Citations

Abstract Background: I-SPY2 is a multicenter phase 2 trial in high risk stage II/III breast cancer (BC) using adaptive randomization within biomarker subtypes to evaluate novel agents added to standard neoadjuvant chemotherapy. The first regimen to graduate based on the predicted probability of a higher pCR rate within predefined subsets was veliparib/carboplatin + paclitaxel (VC+T→AC vs T→AC) in triple negative BC (TNBC). In TNBC the residual cancer burden (RCB) is prognostic, whether as a continuous index or grouped into classes, with pCR (RCB-0) and RCB-I classes having identical survival. Therefore, we evaluated the use of RCB to further discriminate between investigational and control arms. Methods: Site pathologists reported RCB for 99% of subjects in the primary efficacy analysis based on pCR (n=114/115). We compared the distribution of RCB reported as a continuous index in each treatment-subset combination to matched concurrently randomized controls using the Wilcoxon rank sum test for RCB index, and Fisher's Exact test for RCB classes (RCB-0/I vs RCB-II/III). The statistics are descriptive rather than inferential, and given the small sample size have no claim on generalizability. We modified the Bayesian model used to compute the estimated probability of success in a future, randomized, phase 3 trial of 300 subjects, if response were defined by either pCR or RCB-I (RCB0/I), or separately if it were defined by pCR alone. Results: VC+T→AC led to a significantly lower RCB index than T→AC in TNBC (p=0.0021), with a near-significant trend when those with pCR were excluded (p=0.06). There was no significant difference in RCB distributions in the other breast cancer subtypes treated. In TNBC, the odds ratio (OR) for achieving RCB-0/I in the VC+T→AC arm vs control was 8.2 (95% confidence interval (CI): 2.1–35), whereas the OR for achieving pCR was 4.56 (95% CI: 1.25–19.53). The simulations using response information from I-SPY2 to predict the probability of success for VC+T→AC for TNBC in a future phase 3 trial estimated this probability to be 0.99 if modeled using RCB-0/I as the response endpoint, and 0.90 if modeled using pCR as the response endpoint. Conclusions: Use of RCB index and classes provided additional insight into the effect of adding VC to T, appearing to magnify the improved treatment response that had been observed with pCR rates in TNBC. It will be important to test in randomized trials whether a decrease in the RCB index relative to controls, and/or increased rates of RCB-0/I class, are predictive of survival benefit in TNBC. Citation Format: Liu MC, Symmans WF, Yau C, Chen Y-Y, Rugo HS, Olopade OF, Datnow B, Chen B, Feldman M, Kallakury B, Hasteh F, Tickman R, Ritter J, Troxel M, Mhawech-Fauceglia P, Duan X, Berry D, Esserman L, DeMichele A. Residual cancer burden (RCB) with veliparib/carboplatin in the I-SPY2 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-49.

Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1 + CD11a hi CD8 + ) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8 + T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility.

Abstract Rationale Despite shared environmental exposures, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease are usually studied in isolation, and the presence of shared molecular mechanisms is unknown. Objectives We applied an integrative genomic approach to identify convergent transcriptomic pathways in emphysema and IPF. Methods We defined the transcriptional repertoire of chronic obstructive pulmonary disease, IPF, or normal histology lungs using RNA-seq (n = 87). Measurements and Main Results Genes increased in both emphysema and IPF relative to control were enriched for the p53/hypoxia pathway, a finding confirmed in an independent cohort using both gene expression arrays and the nCounter Analysis System (n = 193). Immunohistochemistry confirmed overexpression of HIF1A, MDM2, and NFKBIB members of this pathway in tissues from patients with emphysema or IPF. Using reads aligned across splice junctions, we determined that alternative splicing of p53/hypoxia pathway–associated molecules NUMB and PDGFA occurred more frequently in IPF or emphysema compared with control and validated these findings by quantitative polymerase chain reaction and the nCounter Analysis System on an independent sample set (n = 193). Finally, by integrating parallel microRNA and mRNA-Seq data on the same samples, we identified MIR96 as a key novel regulatory hub in the p53/hypoxia gene-expression network and confirmed that modulation of MIR96 in vitro recapitulates the disease-associated gene-expression network. Conclusions Our results suggest convergent transcriptional regulatory hubs in diseases as varied phenotypically as chronic obstructive pulmonary disease and IPF and suggest that these hubs may represent shared key responses of the lung to environmental stresses.

Abstract Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.

ABSTRACTOrthopedic surgeons sometimes combine recombinant, human BMP‐2 with autograft bone when dealing with problematic osseous fractures. Although some case reports indicate success with this off‐label strategy, there have been no randomized controlled trials. Moreover, a literature search revealed only one pre‐clinical study and this was in a cranial defect model. The present project examined the consequences of combining BMP‐2 with particles of living bone in a rat femoral defect model. Human bone particles were recovered with a reamer‐irrigator‐aspirator (RIA). To allow acceptance of the xenograft as surrogate autograft, rats were administered an immunosuppressive cocktail that does not interfere with bone healing. Implantation of 200 µg living bone particles generated a small amount of new bone and defects did not heal. Graded amounts of BMP‐2 that alone provoked no healing (1.1 µg), borderline healing (5.5 µg), or full healing (11 µg) were added to this amount of bone particles. Addition of BMP‐2 (1.1 µg) increased osteogenesis, and produced bridging in 2 of 7 defects. The combination of BMP‐2 (5.5 µg) and bone particles made healing more reliable and advanced the maturation of the regenerate. Bone formation with BMP‐2 (11 µg) and bone particles showed improved maturation. Thus, the combination of autograft and BMP‐2 may be helpful clinically under conditions where the healing response is suboptimal. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2137–2145, 2016.Clinical significanceThese data support the clinical use of recombinant, human BMP‐2 with autograft bone when treating large segmental osseous defects. The combination leads to greater bone formation and accelerates the maturation of the regenerate.

Deleting neuronal heparan sulfates in a mouse model of Alzheimer’s disease results in faster Aβ clearance, reduced Aβ aggregation, and less amyloid pathology.