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  • American Association for Cancer Research (AACR)  (15)
  • 1
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 24, No. 10 ( 2015-10-01), p. 1574-1584
    Abstract: Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P & lt; 0.05 and FDR & lt; 0.05). These results were replicated (P & lt; 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 2
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 19, No. 1 ( 2010-01-01), p. 245-250
    Abstract: We genotyped 13 single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) region in three population-based case-control studies of epithelial ovarian cancer conducted in the United States, comprising a total of 1,128 and 1,866 non-Hispanic white invasive cases and controls, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06-1.44, P = 0.006]. rs2295190 is a nonsynonymous coding SNP in a neighboring gene called spectrin repeat containing, nuclear envelope 1 (SYNE1), which is involved in nuclear organization and structural integrity, function of the Golgi apparatus, and cytokinesis. An isoform encoded by SYNE1 has been reported to be downregulated in ovarian and other cancers. rs2295190 was genotyped in an additional 12 studies through the Ovarian Cancer Association Consortium, with 5,279 invasive epithelial cases and 7,450 controls. The per-T-allele OR for this 12-study set was 1.09 (95% CI, 1.02-1.17; P = 0.017). Results for the serous subtype in the 15 combined studies were similar to those overall (n = 3,545; OR, 1.09; 95% CI, 1.01-1.18; P = 0.025), and our findings were strongest for the mucinous subtype (n = 447; OR, 1.32; 95% CI, 1.11-1.58; P = 0.002). No association was observed for the endometrioid subtype. In an additional analysis of 1,459 borderline ovarian cancer cases and 7,370 controls, rs2295190 was not associated with risk. These data provide suggestive evidence that the rs2295190 T allele, or another allele in linkage disequilibrium with it, may be associated with increased risk of invasive ovarian cancer. Cancer Epidemiol Biomarkers Prev; 19(1); 244–50
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 854-854
    Abstract: Background: A subset of high grade serous carcinomas may arise from the fallopian tube, while some endometrioid and clear cell carcinomas may derive from endometrial tissue. Previous studies have suggested differences in ovarian cancer risk factors by histologic subtypes, but had limited sample sizes. In the Ovarian Cancer Cohort Consortium (OC3), we evaluated associations of reproductive, hormonal, demographic and lifestyle factors, and family history of cancer with ovarian cancer subtypes. Identification of potential differences in associations among subtypes is important for clarifying ovarian cancer etiology and for developing novel prevention and risk prediction approaches. Methods: Among over 1.2 million women from 21 cohort studies, 4,347 ovarian cancers with histology information were identified during follow-up (3223 serous, 555 endometrioid, 316 mucinous, 253 clear cell). We used competing risks Cox proportional hazards regression to compute risk factor associations by histologic subtype. Models were stratified on study and year of birth and adjusted for age, parity and oral contraceptive use; subtype heterogeneity was evaluated by a likelihood ratio test. Unsupervised hierarchical clustering was used to evaluate patterns of risk factors by histology. Results: Most risk factors showed significant heterogeneity across histologic subtypes. Higher parity was most strongly associated with lower risks of endometrioid (RR per child: 0.79; 95%CI: 0.74-0.85) and clear cell (RR: 0.69; 95%CI: 0.61-0.78) carcinomas (p-het & lt;0.0001). Age at menopause was positively and tubal ligation was inversely associated only with endometrioid and clear cell carcinomas (p-het = 0.02 and 0.003, respectively). Long-term menopausal hormone use ( & gt;5 years) was associated with endometrioid carcinomas (RR: 2.23; 95% CI: 1.46-3.42) and serous carcinomas (RR: 1.66; 95% CI: 1.44-1.92), and inversely associated with clear cell carcinomas (RR: 0.43; 95% CI: 0.20-0.91; p-het = 0.001). Family history of breast cancer was associated with increased risk of serous carcinomas (RR:1.13; 95% CI:1.02-1.27) and endometrioid carcinomas (RR: 1.44; 95% CI: 1.12-1.87; p-het = 0.02). Smoking (per 20 pack years) showed a positive association with mucinous carcinomas (RR: 1.38; 95% CI: 1.09-1.75) and an inverse association with clear cell carcinomas (RR:0.62; 95% CI: 0.46-0.85; p-het = 0.001). In unsupervised hierarchical clustering, serous and mucinous carcinomas clustered in one group and endometrioid and clear cell carcinomas in the other. Conclusion: Our results demonstrate heterogeneous associations of risk factors with ovarian cancer subtypes, supporting the hypothesis that the subtypes develop through different pathways. Most established risk factors were more strongly associated with non-serous carcinomas, suggesting that risk prediction may be more challenging for serous cancers, the most fatal subtype. Citation Format: Nicolas A. Wentzensen, Elizabeth Poole, Alan A. Arslan, Alpa V. Patel, V Wendy Setiawan, Kala Visvanathan, Elisabete Weiderpass, Emily White, Hans-Olov Adami, Louise A. Brinton, Leslie Bernstein, Julie Buring, Lesley M. Butler, Saioa Chamosa, Tess V. Clendenen, Laure Dossus, Renee Fortner, Susan M. Gapstur, Mia M. Gaudet, Inger Torhild Gram, Patricia Hartge, Judith Hoffman-Bolton, Annika Idahl, Michael Jones, Rudolf Kaaks, Vivki Kirsh, Woon-Puay Koh, James V. Lacey, I-Min Lee, Eva Lundin, Melissa Merritt, Ulrike Peters, Jenny Poynter, Sabina Rinaldi, Kim Robien, Thomas Rohan, Dale P. Sandler, Leo J. Schouten, Louise Sjöholm, Sabina Sieri, Anthony Swerdlow, Anne Tjønneland, Britton Trabert, Lynne Wilkens, Alicja Wolk, Hannah P. Yang, Anne Zeleniuch-Jacquotte, Shelley S. Tworoger. Ovarian cancer risk factors by histologic subtypes: evidence for etiologic heterogeneity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 854. doi:10.1158/1538-7445.AM2015-854
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 16 ( 2008-08-15), p. 6669-6679
    Abstract: CHR-2797 is a novel metalloenzyme inhibitor that is converted into a pharmacologically active acid product (CHR-79888) inside cells. CHR-79888 is a potent inhibitor of a number of intracellular aminopeptidases, including leucine aminopeptidase. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines in vitro and in vivo and shows selectivity for transformed over nontransformed cells. Its antiproliferative effects are at least 300 times more potent than the prototypical aminopeptidase inhibitor, bestatin. However, the mechanism by which inhibition of these enzymes leads to proliferative changes is not understood. Gene expression microarrays were used to profile changes in mRNA expression levels in the human promyelocytic leukemia cell line HL-60 treated with CHR-2797. This analysis showed that CHR-2797 treatment induced a transcriptional response indicative of amino acid depletion, the amino acid deprivation response, which involves up-regulation of amino acid synthetic genes, transporters, and tRNA synthetases. These changes were confirmed in other leukemic cell lines sensitive to the antiproliferative effects of CHR-2797. Furthermore, CHR-2797 treatment inhibited phosphorylation of mTOR substrates and reduced protein synthesis in HL-60 cells, both also indicative of amino acid depletion. Treatment with CHR-2797 led to an increase in the concentration of intracellular small peptides, the substrates of aminopeptidases. It is suggested that aminopeptidase inhibitors, such as CHR-2797 and bestatin, deplete sensitive tumor cells of amino acids by blocking protein recycling, and this generates an antiproliferative effect. CHR-2797 is orally bioavailable and currently undergoing phase II clinical investigation in the treatment of myeloid leukemia. [Cancer Res 2008;68(16):6669–79]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 9 ( 2009-05-01), p. 3937-3946
    Abstract: Platelet-derived growth factor (PDGF) receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor, c-KIT, and PDGFR, and has shown clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (PDGFRA mutations) as well as in chronic myeloid leukemia (BCR-PDGFRA translocation), and sunitinib can yield clinical benefit in both settings. However, the discovery of PDGFR activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti-PDGFR therapies, such as sunitinib. Using a high-throughput cancer cell line screening platform, we found that only 2 of 637 tested human tumor-derived cell lines show significant sensitivity to single-agent sunitinib exposure. These two cell lines [a non–small-cell lung cancer (NSCLC) and a rhabdomyosarcoma] showed expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adenosquamous NSCLC cell line, PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens. Moreover, in this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited proliferation. A similar codependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to gastrointestinal stromal tumors, rare tumors that show PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition. [Cancer Res 2009;69(9):3937–46]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3712-3712
    Abstract: Background: Epithelial ovarian cancer is highly heterogeneous, but it is currently not well understood whether variation in histology reflects etiologic heterogeneity. To date, only a limited number of studies have assessed these relationships, with inconsistent results. Methods: We prospectively evaluated the association between risk factors by histological subtypes of incident ovarian cancer (n = 850) in a cohort of 169,491 US women enrolled in the NIH-AARP Diet and Health Study, a cohort established in 1995-1996 with last follow-up to 2006. We constructed Cox models of individual exposures by comparing case subtypes to the entire non-case group. For each exposure, differences in risk estimates across histologic type were assessed using p-values from unconditional logistic regression models that treated serous as the reference category and excluded controls. In addition, we used the likelihood ratio test to determine the significance of heterogeneity across subtypes and the risk factors. Results: Substantial risk differences between histologic subtypes were observed for menopausal hormone therapy (MHT) use, oral contraceptive (OC) use, parity, and body mass index (BMI) (p -heterogeneity=0.01, 0.03, 0.05, 0.03, respectively). MHT users were at increased risk for all histologic subtypes except for mucinous carcinomas, where risk was reduced (OR=0.37; 95% CI: 0.18-0.80). OC users were at significantly decreased risk for serous cancers (OR=0.69; 95% CI: 0.55-0.85), but at slightly increased risk for mucinous (OR=1.72; 95% CI: 0.86-3.42) and clear cell (OR=1.47; 95% CI: 0.64-3.40) tumors. Although parity was inversely associated with risk of all subtypes, the ORs ranged from 0.28 (clear cell) to 0.82 (serous). Obesity was a significant risk factor only for endometrioid cancers (OR=1.64; 95% CI: 1.00-2.70). We also observed differences in the risks associated with smoking by histologic type, albeit the heterogeneity was not statistically significant. Conclusion: We observed significant heterogeneity of risk factor associations across ovarian histologies, with several associations similar to those observed for the same tissue-type of other cancers. For example, BMI was associated with an increased risk of endometrioid ovarian tumors similar to endometrioid endometrial cancers, OC use with decreased risk of serous subtypes as reported for fallopian tube cancers, and OC use with increased risk for mucinous cancers as for colorectal cancers. Although some of these findings were based on small numbers and we cannot exclude occasional misclassification of metastases from other cancer sites (endometrium, colon), our data suggest that phenotypic heterogeneity of ovarian cancers reflects etiologic heterogeneity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3712. doi:10.1158/1538-7445.AM2011-3712
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB216-LB216
    Abstract: Chordomas are rare spinal tumors addicted to expression of the developmental transcription factor brachyury. In chordomas, brachyury is super-enhancer associated and preferentially downregulated by pharmacologic transcriptional CDK inhibition leading to cell death. To understand the underlying basis of this sensitivity, we dissect the brachyury transcription regulatory network and compare the consequences of brachyury degradation with transcriptional CDK inhibition. Brachyury defines the chordoma super-enhancer landscape, autoregulates through binding its super-enhancer, and its locus forms a transcriptional condensate. Both transcriptional CDK inhibition and brachyury degradation disrupt brachyury autoregulation, leading to loss of its transcriptional condensate and transcriptional program. Compared with transcriptional CDK inhibition which globally downregulates transcription leading to cell death, brachyury degradation is much more selective, inducing senescence and sensitizing cells to anti-apoptotic inhibition. These data suggest that brachyury downregulation is a core tenet of transcriptional CDK inhibition and motivates developing strategies to target brachyury and its autoregulatory feedback loop. Citation Format: Hadley E. Sheppard, Alessandra Dall'Agnese, Woojun D. Park, Hamza Shamim, Julien Dubrulle, Hannah L. Johnson, Fabio Stossi, Patricia Cogswell, Josh Sommer, Joan Levy, Tanaz Sharifnia, Mathias J. Wawer, Paul A. Clemons, Behnam Nabet, Nathanael S. Gray, Stuart L. Schreiber, Paul Workman, Richard A. Young, Charles Y. Lin. Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB216.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P5-19-01-P5-19-01
    Abstract: Background Recent advances in technology have made it possible to conduct remote clinical trials that allow individuals to participate from home with comfort, privacy, and ease. Despite these advances, challenges persist in running remote trials, such as survey question redundancies, lack of patient-initiated data-sharing tools, and unclear patient communication around critical enrollment steps. The Women Informed to Screen Depending on Measures of risk (WISDOM) Study is a pragmatic, preference-tolerant randomized control breast cancer screening trial comparing personalized risk-based screening to traditional, annual screening. The study population includes women ages 40-74 without a history of breast cancer or DCIS. Since 2016, study enrollment has been available to all women in the U.S. who meet study eligibility criteria. Since October 2020, WISDOM has implemented multiple strategies to improve participant experience: participant-initiated data-sharing tools and clear participant messaging. This abstract presents the efficacy of these interventions as they relate to increasing patient enrollment in remote, pragmatic clinical trials. Methods The WISDOM Study online enrollment process includes registration, participant study arm selection or randomization, online consent, and enrollment (submission of multiple study surveys over a secure, online platform). Barriers to online enrollment were uncovered through an internally-conducted needs assessment of participants who enrolled between 2019-2020, and participant feedback obtained through phone interviews conducted by WISDOM’s embedded ethics study. Improvements to our online enrollment procedures were executed in October 2020 and included: improving the clarity of study arm selection options, streamlining data collection surveys, and enacting a secure, patient-initiated online data-sharing tool and an online portal feature with auto-launch of critical information. Study metrics were obtained through Google Analytics and Salesforce. Results Prior to the end of 2020, only 62% of the 30,046 participants who registered for the WISDOM Study completed study enrollment. After improving the enrollment process, of the 5,334 participants registered for the study between Jan-June 2021, 69% completed the enrollment process finishing both the online consent and survey forms. Conversion from consent to enrollment went from 78% in January 2020 to 93% in June 2021. Currently, 56% participants complete enrollment in one day. Streamlining online patient questionnaires led to an increase in completion rates, with 75% of participants completing their yearly surveys, compared to 59% prior to April 2021. A secure patient upload feature for data sharing led to 1,054 participants successfully sharing their mammogram reports with WISDOM between March - June 2021. Previously, mammogram reports were missing for 20% of enrolled participants. This feature has enabled WISDOM to process 300 additional mammogram reports per month. Integration of an auto-launch feature in the participant’s portal in Feb 2021 has led to a 17% increase in participants viewing their screening recommendations in Yr 1. Prior to auto-launch, only 59% (n=6328) of Yr 1 screening recommendations and 61% (n=3681) of genetic testing reports were viewed by participants. Since implementation, the numbers increased to 78% (n=8406) and 85% (n=5160), respectively. Conclusions. Streamlining data to the most essential elements, and minimizing the steps required to share clinical documents, complete questionnaires and open key study notification is essential to improving enrollment rates in virtual, pragmatic trials. Patient-initiated data-sharing tools such as the ability for participants to share documents through secure, online portals is one example of success. Citation Format: Patricia Choy, Tomiyuri Lewis, Stephanie Flores, Leah Sabacan, Halle Thannickal, Steffanie Goodman, Yiwey Shieh, Lisa Madlensky, Jeffrey A. Tice, Elad Ziv, Martin Eklund, Amie Blanco, Barry Tong, Deborah Goodman, Nancy Anderson, Heather Harvey, Steele Fors, Hannah Lui Park, Antonia Petruse, Skye Stewart, Samrrah Raouf, Janet Wernisch, Barbara Koenig, Celia Kaplan, Robert Hiatt, Neil Wenger, Vivian Lee, Diane Heditsian, Susie Brain, Dolores Moorehead, Barbara A Parker, Alexander Borowsky, Hoda Anton-Culver, Arash Naeim, Andrea Kaster, Laura van 't Veer, Andrea Z LaCroix, Olufunmilayo I. Olopade, Deepa Sheth, Agustin Garcia, Rachel Lancaster, Jennifer James, Galen Joseph, Wisdom Study, Athena Breast Health Network Investigators and Advocates, Allison Stover Fiscallini, Laura Esserman. The impact of streamlined processes and patient-directed messaging to improve enrollment in a remote, pragmatic clinical trial [abstract] . In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-19-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P5-19-04-P5-19-04
    Abstract: Background:The WISDOM Study is a preference-tolerant pragmatic study, comparing annual mammograms to a risk-based screening. Eligibility includes women ages 40-74 years with no history of breast cancer or DCIS. Participants are enrolled to one study arm: annual screening or risk-based screening (includes genetic testing). Pragmatic trials often involve gathering real-time data over multiple time points. Collecting real-time data sequentially can limit enrollment, delay study assignments, and reduce participant engagement. The WISDOM Study has identified such bottlenecks and has implemented parallel workflows, reducing the overall wait time for participants to complete required study steps. These data highlight how moving participants through the study more efficiently can improve enrollment and retention and inform other pragmatic trials. Methods: WISDOM participants have the option to either choose their study arm or be randomized into one as part of the preference tolerant randomized trial design. Participants then complete breast health questionnaires and genetic testing (if in the risk-based arm). This information is analyzed by the WISDOM breast cancer risk assessment algorithm, the result of which is then communicated to the participant through a screening assignment letter (SAL). Specific data elements, such as breast density found participants’ mammogram reports and genetic testing results are required for study randomization process and risk assessment calculations, respectively. The WISDOM randomization algorithm is stratified by several factors, including breast cancer risk estimated using the Breast Cancer Surveillance Consortium (BCSC) model, which uses mammographic density as a key input variable. The study team changed the workflow to allow participants to proceed to randomization without specific information by imputing both density and risk. Additionally, a parallel workflow improvement process was implemented to obtain mammogram reports while genetic testing was being completed. Results: Before the weighted BCSC and imputed density algorithms were introduced, it took an average of 47 days to randomize participants after completion of the baseline enrollment questionnaires. Now, participants are randomized immediately which has reduced delays by 100%. Prior to implementing the parallel workflow for genetic testing and mammogram ascertainment, genetic testing kits were sent only after mammogram reports were collected and validated. The expected turnaround time for genetic testing results was 30-60 days and on average, results were returned to participants in 42 days. Streamlining the study design to obtain mammogram reports while participants complete their genetic testing has shortened the time for participants to receive their screening assignment letters (SALs) from an average of 160 days to 78 days, a reduction by 49%. In comparison, participants in the annual arm of the study who do not complete genetic testing, receive their SALs after an average of 38 days from enrollment. This is due to long wait times to obtain mammographic densities from outside medical facilities. Conclusions: Creating parallel data ascertainment workflows and reducing sequential steps in the study process has increased completion of individual enrollment activities. Participants now are randomized immediately upon joining the study and have access to their SALs and genetic results more rapidly. This approach eliminated randomization wait times and improved efficiency of the early in the enrollment process. We are evaluating the impact on participant retention going forward. Workflow efficiency is critical to improve the patient experience, and our learnings can inform future trial design, particularly for studies requiring data from outside sources. Citation Format: Tomiyuri Lewis, Stephanie Flores, Leah Sabacan, Patricia Choy, Halle Thannickal, Yiwey Shieh, Jeffrey Tice, Elad Ziv, Lisa Madlensky, Martin Eklund, Christina Yau, Amie Blanco, Barry Tong, Deborah Goodman, Nancy Anderson, Heather Harvey, Steele Fors, Hannah L Park, Samrrah Raouf, Skye Stewart, Janet Wernisch, Barbara Koenig, Celia Kaplan, Robert Hiatt, Neil Wenger, Vivian Lee, Diane Heditsian, Susie Brain, Dolores Moorehead, Barbara A Parker, Alexander Borowsky, Hoda Anton-Culver, Arash Naeim, Andrea Kaster, Laura van ‘t Veer, Andrea Z LaCroix, Olufunmilayo I Olopade, Deepa Sheth, Agustin Garcia, Rachel Lancaster, Michael Plaza, Wisdom Study, Athena Breast Health Network Investigators, Advocate Partners, Allison S Fiscalini, Laura Esserman. The WISDOM study: Reducing sequential steps and implementing parallel workflows in pragmatic trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-19-04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 10
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 10 ( 2022-05-13), p. 2020-2029
    Abstract: Praluzatamab ravtansine (CX-2009) is a conditionally activated Probody drug conjugate (PDC) comprising an anti-CD166 mAb conjugated to DM4, with a protease-cleavable linker and a peptide mask that limits target engagement in normal tissue and circulation. The tumor microenvironment is enriched for proteases capable of cleaving the linker, thereby releasing the mask, allowing for localized binding of CX-2009 to CD166. CX-2009 was evaluated in a phase I/II clinical trial for patients with advanced solid tumors. Patients and Methods: Eligible patients had metastatic cancer receiving ≥2 prior treatments. CX-2009 was administered at escalating doses every 3 weeks (0.25–10 mg/kg) or every 2 weeks (4–6 mg/kg). Primary objective was to determine the safety profile and recommended phase II dose (RP2D). Results: Of 99 patients enrolled, the most prevalent subtype was breast cancer (n = 45). Median number of prior therapies was 5 (range, 1–19). Dose-limiting toxicities were observed at 8 mg/kg every 3 weeks and 6 mg/kg every 2 weeks. On the basis of tolerability, the RP2D was 7 mg/kg every 3 weeks. Tumor regressions were observed at doses ≥4 mg/kg. In the hormone receptor–positive/HER2-nonamplified breast cancer subset (n = 22), 2 patients (9%) had confirmed partial responses, and 10 patients (45%) had stable disease. Imaging with zirconium-labeled CX-2009 confirmed uptake in tumor lesions and shielding of major organs. Activated, unmasked CX-2009 was measurable in 18 of 22 posttreatment biopsies. Conclusions: CD166 is a novel, ubiquitously expressed target. CX-2009 is the first conditionally activated antibody–drug conjugate to CD166 to demonstrate both translational and clinical activity in a variety of tumor types.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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