bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-04-02: Improving immunotherapy response by epigenetic modulation
Authors: Luo N , Estrada VM , Sanders ME , Balko JM
Published: March 2017

The presence of predicted neo-antigens in any given tumor is highly correlated with total somatic mutational burden of the same tumor genome. However, many potential neo-antigens are never transcribed, translated, or presented as antigens, partially because they lie in regions of the genome that are transcriptionally-repressed by cytosine methylation of promoter-CpG islands. Treatment with DNA methyltransferase inhibitors (DNMTi) can hypothetically lead to re-expression of many potential neo-antigens. Furthermore, the presence of neo-antigens have been linked to immunotherapy outcomes in patients. Our hypothesis is that tumors with reduced mutational burden can be maximized for neo-antigen presentation by activating transcription and translation of these sequences through DNMTi treatment. Our preliminary results showed that the DNMTi guadecitabine (SGI-110), a second-generation hypomethylating agent, treatment decreases methyl-cytosine in genomic DNA both in vitro and in vivo. In addition, SGI-110 treatment enhances MHC-II expression on murine mammary carcinoma MMTV-Neu cells upon IFN-γ stimulation in vitro and increases T-cell infiltration in vivo. Currently, we are performing whole-exome-sequencing and RNA-sequencing to track somatic mutations from DNA to RNA. We will further track somatic mutations from RNA→ MHC-presented peptide sequences using MHC immunoprecipitation followed by mass spectroscopy analysis. In addition, we will explore the role of guadecitabine therapeutic priming on response to αPD-L1 immunotherapy. These studies will provide a pre-clinical data to evaluate the potential for combined epigenetic and immune-therapy in a clinical trial for breast cancer.

Citation Format: Luo N, Estrada VM, Sanders ME, Balko JM. Improving immunotherapy response by epigenetic modulation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-04-02.
Abstract P1-04-09: The missing link: Chemicals, epigenetics and breast cancer
Authors: Maund PR , Ermler S , Widschwendter M , Silva E
Published: March 2017

This abstract was not presented at the symposium.
Abstract P1-05-02: Genomic, transcriptomic and immune features of breast cancer according to the patient's body mass index at diagnosis
Authors: Desmedt C , Fornili M ,   ICGC Breast Cancer Working Group, Detours V , van den Eynden G , Salgado R , Maetens M , Brown D , Nik-Zainal S , Sotiriou C , Biganzoli E
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P1-05-16: An integrated molecular analysis of invasive lobular carcinoma
Authors: Lal S , McCart Reed A , Nones K , Wockner L , Song S , Lakhani S , Simpson P
Published: March 2017

Background: Invasive lobular carcinoma (ILC) is the most commonly diagnosed special histological type of breast cancer, accounting for up to 15% of all cases. Accumulating data suggests the biology and clinical features of ILC differ to those of the more commonly diagnosed Invasive Carcinoma of No Special Type (IC-NST), including evidence of there being an overall worse long term outcome associated with ILC. Several large-scale molecular profiling studies have recently been published regarding ILC, highlighting molecular heterogeneity and important drivers of tumour behaviour. We hypothesize that an integrative analysis of gene expression and DNA copy number data will identify novel drivers, and prognostic and predictive biomarkers of lobular phenotype.

Methods: Gene expression and copy number data from ILC tumours profiled in-house (n=25), METABRIC (n=125) and TCGA (n=145) were assembled and analysed. Integration of genome and transcriptome data was performed using two methods. Firstly, by Spearman correlation with a meta-analysis by combining gene level correlation coefficients from each study using a random effects model, weighting each study with inverse variance. Secondly using ANOVA, followed by combining gene level p-values across studies using Stouffers Z-score. Disease specific survival was examined at an individual gene level and using all genes simultaneously (via a Cox Boost analysis) to identify gene expression changes that are associated with poor outcome.

Results: DNA copy number profiling identified recurrent gains (1q, 8q, 16p), losses (11q, 16q) and amplifications (1q32, 8p12-p11.2, 11q13). 11q13 amplifications were prevalent at a higher frequency in patients with poor outcome compared to patients with better outcome. The integrative analysis identified 1928 candidate genes whose expression was associated with gene copy number; as expected being enriched from genome regions highlighted above. One hundred and sixty of these genes were of prognostic significance in the METABRIC ILC cohort, several are known cancer drivers (e.g. PBX1, CCND1) and five new candidates are being investigated as novel prognostic biomarkers by immunohistochemistry.

Conclusions: An integrated molecular analysis of ILC has identified a large number of gene expression changes that are dictated by gene copy number in ILC. Some of these are expected to influence tumour behavior and to highlight aggressive cancers with poor prognosis.

Citation Format: Lal S, McCart Reed A, Nones K, Wockner L, Song S, Lakhani S, Simpson P. An integrated molecular analysis of invasive lobular carcinoma [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-16.
Abstract P1-11-07: Frozen section histology evaluation of surgical margins helps perform single step oncologically safe and cost-effective breast conservation surgery
Authors: Agarwal G , Sonthineni C , Maylivahanan S , Chand G , Mishra A , Agarwal A , Verma AK , Mishra SK , Agrawal V , Krishnani N , Lal P
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P1-11-14: Breast conserving therapy and mastectomy revisited: overall and breast cancer-specific survival and the influence of age, stage, receptor status and comorbidities in 143,376 patients
Authors: Lagendijk M , van Maaren MC , Saadatmand S , Strobbe LJA , Poortmans P , Koppert LB , Tilanus-Linthorst MMA , Siesling S
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P2-01-29: In the era of conservative surgery, can patients presenting with node positive breast cancer be spared axillary node dissection post neoadjuvant chemotherapy? A meta-analysis and review of literature
Authors: Headon H , Chehade HEH , El Tokhy O , Wazir U , Heeney J , Kasem A , Mokbel K
Published: March 2017

Background:The use of sentinel lymph node biopsy (SLNB) following neoadjuvant chemotherapy (NAC) in patients presenting with clinically positive lymph nodes remains controversial.

Methods: A computer-aided search of the literature regarding SLNB in clinically node-positive breast cancer treated with NAC was carried out to identify the false negative rate (FNR), sentinel lymph node identification rate (IR), and axillary pathological complete response (pCR).

Results: Nineteen articles were used in the analysis yielding 3398 patients. The pooled estimate of the FNR was 13% and that of the IR was 91%. The adjusted pCR rate was 47%.

Conclusions: SLNB after NAC in biopsy-proven node positive patients results in reasonably acceptable FNR and IR making it a valid alternative management strategy to axillary dissection. Although the results are not matched with those in clinically node negative patients, a FNR of 13% is very unlikely to adversely affect overall survival. Its impact on locoregional recurrence should be evaluated in adequately powered future studies. More refined patient selection and optimal techniques can improve the FNR and IR in this patient population.

Citation Format: Headon H, Chehade HEH, El Tokhy O, Wazir U, Heeney J, Kasem A, Mokbel K. In the era of conservative surgery, can patients presenting with node positive breast cancer be spared axillary node dissection post neoadjuvant chemotherapy? A meta-analysis and review of literature [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-29.
Abstract P2-04-25: Breast cancer patients after kidney and liver transplantation: A Report from Asan medical center
Authors: Jung I , Kim HJ
Published: March 2017

This abstract was not presented at the symposium.
Abstract P2-07-09: CPM rate among individuals with breast cancer who underwent multiplex gene testing for hereditary cancer: Single institution experience
Authors: Elsayegh N , Gutierrez Barrera AM , Kuerer HM , Hernandez ND , Litton JK , Arun BK
Published: March 2017

Background: Availability of multiplex gene (MPG) testing for hereditary cancer has led to increase use of panel testing versus single gene testing for hereditary cancer. These panels include high, but also moderate penetrance genes. For some of these genes, associated cancer risk and risk management guidelines do not exist. Furthermore there is a high rate of variant of unknown significant (VUS) findings in non-BRCA genes. Currently, in the absence or minimal available data, health care providers and patients are faced with important risk management decisions, especially regarding preventive surgeries, such as prophylactic mastectomy. Currently, there is no data regarding prophylactic mastectomy rate among patients with breast cancer who underwent (MPG) testing. Therefore, our aim was to evaluate the rate of contralateral prophylactic mastectomy (CPM) in a cohort of individuals who underwent multiplex gene testing. Methods: Eight hundred thirty five patients with breast cancer who underwent MPG testing between the years 2013 and 2016 were identified using Institutional Clinical Cancer Genetics Database. Patients with pathogenic, likely pathogenic variants or who had a VUS were included in the analysis. Results: Of 835 patients with a diagnosis of breast cancer; 105 (13%) had a pathogenic or likely pathogenic mutation: 29 (28%) BRCA1, 26 (25%) BRCA2, 11 (11%) ATM, 2 (2%) BARD1, 3 (3%) BRIP, 9 (9%) CHEK2, 1 (1%) MSH2, 1 (1%) NBN, 5 (5%) PALB2, 4 (4%) PTEN, 1 (1%) RAD51C, 5 (5%) TP53, 4 (4%) CDH1, 2 (2%) MUTYH, 1 (1%) PMS2, 1 (1%) APC (1). A total of 102 (12%) VUS were found. Average age of diagnosis was 44 (Range 21-81). CPM rate was 32% (n=66) for the total cohort. Twenty nine % (n=19) of patients with non-BRCA mutations, 24.2% (n=16) with VUS and 46% (n=31) with BRCA mutations opted for CPM. Conclusion: Overall 32% of breast cancer patients with germline mutations or VUS opt for CPM at our institution. The rate for CPM in non- BRCA mutations carriers is high despite no available data regarding contralateral breast cancer risk and benefit of CPM. This finding should be validated in larger cohorts, including identification of reasons behind decision for CPM in these cohorts.

Citation Format: Elsayegh N, Gutierrez Barrera AM, Kuerer HM, Hernandez ND, Litton JK, Arun BK. CPM rate among individuals with breast cancer who underwent multiplex gene testing for hereditary cancer: Single institution experience [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-07-09.
Abstract P2-08-01: Results from a randomized placebo-controlled phase 2 trial evaluating exemestane ± enzalutamide in patients with hormone receptor–positive breast cancer
Authors: Krop I , Abramson V , Colleoni M , Holmes FA , Estevez L , Hart L , Awada A , Zamagni C , Morris P , Schwartzberg L , Chan S , Wheatley D , Guculp A , Biganzoli L , Steinberg J , Gianni L , Trudeau M , Kelly CM , Uppal H , Tudor IC , Peterson A , Winer E , Yardley DA
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P2-08-07: Anti-proliferative and anti-inflammatory estrogen receptor agents for treatment of endocrine-resistant breast cancer
Authors: Josan JS , Pokludova K , Devi S , Srinivasan S , Katzenellenbogen JA , Nettles KW
Published: March 2017

This abstract was not presented at the symposium.
Abstract P2-14-02: OncoGambit: A revolutionary computer -assisted oncology treatment decision
Authors: Bourdeanu L , Martel C , Luu TH
Published: March 2017

This abstract was not presented at the symposium.
Abstract P2-15-02: Attitudes towards tissue donation for rapid autopsy among community and academic oncologists
Authors: Rajagopal PS , Lee A , Puhalla SL
Published: March 2017

Rapid autopsy (RA) refers to the recently developed practice of obtaining research tissue within 2-6 hours following the death of a patient. Such tissue can offer insights into the genomic and proteomic evolution of metastatic disease and possible novel therapeutic targets. Although patients generally have positive attitudes towards RA, RA programs have not been widely established by oncologists at healthcare centers with these capabilities. To identify barriers to our adoption of an RA program, we conducted a 21-item web-based survey of academic and community oncologists in a single institution with regard to knowledge, attitudes and concerns about RA. Twenty-six physicians completed the study out of a possible 98 respondents, with 50% in academic practice and 50% in community practice. 46% were not aware of RA prior to the survey. None of the community physicians had experience with patient tissue donations of any kind. In completing the survey, 85% were willing to ask future patients about participating in RA. 58% of oncologists cited lack of awareness as their primary barrier to participation, while 31% reported discomfort in discussing rapid autopsy with patients or concern about the doctor-patient relationship. A minority of physicians had ethical concerns about the practice. The most popular strategies for increasing awareness of the RA program included distributing informational pamphlets to patients, using a third-party advocate or a discussion with the patient's primary oncologist or NP. 92% of those surveyed stated that being aware of patient interest would make them much more likely to recommend RA to patients. Our study is among the first to clarify barriers among oncologists, particularly community oncologists, to establishing RA programs and suggests that increased information alone with clarification of patient perceptions could provide substantial progress in developing RA programs at tertiary healthcare centers and recruiting patients to these programs.

Citation Format: Rajagopal PS, Lee A, Puhalla SL. Attitudes towards tissue donation for rapid autopsy among community and academic oncologists [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-15-02.
Abstract P3-01-06: Visualizing the real difference between 2-D and 3-D specimen mammography
Authors: Kaufman CS , Zacharias K
Published: March 2017

BACKGROUND: Specimen mammography aids in the determination 1) if the target lesion has been removed and 2) whether there is a clear margin at excision. In the past, two orthogonal views using 2-D imaging has been considered to be equivalent to a three dimensional perspective. Yet tomosynthesis for screening mammography has demonstrated the value of thin sliced imaging over two view screening mammography. In March, 2015, we began using true 3-D tomosynthesis of breast specimens at lumpectomy and have compared 2-D and 3-D specimen mammography.

METHODS: We have examined 125 consecutive breast cancer patients with both 2-D and 3-D imaging of the same specimens since March 2015. The circulating nurse would take the specimen and obtain two orthogonal views using both 2-D and 3-D devices with images sent to the radiology department. It was not felt ethical to blind the surgeon from having both images available to make an intraoperative clinical decision regarding immediate re-excision. We compared the data noted from each method and which method best aided the decision to perform immediate re-excision, and time required to obtain the images.

RESULTS: We have studied 125 patients over 11 months since March 2015. Confirmation of complete lesion excision was easier with 3-D tomosynthesis than with 2-D as the 3-D slice did not include overlying skin or dense breast tissue surrounding the lesion in the image, making the target lesion stand out more clearly. Although the 2-D images appear to have higher contrast than the individual 3-D slices, the tomosynthesis 3-D images contained more actionable data than the 2-D. Also decisions to excise more tissue during the procedure were enabled by the additional information included in the 3-D images. In addition, the 3-D images provided the depth of field to enable accurate re-excision using the Z-axis (see figures). Finally, it took about a minute longer to obtain and review the 3D images, although this difference did not delay surgical decisions nor prolong operative time.

CONCLUSIONS: 3-D specimen tomosynthesis facilitates the reduction of post-operative re-excision for lumpectomy patients by providing more information than 2-D orthogonal views, providing easier, more accurate confirmation of the extent of the target excision. Additionally, serial 1mm slices of the specimen allowed the integration of Z-axis targeting, ensuring that any necessary margin excision during surgery was accomplished immediately with maximum tissue conservation. More studies are planned to further validate these findings of these first 125 patients.

Citation Format: Kaufman CS, Zacharias K. Visualizing the real difference between 2-D and 3-D specimen mammography [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-01-06.
Abstract P3-03-18: An ex-vivo platform predicts anti-tumor outcome of metabolically-targeted, algorithm-driven combination therapy in triple-negative breast cancer
Authors: Goldman A , Majumder B , Dhawan A , Kohandel M , Majumder P , Sengupta S
Published: March 2017

Cancer cells undergo phenotypic cell state transitions in response to chemotherapy as a mechanism that can confer transient resistance. However, such cell state transitions can also unlock unique vulnerabilities that can be exploited using temporally-sequenced combination chemotherapy. Here, utilizing a primary breast cancer ex-vivo functional assay that captures tumor heterogeneity, we report that in response to a chemotherapeutic agent, a subset of cancer cells can mount an acutely-induced phenotypic adaptive resistance to future cytotoxic pressure via the transient acquisition of a unique metabolic state defined by augmented glycolysis together with mitochondrial proficiency. These cells activate two complex, temporally-interdependent pathways that enable a glucose shunt towards the pentose phosphate pathway (PPP), which confers an adaptive cross-tolerance to different chemotherapeutic agents. Mathematically modeling these pathways, and simulating drug schedules, we define a rationally-designed 3-drug combination therapy of metabolic inhibitors and cytotoxic agents, which results in improved cancer survival. Our findings highlight a new bioenergetics-based adaptive resistance mechanism through which cancer cells can survive combinations of chemotherapy. Administration of metabolic inhibitors in rational, temporal sequence with existing chemotherapy can emerge as a new paradigm in the treatment of cancer.

Citation Format: Goldman A, Majumder B, Dhawan A, Kohandel M, Majumder P, Sengupta S. An ex-vivo platform predicts anti-tumor outcome of metabolically-targeted, algorithm-driven combination therapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-18.
Abstract P3-04-25: Role of H19, a long non-coding RNA, in development of resistance to endocrine therapy in breast cancer cells
Authors: Basak P , Chatterjee S , Bhat V , Jin H , Su A , Murphy LC , Raouf A
Published: March 2017

Introduction:

Majority of breast cancer tumors are Estrogen receptor positive (ER+) where antiestrogen therapies (endocrine therapies) are the best therapeutic strategy to treat this type of tumors. However, eventually over 30% of patients will develop resistance to endocrine therapies resulting in disease relapse. We recently showed that the long noncoding RNA, H19, is an estrogen target gene that plays a significant role in estrogen-induced proliferation of the normal and malignant ER+ cells. We therefore hypothesize that H19 expression is also important to the proliferation of endocrine therapy resistant cells. In this study, we examined if estrogen-independent H19 expression is important to the development of endocrine therapy resistance.

Objective:

The overall objective of this project is to use therapy sensitive (MCF-7) and therapy-resistant (LCC9) breast cancer cells as model systems to examine the role of long non-coding RNA H19 in development and maintenance of resistance to endocrine therapy.

Methodology and Results:

We examined the expression of H19 in ER+ breast cancer cells (MCF7) that under the selective pressure of fulvesterant (ICI, ER down regulator) acquire resistance to ICI. We observed that while H19 expression was initially decreased as expected, its expression subsequently increased in the ICI-resistant MCF7 cells. Interestingly, H19 knockdown in MCF7 cells significantly decrease their proliferation as determined by Flowcytometry and made them more sensitive to ICI. We also examined H19 expression in the ICI-resistant LCC9 cells and found that ICI treatment increased H19 expression. Interestingly, H19 knockdown in the LCC9 cells decreased their proliferation and surprisingly made them sensitive to ICI treatment. Previous observations indicate that NOTCH4 receptor (NR4) may be involved in endocrine therapy resistance. Interestingly we found that in presence of ICI, NR4 expression is increased and that forced activation of NR4 markedly increases H19 expression in LCC9 cells.

Conclusion:

Altogether these observations suggest that H19 plays an important role in the development of endocrine therapy resistance and further our understanding of the cellular and molecular mechanisms involved in endocrine therapy resistance. These and similar studies could potentially lead to the development of new therapies to treat therapy resistant tumor cells. Further experiments would reveal if signalling pathways that regulate H19 expression independent of estrogen are useful therapies against endocrine therapy resistant tumors.

Citation Format: Basak P, Chatterjee S, Bhat V, Jin H, Su A, Murphy LC, Raouf A. Role of H19, a long non-coding RNA, in development of resistance to endocrine therapy in breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-25.
Abstract P3-07-07: Inhibition of death-associated protein kinase 1 enhances chemotherapy action against triple-negative breast cancer
Authors: Zhao D , Zhao J , Mazumadar A , Bollu L , Shepherd J , Ma Y , Zhang Y , Hill JL , Savage MI , Brown PH
Published: March 2017

Background: Triple negative breast cancers (TNBCs) are the most aggressive ER negative breast cancers with limited therapy strategies and poor prognosis. P53 gene is frequently mutated in approximately 80% of TNBCs. To identify novel molecular targets for ER negative breast cancer, particularly the more aggressive TNBC, we conducted a human kinome screen and identified death-associated protein kinase 1 (DAPK1) as one of the kinases that are highly expressed in ER negative breast cancer. Deletion or inhibition of DAPK1 suppresses growth of p53-mutant but not p53-wildtype breast cancer cells. Here we investigate whether DAPK1 inhibition will enhance chemotherapy action against p53-mutant TNBCs.

Experimental design and methods: We performed experiments to test cell growth of p53-mutant TNBCs that were treated with DAPK1 siRNA or DAPK1 inhibitors in combination with different doses of chemotherapy drugs including 5-FU (5-Fluorouracil), doxorubicin, cisplatin, PARP inhibitor (BMN673), paclitaxel, gemcitabine and vinorelbine.

Results: Our results show that DAPK1 inhibitors enhance the growth inhibitory effects of cisplatin and PARP inhibitor in p53-mutant TNBCs. Furthermore, combined DAPK1 inhibition (via siRNA knockdown) with cisplatin synergistically inhibits cell growth of p53-mutant TNBCs.

Conclusion: DAPK1 is a novel, promising target for the treatment of triple-negative p53-mutant breast cancer. Our studies demonstrate that DAPK1 inhibition sensitizes TNBCs to the cytotoxic effects of cisplatin or the PARP inhibitor. We are now conducting studies to determine whether DAPK1 inhibition will sensitize TNBC tumors and patient-derived TNBC xenografts to the effects of cisplatin and PARP inhibition. These studies suggest that the combination of DAPK1 inhibition with drugs that interfere with DNA repair will be useful for the treatment of the most aggressive form of breast cancer, triple-negative breast cancer.

Funding: This study was funded by a Susan G. Komen Promise grant (SAB12-00006 to P.H. Brown), a MD Anderson Knowledge Gap Moonshot grant (to P.H. Brown) and a Breast Cancer Research Foundation grant (BCRF 15101807, 2015–2016 to P.H. Brown).

Citation Format: Zhao D, Zhao J, Mazumadar A, Bollu L, Shepherd J, Ma Y, Zhang Y, Hill JL, Savage MI, Brown PH. Inhibition of death-associated protein kinase 1 enhances chemotherapy action against triple-negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-07.
Abstract P3-07-13: Prostate derived Ets factor, a novel driver of breast cancer independent of estrogen signaling axis and a target for immunotherapy of breast cancer
Authors: Sood AK , Mukhopadhyay A , Wang J
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P3-12-05: Estimating costs of relapsing HER2+ breast cancer in Spain
Authors: Colomer R , Ciruelos E , De la Haba J , Martín M , De Salas-Cansado M , Muñoz-Molina B , Albanell J
Published: March 2017

OBJECTIVES: The purpose of this study was to describe the economic impact of recurrences (locoregional or unresectable/metastatic recurrences [MR]) in patients with HER2+ breast cancer (BC) in Spain.

METHODS: A Delphi panel of 15 Spanish oncologists was carried out to define the clinical management (patients' flow and healthcare resources use) of locoregional recurrences (LR) and unresectable or MR in patients with HER2+ BC. Healthcare resources included medication, medical visits, lab and imaging tests, hospitalizations, surgery, adverse events management and treatment of specific metastases (e.g. bone metastases). Additionally, loss of productivity was also estimated. Local unit costs where used in combination with healthcare resources and workdays lost to estimate both the direct and indirect costs of LR and MR in HER2+ BC patients. A deterministic sensitivity analysis was performed to explore the robustness and assess the critical variables of the study.

RESULTS: The estimated distribution of recurrences in HER2+ BC patients was: 90% of MR, 7% of LR and 3% of LR followed by an MR. With respect to MRs, 31% of cases were estimated to receive up to 5 lines of treatment whilst 5% received no treatment (10%, 20% and 21% would receive 2, 3 and 4 treatment lines, respectively, with a median of 3 lines). Treatment regimens including trastuzumab were the most frequently used (in combination with pertuzumab and taxane in 1L, and with other combinations in 4&5L). In 3L, the most common treatment regimen was lapatinib-capecitabine. Total costs, including medical and indirect costs were €235,138, being the direct costs more than 88.7% (€208,682). Both direct and total costs were higher in patients being treated with a higher number of treatment lines, with figures ranging from €38,511 (1L) to €308,869 (5L) and €50,908 (1L) and €358,000 (5L) respectively.

CONCLUSIONS: HER2+ BC patients with a MR were estimated to receive a median of 3 treatment lines and almost one third receives 5 treatment lines. The direct and indirect costs of recurrences are high, with a calculated average total cost of €235,138. Using targeted therapies in earlier stages of HER2+ BC that achieve a reduction of recurrences would achieve significant cost savings in Spain.

Citation Format: Colomer R, Ciruelos E, De la Haba J, Martín M, De Salas-Cansado M, Muñoz-Molina B, Albanell J. Estimating costs of relapsing HER2+ breast cancer in Spain [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-12-05.
Abstract P4-01-11: Diagnostic performance of supplemental screening with molecular breast imaging in women with dense breast tissue
Authors: Redfern RE , Shermis RB , Chen JT , Kudrolli H
Published: March 2017

Purpose: The aim of this study was to retrospectively assess the diagnostic performance of molecular breast imaging (MBI) as a supplementary screening tool for women with dense breast tissue. We had previously reported excellent cancer detection rates and positive predictive values, whereas in this report we present 1-year follow up data and present sensitivity, specificity and negative predictive values. Methods: Molecular Breast Imaging (MBI) was implemented in routine clinical practice at a large, community-based breast imaging center. Women 25 to 90 years of age with dense breasts and negative mammogram results who underwent subsequent screening with 300 MBq (8 mCi) 99mTc-sestamibi MBI were retrospectively analyzed. Outcome measures included sensitivity, specificity, and positive and negative predictive values. Results: In 1,376 women with a complete reference standard, 17 (1.2%) were diagnosed with cancer. MBI detected cancer in 15 subjects such that 2 interval cancers occurred and were considered false negatives. Of those 17 cancers, 1 (5.9%) were ductal carcinoma in situ only, 13 were invasive tumors (76.5%); 1 (5.9%) patient was diagnosed with bilateral disease. Overall sensitivity of MBI in this sample was 88.2% (95% CI 63.6 – 98.5), while specificity was also high at 92.4% (95% CI 90.9 – 93.8). Positive predictive value for recall (PPV1) was 12.7% (95% CI 7.3 – 20.1), while negative predictive value for recall (NPV1) was calculated as 99.8% (95% CI 99.4 – 100.0). Conclusions: When incorporated into a community-based clinical practice environment, MBI demonstrated high sensitivity, specificity and negative predictive value. These results demonstrate the utility of MBI as a supplementary screening tool to mammography for women with dense breasts.

Citation Format: Redfern RE, Shermis RB, Chen JT, Kudrolli H. Diagnostic performance of supplemental screening with molecular breast imaging in women with dense breast tissue [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-01-11.
Abstract P4-02-01: Eribulin induces vascular remodeling and reoxygenation in advanced breast cancer patients: A comparative study with bevacizumab
Authors: Ueda S , Saeki TS , Takeuchi H , Shigekawa T , Yamane T , Kuji I , Osaki A
Published: March 2017

Purpose: Eribulin mesylate (eribulin) is a first-in-class halichondrin B-based microtubule dynamics inhibitor. To understand the mechanism of vascular remodeling of eribulin, we compared optical hemodynamic and blood biomarker changes between eribulin and bevacizumab.

Methods: Patients with advanced breast cancer with stage III/IV were eligible for the study. Patients were assigned to receive either eribulin or single-agent bevacizumab. Diffuse optical spectroscopic imaging (DOSI) measured tissue concentrations of oxy-hemoglobin (O2Hb), deoxy-hemoglobin (HHb), total hemoglobin (tHb) and oxygen saturation (SO2) of breast tumors before and day 7 after the first infusion. Peripheral blood samples were obtained from the patients to measure plasma concentration of VEGF, bFGF, FLT-3L, EGF, G-CSF, TNFα, IL1b, IL4, IL6, IL8, IL10, IL12p40, and TGF-β1.

Results: Baseline DOSI measurement of all 29 patients (eribulin, n = 14 and bevacizumab, n = 15) revealed significantly higher tumor concentrations of O2Hb, HHb, and tHb than that in the normal breast tissue. Eribulin significantly decreased in HHb concentration and increased SO2 during the observation period. This trend was not observed for bevacizumab. Instead, bevacizumab significantly decreased the concentration of O2Hb and tHb. The blood biomarker study revealed that both eribulin and bevacizumab decreased plasma concentrations of VEGF and bFGF, but only eribulin suppressed the plasma concentration of TGF-β1.

Conclusions:

Optical imaging technology revealed that eribulin, but not bevacizumab, induced tumor reoxygenation after the start of infusion. Eribulin had a potent anti-angiogenic properties as well as bevacizumab, while suppression of TGF-β1 observed by only eribulin could be associated with remodeling of the microvasculature through suppression of activated stromal cells.

Citation Format: Ueda S, Saeki TS, Takeuchi H, Shigekawa T, Yamane T, Kuji I, Osaki A. Eribulin induces vascular remodeling and reoxygenation in advanced breast cancer patients: A comparative study with bevacizumab [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-01.
Abstract P4-03-02: Stromal kinome screening identifies a novel regulatory kinase implicated in fibroblast-mediated progression of invasion in triple negative breast cancer tumours
Authors: Giamas G , Grothey T , Grothey A , Stebbing J
Published: March 2017

This abstract was not presented at the symposium.
Abstract P4-03-05: Role of stromal discoidin domain receptor-1 in breast cancer
Authors: Gupta K , Yuan B , Li R
Published: March 2017

This abstract was not presented at the symposium.
Abstract P4-03-14: Stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer
Authors: Reddy JP , Atkinson RL , Larson RA , Burks JK , Smith D , Debeb BG , Ruffell B , Creighton C , Reuben JM , Krishnamurthy S , Symmans WF , Brewster A , Van Laere SJ
Published: March 2017

Introduction: We hypothesized that normal breast tissue in inflammatory breast cancer (IBC) patients contains intrinsic differences, including increased mammary stem cells and macrophage infiltration, which may promote the IBC phenotype.

Materials and Methods: Normal breast tissue at least 5cm away from primary tumors were obtained from mastectomy specimens. This included an initial cohort of 8 IBC patients and 60 non-IBC patients followed by a validation cohort of 19 IBC patients and 25 non-IBC patients. Samples were immunostained for either CD44+CD49f+CD133/2+ stem cell markers or the CD68 macrophage marker and correlated with IBC status. Automated quantitation of positive cells was employed for the validation cohort. We also examined the association between IBC status and previously published tumorigenic stem cell and IBC tumor signatures in the validation cohort samples.

Results: 8 of 8 IBC normal tissue samples expressed CD44+CD49f+CD133/2+ stem cell markers in the initial cohort as opposed to 0/60 non-IBC normal tissue samples (p=0.001). Similarly, the median number of CD44+CD49f+CD133/2+ cells was 25.7 in the IBC validation cohort as opposed to 14.2 in the non-IBC validation cohort (p=0.007). 7 of 8 IBC samples expressed CD68+ macrophages in initial cohort as opposed to 12/48 non-IBC samples (p=0.001). In the validation cohort the median number of CD68+ cells was 3.7 in the IBC cohort vs 1.0 in the non-IBC cohort (p=0.06). Normal tissue of IBC patients was positively associated with a tumorigenic stem cell signature (p=0.02) and with a 79-gene IBC gene signature (p<0.001).

Conclusions: Normal tissue from IBC patients is enriched for both mammary stem cells and macrophages. Further, normal tissue of IBC patients has higher association with both a tumorigenic stem cell signature and IBC-specific tumor signature. Collectively, these data suggest that normal tissue from IBC patients is distinct from non-IBC normal tissue and may support the hypothesis that a primed normal breast contributes to the development of IBC symptoms upon oncogenic insult. Validation of these results in additional normal tissue in cancer-free women would better determine causality.

Citation Format: Reddy JP, Atkinson RL, Larson RA, Burks JK, Smith D, Debeb BG, Ruffell B, Creighton C, Reuben JM, Krishnamurthy S, Symmans WF, Brewster A, Van Laere SJ. Stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-03-14.
Abstract P4-08-03: Mathematical modeling of the unfolded protein response pathway in breast cancer cells
Authors: Shajahan-Haq AN , Demas DM , Clarke R , Baumann WT
Published: March 2017

Over 70% of all breast cancers are estrogen receptor positive (ER+) and are treated with endocrine therapies such as aromatase inhibitors or ER-disruptors as part of the standard of care. However, endocrine resistance remains a major clinical challenge for the successful treatment of this disease. ER+ breast cancer cells can escape endocrine therapy-mediated cell death through adaptations in the unfolded protein response (UPR), an evolutionarily conserved cellular stress response pathway that is linked to many other pathways (autophagy, metabolism, anti-oxidant response). To better understand how the UPR pathway promotes endocrine resistance, we built a mathematical model from quantitative measurements of key UPR signaling molecules following treatment of ER+ MCF7 cells (endocrine sensitive, estrogen dependent) with dithiothreitol (DTT). DTT disrupts or prevents protein disulfide bonding and is a potent inducer of the UPR. The same measurements were also made in two MCF7-derived resistant cell lines: LCC1 (sensitive to ER-disruptors, estrogen independent) and LCC9 (resistant to ER-disruptors, estrogen independent). Determining the (minimal) changes to the MCF7 mathematical model needed to adequately capture the data from the resistant cell lines allows us to create specific hypotheses for how the UPR adapts to help produce resistance to endocrine therapies. These hypotheses, in turn, can lead to drug targets for reversing resistance.

Citation Format: Shajahan-Haq AN, Demas DM, Clarke R, Baumann WT. Mathematical modeling of the unfolded protein response pathway in breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-08-03.
Abstract P4-12-04: Breast cancer subtype, age and lymph node status as predictors of local recurrence following breast-conserving therapy
Authors: Braunstein LZ , Taghian AG , Niemierko A , Salama L , Capuco A , Wong JS , Punglia RS , Bellon JR , MacDonald SM , Harris JR
Published: March 2017

Purpose/Objectives: Advances in breast-conserving therapy (BCT) have yielded local control rates comparable or superior to those of mastectomy. Here, we sought to identify risk factors associated with isolated local recurrence (LR) following BCT.

Materials/Methods: This study included a multi-institutional cohort of 2,233 consecutive breast cancer patients who underwent BCT between 1998 and 2007. Patient characteristics and disease parameters were stratified by age, subtype and nodal status. Biologic subtype was approximated by receptor status and tumor grade. No patients received HER2/neu-directed therapy. The association of clinicopathologic features with LR was evaluated using Cox proportional hazards regression models.

Results: At a median follow-up of 106 months, 69 LR events (3.1%) were observed. Among the overall cohort, 10-year freedom from LR was 95.9%. On univariate Cox regression analysis, risk factors associated with LR included subtype other than luminal A (hazard ratio [HR] for luminal B = 3.01, HER2 = 6.29, triple negative [TNBC] = 4.72; p<0.001 for each), younger age (HR of oldest versus youngest quartile = 0.43; p=0.005), regional lymph node involvement (HR for 4-9 involved nodes = 3.04; >9 nodes = 5.82; p<0.01 for each), positive resection margins (HR = 2.43; p=0.005), and high-grade disease (HR = 5.37; p <0.001). Presence of LVI (HR = 1.56; p=0.06) or 1-3 involved nodes (HR = 1.55; p=0.07) approached significance. Multivariate Cox regression demonstrated an association with LR among those with non-luminal A subtypes (HR for luminal B = 2.64, HER2 = 5.42, TNBC = 4.32; p<0.001 for each), younger age (HR for age >50 = 0.56; p=0.01), and any nodal disease (HR=1.06 per involved node; p<0.004).

Conclusions: BCT yields favorable outcomes for the large majority of patients, although increased LR was observed among those with non-luminal A subtypes, younger age, and increasing lymph node involvement. Risk factors for LR following BCT appear to be converging with those following mastectomy in the current era.

Citation Format: Braunstein LZ, Taghian AG, Niemierko A, Salama L, Capuco A, Wong JS, Punglia RS, Bellon JR, MacDonald SM, Harris JR. Breast cancer subtype, age and lymph node status as predictors of local recurrence following breast-conserving therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-04.
Abstract P4-12-07: CCND1 amplification in early breast cancer patients: Correlation with subtypes and prognosis
Authors: Hanf DC , Fasching PA , Villalobos IE , Gasparyan A , Wachter D , Santiago A , Guzman R , Weihbrecht S , Hanf V , Hartmann A , Beckmann MW , Press MF
Published: March 2017

Background: Mechanisms of progress and recurrence of early breast cancer (BC) have gained importance since several targeted therapeutic options in metastatic breast cancer have been introduced over the last years, especially in hormone receptor positive BC. This study investigates the amplification of cell cycle regulator cyclin D1 gene (CCND1) amplification as one possible progression mechanism.

Patients & Methods: Patients from an unselected cohort of early BC patients were included into this study. A tissue microarray (TMA) was available for n=832 patients with early breast cancer. CCND1 amplification was assessed after FISH (Abbott Vysis LSI CCND1 SpectumOrange/CEP11 SpectrumGreen Probes Kit). A CCND1/CEP11-ratio ≥ 2.0 was considered as amplification. Staining was successful in 545 tumor cores. Amplification results were correlated with clinical patient and tumor characteristics and survival analyses were performed with regard to distant disease free survival and overall survival.

Results: CCND1 amplification was found in 13.6% of patients. Triple negative, luminal A like, luminal B like and HER2 positive tumors were amplified in 7.5%, 7.8%, 18.6% and 15.7% respectively (p = 0.010). CCDN1 amplification was significantly associated with a higher grading and a higher body mass index. Furthermore an amplification was seen more frequently in lobular BC and ductal BC than other histological subtypes.

Survival analysis showed a reduced DDFS for patients with CCDN1-amplification. 5 year DDFS rates were 90.6% for non-amplified tumors and 86.0% for amplified tumors (p, log-rank =0.066 ). 5 year OS rates were 93.0% for non-amplified tumors and 90.1% for amplified tumors (p, log-rank =0.119).

Adjusted for age, tumor size, nodal status and molecular subtype, cox regression showed HR of 1.3 (95% CI: 0.76-2.5, p=0.46) for DDFS and a HR of 1.33 (95% CI: 0.7-2.53, p=0.38) for OS.

Conclusion: With a 13.6% prevalence in all breast cancer patients, mainly present in luminal B like cancers, CCND1-amplification is a genetic aberration associated with an unfavorable prognosis. Within hormone receptor positive women CCDN1 amplification might play a role in treatment resistance mechanisms in early breast cancer patients.

Citation Format: Hanf DC, Fasching PA, Villalobos IE, Gasparyan A, Wachter D, Santiago A, Guzman R, Weihbrecht S, Hanf V, Hartmann A, Beckmann MW, Press MF. CCND1 amplification in early breast cancer patients: Correlation with subtypes and prognosis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-07.
Abstract P4-21-34: Phase II study of gemcitabine, trastuzumab, and pertuzumab for HER2-Positive metastatic breast cancer after prior pertuzumab-based therapy
Authors: Iyengar NM , Smyth L , Lake D , Gucalp A , Singh JC , Traina TA , DeFusco P , Dickler MN , Fornier MN , Goldfarb S , Jhaveri K , Modi S , Troso-Sandoval T , Argolo D , Jack K , Ulaner G , Jochelson M , Baselga J , Norton L , Hudis CA , Dang CT
Published: March 2017

Background: The combination of taxanes with trastuzumab (H) and pertuzumab (P) for first line treatment of HER2-positive metastatic breast cancer (MBC) is associated with improved progression-free survival (PFS) and overall survival (OS). Treatment per physician's choice with anti-HER2 therapy after second line therapy is associated with a median PFS of 3 months. While continued use of H in therapeutic combinations after progression on H-based therapy is common, the efficacy of continuing HP-based treatment after progression on P-based therapy is unknown.

Methods: This is a single arm phase II trial of gemcitabine (G) with HP. Eligible patients had HER2-positive (IHC 3+ or FISH ≥ 2.0) MBC with prior HP-based treatment and ≤ 3 prior chemotherapies. Patients received G (1200 mg/m2) on days 1 and 8 of a q 3 week (w) cycle, and H (8 mg/kg load → 6 mg/kg) and P (840 mg load → 420 mg) q3w. The primary endpoint is PFS at 3 months. Secondary endpoints include OS, safety and tolerability. An exploratory endpoint is to compare PFS by RECIST criteria versus 18-F FDG-PET response criteria. Using a Simon optimal 2-stage design, 21 patients were enrolled in stage 1. The successful 3-month PFS rate for stage 1 was set at 57% to allow accrual to stage 2 for a total of 45 patients. The study therapy will be considered successful if at least 27/45 (60%) patients are progression free at 3 months.

Results: As of June 9, 2016, 28 patients are enrolled; 21 are evaluable at 3 months and 7 have not had 3-month evaluation. At 3 months, 16/21 (76%) are progression free; 5 patients have progressed. The 3 month-PFS results for evaluable patients will be updated. There are no cardiac or febrile neutropenic events to date. Initially, 5 of 22 (23%) patients required G dose reduction (4 due to grade 3 neutropenia and 1 due to grade 3 vomiting) and the study was amended to lower initial G dose to 1000 mg/m2.

Conclusions: The preliminary 3 month-PFS is 76% (95% CI 55% to 89%) in evaluable patients, and updated data will be presented. These findings suggest clinical benefit when P is continued beyond progression.

Citation Format: Iyengar NM, Smyth L, Lake D, Gucalp A, Singh JC, Traina TA, DeFusco P, Dickler MN, Fornier MN, Goldfarb S, Jhaveri K, Modi S, Troso-Sandoval T, Argolo D, Jack K, Ulaner G, Jochelson M, Baselga J, Norton L, Hudis CA, Dang CT. Phase II study of gemcitabine, trastuzumab, and pertuzumab for HER2-Positive metastatic breast cancer after prior pertuzumab-based therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-34.
Abstract P5-02-06: The impact of the introduction of breast cancer screening on a symptomatic breast cancer unit
Authors: Moloney BM , Malone C , Sweeney K , Barry K , McLoughlin R , Larke A , Walsh S , O Connell AM , Ennis R , McCarthy PA , Kerin MJ
Published: March 2017

This abstract was not presented at the symposium.