoto Y , Saito K , Toi M
Published: May 2016

Background

Interleukin (IL) 17 is secreted by T helper 17 cells and tumor cells. It may induce the proliferation of mesenchymal stem cells (MSCs) in the tumor microenvironment directly and/or via fibroblast growth factor (FGF) and granulocyte-colony stimulating factor (G-CSF) production by tumor-associated macrophages. MSCs play various roles in tumor development and progression, by mediating tumor cell migration, promoting angiogenesis, regulating immune responses, and inducing anti-cancer drug resistance. Therefore, in this study, we examined the association of the IL17/FGF/G-CSF axis with both breast cancer development and response to chemotherapy.

Methods

Eighty-nine breast cancer patients (34% with luminal, 45% with HER2, and 21% with triple-negative breast cancer) and 55 healthy volunteers were analyzed. Serum IL17, basic FGF, and G-CSF levels were measured using a Luminex system. The primary objective was to evaluate the difference in IL17 serum levels between breast cancer patients and healthy volunteers. Secondary objectives were to determine the correlation of IL17 levels with the basic FGF and G-CSF levels, pathological complete response (pCR) (if neoadjuvant therapy was administered), and disease-free survival (DFS) in breast cancer patients. Statistical analyses were performed using the Mann-Whitney, chi-squared, and log-rank tests.

Results

Serum levels of IL17 (median, 91.9 vs. 40.3 pg/ml, p<0.0001), basic FGF (median, 63.9 vs. 3.15 pg/ml, p<0.0001), and G-CSF (median, 61.0 vs. 29.4 pg/ml, p<0.0001) were significantly higher in breast cancer patients than in healthy volunteers. IL17 levels were strongly correlated with basic FGF (r=0.86, p<0.0001) and G-CSF (r=0.73, p<0.0001) levels. Among 64 patients who received neoadjuvant therapy, those with low IL17 levels (<91.9 pg/ml) achieved a significantly higher pCR rate than those with high IL17 levels (≥91.9 pg/ml) (56.0% vs. 25.6%, p=0.014). In addition, the DFS at a median follow-up of 35.7 months was significantly higher in patients with low IL17 levels (p=0.0190).

Conclusion

The IL17/FGF/G-CSF axis was upregulated in breast cancer patients and the levels of these markers were inversely correlated with pCR and prognosis. These results may provide novel insight into the role of IL17 in tumor development and have important implications in the development of IL17 as a target in the treatment of breast tumors.

Citation Format: Kawaguchi K, Suzuki E, Yamamoto Y, Saito K, Toi M. Upregulation of the interleukin 17/granulocyte-colony stimulating factor/fibroblast growth factor axis in breast cancer and its negative association with treatment outcome. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-22.
Abstract P4-08-02: APOBEC3B upregulation by the PKC-NFκB pathway in breast cancer
Authors: McCann J , Leonard B , Starrett G , Kosyakovsky L , Molan A , Burns M , McDougle R , Parker P , Brown W , Harris R
Published: May 2016

Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in breast and other cancer. Human papillomavirus (HPV) infection accounts for APOBEC3B upregulation in cervical and head/neck cancers. However, the responsible mechanisms are unclear for non-viral malignancies such as breast cancer. Here, we demonstrate APOBEC3B upregulation through the PKC-NFκB pathway. PKC activation by the diacylglycerol mimic PMA causes specific and dose-responsive increases in APOBEC3B mRNA, protein, and activity levels, which are strongly suppressed by PKC and NFκB inhibition. Induction correlates with RELB (but not RELA) recruitment to endogenous APOBEC3B implicating non-canonical NFκB signaling. Relevance to tumors is supported by PKC inhibitor-mediated APOBEC3B downregulation in multiple breast cancer cell lines. These data establish the first mechanistic link between APOBEC3B and a common signal transduction pathway, suggesting that existing PKC-NFκB inhibitors could be repurposed to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes such as drug resistance and metastases.

Citation Format: McCann J, Leonard B, Starrett G, Kosyakovsky L, Molan A, Burns M, McDougle R, Parker P, Brown W, Harris R. APOBEC3B upregulation by the PKC-NFκB pathway in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-08-02.