bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2097: Gemini vitamin D analogs inhibit estrogen receptor positive and estrogen receptor negative mammary tumorigenesis without hypercalcemic toxicity
Authors: Lee Hong Jin , Paul Shiby , Ji Yan , Atalla Nadi , Thomas Paul E , Maehr Hubert , Uskokovic Milan , Suh Nanjoo
Published: May 2019

Numerous preclinical, epidemiological and clinical studies with vitamin D and analogs have suggested the benefits of vitamin D and analogs for prevention and treatment of cancer. However, the hypercalcemic effects have limited the use of 1α,25(OH)2D3, the hormonally active form of vitamin D, and many of its classical synthetic analogs as potent agents for cancer prevention and treatment. To identify vitamin D analogs with better efficacy and low toxicity, we have tested more than 60 novel Gemini vitamin D analogs, which have a unique structure of two six-carbon chains with a C-20-normal and a C-20-epi side chain. Our initial studies found that some Gemini analogs are many-fold more active than 1α,25(OH)2D3 in growth inhibition assay. We further examined the inhibitory effect of selected Gemini vitamin D analogs against mammary carcinogenesis in vivo by using N-methyl-N-nitrosourea (NMU)-induced mammary tumor model which is ER-positive. Among Gemini vitamin D analogs we tested, Gemini 0072 and Gemini 0097 treated groups showed approximately 60% suppressive activity in NMU-induced mammary tumor growth compared to the control group. In a dose dependent experiment, Gemini 0097 significantly reduced the average tumor burden per rat without affecting the body weight. At all doses tested, Gemini 0097 did not exert any calcemic toxicity. In addition, we determined the inhibitory effect of Gemini 0097 in MCF10DCIS xenograft model of ER-negative mammary tumors. Gemini 0097 significantly inhibited MCF10DCIS xenograft tumor growth without calcemic toxicity. We analyzed the tumor samples and found that the inhibitory effect of Gemini 0097 in vivo was through (a) increasing cyclin dependent kinase inhibitor, p21 and (b) inducing insulin-like growth factor binding protein 3 (IGFBP3) in both ER-positive and ER-negative mammary tumors. Our results suggest that Gemini vitamin D analogs may be potent agents for the prevention and treatment of both ER positive and ER negative breast cancer without calcemic toxicity.
Abstract 4917: The Fallopian tube epithelium as the field of origin for ovarian serous carcinoma
Authors: Levanon Keren , Ng Vivian , Vermeer Paola D , Drapkin Ronny I
Published: May 2019

Ovarian cancer is the most lethal gynecological malignancy in Western countries. Serous carcinoma is the most aggressive sub-type, yet a clear understanding of its pathogenesis, including identification of precursor lesions, is lacking. Research on ovarian carcinogenesis has traditionally focused on the ovarian surface epithelium (OSE), or surface-derived intracortical Mullerian inclusions as the fields of origin. Our recent studies suggest that the Fallopian tube (FT) fimbria, rather than the OSE, may be the site of origin for over 50% of sporadic and hereditary serous carcinomas. The earliest precursor lesion identified, the ‘p53 signature’, is characterized by DNA damage, p53 gene mutations and p53 protein accumulation in normal-appearing secretory epithelial cells. Thus the FT secretory epithelial cell (FTSEC) emerges as a candidate cell-of-origin for most serous carcinomas. We hypothesize that the FTSEC is susceptible to DNA damaging effects associated with ovulation and that repeated and prolonged genotoxic stress leads to the development of precursor lesions, and, eventually, carcinoma. To address this possibility we have taken two approaches. First, using genome-scale approaches, we are defining the unique genetic ‘fingerprint’ of each morphologic step along the continuum from benign FT epithelium to p53 signatures, to intraepithelial carcinoma, and to invasive serous carcinoma. This investigation has identified key elements of signaling pathways that participate in the neoplastic process of serous cells. In addition, we have identified candidate biomarkers that may serve as sentinels of early stage disease. To experimentally address the biology and susceptibility of the serous cell to transformation, we have established an ex vivo co-culture system of FTSECs and ciliated cells that enables us to experimentally manipulate and characterize this epithelium. Specifically, we found that the serous cell has a unique DNA damage response compared to the neighboring ciliated cells. This altered response may contribute to its susceptibility to genotoxic stressors and neoplastic transformation. We have also identified markers that uniquely mark serous versus ciliated cells in this culture system. These markers enabled us to isolate pure FTSECs and immortalize them in culture. We are now able to study the effects of define genetic alterations (for instance, p53, BRCA mutations, c-myc, Akt activation) both in vitro and in vivo with the goal of understanding the underlying mechanism of transformation in this cell type. We hope that this novel approach will provide new insights into the nature of the ‘p53 signature’ and the molecular events that drive tumorigenesis. A firm understanding of these processes is essential for the development of new prevention strategies and therapeutic modalities.
Abstract LB-200: Evidence of efficacy of antibody directed enzyme prodrug therapy (ADEPT) in a Phase I trial in patients with advanced carcinoma.
Authors: Wilkins Duncan K , Mayer Astrid , Sharma Surinder K , Tolner Berend , Francis Roslyn J , Springer Caroline J , Hartley Janet A , Boxer Geoff M , Bell James , Green Alan J , Parker Sweta , Griffin Natalie , Shahbakhti Hassan , Grudus Edward , Chester Kerry A , Begent Richard H
Published: May 2019

Background: Antibody Directed Enzyme Prodrug Therapy (ADEPT) uses an antibody linked to an enzyme to deliver enzyme selectively to tumor deposits. When enzyme has localized to the tumor and cleared from the circulation, a low-toxicity prodrug is given. The prodrug is converted into an active cytotoxic drug by the enzyme in tumor deposits. Each targeted enzyme can convert many molecules of the prodrug and a bystander effect is generated. We have previously reported on dose-finding, immunogenicity, and toxicity in a Phase I clinical trial and that the components of ADEPT function as designed in patients (Mayer A, et al. Clin Cancer Res 2006;12:6509-16). Evidence of efficacy is now reported in relation to total prodrug dose (TPD), toxicity, and repeated treatment.

Methods: A fixed dose of recombinant fusion protein (MFECP1) was administered intravenously (iv). It consisted of single chain Fv targeting carcinoembryonic antigen (CEA) and carboxypeptidase G2 (Tolner B, et al. Nature Protocols 2006;1:1006-21; Tolner B, et al. Nature Protocols 2006;1:1213-22). Bis-iodo phenol mustard prodrug was given iv when carboxypeptidase activity had cleared from the blood. Patients had measurable, previously treated, advanced malignancy. Either 1, 2, or 3 ADEPT treatments were given over 2 to 10 days.

Results: 43 patients with CEA expressing tumors were treated (colorectal, gastro-esophageal, breast, unknown primary, gallbladder, peritoneal, appendix, pancreas). TPD per patient was escalated from 37 mg/m2 to 3226 mg/m2. Thrombocytopenia and neutropenia were the principal side effects, resulting in a maximum tolerated TPD dose of 1200 mg/m2 divided into 2 complete ADEPT treatments. Human anti-enzyme antibody developed in 40% of patients having a single treatment, in 75% of patients after 2 treatments, and in 100% of patients after 3 treatments; it is not yet known whether this will compromise repeated therapy. Efficacy was assessed by 18F FDG-PET using the criteria for partial response defined by Green et al. and shown to predict significant survival prolongation (Eur J Nucl Med Mol Imaging 2008;35:393-406). Four of 9 patients had partial response at TPD ≥ 900 mg/m2. There was a significant correlation between TPD and reduction of tumor FDG uptake (P=0.031). Response was corroborated by falls in serum CA19-9 ≥ 25% in the 3 patients with partial response who had raised levels before treatment. Stable disease by RECIST criteria was seen in 69% of patients having TPD ≥ 900 mg/m2.

Conclusions: Evidence of efficacy was shown at a TPD ≥ 900 mg/m2 with clinically significant responses in 44% of patients. These results support the case for conducting a randomized Phase II clinical trial.
Abstract LB-246: A Phase I and first time in human study of the centromere associated protein E (CENP-E) inhibitor GSK923295A in patients with advanced solid tumors
Authors: Chung Vincent , Fleming Ronald A , Johnson Brendan M. , Gauvin Jennifer L.s. , Lu Emily , Lager Joanne J. , Alberti Dona B. , Williams Brenda , Weber Barbara L. , Holen Kyle D.
Published: May 2019

Background: CENP-E plays a critical role in maintaining and silencing mitotic checkpoint signaling. CENP-E mRNA is overexpressed in a variety of human tumors relative to adjacent normal tissue, suggesting that it may have an important role in tumor cell proliferation. GSK923295A is a potent and selective small molecule inhibitor of CENP-E with broad preclinical activity against solid and hematologic cancer cells in vitro and in murine tumor xenograft models. The purpose of this Phase I study is to determine the maximally tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics of GSK923295A in patients with advanced solid tumors.

Methods: Adult patients with refractory advanced solid tumors are administered GSK923295A by a 1-hour intravenous infusion on days 1, 8, and 15 of 28-day treatment cycles. Doses are escalated in cohorts of 2 patients using an accelerated titration scheme. Transition to a standard (40% or 33%) dose escalation scheme is planned if 2 grade 2 toxicities or 1 DLT are observed in the first treatment cycle. Blood samples are collected on days 1 and 15 over 48 hours to determine the plasma PK of GSK923295A. Pre- and post-treatment FDG-PET and tumor biopsies are performed in selected patients.

Results: Eight patients [4 males, 4 females; median age 54.5 years; cancers of pancreas (2), lung (2), stomach (1), colon (1), parotid gland (1), and liver (1)] have been treated at 10, 20, 40, and 80 mg/m2 (median of 1.5 and total of 15 cycles completed). One DLT (AST elevation) has been reported at 80 mg/m2. We have expanded this dose level to 3 patients. At the 4 dose levels studied thus far, PK appears dose proportional with low intrapatient variability, modest interpatient variability, and no apparent accumulation or time-dependent PK.

Conclusions: One DLT has been observed at the 80 mg/m2 dose level. Evaluation of GSK923295A continues at a dose level of 80 mg/m2.

Dose Level (mg/m2)NDayCmax* (ng/mL)AUC(0-¥)* (ng.h/mL)Clearance* (L/h/m2)Half-life* (h)1021279-377413-61516.3-24.22.72-3.7610215228-409377-76613.1-26.55.22-6.772021546-767992-156012.8-20.19.02-9.7020215499-889927-189010.6-21.68.11-8.9640211300-25302130-71305.61-18.84.50-13.6402151690-24202290-72705.50-17.55.64-20.580212090-25005210-655012.2-15.412.4-13.0*Denotes range from 2 patients.
Abstract LB-331: Bidirectional crosstalk between leptin and IGF-1 signaling transactivates epidermal growth factor receptor and promotes invasion and migration of triple-negative breast cancer cells
Authors: Saxena Neeraj K , Taliaferro Smith LaTonia , Brandon Brandi , Anania Frank A , Sharma Dipali
Published: May 2019

Introduction: Obesity is an independent risk factor for breast cancer and obese breast cancer patients exhibit a higher risk for larger tumor burden, increased metastasis, and poor response to endocrine therapy. Obesity affects breast carcinogenesis by autocrine and paracrine effects of adipocytokine leptin and IGF-1. We have previously shown that leptin induces growth stimulation of breast cancer cells by recruiting histone acetyltransferases and mediator complex to cyclin D1 promoter via activation of Stat3. In the present study, we found a novel bidirectional crosstalk between IGF-1 and leptin signaling that promotes invasion and migration of triple-negative (ER, PR, HER2 negative) breast cancer cells MDA-MB-231, MDA-MB-468, MDA-MB-435, and HCC-1806.

Methods and Results: IGF-1 induced significant tyrosine phosphorylation of leptin receptor (Ob-Rb) and leptin induced tyrosine phosphorylation of IGF-1 receptor (IGF-1R). Combined treatment of leptin and IGF-1 induced synergistic activation of both Ob-Rb and IGF-1R along with activation of Akt and ERK. Furthermore, IGF-1 and leptin synergistically transactivated epidermal growth factor receptor (EGFR) and induced proliferation of triple negative breast cancer cells. We also found that tyrosine phosphorylation of EGFR induced by combined treatment of leptin and IGF-1 was significantly inhibited not only by EGFR tyrosine kinase inhibitor AG1478 but also with a broad-spectrum matrix metalloproteinase inhibitor, GM6001, indicating that leptin and IGF-1 induced EGFR transactivation is dependent on proteolytic release of EGFR ligands. Intriguingly, we also found that combined treatment of leptin and IGF-1 potently induced invasion of triple negative breast cancer cells in Matrigel invasion and quantitative Electric Cell-Substrate Impedance Sensing invasion assays. Inhibition of leptin and IGF-1 mediated EGFR activation using a highly potent, reversible inhibitor of HER1/EGFR tyrosine kinase (erlotinib) or dual EGFR/HER2 kinase inhibitor (lapatinib) effectively inhibited leptin and IGF-1 induced invasion. Also, inhibition of EGFR activation using erlotinib and lapatinib reduced leptin- and IGF-1 induced migration of triple negative breast cancer cells. Conclusions: Taken together, these data indicate a novel bidirectional crosstalk between leptin and IGF-1 signaling that transactivates EGFR and promotes metastatic properties, invasion, and migration of triple negative breast carcinoma cells. Our novel findings indicate the possibility of using EGFR inhibitors erlotinib and lapatinib to counter the pro-cancerous effects of leptin and IGF-1 signaling in triple negative breast cancers.
Abstract P1-08-05: Discovering drug targets for aggressive breast cancer with TP53 missense mutations by a genome-wide screen
Authors: Pal A , Park J , Gonzalez-Malerva L , Eaton S , LaBaer J
Published: May 2019

Breast cancer is a heterogeneous disease and has subtypes with distinct phenotypic and molecular characteristics. Genetically, 30% of all breast tumors and 80% of the basal-like breast cancer (BLBC) subtype harbor mutations in TP53 and numerous sporadic somatic mutations in other genes. This molecular heterogeneity has posed a challenge in developing safe and effective therapeutic regimens to treat a broad spectrum of breast cancer patients, and discovery of intra-subtype along with inter-subtype heterogeneity has added another layer of complexity for targeted therapies. Based on the analysis of somatic mutation profiles in the BLBC subtype, we identified a wide variety of TP53 missense mutations and thousands of co-existing mutations, which led us to hypothesize that intra-subtype heterogeneity is derived from combinatorial effects of neo-morphic (gain-of-function) activities of different types of missense mutant p53 proteins and complex interplay between specific driver mutations in TP53 and a distinct subset of functionally important co-mutations (or “co-drivers”). We ectopically overexpressed the ten most prevalent missense mutations in TP53 found in breast cancer tumors in non-transformed mammary epithelial cells and examined their cellular functions associated with the hallmarks of cancer. The results showed widely different spectrums of phenotypic changes in cell proliferation, resistance to apoptosis, cell invasion, anoikis resistance and cell polarity. As a proof of concept for the 'co-drivers', we knocked-out PTEN in a non-invasive TP53 mutant cell using the CRISPR and shRNA systems. Inactivation of PTEN in non-invasive TP53-mutant cell increased its invasiveness. TP53 mutations and PTEN deletions are frequent in BLBC patients, who have significantly higher rates of metastasis, recurrence and a lower survival rate than the other subtypes. The absence of three signaling hormone receptors, which can be targeted by specific inhibitors, significantly limits available therapies for the majority of BLBC patients to surgery and cytotoxic chemo/radiotherapies. Combination therapies targeting the driver and co-driver gene associated pathways could be quite promising solutions to treat aggressive breast cancer cases. To address this, we have developed a genome-wide CRISPR based gene knock-out screening approach to test the effect of loss-of-function of individual human genes in clinically important TP53 mutant backgrounds that can promote cancer-like behaviors and identify the combinations of 'TP53 mutation and co-driver pathways' that can be targeted by specific inhibitors.

Citation Format: Pal A, Park J, Gonzalez-Malerva L, Eaton S, LaBaer J. Discovering drug targets for aggressive breast cancer with TP53 missense mutations by a genome-wide screen [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 P1-08-05.
Abstract P2-01-01: Prospective study of the need for axillary dissection and outcomes in Z11 eligible patients accounting for the use of nodal RT
Authors: Morrow M , Mamtani A , Patil S , Barrio A , Pilewskie ML , Cody HS , Gemignani M , Sclafani LM , Ho AY , Van Zee KJ
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P2-01-09: The development of nomograms to predict axillary lymph node status in breast cancer patients
Authors: Chen K , Liu J , Zhu L , Song E , Su F , Jacobs L
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P2-01-30: Limited effectiveness of patent blue dye in addition to isotope scanning for identification of sentinel lymph nodes: Cross-sectional real-life study in 1024 breast cancer patients
Authors: Merlin J-L , Rauch P , Leufflen L , Salleron J , Harlé A , Olivier P , Marchal F
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P3-11-06: Development and application of whole processing management for patients with breast carcinoma: A novel management strategy for breast health
Authors: Chen J , Yu K , Liu G , Shao Z , Wu J
Published: May 2019

The reformation on the management strategy of patients led by medical institutions could show the real value of medical services and match the needs of both patients and physicians. A novel patient management strategy, the whole processing management mode, was developed in Department of Breast Surgery, Fudan University Shanghai Cancer Center. Based on the online tools, the e follow-up Wechat public platform, the department provides several humanistic medical services in every aspects of breast health management, such as education, screening and diagnosis, multi-disciplinary comprehensive treatment and follow-up, including the remote medical reports reading. After the application of the novel patient management mode, regular appointments before seeing doctors, triage on-demand are realized. Between Jun-2015 and March-2016, a total of 7,668 person-time patients made the reservation for chemotherapy and over two thousand patients made the reservation for endocrine therapy prescription through the online approach. The total volume of out-patient clinic was 169,246 person-time in 2015, gained a 26.8% increase compared with in 2014. However, the queuing time for consultation was deceased by 28.8% in 2015. The doctor-patient relationship is extended online and the follow-up rate is improved. Between Jun-2015 and December-2015, a total of 823 patients online submitted the medical reports during follow-up period, among those, four patients were found disease relapse or metastasis and were call back to the hospital for further treatment. The novel mode may promote the cooperation among the multi-disciplinary comprehensive treatment teams, realize the hierarchical medical system among the department, and provide guarantee for the clinical and basic research based on the principle of precision medicine.

Citation Format: Chen J, Yu K, Liu G, Shao Z, Wu J. Development and application of whole processing management for patients with breast carcinoma: A novel management strategy for breast health [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 P3-11-06.
Abstract P3-13-18: Technical skill of surgical residents may affect margin status of breast conserving operations
Authors: Komenaka IK , Djenic B , Hsu C-H , Nodora J , Winton L , Bouton M , Martinez ME
Published: May 2019

Background: Quality of patient care and surgical outcomes have come under increased scrutiny. Numerous other studies have examined outcomes at teaching hospitals compared to non-teaching hospitals. The most important factor to determine early success of breast conservation is the attainment of pathologically negative margins. Few studies, however, have examined the effect of teaching residents on margin status. The current study was performed to evaluate the effect teaching residents on margin status after lumpectomy.

Methods: Retrospective review of all patients from July 2006-June 2015 was evaluated. A resident was usually considered the primary surgeon. If the resident was unavailable or unprepared to operate, the attending surgeon was the primary surgeon. As part of the routine evaluation of surgical residents, technical ability was classified as satisfactory or unsatisfactory for level of training. All evaluations of the technical ability of the residents were completed prior to the collection of the current data. The effect of surgical residents' participation and their technical ability to perform lumpectomy was evaluated to determine if there was an effect on margin status. Logistic regression analysis was performed to adjust for clinical variables known to affect margin status.

Results: Of 292 patients, 15% of patients had positive margins. The attending surgeon has positive margin rate of 10.7% vs 16% for Residents (p = 0.32).When technical skill evaluation was included, Residents with unsatisfactory technical skills had positive margin rate of 27% compared to 10.2% for residents with satisfactory skills (p = 0.002). In multivariate logistic regression analysis, operating surgeon remained significantly associated with positive margins. Operations done by residents with satisfactory technical skills or attending surgeon were less likely to have positive margins than those done by residents with unsatisfactory technical skills (OR 0.39, 95% CI 0.22-0.86; p = 0.03). Patients who underwent preoperative chemotherapy were also less like to have positive margins (OR 0.40, 95% CI 0.18-0.91); p = 0.04). In patients with at least 2 years of followup (mean follow up of 48 months) breast cancer specific survival was 94% and 2% had local recurrences as a first event.

Conclusions: Technically ability of residents may affect margin status after lumpectomy. With the increased use of surgical outcomes to measure quality of care in medicine, the importance of teaching surgical residents needs to be considered in future quality of care evaluation.

Citation Format: Komenaka IK, Djenic B, Hsu C-H, Nodora J, Winton L, Bouton M, Martinez ME. Technical skill of surgical residents may affect margin status of breast conserving operations [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 P3-13-18.
Abstract P4-06-07: Fibroblast growth factor receptor activation and breast tumor progression in a mouse xenograft model of obesity
Authors: Wellberg EA , Anderson SM , Jacobsen BM , Johnson S , Kabos P , Sartorius C , MacLean PS
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P5-16-18: The effect of participation in neoadjuvant clinical trials on outcomes in patients with early breast cancer
Authors: Brennan MB , Wang D , Gass P , Hein A , Beckmann MW , Fasching PA
Published: May 2019

Pathological complete response (pCR) has been shown to demonstrate improved outcomes in breast cancer. Often novel treatments, such as taxanes or HER2 based therapies, trastuzumab or pertuzumab, have shown an increase of pCR with possible impact on the prognosis of breast cancer patients. These therapies are usually introduced into the patient population through clinical trials. Therefore, it can be hypothesized participation in neoadjuvant clinical trials might improve the pCR rate in early breast cancer patients. The aim of this study was to explore this association.

Methods: This is a retrospective study of consecutive breast cancer patients who were treated with a neoadjuvant chemotherapy at a single institution. Trial participation status was known for all patients. From 1995 to 2012 the institution participated in 10 different neoadjuvant chemotherapy trials. Outside those clinical trials, patients were treated according to national neoadjuvant therapy guidelines. Patients who took part in clinical trials were compared with patients who did not take part in clinical trials with appropriate univariate tests. Additionally, logistic regression was performed with pCR as the dependent variable and commonly known predictors of pCR (tumor size and molecular subtype) as independent variables. The model was adjusted for age at diagnosis, year of treatment and trial participation status. Furthermore, exploratory survival analyses were performed.

Results: A total of 281 patients were treated within a neoadjuvant clinical trial and 822 patients outside a clinical trial. There are significant differences in the patient populations with regards to age (p=0.0009) and tumor size (<0.0001). pCR rate in patients with trial participation was 21.4% and 19.0% in patients who did not take part in clinical trials. Multivariate logistic regression showed an OR of 1.393 (95%CI 0.937-2.071, p=0.1012). Exploratory survival analyses showed a better prognosis in patients taking part in clinical trials.

Conclusions: This study shows an increased chance of pCR in patients taking part in clinical trials; however the statistical test could not show statistical significance. Most likely the effect can be explained by trial participants having access to drugs which improved pCR rates, such as HER2 based therapies or taxanes.

Citation Format: Brennan MB, Wang D, Gass P, Hein A, Beckmann MW, Fasching PA. The effect of participation in neoadjuvant clinical trials on outcomes in patients with early 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 P5-16-18.
Abstract P6-07-34: The prognostic impact of inositol polyphosphate 5-phosphatase PIPP (INPP5J) expression in breast cancer tissue
Authors: Kondo N , Kim T-S , Wanifuchi Y , Hato Y , Hisada T , Nishimoto M , Nishikawa S , Toyama T
Published: May 2019

Background : Inositol polyphosphate 5-phosphatase PIPP (INPP5J) has been identified as a suppressor of oncogenic PI3K/Akt signaling in breast cancer.INPP5J depletion increases transformation and accelerates oncogene-driven tumor growth in vivo, while paradoxically reducing cell migration, invasion, and metastasis. Therefore, we hypothesized that INPP5J gene expression in human breast cancer tissues would be prognostic in early breast cancer patients over long-term follow-up.

Methods: A total of 478 breast cancer tissue samples collected between 2003 and 2008 was available for analysis. We measured INNPP5J mRNA using a TaqMan gene expression assay. PIK3CA mutation status was evaluated using a TaqMan mutation detection assay. We then investigated the correlations of clinicopathological factors and prognosis with levels of INPP5J mRNA and the PIK3CA mutation status.

Results: INPP5J mRNA was expressed at a low level in 30.1% (144/478) and at a medium to high level in the remaining breast cancer samples. Low INPP5J mRNA correlated with larger tumor (p=0.015), high grade (p<0.0001) and, ER-negativity (p<0.0001). PIK3CA mutations were detected in 46% (63/138) of patients analyzed. We found that disease-free survival (DFS) was significantly worse in patients with low levels of INPP5J (p=0.008). Although DFS and INPP5J levels tended to be associated in estrogen receptor (ER)-positive patients (p=0.052), DFS was significantly worse in patients with wild-type PIK3CA and low INPP5J mRNA expression (p=0.008).

Conclusion: We shows that the level of INPP5J mRNA expression is prognostics in breast cancer patients and that its prognostic impact is affected by PIK3CA mutation status.

Citation Format: Kondo N, Kim T-S, Wanifuchi Y, Hato Y, Hisada T, Nishimoto M, Nishikawa S, Toyama T. The prognostic impact of inositol polyphosphate 5-phosphatase PIPP (INPP5J) expression in breast cancer 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 P6-07-34.
Abstract P6-11-17: Mutations in PIK3R1 activate multiple pathways in breast cancer
Authors: Abukhdeir AM , Turturro SB , Najor MS , Brar SS , Cobleigh MA
Published: May 2019

It has been estimated that by the end of this year, 270,000 American women will be newly diagnosed with breast cancer, while 40,000 women that already have breast cancer will succumb to the disease. Considerable attention has been given to the PI3K signaling cascade following the discovery that PIK3CA is the most frequently mutated oncogene in breast cancer.However, few studies have explored the function of PIK3R1, which is the regulatory domain of the PI3K complex, despite being mutated in ~3% of all breast cancers.

Several studies have demonstrated that expression of PIK3R1 is downregulated in human cancers. Decreased expression of the PIK3R1 protein leads to tumor formation, suggesting its role as a tumor suppressor gene and a potential prognostic marker in breast cancer. However, PIK3R1 is a gene with little pre-clinical evidence to recommend experimental therapies. Despite this lack of evidence, commercial services that perform molecular analyses of tumors suggest the use of an mTOR inhibitor for patients whose breast cancers carry mutant PIK3R1.

In order to determine if mTOR inhibitors were indeed effective in mutant PIK3R1 tumors, we created and characterized a model for mutant PIK3R1 in the non-tumorigenic, human breast epithelial cell line, MCF-10A. Surprisingly, we observed that mTOR inhibitors were ineffective in these cells. However, in searching for other classes of small molecule inhibitors that were effective, we observed that mutations in PIK3R1 sensitized cells to MAPK inhibitors.

Herein, we present the first evidence for the use of targeted therapies in breast cancers carrying mutant PIK3R1. We provide evidence against the use of mTOR inhibitors and provide a rationale for the use of MAPK inhibitors.

Citation Format: Abukhdeir AM, Turturro SB, Najor MS, Brar SS, Cobleigh MA. Mutations in PIK3R1 activate multiple pathways in 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 P6-11-17.
Abstract BL2: The Challenge of Doing Less
Authors: Winer E
Published: May 2019

There are three groups of individuals with breast cancer who present distinct challenges from the standpoint of clinical care and research. First, there are individuals with breast cancer who develop disease that is refractory to all available therapies and ultimately lose their life to breast cancer. Second, there is a large group of women who do not have adequate access to high quality care or choose not to receive it. It is critical, if we are to eliminate mortality from breast cancer, that we bring effective treatment to these individuals. Finally, and importantly, there is a large group of individuals with breast cancer who are unlikely to die from breast cancer and in whom we need to consider minimizing toxic anti-cancer therapy.

In recent years, a number of clinical trials have been conducted to reduce treatment intensity in breast surgery, radiation oncology, and medical oncology. These trials are often difficult to conduct. Both physicians and patients worry about leaving benefit on "the table", and hence many may be reluctant to participate. Many individuals are particularly risk averse when there is the potential for loss. In addition, statistical considerations can be challenging and often result in extremely large trials to demonstrate that there is significant loss of benefit when treatment is de-escalated. While the advantage of de-escalation is a reduction in toxicity, many physicians and patients underestimate the impact of side effects, both long- and short-term, on a patient. Examples of de-escalation trials will be reviewed and possible study designs will be discussed.

Citation Format: Winer E. The Challenge of Doing Less [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr BL2.
Abstract ES11-1: Lymphedema management in 2018: Are we making any progress?
Authors: Mehrara B
Published: May 2019

Lymphedema is a common and morbid complication of cancer treatment. To date, lymphedema treatment has been palliative aiming to prevent disease progression and improve symptoms of swelling. Development of novel therapies for lymphedema has been limited by the fact that the pathophysiology of the disease remains unknown. While it is true that lymphatic injury during surgery is an important initiating event, the mechanisms that regulate the development of the disease in a subset of patients remain unknown. Recent studies in our lab have suggested that the pathophysiology of lymphedema is related to inflammatory changes that occur following surgery. We have shown that CD4+ T cells play a key role in the pathology of lymphedema by orchestrating a variety of changes including tissue fibrosis, lymphatic leakiness, impaired collecting vessel pumping, and changes in the lymphatic smooth muscle cells. More importantly, in preclinical models we have shown that inhibition of this response can prevent development of lymphedema following surgery or reverse it once it has been initiated. These findings have led to novel treatments for lymphedema that may be effective either as standalone therapies or used in conjunction with surgical treatments for lymphedema.

Citation Format: Mehrara B. Lymphedema management in 2018: Are we making any progress? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES11-1.
Abstract ES2-1: The EMT and metastasis controversy: Where things stand in 2018
Authors: Ford H
Published: May 2019

A pubmed search for epithelial-mesenchymal transition (EMT) and metastasis brings up almost 9000 papers, the vast majority which provide a positive link between this developmental process, which is hijacked by many tumor cells, and tumor progression. As the field has evolved, it has become apparent that there is not a “one size fits all” definition for EMT, and that the process is instead plastic, with epithelial and mesenchymal states being on the far left and right ends of a continuum where cells can exist in various intermediate states. How do these different intermediate states contribute to metastasis, if they do at all? And do these EMT cancer cells work in isolation, or do they form part of a cooperative network of heterogeneous tumor cells, together facilitating the metastatic process? In this talk, I will discuss the controversy around whether and how EMT is involved in the metastatic process, and the significant progress that we and other labs across the country have made in understanding its role in, and contribution to, the metastatic cascade.

Citation Format: Ford H. The EMT and metastasis controversy: Where things stand in 2018 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES2-1.
Abstract ES2-3: Exosome-mediated stimulation of metastasis
Authors: Minn A
Published: May 2019

Although cancer cell intrinsic mechanisms are important in driving aggressive features of cancer, stromal cells in the tumor microenvironment also serve critical roles. In particular, heterotypic interaction between cancer cells and stromal fibroblasts can generate signals for cancer progression, therapy resistance, and inflammatory responses. Among the signals resulting from cellular cross-talk include anti-viral pathways that induce interferon-stimulated genes (ISGs). These observations suggest 1) the existence of signals in the tumor microenvironment that mimic a viral infection, 2) resulting activation of anti-viral signaling may contribute to how stromal cells promote aggressive features of cancer, and 3) mechanisms must exist to prevent this anti-viral signaling under non-pathological conditions. We have demonstrated that exosomes and their RNA produced by stromal fibroblasts represents one such “virus mimic” by engaging RNA pattern recognition receptors (PRRs) such as RIG-I. Triggering of stromal NOTCH-MYC by breast cancer cells results in a POL3-driven increase in RN7SL1, an endogenous non-coding RNA normally shielded from PRR recognition by RNA binding proteins SRP9/14. This increase in RN7SL1 alters its stoichiometry with SRP9/14 and generates unshielded RN7SL1 that is deployed in stromal exosomes. After these stromal exosomes are transferred to immune cells, the unshielded RN7SL1 can drive an inflammatory response. Upon exosome transfer to breast cancer cells, unshielded RN7SL1 activates the RIG-I to enhance tumor growth, metastasis, and therapy resistance. The significance of this “virus mimicry” and failure to shield endogenous RN7SL1 from PRR activation is corroborated by evidence from patient tumors and blood. In total, these results demonstrate how exosomes, unshielding of endogenous RNAs, and engagement of pattern recognition receptors couple stromal activation with aggressive features of breast cancer.

Citation Format: Minn A. Exosome-mediated stimulation of metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES2-3.
Abstract ES3-1: Brain metastases of breast cancer
Authors: Steeg P
Published: May 2019

Brain metastases are devastating consequences of breast cancer. Both the lesions and their treatments cause physical and neurocognitive complications. Translational investigations have provided several new insights into the brain metastatic process which are hoped to lead to new preventive and therapeutic approaches. First, DNA sequencing of matched primary tumors and brain metastases revealed that nearly half of the brain lesions harbor potentially actionable mutations not present in the primary tumor. Second, model systems reveal that brain metastatic colonization arises through a complex interplay between the tumor cells and their microenvironment. Astrocytes are found in the normal blood-brain barrier and activate and surround a developing metastasis. They have been reported to modulate metastatic growth via several pathways. Additional investigations have uncovered other mechanistic contributions from activated microglia and other cells. The blood-brain barrier is also a contributor to heterogeneous and insufficient uptake of drugs to brain metastases. When a metastasis forms, the blood-brain barrier is termed a blood-tumor barrier (BTB). Multiple facets of the BBB are altered in the BTB. Alterations to the sphingosine-1 phosphate receptor 3 (S1P3) pathway in neuroinflammatory astrocytes of the BTB functionally altered BTB permeability. These data indicate that the BTB is a tractable structure to improve drug uptake and efficacy. Finally, investigators have identified brain permeable drugs and hormonal therapies that prevent the development of brain metastases in models, and which stand as support for new trials.

Citation Format: Steeg P. Brain metastases of breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES3-1.
Abstract ES4-1: Partial breast irradiation: Efficacy and patient selection
Authors: Coles C
Published: May 2019

Partial breast irradiation is an attractive option for patients and clinicians as a smaller region of the breast is irradiated in (usually) a shorter time period compared with whole breast radiation therapy (RT). The hypothesis for this approach is that a smaller irradiated volume is likely to translate into decreased toxicity, whilst maintaining good local control and survival (efficacy).

This educational lecture will examine in detail the efficacy of the four “modern” large, randomised partial breast RT trials that have been published in the last 5 years. These include the ELIOT, Targit-A, GEC-ESTRO and IMPORT LOW studies1-4.

In addition, the eligibility criteria and baseline characteristics of recruited patients will be considered for each trial in the context of ipsilateral breast tumour relapse rates. Current national and international guidelines regarding patient selection for partial breast RT will also be discussed.

References:

1.Veronesi U et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013 Dec;14(13):1269-77.

2.Vaidya JS et al; TARGIT trialists' group. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014 Feb 15;383(9917):603-13.

3.Strnad V et al; Groupe Européen de Curiethérapie of European Society for Radiotherapy and Oncology (GEC-ESTRO). 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet. 2016 Jan 16;387(10015):229-38.

4.Coles CE et al; IMPORT Trialists. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet. 2017 Sep 9;390(10099):1048-1060.

Citation Format: Coles C. Partial breast irradiation: Efficacy and patient selection [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES4-1.
Abstract ES5-1: Tumor dormancy and recurrence
Authors: Chodosh L
Published: May 2019

Despite early detection and adjuvant therapy, breast cancer remains the leading cause of cancer mortality in women, largely due to distant, incurable recurrences that arise years, or even decades, after treatment of the primary tumor. Recurrent, metastatic tumors arise from the pool of residual local and disseminated tumor cells (DTCs) that survive primary treatment in tissues at sites throughout the body where they persist in a presumed dormant state. Early studies demonstrated that an immunohistochemical assay can detect cytokeratin-positive DTCs in bone marrow aspirates of a substantial fraction of breast cancer patients lacking any clinical signs of metastasis. Importantly, women who harbor detectable DTCs in their bone marrow have a substantially increased risk of distant recurrence, as well as poorer breast cancer-specific and overall survival, and this measure has repeatedly been shown to be an independent predictor of recurrence-free survival and overall survival in multivariate analysis.

Since DTCs constitute the reservoir from which recurrent cancers arise, understanding their biology is a critical priority in cancer research. We hypothesize that effectively disabling the survival mechanisms by which DTCs persist in breast cancer patients following treatment will deplete this critical reservoir of cells, reduce tumor recurrence, and thereby improve survival. At present, however, the mechanisms enabling these cells to survive in a dormant state and ultimately recur are poorly understood and clinical methods to detect DTCs, as well as DTC-directed therapeutic approaches, are still in their infancy.

To address this critical gap and elucidate critical pathways in dormant tumor cell survival, we and others have developed a variety of mouse models for human breast cancer that recapitulate key features of human breast cancer progression, including metastasis, residual disease, dormancy and recurrence. Investigation of these models using both genetic and pharmacological approaches has identified several mediators of dormant DTC survival and recurrence, demonstrated their relevance to pathways that contribute to therapeutic resistance in human breast cancers following targeted therapy or chemotherapy, and revealed that pharmacological targets for dormancy and recurrence may be unique to these stages of tumor progression. These findings have, in turn, led to the initiation of clinical trials to test the ability of targeted therapies to deplete the burden of DTCs in the bone marrow of breast cancer patients and thereby decrease risk of relapse. If successful, the ability to therapeutically target survival mechanisms utilized by DTCs would constitute a powerful, paradigm-shifting approach to preventing cancer recurrence and the mortality associated with it.

Citation Format: Chodosh L. Tumor dormancy and recurrence [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES5-1.