bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4181: Discovery of a selective small molecule inhibitor of Tankyrase by structure-based screening
Authors: Ryu Hwani , Kim Ah-young , Song Jie-Young , Hwang Sang-Gu , Ahn Jiyeon
Published: July 2017

The Wnt/β-catenin signaling pathway is critical for colorectal cancer (CRC) development, progression and metastasis. Tankyrase enzymes (TNKS1 and TANKS2), members of the PARP (Poly(ADP-ribose)polymerases) superfamily, PARsylate and target Axin for degradation via ubiquitin-proteasome pathway, leading to accumulation of β-catenin into nucleus. In addition, aberrant YAP/TAZ singling contributes to anticancer drug resistance, but inhibition of TNKS suppresses YAP/TAZ signaling through stabilizing Angiomotin (AMOT). Therefore, inhibition of TNKS has emerged as an attractive strategy for treatment of cancers. To identify potent and selective small molecule inhibitors of TNKS1, a TNKS1-ligand docking was used for computational-based virtual screen of a chemical library containing 1.6 million compounds and 24 virtual hits were further subjected to in vitro evaluation for TNKS1 inhibition. Using an in vitro TNKS1 enzyme assay, we identified a novel pyridine derivative (AZ236106) significantly inhibited TNKS1 enzyme activity in a concentration-dependent manner, but not PARP1/2. Treatment of AZ236106 stabilized Axin, reduced β-catenin in nucleus and downregulated β-catenin target genes in DLD-1 cells harboring adenomatous polyposis coli (APC) mutation. Moreover, we observed that AZ236106 inhibited accumulation of YAP in the nucleus and expression of YAP garget genes. Combination treatment of AZ236106 with either radiation or PLX4032, a BRAF inhibitor, decreased cell proliferation and increased apoptotic cell death in DLD-1 and SK-MEL28 cells, compare to AZ236106, radiation or PLX4032 alone. Our findings suggest that AZ236106 may have therapeutic potential in cancers, and could be further refined for efficacy and safety to develop a lead compound.

Citation Format: Hwani Ryu, Ah-young Kim, Jie-Young Song, Sang-Gu Hwang, Jiyeon Ahn. Discovery of a selective small molecule inhibitor of Tankyrase by structure-based screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4181. doi:10.1158/1538-7445.AM2017-4181
Abstract 4196: Anti-tumor activity of a TAM kinase-targeting compound in CT-26 syngeneic mouse model
Authors: Lai Shenshen , Zhang Hong , Yan Jun , Zhang Zaihui
Published: July 2017

Aberrant expression of TAM family receptor tyrosine kinases, comprising Tyro3, Axl and Mer, is found in virtually every type of human cancer. The expression levels correlate positively with disease staging and prognostic outcome, attributing to metastasis and drug resistance. The TAM kinases have recently emerged as a dual oncological therapeutic target, owing to their immunosuppressive activity. Apart from targeting tumor-survival/growth pathways their inhibition also unleash the anti-tumor immunity in the tumor microenvironment. In our efforts to develop small-molecule inhibitors targeting the TAM kinases, we identified SLC-391 as one of the most promising preclinical candidates with potent activity towards both Axl and Mer, which play roles in maintaining tumor survival and immunosuppressive tumor microenvironment, respectively. Pharmacodynamic studies of SLC-391 in CT26 syngeneic mouse model revealed increase in the number of NK cells and the ratio of M1/M2-polarized macrophages in the treatment group relative to the vehicle control, followed by the rise of CD8+ T/Treg ratio and reduction in immunosuppressive myeloid cells. This is indicative of sequential engagement and stimulation of pro-inflammatory innate immune response and adaptive immune response. In addition, a synergistic anti-tumor effect was observed when the anti-PD-1 insensitive CT-26 model was treated with a combination of SLC-391 and an anti-PD-1 antibody, suggesting that blocking the Axl/Mer-mediated immunosuppressive pathway may significantly enhance the therapeutic efficacy of immune checkpoint inhibitors. In summary, the anti-tumor activity of SLC-391 is mediated by directly inhibiting tumor cell growth as well as reversing the immunosuppressive tumor microenvironment.

Citation Format: Shenshen Lai, Hong Zhang, Jun Yan, Zaihui Zhang. Anti-tumor activity of a TAM kinase-targeting compound in CT-26 syngeneic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4196. doi:10.1158/1538-7445.AM2017-4196
Abstract 420: Preclinical evaluation of the SF3B1 inhibitor E7107 in triple negative breast cancer
Authors: Sridhar Praveen , Chan Stefanie , Lock Ying-Jie , Petrocca Fabio
Published: July 2017

Triple-negative breast cancers (TNBC) are the most aggressive subtype of breast cancer and account for roughly 15% of human breast cancers. No effective targeted therapies are currently available against these tumors, at least in part due to their genetic and epigenetic heterogeneity. Yet, TNBCs are commonly enriched for cells arrested in a progenitor-like state. We therefore performed a genome-wide siRNA lethality screen to identify selective TNBC dependencies associated with this particular phenotype in vitro. These studies led to the identification of several spliceosome genes, including the core splicing factor SF3B1, as selectively and recurrently essential for progenitor-like (or basal-A) TNBC cell lines. On this basis, we examined the antitumor effect of E7107, a clinically tested SF3B1 inhibitor, on multiple TNBC cell lines. In vitro, treatment with E7107 for 24-48 hr selectively killed basal-A cell lines relative to differentiated luminal cell lines, decreasing viability by ≈40% or more in 5 of 6 basal-A lines tested. E7107-treated cells appeared to die of apoptosis based on immunoblotting for multiple apoptotic markers. In mice, E7107 (5 mg/kg i.v. for 4 consecutive days) suppressed the growth of preformed tumors by ≈80% and ≈50% in 2 different cell-line-derived xenograft models and was remarkably well-tolerated at this dose. Of note, tumor response in vivo closely mirrored cell sensitivity in vitro, suggesting that in vitro analysis provides a fair estimate of TNBC response to E7107 in mice. Amongst 2 additional patient-derived xenograft (PDX) models tested, E7107 inhibited tumor growth by ≈50% in one model. Thus, E7107 was therapeutically active against 3 of 4 xenograft models tested. Preliminary mechanistic studies in vitro and in vivo pointed to MCL1 inactivation as a major mechanism of action of E7107 in top responders. Together, these data suggest that the spliceosome is a druggable target in TNBC, and that E7107 or similar SF3B1 inhibitors could be effective in a TNBC subset that needs to be further defined.

Citation Format: Praveen Sridhar, Stefanie Chan, Ying-Jie Lock, Fabio Petrocca. Preclinical evaluation of the SF3B1 inhibitor E7107 in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 420. doi:10.1158/1538-7445.AM2017-420
Abstract 4200: Targeting cancer stem cells in serous ovarian carcinoma using RP6530, a dual PI3k δ/γ inhibitor
Authors: S Sneha , R Nivetha , Nagare R P. , Viswanadha Srikant , Vakkalanka Swaroop , Ganesan T S.
Published: July 2017

Ovarian cancer is one of the most lethal gynecological malignancies as most patients are diagnosed at an advanced stage and have a poor prognosis. Several studies have prospectively isolated cancer stem cells (CSCs) from samples of tumor from patients with serous adenocarcinoma of the ovary (SOC). This has been achieved by using cell surface antigens or functional assays. Targeting this subpopulation could be critical to overcome drug resistance, recurrence, and hence improve the survival of patients. The PI3K pathway is deregulated in 37% of SOC with PI3Kδ and γ amplified in 16% of tumors (TCGA data). We have used a novel and selective PI3K γ/δ inhibitor (RP6530) with high potency against PI3Kγ (IC50=25 nM) and δ (IC50=33 nM) enzymes and selectivity over α (>300-fold) and β (>100-fold) isoforms. RP6530, an orally active and sensitive small molecule inhibitor, is currently being tested in Phase-1 trials in US and Europe to evaluate its safety and efficacy in patients with hematological malignancies. The objective of this study was to test the efficacy of RP6530 against CSCs of EOC. Spheroids, enriched for CSCs were employed as an approach to evaluate the specific potency of the drug. In the experiments, Salinomycin was used as a control drug that targets CSCs. Initially, we have analyzed 3 cell lines (PEO4, OVCAR-5 and CAOV-2) with and without addition of 5µM RP6530. RP6530 significantly inhibited spheroid formation in PEO4 (0.001) and OVCAR-5 (p<0.05) and CAOV-2 (p<0.01) (mean of ≥3 experiments in triplicate). In cell viability assay, RP6530 had no cytotoxic effect as compared to Cisplatin in any of the cell lines. To evaluate the effect of the compound on CSC, we performed analysis of side population (SP) with Hoechst 33342 at 355 nm by flow cytometry. RP6530 either caused a significant reduction (>50%) in the fraction of SP cells (PEO4 and CAOV-2) or was neutral (OVCAR-5) indicating that the compound preferentially targets CSC in ovarian cancer cell lines. Colony assay revealed significantly lesser number of colonies in RP6530 treated cells. Phosphorylation of Akt that is downstream of PI3 kinase was inhibited in a dose dependent manner in all three cell lines. Evaluation of drugs that are intended to target CSCs is different from that of conventional cytotoxic drugs. Taken together, the results indicate that RP6530 shows potent inhibitory effect on CSCs in ovarian cancer cell lines.

Citation Format: Sneha S, Nivetha R, R P. Nagare, Srikant Viswanadha, Swaroop Vakkalanka, T S. Ganesan. Targeting cancer stem cells in serous ovarian carcinoma using RP6530, a dual PI3k δ/γ inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4200. doi:10.1158/1538-7445.AM2017-4200
Abstract 4212: Natural compounds alone and in combination with platinum drugs found to show significant anti-tumour activity against ovarian cancer cell lines
Authors: Anwar Md Sheikh , Yu Jun Qing , Beale Philip , Huq Fazlul
Published: July 2017

Acquired drug resistance remains major problem in platinum based chemotherapy against ovarian cancer. It is believed that elevated expression of NF-kB and AKT/PKB is one of the prime reasons for acquired drug resistance. Since tumour active natural compounds can dampen NF-kB and AKT/PKB expression, it is thought that platinum drugs in combination with the natural compounds may produce synergism in killing tumor cells. The present study aimed to apply combinations of platinum drugs cisplatin, oxaliplatin, and carboplatin with natural compounds mycophenolic acid, honokiol, cholecalciferol and 6-shogaol to four ovarian cancer cell lines: A2780, A2780CisR, A2780ZD0473R and SKOV-3 towards overcoming drug resistance. IC50 values of single compounds were determined followed by administration of binary combinations. Studies on DNA damage, cellular platinum accumulation, and platinum-DNA binding levels were carried out. Proteomic studies will be done to explore the key proteins involve with drug resistance. Mycophenolic acid (IC50: 1.34-7.83 μM) from Penicillium brevicompactum and 6-shogaol (IC50: 6.79-10.20 μM) from Zingiber officinale showed significant activity against ovarian cancer cell lines. Ginger derived pure compound 6-shogaol showed prominent synergism in combination with platinums when administered as a bolus (0/0h) and with 0/4 h sequence. Honokiol from Magnolia virginia alone and in combination with cisplatin showed significant DNA damage in A2780 cell line whereas cholecalciferol did the same to A2780cisR cell line. Bolus combination of cisplatin and 6-shogoal produced increased cellular platinum accumulation and 3 times more Pt-DNA binding than cisplatin alone treated A2780 cells. Though honokiol and cisplatin (0/0 h) combination have half cellular platinum accumulation in compare to cisplatin alone treated A2780 cells but showed 9 times higher Pt-DNA binding. Cholecalciferol and 6-shogaol in combination with cisplatin also showed promising Pt-DNA in A2780CisR cell line. In conclusion, 6-shogaol, cholecalciferol and honokiol showed significant activity alone and in combination with cisplatin and oxaliplatin against ovarian cancer tumour models.

Note: This abstract was not presented at the meeting.

Citation Format: Md Sheikh Anwar, Jun Qing Yu, Philip Beale, Fazlul Huq. Natural compounds alone and in combination with platinum drugs found to show significant anti-tumour activity against ovarian cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4212. doi:10.1158/1538-7445.AM2017-4212
Abstract 4215: Cancer-related fatigue and physical activity vary by age for black women with a history of breast cancer
Authors: Swen Melody A. , Mann Amandeep , Paxton Raheem , Dean Lorraine T.
Published: July 2017

Purpose: Cancer-related fatigue is the most discomforting symptom among women with a history of breast cancer. Black women are more likely to experience risk factors for cancer-related fatigue, like physical inactivity and obesity, yet cancer-related fatigue studies have not explicitly focused on Black women. This cross-sectional analysis assesses cancer-related fatigue and physical activity among Black female breast cancer survivors.

Methods: In May and July of 2012, 266 members of the Sisters Network, Inc completed an online survey on: demographics, cancer history and treatment, fatigue using the 13-item Function Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, and engagement in ≥150 minutes per week of physical activity (CDC guideline). Multiple linear regression assessed relationships between fatigue and physical activity.

Results: The average participant was 54 (SD=9) with a FACIT score of 13.63, indicating “severe fatigue”. Fatigue was greater (p=0.02) among the 56% of women meeting physical activity guidelines. Multivariable analysis showed that meeting physical activity guidelines (β=-3.01, p=0.01) and higher age group (50-59: -4.75, p=0.001; 60+: -4.38, p=0.01) were associated with greater fatigue. An interaction plot showed that differences in fatigue for those meeting or not meeting physical activity guidelines is largest among Black women under age 50.

Conclusions: Meeting physical activity guidelines was associated with greater cancer-related fatigue, which was most pronounced for those under age 50. Interventions for Black breast cancer survivors with cancer-related fatigue should consider physical activities that can be integrated into existing tasks and provide age-appropriate resources to address physical and emotional fatigue domains.

Keywords: breast cancer; fatigue; age; Black/African-American; physical activity

Citation Format: Melody A. Swen, Amandeep Mann, Raheem Paxton, Lorraine T. Dean. Cancer-related fatigue and physical activity vary by age for black women with a history of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4215. doi:10.1158/1538-7445.AM2017-4215
Abstract 4217: Consumer credit, cancer treatment, and health among women with a history of breast cancer
Authors: Dean Lorraine T. , Schmitz Kathryn H. , Frick Kevin , Nicholas Lauren , Zhang Yuehan , Subramanian SV , Visvanathan Kala
Published: July 2017

Background: Breast cancer treatment may represent an economic shock that may be influenced by, or may influence a cancer survivor’s socio-economic position (SEP). Financial toxicity or economic burden due to cancer treatment and treatment’s adverse effects may be reflected in one’s consumer credit ratings; however, credit’s contribution to individual health for cancer survivors or those managing long-term adverse effects of cancer treatment has not been evaluated. This analysis examined associations between self-rated health outcomes of women with a history of breast cancer, type of cancer treatment, and presence of breast cancer-related lymphedema, a persistent adverse effect of treatment, and consumer credit rating.

Methods: From May to September 2015, 129 women from Pennsylvania and New Jersey were enrolled in the PAL Social and Economic Quality of Life cross-sectional study. All participants had a history of breast cancer, and completed a survey of: demographics, SEP, co-morbidities, SF-12 self-rated health, psychosocial stress, adjuvant cancer treatments (chemotherapy, hormone therapy, radiation), breast cancer-related lymphedema symptoms, and credit quality (5-point scale self-reported as poor to excellent). Multivariable linear regression measured the association between credit and health.

Results: Mean respondent age was 64, with 38.2% reporting excellent and 37.4% reporting very good/good credit. Participants completed cancer treatment on average 11.5 years ago. After adjusting for demographics and SEP, good credit was associated with a 4.5 (p=0.009) point increase in composite physical health t-score and -1.13 (p=0.02) decrease in psychosocial stress compared to women with poor credit, but was not associated with type of cancer treatment or lymphedema.

Conclusion: While credit was associated with self-rated health for women with an average 11.5 year history of breast cancer, current credit quality did not appear to be associated with type of cancer treatment previously received or with the presence of lymphedema, a persistent adverse effect of cancer treatment. It is still possible that cancer treatment may have influenced credit close to time of treatment, and credit was able to rebound since that time. Future work should test causal pathways between credit and health outcomes after cancer diagnosis.

Citation Format: Lorraine T. Dean, Kathryn H. Schmitz, Kevin Frick, Lauren Nicholas, Yuehan Zhang, SV Subramanian, Kala Visvanathan. Consumer credit, cancer treatment, and health among women with a history of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4217. doi:10.1158/1538-7445.AM2017-4217
Abstract 4240: Determination of normative patterns of gene expression levels and breast cancer risk biomarkers in human breast milk
Authors: Ouzounova Maria , Lewis Georgina , Piranlioglu Raziye , Curry-McCoy Tiana , Yoo Wonsuk , Maihle Nita , Kim Sangmi , Korkaya Hasan
Published: July 2017

Parity and breastfeeding influence a woman’s risk of developing breast cancer. Understanding the underlying molecular changes in the breast will facilitate identification of additional factors during pregnancy and postpartum that modify breast cancer risk. Most prior studies in humans on this topic, however, have been cross-sectional studies comparing breast tissue samples from nulliparous versus post-pregnant women, and are limited in their ability to characterize longitudinal changes and within-person variations. Breast milk contains cells of the mature gland, and may have a potential as a noninvasive source for studying molecular characteristics of the pregnancy-associated changes in the breast and their impact on breast cancer risk. The objectives of this study were to (1) determine normative patterns of gene expression levels in longitudinally collected breast milk samples and (2) correlate gene expression data in relation to self-reported measures of psychosocial stress during pregnancy and postpartum period. Our preliminary results showed that the post-pregnancy gene expression levels in breast milk samples can be measured reproducibly over a short period of time. Whole-genome transcriptome analysis revealed that expression levels of the post-pregnancy genes are different in early (less than 3 month postpartum) and late lactation period (more than 6 month postpartum). Moreover cytokine expression profiling correlated expression of inflammatory cytokines with early versus late postpartum period. The unique contribution of this study is to capture longitudinal gene expression data from breast milk samples collected over the course of lactation, hence providing a valuable basis for future studies to identify differential dynamics associated with breast cancer susceptibility.

Note: This abstract was not presented at the meeting.

Citation Format: Maria Ouzounova, Georgina Lewis, Raziye Piranlioglu, Tiana Curry-McCoy, Wonsuk Yoo, Nita Maihle, Sangmi Kim, Hasan Korkaya. Determination of normative patterns of gene expression levels and breast cancer risk biomarkers in human breast milk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4240. doi:10.1158/1538-7445.AM2017-4240
Abstract 4254: Improved understanding of the etiology of breast cancer in young women through evaluation of the genomic landscape
Authors: Wilkerson Matthew D. , Dalgard Clifton L. , Shriver Craig D. , Ellsworth Rachel E.
Published: July 2017

Background Breast cancer is a disease where biological age and age at menopause are established risk factors, thus diagnosis of breast cancer in young women (<40 years, YW) is not common, representing ~6% of breast cancer diagnoses annually. Germline mutations in cancer predisposition genes accounts for ~20% of breast cancer diagnoses in YW, thus the etiology of breast tumors for the majority of YW is unknown.

Methods Frozen tumor specimens and matched genomic DNA samples from 31 women diagnosed <40 years were available. Whole genome sequencing (WGS) was performed by generating sequencing libraries from 1 mg input using the TruSeq PCR-free library preparation workflow and sequencing on the HiSeq X Ten at triple lane depth with 150bp paired-end reads. WGS was analyzed using the Hiseq Analysis Software Tumor Normal Workflow, Bioconductor: deconstructSigs and ad hoc integrated analysis and hypothesis testing.

Results Luminal A tumors from YW had significantly lower somatic mutational loads, copy number alterations and structural variants than other subtypes and structural variants on chromosome 17 were enriched in patients with the HER2-enriched subtype and HER2 status = 3+. Aging was the most common signature (28/31) followed by APOBEC activation (14/31). Signatures associated with defects in mismatch repair (9/31) and polymerase ϵ (10/31) were also detected in >25% of patient tumors. Of the six patients with BRCA defect signatures, three had germline mutations in BRCA2 and one had a CHEK2 mutation. Mutational signatures could cluster patients into two groups, with the youngest patients (<35 years) less likely to have signatures associated with aging but an enrichment in signatures of APOBEC, BRCA mutations and smoking; tumors within this group were more likely to be non-luminal A.

Conclusions Profiling the genome of tumors from YW supports the idea that most tumors are not characterized by profiles associated with genetic predisposition but rather processes such aging, APOBEC activation, mismatch repair, and defects in DNA replication. Of note, breast tumors in the youngest patients (<35) have a different pattern of mutational signatures suggesting that even within YW, etiology differs by age.

Citation Format: Matthew D. Wilkerson, Clifton L. Dalgard, Craig D. Shriver, Rachel E. Ellsworth. Improved understanding of the etiology of breast cancer in young women through evaluation of the genomic landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4254. doi:10.1158/1538-7445.AM2017-4254
Abstract 426: Targeted genome profiling in patients with advanced hepatocellular carcinoma treated with sorafenib
Authors: Kang Wonseok , Kim Kyung , Lee Joon Hyeok , Lim Ho Yeong , Park Woong-Yang , Lee Jeeyun , Paik Yong Han
Published: July 2017

Background/Objectives: Sorafenib is the only approved targeted agent as first-line treatment for advanced hepatocellular carcinoma (HCC). Unfortunately, many HCC patients are initially not responsive to sorafenib. Due to anatomic limitations and underlying liver dysfunction, genomic studies of HCC patients have not been actively pursued yet compared to other solid tumors; especially, in sorafenib-treated subset. In this study, we have retrospectively identified advanced HCC patients who had archival tumor tissues available for targeted genomic sequencing and who had been treated with sorafenib.

Methods: We performed targeted genomic profiling for 381 cancer-related genes from 42 HCC (32 hepatitis B virus-related, 1 alcohol-related, 7 unknown) patients treated with sorafenib at Samsung Medical Center, Seoul, Korea from July 2008 to October 2013. We excluded 2 patients who were lost to follow up for evaluation of treatment response to sorafenib.

Results: Of the 40 patients, there were 5 confirmed PRs, 7 SDs, and 28 PDs. In 40 patients, there were 6 CDKN2B amplifications, 4 NTRK1 amplifications, 2 MET amplifications, 2 FGF19 amplifications, 2 CCND1 amplifications, 1 EGFR amplification, 1 FGF23 amplification and 1 CCNE1 amplification. In cell cycle-related genes, those patients with aberrations were less likely to respond to sorafenib. Of note, two patients whose tumor had CCND1 amplifications had de novo resistance to sorafenib.

Conclusions: Our study demonstrates inter-patient heterogeneity in advanced HCC patients and the role of cell cycle-associated genes in resistance mechanism to sorafenib is being investigated.

Citation Format: Wonseok Kang, Kyung Kim, Joon Hyeok Lee, Ho Yeong Lim, Woong-Yang Park, Jeeyun Lee, Yong Han Paik. Targeted genome profiling in patients with advanced hepatocellular carcinoma treated with sorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 426. doi:10.1158/1538-7445.AM2017-426
Abstract 4264: Smoking exposure and quantitative levels of estrogen-receptor expression in ER+ breast tumors
Authors: Butler Eboneé N. , Baron John A. , Bensen Jeannette T. , Chen Mengjie , Conway Kathleen , Olshan Andrew F. , Troester Melissa
Published: July 2017

Introduction: Smoking is a suspected risk factor for breast cancer and has been linked to increased risk of estrogen-receptor positive (ER+) disease in some epidemiologic studies. Cigarette smoke has also been shown to have antiestrogenic effects, leading to a potentially contradictory hypothesis that smoking would lead to decreased risk of breast tumors driven by estrogen-signaling. Binary classification of breast tumors with respect to ER may mask quantitative associations between smoking and ER expression. Methods: Using data from the Carolina Breast Cancer Study (CBCS), we examined relationships between smoking and quantitative levels of ER expression from tumors of 1,297 women with ER+ disease (i.e., ≥ 10% of tumor cells ER+ by immunohistochemical analysis). We used multinomial logistic regression to estimate associations between categorical measures of smoking and quartiles of ER protein or ESR1 mRNA expression, represented by odds ratios (OR) and 95% confidence intervals (95% CI). We also examined associations between smoking and quantitative ER levels among women with ER+ breast tumors, stratified by menopausal status. Multivariate regression models include adjustment for age, race, stage, grade, and tumor size. Results: Quantitative ESR1 was positively associated with any history of smoking (i.e., current at time of diagnosis or former smoking) (OR: 1.96 and 95% CI: 1.24 to 3.10). In addition, smoking more than 1 pack of cigarettes per day was associated with high ESR1 expression (OR: 3.19 and 95% CI: 1.29 to 7.91) as was smoking duration of > 20 years (OR: 2.08 and 95% CI: 1.16 to 3.74). Among former smokers, we observed higher ESR1 expression among those who quit 5-10 years prior to diagnosis. The magnitudes of association between smoking and quantitative levels of ESR1 expression were similar for both pre- and post-menopausal women, but were not reflected in similar association on the protein level. Conclusions: Among women with ER+ breast cancer, smoking dose and duration was positively associated with elevated ESR1 mRNA levels, regardless of menopausal status. Absence of this association for protein suggests that ESR1 RNA merits further consideration, but may suggest that ESR1 RNA more sensitively captures biological differences than ER protein expression.

Citation Format: Eboneé N. Butler, John A. Baron, Jeannette T. Bensen, Mengjie Chen, Kathleen Conway, Andrew F. Olshan, Melissa Troester. Smoking exposure and quantitative levels of estrogen-receptor expression in ER+ breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4264. doi:10.1158/1538-7445.AM2017-4264
Abstract 4265: Risks of familial breast cancer associated with known and proposed breast cancer susceptibility genes
Authors: Maxwell Kara N. , Slavin Thomas Paul , Lilyquist Jenna M. , Vijai Joseph , Neuhausen Susan L. , Hart Steven N. , Ravichandran Vignesh , Thomas Tinu , Maria Ann , Schrader Kasmintan A. , Moore Raymond , Hu Chunling , Wubbenhorst Brad , Wenz Brandon M. , D'Andrea Kurt , Domchek Susan M. , Robson Mark E. , Peterlongo Paulo , Radice Paolo , Ford James M. , Garber Judy E. , Szabo Csilla , Offit Kenneth , Nathanson Katherine L. , Couch Fergus J. , Weitzel Jeffrey N.
Published: July 2017

A better understanding of gene-specific risks for development of breast cancer will lead to improved screening, prevention, and therapeutic strategies for individuals identified to carry germline mutations. We performed targeted massively-parallel sequencing to identify mutations and large genomic rearrangements in 26 known or proposed breast cancer susceptibility genes in 2134 BRCA-negative women with familial breast cancer (FBC). A case-control analysis was performed comparing the frequency of internally classified mutations identified in FBC cases to that in non-Finnish European controls from the Exome Aggregation Consortium (ExAC) excluding samples from The Cancer Genome Atlas. Including large genomic rearrangements, mutations were identified in 8.2% of FBC cases compared to 6.2% of ExAC controls, including mutations in high-penetrance genes (0.6% in cases vs. 0.1% in controls), moderate-penetrance genes (3.7% vs 1.7%), and seven cases with two mutations (0.3%). The remainder of FBC cases and ExAC controls had mutations in proposed breast cancer genes (1.6% of cases vs 2.4% of controls), Lynch syndrome genes (0.5% vs. 0.5%) or were heterozygous MUTYH carriers (1.5% vs. 1.5%). Case-control analysis demonstrated significant associations with FBC for ATM, PALB2, and TP53 mutations (OR>3.0, p<10-4), BARD1 mutations (OR=3.2, p=0.012), and CHEK2 truncating mutations (OR=1.6, p=0.041). Our results therefore demonstrate that only approximately 4% of BRCA1/2 negative FBC patients have mutations in genes definitively associated with breast cancer at this time. Large case-control studies are needed to fully evaluate the breast cancer risks associated with moderate penetrance and proposed breast cancer susceptibility genes.

Citation Format: Kara N. Maxwell, Thomas Paul Slavin, Jenna M. Lilyquist, Joseph Vijai, Susan L. Neuhausen, Steven N. Hart, Vignesh Ravichandran, Tinu Thomas, Ann Maria, Kasmintan A. Schrader, Raymond Moore, Chunling Hu, Brad Wubbenhorst, Brandon M. Wenz, Kurt D'Andrea, Susan M. Domchek, Mark E. Robson, Paulo Peterlongo, Paolo Radice, James M. Ford, Judy E. Garber, Csilla Szabo, Kenneth Offit, Katherine L. Nathanson, Fergus J. Couch, Jeffrey N. Weitzel. Risks of familial breast cancer associated with known and proposed breast cancer susceptibility genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4265. doi:10.1158/1538-7445.AM2017-4265
Abstract 427: A path towards determining tumor mutation burden and identifying neoantigens using next-generation sequencing (NGS)
Authors: So Alex , Kaplan Shannon , Wang Nai-yu , Zhang Shile , Wise Aaron , Kruglyak Kristina , Gutekunst Karen
Published: July 2017

Introduction: The recent clinical demonstrations that cancer immunotherapy is effective for some patients, but not others has led to widespread interest in identifying cancer genetic factors that can predict positive response. Importantly, it has been shown by various studies that tumor mutation burden (TMB) and predicted neoantigen load correlate with patient response to checkpoint inhibitors. This project aims to develop a clinical next-generation sequencing (NGS) assay that utilizes TMB and neoantigen information to guide cancer immunotherapy selection.

Experimental Procedures: Whole exome sequencing (WES) and whole transcriptome sequencing (WTS) libraries were generated using Illumina’s TruSeq® Exome and RNA Access library preparation kits, respectively. The samples were pair-end sequenced (2x75bp) using HiSeq® 2000 and 2500 instruments.

Data Summary: Here, we demonstrate a workflow using tumor/normal WES and tumor-only WTS to determine expressed TMB. Using the WES data, we were also able to accurately identify human leukocyte antigen (HLA) major histocompatibility complex (MHC) Class I genes at four-digit resolution. We then identified putative neoantigens, defined as peptides with mutated amino acids, that were expressed in the tumor samples and predicted to bind to the respective HLA sequences. In addition, as a path towards developing a clinical assay for TMB and neoantigen determination, we tested the ability of reagents developed for Illumina’s Trusight® Tumor 170 panel to be used for an exome panel. With workflow modifications, we achieved comparable quality of sequencing metrics as compared to the TruSeq® Exome kit.

Conclusion: Our data demonstrate a path towards developing a clinical assay that can be used to assess TMB and neoantigen candidates.

Citation Format: Alex So, Shannon Kaplan, Nai-yu Wang, Shile Zhang, Aaron Wise, Kristina Kruglyak, Karen Gutekunst. A path towards determining tumor mutation burden and identifying neoantigens using next-generation sequencing (NGS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 427. doi:10.1158/1538-7445.AM2017-427
Abstract 4270: Family history in first degree relatives and risk of gastric cancer in the alpha-tocopherol, beta-carotene cancer prevention study
Authors: Song Minkyo , Camargo Maria Constanza , Weinstein Stephanie J. , Albanes Demetrius , Rabkin Charles S.
Published: July 2017

Background: Studies of the familial associations of gastric cancer risk have largely been limited to case-control approaches which are susceptible to recall bias and cannot distinguish temporality. Furthermore, associations with family history could be explained by shared exposure to Helicobacter pylori infection, the most important environmental risk factor for gastric cancer. Notably, the risks of early onset disease and diffuse-type tumors are thought to have a greater genetic component. We therefore examined in a prospective study the associations of gastric cancer risk with history of gastric cancer in first degree relatives, controlling for H. pylori infection.

Methods: We selected 405 incident gastric cancer cases and 4,129 controls with known H. pylori serology status from the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study among male smokers aged 50-69 at baseline. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression with adjustment for H. pylori and other potential confounders. All statistical tests were two-sided.

Results: Family history of gastric cancer was associated with increased risk (OR=1.84, 95% CI=1.32-2.58). The association appeared stronger with gastric cancer in siblings (OR=2.87, 95% CI=1.64-5.03) than with gastric cancer in parents (OR=1.53, 95% CI=1.05-2.24). Distinguishing cases by anatomic subsite, the family history association was significant for noncardia gastric cancer (n=305; OR=2.15, 95% CI=1.50-3.07), but not for cardia cancer (n=100; OR=1.25, 95% CI=0.63-2.49). With regard to histological subtype, family history was significantly associated with both diffuse-type (n=90; OR=2.12, 95% CI=1.10-4.12) and intestinal-type (n=153; OR=1.70, 95% CI=1.02-2.83) gastric cancer. In age-specific analyses, the association with family history was strongest in the youngest age-group at baseline 50-54 years (OR=3.42, 95% CI=1.85-6.30) and absent in the oldest age group 65-69 years (OR=0.85, 95% CI=0.28-2.58).

Conclusion: The results suggest that certain subtypes of sporadic gastric cancer are strongly associated with family history of gastric cancer. These associations do not appear to be explained by the associations with H. pylori infection.

Citation Format: Minkyo Song, Maria Constanza Camargo, Stephanie J. Weinstein, Demetrius Albanes, Charles S. Rabkin. Family history in first degree relatives and risk of gastric cancer in the alpha-tocopherol, beta-carotene cancer prevention study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4270. doi:10.1158/1538-7445.AM2017-4270
Abstract 4280: FH (rs367543046, chr1:241661227 A/ATTT) heterozygous carrier status does not confer risk to hereditary leiomyomatosis and renal cell cancer (HLRCC) and prostate cancer
Authors: Walsh Michael F. , Mandelker Diana , Vijai Joseph , Musheyev David , Kennedy Jennifer , Stadler Zsofia , Kemel Yelena , Topka Sabine , Cadoo Karen , Carlo Maria , Ladanyi Marc , Robson Mark , Offit Kenneth , Zhang Liying
Published: July 2017

Fumarate Hydratase (FH) mutations underpin the autosomal recessive syndrome Fumarate Hydratase deficiency and the autosomal dominant syndrome Hereditary Leiomyomatous and Renal Cell Carcinoma (HLRCC). The variant rs367543046, a duplication leading to p. Lys477_Asn478insLys in FH has strong evidence for risk towards fumarate hydratase deficiency when occurring in trans to another germline alteration in the FH gene. In addition, this variant in the heterozygous state has been reported in ClinVar to predispose to the autosomal dominant condition HLRCC, given other heterozygous mutations have shown to be pathogenic. Population level data is sparse to determine the variant’s impact in the heterozygous state. Here, we show in a series of 1375 cancer cases the (rs367543046, chr1: 241661227 A/ATTT), variant detected in 7 (0.5%) individuals with cancer. One patient with bladder cancer had a history of uterine leiomyomas, but the immunohistochemistry for 2SC was negative, suggesting that the leiomyomas were not associated with HLRCC. None of the other 6 carriers of this variant had any features of HLRCC. Notably, this variant was not detected in any of the patients with renal cancer (n=178) participating in the study. Since 4/7 prostrate cancer patients of Ashkenazi ethnicity harbored this variant, we performed a genetic epidemiology study using 856 Ashkenazi Jewish prostate cancer patients. The allele frequencies were compared with 557 Ashkenazi Jewish non-cancer controls. A fisher’s two sided exact test showed that the variant is not associated with prostate cancer in Jews (P=1, OR 1.12(CI 95% 0.21-7.25). Our findings suggest that the variant, which is pathogenic for autosomal recessive fumarate hydratase deficiency does not confer pathogenicity in the heterozygous form for Hereditary Leiomyomatous and Renal Cell Carcinoma or prostate cancer.

Ashkenazi Jewish Prostate Cancer Patients vs Ashkenazi Jewish Non-Cancer PatientsAttributeAshkenazi Jewish Prostate Cancer PatientsAshkenazi Jewish Non-Cancer patientsCT53CC17071151

Citation Format: Michael F. Walsh, Diana Mandelker, Joseph Vijai, David Musheyev, Jennifer Kennedy, Zsofia Stadler, Yelena Kemel, Sabine Topka, Karen Cadoo, Maria Carlo, Marc Ladanyi, Mark Robson, Kenneth Offit, Liying Zhang. FH (rs367543046, chr1:241661227 A/ATTT) heterozygous carrier status does not confer risk to hereditary leiomyomatosis and renal cell cancer (HLRCC) and prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4280. doi:10.1158/1538-7445.AM2017-4280
Abstract 4283: BRCA1 and BRCA 2 mutation predictions using BRACAPRO and MYRIAD models in patients with Korean ethnicity
Authors: Eoh Kyung Jin , Park Hyung Seok , Park Ji Soo , Lee Seung-Tae , Han Jeongwoo , Lee Jung-Yun , Kim Sunghoon , Kim Sang Wun , Kim Young Tae , Nam Eun Ji
Published: July 2017

Introduction: This study is aimed to compare the predictive efficacy of BRCAPRO and MYRIAD BRCA risk calculator in patients tested in Korean ethnicity.

Methods: Individuals, who received gene test on BRCA mutation from November 2010 to August 2016, were recruited from database of department of obstetrics and gynecology at a single institute in Korea. Observed BRCA1 and BRCA2 mutation status was compared with predicted carrier probabilities under the BRCAPRO, and MYRIAD BRCA risk calculator. Risk assessment for all patients was calculated using the CancerGene assessment software.

Results: Total of 279 patients was recruited, and 99.3% (277 out of 279) had Korean ethnicity. The mean age at presentation was 52 years. Out of the 279 individuals, 206 had ovarian cancer, 36 had breast cancer, 26 had double primary ovarian/breast cancer, and 11 had no cancer. Fifty five individuals had family history of ovarian/breast cancer in first degree relatives. Sixty three patients (22.6%) tested positive for a BRCA mutation (45 BRCA1, 18 BRCA2). The mean BRCAPRO and MYRIAD score for all patients was 6.4% and 7.7%, respectively. The BRCAPRO and MYRIAD scores were significantly higher for patients who tested positive for a BRCA mutation (30.4% vs. 6.3%, P < 0.001, 12.1% vs. 7.7%, P < 0.001, respectively). The area under the receiver operating characteristics curves were 0.762, and 0.751 for all patients for the BRCAPRO and MYRIAD score to predict the risk of carrying a BRCA mutation.

Conclusion: BRCAPRO and MYRIAD appear to be valid risk assessment tools for determining the risk of carrying a BRCA mutation in Korean ethnicity.

Citation Format: Kyung Jin Eoh, Hyung Seok Park, Ji Soo Park, Seung-Tae Lee, Jeongwoo Han, Jung-Yun Lee, Sunghoon Kim, Sang Wun Kim, Young Tae Kim, Eun Ji Nam. BRCA1 and BRCA 2 mutation predictions using BRACAPRO and MYRIAD models in patients with Korean ethnicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4283. doi:10.1158/1538-7445.AM2017-4283
Abstract 4287: HABP2 p.G534E variant in patients with family history of thyroid and breast cancer
Authors: Pinheiro Maisa , Drigo Sandra A. , Marchi Fabio A. , Tonhosolo Renata , Andrade Sonia C. , Jurisica Igor , Kowalski Luiz P. , Achatz Maria Isabel W. , Rogatto Silvia R.
Published: July 2017

Background. Familial Papillary Thyroid Carcinoma (PTC) has been recently associated with the HABP2 p.G534E mutation. In this study we evaluated the putative association of the HABP2 p.G534E mutation and familial history of PTC and Breast Carcinoma (BC) in the Brazilian population.

Methods. Germline mutations of twenty unrelated individuals with personal and/or family history of PTC and/or BC were identified by whole exome sequencing (WES), using Nextera Exome Enrichment kit and HiSeq200 platform (Illumina). Two cases were positive for p.G534E. Family members from both positive cases (seven from Family 1 and three from Family 2) were recruited for segregation analysis. An additional patient and three relatives (Family 3) with history of PTC and BC were included for validation. Fifty frozen PTC tumor samples and 170 healthy Brazilian individuals were also screened for the HABP2 variant. Confirmation and validation were performed by Sanger sequencing.

Results. Interestingly, Family 1 reported a consanguineous history, reflected in two homozygous cases: the proband (PTC) and his unaffected sister. Also, only one (BC) out of eight tested members was negative for p.G534E. In the Family 2, the only patient diagnosed with PTC was negative for the mutation, while three relatives were positive for the same loci. The index case (PTC) from Family 3, was wild type for HABP2 and three relatives tested were positive carriers. In PTC tumor samples the Allele Frequency (AF) was 0.04: two heterozygous and one homozygous for p.G534E. Among 170 healthy individuals, five were heterozygous for the variant, representing an AF of 0.0147. The two index patients evaluated by WES also presented interesting pathogenic variants in genes potentially associated with deregulation of the extracellular matrix organization pathway (CTSB, TNXB, COL4A3, COL16A1, COL24A1, COL5A2, NID1, LOXL2, MMP11, TRIM24 and MUSK) and DNA repair function (NBN and MSH2).

Conclusion. Our findings suggest that HABP2 is not a predisposition gene involved in familial PTC and BC.

Financial Support: FAPESP (2013/01867-8 and 2014/03983-8) and CNPq (481132/2012-0)

Note: This abstract was not presented at the meeting.

Citation Format: Maisa Pinheiro, Sandra A. Drigo, Fabio A. Marchi, Renata Tonhosolo, Sonia C. Andrade, Igor Jurisica, Luiz P. Kowalski, Maria Isabel W. Achatz, Silvia R. Rogatto. HABP2 p.G534E variant in patients with family history of thyroid and breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4287. doi:10.1158/1538-7445.AM2017-4287