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1. Association of personalized and tumor-informed ctDNA with patient survival outcomes in pancreatic adenocarcinoma.

Author

Botta, Gregory, Abdelrahim, Maen, Drengler, Ronald, Aushev, Vasily, Esmail, Abdullah, Laliotis, George, Brewer, Chris, George, Giby, Abbate, Steven, Chandana, Sreenivasa, Tejani, Mohamedtaki, Malla, Midhun, Bansal, Dhruv, Rivero-Hinojosa, Samuel, Spickard, Erik, McCormick, Nicole, Cecchini, Michael, Lacy, Jill, Fei, Naomi, Kasi, Pashtoon, Kasi, Anup, Dayyani, Farshid, Hanna, Diana, Sharma, Shruti, Malhotra, Meenakshi, Aleshin, Alexey, Liu, Minetta, and Jurdi, Adham

Subjects
KRAS, ctDNA, molecular residual disease, pancreatic adenocarcinoma, Humans, Circulating Tumor DNA, Male, Pancreatic Neoplasms, Female, Aged, Middle Aged, Retrospective Studies, Carcinoma, Pancreatic Ductal, Aged, 80 and over, Precision Medicine, Adult, Biomarkers, Tumor, Adenocarcinoma
Abstract

INTRODUCTION: Personalized and tumor-informed circulating tumor DNA (ctDNA) testing is feasible and allows for molecular residual disease (MRD) identification in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: In this retrospective analysis of commercial cases from multiple US institutions, personalized, tumor-informed, whole-exome sequenced, and germline-controlled ctDNA levels were quantified and analyzed in patients with PDAC. Plasma samples (n = 1329) from 298 clinically validated patients were collected at diagnosis, perioperatively (MRD-window; within 2-12 weeks after surgery, before therapy), and during surveillance (>12 weeks post-surgery if no ACT or starting 4 weeks post-ACT) from November 2019 to March 2023. RESULTS: Of the initially diagnosed patients with stages I-III PDAC who went for resection, the median follow-up time from surgery was 13 months (range 0.1-214). Positive ctDNA detection rates were 29% (29/100) and 29.6% (45/152) during the MRD and surveillance windows, respectively. Positive ctDNA detection was significantly associated with shorter DFS within the MRD window (median DFS of 6.37 months for ctDNA-positive vs 33.31 months for ctDNA-negative patients; HR: 5.45, P

Published
2024

2. Assessment of circulating tumor DNA in patients with locally advanced rectal cancer treated with neoadjuvant therapy

Author

Molinari, Chiara, Marisi, Giorgia, Laliotis, George, Spickard, Erik, Rapposelli, Ilario Giovanni, Petracci, Elisabetta, George, Giby V., Dutta, Punashi, Sharma, Shruti, Malhotra, Meenakshi, Prochowski Iamurri, Andrea, Feliciani, Giacomo, Liu, Minetta C., Ulivi, Paola, Canale, Matteo, Saragoni, Luca, Gallo, Graziana, Frassineti, Giovanni Luca, Muratore, Margherita, Romeo, Antonino, Jurdi, Adham, Martinelli, Giovanni, and Passardi, Alessandro

Published
2024
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3. Monitoring response to neoadjuvant chemotherapy in triple negative breast cancer using circulating tumor DNA

Author

Chen, Jennifer H., Addanki, Sridevi, Roy, Dhruvajyoti, Bassett, Roland, Kalashnikova, Ekaterina, Spickard, Erik, Kuerer, Henry M., Meas, Salyna, Sarli, Vanessa N., Korkut, Anil, White, Jason B., Rauch, Gaiane M., Tripathy, Debu, Arun, Banu K., Barcenas, Carlos H., Yam, Clinton, Sethi, Himanshu, Rodriguez, Angel A., Liu, Minetta C., Moulder, Stacy L., and Lucci, Anthony

Published
2024
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4. Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial

Author

Verschoor, Yara L., van de Haar, Joris, van den Berg, José G., van Sandick, Johanna W., Kodach, Liudmila L., van Dieren, Jolanda M., Balduzzi, Sara, Grootscholten, Cecile, IJsselsteijn, Marieke E., Veenhof, Alexander A. F. A., Hartemink, Koen J., Vollebergh, Marieke A., Jurdi, Adham, Sharma, Shruti, Spickard, Erik, Owers, Emilia C., Bartels-Rutten, Annemarieke, den Hartog, Peggy, de Miranda, Noel F. C. C., van Leerdam, Monique E., Haanen, John B. A. G., Schumacher, Ton N., Voest, Emile E., and Chalabi, Myriam

Published
2024
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7. Circulating tumor DNA status and dynamics predict recurrence in patients with resected extrahepatic cholangiocarcinoma

Author

Yoo, Changhoon, Jeong, Hyehyun, Jeong, Jae Ho, Kim, Kyu-pyo, Lee, Seonmin, Ryoo, Baek-Yeol, Hwang, Dae Wook, Lee, Jae Hoon, Moon, Deog-Bog, Kim, Ki-Hun, Lee, Sang Soo, Song, Tae Jun, Oh, Dongwook, Lee, Myung Ah, Chon, Hong Jae, Lee, Ji Sung, Laliotis, George, Rivero-Hinojosa, Samuel, Spickard, Erik, Renner, Derrick, Dutta, Punashi, Palsuledesai, Charuta C., Sharma, Shruti, Malhotra, Meenakshi, Jurdi, Adham, and Liu, Minetta C.

Published
2024
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8. Author Correction: Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial

Author

Verschoor, Yara L., van de Haar, Joris, van den Berg, José G., van Sandick, Johanna W., Kodach, Liudmila L., van Dieren, Jolanda M., Balduzzi, Sara, Grootscholten, Cecile, IJsselsteijn, Marieke E., Veenhof, Alexander A. F. A., Hartemink, Koen J., Vollebergh, Marieke A., Jurdi, Adham, Sharma, Shruti, Spickard, Erik, Owers, Emilia C., Bartels-Rutten, Annemarieke, den Hartog, Peggy, de Miranda, Noel F. C. C., van Leerdam, Monique E., Haanen, John B. A. G., Schumacher, Ton N., Voest, Emile E., and Chalabi, Myriam

Published
2024
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9. Longitudinal ctDNA measurements for treatment response monitoring in patients with metastatic colorectal cancer undergoing systemic therapy: The ORCA trial.

Author

van Steijn, Denise, Laliotis, George, Spickard, Erik Anthony, Schraa, Suzanna J., van der Baan, Frederieke H, Punt, Cornelis J. A., van den Broek, Daan, Sharma, Shruti, Sethi, Himanshu, Liu, Minetta C., Jurdi, Adham A, Kok, Niels FM, Koopman, Miriam, Vink, Geraldine R, and Fijneman, Remond

Published
2025
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10. Monitoring Response to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer Using Circulating Tumor DNA

Author

Chen, Jennifer H., primary, Addanki, Sridevi, additional, Roy, Dhruvajyoti, additional, Bassett, Roland, additional, Kalashnikova, Ekaterina, additional, Spickard, Erik, additional, Kuerer, Henry M., additional, Meas, Salyna, additional, Sarli, Vanessa N., additional, Korkut, Anil, additional, White, Jason B., additional, Rauch, Gaiane M., additional, Tripathy, Debu, additional, Arun, Banu K., additional, Barcenas, Carlos H., additional, Yam, Clinton, additional, Sethi, Himanshu, additional, Rodriguez, Angel A., additional, Liu, Minetta C., additional, Moulder, Stacy L., additional, and Lucci, Anthony, additional

Published
2024
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11. Abstract A002: A phase II study of peri-operative modified FOLFIRINOX in localized pancreatic ductal adenocarcinoma (PDAC)

Author

Cecchini, Michael, primary, Salem, Ronald, additional, Robert, Marie, additional, Czerniak, Suzanne, additional, Rajaei, Moein, additional, Townsend, Jeffrey, additional, Blaha, Ondrej, additional, Zelterman, Daniel, additional, Thumar, Jaykumar, additional, Kortmansky, Jeremy, additional, Zaheer, Wajih, additional, Fischbach, Neal, additional, Persico, Justin, additional, Stein, Stacey, additional, Khan, Sajid, additional, Cha, Charles, additional, Billingsley, Kevin, additional, Kunstman, John, additional, Chowdhury, Sumedha, additional, Tseng, Robert, additional, Mauricio, Carlos, additional, Yugawa, Deanne, additional, Escobar-Hoyos, Luisa, additional, Johung, Kimberly, additional, Wiess, Christina, additional, Spickard, Erik, additional, Aushev, Vasily N., additional, Laliotis, George, additional, Jurdi, Adham, additional, Liu, Minetta C., additional, and Lacy, Jill, additional

Published
2024
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12. Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Clinical Trial

Author

Cecchini, Michael, Salem, Ronald R., Robert, Marie, Czerniak, Suzanne, Blaha, Ondrej, Zelterman, Daniel, Rajaei, Moein, Townsend, Jeffrey P., Cai, Guoping, Chowdhury, Sumedha, Yugawa, Deanne, Tseng, Robert, Mejia Arbelaez, Carlos, Jiao, Jingjing, Shroyer, Kenneth, Thumar, Jaykumar, Kortmansky, Jeremy, Zaheer, Wajih, Fischbach, Neal, Persico, Justin, Stein, Stacey, Khan, Sajid A., Cha, Charles, Billingsley, Kevin G., Kunstman, John W., Johung, Kimberly L., Wiess, Christina, Muzumdar, Mandar D., Spickard, Erik, Aushev, Vasily N., Laliotis, George, Jurdi, Adham, Liu, Minetta C., Escobar-Hoyos, Luisa, and Lacy, Jill

Abstract

IMPORTANCE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection. OBJECTIVE: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival. DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-arm, phase 2 nonrandomized clinical trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023. INTERVENTIONS: Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression. MAIN OUTCOMES AND MEASURES: The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator. RESULTS: Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07). CONCLUSIONS AND RELEVANCE: This nonrandomized clinical trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02047474

Published
2024
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15. Investigating the Mechanisms of in vivo Cellular Reprogramming and Transorganogenesis in Caenorhabditis elegans

Author

Spickard, Erik Anthony

Subjects
Cellular biology, Developmental biology, Molecular biology, C. elegans, ELT-7, Reprogramming, RNAseq, Transdifferentiation, transorganogenesis
Abstract

Cellular reprogramming has the potential to treat numerous degenerative diseases and repair injured organs, but safe and effective therapeutic applications require deeper understanding of the molecular and cellular consequences of forced cell fate changes. The model organism Caenorhabditis elegans can be used to study cellular reprogramming in vivo and features diverse reprogramming-related events, including: the multipotency-to-commitment transition during embryogenesis, naturally occurring transdifferentiation, and forced reprogramming of the germline and differentiated somatic cells. A remarkable finding from a previous study showed that ectopic expression of the transcription factor ELT-7 alone is capable of triggering transdifferentiation of the pharynx into intestine-like tissue, and “transorganogenesis” of the entire uterus into a well-formed intestine-like organ. However, the molecular mechanisms involved in this process are largely unknown.In this work, I primarily utilize reverse genetic screening and time course mRNA-sequencing methods to probe the ability of ELT-7 to initiate reprogramming and to identify biological processes involved in somatic gonad-to-intestine transorganogenesis. I find that reprogramming to intestine mirrors embryonic endoderm development, engaging most, if not all, of the endoderm gene regulatory network (GRN). Three chromatin-associated factors are identified that appear to be playing important roles in ELT-7-directed transorganogenesis, suggesting that establishment of proper chromatin architecture may define a permissive cellular context for reprogramming into intestine. Bioinformatics analysis of the ELT-7-directed reprogramming temporal transcriptional profile shows that widespread gene expression changes occur even in some non-reprogrammed tissues, indicating significant cell fate elasticity and suggesting cell type-specific modes for cell fate maintenance. Finally, and somewhat surprisingly, gene expression changes following ectopic ELT-7 expression reveal the activation of an intracellular pathogen response (IPR) that correlates both spatially and temporally with cellular reprogramming and may be promoting somatic gonad-to-intestine transorganogenesis.This work presents the gene expression dynamics of in vivo cellular reprogramming and characterizes the distinct biological processes involved. These findings suggest that the cell type-specific reprogramming ability of ELT-7 may rely on the robust endoderm GRN and require a cellular context that is capable of activating the IPR. These data will enable further targeted research into the mechanisms of transorganogenesis and may lead to the discovery of similar phenomena in C. elegans and other organisms.

Published
2019

16. Abstract PD17-03: Cell-free DNA monitoring in a phase II study of adjuvant endocrine therapy with CDK 4/6 inhibitor ribociclib for localized HR+/HER2- breast cancer (LEADER)

Author

Medford, Arielle J., primary, Scarpetti, Lauren, additional, Niemierko, Andrzej, additional, Isakoff, Steven J., additional, Moy, Beverly, additional, Wander, Seth A., additional, Deluca, Elizabeth, additional, Abraham, Elizabeth, additional, Shin, Jennifer, additional, Schnipper, Lowell, additional, Comander, Amy E., additional, Mulvey, Therese, additional, Spickard, Erik, additional, Kalashnikova, Ekaterina, additional, Rodriguez, Angel, additional, Ellisen, Leif, additional, Bardia, Aditya, additional, and Spring, Laura M., additional

Published
2023
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18. The multipotency‐to‐commitment transition in <italic>Caenorhabditis elegans</italic>—implications for reprogramming from cells to organs.

Author

Spickard, Erik A., Joshi, Pradeep M., and Rothman, Joel H.

Subjects
*MULTIPOTENT stem cells, *CAENORHABDITIS elegans, *CELL differentiation, *ENDODERM, *DEVELOPMENTAL biology
Abstract

In animal embryos, cells transition from a multipotential state, with the capacity to adopt multiple fates, into an irreversible, committed state of differentiation. This multipotency‐to‐commitment transition (MCT) is evident from experiments in which cell fate is reprogrammed by transcription factors for cell type‐specific differentiation, as has been observed extensively in Caenorhabditis elegans. Although factors that direct differentiation into each of the three germ layer types cannot generally reprogram cells after the MCT in this animal, transcription factors for endoderm development are able to do so in multiple differentiated cell types. In one case, these factors can redirect the development of an entire organ in the process of “transorganogenesis”. Natural transdifferentiation also occurs in a small number of differentiated cells during normal C. elegans development. We review these reprogramming and transdifferentiation events, highlighting the cellular and developmental contexts in which they occur, and discuss common themes underlying direct cell lineage reprogramming. Although certain aspects may be unique to the model system, growing evidence suggests that some mechanisms are evolutionarily conserved and may shed light on cellular plasticity and disease in humans. [ABSTRACT FROM AUTHOR]

Published
2018
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20. Molecular residual disease (MRD) detection using bespoke circulating tumor DNA (ctDNA) assays in localized soft tissue sarcoma (STS).

Author

Salawu, Abdulazeez, Demicco, Elizabeth, Chung, Peter W. M., Feeney, Jordan, Spickard, Erik, Rathore, Richa, Lee, Jasmine, Wong, Philip, Malone, Eoghan Ruadh, Catton, Charles, Arones, Limore, Phillips, Madeline J., Ferguson, Peter Charles, Wunder, Jay, Tin, Tony, Sethi, Himanshu, Liu, Minetta C., Shultz, David Benjamin, and Abdul Razak, Albiruni Ryan

Published
2023
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