bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-14-05: Capecitabine in early breast cancer: A meta-analysis of randomized controlled trials
Authors: Natori A , Ethier J-L , Amir E , Cescon DW
Published: March 2017

Background

Capecitabine is an effective therapy for metastatic breast cancer. Its role in early breast cancer is uncertain due to conflicting data from randomized controlled trials (RCTs).

Methods

PubMed and major conference proceedings were searched to identify RCTs comparing standard chemotherapy (defined as cyclophosphamide/methotrexate/5-fluorouracil, anthracycline-based regimens or anthracycline/taxane combinations) with or without capecitabine in the neo-adjuvant or adjuvant setting. Hazard ratios (HR) for disease-free (DFS) and overall survival (OS), as well as odds ratios (ORs) for safety and tolerability were extracted or calculated and pooled in a meta-analysis. Subgroup analysis compared triple negative breast cancer (TNBC) to non-TNBC and whether capecitabine was given in addition to or in place of standard chemotherapy. Meta-regression was used to explore the influence of TNBC on OS.

Results

Eight studies comprising 9302 patients were included. In unselected patients, capecitabine did not influence DFS (HR 0.99, p=0.93) or OS (HR 0.90, p=0.36). There was a significant difference in DFS when capecitabine was given in addition to, compared to in place of standard treatment (HR 0.92 vs. 1.62, interaction p=0.002). Addition of capecitabine to standard chemotherapy was associated with significantly improved DFS in TNBC vs non-TNBC (HR 0.72 vs. 1.01, interaction p=0.02). Meta-regression confirmed this association with OS (R=-0.967, p=0.007). Capecitabine increased Grade 3/4 diarrhea (OR 2.33, p<0.001) and hand foot syndrome (OR 8.08, p<0.001), and resulted in more frequent treatment discontinuation (OR 3.80, p<0.001).

Conclusion

Adding capecitabine to standard chemotherapy appears to improve DFS and OS in TNBC, but increases adverse events in keeping with its known toxicity profile. Consideration of this treatment is warranted, especially in high-risk patients.

Citation Format: Natori A, Ethier J-L, Amir E, Cescon DW. Capecitabine in early breast cancer: A meta-analysis of randomized controlled trials [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 P5-14-05.
Abstract P5-14-10: Weekly doxorubicin and daily oral cyclophosphamide followed by nab-paclitaxel for adjuvant therapy of high-risk localized breast cancer
Authors: Cho E , Wu Q , Rubinstein L , Linden H , Gralow J , Specht J , Gadi V , Ellis G
Published: March 2017

BACKGROUND: The addition of taxanes to anthracycline-based adjuvant chemotherapy has improved disease free survival (DFS) in women with high-risk early-stage breast cancer. Many studies have sought to optimize the dose intensity and density of these agents to produce improvements in outcome and tolerability. The purpose of this study was to assess the use of metronomic doxorubicin plus daily oral cyclophosphamide (AC) for 12 weeks followed by nab-paclitaxel (nP) for 12 weeks in this population. Those patients with Her2 positive disease were also given adjuvant trastuzumab.

METHODS: A non-randomized phase II clinical trial was designed to (1) test the DFS at 2 years compared to historical controls, (2) assess dose intensity delivered, (3) assess use of nP in the adjuvant setting, and (4) evaluate toxicities associated with the regimen. Overall survival (OS) was a secondary outcome. The dosing of A was 24mg/m2 IV qweek and C was 60mg/m2 oral daily; nP, 100mg/m2 IV qweek.

RESULTS: Sixty patients were enrolled on the study with a median follow-up of 6 years and a median age of 50 (range 30-69). 58% of patients had node positive disease. Receptor categories included hormone receptor positive (ER positive or PR positive) and HER2 negative (n=24; 40%); ER negative, PR negative, and HER2 negative (triple negative; n=19; 32%); or HER2 positive (n=17; 28%). DFS at 2 years was 93% (1 death, 3 recurrence) and at 6 years was 82%, comparable to historical controls. OS at 2 years and 6 years was 98% and 88%, respectively. Mean dose intensity was greater than 90% for AC and 88% for nP. Treatment was well-tolerated with the most common grade ≥3 toxicity being neutropenia and a 2% incidence of febrile neutropenia.

Disease-free survival and overall survival at 2 and 6 years 2 year 6 year  DFS %OS %DFS %OS %All patients93988288ER+ or PR+, HER2-921007979Triple negative89957989HER2+10010088100

CONCLUSSIONS: Patients achieved similar DFS to that seen in historical controls with similar rates of adverse events. Since nP dosing was 100 mg/m2, even with 88% dose intensity, the delivered taxane dose is greater than standard weekly paclitaxel. Notably disease control was particularly impressive in the triple negative subtype, which has been shown to benefit from nP over standard paclitaxel in the neoadjuvant setting in the GeparSepto (GBG 69) trial. Metronomic AC followed by nP is a safe, effective option for delivery of adjuvant chemotherapy for high-risk patients.

Citation Format: Cho E, Wu Q, Rubinstein L, Linden H, Gralow J, Specht J, Gadi V, Ellis G. Weekly doxorubicin and daily oral cyclophosphamide followed by nab-paclitaxel for adjuvant therapy of high-risk localized 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 P5-14-10.
Abstract P5-15-14: Metronomic capecitabine in heavily pretreated metastatic triple negative breast cancer
Authors: El-Sadda WM
Published: March 2017

This abstract was not presented at the symposium.
Abstract P5-15-17: Platinum salts in advanced breast cancer: A systematic review and meta-analysis of randomized clinical trials
Authors: Petrelli F , Barni S , Bregni G , de Braud F , Di Cosimo S
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P5-16-27: Variation in the use of neoadjuvant chemotherapy for breast cancer in the Netherlands. A lack of consensus
Authors: Spronk PER , Bommel van ACM , Siesling S , Vrancken Peeters M-JT , Smorenburg CM
Published: March 2017

Introduction

Neoadjuvant chemotherapy (NAC) is an important initial strategy in the management of stage III locally advanced breast cancer (LABC) as being advised in our national guidelines. Furthermore, NAC is increasingly being used in stage II BC for downsizing the tumour in order to enable breast conservation therapy (BST). The aim of this study was to examine which patient-, tumour- and hospital related factors influence its use in clinical daily practice. In addition, we investigated the preferences of the surgical- and medical- oncologist as well as the patients'.

Methods

(1) All operated women [aged 18-70] from January 2011 to September 2015 were selected from the multidisciplinary NABON Breast Cancer Audit (NBCA). Multivariable logistic regression was used to assess significant independent predictors of NAC use. (2) Both specialists and ex-patients were provided with a survey about decision-making.

Results

Overall, 21% of stage II (N=18011) and 70% of stage III patients (N=1715) received NAC. Factors associated with NAC utilization included young age, a diagnostic MRI, histology, large tumour size, more advanced nodal disease, hormone-receptor negative tumours and participation in neoadjuvant trials.After case mix correction variation between hospitals remained (range 10% – 90%). Evidenced by additional survey research, reasons for indication of NAC vary widely among specialists (response rate of 24%; N=100). From the patient survey (response rate of 52%; N=390) it appears that in patients where chemotherapy is recommended, 50% was not informed about the option of NAC.

Conclusion

There is considerable variation in the use of NAC for BC in the Netherlands. Although various patient, tumor and institutional factors are associated with the use of NAC, these can only explain part of the observed variation in treatment patterns between hospitals. Survey research shows a need for uniformity of selection criteria in the use of NAC between specialists. Also, the information necessary for patients to decide on which treatment option they prefer seems far from complete in clinical practice.

Citation Format: Spronk PER, Bommel van ACM, Siesling S, Vrancken Peeters M-JT, Smorenburg CM. Variation in the use of neoadjuvant chemotherapy for breast cancer in the Netherlands. A lack of consensus [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 P5-16-27.
Abstract P6-01-10: Estrogen receptor β2 and β5 increase expression of ABCG2 and drug resistance of the triple- negative breast cancer cell line SUM159
Authors: Faria M , Gustafsson J-A , Strom A
Published: March 2017

Recent clinical studies indicate that estrogen receptor β2 (ERβ2) and β5 (ERβ5) expression in TNBC correlates to worse prognosis. We have expressed ERβ2 and ERβ5 in the triple negative cell line SUM159. Estrogen receptors β2 and β5 are highly similar to estrogen receptor β1, except for a truncated C-terminus making the remaining ligand -binding domain incapable of binding to estrogen. In addition, at the C-terminus, ER β2 and β5 have a unique peptide each of 27 and 4 amino acids in length respectively. Stably expressing ERβ2 and ERβ5 using a transposon integrated, tetracycline- regulated expression system increases expression of the drug resistance gene, ABCG2 in the triple negative SUM159 cells. Furthermore, we also find that the cells become more resistant to treatments with paclitaxel. We find that ERβ2 and ERβ5 interact with HIF-1α and HIF-2α and are recruited to HIF response elements (HRE's) in chromatin. In agreement with this, we find that ERβ2 and ERβ5 are recruited to the ABCG2 promoter, which contains HRE's and is known to be a target of HIF signaling. We propose that ERβ2 and ERβ5 play a role in chemo - resistance of TNBC and that targeting these factors may reduce chemo resistance thus preventing tumor-relapses and their associated mortalities.

Citation Format: Faria M, Gustafsson J-A, Strom A. Estrogen receptor β2 and β5 increase expression of ABCG2 and drug resistance of the triple- negative breast cancer cell line SUM159 [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 P6-01-10.
Abstract P6-02-08: Modulation of indoleamine 2, 3-dioxygenase (IDO1) expression in breast cancer cells by activated CD8+ T cells is controlled by DNA promoter methylation
Authors: Gu F , Noonepalle SK , Lee E-J , Choi J-H , Shull AY , Pei L , Sreekumar A , Ambs S , Shi H
Published: March 2017

Tumor infiltrating lymphocytes (TILs) play a critical role in regulating the immunomodulatory properties of triple negative breast cancer (TNBC). However, the specific adaptations that TNBC tumors undergo when challenged by lymphocyte infiltration remain unclear. In order to address this gap in knowledge, we conducted an immuno-phenotype comparison using mRNA sequencing between the TNBC cell line MDA-MB-231 and the luminal breast cancer cell line MCF7 after both were co-cultured with activated human T-cells. Although the cytokine-induced immune signature of the two cell lines were similar, MDA-MD-231 cells were able to transcribe the tryptophan catabolizing enzyme IDO1 at a significantly higher level than MCF7 cells. Stimulation with IFNg was able to differentially induce IDO protein expression and enzymatic activity in ER- cell lines compared to ER+ cell lines, though no differences were observed in upstream JAK/STAT1 signaling or IDO1 mRNA stability between the two cell lines. Further experiments showed that treatment with the demethylating agent 5-aza-deoxycytidine was able to reverse suppression of IDO1 expression in MCF7 cells, suggesting that DNA methylation serves as a potential determinant in IDO1 induction. Analysis of TCGA and other previously published breast cancer datasets revealed subtype-specific mRNA and promoter methylation differences in IDO1, with TNBC/basal-like subtypes exhibiting lower promoter methylation and higher mRNA expression than ER+/luminal subtypes. Bisulfite pyrosequencing validated the subtype-specific association of decreased promoter methylation with increased IDO1 expression in breast cancer cell lines and an independent cohort of primary breast tumors. In addition, decreased IDO1 promoter methylation and elevated IDO1 expression in basal-like breast tumors was found to be associated with increased levels of kynurenine, the metabolic product of IDO1, as well as higher numbers of CD8+ TILs. Furthermore, high kynurenine levels in breast tumors were associated with worse patient survival. Taken together, these findings suggest that subtype-specific IDO1 promoter methylation regulates the ability of breast tumors to escape from antitumor immune responses driven by CD8+ TILs and could be used as a predictive biomarker for IDO inhibitor-based immunotherapy.

Citation Format: Gu F, Noonepalle SK, Lee E-J, Choi J-H, Shull AY, Pei L, Sreekumar A, Ambs S, Shi H. Modulation of indoleamine 2, 3-dioxygenase (IDO1) expression in breast cancer cells by activated CD8+ T cells is controlled by DNA promoter methylation [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 P6-02-08.
Abstract P6-02-09: Hyperglycaemia and fibronectin: The criminal partnership during breast cancer progression
Authors: Zielinska HA , Bahl A , Holly JMP , Perks CM
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P6-03-03: Tropomyosin-related kinase A is overexpressed in HER2-positive breast cancers
Authors: Faulkner S , Roselli S , Oldmeadow C , Attia J , Forbes JF , Walker MM , Hondermarck H
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P6-07-07: ESR1 amplification and 5'-3' exon imbalance in metastatic breast cancer
Authors: Oesterreich S , Basudan A , Preideigkeit N , Hartmaier RJ , Bahreini A , Gyanchandani R , Leone JP , Lucas PC , Hamilton RL , Brufsky AM , Lee AV
Published: March 2017

BACKGROUND: Growing evidence indicates that base pair mutations in ESR1 are relatively uncommon in newly diagnosed, treatment-naive breast cancer, but frequently acquired in hormone-resistant metastatic breast cancer (MBC). We and others have recently identified ESR1 gene fusion and amplification in MBC, with the ESR1 fusions generally encompassing AF1 and the DNA binding domain. The genomic break required for gene fusions often results in an imbalance in the DNA copy number of exons around the break. We examined ESR1 amplification and 5' and 3' exon copy number imbalance in MBC.

MATERIALS and METHODS: We designed NanoString DNA hybridization probes against coding and non-coding exons (n=9) in ESR1 and 15 reference probes. We analyzed 128 samples consisting of 61 ER-positive and 44 ER-negative metastases, and 23 primary breast cancers. DNA copy number (CN) was determined using nSolver, with >2.7CN as copy number gain, and >10 as CN amplification. ESR1 CN was calculated by averaging the DNA copy number obtained from all coding exons. The 5'-3' copy number ratio was the average copy number of the 5' exons (3-6) divided by the 3' exons (7-10).

RESULTS: 8 (13%) ER positive metastatic breast cancers showed ESR1 amplification with 5 (8%) having >2.7CN, and 3 (5%) with >10CN. In contrast, in ER-negative metastases, we did not detect any samples with amplification >10CN, and a gain (>2.7 CN) in one case. Similarly, in ER+ primary cancers we did not detect any samples with >10 CN amplifications and 2 samples with CN gain (>2.7 CN). ESR1 showed 5'-3' CN imbalance in 1 primary (5%) and in 5 metastatic (5%) breast cancers. We are currently confirming and expanding these data in a larger dataset.

CONCLUSIONS: In addition to ESR1 mutations, ESR1 CN amplifications and 5'-3' imbalance are represent frequent occurrences in endocrine resistant breast cancer. Future studies are aimed at understanding whether the observed exon imbalances are associated with generation of fusion proteins, and whether and how ESR1 amplifications cause changes in endocrine treatment response.

Citation Format: Oesterreich S, Basudan A, Preideigkeit N, Hartmaier RJ, Bahreini A, Gyanchandani R, Leone JP, Lucas PC, Hamilton RL, Brufsky AM, Lee AV. ESR1 amplification and 5'-3' exon imbalance in metastatic 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 P6-07-07.
Abstract P6-09-46: A comprehensive analysis of GNAS DNA copy number, levels of mRNA and protein expression in primary breast cancer
Authors: Tomiguchi M , Yamamoto Y , Yamamoto-Ibusuki M , Goto-Yamaguchi L , Fujiki Y , Sueta A , Takeshita T , Iwase H
Published: March 2017

Background: Result of recent advances in genetics, guanine nucleotide binding protein, alpha stimulating (GNAS), transducer of signals from G-protein coupled receptors, has been noted that this factor is related with the onset and progression of tumor in various cancers. We aimed to analyze gene amplification, mRNA and protein expression of GNAS and their potential association with clinicopathological factors and prognosis in primary breast cancer.

Methods: The cohort of this study included 432 primary invasive breast cancer patients treated with standard care at Kumamoto University Hospital between June 2000 and January 2011. We performed a comprehensive analysis of GNAS at the levels of gene copy number, mRNA and GNAS protein expression analyzed by qPCR, qRT-PCR and immunohistochemistry (IHC), respectively. In the IHC assessment of GNAS protein expression, an H-score<150 was observed in 191 patients (44.2%), who were defined as having a low protein expression level, and an H-score≥150 was observed in 241 patients (55.8%) who were defined as having a high protein expression level.

Results: The median age at diagnosis was 60 (range 27-93). Three hundred fifteen (72.9%) of these were postmenopausal women. One hundred forty two patients (32.9%) had axillary lymph node metastasis. The median Ki67 labeling index was 23.6 (range 0.5-97.0). The subtypes were 321 ER+/HER2-, 24 ER+/HER2+, 34 ER-/HER2+ and 53 ER-/HER2-. Three hundred twenty one patients (75.9%) were treated with endocrine therapy and 146 patients (34.6%) chemotherapy. Most notably, a low levels of GNAS protein expression was observed in 191(44.2%) patients, and was positivity associated with Ki67 (P=0.028). Furthermore, univariate and multivariate analysis revealed that low GNAS protein expression was significantly related with poor relapse-free survival rate (Log-rank test; P=0.0013, OR:0.40, 05%CI:0.22-0.70) and breast cancer specific survival rate (Log-rank-test; P=0.041, OR:0.43, 95%CI:0.19-0.97). GNAS amplification and mRNA expression were not correlated with prognoses.

Conclusion: Contrary to expectations, GNAS expression was positively related with favorable tumor characteristics. Expression levels of GNAS protein may be an independent prognostic factor for primary breast cancer.

Citation Format: Tomiguchi M, Yamamoto Y, Yamamoto-Ibusuki M, Goto-Yamaguchi L, Fujiki Y, Sueta A, Takeshita T, Iwase H. A comprehensive analysis of GNAS DNA copy number, levels of mRNA and protein expression in primary 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 P6-09-46.
Abstract P6-09-49: Three-gene signature predictive of high residual risk of recurrence after adjuvant chemotherapy in ER-positive HER2-negative breast cancer
Authors: Györffy B , Ocana A , Herman P , Hatzis C , Pandiella A , Pusztai L
Published: March 2017

Background: A proportion of ER-positive, HER2-negative patients treated with both adjuvant endocrine and chemotherapy continue to remain high risk for recurrence. These individuals are the ideal patient population for future adjuvant trials.

Methods: We used gene expression data from ER+/HER2- patients who received adjuvant endocrine and chemotherapy. We utilized a training cohort of multiple gene expression datasets (N=131; GSE16391, GSE21653, GSE17907, GSE19615, GSE16716, GSE45255) and a validation cohort (N=277; GSE25066) from similarly treated ER+ patients. All data sets were generated with Affymetrix HGU133 arrays. Cox proportional hazards regression was performed across all genes using all possible cutoff values between the lower and upper quartile. Genes were ranked according to the estimated hazard rates for relapse. The top three genes were combined into a final signature that used the mean expression of these genes as the predictive score. Statistical analyses were performed in the R environment.

Results: The final signature capable to predict survival consisted of three genes, MX1, MBD4, and ZWINT. Each of these genes achieved high significance in a univariate analysis: MX1 HR=5.7 (p=1.8E-04) and HR=4.7 (p=1.3E-03), MBD4 HR=3.4 (p=2.8E-04) and HR=4.3 (p=4.4E-04), and ZWINT HR=4.4 (p=1E-03) and HR=3.7 (p=8.5E-03) in the training and validation cohorts, respectively. Using the mean expression of the three genes, the estimated hazard rates for survival were 20.5 (p=2.5E-05) and 17.5 (p=1E-04) in the two cohorts, respectively. Only one patient relapsed in each cohort. In a multivariate analysis including grade and lymph node status as covariates (size was not available), the three-gene signature retained significance (HR=13.2, p=0.011; and HR=13.9, p=0.01 in the two cohorts, respectively), while only lymph node status (HR=3.6, p=0.007) was significant in the validation cohort and no clinical variable was significant in the training cohort.

Conclusions: High expression of a 3-gene signature can identify ER+ patients who remain at very high risk for recurrence despite current adjuvant endocrine and chemotherapy.

Citation Format: Györffy B, Ocana A, Herman P, Hatzis C, Pandiella A, Pusztai L. Three-gene signature predictive of high residual risk of recurrence after adjuvant chemotherapy in ER-positive HER2-negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-49.
Abstract P6-09-51: The REQUITE-AB study: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in breast cancer patients
Authors: Rattay T , Johnson K , Azria D , Chang-Claude J , Davidson S , Dunning A , de Ruyscher D , Guiterrez-Enriquez S , Lambin P , Rancati T , Rosenstein B , Seibold P , Symonds RP , Thierens H , Valdagni R , Vega A , Webb A , Wenz F , West C , Talbot C
Published: March 2017

Clinically significant side-effects from radiotherapy affect around a quarter of breast cancer patients and may impact considerably on outcomes from treatment. An increasing number of replicated genetic associations for radiotherapy toxicity are being reported[1],[2]. The international REQUITE consortium aims to validate genetic markers and clinical factors implicated in radiotoxicity. The purpose of the REQUITE-AB project is to develop an integrated set of predictors for acute radiotherapy side-effects in breast cancer patients to be used as a clinical decision-making tool.

As part of the REQUITE prospective cohort study, 2,000 patients eligible for adjuvant breast radiotherapy will be recruited in nine centres across Europe and North America between April 2014 and August 2016, with centralised data management, biobanking and two years' follow-up using a standardised data collection protocol. Patient characteristics and treatment details being captured also include dose-volume histograms and DICOM files. Genotyping will take place in fall 2016. Primary endpoints are acute skin toxicity (CTC-AE v4.0) and quality-of-life (QoL) on completion of radiotherapy and at 3 months from start of radiotherapy. Secondary endpoints are late side-effects including change in breast appearance.

1,766 breast cancer patients have been recruited to date with standardized documentation of toxicity and QoL. Among patients who completed radiotherapy so far, 21.6% of patients developed grade 2 skin toxicity (brisk erythema) and 1.3% grade 3 (moist desquamation). The ability of patient, treatment and genetic variables to predict clinical outcomes and QoL will be examined.

The REQUITE study includes the largest radiogenomics cohort of breast cancer patients to date recruited under a single standardised protocol. Findings of the REQUITE-AB project are likely to inform the development of interventional biomarker trials and personalise breast cancer care in the future.

[1] Talbot et al, Br J Cancer, 2012; 107: 748-53.

[2] Seibold et al, Int J Radiat Oncol Biol Phys, 2015; 92: 1084-92.

Citation Format: Rattay T, Johnson K, Azria D, Chang-Claude J, Davidson S, Dunning A, de Ruyscher D, Guiterrez-Enriquez S, Lambin P, Rancati T, Rosenstein B, Seibold P, Symonds RP, Thierens H, Valdagni R, Vega A, Webb A, Wenz F, West C, Talbot C. The REQUITE-AB study: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in breast cancer patients [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 P6-09-51.
Abstract P6-09-52: Prognostic factors in breast cancer (BC) associated with the development of brain metastases (BM): A retrospective study of 726 pts
Authors: Santa Cruz O , Tsoutsou P , Anchisi S , Khanfir K , Negretti L , Girardet C , Ozsoy O , Ozsahin M
Published: March 2017

This abstract was not presented at the symposium.
Abstract P6-09-54: Long-term recurrence risk and risk-based follow-up after breast cancer treatment
Authors: Siesling S , Witteveen A , de Munck L , Groothuis-Oudshoorn K , Sonke G , Klaase J , Boersma L , Poortmans P , IJzerman M
Published: March 2017

This abstract was not presented at the symposium.
Abstract P6-11-16: PYTHIA: A phase II study of palbociclib plus fulvestrant versus placebo plus fulvestrant for pretreated patients with ER+/HER2- metastatic breast cancer
Authors: Zardavas D , Regan M , Maibach R , Ruepp B , Hiltbrunner A , Blacher L , Goulioti T , Gelber R , Flamen P , Piccart M , Malorni L
Published: March 2017

This abstract was not presented at the symposium.
Abstract P6-17-01: Adjuvant treatment with zoledronic acid (ZOL) in stage II/III breast cancer. The AZURE trial (BIG 01/04) 10 year follow-up
Authors: Coleman R , Collinson M , Bell R , Marshall H , Dodwell D , Keane M , Gil M , Gregory W , Cameron D
Published: March 2017

This abstract was not presented at the symposium.
Abstract PD8-03: Differences in the mutational landscape in African Americans and Caucasians with triple negative breast cancer
Authors: Ademuyiwa FO , Tao Y , Luo J
Published: March 2017

Background-Triple negative breast cancer (TNBC) occurs at a higher frequency in African American (AA) premenopausal women compared with Caucasians. It is unclear if the biology and clinical outcome of TNBC is different in AA versus Caucasians. In this study, we sought to evaluate differences in the molecular pathology of TNBC in a large cohort of AA and Caucasians.

Methods-Using publicly available data from The Cancer Genome Atlas, we identified all patients with TNBC who had information on race. We analyzed the differences in clinical characteristics and tumor somatic mutations by race from whole exome sequencing using student's t test or one-way ANOVA for continuous variables and chi square or Fisher's test for categorical variables. Exome sequencing was performed with coverage of ≥70% and at a depth of 20x.

Results-A total of 1104 primary breast cancer patients were identified, of which 178 (16%) had TNBC. Overall, TNBC was more frequent in AA than in Caucasians (33.3% versus 14.9%; p value <0.001). More AA than Caucasians were classified as basal-like from PAM50 gene expression analysis (34.8% versus 16.1%; p value 0.001). No differences in the TNBC cohort were observed, 91% of AA were basal-like versus 81% of Caucasians (p value 0.842). Median tumor somatic mutation counts were higher in AA (39.5) versus Caucasians (34) (p value 0.022). However, no racial differences in the mutation counts in TNBC were observed (AA=56, Caucasians=60, p value 0.399). Somatic mutation analysis revealed racial differences in specific high prevalence (>5%) genes in all patients- [TP53 alterations: 46% in AA versus 27% in Caucasians; p value <0.001, PIK3CA alterations: 23% in AA versus 34% in Caucasians; p value 0.019, and MLL3 alterations: 12% in AA versus 6% in Caucasians; p value 0.028]. The TNBC patients did not have any specific high prevalence (>5%) genes associated with racial differences. AA with breast cancer had a shorter time to progression (TTP) (hazard ratio 1.62, p value 0.014) and worse disease free survival (DFS) than Caucasians. However, racial difference in TTP or DFS were not observed in the TNBC patients.

Conclusion-The mutational landscape of breast cancer may be different between AA and Caucasians, but appears to be similar in both races in the cohort with TNBC. Our findings have 2 implications: racial disparities in breast cancer may largely be due to differences in those with hormone receptor positive disease, and secondly, the higher frequency of TNBC in AA is unlikely due to differences in molecular features, but other modifiable factors.

Citation Format: Ademuyiwa FO, Tao Y, Luo J. Differences in the mutational landscape in African Americans and Caucasians with triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD8-03.
Abstract A27: Addiction to the NF-κB–triggered IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells
Authors: Tominaga Kana , Gotoh Noriko
Published: March 2017

An inflammatory microenvironment contributes to tumorigenesis. The pro-inflammatory transcription factor nuclear factor-kappa B (NF-kappa B) is known to play important roles, but how it regulates cancer stem cells (CSCs) remains largely unclear. We comprehensively analyzed which targets of NF-kappa B are activated by heregulin (HRG), a tumor sphere-forming ligand, in breast cancer cells. We identified many cytokines downstream of HRG-phosphatidyl inositol 3 kinase (PI3K)-NF-kappa B signaling. Insulin-like growth factor 2 (IGF2) was identified as a key downstream target; IGF2 treatment induced tumor spheres in most samples of patient-derived primary breast cancer cells, and anti-IGF2 antibody treatment greatly reduced HRG-induced tumor sphere formation, even though many other cytokines were simultaneously produced. The IGF2 receptor, IGF-1R, was specifically expressed at high levels in CSC-enriched populations in freshly obtained primary breast cancer cells. Moreover, IGF2-PI3K signaling induced expression of a stemness transcription factor, ID1, and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft (PDX) model. Thus, NF-kappa B may trigger IGF2-ID1-IGF2 positive feedback circuits and PI3K-mediated feed-forward circuits that allow cancer stem-like cells to appear; it may then stabilize the feedback circuits, to which the cancer stem-like cells become addicted. Because the stemness circuits may be the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.

Citation Format: Kana Tominaga, Noriko Gotoh. Addiction to the NF-κB–triggered IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A27.
The 4Ps of Breast Cancer Chemoprevention: Putting Proven Principles into Practice
Authors: Jordan V. Craig
Published: March 2017

The pioneering Royal Marsden Tamoxifen Prevention Trial recruited 2,471 eligible high-risk women to be randomized to either placebo or tamoxifen (20 mg daily) for 8 years. Breast cancer incidence was evaluated at a median of 18.4 years from the start of the study. There was a 32% reduction in estrogen/progesterone receptor (ER/PR)–positive breast cancers after tamoxifen treatment finished. Translational research, to study “the good, the bad, and the ugly of tamoxifen” in the 1980s, subsequently ensured women's safety from possible increases in osteoperosis, coronary heart disease, and endometrial cancer. Other tamoxifen chemoprevention trials followed. The result of laboratory research was the unanticipated discovery of raloxifene to prevent osteoporosis and breast cancer at the same time. A new group of medicines, now known as selective ER modulators, was established. Indeed, the ability to prevent or delay multiple diseases with a single cheap medicine has the potential to alleviate pressure on health care systems that are overwhelmed. It is a priority to educate physicians appropriately to apply recommended proven medicines as preventives. Cancer Prev Res; 10(4); 219–22. ©2017 AACR.

See related article by Detre, et al., Cancer Prev Res 2017;10(3):171–6.
Abstract IA12: Combating antigen escape with CD19/CD20 bispecific CAR-T cell therapy
Authors: Zah Eugenia , Lin Meng-Yin , Jensen Michael C. , Silva-Benedict Anne , Chen Yvonne Y.
Published: March 2017

T cells expressing chimeric antigen receptors (CARs) specific for the B-cell marker CD19 have shown impressive results in the treatment of B-cell malignancies. However, multiple clinical trials have also demonstrated the vulnerability of single-input CD19 CAR-T cell therapy to antigen escape, in which patients relapse with the emergence of CD19 tumor cells. Here, we report on the rational design and systematic optimization of bispecific CAR-T cells that trigger robust cytotoxicity against target cells expressing either CD19 or CD20. We demonstrate that optimized bi-specific CARs can rapidly eliminate large, engrafted tumors in vivo. We further demonstrate the bi-specific CAR-T cells ability to prevent tumor escape while single-input CD19 CAR-T cells succumb to the selective expansion of CD19 mutant cells, which are shown to arise spontaneously in engrafted mice. The CD19-OR-CD20 CAR is fully compatible with existing T-cell manufacturing procedures and implementable by current clinical protocols. These results present an effective solution to the challenge of antigen escape in CD19 CAR T-cell therapy, and they highlight the utility of structure-based rational design in the development of receptors with higher-level complexity.

Citation Format: Eugenia Zah, Meng-Yin Lin, Michael C. Jensen, Anne Silva-Benedict, Yvonne Y. Chen. Combating antigen escape with CD19/CD20 bispecific CAR-T cell therapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr IA12.
Abstract PR06: A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models
Authors: Everett Katy , Kraman Matthew , Kmiecik Katarzyna , Allen Natalie , Faroudi Mustapha , Zimarino Carlo , Wydro Mateusz , Doody Jacqueline
Published: March 2017

Combining immunotherapeutic antibodies for treatment of cancer patients has shown benefits over single agent treatment. For example, the addition of anti-PD-1 antibodies to anti-CTLA-4 treatment in advanced melanoma patients has increased objective response rates from 19% to 57.6% (Larkin,J et al. 2015. NEJM 373:23-34). An alternative to combining two antibodies is the development of bispecific antibodies that not only bring two biologies together but may result in novel mechanisms of action that are impossible to attain with combinations.

Lymphocyte Activation Gene-3 (LAG-3) is a member of the Ig superfamily expressed on activated T cells, NK cells, pDCs, B cells, γδ T cells and participates in immune suppression, particularly through persistent strong expression in a percentage of regulatory T cells (Tregs). Programmed Cell Death receptor (PD-1) binds to its ligand PD-L1, expressed not only on activated immune cells to inhibit cellular immune responses but also on tumour cells. Expression of LAG-3 and PD-1 leads to T cell exhaustion, allowing tumour escape from immune surveillance. Combining inhibitory antibodies to PD-1 and LAG-3 reactivates T cells leading to efficacy in murine models over single treatment (Woo,S-R et al. 2012. Cancer Res. 15: 917-27) which prompted interest in the development of a LAG-3 and PD-L1 bispecific antibody for inhibiting tumour growth.

A murine-specific anti-LAG-3 and PD-L1 mAb²TM (bispecific antibody) was engineered which binds both antigens simultaneously and with nanomolar affinities. The anti-LAG-3/PD-L1 mAb² inhibits LAG-3 binding to MHCII and PD-L1 binding to PD-1 and CD80, resulting in T cell activation in an in vitro assay. This potency translates into in vivo efficacy, where the anti-LAG-3/PD-L1 mAb² decreased tumour burden in the MC38 colon carcinoma tumour model, both in early-established or well-established tumours. At the end of the study tumour-free animals were more numerous in the LAG-3/PD-L1 bispecific group than in the group given a combination of individual anti-LAG-3 and PD-L1 antibodies. The results were recapitulated in the CT26 murine colon cancer model, where the LAG-3/PD-L1 mAb² showed an increase of anti-tumour activity as compared to the combination of anti-LAG-3 and anti-PD-L1 antibodies. Thus, the preclinical data supports developing an anti-human LAG-3/PD-L1 mAb² for the treatment of cancer patients.

This abstract is also being presented as Poster A27.

Citation Format: Katy Everett, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody. A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr PR06.
Disease-Associated Changes in Bile Acid Profiles and Links to Altered Gut Microbiota
Authors: Joyce Susan A. , Gahan Cormac G.M.
Published: March 2017

The gastrointestinal microbiota plays a central role in the host metabolism of bile acids through deconjugation and dehydroxylation reactions, which generate unconjugated free bile acids and secondary bile acids respectively. These microbially generated bile acids are particularly potent signalling molecules that interact with host bile acid receptors (including the farnesoid X receptor, vitamin D receptor and TGR5 receptor) to trigger cellular responses that play essential roles in host lipid metabolism, electrolyte transport and immune regulation. Perturbations of microbial populations in the gut can therefore profoundly alter bile acid profiles in the host to impact upon the digestive and signalling properties of bile acids in the human superorganism. A number of recent studies have clearly demonstrated the occurrence of microbial disturbances allied to alterations in host bile acid profiles that occur across a range of disease states. Intestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), short bowel syndrome and Clostridium difficile infection all exhibit concurrent alterations in the composition of the gut microbiota and changes to host bile acid profiles. Similarly, extraintestinal diseases and syndromes such as asthma and obesity may be linked to aberrant bile acid profiles in the host. Here, we focus upon recent studies that highlight the links between alterations to gut microbial communities and altered bile acid profiles across a range of diseases from asthma to IBD.
Intestinal Farnesoid X Receptor Signaling Modulates Metabolic Disease
Authors: Gonzalez Frank J. , Jiang Changtao , Xie Cen , Patterson Andrew D.
Published: March 2017

Farnesoid X receptor (FXR) regulates the synthesis, transport and enterohepatic circulation of bile acids (BA) by modulating the expression of related genes in the liver and small intestine. The composition of the gut microbiota is correlated with metabolic diseases, notably obesity and non-alcoholic fatty acid disease (NAFLD). Recent studies revealed that bacterial metabolism of BA can modulate FXR signaling in the intestine by altering the composition and concentrations of FXR agonist and antagonist. FXR agonist enhances while FXR antagonist suppresses obesity, NAFLD and insulin resistance. The role of intestinal FXR in metabolic disease was firmly established by the analysis of mice lacking FXR that are metabolic resistant to HFD-induced metabolic disease. This is mediated by FXR modulating in part the expression of genes involved in ceramide synthesis in the small intestine. In ileum of obese mice due to the presence of endogenous FXR agonists produced in the liver, these genes are activated, while in mice with altered levels of specific gut bacteria, levels of an FXR antagonist, tauro-β-muricholic acid (T-β-MCA) increase and FXR signaling and ceramide synthesis are repressed. T-β-MCA, which is metabolized in wild-type mice, led to the discovery of glycine-β-muricholic acid (Gly-MCA) that is stable in the intestine and a potent inhibitor of FXR signaling. These studies reveal that ceramides produced in the ileum under the control of FXR, influence metabolic disease, and suggest that novel FXR antagonist such as Gly-MCA that specifically inhibit intestine FXR, could serve as potential drug for the treatment of metabolic disease.
Farnesoid X Receptor an Emerging Target to Combat Obesity
Authors: De Magalhaes Filho C. Daniel , Downes Michael , Evans Ronald M.
Published: March 2017

Obesity and its associated diseases, including type 2 diabetes, have reached epidemic levels worldwide. However, available treatment options are limited and ineffective in managing the disease. There is therefore an urgent need for the development of new pharmacological solutions. The bile acid (BA) Farnesoid X receptor (FXR) has recently emerged as an attractive candidate. Initially described for their role in lipid and vitamin absorption from diet, BAs are hormones with powerful effects on whole body lipid and glucose metabolism. In this review, we focus on FXR and how 2 decades of work on this receptor, both in rodents and humans, have led to the development of drug agonists with potential use in humans for treatment of conditions ranging from obesity-associated diseases to BA dysregulation.
Impact of Fibroblast Growth Factors 19 and 21 in Bariatric Metabolism
Authors: Patton Ashley , Khan Farooq H. , Kohli Rohit
Published: March 2017

Background: Bariatric surgery is a popular and effective therapeutic intervention for obesity, which is an abnormal health condition that is prevalent worldwide. Metabolic improvements that precede weight loss after bariatric surgery may be mediated, in part, through the fibroblast growth factor (FGF) 15/19 and FGF21 signaling pathways. Both FGF15/19 and FGF21 are hormone-like members of the FGF family and exert their metabolic effects in an endocrine manner. Enhanced bile acid recycling after bariatric surgery leads to increased circulating levels of FGF15/19 in the distal small intestine. Synthesis of FGF21 is upregulated predominately in the fasting state through peroxisome proliferator-activated receptor pathways and to a lesser extent by FGF15/19. Key Messages: The biological functions of FGF15/19 and FGF21 are diverse and complicated. The tissue targeted effects of FGF15/19 and FGF21 of importance after bariatric surgery include the regulation of hepatic bile acid biosynthesis and ketogenesis as well as thermogenesis in adipose tissue, respectively. Furthermore, FGF15/19 and FGF21 function to regulate carbohydrate and lipid metabolism. Conclusion: The long-term effects of bariatric surgery on weight loss are undisputable. However, the mechanism for improvements in glucose and lipid homeostasis observed shortly after bariatric surgery is less understood. This review article attempts to describe the known metabolic effects of FGF15/19 and FGF21 that may potentiate these improvements after bariatric surgery.
Progress in the Molecular Characterization of Hepatobiliary Transporters
Authors: Keppler Dietrich
Published: March 2017

Over the last 25 years, our understanding of the driving forces for hepatobiliary elimination and knowledge of the molecular basis of uptake and efflux transport in hepatocytes have undergone fundamental changes. This refers to bile acids and many other endogenous substances as well as to drugs that are eliminated on the hepatobiliary route. In this development, not only molecular cloning, functional characterization, and localization of transporters were decisive, but also the discovery of hereditary mutations in genes encoding sinusoidal uptake transporters and canalicular export pumps in humans and rodents. Uptake by passive diffusion and elimination into bile driven by the electrochemical gradient are no longer considered relevant for hepatobiliary elimination in the intact organism. Furthermore, insights into the relative roles of uptake transporters and unidirectional ATP-driven efflux pumps were obtained when we established double-transfected polarized cell lines stably expressing, as an example, the hepatocellular uptake transporter OATP1B3 and the apical (canalicular) efflux pump multidrug resistance protein 2 (MRP2; ABCC2). ATP-dependent efflux transporters localized to the basolateral (sinusoidal) hepatocyte membrane, particularly MRP3 (ABCC3) and MRP4 (ABCC4), pump substances from hepatocytes into sinusoidal blood. Bile acids are substrates for human MRP4 in the presence of physiological concentrations of reduced glutathione, which undergoes co-transport. These efflux pumps have been recognized in recent years to play an important compensatory role in cholestasis and to contribute to the balance between uptake and efflux of bile acids and other organic anions during the vectorial transport from blood into bile. This sinusoidal efflux not only enables subsequent renal elimination but also facilitates the re-uptake of substances into neighboring hepatocytes located more centrally and downstream in the sinusoid.