Citations

Abstract Background: CTCs are associated with clinical outcomes in metastatic breast cancer irrespective of ER/PR/HER2 status. Some data support the prognostic relevance of serial CTC enumeration relative to adjuvant chemotherapy in early stage breast cancer. However, data from a large scale study focused on HER2 directed therapy for HER2+ disease have been lacking. We therefore sought to prospectively evaluate the effect of trastuzumab +/- lapatinib on CTCs and assess the prognostic/predictive value of CTC monitoring in HER2+ early stage breast cancer patients (pts). Methods: The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO; NCT00490139) Trial is an international, randomized, open-label phase III study of two targeted agents for HER2+ breast cancer. From June 2007 to July 2011, 8381 pts were randomised from 946 sites in 44 countries to 1 of 4 arms with sequential or concurrent chemotherapy: (i) 52 wks of trastuzumab (T); (ii) 52 wks of oral lapatinib (L); (iii) 12 or 18 wks of T followed by a washout and then 34 or 38 wks of L; or (iv) 52 wks of L+T. 540 (6%) pts provided optional informed consent and up to 30 mL peripheral blood suitable for CTC analyses at baseline with additional collections at 13 or 19 wks, 52 wks, 18 mos, 24 mos, and recurrence. CTC analyses are being conducted in three laboratories (Mayo Clinic Rochester, n=431; Institut Jules Bordet and University of Munich, n=109). 2-3 x 10 mL CellSave™ samples are pooled and processed at each time point for CTC enumeration and HER2 expression using the immunomagnetic/immunofluorescence assay (CellSearch™). A round-robin concordance project was done between Mayo Clinic Rochester and Institut Jules Bordet before embarking on the primary correlative work. Results: At baseline, 20% pts had detectable (i.e., ≥1) EpCAM+/CK+/DAPI+/CD45- CTCs, and 16% pts had detectable EpCAM+/CK+/DAPI+/CD45-/HER2+ CTCs. Correlative analyses with clinical outcome are ongoing with plans for completion by Fall 2014. Conclusions: CTCs were detected in 20% of pts with HER2+ early stage breast cancer. This is similar to the frequency of detection in mixed early stage breast cancer populations relative to ER/PR and HER2 status. Concordance of enumeration and HER2 assessments between the two experienced laboratories, and correlation between disease free survival and CTC findings (from serial samples collected at baseline, during the course of HER2 directed therapy, and at set intervals of follow-up) will be reported. Citation Format: Minetta C Liu, Brigitte Rack, Amylou C Dueck, David W Hillman, Michael B Campion, Monica M Reinholz, Kevin C Halling, Christos Sotiriou, Françoise Rothé, Marion Maetens, Ghizlane Rouas, Wolfgang Janni, Antonio C Wolff, Lyndsay N Harris, Julie R Gralow, Kathleen I Pritchard, Susan Ellard, Nguyet A Le-Lindqwister, Frances Boyle, Evandro De Azambuja, Martine J Piccart-Gebhart, Michail Ignatiadis, Edith A Perez. Circulating tumor cell (CTC) enumeration and HER2 assessment as predictors of breast cancer outcomes in the ALTTO (BIG 2-06, Alliance N063D) Trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-01.

Abstract Background: Further stratification of the 70-gene MammaPrintTM signature into ‘high’ and ‘ultra-high’ risk groups may help predict chemo-sensitivity. In I-SPY 2, patients were classified as MammaPrint High1 (MP1) or MammaPrint (ultra) High2 (MP2), with MP2 defined as MP_score <-0.154. MP1/MP2 classification was added to HR and HER2 to define the cancer subtypes used in the I-SPY 2 adaptive randomization engine. Neratinib (N), one of the experimental agents evaluated in I-SPY 2, graduated in the HR-HER2+ signature. All patients received at least standard chemotherapy (paclitaxel followed by doxorubicin/cyclophosphamide; T->AC). HER2- patients were randomized to receive N+T- >AC vs. T->AC. For HER2+ patients, neratinib was administered in place of trastuzumab (N+T->AC vs. H+T->AC). Here, we assess the performance of MP1/MP2 class as a specific biomarker of neratinib response. Methods: 115 patients in the neratinib arm and 76 concurrently randomized controls had Agilent 44K microarrays and pCR data available for analysis. We assess association between MP1/MP2 and response in the neratinib and control arms alone using Fisher’s exact test, and relative performance between arms (biomarker x treatment interaction, likelihood ratio p < 0.05) using a logistic model. This analysis is also performed adjusting for HR status as a covariate, and in receptor subsets. Our study is exploratory with no claims for generalizability of the data. Statistical calculations are descriptive (e.g. p-values are measures of distance with no inferential content). Our analyses do not adjust for multiplicities of other biomarkers in the trial but outside this study. Results: There are 133 MP1 patients (neratinib: 74, Control: 59) and 58 MP2 patients (neratinib: 41, Control: 17), 84% (49) of which are Her2-. The distribution of pCR rates among MP1/MP2 dichotomized groups are summarized in Table 1. Neratinib (n=115)Control (n=76)MP1 (n=74)MP2 (n=41)MP1 (n=59)MP2 (n=17)HER2- (n=105)0 / 1715 / 337 / 395 / 16HER2+ (n=86)22 / 574 / 85 / 200 / 1 MP2, one of the 10 eligible signatures, did not meet the graduation threshold; and MP1/MP2 did not show a significant biomarker x treatment interaction (OR in neratinib relative to control arm = 1.25). The MP1/MP2 x treatment interaction remains non-significant after adjustment for HR and HER2 status (p=0.54). In HER2- patients receiving neratinib, 45% (15/33) of MP2 patients achieved a pCR, compared to 0% (0/17) of MP1 patients. In the HER2- controls, there is a 31% pCR rate in MP2 (5/16) vs. 18% in MP1 (7/39) patients (OR=2.14). This difference in performance between treatment arms appears significant (p=0.041). 90% of HER2+ patients are MP1, thus MP1/MP2 status x treatment interaction within the HER2+ subtype cannot be evaluated. Conclusion: Within the I-SPY 2 population as a whole, MP1/MP2 stratification does not appear to be a specific biomarker of response to neratinib relative to the control arm. The number of HER2- patients is small and precludes any definitive conclusion, but these data motivate further investigation of the biological mechanisms distinguishing MP1 from MP2 to better understand chemotherapy and/or neratanib responsiveness. Citation Format: Christina Yau, Denise M Wolf, Ashish Sanil, Jo Chien, Anne Wallace, Judy Boughey, Doug Yee, Debu Tripathy, Angela DeMichele, Rita Nanda, Steven Chiu, Claudine Isaacs, Kathy Albain, Hank Kaplan, Stacey Moulder, Rebecca Viscusi, Donald Northfelt, Kirsten Edmiston, Anthony Elias, Toncred Styblo, Barbara Haley, Lamorna Brown-Swigart, Susan Flynn, Gillian L Hirst, Meredith Buxton, Nola Hylton, Melissa Paoloni, W Fraser Symmans, Laura Esserman, Don Berry, Minetta C Liu, John W Park, Laura van 't Veer. MammaPrint High1/High2 risk class as a biomarker of response to neratinib plus standard neoadjuvant therapy for breast cancer in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-29.

Abstract Background: We hypothesize that response to the pan-ERBB inhibitor, neratinib (N), may be predicted by pre-treatment HER2-EGFR signaling. In the I-SPY 2 TRIAL, N graduated in the HR-/HER2+ signature. All patients received at least standard chemotherapy. For HER2+ patients, N was administered in place of trastuzumab. We evaluated 18 HER family signaling proteins as biomarkers of N response using reverse phase protein microarray (RPMA) data from pre-treatment LCM purified tumor epithelium. Methods: 168 patients (N: 106, concurrent controls: 62) had RPMA and pCR data. 18 biomarkers relating to HER family signaling were evaluated: AKT S473, AKT T308, EGFR, EGFR Y1068, EGFR Y1148, EGFR Y1173, EGFR Y992, ERBB2, ERBB2 Y1248, ERBB3 total, ERBB3 Y1289, ERK1/2 T202/Y204, Heregulin, mTOR, mTOR S2448, PI3K p85 Y458/p55 Y199, PTEN S380, and SHC Y317. We assessed association between biomarker and response in the N and control arms alone (likelihood ratio test), and relative performance between arms (biomarker x treatment interaction) using a logistic model. Analysis was also performed adjusting for HR/HER2 status. In an exploratory analysis, we selected the marker with the greatest interaction (phosphorylated EGFR (Y1173)) to dichotomize patients optimally based on the data and assessed it in the context of the graduating signature by adding the EGFR Y1173-High patients to the HR-/HER2+ subtype and evaluating the treatment effect in this ‘biomarker-positive’ group. Our study is exploratory with no claims for generalizability of the data and does not account for multiplicities. Statistical calculations are descriptive (e.g. p-values are measures of distance with no inferential content). Results: 7 HER pathway markers (EGFR Y1068, EGFR Y1173, EGFR Y992, ERBB2 total, ERBB2 Y1248, ERBB3 Y1289, SHC Y317) are associated with response in the N but not the control arm. However, the difference in performance between arms did not reach significance by permutation testing. Adjusting for HR/HER2 status, EGFR Y1173 shows a significant biomarker x treatment interaction (p = 0.049). In an exploratory analysis, we dichotomized patients by their EGFR Y1173 levels and evaluated the distribution of pCR rates (Table 1). Neratinib (n=106)Control (n=62)EGFR Y1173 Low (n=31)EGFR Y1173 High (n=75)EGFR Y1173 Low (n=29)EGFR Y1173 High (n=33)HR-/HER2+ (n=28)0 / 412 / 181 / 11 / 5Not HR-/HER2+ (n=140)3 / 2724 / 575 / 285 / 28Table 1 OR between EGFR Y1173 groups in the N relative to control arm is 10.1. When EGFR Y1173 High patients are added to the graduating HR-/HER2+ subset, the OR associated with treatment is 3.2 and is comparable to that in the HR-/HER2+ signature (OR: 2.1), while increasing the prevalence of biomarker-positive patients by ∼50%. Evaluation of EGFR Y1173 under the I-SPY 2 Bayesian model is pending. Conclusion: Our sample size is too small to draw definitive conclusions. Our exploratory analysis reveals that HER family phosphoproteins associate with response to N, but only phosphorylated EGFR Y1173 appears to add value to the graduating signature. Given that this biomarker would expand the patient population that may benefit, it merits evaluation in other ongoing trials of neratinib. Citation Format: Julia D Wulfkuhle, Christina Yau, Denise M Wolf, Rosa I Gallagher, Ashish Sanil, Lamorna Brown-Swigart, Susan Flynn, Gillian Hirst, I-SPY 2 TRIAL Investigators, Meredith Buxton, Angela DeMichele, Nola Hylton, William F Symmans, Laura van't Veer, Douglas Yee, Melissa Paoloni, Laura Esserman, Donald Berry, Minetta C Liu, John W Park, Emanuel F Petricoin III. Evaluation of HER family protein signaling network as a predictive biomarker for pCR for breast cancer patients treated with neratinib in the I-SPY 2 trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-15.

Abstract Background First identified as an estrogen-inducible gene in a breast cancer cell line, LIV-1 is a multispan transmembrane protein of the solute-carrier family 39 with putative zinc transporter and metalloproteinase activity. As a downstream target of STAT3, it promotes the epithelial-to-mesenchymal transition that is important in the malignant progression to metastasis. LIV-1 is expressed in a number of cancers with the highest prevalence and level of expression in breast, prostate, and melanoma. Additionally, LIV-1 has been linked with malignant progression to metastasis and associated with lymph node involvement in breast cancer. Normal tissue expression is predominantly limited to hormonally regulated tissues, including breast and prostate. In metastatic breast cancer tissue samples, the current validated immunohistochemistry assay for LIV-1 has detected moderate to high expression in 82% of samples tested, with 88% positivity in hormone receptor-positive tumors and 73% in triple-negative tumors. SGN-LIV1A is an antibody-drug conjugate (ADC) composed of a humanized anti-LIV-1 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. In vitro, SGN-LIV1A shows target-specific internalization and cytotoxic activity against LIV-1-positive neoplastic cell lines. Significant dose-dependent tumor regression was demonstrated in mouse xenograft models. Methods The primary objective of this first-in-human phase 1, open label, multicenter study is to evaluate the safety and tolerability, and to identify the maximum tolerated dose of SGN-LIV1A using a 3+3 dose-escalation study design. Pharmacokinetics, immunogenicity, and antitumor activity will also be evaluated (ClinicalTrials.gov #NCT01969643). Enrollment to this US-based trial began in late 2013. Eligible patients are adult females who have hormone receptor-positive/HER2-negative or triple-negative metastatic breast cancer. Tumor tissue must be positive for expression of LIV-1 per central assessment. Patients must have received at least 2 prior cytotoxic regimens in the metastatic setting and have measurable disease per RECIST v1.1. Pre-existing neuropathy ≥ Grade 2 is not permitted. SGN-LIV1A is administered intravenously every 3 weeks at protocol-defined doses starting at 0.5 mg/kg. Patients who achieve an objective response or stable disease per RECIST v1.1 are eligible to continue treatment until disease progression. At the completion of dose escalation, expansion cohorts may be opened to enroll patients with specific breast cancer subtypes to further define safety and antitumor activity. Tumor biopsies are being obtained at baseline and after one cycle of treatment to evaluate the role of LIV-1 expression, target saturation, and other tumor-specific measurements in the antitumor activity of SGN-LIV1A. Citation Format: Andres Forero, Howard Burris III, Patricia LoRusso, Jennifer Specht, Kathy Miller, Monica Mita, Minetta C Liu, Shanu Modi, Lajos Pusztai, Django Sussman, Ana Kostic. SGN-LIV1A: A phase 1 trial evaluating a novel antibody-drug conjugate in patients with LIV-1-positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-3-01.

Abstract Background: I-SPY 2 is a multicenter, phase II neoadjuvant trial in women with high-risk stage II/III breast cancer using adaptive randomization within biomarker subtypes to evaluate novel agents added to standard chemotherapy. Primary endpoint is pathologic complete response (pCR). Goal is to identify regimens that meet a high Bayesian predictive probability of statistical significance in a neoadjuvant 300-patient phase III trial defined by hormone-receptor (HR), HER2 status, and MammaPrint (MP). Experimental regimens may “graduate” in 1 of 10 signatures, with a maximum of 120 patients. We report efficacy results for neratinib (N). Methods: Tumors ≥2.5cm by clinical exam & ≥2cm by imaging are eligible for screening. MP low risk/HR+/HER2- tumors are ineligible for randomization. Patients receive chemotherapy (paclitaxel qwk x 12, doxorubicin and cyclophosphamide q2-3 wk x 4, T->AC). HER2- pts were randomized to N+T->AC vs. T->AC and HER2+ pts to N+T->AC vs. trastuzumab+T->AC. Analysis is intent-to-treat with pts who switch to non-protocol therapy regarded as non-pCRs. We provide estimated pCR rates (95% Bayesian probability intervals), probabilities of superiority of neratinib over control, and Bayesian predictive probabilities of success in an equally randomized phase III trial. Results: Neratinib met the predictive probability criterion in HR-/HER2+, “graduated”, and accrual ceased [115 N patients (65 HER2+), 78 concurrently randomized controls (22 HER2+)]. The table shows results for all 10 signatures. Two patients (1 N and 1 control) withdrew consent and are not included. Conclusion: I-SPY 2's standing trial mechanism efficiently evaluates agents in biomarker-defined patient subsets. In a modest number of patients, adaptive randomization successfully identified a biomarker signature (HR-/HER2+) for neratinib's further development. All HER2+ and MP+ tumors may also benefit from this regimen, consistent with preclinical data. Evaluation in I-SPY 3, a phase III registration trial, is planned. SignatureEstimated pCR Rate (95% probability interval)Probability NeratinibIs Superior to ControlPredictive Probability of Success in Phase IIINeratinibControlALL32% (28-36%)23% (19%-28%)92%44%HR+23% (18%-28%)17% (11%-22%)81%40%HR-43% (37%-49%)31% (24%-38%)89%53%HER2+39% (33%-45%)23% (15%-30%)95%73%HER2-26% (21%-32%)24% (18%-29%)63%20%MP+*45% (38%-53%)29% (20%-39%)91%66%HR-/HER2-36% (29%-43%)30% (23%-38%)72%34%HR-/HER2+55% (46%-64%)32% (22%-43%)94%78%HR+/HER2+31% (24%-37%)17% (10%-24%)91%65%HR+/HER2-14% (8%-19%)16% (10%-21%)39%12%* MammaPrint 44K Array Low/High score was adjusted to MammaPrint High1 (MP-) or High2 (MP+), using a pre-defined median cut-point of I-SPY 1 participants, who fit the eligibility criteria of I-SPY 2. Citation Format: John W. Park, Minetta C. Liu, Douglas Yee, Angela DeMichele, Laura van 't Veer, Nola Hylton, Fraser Symmans, Meredith B. Buxton, A. Jo Chien, Amy Wallace, Michelle Melisko, Richard Schwab, Judy Boughey, Debashish Tripathy, Hank Kaplan, Rita Nanda, Stephen Chui, Kathy S. Albain, Stacy Moulder, Anthony Elias, Julie E. Lang, Kirsten Edminston, Donald Northfelt, David Euhus, Qamar Khan, Julia Lyandres, Sarah E. Davis, Christina Yau, Ashish Sanil, Laura J. Esserman, Donald A. Berry. Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT227. doi:10.1158/1538-7445.AM2014-CT227

Abstract Dysregulation of the intrinsic DNA methylation landscape is a ubiquitous feature of human carcinogenesis, manifested by global hypomethylation and promoter-specific hypermethylation, ultimately resulting in genome instability and tumor suppressor gene silencing, respectively. Alterations in DNA methylation are particularly apparent in hepatocellular carcinoma (HCC) which afflicts roughly 750,000 new patients each year [1]. Indeed, it has been demonstrated that a variety of tumor suppressor genes (e.g. p53, E-cadherin) are hypermethylated and silenced in HCC [2-4]. Importantly, HCC is accompanied by the premalignant stage of cirrhosis in 80% of cases. One major roadblock to understanding the methylome in HCC is the presence of multiple etiologies such as Hepatitis C virus (HCV), Hepatitis B virus (HBV), and chronic alcoholism. Therefore, we performed genome-wide methylation profiling to dissect the methylation patterns of more than 170 primary liver samples to stratify etiologic and stage-specific changes in the DNA methylation landscape. Our results profile the DNA methylation landscape across normal, cirrhotic, and HCC livers in the largest study of its kind to date. We unveil distinct locus-specific and large-scale effects of HCV, HBV, and chronic alcoholism in hepatocarcinogenesis. Furthermore, analysis indicates a specific methylation profile for individual etiologies as well as conserved patterns throughout cirrhosis and hepatocellular carcinoma. Our study demonstrates that each etiology contains potential biomarkers and targets for downstream clinical therapeutics. This study is our first step toward defining the epigenome in cirrhosis and hepatocellular carcinoma and will be combined with future genomic and epimutational data (e.g. transcription, histone modifications, miRNA) to determine the true extent and interplay between epigenetic marks across different stages of liver cancer. Overall, this research has the potential to improve our understanding of epigenetics and result in diagnostic, prognostic, and therapeutic epigenetic signatures in cirrhosis and hepatocellular carcinoma, which are expected to allow for more timely and efficient detection of disease. 1. Jemal, A., et al., Global cancer statistics. CA: a cancer journal for clinicians, 2011. 61(2): p. 69-90. 2. Tischoff, I. and A. Tannapfe, DNA methylation in hepatocellular carcinoma. World journal of gastroenterology : WJG, 2008. 14(11): p. 1741-8. 3. Calvisi, D.F., et al., Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. The Journal of clinical investigation, 2007. 117(9): p. 2713-22. 4. Lambert, M.P., et al., Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake. Journal of hepatology, 2011. 54(4): p. 705-15. Citation Format: Ryan A. Hlady, Rochelle Tiedemann, William Puszyk, Chen Liu, Jeong-Hyeon Choi, Keith D. Robertson. Identification of common and unique epigenetic signatures of chronic hepatitis infection and alcohol abuse in human liver disease. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2309. doi:10.1158/1538-7445.AM2014-2309

Abstract Introduction: Liver microenvironment is a critical determinant for development and progression of liver metastasis. Under TGF-β stimulation, hepatic stellate cells (HSCs), which are liver specific pericytes, transdifferentiate into myofibroblasts that promote tumor implantation and growth in the liver. The regulation of this HSC activation process in the liver however remains poorly understood. In this study, we tested a hypothesis that actin binding protein vasodilator-stimulated phosphoprotein (VASP), previously implicated in focal adhesion and migration of HSCs, may regulate the TGF-β mediated HSC activation process by interacting with and regulating TGF-β receptors. Methods: VASP shRNA and siRNA were used to knockdown VASP in primary human HSCs and LX2, an immortalized HSC cell line. TGF-β activation of HSCs was quantitated by immunofluorescence staining (IF) for alpha-smooth muscle actin (α-SMA) and Western blot analysis (WB) for α-SMA, fibronectin and P-SMAD2. Total TGF-β receptor levels were determined by WB, and plasma membrane TβRII was quantitated by biotinylation of cell surface proteins approach. Protein subcellular localization was investigated by IF and protein interactions were determined by double IF and co-immunoprecipitation (IP). Regulation of stellate cell VASP by HSC/tumor interactions was investigated by IF on human colorectal liver metastases and the role of stellate cell VASP in tumor growth was studied in a tumor/HSC coimplantation mouse model. Results: TGF-β1 induced more than 60% of human primary HSCs into myofibroblasts as determined by α-SMA IF. Two different VASP shRNAs significantly reduced this effect of TGF-β1 on HSC activation (P<0.05). The effect of VASP knockdown on HSC activation was confirmed in LX2 cells as well as using a VASP siRNA approach. VASP knockdown increased total TGF receptor protein levels with no effects on SMAD2 and 3 protein levels. VASP interacted with TβRII as evidenced by double IF and co-IP. Biotin-labeling of cell surface proteins and IF revealed that VASP knockdown reduced TβRII protein level at the plasma membrane and that VASP overexpression increased TβRII at the plasma membrane. Concurrently, VASP knockdown reduced plasma membrane localization of Rab11a, a small GTPase that marks recycling endosomes and is essential for recycling of plasma membrane receptors. VASP/Rab11 interactions were confirmed by IF and co-IP. Furthermore, we found that VASP knockdown HSCs significantly reduced tumor growth in mice as compared to control HSCs in a HSC/tumor coimplantation model. In patients, metastasis of colorectal cancer cells in liver sinusoids induced upregulation of VASP and α-SMA in adjacent HSCs as revealed by IF on biopsies of human colorectal liver metastases. Conclusions: Our studies demonstrate a requirement of VASP in the TGF-β dependent HSC activation in the tumor microenvironment and ensuing tumor growth. VASP interacts with Rab11 and regulates Rab11 positive recycling endosomal function thereby promoting TβRII recycling back to the plasma membrane in HSCs. VASP in the tumor microenvironment thus presents a therapeutic target for reducing tumor implantation and metastatic growth in the liver. Citation Format: Kangsheng Tu, Jiachu Li, Chunsheng Liu, Vijay H. Shah, Ningling Kang. Vasodilator-stimulated phosphoprotein promotes TGF-beta mediated myofibroblastic activation by regulating recycling of TGF-beta receptor II to the plasma membrane. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A70. doi:10.1158/1538-7445.CHTME14-A70

BACKGROUNDPostmenopausal women with breast cancer receiving aromatase inhibitors are at an increased risk of bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report described the 5‐year follow‐up results.METHODSA total of 551 postmenopausal women with breast cancer who completed tamoxifen treatment and were undergoing daily letrozole treatment were randomized to either upfront (274 patients) or delayed (277 patients) ZA at a dose of 4 mg intravenously every 6 months. In the patients on the delayed treatment arm, ZA was initiated for a postbaseline bone mineral density T‐score of <‐2.0 or fracture.RESULTSThe incidence of a 5% decrease in the total lumbar spine bone mineral density at 5 years was 10.2% in the upfront treatment arm versus 41.2% in the delayed treatment arm (P<.0001). A total of 41 patients in the delayed treatment arm were eventually started on ZA. With the exception of increased NCI Common Toxicity Criteria (CTC) grade 1/2 elevated creatinine and fever in the patients treated on the upfront arm and cerebrovascular ischemia among those in the delayed treatment arm, there were no significant differences observed between arms with respect to the most common adverse events of arthralgia and back pain. Osteoporosis occurred less frequently in the upfront treatment arm (2 vs 8 cumulative cases), although this difference was not found to be statistically significant. Bone fractures occurred in 24 patients in the upfront treatment arm versus 25 patients in the delayed treatment arm.CONCLUSIONSImmediate treatment with ZA prevented bone loss compared with delayed treatment in postmenopausal women receiving letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not found to be significantly different between treatment arms. Cancer 2015;121:2537–2543. © 2015 American Cancer Society.

Background Self-reported diabetes has been found to be valid to evaluate people's diabetes status in the population of several countries. However, no such study has been conducted to assess the validity of self-reported diabetes in the Chinese population, the largest population with the highest rate of diabetes. The aim of our study is to evaluate the validity of self-reported diabetes among the middle-aged and older Chinese population. Methods Data from 11 601 participants, aged ≥45, of the China Health and Retirement Longitudinal Study (CHARLS) during 2011–2012, were analysed. Prevalent self-reported diabetes was compared with reference definition defined by fasting glucose, glycated haemoglobin and medication use. Sensitivity, specificity, positive predicted value, negative predicted value and κ value were calculated overall, by 5-year age groups, by education levels and by living areas. Results The sensitivity of prevalent self-reported diabetes was 41.5%, and the specificity was 98.6%. The sensitivity of self-reported diabetes increased with education levels, and was much higher among urban residents than rural residents (58.2% vs 35.0%). The specificity was above 98% among all age groups, in different education levels, and in rural and urban areas. Self-reported diabetes had substantial agreement with reference definition among participants with above vocational school education or those living in urban areas (κ=0.658 and 0.646, respectively). Conclusions Although the sensitivity of self-reported diabetes was poor among middle-aged and older Chinese adults, the specificity and positive predictive values were fairly good. Furthermore, self-reported diabetes performed well among those with more than vocational school educations or those living in urban areas.