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1. Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without Mammalian Target of Rapamycin Inhibitors in Patients with Fibrolamellar Carcinoma

Author

Ghassan K. Abou-Alfa, Tim Meyer, Richard Kinh Gian Do, Sarina A. Piha-Paul, Joseph S. Light, Scott Sherrin, Amin Yaqubie, Alison Clemens O’Neill, James J. Harding, Raed Al-Rajabi, Crystal S. Denlinger, Pablo Cano, Albert S. Cornelius, Eileen M. O'Reilly, Daniel DiPrimeo, Lisa D. Eli, John D. Gordan, and David B. Solit

Subjects
neratinib, fibrolamellar carcinoma, summit phase 2 basket study, pan-her kinase inhibition, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Introduction: Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including HER2, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC. Methods: Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint. Results: Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0–21.8) and the disease control rate was 13.3% (95% CI: 1.7–40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (n = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (n = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy. Conclusion: In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.

Published
2024
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2. STING‐ATF3/type I interferon crosstalk: A potential target to improve anti‐tumour immunity in chemotherapy‐treated urothelial carcinoma

Author

Alexandra Fauvre, Margot Machu, Audrey Merienne, Nadia Vie, Thomas Bessede, Mathilde Robin, Veronique Garambois, Clara Taffoni, Nadine Laguette, Nadine Gervois‐Segain, Anne Jarry, Nathalie Labarriere, Yves Allory, Christel Larbouret, Laurent Gros, Diego Tosi, David B. Solit, Philippe Pourquier, Nadine Houédé, and Celine Gongora

Subjects
Medicine (General), R5-920
Published
2024
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3. Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy

Author

Charlotte S. Walmsley, Philip Jonsson, Michael L. Cheng, Sean McBride, Christopher Kaeser, Herbert Alberto Vargas, Vincent Laudone, Barry S. Taylor, Rajya Kappagantula, Priscilla Baez, Allison L. Richards, Anne Marie Noronha, Dilmi Perera, Michael Berger, David B. Solit, Christine A. Iacobuzio-Donahue, Howard I. Scher, Mark T. A. Donoghue, Wassim Abida, and Alison M. Schram

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient with metastatic castration-resistant prostate cancer (mCRPC) with a germline BRCA2 mutation who developed acquired resistance to PARP inhibition. Extensive genomic interrogation of cell-free DNA (cfDNA) and tissue at baseline, post-progression, and postmortem revealed ten unique BRCA2 reversion mutations across ten sites. While several of the reversion mutations were private to a specific site, nine out of ten tumors contained at least one mutation, suggesting a powerful clonal selection for reversion mutations in the presence of therapeutic pressure by PARP inhibition. Variable cfDNA shed was seen across tumor sites, emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance. This report provides a genomic portrait of the temporal and spatial heterogeneity of prostate cancer under the selective pressure of a PARP inhibition and exposes limitations in the current strategies for detection of reversion mutations.

Published
2024
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4. Clinical-genomic determinants of immune checkpoint blockade response in head and neck squamous cell carcinoma

Author

Cristina Valero, Mahdi Golkaram, Joris L. Vos, Bin Xu, Conall Fitzgerald, Mark Lee, Shannon Kaplan, Catherine Y. Han, Xin Pei, Reith Sarkar, Lillian A. Boe, Abhinav Pandey, Elizabeth S. Koh, Charlotte L. Zuur, David B. Solit, Traci Pawlowski, Li Liu, Alan L. Ho, Diego Chowell, Nadeem Riaz, Timothy A. Chan, and Luc G.T. Morris

Subjects
Immunology, Oncology, Medicine
Abstract

BACKGROUND Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is generally an incurable disease, with patients experiencing median survival of under 10 months and significant morbidity. While immune checkpoint blockade (ICB) drugs are effective in approximately 20% of patients, the remaining experience limited clinical benefit and are exposed to potential adverse effects and financial costs. Clinically approved biomarkers, such as tumor mutational burden (TMB), have a modest predictive value in HNSCC.METHODS We analyzed clinical and genomic features, generated using whole-exome sequencing, in 133 ICB-treated patients with R/M HNSCC, of whom 69 had virus-associated and 64 had non-virus-associated tumors.RESULTS Hierarchical clustering of genomic data revealed 6 molecular subtypes characterized by a wide range of objective response rates and survival after ICB therapy. The prognostic importance of these 6 subtypes was validated in an external cohort. A random forest-based predictive model, using several clinical and genomic features, predicted progression-free survival (PFS), overall survival (OS), and response with greater accuracy than did a model based on TMB alone. Recursive partitioning analysis identified 3 features (systemic inflammatory response index, TMB, and smoking signature) that classified patients into risk groups with accurate discrimination of PFS and OS.CONCLUSION These findings shed light on the immunogenomic characteristics of HNSCC tumors that drive differential responses to ICB and identify a clinical-genomic classifier that outperformed the current clinically approved biomarker of TMB. This validated predictive tool may help with clinical risk stratification in patients with R/M HNSCC for whom ICB is being considered.FUNDING Fundación Alfonso Martín Escudero, NIH R01 DE027738, US Department of Defense CA210784, The Geoffrey Beene Cancer Research Center, The MSKCC Population Science Research Program, the Jayme Flowers Fund, the Sebastian Nativo Fund, and the NIH/NCI Cancer Center Support Grant P30 CA008748.

Published
2023
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5. Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers

Author

James J. Harding, Sarina A. Piha-Paul, Ronak H. Shah, Jessica J. Murphy, James M. Cleary, Geoffrey I. Shapiro, David I. Quinn, Irene Braña, Victor Moreno, Mitesh Borad, Sherene Loi, Iben Spanggaard, Haeseong Park, James M. Ford, Mónica Arnedos, Salomon M. Stemmer, Christelle de la Fouchardiere, Christos Fountzilas, Jie Zhang, Daniel DiPrimeo, Casey Savin, S. Duygu Selcuklu, Michael F. Berger, Lisa D. Eli, Funda Meric-Bernstam, Komal Jhaveri, David B. Solit, and Ghassan K. Abou-Alfa

Subjects
Science
Abstract

In biliary tract cancer HER2 alterations correlate with poor prognosis. Here, the authors present the results of a phase II clinical trial reporting the efficacy and safety of the tyrosine kinase inhibitor neratinib in patients with HER2-mutation positive advanced biliary tract cancers.

Published
2023
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6. FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation

Author

Joshua I. Warrick, Wenhuo Hu, Hironobu Yamashita, Vonn Walter, Lauren Shuman, Jenna M. Craig, Lan L. Gellert, Mauro A. A. Castro, A. Gordon Robertson, Fengshen Kuo, Irina Ostrovnaya, Judy Sarungbam, Ying-bei Chen, Anuradha Gopalan, Sahussapont J. Sirintrapun, Samson W. Fine, Satish K. Tickoo, Kwanghee Kim, Jasmine Thomas, Nagar Karan, Sizhi Paul Gao, Timothy N. Clinton, Andrew T. Lenis, Timothy A. Chan, Zhiyu Chen, Manisha Rao, Travis J. Hollman, Yanyun Li, Nicholas D. Socci, Shweta Chavan, Agnes Viale, Neeman Mohibullah, Bernard H. Bochner, Eugene J. Pietzak, Min Yuen Teo, Gopa Iyer, Jonathan E. Rosenberg, Dean F. Bajorin, Matthew Kaag, Suzanne B. Merrill, Monika Joshi, Rosalyn Adam, John A. Taylor, Peter E. Clark, Jay D. Raman, Victor E. Reuter, Yu Chen, Samuel A. Funt, David B. Solit, David J. DeGraff, and Hikmat A. Al-Ahmadie

Subjects
Science
Abstract

Bladder cancer can often exhibit genomic and morphological heterogeneity. Here, the authors use genomics analysis to show lineage plasticity of bladder cancers with squamous differentiation, and identify key transcription factors related to this morphological and immune heterogeneity.

Published
2022
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7. Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets

Author

Benjamin A. Nacev, Francisco Sanchez-Vega, Shaleigh A. Smith, Cristina R. Antonescu, Evan Rosenbaum, Hongyu Shi, Cerise Tang, Nicholas D. Socci, Satshil Rana, Rodrigo Gularte-Mérida, Ahmet Zehir, Mrinal M. Gounder, Timothy G. Bowler, Anisha Luthra, Bhumika Jadeja, Azusa Okada, Jonathan A. Strong, Jake Stoller, Jason E. Chan, Ping Chi, Sandra P. D’Angelo, Mark A. Dickson, Ciara M. Kelly, Mary Louise Keohan, Sujana Movva, Katherine Thornton, Paul A. Meyers, Leonard H. Wexler, Emily K. Slotkin, Julia L. Glade Bender, Neerav N. Shukla, Martee L. Hensley, John H. Healey, Michael P. La Quaglia, Kaled M. Alektiar, Aimee M. Crago, Sam S. Yoon, Brian R. Untch, Sarah Chiang, Narasimhan P. Agaram, Meera R. Hameed, Michael F. Berger, David B. Solit, Nikolaus Schultz, Marc Ladanyi, Samuel Singer, and William D. Tap

Subjects
Science
Abstract

Sarcomas are rare tumours with many different subtypes and clinical outcomes; a broader knowledge of their genetic features is required. Here, the authors analyse 2138 soft tissue and bone sarcomas across 45 subtypes using MSK-IMPACT targeted sequencing and find genomic groups that are distinct from histological subgroups.

Published
2022
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8. AKT mutant allele-specific activation dictates pharmacologic sensitivities

Author

Tripti Shrestha Bhattarai, Tambudzai Shamu, Alexander N. Gorelick, Matthew T. Chang, Debyani Chakravarty, Elena I. Gavrila, Mark T. A. Donoghue, JianJong Gao, Swati Patel, Sizhi Paul Gao, Margaret H. Reynolds, Sarah M. Phillips, Tara Soumerai, Wassim Abida, David M. Hyman, Alison M. Schram, David B. Solit, Lillian M. Smyth, and Barry S. Taylor

Subjects
Science
Abstract

How different oncogenic Akt mutants can affect the response to Akt inhibitors is currently unclear. Here, the authors analyse somatic mutations of Akt1-3 isoforms in several human cancers, investigate their oncogenic effects and therapeutic relevance in vitro and confirm some of their data in a clinical trial testing the AKT inhibitor capivasertib in patients with solid tumors harboring AKT alterations.

Published
2022
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9. HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway

Author

Alison E. Smith, Emanuela Ferraro, Anton Safonov, Cristina Bernado Morales, Enrique J. Arenas Lahuerta, Qing Li, Amanda Kulick, Dara Ross, David B. Solit, Elisa de Stanchina, Jorge Reis-Filho, Neal Rosen, Joaquín Arribas, Pedram Razavi, and Sarat Chandarlapaty

Subjects
Science
Abstract

Resistance to HER2 inhibition in HER2- amplified breast cancer is common in the metastatic setting and the underlying molecular mechanisms remain unknown. Here, the authors, perform genomic profiling of 733 HER2-amplified breast cancers and propose genetic activation of MAPK as a resistance mechanism.

Published
2021
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10. Molecular and phenotypic profiling of colorectal cancer patients in West Africa reveals biological insights

Author

Olusegun Isaac Alatise, Gregory C. Knapp, Avinash Sharma, Walid K. Chatila, Olukayode A. Arowolo, Olalekan Olasehinde, Olusola C. Famurewa, Adeleye D. Omisore, Akinwumi O. Komolafe, Olaejinrinde O. Olaofe, Aba I. Katung, David E. Ibikunle, Adedeji A. Egberongbe, Samuel A. Olatoke, Sulaiman O. Agodirin, Olusola A. Adesiyun, Ademola Adeyeye, Oladapo A. Kolawole, Akinwumi O. Olakanmi, Kanika Arora, Jeremy Constable, Ronak Shah, Azfar Basunia, Brooke Sylvester, Chao Wu, Martin R. Weiser, Ken Seier, Mithat Gonen, Zsofia K. Stadler, Yelena Kemel, Efsevia Vakiani, Michael F. Berger, Timothy A. Chan, David B. Solit, Jinru Shia, Francisco Sanchez-Vega, Nikolaus Schultz, Murray Brennan, J. Joshua Smith, and T. Peter Kingham

Subjects
Science
Abstract

Understanding the molecular and phenotypic profile of colorectal cancer (CRC) in West Africa is important for early detection and treatment. Here, the authors use a multigene next-generation sequencing panel to identify genomic differences in Nigerian CRCs compared to those from TCGA and MSKCC cohorts.

Published
2021
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11. Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS

Author

A. Rose Brannon, Gowtham Jayakumaran, Monica Diosdado, Juber Patel, Anna Razumova, Yu Hu, Fanli Meng, Mohammad Haque, Justyna Sadowska, Brian J. Murphy, Tessara Baldi, Ian Johnson, Ryan Ptashkin, Maysun Hasan, Preethi Srinivasan, Anoop Balakrishnan Rema, Ivelise Rijo, Aaron Agarunov, Helen Won, Dilmi Perera, David N. Brown, Aliaksandra Samoila, Xiaohong Jing, Erika Gedvilaite, Julie L. Yang, Dennis P. Stephens, Jenna-Marie Dix, Nicole DeGroat, Khedoudja Nafa, Aijazuddin Syed, Alan Li, Emily S. Lebow, Anita S. Bowman, Donna C. Ferguson, Ying Liu, Douglas A. Mata, Rohit Sharma, Soo-Ryum Yang, Tejus Bale, Jamal K. Benhamida, Jason C. Chang, Snjezana Dogan, Meera R. Hameed, Jaclyn F. Hechtman, Christine Moung, Dara S. Ross, Efsevia Vakiani, Chad M. Vanderbilt, JinJuan Yao, Pedram Razavi, Lillian M. Smyth, Sarat Chandarlapaty, Gopa Iyer, Wassim Abida, James J. Harding, Benjamin Krantz, Eileen O’Reilly, Helena A. Yu, Bob T. Li, Charles M. Rudin, Luis Diaz, David B. Solit, Maria E. Arcila, Marc Ladanyi, Brian Loomis, Dana Tsui, Michael F. Berger, Ahmet Zehir, and Ryma Benayed

Subjects
Science
Abstract

Liquid biopsies allow the non-invasive detection of somatic mutations from tumours. Here, the authors develop and test MSK-ACCESS, an NGS-based clinical assay for identifying low frequency mutations in 129 genes and describe how it benefits patients in the clinic.

Published
2021
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12. Tumor fraction-guided cell-free DNA profiling in metastatic solid tumor patients

Author

Dana W. Y. Tsui, Michael L. Cheng, Maha Shady, Julie L. Yang, Dennis Stephens, Helen Won, Preethi Srinivasan, Kety Huberman, Fanli Meng, Xiaohong Jing, Juber Patel, Maysun Hasan, Ian Johnson, Erika Gedvilaite, Brian Houck-Loomis, Nicholas D. Socci, S. Duygu Selcuklu, Venkatraman E. Seshan, Hongxin Zhang, Debyani Chakravarty, Ahmet Zehir, Ryma Benayed, Maria Arcila, Marc Ladanyi, Samuel A. Funt, Darren R. Feldman, Bob T. Li, Pedram Razavi, Jonathan Rosenberg, Dean Bajorin, Gopa Iyer, Wassim Abida, Howard I. Scher, Dana Rathkopf, Agnes Viale, Michael F. Berger, and David B. Solit

Subjects
Liquid biopsy, Plasma DNA, Molecular diagnostic, Cancer, Sequencing, Noninvasive, Medicine, Genetics, QH426-470
Abstract

Abstract Background Cell-free DNA (cfDNA) profiling is increasingly used to guide cancer care, yet mutations are not always identified. The ability to detect somatic mutations in plasma depends on both assay sensitivity and the fraction of circulating DNA in plasma that is tumor-derived (i.e., cfDNA tumor fraction). We hypothesized that cfDNA tumor fraction could inform the interpretation of negative cfDNA results and guide the choice of subsequent assays of greater genomic breadth or depth. Methods Plasma samples collected from 118 metastatic cancer patients were analyzed with cf-IMPACT, a modified version of the FDA-authorized MSK-IMPACT tumor test that can detect genomic alterations in 410 cancer-associated genes. Shallow whole genome sequencing (sWGS) was also performed in the same samples to estimate cfDNA tumor fraction based on genome-wide copy number alterations using z-score statistics. Plasma samples with no somatic alterations detected by cf-IMPACT were triaged based on sWGS-estimated tumor fraction for analysis with either a less comprehensive but more sensitive assay (MSK-ACCESS) or broader whole exome sequencing (WES). Results cfDNA profiling using cf-IMPACT identified somatic mutations in 55/76 (72%) patients for whom MSK-IMPACT tumor profiling data were available. A significantly higher concordance of mutational profiles and tumor mutational burden (TMB) was observed between plasma and tumor profiling for plasma samples with a high tumor fraction (z-score≥5). In the 42 patients from whom tumor data was not available, cf-IMPACT identified mutations in 16/42 (38%). In total, cf-IMPACT analysis of plasma revealed mutations in 71/118 (60%) patients, with clinically actionable alterations identified in 30 (25%), including therapeutic targets of FDA-approved drugs. Of the 47 samples without alterations detected and low tumor fraction (z-score

Published
2021
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13. Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis

Author

Teng Gao, Ryan Ptashkin, Kelly L. Bolton, Maria Sirenko, Christopher Fong, Barbara Spitzer, Kamal Menghrajani, Juan E. Arango Ossa, Yangyu Zhou, Elsa Bernard, Max Levine, Juan S. Medina Martinez, Yanming Zhang, Sebastià Franch-Expósito, Minal Patel, Lior Z. Braunstein, Daniel Kelly, Mariko Yabe, Ryma Benayed, Nicole M. Caltabellotta, John Philip, Ederlinda Paraiso, Simon Mantha, David B. Solit, Luis A. Diaz, Michael F. Berger, Virginia Klimek, Ross L. Levine, Ahmet Zehir, Sean M. Devlin, and Elli Papaemmanuil

Subjects
Science
Abstract

Patients with solid cancers have high rates of clonal haematopoiesis associated with increased risk of secondary leukemias. Here, by using peripheral blood sequencing data from patients with solid non-hematologic cancer, the authors profile the landscape of mosaic chromosomal alterations and gene mutations, defining patients at high risk of leukemia progression.

Published
2021
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14. Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer

Author

Ana C. Garrido-Castro, Cristina Saura, Romualdo Barroso-Sousa, Hao Guo, Eva Ciruelos, Begoña Bermejo, Joaquin Gavilá, Violeta Serra, Aleix Prat, Laia Paré, Pamela Céliz, Patricia Villagrasa, Yisheng Li, Jennifer Savoie, Zhan Xu, Carlos L. Arteaga, Ian E. Krop, David B. Solit, Gordon B. Mills, Lewis C. Cantley, Eric P. Winer, Nancy U. Lin, and Jordi Rodon

Subjects
Buparlisib, BKM120, Triple-negative breast cancer, PI3K pathway, Phase 1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer. Methods This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies. Results Fifty patients were enrolled. Median number of cycles was 2 (range 1–10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6–2.3). Median OS was 11.2 months (95% CI 6.2–25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease. Conclusions Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer. Trial registration NCT01790932 . Registered on 13 February 2013; NCT01629615 . Registered on 27 June 2012.

Published
2020
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15. Protein-altering germline mutations implicate novel genes related to lung cancer development

Author

Xuemei Ji, Semanti Mukherjee, Maria Teresa Landi, Yohan Bosse, Philippe Joubert, Dakai Zhu, Ivan Gorlov, Xiangjun Xiao, Younghun Han, Olga Gorlova, Rayjean J. Hung, Yonathan Brhane, Robert Carreras-Torres, David C. Christiani, Neil Caporaso, Mattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, Chu Chen, Jinyoung Byun, Konstantin H. Dragnev, John K. Field, Lambertus FA. Kiemeney, Philip Lazarus, Shan Zienolddiny, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Pier A. Bertazzi, Angela C. Pesatori, Nancy Diao, Li Su, Lei Song, Ruyang Zhang, Natasha Leighl, Jakob S. Johansen, Anders Mellemgaard, Walid Saliba, Christopher Haiman, Lynne Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Erik H. F. M. van der Heijden, Jin Hee Kim, Michael P. A. Davies, Michael W. Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C. Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Gary E. Goodman, Angela Cox, Fiona Taylor, Penella Woll, Erich Wichmann, Thomas Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances Shepherd, Ming-Sound Tsao, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M. Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Lesley M. Butler, Kenneth Offit, Preethi Srinivasan, Chaitanya Bandlamudi, Matthew D. Hellmann, David B. Solit, Mark E. Robson, Charles M. Rudin, Zsofia K. Stadler, Barry S. Taylor, Michael F. Berger, Richard Houlston, John McLaughlin, Victoria Stevens, David C. Nickle, Ma’en Obeidat, Wim Timens, María Soler Artigas, Sanjay Shete, Hermann Brenner, Stephen Chanock, Paul Brennan, James D. McKay, and Christopher I. Amos

Subjects
Science
Abstract

In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.

Published
2020
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16. Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Author

Kwanghee Kim, Wenhuo Hu, François Audenet, Nima Almassi, Aphrothiti J. Hanrahan, Katie Murray, Aditya Bagrodia, Nathan Wong, Timothy N. Clinton, Shawn Dason, Vishnu Mohan, Sylvia Jebiwott, Karan Nagar, Jianjiong Gao, Alex Penson, Chris Hughes, Benjamin Gordon, Ziyu Chen, Yiyu Dong, Philip A. Watson, Ricardo Alvim, Arijh Elzein, Sizhi P. Gao, Emiliano Cocco, Alessandro D. Santin, Irina Ostrovnaya, James J. Hsieh, Irit Sagi, Eugene J. Pietzak, A. Ari Hakimi, Jonathan E. Rosenberg, Gopa Iyer, Herbert A. Vargas, Maurizio Scaltriti, Hikmat Al-Ahmadie, David B. Solit, and Jonathan A. Coleman

Subjects
Science
Abstract

The advancement of upper tract urothelial carcinoma (UTUC) research is hampered by the lack of disease-specific models. Here, the authors report patient derived xenograft and cell line models of UTUC, and show that these models retain the genomic and biological heterogeneity of human disease.

Published
2020
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17. Author Correction: FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation

Author

Joshua I. Warrick, Wenhuo Hu, Hironobu Yamashita, Vonn Walter, Lauren Shuman, Jenna M. Craig, Lan L. Gellert, Mauro A. A. Castro, A. Gordon Robertson, Fengshen Kuo, Irina Ostrovnaya, Judy Sarungbam, Ying-bei Chen, Anuradha Gopalan, Sahussapont J. Sirintrapun, Samson W. Fine, Satish K. Tickoo, Kwanghee Kim, Jasmine Thomas, Nagar Karan, Sizhi Paul Gao, Timothy N. Clinton, Andrew T. Lenis, Timothy A. Chan, Ziyu Chen, Manisha Rao, Travis J. Hollman, Yanyun Li, Nicholas D. Socci, Shweta Chavan, Agnes Viale, Neeman Mohibullah, Bernard H. Bochner, Eugene J. Pietzak, Min Yuen Teo, Gopa Iyer, Jonathan E. Rosenberg, Dean F. Bajorin, Matthew Kaag, Suzanne B. Merrill, Monika Joshi, Rosalyn Adam, John A. Taylor, Peter E. Clark, Jay D. Raman, Victor E. Reuter, Yu Chen, Samuel A. Funt, David B. Solit, David J. DeGraff, and Hikmat A. Al-Ahmadie

Subjects
Science
Published
2022
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18. Monitoring the Induction of Heat Shock Factor 1/Heat Shock Protein 70 Expression following 17-Allylamino-Demethoxygeldanamycin Treatment by Positron Emission Tomography and Optical Reporter Gene Imaging

Author

Mikhail Doubrovin, Jian T. Che, Inna Serganova, Ekaterina Moroz, David B. Solit, Lyudmila Ageyeva, Tatiana Kochetkova, Nagavarakishore Pillarsetti, Ronald Finn, Neal Rosen, and Ronald G. Blasberg

Subjects
Biology (General), QH301-705.5, Medical technology, R855-855.5
Abstract

The cell response to proteotoxic cell stresses is mediated primarily through activation of heat shock factor 1 (HSF1). This transcription factor plays a major role in the regulation of the heat shock proteins (HSPs), including HSP70. We demonstrate that an [ 124 I]iodide-pQHNIG70 positron emission tomography (PET) reporter system that includes an inducible HSP70 promoter can be used to image and monitor the activation of the HSF1/HSP70 transcription factor in response to drug treatment (17-allylamino-demethoxygeldanamycin [17-AAG]). We developed a dual imaging reporter (pQHNIG70) for noninvasive imaging of the heat shock response in cell culture and living animals previously and now study HSF1/HSP70 reporter activation in both cell culture and tumor-bearing animals following exposure to 17-AAG. 17-AAG (10–1,000 nM) induced reporter expression; a 23-fold increase was observed by 60 hours. Good correspondence between reporter expression and HSP70 protein levels were observed. MicroPET imaging based on [ 124 I]iodide accumulation in pQHNIG70-transduced RG2 xenografts showed a significant 6.2-fold reporter response to 17-AAG, with a corresponding increase in tumor HSP70 and in tumor human sodium iodide symporter and green fluorescent protein reporter proteins. The HSF1 reporter system can be used to screen anticancer drugs for induction of cytotoxic stress and HSF1 activation both in vitro and in vivo.

Published
2012
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19. Final Results of a Phase I Trial of WST-11 (TOOKAD Soluble) Vascular-targeted Photodynamic Therapy for Upper Tract Urothelial Carcinoma

Author

Wesley Yip, Daniel D. Sjoberg, Lucas M. Nogueira, Andrew T. Tracey, Ricardo G. Alvim, Peter A. Reisz, Quinlan Demac, Nicole E. Benfante, Rand W. Vanden Berg, Kwanghee Kim, Hikmat Al-Ahmadie, Oscar Lin, Bernard H. Bochner, Guido Dalbagni, S. Machele Donat, Eugene J. Pietzak, A. Ari Hakimi, David B. Solit, Avigdor Scherz, Dean F. Bajorin, and Jonathan A. Coleman

Subjects
Urology
Published
2023

20. Overcoming Barriers to Tumor Genomic Profiling through Direct-to-Patient Outreach

Author

Seyram A. Doe-Tetteh, Sabrina Y. Camp, Dalicia Reales, Jett Crowdis, Anne Marie Noronha, Bernadette Wolff, Tina Alano, Jesse Galle, S. Duygu Selcuklu, Agnes Viale, Nicholas D. Socci, Ying L. Liu, William P. Tew, Carol Aghajanian, Marc Ladanyi, Meng Xiao He, Saud H. AlDubayan, Roei David Mazor, Ofer Shpilberg, Oshrat Hershkovitz-Rokah, Jose A. Riancho, Jose L. Hernandez, M. Carmen Gonzalez-Vela, Justin J. Buthorn, Manda Wilson, Amy E. Webber, Mariko Yabe, Kseniya Petrova-Drus, Marc Rosenblum, Benjamin H. Durham, Omar Abdel-Wahab, Michael F. Berger, Mark T.A. Donoghue, Andrew L. Kung, Julia Glade Bender, Neerav N. Shukla, Samuel A. Funt, Ahmet Dogan, Robert A. Soslow, Hikmat Al-Ahmadie, Darren R. Feldman, Eliezer M. Van Allen, Eli L. Diamond, and David B. Solit

Subjects
Cancer Research, Oncology
Abstract

Purpose: To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. Experimental Design: Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype. Results: A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6–40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. Conclusions: Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment.

Published
2023

21. KDM6A Loss Triggers an Epigenetic Switch That Disrupts Urothelial Differentiation and Drives Cell Proliferation in Bladder Cancer

Author

Hong Qiu, Vladimir Makarov, Jennifer K. Bolzenius, Angela Halstead, Yvonne Parker, Allen Wang, Gopakumar V. Iyer, Hannah Wise, Daniel Kim, Varna Thayaparan, Daniel J. Lindner, Georges-Pascal Haber, Angela H. Ting, Bing Ren, Timothy A. Chan, Vivek Arora, David B. Solit, and Byron H. Lee

Subjects
Cancer Research, Oncology
Abstract

Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations affect the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 interacted with KDM6A to activate genes instructing urothelial differentiation. KDM6A-deficient cells displayed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn repressed FOXA1-target genes and activated cell-cycle progression genes. Importantly, ATF3 depletion reversed the cell proliferation phenotype induced by KDM6A deficiency. These data establish that KDM6A loss engenders an epigenetic state that drives tumor growth in an ATF3-dependent manner, creating a potentially targetable molecular vulnerability.Significance:A gain-of-function epigenetic switch that disrupts differentiation is triggered by inactivating KDM6A mutations in bladder cancer and can serve as a potential target for novel therapies.

Published
2023

22. Molecular Characterization of Acquired Resistance to KRASG12C-EGFR Inhibition in Colorectal Cancer

Author

Rona Yaeger, Riccardo Mezzadra, Jenna Sinopoli, Yu Bian, Michelangelo Marasco, Esther Kaplun, Yijun Gao, HuiYong Zhao, Arnaud Da Cruz Paula, Yingjie Zhu, Almudena Chaves Perez, Kalyani Chadalavada, Edison Tse, Sudhir Chowdhry, Sydney Bowker, Qing Chang, Besnik Qeriqi, Britta Weigelt, Gouri J. Nanjangud, Michael F. Berger, Hirak Der-Torossian, Kenna Anderes, Nicholas D. Socci, Jinru Shia, Gregory J. Riely, Yonina R. Murciano-Goroff, Bob T. Li, James G. Christensen, Jorge S. Reis-Filho, David B. Solit, Elisa de Stanchina, Scott W. Lowe, Neal Rosen, and Sandra Misale

Subjects
Oncology
Abstract

With the combination of KRASG12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRASG12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRASG12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance. Significance: Clinical resistance to KRASG12C–EGFR inhibition primarily prevents suppression of ERK signaling. Most resistance mechanisms are subclonal, whereas KRASG12C amplification rises over time to drive a higher portion of resistance. This recurrent resistance mechanism leads to oncogene-induced senescence upon drug withdrawal and creates a potential vulnerability to senolytic approaches.

Published
2022

23. Long-term Outcomes of Local and Metastatic Small Cell Carcinoma of the Urinary Bladder and Genomic Analysis of Patients Treated With Neoadjuvant Chemotherapy

Author

Min Yuen Teo, Brendan J. Guercio, Arshi Arora, Xueli Hao, Ashley M. Regazzi, Timothy Donahue, Harry W. Herr, Alvin C. Goh, Eugene K. Cha, Eugene Pietzak, Sherri M. Donat, Guido Dalbagni, Bernard H. Bochner, Semra Olgac, Judy Sarungbam, S. Joseph Sirintrapun, Ying-Bei Chen, Anuradha Gopalan, Samson W. Fine, Satish K. Tickoo, Victor E. Reuter, Britta Weigelt, Anne M. Schultheis, Samuel A. Funt, Dean F. Bajorin, David B. Solit, Gopa Iyer, Irina Ostrovnaya, Jonathan E. Rosenberg, and Hikmat Al-Ahmadie

Subjects
Urinary Bladder Neoplasms, Oncology, Chemotherapy, Adjuvant, Urology, Urinary Bladder, Humans, Genomics, Carcinoma, Small Cell, Cystectomy, Article, Neoadjuvant Therapy, Retrospective Studies, Xeroderma Pigmentosum Group D Protein
Abstract

INTRODUCTION: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. RESULTS: One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (

Published
2022

24. Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort

Author

Kanika Arora, Thinh N. Tran, Yelena Kemel, Miika Mehine, Ying L. Liu, Subhiksha Nandakumar, Shaleigh A. Smith, A. Rose Brannon, Irina Ostrovnaya, Konrad H. Stopsack, Pedram Razavi, Anton Safonov, Hira A. Rizvi, Matthew D. Hellmann, Joseph Vijai, Thomas C. Reynolds, James A. Fagin, Jian Carrot-Zhang, Kenneth Offit, David B. Solit, Marc Ladanyi, Nikolaus Schultz, Ahmet Zehir, Carol L. Brown, Zsofia K. Stadler, Debyani Chakravarty, Chaitanya Bandlamudi, and Michael F. Berger

Subjects
Genetics, Population, Oncology, Neoplasms, Humans, Precision Medicine, Polymorphism, Single Nucleotide, White People, Article
Abstract

Accurate ancestry inference is critical for identifying genetic contributors of cancer disparities among populations. Although methods to infer genetic ancestry have historically relied upon genome-wide markers, the adaptation to targeted clinical sequencing panels presents an opportunity to incorporate ancestry inference into routine diagnostic workflows. We show that global ancestral contributions and admixture of continental populations can be quantitatively inferred using markers captured by the MSK-IMPACT clinical panel. In a pan-cancer cohort of 45,157 patients, we observed differences by ancestry in the frequency of somatic alterations, recapitulating known associations and revealing novel associations. Despite the comparable overall prevalence of driver alterations by ancestry group, the proportion of patients with clinically actionable alterations was lower for African (30%) compared with European (33%) ancestry. Although this result is largely explained by population-specific cancer subtype differences, it reveals an inequity in the degree to which different populations are served by existing precision oncology interventions. Significance: We performed a comprehensive analysis of ancestral associations with somatic mutations in a real-world pan-cancer cohort, including >5,000 non-European individuals. Using an FDA-authorized tumor sequencing panel and an FDA-recognized oncology knowledge base, we detected differences in the prevalence of clinically actionable alterations, potentially contributing to health care disparities affecting underrepresented populations. This article is highlighted in the In This Issue feature, p. 2483

Published
2022

25. Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer

Author

Walid K. Chatila, Jin K. Kim, Henry Walch, Michael R. Marco, Chin-Tung Chen, Fan Wu, Dana M. Omer, Danny N. Khalil, Karuna Ganesh, Xuan Qu, Anisha Luthra, Seo-Hyun Choi, Yu-Jui Ho, Ritika Kundra, Katharine I. Groves, Oliver S. Chow, Andrea Cercek, Martin R. Weiser, Maria Widmar, Iris H. Wei, Emmanouil P. Pappou, Garrett M. Nash, Philip B. Paty, Qian Shi, Efsevia Vakiani, S. Duygu Selcuklu, Mark T. A. Donoghue, David B. Solit, Michael F. Berger, Jinru Shia, Raphael Pelossof, Paul B. Romesser, Rona Yaeger, J. Joshua Smith, Nikolaus Schultz, Francisco Sanchez-Vega, and Julio Garcia-Aguilar

Subjects
Treatment Outcome, Rectal Neoplasms, Humans, Chemoradiotherapy, Genomics, General Medicine, Neoplasm Recurrence, Local, Transcriptome, Neoadjuvant Therapy, Article, General Biochemistry, Genetics and Molecular Biology, Neoplasm Staging, Retrospective Studies
Abstract

The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival.

Published
2022

26. Analytical Validation and Performance Characteristics of Molecular Serum Biomarkers, miR-371a-3p and miR-372-3p, for Male Germ Cell Tumors, in a Clinical Laboratory Setting

Author

Fei Ye, Darren R. Feldman, Alisa Valentino, Rachel So, Maria Bromberg, Shah Khan, Samuel A. Funt, Joel Sheinfeld, David B. Solit, Melissa S. Pessin, and Ellinor I. Peerschke

Subjects
Male, MicroRNAs, Testicular Neoplasms, Biomarkers, Tumor, Humans, Molecular Medicine, Neoplasms, Germ Cell and Embryonal, Laboratories, Clinical, Pathology and Forensic Medicine
Abstract

Detection of serum embryonic miRNAs miR-371a-3p and miR-372-3p has been proposed to aid in diagnosis, prognosis, and management of patients with testicular germ cell tumors (GCTs). This study describes the analytical validation and performance of a laboratory-developed test to detect these miRNA targets by stem loop real-time quantitative RT-PCR (RT-qPCR) in serum from patients with GCTs. The assay was standardized using an exogenous spike-in control of nonhuman miRNA from Caenorhabditis elegans (cel-miR-39-3p) to assess extraction efficiency, and an endogenous housekeeping miRNA, miR-30b-5p, to control for miRNA normalization. miRNA results were expressed as relative expression level, using the comparative threshold cycle method (2

Published
2022

27. A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma

Author

Phillip M. Rappold, Lynda Vuong, Josef Leibold, Nicholas H. Chakiryan, Michael Curry, Fengshen Kuo, Erich Sabio, Hui Jiang, Briana G. Nixon, Ming Liu, Anders E. Berglund, Andrew W. Silagy, Eduardo A. Mascareno, Mahdi Golkaram, Mahtab Marker, Albert Reising, Alexander Savchenko, John Millholland, Ying-Bei Chen, Paul Russo, Jonathan Coleman, Ed Reznik, Brandon J. Manley, Irina Ostrovnaya, Vladimir Makarov, Renzo G. DiNatale, Kyle A. Blum, Xiaoxiao Ma, Diego Chowell, Ming O. Li, David B. Solit, Scott W. Lowe, Timothy A. Chan, Robert J. Motzer, Martin H. Voss, and A. Ari Hakimi

Subjects
Inflammation, Mice, Oncology, Interleukin-6, Biomarkers, Tumor, Tumor Microenvironment, Animals, Neoplasm Recurrence, Local, Prognosis, Carcinoma, Renal Cell, Kidney Neoplasms, Article, Adenosine A2 Receptor Antagonists
Abstract

It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC. Significance: Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model. This article is highlighted in the In This Issue feature, p. 2221

Published
2022

28. Supplementary Figure 6 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

C106 resistant cells drug withdrawal and Patient #12 MSK-Impact data

Published
2023

29. Supplementary Table 2 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Patients Progression Cell Free DNA data

Published
2023

30. Supplementary Figure from Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort

Author

Michael F. Berger, Chaitanya Bandlamudi, Debyani Chakravarty, Zsofia K. Stadler, Carol L. Brown, Ahmet Zehir, Nikolaus Schultz, Marc Ladanyi, David B. Solit, Kenneth Offit, Jian Carrot-Zhang, James A. Fagin, Thomas C. Reynolds, Joseph Vijai, Matthew D. Hellmann, Hira A. Rizvi, Anton Safonov, Pedram Razavi, Konrad H. Stopsack, Irina Ostrovnaya, A. Rose Brannon, Shaleigh A. Smith, Subhiksha Nandakumar, Ying L. Liu, Miika Mehine, Yelena Kemel, Thinh N. Tran, and Kanika Arora

Abstract

Supplementary Figure from Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort

Published
2023

31. Supplementary Table 1 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Patients Characteristics

Published
2023

32. Supplementary Figure 2 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

C106 cell lines single cell sequencing analysis

Published
2023

33. Supplementary Figure 3 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

RW7213 cell lines sequencing analysis

Published
2023

34. Data from Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort

Author

Michael F. Berger, Chaitanya Bandlamudi, Debyani Chakravarty, Zsofia K. Stadler, Carol L. Brown, Ahmet Zehir, Nikolaus Schultz, Marc Ladanyi, David B. Solit, Kenneth Offit, Jian Carrot-Zhang, James A. Fagin, Thomas C. Reynolds, Joseph Vijai, Matthew D. Hellmann, Hira A. Rizvi, Anton Safonov, Pedram Razavi, Konrad H. Stopsack, Irina Ostrovnaya, A. Rose Brannon, Shaleigh A. Smith, Subhiksha Nandakumar, Ying L. Liu, Miika Mehine, Yelena Kemel, Thinh N. Tran, and Kanika Arora

Abstract

Accurate ancestry inference is critical for identifying genetic contributors of cancer disparities among populations. Although methods to infer genetic ancestry have historically relied upon genome-wide markers, the adaptation to targeted clinical sequencing panels presents an opportunity to incorporate ancestry inference into routine diagnostic workflows. We show that global ancestral contributions and admixture of continental populations can be quantitatively inferred using markers captured by the MSK-IMPACT clinical panel. In a pan-cancer cohort of 45,157 patients, we observed differences by ancestry in the frequency of somatic alterations, recapitulating known associations and revealing novel associations. Despite the comparable overall prevalence of driver alterations by ancestry group, the proportion of patients with clinically actionable alterations was lower for African (30%) compared with European (33%) ancestry. Although this result is largely explained by population-specific cancer subtype differences, it reveals an inequity in the degree to which different populations are served by existing precision oncology interventions.Significance:We performed a comprehensive analysis of ancestral associations with somatic mutations in a real-world pan-cancer cohort, including >5,000 non-European individuals. Using an FDA-authorized tumor sequencing panel and an FDA-recognized oncology knowledge base, we detected differences in the prevalence of clinically actionable alterations, potentially contributing to health care disparities affecting underrepresented populations.This article is highlighted in the In This Issue feature, p. 2483

Published
2023

35. Data from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

With the combination of KRASG12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRASG12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRASG12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance.Significance:Clinical resistance to KRASG12C–EGFR inhibition primarily prevents suppression of ERK signaling. Most resistance mechanisms are subclonal, whereas KRASG12C amplification rises over time to drive a higher portion of resistance. This recurrent resistance mechanism leads to oncogene-induced senescence upon drug withdrawal and creates a potential vulnerability to senolytic approaches.This article is highlighted in the In This Issue feature, p. 1

Published
2023

36. Supplementary Figure 4 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Generation of acquired resistance PDX model

Published
2023

37. Data from A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma

Author

A. Ari Hakimi, Martin H. Voss, Robert J. Motzer, Timothy A. Chan, Scott W. Lowe, David B. Solit, Ming O. Li, Diego Chowell, Xiaoxiao Ma, Kyle A. Blum, Renzo G. DiNatale, Vladimir Makarov, Irina Ostrovnaya, Brandon J. Manley, Ed Reznik, Jonathan Coleman, Paul Russo, Ying-Bei Chen, John Millholland, Alexander Savchenko, Albert Reising, Mahtab Marker, Mahdi Golkaram, Eduardo A. Mascareno, Andrew W. Silagy, Anders E. Berglund, Ming Liu, Briana G. Nixon, Hui Jiang, Erich Sabio, Fengshen Kuo, Michael Curry, Nicholas H. Chakiryan, Josef Leibold, Lynda Vuong, and Phillip M. Rappold

Abstract

It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC.Significance:Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model.This article is highlighted in the In This Issue feature, p. 2221

Published
2023

38. Supplementary Figure 1 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Characterization of acquired resistance in vitro models

Published
2023

39. Supplementary Figure 5 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Oncoprint of baseline alterations in CRC patients who developed resistance to KRAS G12C and EGFR inhibitors

Published
2023

40. Supplementary Data from Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort

Author

Michael F. Berger, Chaitanya Bandlamudi, Debyani Chakravarty, Zsofia K. Stadler, Carol L. Brown, Ahmet Zehir, Nikolaus Schultz, Marc Ladanyi, David B. Solit, Kenneth Offit, Jian Carrot-Zhang, James A. Fagin, Thomas C. Reynolds, Joseph Vijai, Matthew D. Hellmann, Hira A. Rizvi, Anton Safonov, Pedram Razavi, Konrad H. Stopsack, Irina Ostrovnaya, A. Rose Brannon, Shaleigh A. Smith, Subhiksha Nandakumar, Ying L. Liu, Miika Mehine, Yelena Kemel, Thinh N. Tran, and Kanika Arora

Abstract

Supplementary Data from Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort

Published
2023

41. Supplementary Table 3 from Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Author

Sandra Misale, Neal Rosen, Scott W. Lowe, Elisa de Stanchina, David B. Solit, Jorge S. Reis-Filho, James G. Christensen, Bob T. Li, Yonina R. Murciano-Goroff, Gregory J. Riely, Jinru Shia, Nicholas D. Socci, Kenna Anderes, Hirak Der-Torossian, Michael F. Berger, Gouri J. Nanjangud, Britta Weigelt, Besnik Qeriqi, Qing Chang, Sydney Bowker, Sudhir Chowdhry, Edison Tse, Kalyani Chadalavada, Almudena Chaves Perez, Yingjie Zhu, Arnaud Da Cruz Paula, HuiYong Zhao, Yijun Gao, Esther Kaplun, Michelangelo Marasco, Yu Bian, Jenna Sinopoli, Riccardo Mezzadra, and Rona Yaeger

Abstract

Patients Longitudinal Cell Free DNA data

Published
2023

42. Supplementary Figure from A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma

Author

A. Ari Hakimi, Martin H. Voss, Robert J. Motzer, Timothy A. Chan, Scott W. Lowe, David B. Solit, Ming O. Li, Diego Chowell, Xiaoxiao Ma, Kyle A. Blum, Renzo G. DiNatale, Vladimir Makarov, Irina Ostrovnaya, Brandon J. Manley, Ed Reznik, Jonathan Coleman, Paul Russo, Ying-Bei Chen, John Millholland, Alexander Savchenko, Albert Reising, Mahtab Marker, Mahdi Golkaram, Eduardo A. Mascareno, Andrew W. Silagy, Anders E. Berglund, Ming Liu, Briana G. Nixon, Hui Jiang, Erich Sabio, Fengshen Kuo, Michael Curry, Nicholas H. Chakiryan, Josef Leibold, Lynda Vuong, and Phillip M. Rappold

Abstract

Supplementary Figure from A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma

Published
2023

43. Supplementary Figure S3 from Mutant N-RAS Protects Colorectal Cancer Cells from Stress-Induced Apoptosis and Contributes to Cancer Development and Progression

Author

Kevin M. Haigis, David B. Solit, Mark Philips, Channing J. Der, James M. Bugni, Jessica Gierut, Gerald C. Chu, Adam J. Bass, Shouyong Peng, Efsevia Vakiani, Sérgia Velho, and Yufang Wang

Abstract

Supplementary Figure S3 PDF file 66K,Additional data related to the proliferative and apoptotic phenotypes of CRC cells expressing mutant Ras

Published
2023

44. Supplementary Figures 1-11 from BRAFL597 Mutations in Melanoma Are Associated with Sensitivity to MEK Inhibitors

Author

William Pao, Zhongming Zhao, Antoni Ribas, Jeffrey A. Sosman, Cindy L. Vnencak-Jones, James L. Netterville, David B. Solit, Neal Rosen, John A. Glaspy, Viviana Bozon, Donna J. Hicks, Pamela L. Lyle, Suzanne Branch, Zengliu Su, Mohammad Atefi, Peilin Jia, Donald Hucks, Charles Ng, Katherine Hutchinson, Junfeng Xia, and Kimberly Brown Dahlman

Abstract

PDF file - 480K

Published
2023

45. Table S4 from AACR Project GENIE: Powering Precision Medicine through an International Consortium

Author

Hongxin Zhang, Ahmet Zehir, Emily Yu, Thomas V. Yu, Celeste Yu, Stuart Watt, Chetna Wathoo, Lucy L. Wang, Emile E. Voest, Carl Virtanen, Victor E. Velculescu, Harm van Tinteren, Tony van de Velde, Laura J. Van 'T Veer, Eliezer M. Van Allen, Stacy B. Thomas, Jelle J. ten Hoeve, Barry S. Taylor, Shawn M. Sweeney, Thomas P. Stricker, Natalie H. Stickle, Parin Sripakdeevong, Jean Charles Soria, Gabe S. Sonke, David B. Solit, Lillian L. Siu, Priyanka Shivdasani, Kenna R Mills Shaw, Nikolaus Schultz, Deborah Schrag, Charles L. Sawyers, Mark J. Routbort, Barrett J. Rollins, Brendan Reardon, Trevor J. Pugh, Ben Ho Park, John A. Orechia, Larsson Omberg, Petra M. Nederlof, Nathanael D. Moore, Gordon Mills, Clinton Miller, Christine M. Micheel, Funda Meric-Bernstam, Gerrit A. Meijer, David S. Maxwell, Ian Maurer, Laura E. MacConaill, Zhibin Lu, David Liu, James Lindsay, Neal I. Lindeman, Mia A. Levy, Eva M. Lepisto, Michele L. LeNoue-Newton, Céline Lefebvre, Marc Ladanyi, Ritika Kundra, Priti Kumari, Walter Kinyua, Cyriac Kandoth, Suzanne Kamel-Reid, David M. Hyman, Jan Hudeček, Hugo Horlings, Stephanie Hintzen, Zachary J. Heins, Justin Guinney, Benjamin E. Gross, Christopher D. Gocke, Stu Gardos, Francisco Garcia, Jianjiong Gao, P. Andrew Futreal, Matthew D. Ducar, Raymond N. DuBois, Semih Dogan, Catherine Del Vecchio Fitz, Nancy E. Davidson, Kristen K. Dang, Debyani Chakravarty, Ethan Cerami, Fabien Calvo, Mariska Bierkens, Michael F. Berger, Philippe L. Bedard, José Baselga, Alexander S. Baras, Monica Arnedos, and Fabrice André

Abstract

Table S4

Published
2023

47. Figure S1-7 from Accelerating Discovery of Functional Mutant Alleles in Cancer

Author

Barry S. Taylor, David M. Hyman, David B. Solit, Neal Rosen, Michael F. Berger, José Baselga, Nikolaus Schultz, Marc Ladanyi, Sarat Chandarlapaty, Maria E. Arcila, Ryma Benayed, Ahmet Zehir, Gowtham Jayakumaran, Nicholas D. Socci, Dalicia N. Reales, Bob T. Li, Pedram Razavi, Ritika Kundra, Selcuk Onur Sumer, JianJiong Gao, Christopher Harris, Swati Patel, Tambudzai Shamu, Alexander Gorelick, Alexander Penson, Cyriac Kandoth, Sarah Phillips, Debyani Chakravarty, Philip Jonsson, Mark T.A. Donoghue, Craig M. Bielski, Alison M. Schram, Tripti Shrestha Bhattarai, and Matthew T. Chang

Abstract

Supplementary Figures 1-7

Published
2023

48. Supplementary Figures 1 - 4 from Somatic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma

Author

Jonathan E. Rosenberg, Levi A. Garraway, Alan D'Andrea, Stacey Gabriel, David B. Solit, Dean F. Bajorin, Toni K. Choueiri, Bernard H. Bochner, Philip Kantoff, Gad Getz, Michael Lawrence, Jesse Boehm, Victor Reuter, Justine A. Barletta, Sabina Signoretti, Angela Qu, Deborah Farlow, Namrata Gupta, Samira Bahl, Richard Bambury, Elizabeth A. Guancial, Jaegil Kim, Ilana Garcia-Grossman, John Sfakianos, Kevin W. O'Connor, Gregory V. Kryukov, Irina Ostrovnaya, Cong Zhu, Hikmat Al-Ahmadie, Nikhil Wagle, Gopa Iyer, Philip Kim, Kent W. Mouw, and Eliezer M. Van Allen

Abstract

Supplementary Figure 1. Mutation rates by cohort. Supplementary Figure 2. ERCC2 mutations. Supplementary Figure 3. ERCC2 mutation status and overall survival. Supplementary Figure 4. ERCC2 mutations occur in highly conserved regions.

Published
2023

49. Supplementary Tables 1-2, 4, 7, 9, 10-11 from BRAFL597 Mutations in Melanoma Are Associated with Sensitivity to MEK Inhibitors

Author

William Pao, Zhongming Zhao, Antoni Ribas, Jeffrey A. Sosman, Cindy L. Vnencak-Jones, James L. Netterville, David B. Solit, Neal Rosen, John A. Glaspy, Viviana Bozon, Donna J. Hicks, Pamela L. Lyle, Suzanne Branch, Zengliu Su, Mohammad Atefi, Peilin Jia, Donald Hucks, Charles Ng, Katherine Hutchinson, Junfeng Xia, and Kimberly Brown Dahlman

Abstract

PDF file - 105K, Tables describing the somatic SNPs and indels identified by WGS, SV validation results, PCR primers used for validation, and tumor measurements from the patient treated with TAK-733

Published
2023

50. Figure S2 from Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer

Author

Nikolaus Schultz, David B. Solit, Barry S. Taylor, Laura Tang, Michael F. Berger, David H. Ilson, Neal Rosen, Marc Ladanyi, Maurizio Scaltriti, David M. Hyman, Ahmet Zehir, Sumit Middha, Marinela Capanu, Mark E. Robson, Jinru Shia, Daniela Molena, David R. Jones, Valerie W. Rusch, Zsofia K. Stadler, Manjit Bains, Daniel G. Coit, Hans Gerdes, Mark Schattner, Vivian E. Strong, Liying Zhang, David P. Kelsen, Benjamin E. Gross, Zachary J. Heins, Jianjiong Gao, Efsevia Vakiani, Nancy Bouvier, Ritika Kundra, Yaelle Tuvy, Jamie C. Riches, Geoffrey Y. Ku, Jaclyn F. Hechtman, Walid K. Chatila, Philip Jonsson, Francisco Sanchez-Vega, and Yelena Y. Janjigian

Abstract

Concordance between copy-number inferred from next generation sequencing and protein overexpression by IHC or gene amplification by FISH.

Published
2023

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