Search

Your search keyword '"Richard B, Lanman"' showing total 434 results
Start Over Author "Richard B, Lanman"
434 results on '"Richard B, Lanman"'

1. Habitat suitability assessment for tule elk in the San Francisco Bay and Monterey Bay areas

Author

Thomas Connor, Thomas J. Batter, Cristen O. Langner, Jeff Cann, Cynthia McColl, and Richard B. Lanman

Subjects
cervus canadensis nannodes, elk, habitat suitability, restoration, tule elk, Science
Abstract

While California’s statewide tule elk (Cervus canadensis nannodes) population has recovered from two or three individual survivors in the late 19th century, the subspecies exists today in numerous widely disjunct populations, leaving vast areas of the species’ former range uninhabited. Large unoccupied areas of historic tule elk range include the Santa Cruz Mountains and the northern Diablo and northern Santa Lucia ranges. Natural range expansion by existing populations into these areas is blocked by major highways and urban development; although, before considering tule elk translocations, it is necessary to assess the habitat suitability there. To this end, we fit a resource selection function (RSF) using generalized linear mixed models to GPS collar data collected from nearby radio collared tule elk and used several environmental GIS layers to capture important habitat characteristics. We fit the RSF in a habitat use versus availability framework with only linear and quadratic terms and used stepwise model selection ranked by AICc to maximize its generalizability, enabling transferability to our unoccupied study area. We also used k-fold cross validation to evaluate our RSF and found it predicted habitat within the San Luis Reservoir herd well. The fit habitat relationships mostly followed expectations based on tule elk ecology, including positive responses to herbaceous vegetation cover and waterbody proximity, and negative responses to high tree cover and high puma habitat suitability. Our RSF accurately predicted currently occupied elk habitat as suitable and found well over 500,000 ha (2,000 mi2) of suitable but unoccupied habitat throughout the northern Diablo Range, the inland and coastal sides of the Santa Cruz Mountains, and the northern Santa Lucia Range. Assuming translocations, and construction and improvement of highway wildlife crossings, our results support the potential for re-establishing tule elk in these regions, which are more coastal and mesic than the species’ current habitat in the central Diablo and northern Gabilan ranges.

Published
2023
Full Text
View/download PDF

2. Review of considerations for restoration of tule elk to the San Francisco Peninsula and northern Monterey Bay counties of California

Author

Richard B. Lanman, William C. Leikam, Monica V. Arellano, Alan Leventhal, Valentin Lopez, Ryan A. Phillips, Julie A. Phillips, and Kristin Denryter

Subjects
cervus canadensis nannodes, historical ecology, roosevelt elk, translocation, tule elk wildlife corridor, wildlife passage, Science
Abstract

Successful translocations of tule elk (Cervus canadensis nannodes) have been conducted since the early 1900s, with their state population rising from a nadir of as few as three surviving individuals to about 500 when reintroductions began, and to over 5,700 by 2017. However, natural range expansion of extant populations is currently limited by heavily trafficked major highways and urban areas with dense human populations. We determined that the San Francisco Peninsula and northern Monterey Bay counties (the study area) offer 193,973 ha (479,308 acres) of protected open space, several orders of magnitude greater than coastal tule elk home range size. Habitat suitability is supported by abundant historical observer, museum, and archeological records of elk located in this region. The nearest elk population to the study area is in eastern Santa Clara County and has grown from 65 animals that were translocated to Mt. Hamilton in the Diablo Range from 1978–1981 to at least 90 in five–six separate herds counted by aerial and photographic surveys in 2019. United States (U.S.) Highway 101 and metropolitan San Jose remain barriers to western range extension. Translocation and/or construction of freeway over- and under-crossings may enable westward range expansion to a less arid region, contributing to increased resilience of tule elk to climate change, and bringing aesthetic, financial, and ecological benefits of this once native ungulate grazer to the area.

Published
2022
Full Text
View/download PDF

4. Genomic profile of advanced breast cancer in circulating tumour DNA

Author

Belinda Kingston, Rosalind J. Cutts, Hannah Bye, Matthew Beaney, Giselle Walsh-Crestani, Sarah Hrebien, Claire Swift, Lucy S. Kilburn, Sarah Kernaghan, Laura Moretti, Katie Wilkinson, Andrew M. Wardley, Iain R. Macpherson, Richard D. Baird, Rebecca Roylance, Jorge S. Reis-Filho, Michael Hubank, Iris Faull, Kimberly C. Banks, Richard B. Lanman, Isaac Garcia-Murillas, Judith M. Bliss, Alistair Ring, and Nicholas C. Turner

Subjects
Science
Abstract

Circulating tumour DNA can provide useful information on disease burden. Here, the authors analysed circulating tumour DNA from 800 patients from a breast cancer clinical trial and investigate the subclonal nature of the disease, and identify DNA mutations associated with resistance and poor survival.

Published
2021
Full Text
View/download PDF

5. The economic value of liquid biopsy for genomic profiling in advanced non-small cell lung cancer

Author

Doreen A. Ezeife, Eldon Spackman, Rosalyn A. Juergens, Janessa J. Laskin, Jason S. Agulnik, Desiree Hao, Scott A. Laurie, Jennifer H. Law, Lisa W. Le, Lesli A. Kiedrowski, Barbara Melosky, Frances A. Shepherd, Victor Cohen, Paul Wheatley-Price, Rachel Vandermeer, Janice J. Li, Roxanne Fernandes, Aria Shokoohi, Richard B. Lanman, and Natasha B. Leighl

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

Background: Liquid biopsy (LB) can detect actionable genomic alterations in plasma circulating tumor circulating tumor DNA beyond tissue testing (TT) alone in advanced non-small cell lung cancer (NSCLC) patients. We estimated the cost-effectiveness of adding LB to TT in the Canadian healthcare system. Methods: A cost-effectiveness analysis was conducted using a decision analytic Markov model from the Canadian public payer (Ontario) perspective and a 2-year time horizon in patients with treatment-naïve stage IV non-squamous NSCLC and ⩽10 pack-year smoking history. LB was performed using the comprehensive genomic profiling Guardant360™ assay. Standard of care TT for each participating institution was performed. Costs and outcomes of molecular testing by LB + TT were compared to TT alone. Transition probabilities were calculated from the VALUE trial (NCT03576937). Sensitivity analyses were undertaken to assess uncertainty in the model. Results: Use of LB + TT identified actionable alterations in more patients, 68.5 versus 52.7% with TT alone. Use of the LB + TT strategy resulted in an incremental cost savings of $3065 CAD per patient (95% CI, 2195–3945) and a gain in quality-adjusted life-years of 0.02 (95% CI, 0.01–0.02) versus TT alone. More patients received chemo-immunotherapy based on TT with higher overall costs, whereas more patients received targeted therapy based on LB + TT with net cost savings. Major drivers of cost-effectiveness were drug acquisition costs and prevalence of actionable alterations. Conclusion: The addition of LB to TT as initial molecular testing of clinically selected patients with advanced NSCLC did not increase system costs and led to more patients receiving appropriate targeted therapy.

Published
2022
Full Text
View/download PDF

6. Clinical implications of plasma circulating tumor DNA in gynecologic cancer patients

Author

Lindsey M. Charo, Ramez N. Eskander, Ryosuke Okamura, Sandip P. Patel, Mina Nikanjam, Richard B. Lanman, David E. Piccioni, Shumei Kato, Michael T. McHale, and Razelle Kurzrock

Subjects
circulating tumor DNA, gynecologic cancer, liquid biopsy, matched therapy, mutation allele frequency, next‐generation sequencing, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Molecular characterization of cancers is important in dictating prognostic factors and directing therapy. Next‐generation sequencing of plasma circulating tumor DNA (ctDNA) offers less invasive, more convenient collection, and a more real‐time representation of a tumor and its molecular heterogeneity than tissue. However, little is known about the clinical implications of ctDNA assessment in gynecologic cancer. We describe the molecular landscape identified on ctDNA, ctDNA concordance with tissue‐based analysis, and factors associated with overall survival (OS) in gynecologic cancer patients with ctDNA analysis. We reviewed clinicopathologic and genomic information for 105 consecutive gynecologic cancer patients with ctDNA analysis, including 78 with tissue‐based sequencing, enrolled in the Profile‐Related Evidence Determining Individualized Cancer Therapy (NCT02478931) trial at the University of California San Diego Moores Cancer Center starting July 2014. Tumors included ovarian (47.6%), uterine (35.2%), cervical (12.4%), vulvovaginal (2.9%), and unknown gynecologic primary (1.9%). Most ovarian and uterine cancers (86%) were high grade. 34% (N = 17) of ovarian cancers had BRCA alterations, and 22% (N = 11) were platinum sensitive. Patients received median 2 (range 0–13) lines of therapy prior to ctDNA collection. Most (75.2%) had at least one characterized alteration on ctDNA analysis, and the majority had unique genomic profiles on ctDNA. Most common alterations were TP53 (N = 59, 56.2% of patients), PIK3CA (N = 26, 24.8%), KRAS (N = 14, 13.3%), BRAF (N = 10, 9.5%), ERBB2 (N = 8, 7.6%), and MYC (N = 8, 7.6%). Higher ctDNA maximum mutation allele frequency was associated with worse OS [hazard ratio (HR): 1.91, P = 0.03], while therapy matched to ctDNA alterations (N = 33 patients) was independently associated with improved OS (HR: 0.34, P = 0.007) compared to unmatched therapy (N = 28 patients) in multivariate analysis. Tissue and ctDNA genomic results showed high concordance unaffected by temporal or spatial factors. This study provides evidence for the utility of ctDNA in determining outcome and individualizing cancer therapy in patients with gynecologic cancer.

Published
2021
Full Text
View/download PDF

7. Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer

Author

Hitendra Patel, Ryosuke Okamura, Paul Fanta, Charmi Patel, Richard B. Lanman, Victoria M. Raymond, Shumei Kato, and Razelle Kurzrock

Subjects
Pancreatic cancer, Next-generation sequencing, Circulating tumor DNA, KRAS, Molecular oncology, Targeted therapy, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Treatment outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal. There are unmet needs for understanding the biologic basis of this malignancy using novel next-generation sequencing technologies. Herein, we investigated the clinical utility of circulating tumor DNA (ctDNA) (the liquid biopsy) in this malignancy. Methods ctDNA was analyzed in 112 patients with PDAC (54–73 genes) and tissue DNA in 66 patients (315 genes) (both clinical-grade next-generation sequencing). Number of alterations, %ctDNA, concordance between ctDNA and tissue DNA, and correlation of ctDNA results with survival were assessed. Results The most common genes altered in ctDNA were TP53 (46% of patients, N = 51) and KRAS (44%, N = 49). Median number of characterized ctDNA alterations per patient was 1 (range, 0–6), but patients with advanced PDAC had significantly higher numbers of ctDNA alterations than those with surgically resectable disease (median, 2 versus 0.5, P = 0.04). Overall, 75% (70/94) of advanced tumors had ≥ 1 ctDNA alteration. Concordance rate between ctDNA and tissue DNA alterations was 61% for TP53 and 52% for KRAS. Concordance for KRAS alterations between ctDNA and tissue DNA from metastatic sites was significantly higher than between ctDNA and primary tumor DNA (72% vs 39%, P = 0.01). Importantly, higher levels of total %ctDNA were an independent prognostic factor for worse survival (hazard ratio, 4.35; 95% confidence interval, 1.85–10.24 [multivariate, P = 0.001]). A patient with three ctDNA alterations affecting the MEK pathway (GNAS, KRAS, and NF1) attained a response to trametinib monotherapy ongoing at 6 months. Conclusions Our findings showed that ctDNA often harbored unique alterations some of which may be targetable and that significantly greater numbers of ctDNA alterations occur in advanced versus resectable disease. Furthermore, higher ctDNA levels were a poor prognostic factor for survival.

Published
2019
Full Text
View/download PDF

8. Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort

Author

Stephen R. Fairclough, Lesli A. Kiedrowski, Jessica J. Lin, Ori Zelichov, Gabi Tarcic, Thomas E. Stinchcombe, Justin I. Odegaard, Richard B. Lanman, Alice T. Shaw, and Rebecca J. Nagy

Subjects
Cell-free DNA, cfDNA, Genomic evolution, Acquired resistance, Osimertinib, Guardant360, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Cell-free DNA (cfDNA) next-generation sequencing has the potential to capture tumor heterogeneity and genomic evolution under treatment pressure in a non-invasive manner. Here, we report the detection of EGFR L792 mutations, a non-covalent mechanism of osimertinib resistance, using Guardant360 cfDNA testing in a patient with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) whose disease progressed on osimertinib. We subsequently analyzed a large cohort of over 1800 additional patient samples harboring an EGFR T790M mutation and identified a concomitant L792 mutation in a total of 22 (1.2%) cases. In vitro functional assays demonstrated that the EGFR L858R/T790M/L792F/H mutations conferred intermediate-level resistance to osimertinib. Further understanding of potential acquired resistance mechanisms to targeted therapy may help inform treatment strategy in EGFR-mutant NSCLC.

Published
2019
Full Text
View/download PDF

9. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer

Author

Luigi Formisano, Yao Lu, Alberto Servetto, Ariella B. Hanker, Valerie M. Jansen, Joshua A. Bauer, Dhivya R. Sudhan, Angel L. Guerrero-Zotano, Sarah Croessmann, Yan Guo, Paula Gonzalez Ericsson, Kyung-min Lee, Mellissa J. Nixon, Luis J. Schwarz, Melinda E. Sanders, Teresa C. Dugger, Marcelo Rocha Cruz, Amir Behdad, Massimo Cristofanilli, Aditya Bardia, Joyce O’Shaughnessy, Rebecca J. Nagy, Richard B. Lanman, Nadia Solovieff, Wei He, Michelle Miller, Fei Su, Yu Shyr, Ingrid A. Mayer, Justin M. Balko, and Carlos L. Arteaga

Subjects
Science
Abstract

Era+ breast cancer patients often develop resistance to endocrine therapy. Here, the authors show that FGFR1 amplification is a resistance mechanism to CDK4/6 inhibitor and endocrine therapy and that combined treatment with FGFR, CDK4/6, and anti-estrogens is a potential therapeutic strategy in Era+ breast cancer tumors.

Published
2019
Full Text
View/download PDF

10. Ancient DNA analysis of archaeological specimens extends Chinook salmon's known historic range to San Francisco Bay's tributaries and southernmost watershed.

Author

Richard B Lanman, Linda Hylkema, Cristie M Boone, Brian Allée, Roger O Castillo, Stephanie A Moreno, Mary Faith Flores, Upuli DeSilva, Brittany Bingham, and Brian M Kemp

Subjects
Medicine, Science
Abstract

Understanding a species' historic range guides contemporary management and habitat restoration. Chinook salmon (Oncorhynchus tshawytscha) are an important commercial and recreational gamefish, but nine Chinook subspecies are federally threatened or endangered due to anthropogenic impacts. Several San Francisco Bay Area streams and rivers currently host spawning Chinook populations, but government agencies consider these non-native hatchery strays. Through the morphology-based analysis of 17,288 fish specimens excavated from Native American middens at Mission Santa Clara (CA-SCL-30H), Santa Clara County, circa 1781-1834 CE, 88 salmonid vertebrae were identified. Ancient DNA sequencing identified three separate individuals as Chinook salmon and the remainder as steelhead/rainbow trout (Oncorhynchus mykiss). These findings comprise the first physical evidence of the nativity of salmon to the Guadalupe River in San Jose, California, extending their documented historic range to include San Francisco Bay's southernmost tributary watershed.

Published
2021
Full Text
View/download PDF

11. Analysis of cell-free circulating tumor DNA in 419 patients with glioblastoma and other primary brain tumors

Author

David E Piccioni, Achal Singh Achrol, Lesli A Kiedrowski, Kimberly C Banks, Najee Boucher, Garni Barkhoudarian, Daniel F Kelly, Tiffany Juarez, Richard B Lanman, Victoria M Raymond, Minhdan Nguyen, Judy D Truong, Annie Heng, Jaya Gill, Marlon Saria, Sandeep C Pingle, and Santosh Kesari

Subjects
cell-free DNA, ctDNA, genomic profiling, glioblastoma, Guardant360, liquid biopsy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Aim: Genomically matched trials in primary brain tumors (PBTs) require recent tumor sequencing. We evaluated whether circulating tumor DNA (ctDNA) could facilitate genomic interrogation in these patients. Methods: Data from 419 PBT patients tested clinically with a ctDNA NGS panel at a CLIA-certified laboratory were analyzed. Results: A total of 211 patients (50%) had ≥1 somatic alteration detected. Detection was highest in meningioma (59%) and gliobastoma (55%). Single nucleotide variants were detected in 61 genes, with amplifications detected in ERBB2, MET, EGFR and others. Conclusion: Contrary to previous studies with very low yields, we found half of PBT patients had detectable ctDNA with genomically targetable off-label or clinical trial options for almost 50%. For those PBT patients with detectable ctDNA, plasma cfDNA genomic analysis is a clinically viable option for identifying genomically driven therapy options.

Published
2019
Full Text
View/download PDF

12. Detection of ERBB2 (HER2) Gene Amplification Events in Cell-Free DNA and Response to Anti-HER2 Agents in a Large Asian Cancer Patient Cohort

Author

Jeeyun Lee, Aleksandra Franovic, Yukimasa Shiotsu, Seung Tae Kim, Kyoung-Mee Kim, Kimberly C. Banks, Victoria M. Raymond, and Richard B. Lanman

Subjects
cfDNA, ERBB2, HER2, liquid biopsy, NGS, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: HER2 antagonists have marked activity and are approved for the treatment of HER2 overexpressing breast and gastric cancers. Recent studies have shown that ERBB2 (HER2) gene amplification and overexpression may also be actionable in other tumor types. Inter- and intratumoral heterogeneity in HER2 status, however, poses a significant challenge in identifying patients that may benefit from HER2-targeted therapies. ERBB2 amplification as identified by circulating cell-free DNA (cfDNA), which circumvents tissue heterogeneity issues, is emerging as a robust biomarker predictive of response to anti-HER2 agents. Here, the prevalence and genomic landscape of ERBB2 alterations detectable by next-generation sequencing (NGS) of cfDNA was evaluated in a large cohort of Asian patients with advanced solid tumors.Methods: Results were queried for consecutive patients (n = 469) tested by a comprehensive 70/73-gene cfDNA NGS assay (Guardant360®) between November 2015 and June 2018. Patients with ERBB2 gene alterations including copy number amplifications (CNAs), single nucleotide variants (SNVs), and insertion-deletions (indels) were identified.Results:ERBB2 alterations were detected in 52 patients (11.1%); ERBB2 SNVs, CNAs, and indels were found in 27 (5.8%), 27 (5.8%), and 10 (2.1%) patients, respectively. ERBB2 amplification was most frequently identified in gastric (21.4%; 6/28), colorectal (11.1%; 5/45), lung (3.9%; 9/231), and breast (3.2%; 1/31) cancer patients. ERBB2 amplification was often mutually exclusive with other oncogenic alterations in gastric (83.3%; 5/6) and colorectal (60%; 3/5) cancer patients. ERBB2 copy number gains were also highest in gastric and colorectal cancers (median 4.8 and 6.6, respectively). We further report two cases of advanced gastric cancer patients, one treatment naïve, and the other having failed four lines of therapy, whose ERBB2 CNAs were identified by cfDNA and derived clinical benefit from HER2-based therapies.Conclusion: Our data indicate that ERBB2 amplification is a common event in solid tumors among Asian cancer patients. High ERBB2 incidence and copy number gains were observed in gastric and colorectal cancer patients, often in the absence of other oncogenic mutations, underscoring its likely role as the driver alteration in those settings. Finally, we show the potential of comprehensive cfDNA testing in identifying patients who are most likely to benefit from HER2-targeted therapies.

Published
2019
Full Text
View/download PDF

13. Author Correction: Genomic profile of advanced breast cancer in circulating tumor DNA

Author

Belinda Kingston, Rosalind J. Cutts, Hannah Bye, Matthew Beaney, Giselle Walsh-Crestani, Sarah Hrebien, Claire Swift, Lucy S. Kilburn, Sarah Kernaghan, Laura Moretti, Katie Wilkinson, Andrew M. Wardley, Iain R. Macpherson, Richard D. Baird, Rebecca Roylance, Jorge S. Reis-Filho, Michael Hubank, Iris Faull, Kimberly C. Banks, Richard B. Lanman, Isaac Garcia-Murillas, Judith M. Bliss, Alistair Ring, and Nicholas C. Turner

Subjects
Science
Published
2021
Full Text
View/download PDF

15. MAF file for CNVs from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

MAF file for copy number variations identified in the cohort

Published
2023
Full Text
View/download PDF

16. Figure S1 from EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer

Author

Yelena Y. Janjigian, Nikolaus Schultz, Maurizio Scaltriti, Jorge A. Carrasquillo, David B. Solit, Jason S. Lewis, Barry S. Taylor, Elisa de Stanchina, Michael F. Berger, Wolfgang A. Weber, David H. Ilson, Christine A. Iacobuzio-Donahue, Heiko Schöder, Neeta Pandit-Taskar, Steven M. Larson, Richard B. Lanman, Rebecca J. Nagy, Todd Hembrough, Yuan Tian, Fabiola Cecchi, Besnik Qeriqi, Marissa Mattar, Marinela Capanu, Mario E. Lacouture, Karen Brown, Robert A. Lefkowitz, David P. Kelsen, Mark Schattner, Efsevia Vakiani, Joanne Soong, Gouri J. Nanjangud, Nancy Bouvier, Christopher J. Fong, Helen Won, Yaelle Tuvy, Geoffrey Y. Ku, Pau Castel, Jaclyn F. Hechtman, and Francisco Sanchez-Vega

Abstract

Additional results for dual probe EGFR and ERBB2 FISH from Patients 9, 30 and 32.

Published
2023
Full Text
View/download PDF

17. Supplementary Figure S2 from Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

Author

David M. Hyman, Funda Meric-Bernstam, David B. Solit, Barry S. Taylor, José Baselga, Richard Bryce, Alshad S. Lalani, Melanie Dujka, Lisa D. Eli, Feng Xu, Grace Mann, Maurizio Scaltriti, Yanyan Cai, Aliaksandra Samoila, Myra Melcer, S. Duygu Selcuklu, Catherine Zimel, Elena I. Gavrila, Komal Jhaveri, Sarat Chandarlapaty, Gary A. Ulaner, Rebecca J. Nagy, Richard B. Lanman, Alexander N. Gorelick, François-Clement Bidard, Andrés Cervantes, Xavier Gonzàlez-Farré, Lee S. Schwartzberg, Joohyuk Sohn, Valentina Boni, Victor Moreno, Monica Arnedos, Morten Mau-Sørensen, Iben Spanggaard, Adam M. Brufksy, Macarena I. de la Fuente, Carlos L. Arteaga, Ingrid A. Mayer, Dejan Juric, Geoffrey I. Shapiro, Janice Lu, Sherene Loi, Cristina Saura, Alison M. Schram, Helen H. Won, Sarina A. Piha-Paul, and Lillian M. Smyth

Abstract

Overall sequencing CONSORT diagram. Flow diagram of study patients and analyzed biospecimens processed through and selected for central sequencing using MSK-IMPACT and Guardant360. cfDNA, cell-free DNA; FFPE, formalin-fixed paraffin-embedded; MSK-IMPACT, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets; QC, quality control.

Published
2023
Full Text
View/download PDF

18. Supplemental Data File from Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma

Author

Daniel V.T. Catenacci, Namrata Setia, Shu-Yuan Xiao, John Hart, Alexa Schrock, Todd Hembrough, Fabiola Cecchi, Richard B. Lanman, Rebecca J. Nagy, Emily O'Day, David Xu, Leah Chase, Samantha Lomnicki, Heewon A. Kwak, Lindsay Alpert, and Steven B. Maron

Abstract

Detailed patient information who were treated with anti-EGFR therapy

Published
2023
Full Text
View/download PDF

20. Supplementary Table S4 from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

Treatment history for patients enrolled on the PancSeq protocol.

Published
2023
Full Text
View/download PDF

21. Data from Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

Author

David M. Hyman, Funda Meric-Bernstam, David B. Solit, Barry S. Taylor, José Baselga, Richard Bryce, Alshad S. Lalani, Melanie Dujka, Lisa D. Eli, Feng Xu, Grace Mann, Maurizio Scaltriti, Yanyan Cai, Aliaksandra Samoila, Myra Melcer, S. Duygu Selcuklu, Catherine Zimel, Elena I. Gavrila, Komal Jhaveri, Sarat Chandarlapaty, Gary A. Ulaner, Rebecca J. Nagy, Richard B. Lanman, Alexander N. Gorelick, François-Clement Bidard, Andrés Cervantes, Xavier Gonzàlez-Farré, Lee S. Schwartzberg, Joohyuk Sohn, Valentina Boni, Victor Moreno, Monica Arnedos, Morten Mau-Sørensen, Iben Spanggaard, Adam M. Brufksy, Macarena I. de la Fuente, Carlos L. Arteaga, Ingrid A. Mayer, Dejan Juric, Geoffrey I. Shapiro, Janice Lu, Sherene Loi, Cristina Saura, Alison M. Schram, Helen H. Won, Sarina A. Piha-Paul, and Lillian M. Smyth

Abstract

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib.Significance:HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.This article is highlighted in the In This Issue feature, p. 161

Published
2023
Full Text
View/download PDF

22. Supplementary Figures from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

Supplementary Figure S1: Overview of workflow and data generation. Supplementary Figure S2: Analysis of neoplastic cellularity. Supplementary Figure S3: Recurrent copy number alterations. Supplementary Figure S4: Mutational signature analysis. Supplementary Figure S5: Analysis of PDAC gene expression signatures. Supplementary Figure S6: Clinically relevant alterations in the cohort.

Published
2023
Full Text
View/download PDF

23. Supplementary Data from Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

Author

David M. Hyman, Funda Meric-Bernstam, David B. Solit, Barry S. Taylor, José Baselga, Richard Bryce, Alshad S. Lalani, Melanie Dujka, Lisa D. Eli, Feng Xu, Grace Mann, Maurizio Scaltriti, Yanyan Cai, Aliaksandra Samoila, Myra Melcer, S. Duygu Selcuklu, Catherine Zimel, Elena I. Gavrila, Komal Jhaveri, Sarat Chandarlapaty, Gary A. Ulaner, Rebecca J. Nagy, Richard B. Lanman, Alexander N. Gorelick, François-Clement Bidard, Andrés Cervantes, Xavier Gonzàlez-Farré, Lee S. Schwartzberg, Joohyuk Sohn, Valentina Boni, Victor Moreno, Monica Arnedos, Morten Mau-Sørensen, Iben Spanggaard, Adam M. Brufksy, Macarena I. de la Fuente, Carlos L. Arteaga, Ingrid A. Mayer, Dejan Juric, Geoffrey I. Shapiro, Janice Lu, Sherene Loi, Cristina Saura, Alison M. Schram, Helen H. Won, Sarina A. Piha-Paul, and Lillian M. Smyth

Abstract

Supplementary data

Published
2023
Full Text
View/download PDF

24. Supplementary Experimental Methods from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

Supplementary Experimental Methods

Published
2023
Full Text
View/download PDF

25. Supplementary Data from Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion

Author

Lecia V. Sequist, Aaron N. Hata, Beni Wolf, Sai-Hong I. Ou, Corinne Clifford, Erica K. Evans, Alice T. Shaw, Rebecca S. Heist, A. John Iafrate, Mari Mino-Kenudson, Dora Dias-Santagata, Richard B. Lanman, Rebecca J. Nagy, Jessica J. Lin, Varuna Nangia, Amanda K. Riley, Satoshi Yoda, Wenjia Su, Subba R. Digumarthy, Mandeep K. Banwait, Nicolas Marcoux, Viola W. Zhu, Inga T. Lennes, Justin F. Gainor, Jochen K. Lennerz, Hideko Isozaki, and Zofia Piotrowska

Abstract

Supplementary Data and Methods

Published
2023
Full Text
View/download PDF

26. MAF file for mutations from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

MAF file for mutations identified in the cohort

Published
2023
Full Text
View/download PDF

27. Supplementary Data from Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer

Author

Scott Kopetz, Ryan B. Corcoran, Igor F. Tsigelny, AmirAli Talasaz, Richard B. Lanman, Funda Meric-Bernstam, Rebecca J. Nagy, Kimberly C. Banks, Chloe E. Atreya, W. Michael Korn, Matthew McKinney, Allan Andresson Lima Pereira, Donna Niedzwiecki, Aparna R. Parikh, Leanne G. Ahronian, Jonathan M. Loree, and John H. Strickler

Abstract

Suppementary Table S1: Gene lists and exon coverage; Supplementary Table S2: Patient Demographics; Supplementary Table S3. Mutational landscape in cfDNA; Supplementary Figure S1: Schema for identification of unique patient cases for analysis; Supplementary Figure S2. Impact of the number of mechanisms of resistance to anti-EGFR therapy on clonality and relative mutant allele frequency; Supplementary Figure S3: Clonal dynamics during anti-EGFR therapy in patient #18.

Published
2023
Full Text
View/download PDF

30. Data from Genomic Profiling of Blood-Derived Circulating Tumor DNA from Patients with Colorectal Cancer: Implications for Response and Resistance to Targeted Therapeutics

Author

Razelle Kurzrock, Scott M. Lippman, Richard B. Lanman, Victoria M. Raymond, Ryosuke Okamura, Lawrence Leichman, Paul T. Fanta, Shumei Kato, and In Sil Choi

Abstract

Molecular profiling of circulating tumor DNA (ctDNA) is a promising noninvasive tool. Here, next-generation sequencing (NGS) of blood-derived ctDNA was performed in patients with advanced colorectal cancer. We investigated ctDNA-derived genomic alterations, including potential actionability, concordance with tissue NGS, and serial dynamics in 78 patients with colorectal cancer using a clinical-grade NGS assay that detects single nucleotide variants (54–73 genes) and selected copy-number variants, fusions, and indels. Overall, 63 patients [80.8% (63/78)] harbored ctDNA alterations; 59 [75.6% (59/78)], ≥1 characterized alteration (variants of unknown significance excluded). All 59 patients had actionable alterations potentially targetable with FDA-approved drugs [on-label and/or off-label (N = 54) or with experimental drugs in clinical trials (additional five patients); University of California San Diego Molecular Tumor Board assessment]: 45, by OncoKB (http://oncokb.org/#/). The tissue and blood concordance rates for common specific alterations ranged from 62.3% to 86.9% (median = 5 months between tests). In serial samples from patients on anti-EGFR therapy, multiple emerging alterations in genes known to be involved in therapeutic resistance, including KRAS, NRAS, BRAF, EGFR, ERBB2, and MET were detected. In conclusion, over 80% of patients with stage IV colorectal cancer had detectable ctDNA, and the majority had potentially actionable alterations. Concordance between tissue and blood was between 62% and 87%, despite a median of 5 months between tests. Resistance alterations emerged on anti-EGFR therapy. Therefore, biopsy-free, noninvasive ctDNA analysis provides data relevant to the clinical setting. Importantly, sequential ctDNA analysis detects patterns of emerging resistance allowing for precision planning of future therapy.

Published
2023
Full Text
View/download PDF

31. Supplementary Figure Legends from EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer

Author

Yelena Y. Janjigian, Nikolaus Schultz, Maurizio Scaltriti, Jorge A. Carrasquillo, David B. Solit, Jason S. Lewis, Barry S. Taylor, Elisa de Stanchina, Michael F. Berger, Wolfgang A. Weber, David H. Ilson, Christine A. Iacobuzio-Donahue, Heiko Schöder, Neeta Pandit-Taskar, Steven M. Larson, Richard B. Lanman, Rebecca J. Nagy, Todd Hembrough, Yuan Tian, Fabiola Cecchi, Besnik Qeriqi, Marissa Mattar, Marinela Capanu, Mario E. Lacouture, Karen Brown, Robert A. Lefkowitz, David P. Kelsen, Mark Schattner, Efsevia Vakiani, Joanne Soong, Gouri J. Nanjangud, Nancy Bouvier, Christopher J. Fong, Helen Won, Yaelle Tuvy, Geoffrey Y. Ku, Pau Castel, Jaclyn F. Hechtman, and Francisco Sanchez-Vega

Abstract

Supplementary Figure Legends

Published
2023
Full Text
View/download PDF

32. Supplementary Figures from Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion

Author

Lecia V. Sequist, Aaron N. Hata, Beni Wolf, Sai-Hong I. Ou, Corinne Clifford, Erica K. Evans, Alice T. Shaw, Rebecca S. Heist, A. John Iafrate, Mari Mino-Kenudson, Dora Dias-Santagata, Richard B. Lanman, Rebecca J. Nagy, Jessica J. Lin, Varuna Nangia, Amanda K. Riley, Satoshi Yoda, Wenjia Su, Subba R. Digumarthy, Mandeep K. Banwait, Nicolas Marcoux, Viola W. Zhu, Inga T. Lennes, Justin F. Gainor, Jochen K. Lennerz, Hideko Isozaki, and Zofia Piotrowska

Abstract

Supplementary Figures

Published
2023
Full Text
View/download PDF

34. Table S6 from The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Author

AmirAli Talasaz, Richard B. Lanman, Darya I. Chudova, Helmy Eltoukhy, Arthur M. Baca, Rebecca J. Nagy, Justin I. Odegaard, Philip C. Mack, David R. Gandara, Reza Mokhtari, James V. Vowles, Stefanie A. Mortimer, Stephen R. Fairclough, Kimberly C. Banks, and Oliver A. Zill

Abstract

Driver alteration prevalence in the cfDNA cohort versus in TCGA

Published
2023
Full Text
View/download PDF

35. Supplementary Data from Cell-free Circulating Tumor DNA Variant Allele Frequency Associates with Survival in Metastatic Cancer

Author

Funda Meric-Bernstam, Richard B. Lanman, Victoria M. Raymond, David R. Fogelman, Siqing Fu, Vivek Subbiah, David S. Hong, Ahmed O. Kaseb, Milind Javle, Senthilkumar Damodaran, Cathy Eng, Kenna R. Mills Shaw, Nora S. Sanchez, Filip Janku, Kenneth R. Hess, and Seyed Pairawan

Abstract

Supplemental Tables 1, 2, 3 and Supplemental Figure 1

Published
2023
Full Text
View/download PDF

36. Figure S4 from Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies

Author

AmirAli Talasaz, Darya I. Chudova, Richard B. Lanman, Helmy Eltoukhy, Cloud P. Paweletz, Lesli A. Kiedrowski, Christine E. Lee, Rebecca J. Nagy, Diana Abdueva, Reza Mokhtari, Marcin Sikora, Oliver A. Zill, Stephen R. Fairclough, Kimberly C. Banks, Bryan C. Ulrich, James V. Vowles, Stefanie Mortimer, John J. Vincent, and Justin I. Odegaard

Abstract

Quantitative precision of Digital Sequencing results. (a) SNV VAFs in 375 consecutive SNV control runs. (b) Indel and fusion VAFs (left y-axis) and CNA copy number (right y-axis) in consecutive CFI control runs. (c) Variation distribution of DS results in 375 consecutive analyses of a single SNV control lot (blue) and multiple consecutive lots of indel (red), fusion (grey), and CNA (orange) controls.

Published
2023
Full Text
View/download PDF

37. Table S2 from Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies

Author

AmirAli Talasaz, Darya I. Chudova, Richard B. Lanman, Helmy Eltoukhy, Cloud P. Paweletz, Lesli A. Kiedrowski, Christine E. Lee, Rebecca J. Nagy, Diana Abdueva, Reza Mokhtari, Marcin Sikora, Oliver A. Zill, Stephen R. Fairclough, Kimberly C. Banks, Bryan C. Ulrich, James V. Vowles, Stefanie Mortimer, John J. Vincent, and Justin I. Odegaard

Abstract

Detailed results of Digital Sequencing and clinical ddPCR comparison. Results shown in individual 2x2 tables for each biomarker tested. *Note, all discordances were below DFCI ddPCR's reportable range. Detailed clinical information for each is presented in Supplemental Table 3.

Published
2023
Full Text
View/download PDF

38. Data from Circulating Tumor DNA Sequencing Analysis of Gastroesophageal Adenocarcinoma

Author

Daniel V.T. Catenacci, Jeeyun Lee, Seung Tae Kim, Richard B. Lanman, Rebecca J. Nagy, Lesli A. Kiedrowski, Julie Johnson, Stacie Landron, Smita S. Joshi, Kelly L. Moore, Sara Kochanny, Samantha Lomnicki, Leah M. Chase, and Steven B. Maron

Abstract

Purpose:Gastroesophageal adenocarcinoma (GEA) has a poor prognosis and few therapeutic options. Utilizing a 73-gene plasma-based next-generation sequencing (NGS) cell-free circulating tumor DNA (ctDNA-NGS) test, we sought to evaluate the role of ctDNA-NGS in guiding clinical decision-making in GEA.Experimental Design:We evaluated a large cohort (n = 2,140 tests; 1,630 patients) of ctDNA-NGS results (including 369 clinically annotated patients). Patients were assessed for genomic alteration (GA) distribution and correlation with clinicopathologic characteristics and outcomes.Results:Treatment history, tumor site, and disease burden dictated tumor-DNA shedding and consequent ctDNA-NGS maximum somatic variant allele frequency. Patients with locally advanced disease having detectable ctDNA postoperatively experienced inferior median disease-free survival (P = 0.03). The genomic landscape was similar but not identical to tissue-NGS, reflecting temporospatial molecular heterogeneity, with some targetable GAs identified at higher frequency via ctDNA-NGS compared with previous primary tumor-NGS cohorts. Patients with known microsatellite instability-high (MSI-High) tumors were robustly detected with ctDNA-NGS. Predictive biomarker assessment was optimized by incorporating tissue-NGS and ctDNA-NGS assessment in a complementary manner. HER2 inhibition demonstrated a profound survival benefit in HER2-amplified patients by ctDNA-NGS and/or tissue-NGS (median overall survival, 26.3 vs. 7.4 months; P = 0.002), as did EGFR inhibition in EGFR-amplified patients (median overall survival, 21.1 vs. 14.4 months; P = 0.01).Conclusions:ctDNA-NGS characterized GEA molecular heterogeneity and rendered important prognostic and predictive information, complementary to tissue-NGS.See related commentary by Frankell and Smyth, p. 6893

Published
2023
Full Text
View/download PDF

39. Suppl. Figure S3 from Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non–Small Cell Lung Cancer

Author

Pasi A. Jänne, Yu Imamura, Daniel B. Costa, Paul A. VanderLaan, Amanda J. Redig, Emily S. Chambers, Marzia Capelletti, Richard B. Lanman, Rebecca J. Nagy, Mizuki Nishino, Hideo Baba, Masayuki Watanabe, Paul T. Kirschmeier, Cloud P. Paweletz, Bryan C. Ulrich, Giulia C. Leonardi, Elena V. Ivanova, Jihyun Choi, Sangeetha Palakurthi, Stephen Wang, Man Xu, Frederick H. Wilson, Lynette M. Sholl, Mark M. Awad, and Magda Bahcall

Abstract

DFCI358 signaling with respect to mTOR; crizotinib+trametinib combination;RTK activation

Published
2023
Full Text
View/download PDF

40. Data from Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non–small Cell Lung Cancer

Author

Vassiliki A. Papadimitrakopoulou, Richard B. Lanman, Justin I. Odegaard, Daniel Dix, Miguel A. Villalona-Calero, Karen L. Reckamp, Stephen G. Divers, Davey B. Daniel, Victoria M. Raymond, Ray D. Page, and Natasha B. Leighl

Abstract

Purpose:Complete and timely tissue genotyping is challenging, leading to significant numbers of patients with newly diagnosed metastatic non–small cell lung cancer (mNSCLC) being undergenotyped for all eight genomic biomarkers recommended by professional guidelines. We aimed to demonstrate noninferiority of comprehensive cell-free DNA (cfDNA) relative to physician discretion standard-of-care (SOC) tissue genotyping to identify guideline-recommended biomarkers in patients with mNSCLC.Patients and Methods:Prospectively enrolled patients with previously untreated mNSCLC undergoing physician discretion SOC tissue genotyping submitted a pretreatment blood sample for comprehensive cfDNA analysis (Guardant360).Results:Among 282 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 60 patients versus 77 cfDNA identified patients (21.3% vs. 27.3%; P < 0.0001 for noninferiority). In tissue-positive patients, the biomarker was identified alone (12/60) or concordant with cfDNA (48/60), an 80% cfDNA clinical sensitivity for any guideline-recommended biomarker. For FDA-approved targets (EGFR, ALK, ROS1, BRAF) concordance was >98.2% with 100% positive predictive value for cfDNA versus tissue (34/34 EGFR-, ALK-, or BRAF-positive patients). Utilizing cfDNA, in addition to tissue, increased detection by 48%, from 60 to 89 patients, including those with negative, not assessed, or insufficient tissue results. cfDNA median turnaround time was significantly faster than tissue (9 vs. 15 days; P < 0.0001). Guideline-complete genotyping was significantly more likely (268 vs. 51; P < 0.0001).Conclusions:In the largest cfDNA study in previously untreated mNSCLC, a validated comprehensive cfDNA test identifies guideline-recommended biomarkers at a rate at least as high as SOC tissue genotyping, with high tissue concordance, more rapidly and completely than tissue-based genotyping.See related commentary by Meador and Oxnard, p. 4583

Published
2023
Full Text
View/download PDF

41. Data from Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion BRCA Mutations among Patients with Advanced Solid Tumors

Author

Massimo Cristofanilli, Aditya Bardia, Richard B. Lanman, Stephen R. Fairclough, Victoria M. Raymond, Benjamin L. Maughan, Neeraj Agarwal, Benjamin B. Bridges, Barbara A. Parker, Adam M. Brufsky, Alice C. Fan, Benedito A. Carneiro, Sandip P. Patel, Mohammad Amin Nezami, Michael B. Lilly, Tracy Nance, Aaron Hardin, Jennifer Yen, Oliver Sartor, Thereasa A. Rich, and Neelima Vidula

Abstract

Purpose:PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) BRCA1/2 mutations. Acquired reversions can restore BRCA1/2 function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in BRCA1/2 has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of BRCA1/2 mutations.Experimental Design:Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion–deletion mutations (indels) in BRCA1/2, and distinguishes somatic/reversion from germline mutations with high accuracy.Results:Among 828 patients, one or more deleterious BRCA1/2 mutations were detected in 60 (7.2%) patients, including germline (n = 42) and somatic (n = 18) mutations. Common coexisting mutations included TP53 (61.6%), MYC (30%), PIK3CA (26.6%), BRAF (15%), and ESR1 (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9 of 42 (21.4%) germline BRCA1/2-mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion BRCA mutations under therapeutic pressure from initial PARPi exposure, which contributed to subsequent resistance to PARPi and platinum therapy.Conclusions:cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic BRCA1/2 mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical utility of these findings to guide precision medicine approaches for patients with advanced malignancies.

Published
2023
Full Text
View/download PDF

42. Supplementary Methods from Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non–Small Cell Lung Cancer

Author

Pasi A. Jänne, Yu Imamura, Daniel B. Costa, Paul A. VanderLaan, Amanda J. Redig, Emily S. Chambers, Marzia Capelletti, Richard B. Lanman, Rebecca J. Nagy, Mizuki Nishino, Hideo Baba, Masayuki Watanabe, Paul T. Kirschmeier, Cloud P. Paweletz, Bryan C. Ulrich, Giulia C. Leonardi, Elena V. Ivanova, Jihyun Choi, Sangeetha Palakurthi, Stephen Wang, Man Xu, Frederick H. Wilson, Lynette M. Sholl, Mark M. Awad, and Magda Bahcall

Abstract

Detailed description of methodology and reagents

Published
2023
Full Text
View/download PDF

43. Supplementary Figures 1,2, 3 from Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non–Small Cell Lung Cancer

Author

Robert C. Doebele, Alice T. Shaw, Richard B. Lanman, Kurtis D. Davies, Dara L. Aisner, William T. Purcell, Saiama N. Waqar, Joseph Diaz, Christine E. Lee, Anh T. Le, Victoria M. Raymond, Ben M. Chue, Benjamin Levy, Kimberly C. Banks, Collin M. Blakely, and Caroline E. McCoach

Abstract

Supplementary Figures 1,2, 3

Published
2023
Full Text
View/download PDF

44. Data from Molecular Profiling of Hepatocellular Carcinoma Using Circulating Cell-Free DNA

Author

Razelle Kurzrock, Sadakatsu Ikeda, Funda Meric-Bernstam, James C. Yao, Robert A. Wolff, Kanwal P.S. Raghav, Abedul Haque, Bhawana George, Kenna R. Mills-Shaw, AmirAli Talasaz, Richard B. Lanman, Kimberly C. Banks, Asif Rashid, Manal M. Hassan, Hesham M. Amin, Jeffrey Morris, Lianchun Xiao, Wei Qiao, Roberto Carmagnani Pestana, Marc Uemura, Reham Abdel-Wahab, Kian H. Lim, Andrea G. Bocobo, Benjamin Tan, Robin K. Kelley, Shiraj Sen, Nora S. Sánchez, and Ahmed O. Kaseb

Abstract

Purpose:Molecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies.Experimental Design:We analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA).Results:A total of 153/206 (74.3%) were men; median age, 62 years (range, 18–91 years). A total of 181/206 patients had ≥1 alteration. The total number of alterations was 680 (nonunique); median number of alterations/patient was three (range, 1–13); median mutant allele frequency (% cfDNA), 0.49% (range, 0.06%–55.03%). TP53 was the common altered gene [>120 alterations (non-unique)] followed by EGFR, MET, ARID1A, MYC, NF1, BRAF, and ERBB2 [20–38 alterations (nonunique)/gene]. Of the patients with alterations, 56.9% (103/181) had ≥1 actionable alterations, most commonly in MYC, EGFR, ERBB2, BRAF, CCNE1, MET, PIK3CA, ARID1A, CDK6, and KRAS. In these genes, amplifications occurred more frequently than mutations. Hepatitis B (HBV)-positive patients were more likely to have ERBB2 alterations, 35.7% (5/14) versus 8.8% HBV-negative (P = 0.04).Conclusions:This study represents the first large-scale analysis of blood-derived ctDNA in HCC in United States. The genomic distinction based on HCC risk factors and the high percentage of potentially actionable genomic alterations suggests potential clinical utility for this technology.

Published
2023
Full Text
View/download PDF

46. Supplemental Figure S3 from Co-occurring Alterations in the RAS–MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer

Author

Collin M. Blakely, Trever G. Bivona, Tianhong Li, Lyudmila Bazhenova, Jose Pacheco, D. Ross Camidge, Caroline E. McCoach, Eric A. Collisson, James S. Fraser, Alexander M. Wolff, Victor R. Olivas, Kimberly Newsom, Petr Starostik, Boris C. Bastian, Iwei Yeh, Ryan B. Corcoran, Brandon Nadres, Ferran Fece de la Cruz, Nir Peled, Frederic J. Kaye, Richard B. Lanman, Victoria M. Raymond, Wei Wu, Philippe Gui, and Julia K. Rotow

Abstract

MET tyrosine kinase domain modeling location of the F1200 residue

Published
2023
Full Text
View/download PDF

47. Supplemental Table 1 from Co-occurring Alterations in the RAS–MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer

Author

Collin M. Blakely, Trever G. Bivona, Tianhong Li, Lyudmila Bazhenova, Jose Pacheco, D. Ross Camidge, Caroline E. McCoach, Eric A. Collisson, James S. Fraser, Alexander M. Wolff, Victor R. Olivas, Kimberly Newsom, Petr Starostik, Boris C. Bastian, Iwei Yeh, Ryan B. Corcoran, Brandon Nadres, Ferran Fece de la Cruz, Nir Peled, Frederic J. Kaye, Richard B. Lanman, Victoria M. Raymond, Wei Wu, Philippe Gui, and Julia K. Rotow

Abstract

Demographics of the METex14-mutated and EGFR-mutated cohorts.

Published
2023
Full Text
View/download PDF

48. Data from Co-occurring Alterations in the RAS–MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer

Author

Collin M. Blakely, Trever G. Bivona, Tianhong Li, Lyudmila Bazhenova, Jose Pacheco, D. Ross Camidge, Caroline E. McCoach, Eric A. Collisson, James S. Fraser, Alexander M. Wolff, Victor R. Olivas, Kimberly Newsom, Petr Starostik, Boris C. Bastian, Iwei Yeh, Ryan B. Corcoran, Brandon Nadres, Ferran Fece de la Cruz, Nir Peled, Frederic J. Kaye, Richard B. Lanman, Victoria M. Raymond, Wei Wu, Philippe Gui, and Julia K. Rotow

Abstract

Purpose:Although patients with advanced-stage non–small cell lung cancers (NSCLC) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.Experimental Design:Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC.Results:Prominent co-occurring RAS–MAPK pathway gene alterations (e.g., in KRAS, NF1) were detected in NSCLCs with METex14 skipping alterations as compared with EGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS–MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical METex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib.Conclusions:Our study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.

Published
2023
Full Text
View/download PDF

49. Supplementary Table 2 from Genomic Alterations in Circulating Tumor DNA from Diverse Cancer Patients Identified by Next-Generation Sequencing

Author

Razelle Kurzrock, Lyudmila Bazhenova, Richard B. Lanman, AmirAli Talasaz, Sadakatsu Ikeda, David E. Piccioni, In Sil Choi, Kimberly C. Banks, Paul T. Fanta, Shumei Kato, Ranajoy Chattopadhyay, and Maria Schwaederle

Abstract

68 gene panel (ctDNA) comprising amplifications in 16 genes as well as some fusions and indels.

Published
2023
Full Text
View/download PDF

50. Data from Genomic Alterations in Circulating Tumor DNA from Diverse Cancer Patients Identified by Next-Generation Sequencing

Author

Razelle Kurzrock, Lyudmila Bazhenova, Richard B. Lanman, AmirAli Talasaz, Sadakatsu Ikeda, David E. Piccioni, In Sil Choi, Kimberly C. Banks, Paul T. Fanta, Shumei Kato, Ranajoy Chattopadhyay, and Maria Schwaederle

Abstract

Noninvasive genomic profiling of tumors may be possible with next-generation sequencing (NGS) of blood-derived circulating tumor DNA (ctDNA), but proof of concept in a large cohort of patients with diverse cancers has yet to be reported. Here we report the results of an analysis of plasma-derived ctDNA from 670 patients with diverse cancers. The tumors represented in the patient cohort were mainly gastrointestinal (31.8%), brain (22.7%), or lung (20.7%). ctDNA obtained from most patients [N = 423 (63%)] displayed at least one alteration. The most frequent alterations seen, as characterized mutations or variants of unknown significance, occurred in TP53 (32.5% of patients), EGFR (13%), KRAS (12.5%), and PIK3CA (9.1%); for characterized alterations, 30.7% (TP53), 7.6% (EGFR), 12.2% (KRAS), and 7.7% (PIK3CA). We found that 32% of brain tumors had at least one ctDNA alteration. Head and neck tumors were independently associated with a higher number of alterations in a multivariable analysis (P = 0.019). Notably, 320/670 (48%) of patients displayed potentially actionable alterations, with 241 patients possible candidates for on-label or off-label treatment with an FDA-approved drug. Several illustrations of the clinical utility of the information obtained for improving treatment of specific patients is provided. Our findings demonstrate the feasibility and impact of genomic profiling of tumors by ctDNA NGS, greatly encouraging broader investigations of the application of this technology for precision medicine in cancer management. Cancer Res; 77(19); 5419–27. ©2017 AACR.

Published
2023
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results