Search

Your search keyword '"Lenz, Heinz‐Josef"' showing total 2,959 results
Start Over Author "Lenz, Heinz‐Josef"
2,959 results on '"Lenz, Heinz‐Josef"'

1. Genomic, immunologic, and prognostic associations of TROP2 (TACSTD2) expression in solid tumors.

Author

Morgenstern-Kaplan, Dan, Kareff, Samuel, Trabolsi, Asaad, Rodriguez, Estelamari, Krause, Harris, Ribeiro, Jennifer, Tan, Heng, Antonarakis, Emmanuel, Lou, Emil, Nagasaka, Misako, Algaze, Sandra, Lenz, Heinz-Josef, Liu, Stephen, Halmos, Balazs, Hoon, Dave, Seeber, Andreas, Ma, Patrick, El-Deiry, Wafik, Vanderwalde, Ari, and Lopes, Gilberto

Subjects
TROP2, precision oncology, targeted therapy, tumor genetics, Humans, Antigens, Neoplasm, Cell Adhesion Molecules, Prognosis, Female, Neoplasms, Male, Middle Aged, Biomarkers, Tumor, Aged, Genomics, Mutation
Abstract

BACKGROUND: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. METHODS: Breast (N = 11 246), colorectal (N = 15 425), hepatocellular (N = 433), pancreatic (N = 5488), and urothelial (N = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. RESULTS: Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors. CONCLUSIONS: TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.

Published
2024

6. Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial

Author

Bullock, Andrea J., Schlechter, Benjamin L., Fakih, Marwan G., Tsimberidou, Apostolia M., Grossman, Joseph E., Gordon, Michael S., Wilky, Breelyn A., Pimentel, Agustin, Mahadevan, Daruka, Balmanoukian, Ani S., Sanborn, Rachel E., Schwartz, Gary K., Abou-Alfa, Ghassan K., Segal, Neil H., Bockorny, Bruno, Moser, Justin C., Sharma, Sunil, Patel, Jaymin M., Wu, Wei, Chand, Dhan, Rosenthal, Katherine, Mednick, Gabriel, Delepine, Chloe, Curiel, Tyler J., Stebbing, Justin, Lenz, Heinz-Josef, O’Day, Steven J., and El-Khoueiry, Anthony B.

Published
2024
Full Text
View/download PDF

8. Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Author

Chen, Zhishan, Guo, Xingyi, Tao, Ran, Huyghe, Jeroen R., Law, Philip J., Fernandez-Rozadilla, Ceres, Ping, Jie, Jia, Guochong, Long, Jirong, Li, Chao, Shen, Quanhu, Xie, Yuhan, Timofeeva, Maria N., Thomas, Minta, Schmit, Stephanie L., Díez-Obrero, Virginia, Devall, Matthew, Moratalla-Navarro, Ferran, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah E. W., Svinti, Victoria, Donnelly, Kevin, Farrington, Susan M., Blackmur, James, Vaughan-Shaw, Peter G., Shu, Xiao-Ou, Lu, Yingchang, Broderick, Peter, Studd, James, Harrison, Tabitha A., Conti, David V., Schumacher, Fredrick R., Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Oh, Jae Hwan, Kim, Jeongseon, Jee, Sun Ha, Jung, Keum Ji, Kweon, Sun-Seog, Shin, Min-Ho, Shin, Aesun, Ahn, Yoon-Ok, Kim, Dong-Hyun, Oze, Isao, Wen, Wanqing, Matsuo, Keitaro, Matsuda, Koichi, Tanikawa, Chizu, Ren, Zefang, Gao, Yu-Tang, Jia, Wei-Hua, Hopper, John L., Jenkins, Mark A., Win, Aung Ko, Pai, Rish K., Figueiredo, Jane C., Haile, Robert W., Gallinger, Steven, Woods, Michael O., Newcomb, Polly A., Duggan, David, Cheadle, Jeremy P., Kaplan, Richard, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Jukka-Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri A., Rissanen, Harri, Pukkala, Eero, Eriksson, Johan G., Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie J., Ruiz-Narvaez, Edward, Palmer, Julie R., Buchanan, Daniel D., Platz, Elizabeth A., Visvanathan, Kala, Ulrich, Cornelia M., Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter T., Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha L., Potter, John D., Tsilidis, Kostas K., Schulze, Matthias B., Gunter, Marc J., Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Bishop, D. Timothy, Giles, Graham G., Southey, Melissa C., Idos, Gregory E., McDonnell, Kevin J., Abu-Ful, Zomoroda, Greenson, Joel K., Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu-Ru, Steinfelder, Robert, Keku, Temitope O., van Guelpen, Bethany, Hudson, Thomas J., Hampel, Heather, Pearlman, Rachel, Berndt, Sonja I., Hayes, Richard B., Martinez, Marie Elena, Thomas, Sushma S., Pharoah, Paul D. P., Larsson, Susanna C., Yen, Yun, Lenz, Heinz-Josef, White, Emily, Li, Li, Doheny, Kimberly F., Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew T., Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David J., Joshi, Amit D., Schafmayer, Clemens, Scacheri, Peter C., Kundaje, Anshul, Schoen, Robert E., Hampe, Jochen, Stadler, Zsofia K., Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Edlund, Christopher K., Gauderman, W. James, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen J., van Duijnhoven, Franzel, Feskens, Edith J. M., Sakoda, Lori C., Gago-Dominguez, Manuela, Wolk, Alicja, Pardini, Barbara, FitzGerald, Liesel M., Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie A., Kooperberg, Charles, Li, Christopher I., Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Le Marchand, Loic, Wu, Anna H., Qu, Chenxu, McNeil, Caroline E., Coetzee, Gerhard, Hayward, Caroline, Deary, Ian J., Harris, Sarah E., Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Lau, Ken S., Zhao, Hongyu, Hsu, Li, Cai, Qiuyin, Dunlop, Malcolm G., Gruber, Stephen B., Houlston, Richard S., Moreno, Victor, Casey, Graham, Peters, Ulrike, Tomlinson, Ian, and Zheng, Wei

Published
2024
Full Text
View/download PDF

11. Evaluation of markers of immunity in different metastatic immune microenvironments suggests more suppression within breast to liver metastases in breast cancer

Author

Hsu, Robert, Al-zubeidy, Batul, Flores, Daniel, Nazarian, Ari, Baugh, Aaron, Gonzalez, Edgar, Castanon, Sofi, Xiu, Joanne, Kang, Irene, Spicer, Darcy, Lenz, Heinz Josef, Dara, Lily, Ademuyiwa, Foluso O., Korn, W. Michael, Irshad, Sheeba, Chan, Isaac S., and Roussos Torres, Evanthia T.

Published
2024
Full Text
View/download PDF

13. Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial

Author

Ahn, Daniel H., Ridinger, Maya, Cannon, Timothy L., Mendelsohn, Lawrence, Starr, Jason S., Hubbard, Joleen M., Kasi, Anup, Barzi, Afsaneh, Samuëlsz, Errin, Karki, Anju, Subramanian, Ramanand A., Yemane, Divora, Kim, Roy, Wu, Chu-Chiao, Croucher, Peter J.P., Smeal, Tod, Kabbinavar, Fairooz F., and Lenz, Heinz-Josef

Published
2024
Full Text
View/download PDF

14. Bintrafusp Alfa: A Bifunctional Fusion Protein Targeting PD-L1 and TGF-β, in Patients with Pretreated Colorectal Cancer: Results from a Phase I Trial

Author

Spira, Alexander, Wertheim, Michael S, Kim, Edward J, Tan, Benjamin, Lenz, Heinz-Josef, Nikolinakos, Petros, Rich, Patricia L, Jehl, Genevieve, Machl, Andreas, Ito, Rena, Gulley, James L, and Kopetz, Scott

Subjects
Cancer, Digestive Diseases, Colo-Rectal Cancer, Humans, B7-H1 Antigen, Transforming Growth Factor beta, Antibodies, Monoclonal, Immunologic Factors, Colorectal Neoplasms, bintrafusp alfa, colorectal cancer, phase I, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Colorectal cancer (CRC) is a heterogeneous and complex disease with limited treatment options. Targeting transforming growth factor β (TGF-β) and programmed death ligand 1 pathways may enhance antitumor efficacy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed cell death ligand 1. We report results from an expansion cohort of a phase I study (NCT02517398) in patients with heavily pretreated advanced CRC treated with bintrafusp alfa. As of May 15, 2020, 32 patients with advanced CRC had received bintrafusp alfa for a median duration of 7.1 weeks. The objective response rate was 3.1% and the disease control rate was 6.3% (1 partial response, 1 stable disease); 2 patients were not evaluable. The safety profile was consistent with previously reported data.

Published
2023

16. Patient Care Satisfaction and Emergency Room Utilization among Young Adult Colorectal Cancer Survivors during the SARS-CoV-2 Pandemic: Lessons Learned

Author

Kagramanov, Dalia, Miller, Kimberly A, Gallagher, Phuong, Freyer, David R, Milam, Joel E, Lenz, Heinz-Josef, and Barzi, Afsaneh

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Digestive Diseases, Colo-Rectal Cancer, Aging, Rehabilitation, Prevention, Coronaviruses, Cancer, Good Health and Well Being, colorectal cancer survivor, emergency utilization, SARS-CoV-2, care satisfaction, pandemic, Biomedical and clinical sciences
Abstract

Introduction: Survivors of colorectal cancer (CRC) are at risk for late effects of therapy and recurrence of cancer. With recurrence rates ranging between 30−40%, follow-up care is needed for both early detection and management of late effects. Cancer care delivery for CRC patients was significantly disrupted by the SARS-CoV-2 pandemic, with decreases of 40% in such services in the United States between April 2020 and 2019. Survivors were left with fewer options for care, potentially causing increases in emergency room (ER) utilization. Methods: This cross-sectional study examined the patterns of ER utilization during the SARS-CoV-2 pandemic among young adult CRC survivors and assessed the relationship between self-reported care satisfaction and ER use. Eligible participants were colon or rectal cancer survivors diagnosed between 18−39 years of age, 6−36 months from diagnosis/relapse, English speaking and residing in the United States. Multivariable logistic regression assessed the association between patient care satisfaction and ER utilization, adjusting for pandemic factors. Covariates were chosen by significance of p < 0.1 at the univariate level and perceived clinical significance. Results: The overall sample (N = 196) had mean age (SD) 32.1 (4.5); 59% were male. Tumor location was colon or rectal in 42% and 57%, respectively, and the majority (56%) were diagnosed with stage 2 disease; 42.6% reported relapsed disease, and 20% had an ostomy. Most survivors (72.5%) had between 1−4 visits to an ER in the last 12 months and were categorized as normal utilizers. Approximately 24.7% of the sample had greater than 4 visits to the ER in the last 12 months and were categorized as super-utilizers. CRC survivors that reported a delay in their follow-up care as a result of the pandemic were two times (OR: 2.05, 95% CI 0.99, 4.24) more likely to be super-utilizers of the ER. Higher self-reported satisfaction with care was associated with a 13.7% lower likelihood of being a super-utilizer (OR: 0.86, 95%CI: −0.68, 1.09). Conclusions: This study found strong associations between delays in care, self-reported care satisfaction, and being a super-utilizer of the ER during the pandemic among young adult CRC survivors off treatment. Increasing patient satisfaction and minimizing care interruptions amongst this vulnerable population may aid in mitigating over-utilization in the ER during an ongoing pandemic.

Published
2023

20. Eliciting anti-cancer immunity by genetically engineered multifunctional exosomes

Author

Cheng, Qinqin, Dai, Zhefu, Smbatyan, Goar, Epstein, Alan L, Lenz, Heinz-Josef, and Zhang, Yong

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Immunotherapy, Breast Cancer, Immunization, Bioengineering, Women's Health, Nanotechnology, Vaccine Related, Biotechnology, Cancer, 5.1 Pharmaceuticals, 5.2 Cellular and gene therapies, Animals, Antineoplastic Agents, Immunological, ErbB Receptors, Exosomes, Humans, Mice, Triple Negative Breast Neoplasms, exosomes, extracellular vesicles, immunotherapy, protein engineering, synthetic biology, triple negative breast cancer, Biological Sciences, Technology, Medical and Health Sciences, Genetics, Clinical sciences, Medical biotechnology
Abstract

Exosomes are cell-derived nanovesicles involved in regulating intercellular communications. In contrast to conventional nanomedicines, exosomes are characterized by unique advantages for therapeutic development. Despite their major successes in drug delivery, the full potential of exosomes for immunotherapy remains untapped. Herein we designed genetically engineered exosomes featured with surfaced-displayed antibody targeting groups and immunomodulatory proteins. Through genetic fusions with exosomal membrane proteins, Expi293F cell-derived exosomes were armed with monoclonal antibodies specific for human T-cell CD3 and epidermal growth factor receptor (EGFR) as well as immune checkpoint modulators, programmed death 1 (PD-1) and OX40 ligand (OX40L). The resulting genetically engineered multifunctional immune-modulating exosomes (GEMINI-Exos) can not only redirect and activate T cells toward killing EGFR-positive triple negative breast cancer (TNBC) cells but also elicit robust anti-cancer immunity, giving rise to highly potent inhibition against established TNBC tumors in mice. GEMINI-Exos represent candidate agents for immunotherapy and may offer a general strategy for generating exosome-based immunotherapeutics with desired functions and properties.

Published
2022

23. Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer

Author

Arai, Hiroyuki, Yang, Yan, Baca, Yasmine, Millstein, Joshua, Denda, Tadamichi, Ou, Fang-Shu, Innocenti, Federico, Takeda, Hiroyuki, Kubota, Yohei, Doi, Ayako, Horie, Yoshiki, Umemoto, Kumiko, Izawa, Naoki, Wang, Jingyuan, Battaglin, Francesca, Jayachandran, Priya, Algaze, Sandra, Soni, Shivani, Zhang, Wu, Goldberg, Richard M., Hall, Michael J., Scott, Aaron James, Hwang, Jimmy J., Lou, Emil, Weinberg, Benjamin A., Marshall, John, Goel, Sanjay, Xiu, Joanne, Michael Korn, W., Venook, Alan P., Sunakawa, Yu, and Lenz, Heinz-Josef

Published
2024
Full Text
View/download PDF

26. PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system

Author

Zimmer, Kai, Kocher, Florian, Untergasser, Gerold, Kircher, Brigitte, Amann, Arno, Baca, Yasmine, Xiu, Joanne, Korn, W. Micheal, Berger, Martin D., Lenz, Heinz-Josef, Puccini, Alberto, Fontana, Elisa, Shields, Anthony F., Marshall, John L., Hall, Michael, El-Deiry, Wafik S., Hsiehchen, David, Macarulla, Teresa, Tabernero, Josep, Pichler, Renate, Khushman, Moh’d, Manne, Upender, Lou, Emil, Wolf, Dominik, Sokolova, Viktorija, Schnaiter, Simon, Zeimet, Alain G., Gulhati, Pat, Widmann, Gerlig, and Seeber, Andreas

Published
2023
Full Text
View/download PDF

28. Site-specific antibody-drug conjugates with variable drug-to-antibody-ratios for AML therapy

Author

Dai, Zhefu, Zhang, Xiao-Nan, Cheng, Qinqin, Fei, Fan, Hou, Tianling, Li, Jiawei, Abdolvahabi, Alireza, Watanabe, Junji, Pei, Hua, Smbatyan, Goar, Xie, Jianming, Lenz, Heinz-Josef, Louie, Stan G, and Zhang, Yong

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Immunization, Cancer, Hematology, Biotechnology, 5.1 Pharmaceuticals, Antibodies, Monoclonal, Antineoplastic Agents, Humans, Immunoconjugates, Leukemia, Myeloid, Acute, Pharmaceutical Preparations, Acute myeloid leukemia, Antibody-drug conjugate, Protein engineering, Targeted therapy, Biomedical Engineering, Chemical Engineering, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences, Biomedical engineering
Abstract

Random conjugations of chemotherapeutics to monoclonal antibodies result in heterogeneous antibody-drug conjugates (ADCs) with suboptimal pharmacological properties. We recently developed a new technology for facile generation of homogeneous ADCs by harnessing human CD38 catalytic domain and its dinucleotide-derived covalent inhibitor, termed ADP-ribosyl cyclase-enabled ADCs (ARC-ADCs). Herein we advance this technology by designing and synthesizing ARC-ADCs with customizable drug-to-antibody ratios (DARs). Through varying numbers and locations of CD38 fused to an antibody targeting human C-type lectin-like molecule-1 (hCLL-1), ARC-ADCs featuring DARs of 2 and 4 were rapidly generated via a single step with cytotoxic monomethyl auristatin F (MMAF) as payloads. In contrast to anti-hCLL-1 ARC-ADC carrying 2 drug molecules, anti-hCLL-1 ARC-ADC with a DAR of 4 shows highly potent activity in killing hCLL-1-positive acute myeloid leukemia (AML) cells both in vitro and in vivo. This work provides novel ADC candidates for combating AML and supports ARC-ADC as a general and versatile approach for producing site-specific ADCs with defined DARs.

Published
2021

29. Pan-cancer analysis of RNA expression of ANGIOTENSIN-I-CONVERTING ENZYME 2 reveals high variability and possible impact on COVID-19 clinical outcomes.

Author

Elliott, Andrew, Saul, Michelle, Zeng, Jia, Marshall, John, Kim, Edward, Nagasaka, Misako, Lenz, Heinz-Josef, Schwartzberg, Lee, Spetzler, David, Abraham, Jim, Xiu, Joanne, Stafford, Phillip, and Michael Korn, W

Subjects
Aged, Angiotensin-Converting Enzyme 2, COVID-19, Case-Control Studies, Female, Humans, Male, Middle Aged, Neoplasms, RNA, Serine Endopeptidases, Tumor Microenvironment, Exome Sequencing
Abstract

Patients with cancer demonstrate particularly poor outcomes from COVID-19. To provide information essential for understanding the biologic underpinnings of this association, we analyzed whole-transcriptome RNA expression data obtained from a large cohort of cancer patients to characterize expression of ACE2, TMPRSS2, and other proteases that are involved in viral attachment to and entry into target cells. We find substantial variability of expression of these factors across tumor types and identify subpopulations expressing ACE2 at very high levels. In some tumor types, especially in gastrointestinal cancers, expression of ACE2 and TMPRSS2 is highly correlated. Furthermore, we found infiltration with T-cell and natural killer (NK) cell infiltration to be particularly pronounced in ACE2-high tumors. These findings suggest that subsets of cancer patients exist with gene expression profiles that may be associated with heightened susceptibility to SARS-CoV-2 infection, in whom malignant tumors function as viral reservoir and possibly promote the frequently detrimental hyper-immune response in patients infected with this virus.

Published
2021

30. Human‐specific polymorphic pseudogenization of SIGLEC12 protects against advanced cancer progression

Author

Siddiqui, Shoib S, Vaill, Michael, Do, Raymond, Khan, Naazneen, Verhagen, Andrea L, Zhang, Wu, Lenz, Heinz‐Josef, Johnson‐Pais, Teresa L, Leach, Robin J, Fraser, Gary, Wang, Charles, Feng, Gen‐Sheng, Varki, Nissi, and Varki, Ajit

Subjects
Biological Sciences, Genetics, Cancer, Human Genome, Urologic Diseases, Biotechnology, 2.1 Biological and endogenous factors, advanced carcinoma, dot blot, immunohistochemistry, pseudogenization, SIGLEC12, Biological sciences
Abstract

Compared with our closest living evolutionary cousins, humans appear unusually prone to develop carcinomas (cancers arising from epithelia). The SIGLEC12 gene, which encodes the Siglec-XII protein expressed on epithelial cells, has several uniquely human features: a fixed homozygous missense mutation inactivating its natural ligand recognition property; a polymorphic frameshift mutation eliminating full-length protein expression in ~60%-70% of worldwide human populations; and, genomic features suggesting a negative selective sweep favoring the pseudogene state. Despite the loss of canonical sialic acid binding, Siglec-XII still recruits Shp2 and accelerates tumor growth in a mouse model. We hypothesized that dysfunctional Siglec-XII facilitates human carcinoma progression, correlating with known tumorigenic signatures of Shp2-dependent cancers. Immunohistochemistry was used to detect Siglec-XII expression on tissue microarrays. PC-3 prostate cancer cells were transfected with Siglec-XII and transcription of genes enriched with Siglec-XII was determined. Genomic SIGLEC12 status was determined for four different cancer cohorts. Finally, a dot blot analysis of human urinary epithelial cells was established to determine the Siglec-XII expressors versus non-expressors. Forced expression in a SIGLEC12 null carcinoma cell line enriched transcription of genes associated with cancer progression. While Siglec-XII was detected as expected in ~30%-40% of normal epithelia, ~80% of advanced carcinomas showed strong expression. Notably, >80% of late-stage colorectal cancers had a functional SIGLEC12 allele, correlating with overall increased mortality. Thus, advanced carcinomas are much more likely to occur in individuals whose genomes have an intact SIGLEC12 gene, likely because the encoded Siglec-XII protein recruits Shp2-related oncogenic pathways. The finding has prognostic, diagnostic, and therapeutic implications.

Published
2021

32. Elucidating the Risk of Colorectal Cancer for Variants in Hereditary Colorectal Cancer Genes

Author

Wang, Xiaoliang, Huyghe, Jeroen R., Joo, Jihoon E., Georgeson, Peter, Arndt, Volker, Berndt, Sonja I., Bézieau, Stéphane, Bien, Stephanie A., Bishop, D. Timothy, Brenner, Hermann, Brezina, Stefanie, Burnett-Hartman, Andrea, Campbell, Peter T., Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Cremolini, Chiara, Diergaarde, Brenda, Figueiredo, Jane C., FitzGerald, Liesel M., Gago-Dominguez, Manuela, Gallinger, Steven, Giles, Graham G., Gsu, Andrea, Gunter, Marc J., Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lenz, Heinz-Josef, Li, Christopher I., Li, Li, Lin, Yi, Lindblom, Annika, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Newton, Christina C., Obón-Santacana, Mireia, Ogino, Shuji, Pai, Rish K., Palmer, Julie R., Pearlman, Rachel, Pharoah, Paul D.P., Phipps, Amanda I., Platz, Elizabeth A., Potter, John D., Rennert, Gad, Sakoda, Lori C., Schafmayer, Clemens, Schmit, Stephanie L., Schoen, Robert E., Slattery, Martha L., Stadler, Zsofia K., Steinfelder, Robert S., Thibodeau, Stephen N., Ulrich, Cornelia M., Um, Caroline Y., van Duijnhoven, Franzel J.B., Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weinstein, Stephanie J., White, Emily, Winship, Ingrid M., Wolk, Alicja, Gruber, Stephen B., Jenkins, Mark A., Mahmood, Khalid, Thomas, Minta, Qu, Conghui, Hsu, Li, Buchanan, Daniel D., and Peters, Ulrike

Published
2023
Full Text
View/download PDF

33. ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal–Anal Task Forces whitepaper

Author

Dasari, Arvind, Morris, Van K, Allegra, Carmen J, Atreya, Chloe, Benson, Al B, Boland, Patrick, Chung, Ki, Copur, Mehmet S, Corcoran, Ryan B, Deming, Dustin A, Dwyer, Andrea, Diehn, Maximilian, Eng, Cathy, George, Thomas J, Gollub, Marc J, Goodwin, Rachel A, Hamilton, Stanley R, Hechtman, Jaclyn F, Hochster, Howard, Hong, Theodore S, Innocenti, Federico, Iqbal, Atif, Jacobs, Samuel A, Kennecke, Hagen F, Lee, James J, Lieu, Christopher H, Lenz, Heinz-Josef, Lindwasser, O Wolf, Montagut, Clara, Odisio, Bruno, Ou, Fang-Shu, Porter, Laura, Raghav, Kanwal, Schrag, Deborah, Scott, Aaron J, Shi, Qian, Strickler, John H, Venook, Alan, Yaeger, Rona, Yothers, Greg, You, Y Nancy, Zell, Jason A, and Kopetz, Scott

Subjects
Cancer, Clinical Research, Colo-Rectal Cancer, Digestive Diseases, Good Health and Well Being, Biomarkers, Tumor, Circulating Tumor DNA, Colon, Colorectal Neoplasms, Humans, Liquid Biopsy, National Cancer Institute (U.S.), Neoplasm, Residual, Rectal Neoplasms, United States, Oncology and Carcinogenesis
Abstract

An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal-Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.

Published
2020

34. Safety and Efficacy of Durvalumab and Tremelimumab Alone or in Combination in Patients with Advanced Gastric and Gastroesophageal Junction Adenocarcinoma

Author

Kelly, Ronan J, Lee, Jeeyun, Bang, Yung-Jue, Almhanna, Khaldoun, Blum-Murphy, Mariela, Catenacci, Daniel VT, Chung, Hyun Cheol, Wainberg, Zev A, Gibson, Michael K, Lee, Keun-Wook, Bendell, Johanna C, Denlinger, Crystal S, Chee, Cheng Ean, Omori, Takeshi, Leidner, Rom, Lenz, Heinz-Josef, Chao, Yee, Rebelatto, Marlon C, Brohawn, Philip Z, He, Peng, McDevitt, Jennifer, Sheth, Siddharth, Englert, Judson M, and Ku, Geoffrey Y

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Precision Medicine, Clinical Research, Clinical Trials and Supportive Activities, Digestive Diseases, Minority Health, Rare Diseases, Cancer, Patient Safety, Orphan Drug, Health Disparities, 6.1 Pharmaceuticals, 6.2 Cellular and gene therapies, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, B7-H1 Antigen, CTLA-4 Antigen, Circulating Tumor DNA, Esophagogastric Junction, Female, Humans, Interferon-gamma, Male, Middle Aged, Prospective Studies, Stomach Neoplasms, Transcriptome, Young Adult, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeThis randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer.Patients and methodsSecond-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months.ResultsA total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively.ConclusionsResponse rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.

Published
2020

35. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author

Fernandez-Rozadilla, Ceres, Timofeeva, Maria, Chen, Zhishan, Law, Philip, Thomas, Minta, Schmit, Stephanie, Díez-Obrero, Virginia, Hsu, Li, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah, Svinti, Victoria, Donnelly, Kevin, Farrington, Susan, Blackmur, James, Vaughan-Shaw, Peter, Shu, Xiao-ou, Long, Jirong, Cai, Qiuyin, Guo, Xingyi, Lu, Yingchang, Broderick, Peter, Studd, James, Huyghe, Jeroen, Harrison, Tabitha, Conti, David, Dampier, Christopher, Devall, Mathew, Schumacher, Fredrick, Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Moratalla-Navarro, Ferran, Oh, Jae Hwan, Kim, Jeongseon, Jee, Sun Ha, Jung, Keum Ji, Kweon, Sun-Seog, Shin, Min-Ho, Shin, Aesun, Ahn, Yoon-Ok, Kim, Dong-Hyun, Oze, Isao, Wen, Wanqing, Matsuo, Keitaro, Matsuda, Koichi, Tanikawa, Chizu, Ren, Zefang, Gao, Yu-Tang, Jia, Wei-Hua, Hopper, John, Jenkins, Mark, Win, Aung Ko, Pai, Rish, Figueiredo, Jane, Haile, Robert, Gallinger, Steven, Woods, Michael, Newcomb, Polly, Duggan, David, Cheadle, Jeremy, Kaplan, Richard, Maughan, Timothy, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Lukka-Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri, Rissanen, Harri, Pukkala, Eero, Eriksson, Johan, Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Zanke, Brent, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie, Ruiz-Narvaez, Edward, Palmer, Julie, Buchanan, Daniel, Platz, Elizabeth, Visvanathan, Kala, Ulrich, Cornelia, Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter, Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha, Potter, John, Tsilidis, Konstantinos, Schulze, Matthias, Gunter, Marc, Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Stern, Mariana, Pardamean, Bens, Bishop, Timothy, Giles, Graham, Southey, Melissa, Idos, Gregory, McDonnell, Kevin, Abu-Ful, Zomoroda, Greenson, Joel, Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu-Ru, Steinfelder, Robert, Keku, Temitope, van Guelpen, Bethany, Hudson, Thomas, Hampel, Heather, Pearlman, Rachel, Berndt, Sonja, Hayes, Richard, Martinez, Marie Elena, Thomas, Sushma, Corley, Douglas, Pharoah, Paul, Larsson, Susanna, Yen, Yun, Lenz, Heinz-Josef, White, Emily, Li, Li, Doheny, Kimberly, Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew, Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David, Joshi, Amit, Schafmayer, Clemens, Scacheri, Peter, Kundaje, Anshul, Nickerson, Deborah, Schoen, Robert, Hampe, Jochen, Stadler, Zsofia, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Papadopoulos, Nickolas, Edlund, Chistopher, Gauderman, William, Thomas, Duncan, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen, van Duijnhoven, Franzel, Feskens, Edith, Sakoda, Lori, Gago-Dominguez, Manuela, Wolk, Alicja, Naccarati, Alessio, Pardini, Barbara, FitzGerald, Liesel, Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie, Kooperberg, Charles, Li, Christopher, Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Tangen, Catherine, Mardis, Elaine, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Haiman, Christopher, Le Marchand, Loic, Wu, Anna, Qu, Chenxu, McNeil, Caroline, Coetzee, Gerhard, Hayward, Caroline, Deary, Ian, Harris, Sarah, Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Moreno, Victor, Casey, Graham, Gruber, Stephen, Tomlinson, Ian, Zheng, Wei, Dunlop, Malcolm, Houlston, Richard, and Peters, Ulrike

Published
2023
Full Text
View/download PDF

36. Impact of genetic variants involved in the lipid metabolism pathway on progression free survival in patients receiving bevacizumab-based chemotherapy in metastatic colorectal cancer: a retrospective analysis of FIRE-3 and MAVERICC trials

Author

Wang, Jingyuan, Millstein, Joshua, Yang, Yan, Stintzing, Sebastian, Arai, Hiroyuki, Battaglin, Francesca, Kawanishi, Natsuko, Soni, Shivani, Zhang, Wu, Mancao, Christoph, Cremolini, Chiara, Liu, Tianshu, Heinemann, Volker, Falcone, Alfredo, Shen, Lin, and Lenz, Heinz-Josef

Published
2023
Full Text
View/download PDF

37. Evaluating sex as a predictive marker for response to bevacizumab in metastatic colorectal carcinoma: Pooled analysis of 3,369 patients in the ARCAD database

Author

Margalit, Ofer, Harmsen, William S., Shacham-Shmueli, Einat, Voss, Molly M., Boursi, Ben, Wagner, Anna D., Cohen, Romain, Olswold, Curtis L., Saltz, Leonard B., Goldstein, Daniel A., Hurwitz, Herbert, Tebbutt, Niall C., Kabbinavar, Fairooz F., Adams, Richard A., Chibaudel, Benoist, Grothey, Axel, Yoshino, Takayuki, Zalcberg, John, de Gramont, Aimery, Shi, Qian, and Lenz, Heinz-Josef

Published
2023
Full Text
View/download PDF

39. Benefit from upfront FOLFOXIRI and bevacizumab in BRAFV600E-mutated metastatic colorectal cancer patients: does primary tumour location matter?

Author

Moretto, Roberto, Elliott, Andrew, Rossini, Daniele, Intini, Rossana, Conca, Veronica, Pietrantonio, Filippo, Sartore-Bianchi, Andrea, Antoniotti, Carlotta, Rasola, Cosimo, Scartozzi, Mario, Salati, Massimiliano, Pella, Nicoletta, Calegari, Maria Alessandra, Carullo, Martina, Corti, Francesca, Mauri, Gianluca, Fassan, Matteo, Masi, Gianluca, Brodskiy, Pavel, Lenz, Heinz-Josef, Shields, Anthony, Lonardi, Sara, Korn, Michael, and Cremolini, Chiara

Published
2022
Full Text
View/download PDF

40. Associations of Physical Activity With Survival and Progression in Metastatic Colorectal Cancer: Results From Cancer and Leukemia Group B (Alliance)/SWOG 80405.

Author

Guercio, Brendan J, Zhang, Sui, Ou, Fang-Shu, Venook, Alan P, Niedzwiecki, Donna, Lenz, Heinz-Josef, Innocenti, Federico, O'Neil, Bert H, Shaw, James E, Polite, Blase N, Hochster, Howard S, Atkins, James N, Goldberg, Richard M, Sato, Kaori, Ng, Kimmie, Van Blarigan, Erin, Mayer, Robert J, Blanke, Charles D, O'Reilly, Eileen M, Fuchs, Charles S, and Meyerhardt, Jeffrey A

Subjects
Cancer, Digestive Diseases, Clinical Research, Colo-Rectal Cancer, Good Health and Well Being, Aged, Antineoplastic Combined Chemotherapy Protocols, Clinical Trials, Phase III as Topic, Cohort Studies, Colorectal Neoplasms, Disease Progression, Exercise, Female, Humans, Male, Middle Aged, Prospective Studies, Randomized Controlled Trials as Topic, Surveys and Questionnaires, United States, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeRegular physical activity is associated with reduced risk of recurrence and mortality in patients with nonmetastatic colorectal cancer. Its influence on patients with advanced/metastatic colorectal cancer (mCRC) has been largely unexplored.Patients and methodsWe conducted a prospective cohort study nested in Cancer and Leukemia Group B (Alliance)/SWOG 80405 (ClinicalTrials.gov identifier: NCT00265850), a National Cancer Institute-sponsored phase III trial of systemic therapy for mCRC. Within 1 month after therapy initiation, patients were invited to complete a validated questionnaire that reported average physical activity over the previous 2 months. On the basis of responses, we calculated metabolic equivalent task (MET) hours per week to quantify physical activity. The primary end point of the clinical trial and this companion study was overall survival (OS). Secondary end points included progression-free survival (PFS) and first grade 3 or greater treatment-related adverse events. To minimize confounding by poor and declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and used Cox proportional hazards regression analysis to adjust for known prognostic factors, comorbidities, and weight loss.ResultsThe final cohort included 1,218 patients. Compared with patients engaged in less than 3 MET hours per week of physical activity, patients engaged in 18 or more MET hours per week experienced an adjusted hazard ratio for OS of 0.85 (95% CI, 0.71 to 1.02; PTrend = .06) and for PFS of 0.83 (95% CI, 0.70 to 0.99; PTrend = .01). Compared with patients engaging in less than 9 MET hours per week, patients engaging in 9 or more MET hours per week experienced an adjusted hazard ratio for grade 3 or greater treatment-related adverse events of 0.73 (95% CI, 0.62 to 0.86; PTrend < .001).ConclusionAmong patients with mCRC in Cancer and Leukemia Group B (Alliance)/SWOG 80405, association of physical activity with OS was not statistically significant. Greater physical activity was associated with longer PFS and lower adjusted risk for first grade 3 or greater treatment-related adverse events.

Published
2019

41. MAVERICC, a Randomized, Biomarker-stratified, Phase II Study of mFOLFOX6-Bevacizumab versus FOLFIRI-Bevacizumab as First-line Chemotherapy in Metastatic Colorectal CancerPhase II study of mFOLFOX6-BV vs. FOLFIRI-BV in mCRC

Author

Parikh, Aparna R, Lee, Fa-Chyi, Yau, Linda, Koh, Han, Knost, James, Mitchell, Edith P, Bosanac, Ivan, Choong, Nicholas, Scappaticci, Frank, Mancao, Christoph, and Lenz, Heinz-Josef

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Cancer, Colo-Rectal Cancer, Digestive Diseases, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Biomarkers, Tumor, Camptothecin, Colorectal Neoplasms, DNA-Binding Proteins, Endonucleases, Female, Fluorouracil, Humans, Irinotecan, Leucovorin, Male, Middle Aged, Neoplasm Metastasis, Organoplatinum Compounds, Prognosis, Survival Rate, Vascular Endothelial Growth Factor A, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeMAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC).Patients and Methods: MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/β-actin mRNA expression level and region.ResultsOf 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS [HR = 0.79; 95% CI (confidence interval): 0.61-1.01; P = 0.06] and OS (HR = 0.76; 95% CI: 0.56-1.04; P = 0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR = 0.84; 95% CI: 0.56-1.26; P = 0.40; OS, HR = 0.80; 95% CI: 0.51-1.26; P = 0.33). Across treatment groups, high plasma VEGF-A levels (>5.1 pg/mL) were observed with shorter PFS (HR = 1.19; 95% CI: 0.93-1.53; P = 0.17) and significantly shorter OS (HR = 1.64; 95% CI: 1.20-2.24; P < 0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable with those reported previously.ConclusionsFirst-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these bevacizumab-containing regimens.

Published
2019

42. Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Author

Schmit, Stephanie L, Edlund, Christopher K, Schumacher, Fredrick R, Gong, Jian, Harrison, Tabitha A, Huyghe, Jeroen R, Qu, Chenxu, Melas, Marilena, Van Den Berg, David J, Wang, Hansong, Tring, Stephanie, Plummer, Sarah J, Albanes, Demetrius, Alonso, M Henar, Amos, Christopher I, Anton, Kristen, Aragaki, Aaron K, Arndt, Volker, Barry, Elizabeth L, Berndt, Sonja I, Bezieau, Stéphane, Bien, Stephanie, Bloomer, Amanda, Boehm, Juergen, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buchanan, Daniel D, Butterbach, Katja, Caan, Bette J, Campbell, Peter T, Carlson, Christopher S, Castelao, Jose E, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Cheng, Iona, Cheng, Ya-Wen, Chin, Lee Soo, Church, James M, Church, Timothy, Coetzee, Gerhard A, Cotterchio, Michelle, Correa, Marcia Cruz, Curtis, Keith R, Duggan, David, Easton, Douglas F, English, Dallas, Feskens, Edith JM, Fischer, Rocky, FitzGerald, Liesel M, Fortini, Barbara K, Fritsche, Lars G, Fuchs, Charles S, Gago-Dominguez, Manuela, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Giovannucci, Edward L, Gogarten, Stephanie M, Gonzalez-Villalpando, Clicerio, Gonzalez-Villalpando, Elena M, Grady, William M, Greenson, Joel K, Gsur, Andrea, Gunter, Marc, Haiman, Christopher A, Hampe, Jochen, Harlid, Sophia, Harju, John F, Hayes, Richard B, Hofer, Philipp, Hoffmeister, Michael, Hopper, John L, Huang, Shu-Chen, Huerta, Jose Maria, Hudson, Thomas J, Hunter, David J, Idos, Gregory E, Iwasaki, Motoki, Jackson, Rebecca D, Jacobs, Eric J, Jee, Sun Ha, Jenkins, Mark A, Jia, Wei-Hua, Jiao, Shuo, Joshi, Amit D, Kolonel, Laurence N, Kono, Suminori, Kooperberg, Charles, Krogh, Vittorio, Kuehn, Tilman, Küry, Sébastien, LaCroix, Andrea, Laurie, Cecelia A, Lejbkowicz, Flavio, Lemire, Mathieu, Lenz, Heinz-Josef, and Levine, David

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Digestive Diseases, Human Genome, Prevention, Colo-Rectal Cancer, Clinical Research, Genetics, Cancer, 2.1 Biological and endogenous factors, Case-Control Studies, Colorectal Neoplasms, Ethnicity, Follow-Up Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Prognosis, United States, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundPrevious genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.MethodsWe conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.ResultsThe discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.ConclusionsThis study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Published
2019

45. Genetic variants involved in the cGAS-STING pathway predict outcome in patients with metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials

Author

Wang, Jingyuan, Xiao, Yi, Loupakis, Fotios, Stintzing, Sebastian, Yang, Yan, Arai, Hiroyuki, Battaglin, Francesca, Kawanishi, Natsuko, Jayachandran, Priya, Soni, Shivani, Zhang, Wu, Mancao, Christoph, Cremolini, Chiara, Liu, Tianshu, Heinemann, Volker, Falcone, Alfredo, Shen, Lin, Millstein, Joshua, and Lenz, Heinz-Josef

Published
2022
Full Text
View/download PDF

48. Age and comorbidity association with survival outcomes in metastatic colorectal cancer: CALGB 80405 analysis

Author

McCleary, Nadine J., Zhang, Sui, Ma, Chao, Ou, Fang-Shu, Bainter, Tiffany M., Venook, Alan P., Niedzwiecki, Donna, Lenz, Heinz-Josef, Innocenti, Federico, O'Neil, Bert H., Polite, Blase N., Hochster, Howard S., Atkins, James N., Goldberg, Richard M., Ng, Kimmie, Mayer, Robert J., Blanke, Charles D., O'Reilly, Eileen M., Fuchs, Charles S., and Meyerhardt, Jeffrey A.

Published
2022
Full Text
View/download PDF

49. Plant-based diet and survival among patients with metastatic colorectal cancer.

Author

Cheng, En, Ou, Fang-Shu, Gatten, Clare, Ma, Chao, Venook, Alan P, Lenz, Heinz-Josef, O'Reilly, Eileen M, Campbell, Peter T, Kuang, Chaoyuan, Caan, Bette J, Blanke, Charles D, Ng, Kimmie, and Meyerhardt, Jeffrey A

Subjects
PLANT-based diet, WHOLE grain foods, FOOD of animal origin, OVERALL survival, COLORECTAL cancer, SOFT drinks
Abstract

Background A plant-based diet is associated with better survival among patients with nonmetastatic colorectal cancer (CRC), but its association in metastatic CRC is unknown. Methods Using an National Cancer Institute–sponsored trial (CALGB/SWOG 80405), we included 1284 patients who completed validated food frequency questionnaires at the initiation of metastatic CRC treatment. We calculated 3 indices: overall plant-based diet index (PDI), which emphasized consumption of all plant foods while reducing animal food intake; healthful plant-based diet index (hPDI), which emphasized consumption of healthful plant foods such as whole grains, fruits, and vegetables; and unhealthful plant-based diet index (uPDI), which emphasized consumption of less healthful plant foods such as fruit juices, refined grains, and sugar-sweetened beverages. We estimated the associations of 3 indices (quintiles) with overall survival (OS) and progression-free survival (PFS) using multivariable Cox proportional hazards regression. Results We observed 1100 deaths and 1204 progression events (median follow-up = 6.1 years). Compared with the lowest quintile, patients in the highest quintile of PDI had significantly better survival (hazard ratio [HR] for OS = 0.76 [0.62-0.94], P trend = .004; PFS = 0.81 [0.66-0.99], P trend = .09). Similar findings were observed for hPDI (HR for OS = 0.81 [0.65-1.01], P trend = .053; PFS = 0.80 [0.65-0.98], P trend = .04), whereas uPDI was not associated with worse survival (HR for OS = 1.16 [0.94-1.43], P trend = .21; PFS = 1.12 [0.92-1.36], P trend = .42). Conclusions Our study suggests that a plant-based diet, especially when rich in healthful plant foods, is associated with better survival among patients with metastatic CRC. The cause of survival benefits warrants further investigation. [ABSTRACT FROM AUTHOR]

Published
2025
Full Text
View/download PDF

50. Clinical Applications of Circulating Tumor DNA Profiling in GI Cancers.

Author

Battaglin, Francesca and Lenz, Heinz-Josef

Subjects
NUCLEIC acid analysis, GASTROINTESTINAL tumors, EARLY detection of cancer, TUMOR markers, BODY fluid examination, CELL lines, METASTASIS, GENE expression profiling, EXTRACELLULAR space, INDIVIDUALIZED medicine, CANCER genes, PATIENT monitoring, GENETIC mutation, MOLECULAR diagnosis
Abstract

Over the next few years, the analysis of circulating tumor DNA (ctDNA) through liquid biopsy is expected to enter clinical practice and revolutionize the approach to biomarker testing and treatment selection in GI cancers. In fact, growing evidence support the use of ctDNA testing as a noninvasive, effective, and highly specific tool for molecular profiling in GI cancers. Analysis of blood ctDNA has been investigated in multiple settings including early tumor detection, minimal residual disease evaluation, tumor diagnosis and evaluation of prognostic/predictive biomarkers for targeted treatment selection, longitudinal monitoring of treatment response, and identification of resistance mechanisms. Here, we review the clinical applications, advantages, and limitations of ctDNA profiling for precision oncology in GI cancers. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results