Citations

Abstract Background: This is an update of the safety and efficacy of durvalumab monotherapy in pts with locally advanced/metastatic urothelial carcinoma (UC) from an ongoing, phase 1/2 open-label study (NCT01693562). Methods: Pts received 10 mg/kg every 2 weeks up to 12 months or until unacceptable toxicity, progression, or starting another anticancer therapy. Pts were stratified by tumor PD-L1 expression (Ventana PD-L1 [SP263] Assay [PD-L1 cutoff: ≥25% of tumor cells and/or immune cells with membrane staining]) and treatment line. Results: As of the data cutoff (16Oct2017), 201 UC pts with Stage IV disease received treatment, with a median follow-up of 16.9 months (range, 0.4-37.7). Across treatment lines, objective response rate (ORR) by blinded independent central review was 17.4% (95% CI, 12.4, 23.4) in all pts; 27.5% in the PD-L1 ≥25% group vs 5.8% in the PD-L1 <25% group. The responses have been durable regardless of PD-L1 status, with the median duration of response not yet reached in the PD-L1 ≥25% group and 12.2 months in the PD-L1 <25% group. Responses lasted ≥12 mo in 62.9% of responders (max 25.7+ mo). Overall, median OS was 10.5 months (95% CI, 6.9, 15.7); 19.8 months in the PD-L1 ≥25% group vs 4.8 months in the PD-L1 <25% group (Table). Pts previously treated with platinum based chemotherapy also reported similar durable responses. At least one treatment-related AE was reported in 120 pts (59.7%), including fatigue (39 [19.4%]), decreased appetite and rash (18 [9.0%] each), and diarrhea (16 [8.0%]). Grade 3/4 treatment-related AEs occurred in 19 (9.5%) pts; 6 (3.0%) treatment discontinuations and 2 (1.0%) deaths were attributed to treatment-related AEs. Conclusions: With extended follow-up, durvalumab continues to show durable clinical activity in UC pts, especially in the PD-L1 ≥25% group with an acceptable toxicity profile. PD-L1 ≥25%PD-L1 <25%PD-L1 unknownTotalAll UCn=102n=86n=13N=201Confirmed ORR, %27.55.815.417.4(95% CI)(19.1, 37.2)(1.9, 13.0)(1.9, 45.4)(12.4, 23.4)CR, %7.83.57.76.0PR, %19.62.37.711.4Median DoR, monthsNR12.2NRNR(min, max)(2.7, 25.7+)(8.6, 21.7+)(14.5+, 14.6+)(2.7, 25.7+)Median PFS, months (95% CI)1.9 (1.4, 2.7)1.4 (1.3, 1.5)2.8 (1.4, NE)1.5 (1.4, 1.8)6-month PFS rate, %28.68.625.220.412-month PFS rate, %22.37.125.216.2Median OS, months (95% CI)19.8 (9.3, NE)19.8 (9.3, NE)4.8 (3.3, 8.1)NR (4.9, NE)10.5 (6.9, 15.7)6-month OS rate, %67.645.869.258.912-month OS rate, %57.629.561.546.6 Citation Format: Peter O'Donnell, Christophe Massard, Bhumsuk Keam, Sang-We Kim, Terry Friedlander, Myung-Ju Ahn, Michael Ong, Michael Gordon, Marcus Butler, Scott Antonia, Gerardo Colon-Otero, Martin Gutierrez, Sumati Gupta, Alexander Spira, Alexandra Drakaki, Michele Maio, Feng Xiao, Natasha Angra, Shaad Abdullah, Thomas Powles. Updated efficacy and safety profile of durvalumab monotherapy in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT031.

Abstract In the United States, over 80% of prostate cancer patients die with bone metastases. Second-line hormonal therapies, such as enzalutamide, only improve overall patient survival by a few months in about 50% of patients, and almost all patients develop drug resistance. Thus, there is an urgent need to determine the mechanisms of drug resistance in order to provide better treatments for prostate cancer bone metastasis. Enzalutamide is a small-molecule inhibitor of the androgen receptor. Our study showed that although enzalutamide inhibited the tumor growth of castration-resistant prostate cancer C4-2B cells when xenografted subcutaneously, it had no effect on the growth of C4-2B tumors in the bone or on the development of bone lesions. These data suggested a crucial role of the microenvironment in enzalutamide resistance in prostate cancer bone metastasis. To dissect the role of enzalutamide on the bone microenvironment, we treated bone cells, both osteoblasts and osteoclasts, with enzalutamide. We found that enzalutamide significantly and specifically reduced the TGF-β type II receptor (TGFBR2) protein in osteoblasts. This observation was also confirmed in prostate cancer bone metastatic tissue microarray, in which we performed immunohistochemistry and found a significant decrease of TGFBR2 expression specifically in cancer-associated osteoblasts from patients who had undergone treatment with second-line hormonal therapies, either enzalutamide or abiraterone. Statistical analysis showed that the decrease of TGFBR2 in cancer-associated osteoblasts was a causative effect from the hormonal therapies. To determine the role of TGFBR2 in the osteoblasts during bone metastasis, we used a mouse model (Tgfbr2Col1CreERT KO) with inducible Tgfbr2 knockout specifically in the osteoblasts. We found that loss of TGFBR2 in osteoblasts significantly promoted prostate cancer bone metastasis. Together, our data showed for the first time that reduction of TGFBR2 in osteoblasts by enzalutamide causes resistance to the drug in prostate cancer bone metastasis. Citation Format: Alexandra Vander Ark, Erica Woodford, Xiangqi Meng, Sourik Ganguly, Xiaotun Zhang, Zachary Madaj, Xiaohong Li. Reduction of TGFBR2 in osteoblasts by enzalutamide causes drug resistance in prostate cancer bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4898.

Abstract Patients diagnosed with ovarian cancer face an average 5 year survival rate of 46%; low survival is driven by early and ongoing intraperitoneal dissemination and metastasis of the tumor. Among the different histotypes of ovarian cancer, ovarian clear cell carcinoma (OCCC) has a particularly poor prognosis when diagnosed in late stage, as these tumors tend to be chemoresistant, leaving no effective therapeutic options. Intraperitoneal metastasis requires cells to become anoikis resistant, where apoptosis normally induced by loss of attachment is suppressed. We seek to better understand the mechanisms involved in anoikis resistance in OCCC, which in the future could lead to new therapeutic strategies for these patients. We have found that Serine Protease Inhibitor Kazal type 1 (SPINK1), an endogenous inhibitor of trypsin like serine proteases, is also an important regulator of anoikis resistance in some ovarian cancers. In this study, we aimed to dissect the role of SPINK1 specifically in OCCC, defining its contribution to anoikis resistance using cultured OCCC cell lines and elucidating its mechanism of action. We compared anoikis resistance of cells with endogenous SPINK1 expression versus cells in which SPINK1 was silenced using lentiviral shRNA constructs, when culturing cells on ultra-low attachment plates to mimic cell detachment from the extracellular matrix. We found that knockdown of SPINK1 reduced survival and stimulated apoptotic pathways in OCCC cells grown under detached conditions, implicating SPINK1 in anoikis resistance of OCCC cells. As a secreted protease inhibitor, SPINK1 may be expected to confer anoikis resistance by inhibiting an extracellular serine protease involved in triggering anoikis. Because many proteases represent potential targets of SPINK1, we have designed a strategy using Activity Based Protein Profiling (ABPP) to discover the targets of SPINK1 from among this large pool of candidates. In pilot studies, we have successfully used a novel activity-based probe to covalently label the active sites of serine proteases secreted from OCCC cells. In ongoing efforts, we are optimizing methods to identify labeled proteases with high sensitivity using tandem mass spectrometry. We will then identify those proteases regulated by SPINK1 through comparison of labeled proteomes from OCCC cells with and without SPINK1 treatment,, and candidate proteases will be further analyzed for their role in triggering anoikis. The identification of SPINK1 regulated proteases that are responsible for mediating anoikis in our models will give insight into important mechanisms whereby tumor cells acquire resistance to anoikis in OCCC. In-depth understanding of anoikis resistance, a critical component of ovarian cancer progression and metastasis, may lead to novel biomarkers of disease progression as well as important therapeutic targets. Citation Format: Christine Mehner, Mathew A. Coban, Alexandra Hockla, Derek C. Radisky, Evette S. Radisky. Serine protease inhibitor Kazal type 1 (SPINK1) drives anoikis resistance in ovarian clear cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 442.

Abstract Background: We previously identified 5 SNPs at 4 susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (Cerhan et al, Nat Gen 2014;46:1233-8); however, much of the heritability remains unexplained. To further elucidate genetic susceptibility to DLBCL, we sought to validate 2 loci at 3q13.33 and 3p24.1 that were suggestive in the original report. Methods: We selected two SNPs rs9831894 (3q13.33) and rs6773363 (3p24.1) for de novo replication from studies at the Mayo Clinic, MD Anderson, and Memorial Sloan Kettering. Logistic regression was used to estimate odds ratios (ORs), using a log-additive model, and adjusting for age, gender and significant eigenvectors for each genotyping center separately. For both SNPs, we then conducted a meta-analysis of all replication studies (n=3) and our original GWAS studies (n=4), encompassing in total 5662 cases and 9237 controls for rs9831894, and 5510 cases and 12,817 controls for rs6773363. Meta-analysis was conducted using the fixed-effects inverse variance method based on the β estimates and standard errors from each study. Results: In a meta-analysis of the 4 original GWAS scans (3856 cases and 7666 controls), rs9831894 (MAF=0.40) was associated with DLBCL risk (OR=0.84, P=4.52 x 10-9) and this replicated in a meta-analysis of the 3 studies with de novo genotyping (OR=0.80, P=4.17 x 10-5); the overall meta-analysis showed a strong association with DLBCL risk (OR=0.83, P=3.62 x 10-13). This locus maps near a plausible candidate gene, CD86, a protein coding gene and a member of the immunoglobulin superfamily that encodes a type I membrane protein. Binding of CD86 with cytotoxic T-lymphocyte-associated protein 4 negatively regulates T-cell activation and diminishes the immune response, while binding of CD86 with CD28 antigen is a costimulatory signal for activation of the T-cell. In a meta-analysis of the same 4 GWAS scans, rs6773363 (MAF=0.45) was tentatively associated with DLBCL risk (OR=1.17, P= 3.68 x 10-7) and this replicated in a meta-analysis of the studies with de novo genotyping (OR=1.27, P=3.78 x 10-7); the overall meta-analysis showed a strong association with DLBCL risk (OR=1.20, P=2.31 x 10-12). This locus also maps near a plausible candidate gene, eomesodermin (EOMES), a transcription factor crucial for embryonic development of the central nervous system and also putatively involved in T-cell differentiation in viral infection defense. Conclusion: In this follow-up analysis of our initial GWAS, we have identified two additional loci associated with risk of DLBCL, the most common lymphoma subtype. These loci provide additional evidence for the role of immune function in the etiology of DLBCL. Citation Format: Geffen Kleinstern, Michelle Hildebrand, Vijai Joseph, Sonja I. Berndt, Hervé Ghesquières, James McKay, Sophia S. Wang, Alexandra Nieters, David Cox, Alain Monnereau, Angela R. Brooks-Wilson, Qing Lan, Mads Melbye, Rebecca D. Jackson, Lauren R. Teras, Mark P. Purdue, Claire M. Vajdic, Demetrius Albanes, Anne Zeleniuch-Jacquotte, Simon Crouch, Yawei Zhang, Susan L. Slager, Xifeng Wu, Karin E. Smedby, Gilles Salles, Christine F. Skibola, Nathaniel Rothman, Stephen J. Chanock, James R. Cerhan. Inherited variants at 3q13.33 and 3p24.1 influences risk of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 221.

Abstract Introduction: Many forms of cancer screening involve imaging technologies utilizing radiation. Broad media coverage of radiation-related health risks may shape the public's perceptions of imaging-based cancer screening, such as mammography. In turn, this may impact patient outcomes by affecting cancer screening decisions. Our primary aim was to evaluate population differences in beliefs about medical radiation exposure in the United States and associations with mammography screening rates in women. Methods: We analyzed data from the National Cancer Institute's Health Information National Trends Survey (HINTS) 2012 administration. Bivariate and multivariate regression analyses were used to evaluate associations of sex, ethnicity, age, annual income, and education with perceptions of harm from medical test radiation exposure. Additional analyses evaluated the role of radiation perception on compliance with current mammography screening recommendations from the United States Preventive Services Task Force. Results: Approximately one-third of respondents indicated that they worried about medical imaging-related radiation exposure. Respondents who perceived medical imaging radiation as harmful to health were more likely to be female, be diagnosed with cancer, have less formal education, report lower socioeconomic status, and identify as an ethnic minority. Most female participants were not in compliance with current breast cancer screening recommendations (weighted percentage = 83.8%). Annual income (p = 0.042) and ethnicity (p = 0.0478) were two variables that were significantly associated with adherence to the recommended mammography screening paradigm. Women without health insurance were more likely to worry about medical imaging-related radiation (p=0.073). Neither health insurance (95%CI = 0.29, 4.99) nor excess worry about radiation exposure from medical imaging devices (95%CI=0.42, 1.89) predicted compliance to mammography screening, after adjusting for relevant sociodemographic variables. Conclusions: These results indicate that some populations may be more concerned about harm from medical device-related radiation than others. Identifying these populations may help improve future cancer patient outcomes by promoting targeted health interventions and communication strategies for these individuals. Women may be more likely to perceive medical imaging radiation exposure as harmful to health, however this alone could not account for why the majority of female respondents were not adhering to recommended mammograms screening guidelines. Future studies are needed to identify the major contributor to low breast cancer screening rates in the United States. Citation Format: Kekoa Taparra, Kay M. Pepin, Alexandra J. Greenberg-Worisek. Associations between perceived medical device-related radiation harm and adherence to mammography screening guidelines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4241.

Throughout the years, scientific and personal research has led us on a historical journey to learn about the life of Beauchêne fils (Edme François Chauvot de Beauchêne), a French clinical anatomist, prosector, and surgeon responsible for introducing the disarticulated skull technique and the first citation of an intraneural cyst. This letter describes our research, travels, and conversations intended to uncover the fascinating history of Beauchêne fils and his family and our journey full of unexpected twists and turns. During a trip to Paris, we learned of a possible inspiration for the disarticulated skull technique from skulls afflicted with la teigne (Tinea corporis, ring worm) at the Musée Dupuytren. We toured the estate of his family's summer home in Paron, France, where we discovered a portrait of Beauchêne fils’ father that had been misidentified in our recent publication. We also discovered the date of death and elusive burial site of Beauchêne fils in Père Lachaise cemetery in Paris. We hope to bring to light the life and contributions of a nearly unknown figure who influenced not only research on intraneural ganglion cysts and the articular theory, but also the future of the field of anatomy. Clin. Anat. 31:1194–1198, 2018. © 2018 Wiley Periodicals, Inc.