Cancer Cell (April 2025)

Summary

The Marathon of Hope Cancer Centres Network (MOHCCN), led by the Terry Fox Research Institute and the Terry Fox Foundation, unites researchers, clinicians, patients, funders, and other partners across Canada to accelerate precision oncology, promote collaboration and data sharing, and ultimately improve patient outcomes. This overview outlines the Network’s goals, history, and challenges and opportunities. We also highlight progress towards the “MOHCCN Gold Cohort”, a shared resource of clinical and genomic data from 15,000 patients. 

Click here to access the online publication (this link should provide access to the full text until May 23, 2025, to those who do not have a journal subscription - if you have any issues, please contact Véronique at vleblanc@tfri.ca).

doi: 10.1016/j.ccell.2025.03.014

Click here to download an updated version of Table S1 (collaborators, funding partners and acknowledgements).

Click here to download an additional supplementary document with the following information:

• Supplementary Figure 1: Organizational chart depicting the MOHCCN’s governance structure.
• Supplementary Table 1: MOHCCN working groups (including mandates and outputs).
• Supplementary Table 2: List of cancer types and subtypes represented within the categories shown in Figure 2.
• Please note that this information is accurate as of the time of publication. For the latest information, please see the links below.

Links to resources and further reading:

• Policies and guidelines - Policies, guidelines, data models, and other documents developed by Network working groups and endorsed by Network leadership.
• Mission & Vision - Also includes a brief history of Terry Fox and his Marathon of Hope.
• Network-funded projects
• Network members and partners (individual and institutional)
• Network consortia
• Working groups
• Network Voices - First-person pieces from Network members and collaborators on topics of expertise. Include patient stories from Patient Working Group members and from individuals contributing their biospecimens and data to the MOHCCN Gold Cohort. 
• Patient Hub - Resources developed for people experiencing cancer by the MOHCCN Patient Working Group.
• Gold Cohort - Description of the Network's Gold Cohort resource in plain language.
• Governance structure
• Funding model

Mona Teng, Jiacheng Guo, Xin Xu, Xinpei Ci, Yulin Mo, Yakup Kohen, Zuyao Ni, Sujun Chen, Wang Yuan Guo, Martin Bakht, Shengyu Ku, Michael Sigouros, Wenqin Luo, Colette Maya Macarios, Ziting Xia, Moliang Chen, Sami Ul Haq, Wen Yang, Alejandro Berlin, Theo van der Kwast, Leigh Ellis, Amina Zoubeidi, Gang Zheng, Jie Ming, Yuzhuo Wang, Haissi Cui, Benjamin H. Lok, Brian Raught, Himisha Beltran, Jun Qin, Housheng Hansen He

Abstract

Circular RNA (circRNA) is a class of noncoding RNA with regulatory potentials. Its role in the transdifferentiation of prostate and lung adenocarcinoma into neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC) remains unexplored. Here, we identified circRMST as an exceptionally abundant circRNA predominantly expressed in NEPC and SCLC, with strong conservation between humans and mice. Functional studies using shRNA, siRNA, CRISPR-Cas13, and Cas9 consistently demonstrate that circRMST is essential for tumor growth and the expression of ASCL1, a master regulator of neuroendocrine fate. Genetic knockout of Rmst in NEPC genetic engineered mouse models prevents neuroendocrine transdifferentiation, maintaining tumors in an adenocarcinoma state. Mechanistically, circRMST physically interacts with lineage transcription factors NKX2-1 and SOX2. Loss of circRMST induces NKX2-1 protein degradation through autophagy-lysosomal pathway and alters the genomic binding of SOX2, collectively leading to the loss of ASCL1 transcription.

Abdul R Farooq, Amy X Zhang, Michelle Chan-Seng-Yue, James T Topham, Grainne M O'Kane, Gun Ho Jang, Sandra Fischer, Anna Dodd, Spring Holter, Julie Wilson, Robert C Grant, Kyaw Lwin Aung, George Zogopoulos, Elena Elimova, Rebecca Prince, Raymond Jang, Malcolm Moore, James Biagi, Patricia Tang, Rachel Goodwin, Oliver F Bathe, Marco Marra, Janessa Laskin, Daniel J Renouf, David F Schaeffer, Joanna M Karasinska, Faiyaz Notta, Steven Gallinger, Jennifer J Knox, Erica S Tsang

Abstract

Tandem duplicator phenotype (TDP) consists of distinct genomic rearrangements where tandem duplications are randomly distributed. In this study, we characterized the prevalence and outcomes of TDP in a large series of prospectively sequenced tumors from patients with pancreatic ductal adenocarcinomas (PDAC). Whole-genome sequencing (WGS) was performed in 530 PDAC cases from the PanCuRx Initiative, COMPASS and PanGen/POG trials in Canada. Of 530 cases, 52 were identified as TDP (9.8%; 13 resected, 39 advanced). Etiological subgroups of TDP included BRCA1 (n = 9), CCNE1 (n = 4), and unknown (n = 39). Presence of TDP was not prognostic in resected specimens (p = 0.77) compared with non-HRD and non-TDP cases, described as typicals. In advanced cases, when stratified for only classical subtype cases, platinum therapy was correlated with longer response in non-BRCA1 TDP vs. typicals (p = 0.0036). There was no difference in overall survival between TDP and typicals (p = 0.5).TDP represents a potential novel targetable subgroup for chemotherapy selection in PDAC.

PubMed ID: 40185871

Xin Xu, Helen Zhu, Rupert Hugh-White, Julie Livingstone, Stefan Eng, Nicole Zeltser, Yujuan Wang, Kinga Pajdzik, Sujun Chen, Kathleen E. Houlahan, Wenqin Luo, Shun Liu, Xi Xu, Minzhi Sheng, Wang Yuan Guo, Jaron Arbet, Yuxi Song, Miranda Wang, Yong Zeng, Shiyan Wang, Guanghui Zhu, Tingxiao Gao, Wei Chen, Xinpei Ci, Wenjie Xu, Kexin Xu, Michele Orain, Valerie Picard, Helene Hovington, Alain Bergeron, Louis Lacombe, Bernard Têtu, Yves Fradet, Mathieu Lupien, Gong-Hong Wei, Marianne Koritzinsky, Robert G. Bristow, Neil E. Fleshner, Xue Wu, Yang Shao, Chuan He, Alejandro Berlin, Theodorus van der Kwast, Hon Leong, Paul C. Boutros, Housheng Hansen He

Abstract

Nonmutational epigenetic reprogramming is a crucial mechanism contributing to the pronounced heterogeneity of prostate cancer (PCa). Among these mechanisms, N6-methyladenosine (m6A)-modified long non-coding RNAs (lncRNAs) have emerged as key players. However, the precise roles of m6A-modified lncRNAs in PCa remain to be elucidated. In this study, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted on primary and metastatic PCa samples, leading to the identification of 21 lncRNAs exhibiting differential methylation and expression patterns. We further established a PCa prognostic signature, named m6A-modified lncRNA score (mLs), based on 9 differential methylated lncRNAs in 4 multicenter cohorts. The high mLs score cohort exhibited a tendency for earlier biochemical recurrence (BCR) compared to the low mLs score cohort. Remarkably, the predictive performance of the mLs score surpassed that of five previously reported lncRNA-based signatures. Functional enrichment analysis underscored a negative correlation between the mLs score and lipid metabolism. Additionally, through MeRIP-qPCR, we pinpointed a hub gene, MIR210HG, which was validated through in vitro and in vivo experiments. These findings collectively illuminate the landscape of m6A-methylated lncRNAs in PCa tissue via MeRIP-seq and harness this information to prognosticate PCa outcomes using the mLs score. Furthermore, our study validates, both experimentally and mechanistically, the facilitative role of MIR210HG in driving PCa progression.

PubMed ID: 37758909

Marco M. Buttigieg, Caitlyn Vlasschaert, Alexander G. Bick, Robert J. Vanner, Michael J. Rauh

*This work was supported in part by an MOHCCN Clinician-Scientist Award awarded to Dr. Robert Vanner

Abstract

PubMed ID: 40037357

Sevtap Savas, Georgia Skardasi, Aaron A. Curtis, Beverly Pausche, Jennifer Coish, John King, Cyndi Corbett, Marcelo F. Martinez, Judy Donovan Whitty, Sharon Jennings, Cara MacInnis & Angela Hyde

Abstract

Background: Precision Medicine in oncology is a rapidly evolving field aiming to prevent and treat cancers based on detailed patient and tumor characteristics. To better develop research studies, healthcare services and policies, and access to Precision Medicine, integration of insight and experiences of cancer patients and family members is required.

Objectives: In this paper, we describe the patient and family priorities regarding Precision Medicine as identified by the Atlantic Cancer Consortium Patient Advisory Committee (ACC PAC).

Methods: The ACC PAC was formed in January 2024 and met virtually five times between January and May of 2024. It included a diverse set of 12 patients and family members of patients from across the Atlantic Canadian provinces, a coordinator, an oncologist/clinician-scientist, and a cancer scientist. During meetings, the committee focused on identifying patient and family priorities in Atlantic Canada. Three guests with lived experiences were invited to further diversify the committee’s discussions. Discussions were summarized by the coordinator and cancer scientist. Summaries were then reviewed by the ACC PAC members in September 2024.

Results: The ACC PAC identified priorities on two general themes: (1) preventing and addressing cancer’s effects on the whole person/family (for example, by accessible information and support programs), and (2) understanding and accessing Precision Medicine (for example, by research, education, and wider implementation). While the ACC PAC members were optimistic about the utility of Precision Oncology, they also made it clear that it was unlikely to be sufficient without a team-based, holistic and equitable approach to cancer care. Better quality healthcare, education, resources, and effort by all stakeholders were established as essential for effective cancer control and Precision Medicine.

Conclusions: A key responsibility falls on the shoulders of funders, organizations, policy-makers and governments in addressing cancer’s effects, improving public knowledge of cancer and Precision Medicine, and improving access to high-quality healthcare and precision medicines. Patient partners and committees such as the ACC PAC can inform and help every step of these efforts with their patient-centered insights and perspectives.

Plain English summary

In early 2024, we formed the Atlantic Cancer Consortium Patient Advisory Committee (ACC PAC). Our group includes patients and family members affected by cancer from all four provinces of Atlantic Canada, in addition to a coordinator, an oncologist/clinician-scientist, and a cancer scientist. Together, we have identified patient and family priorities as they relate to cancer and Precision Medicine. Here we describe these priorities and our recommendations. Precision Medicine is an emerging cancer care strategy. In this strategy, a person’s circumstances and detailed disease features are considered so that the person can get the best possible care. In cancer, Precision Medicine strategy can help improve treatment success and patient outcomes. Our work indicates that while Precision Medicine strategy is promising, it requires more understanding, research, education, and accessibility. In addition, there is a need for holistic and equitable care that is accessible to all and that involves various care providers that support the patient and family. We recommend that all stakeholders work together efficiently to address the issues faced by the individuals and families affected by cancer in the region. The heaviest responsibility to address these issues lies on healthcare organizations and governments.

Subin Punnen, Veronika Csizmok, Connor Frey, Richard Gilbert, David F. Schaeffer, Stephen Yip, Marco A. Marra, Janessa Laskin, Michael Bleszynski, Daniel R. Owen

Abstract

Background: Pancreatic hepatoid carcinoma (PHC) is a rare and poorly characterized malignancy, with approximately 50 reported cases in the literature. Pure PHC, which lacks any features of adenocarcinoma or neuroendocrine differentiation, is a subset of this population and is extremely rare. Data on its management and genomic findings are limited, and further characterization may provide helpful information in caring for these patients. Case Presentation: A 42-year-old female was found to have a large, well-circumscribed mass in the body of the pancreas with elevated serum alpha-fetoprotein. Imaging demonstrated an 8.5 cm pancreatic lesion with no other disease. Endoscopic ultrasound-guided biopsy revealed a bile-producing carcinoma with morphological and immunohistochemical features consistent with hepatocellular carcinoma. She underwent a subtotal pancreatectomy and splenectomy, and pathologic evaluation confirmed a well-differentiated pure PHC confined to the pancreas. Whole genome and transcriptome analysis showed microsatellite stability, an elevated tumour mutation burden, copy number alterations in Chr19p13.3, and no mutations typically seen in pancreatic ductal adenocarcinoma (PDAC). These findings support the diagnosis of a pure hepatoid carcinoma with clinical, histopathological, and genomic characteristics resembling hepatocellular carcinoma. She remains disease free at 9 months without adjuvant therapy. Conclusion: This case demonstrates further characterization of a rare pancreatic lesion and illustrates the importance of integrated histopathological and genomic analyses in characterizing rare malignancies. Additionally, our findings suggest that pure PHC may be a distinct entity rather than a variant of PDAC.

Felix E G Beaudry, Zhihao Li, Ayelet Borgida, Anudari Zorigtbaatar, Xin Wang, Maggie Hildebrand, Oumaima Hamza, Gun Ho Jang, Roxana Bucur, Anna Dodd, Julie Wilson, Rebecca C Auer, Samuel Saibil, Erica S Tsang, Arndt Vogel, Grainne M O'Kane, Steven Gallinger, Jennifer J Knox, Faiyaz Notta, Gonzalo Sapisochin, Robert C Grant

Abstract

Comprehensive molecular profiling can identify alterations in biliary tract cancer (BTC) potentially treatable with targeted therapies. However, the impact of whole-genome and transcriptome sequencing (WGTS) on therapeutic decision-making in a public healthcare system is unknown. Here, BTC patients prospectively received WGTS to inform clinical care at a large Canadian academic cancer center. We characterized the proportion of targetable alterations, the treatment recommendations generated by a molecular tumor board, targeted therapies received, patient outcomes, and the financing of these treatments. A total of 55 patients with BTC prospectively underwent WGTS to inform clinical care. Of those 55, 28 (51%, 95% CI 38–64%) harbored targetable alterations. Molecular tumor boards recommended consideration of targeted therapies for 43 (78% CI: 66–87%) of 55 cases. Among the 15 patients who progressed to second-line therapy and harbored targetable alterations, 8 received nine targeted therapies. No targeted therapies were funded through the public system, and most therapies were funded through compassionate access programs from companies. These results highlight the challenges and potential for inequities when implementing precision oncology in a publicly funded healthcare system.

Emanuel Krebs, Deirdre Weymann, Cheryl Ho, Ian Bosdet, Janessa Laskin, Howard J. Lim, Stephen Yip, Aly Karsan, Timothy P. Hanna, Samantha Pollard, Dean Regier

Abstract

Background: Multi-gene panel sequencing streamlines treatment selection for advanced non-small cell lung cancer (NSCLC). Implementation continues to be uneven across jurisdictions, partly due to uncertain clinical and economic impacts. In British Columbia (BC), Canada, the public healthcare system reimbursed a multi-gene panel in September 2016. This study determined the population-level cost-effectiveness of publicly reimbursed multi-gene panel sequencing compared to single-gene testing for advanced NSCLC.

Methods: Our population-based retrospective study design used patient-level linked administrative health databases. We considered adult BC residents with a panel-eligible lung cancer diagnosis between September 2016 and December 2018. Using a machine learning approach, we conducted 1:1 genetic algorithm matching of recipients receiving multi-gene panel sequencing to controls receiving single-gene testing, maximising balance on observed demographic and clinical characteristics. Following matching, we estimated mean three-year survival time and costs (public healthcare payer perspective; 2021 CAD) and calculated the incremental net monetary benefit (INMB) for life-years gained (LYG) at conventional willingness-to-pay thresholds using inverse probability of censoring weighted linear regression and nonparametric bootstrapping.

Findings: We matched 858 panel-eligible advanced NSCLC patients to controls, achieving balance for the 16 included covariates. Average test turnaround times were 18.6 days for multi-gene panel sequencing and 7.0 days for single-gene testing. After matching, mean incremental costs were $3529 (95% CI: -$4268, $10,942) and mean incremental LYG were 0.08 (95% CI: -0.04, 0.18). Among the 1000 bootstrap samples, 14.5% had lower costs and increased survival and 78.6% had higher costs and increased survival. The INMB was $523 (95% CI: -$6256, $7023) at $50,000/LYG, with a 57.5% probability of being cost-effective, and $4575 (95% CI: -$5468, $14,064) at $100,000/LYG, with an 84.0% probability of being cost-effective.

Interpretation: Using population-based real-world data, we found a moderate to high probability that panel-based testing to inform targeted treatment for NSCLC would be cost-effective at higher thresholds.

Kieran O’Neill, Erin Pleasance, Jeremy Fan, Vahid Akbari, Glenn Chang, Katherine Dixon, Veronika Csizmok, Signe MacLennan, Vanessa Porter, Andrew Galbraith, Cameron J. Grisdale, Luka Culibrk, John H. Dupuis, Richard Corbett, James Hopkins, Reanne Bowlby, Pawan Pandoh, Duane E. Smailus, Dean Cheng, Tina Wong, Connor Frey, Yaoqing Shen, Luis F. Paulin, Fritz J. Sedlazeck, Jessica M.T. Nelson, Eric Chuah, Karen L. Mungall, Richard A. Moore, Robin Coope, Andrew J. Mungall, Melissa K. McConechy, Laura M. Williamson, Kasmintan A. Schrader, Stephen Yip, Marco A. Marra, Janessa Laskin, Steven J.M. Jones

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Abstract

The Long-Read Personalized OncoGenomics (POG) dataset comprises a cohort of 189 patient tumors and 41 matched normal samples sequenced using the Oxford Nanopore Technologies PromethION platform. This dataset from the POG program and the Marathon of Hope Cancer Centres Network includes DNA and RNA short-read sequence data, analytics, and clinical information. We show the potential of long-read sequencing for resolving complex cancer-related structural variants, viral integrations, and extrachromosomal circular DNA. Long-range phasing facilitates the discovery of allelically differentially methylated regions (aDMRs) and allele-specific expression, including recurrent aDMRs in the cancer genes RET and CDKN2A. Germline promoter methylation in MLH1 can be directly observed in Lynch syndrome. Promoter methylation in BRCA1 and RAD51C is a likely driver behind homologous recombination deficiency where no coding driver mutation was found. This dataset demonstrates applications for long-read sequencing in precision medicine and is available as a resource for developing analytical approaches using this technology.

PubMed ID: 39406235

doi: 10.1016/j.xgen.2024.100674

Yuka Takemon, Erin D. Pleasance, Alessia Gagliardi, Christopher S. Hughes, Veronika Csizmok, Kathleen Wee, Diane L. Trinh, Ryan D. Huff, Andrew J. Mungall, Richard A. Moore, Eric Chuah, Karen L. Mungall, Eleanor Lewis, Jessica Nelson, Howard J. Lim, Daniel J. Renouf, Steven JM. Jones, Janessa Laskin, Marco A. Marra

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Abstract

Background: Loss-of-function (LOF) alterations in tumour suppressor genes cannot be directly targeted. Approaches characterising gene function and vulnerabilities conferred by such mutations are required.

Methods: Here, we computationally map genetic networks of KMT2D, a tumour suppressor gene frequently mutated in several cancer types. Using KMT2D loss-of-function (KMT2D^LOF) mutations as a model, we illustrate the utility of in silico genetic networks in uncovering novel functional associations and vulnerabilities in cancer cells with LOF alterations affecting tumour suppressor genes.

Results: We revealed genetic interactors with functions in histone modification, metabolism, and immune response and synthetic lethal (SL) candidates, including some encoding existing therapeutic targets. Notably, we predicted WRN as a novel SL interactor and, using recently available WRN inhibitor (HRO761 and VVD-133214) treatment response data, we observed that KMT2D mutational status significantly distinguishes treatment-sensitive MSI cell lines from treatment-insensitive MSI cell lines.

Conclusions: Our study thus illustrates how tumour suppressor gene LOF alterations can be exploited to reveal potentially targetable cancer cell vulnerabilities.

Deirdre Weymann, Emanuel Krebs, Dean Regier

Abstract

Objective: To compare theoretical strengths and limitations of common immortal time adjustment methods, propose a new approach using multiple imputation (MI), and provide practical guidance for using MI in precision medicine evaluations centered on a real-world case study.

PubMed ID: 39225454

doi: 10.1111/1475-6773.14376

Samantha Pollard, Morgan Ehman, Anna Hernansen, Deirdre Weymann, Emanuel Krebs, Cheryl Ho, Howard J. Lim, Steven Jones, Yvonne Bombard, Timothy P. Hanna, Chiquita Hessels, Holly Longstaff, Robert Cook-Deegan, Tanie Bubela, Dean Regier

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Abstract

PubMed ID: 39116357

doi: 10.1200/PO.24.00184

Theodore B. Verhey, Heewon Seo, Aaron Gillmor, Varsha Thoppey-Manoharan, David Schriemer, Sorana Morrissy

Abstract

Advances in molecular profiling have facilitated generation of large multi-modal datasets that can potentially reveal critical axes of biological variation underlying complex diseases. Distilling biological meaning, however, requires computational strategies that can perform mosaic integration across diverse cohorts and datatypes. Here, we present mosaicMPI, a framework for discovery of low to high-resolution molecular programs representing both cell types and states, and integration within and across datasets into a network representing biological themes. Using existing datasets in glioblastoma, we demonstrate that this approach robustly integrates single cell and bulk programs across multiple platforms. Clinical and molecular annotations from cohorts are statistically propagated onto this network of programs, yielding a richly characterized landscape of biological themes. This enables deep understanding of individual tumor samples, systematic exploration of relationships between modalities, and generation of a reference map onto which new datasets can rapidly be mapped. mosaicMPI is available at https://github.com/MorrissyLab/mosaicMPI.

PubMed ID: 38813827

doi: 10.1093/nar/gkae442

Jakob Hofvander, Alvin Qiu, Kiera Lee, Misha Bilenky, Annaïck Carles, Qi Cao, Michelle Moksa, Jonathan Steif, Edmund Su, Afroditi Sotiriou, Angela Goytain, Lesley A. Hill, Sam Singer, Irene L. Andrulis, Jay S. Wunder, Fredrik Mertens, Ana Banito, Kevin B. Jones, T. Michael Underhill, Torsten O. Nielsen, Martin Hirst

Abstract

Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy characterized by a pathognomonic chromosomal translocation leading to the formation of the SS18::SSX fusion oncoprotein. SS18::SSX associates with mammalian BAF complexes suggesting deregulation of chromatin architecture as the oncogenic driver in this tumour type. To examine the epigenomic state of SyS we performed comprehensive multi-omics analysis on 52 primary pre-treatment human SyS tumours. Our analysis revealed a continuum of epigenomic states across the cohort at fusion target genes independent of rare somatic genetic lesions. We identify cell-of-origin signatures defined by enhancer states and reveal unexpected relationships between H2AK119Ub1 and active marks. The number of bivalent promoters, dually marked by the repressive H3K27me3 and activating H3K4me3 marks, has strong prognostic value and outperforms tumor grade in predicting patient outcome. Finally, we identify SyS defining epigenomic features including H3K4me3 expansion associated with striking promoter DNA hypomethylation in which SyS displays the lowest mean methylation level of any sarcoma subtype. We explore these distinctive features as potential vulnerabilities in SyS and identify H3K4me3 inhibition as a promising therapeutic strategy.

note: this article is a preprint and has not been peer-reviewed. [what does this mean?]

PubMed ID: 38798672

doi: 10.1101/2024.05.14.594262

Laura K. Hilton, Henry S. Ngu, Brett Collinge, Kostiantyn Dreval, Susana Ben-Neriah, Christopher K. Rushton, Jasper C H Wong, Manuela Cruz, Andrew Roth, Merrill Boyle, Barbara Meissner, Graham W. Slack, Pedro Farinha, Jeffrey W. Craig, Alina S. Gerrie, Ciara L. Freeman, Diego Villa, Judith A. Rodrigo, Kevin Song, Michael Crump, Lois Shepherd, Annette E Hay, John Kuruvilla, Kerry J. Savage, Robert Kridel, Aly Karsan, Marco A. Marra, Laurie H. Sehn, Christian Steidl, Ryan D. Morin, David W. Scott

Abstract

Purpose: Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship.

Patients and methods: Outcomes were examined in a population-based cohort of 221 patients with DLBCL who experienced progression/relapse after frontline treatment and were treated with second-line (immuno)chemotherapy with an intention-to-treat with autologous stem-cell transplantation (ASCT). Serial DLBCL biopsies from a partially overlapping cohort of 129 patients underwent molecular characterization, including whole-genome or whole-exome sequencing in 73 patients.

Results: Outcomes to second-line therapy and ASCT are superior for late relapse (>2 years postdiagnosis) versus primary refractory (<9 months) or early relapse (9-24 months). Diagnostic and relapse biopsies were mostly concordant for cell-of-origin classification and genetics-based subgroup. Despite this concordance, the number of mutations exclusive to each biopsy increased with time since diagnosis, and late relapses shared few mutations with their diagnostic counterpart, demonstrating a branching evolution pattern. In patients with highly divergent tumors, many of the same genes acquired new mutations independently in each tumor, suggesting that the earliest mutations in a shared precursor cell constrain tumor evolution toward the same genetics-based subgroups at both diagnosis and relapse.

Conclusion: These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease and have implications for optimal patient management.

PubMed ID: 37319384

doi: 10.1200/JCO.23.00570

Khoudia Diop, Reilly Pidgeon, Awa Diop, Myriam Benlaïfaoui, Wiam Belkaid, Julie Malo, Eve Bernet, Frederic Veyrier, Maxime Jacq, Yves Brun, Arielle Elkrief, Bastien Castagner, Bertrand Routy, Corentin Richard

Abstract

A polyphasic taxonomic approach, incorporating analysis of phenotypic features, cellular fatty acid profiles, 16S rRNA gene sequences, and determination of average nucleotide identity (ANI) plus digital DNA–DNA hybridization (dDDH), was applied to characterize an anaerobic bacterial strain designated KD22T isolated from human feces. 16S rRNA gene-based phylogenetic analysis showed that strain KD22T was found to be most closely related to species of the genus Gabonibacter. At the 16S rRNA gene level, the closest species from the strain KD22T corresponded with Gabonibacter massiliensis GM7T, with a similarity of 97.58%. Cells of strain KD22T were Gram-negative coccobacillus, positive for indole and negative for catalase, nitrate reduction, oxidase, and urease activities. The fatty acid analysis demonstrated the presence of a high concentration of iso-C15: 0 (51.65%). Next, the complete whole-genome sequence of strain KD22T was 3,368,578 bp long with 42 mol% of DNA G + C contents. The DDH and ANI values between KD22T and type strains of phylogenetically related species were 67.40% and 95.43%, respectively. These phylogenetic, phenotypic, and genomic results supported the affiliation of strain KD22T as a novel bacterial species within the genus Gabonibacter. The proposed name is Gabonibacter chumensis and the type strain is KD22T (= CSUR Q8104T = DSM 115208 T).

PubMed ID: 37742282

doi: 10.1007/s00203-023-03671-0

Bertrand Routy, John G. Lenehan, Wilson H. Miller Jr, Rahima Jamal, Meriem Messaoudene, Brendan A. Daisley, Cecilia Hes, Kait F. Al, Laura Martinez-Gili, Michal Punčochář, Scott Ernst, Diane Logan, Karl Belanger, Khashayar Esfahani, Corentin Richard, Marina Ninkov, Gianmarco Piccinno, Federica Armanini, Federica Pinto, Mithunah Krishnamoorthy, Rene Figueredo, Pamela Thebault, Panteleimon Takis, Jamie Magrill, LeeAnn Ramsay, Lisa Derosa, Julian R. Marchesi, Seema Nair Parvathy, Arielle Elkrief, Ian R. Watson, Rejean Lapointe, Nicola Segata, S. M. Mansour Haeryfar, Benjamin H. Mullish, Michael S. Silverman, Jeremy P. Burton, Saman Maleki Vareki

Abstract

Fecal microbiota transplantation (FMT) represents a potential strategy to overcome resistance to immune checkpoint inhibitors in patients with refractory melanoma; however, the role of FMT in first-line treatment settings has not been evaluated. We conducted a multicenter phase I trial combining healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in 20 previously untreated patients with advanced melanoma. The primary end point was safety. No grade 3 adverse events were reported from FMT alone. Five patients (25%) experienced grade 3 immune-related adverse events from combination therapy. Key secondary end points were objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses. The objective response rate was 65% (13 of 20), including four (20%) complete responses. Longitudinal microbiome profiling revealed that all patients engrafted strains from their respective donors; however, the acquired similarity between donor and patient microbiomes only increased over time in responders. Responders experienced an enrichment of immunogenic and a loss of deleterious bacteria following FMT. Avatar mouse models confirmed the role of healthy donor feces in increasing anti-PD-1 efficacy. Our results show that FMT from healthy donors is safe in the first-line setting and warrants further investigation in combination with immune checkpoint inhibitors. ClinicalTrials.gov identifier NCT03772899.

PubMed ID: 37414899

doi: 10.1038/s41591-023-02453-x

Rahima Jamal, Meriem Messaoudene, Marina de Figuieredo, Bertrand Routy

Abstract

The gut microbiota has rapidly emerged as one of the “hallmarks of cancers” and a key contributor to cancer immunotherapy. Metagenomics profiling has established the link between microbiota compositions and immune checkpoint inhibitors response and toxicity, while murine experiments demonstrating the synergistic benefits of microbiota modification with immune checkpoint inhibitors (ICIs) pave a clear path for translation. Fecal microbiota transplantation (FMT) is one of the most effective treatments for patients with Clostridioides difficile, but its utility in other disease contexts has been limited. Nonetheless, promising data from the first trials combining FMT with ICIs have provided strong clinical rationale to pursue this strategy as a novel therapeutic avenue. In addition to the safety considerations surrounding new and emerging pathogens potentially transmissible by FMT, several other challenges must be overcome in order to validate the use of FMT as a therapeutic option in oncology. In this review, we will explore how the lessons learned from FMT in other specialties will help shape the design and development of FMT in the immuno-oncology arena.

PubMed ID: 37003055

doi: 10.1016/j.smim.2023.101754

Samantha Pollard, Deirdre Weymann, Brandon Chan, Morgan Ehman, Sarah Wordsworth, James Buchanan, Timothy P. Hanna, Cheryl Ho, Howard J. Lim, Paula K. Lorgelly, Adam J. N. Raymakers, Christopher McCabe, Dean A. Regier

Abstract

Objectives: Precision oncology is generating vast amounts of multiomic data to improve human health and accelerate research. Existing clinical study designs and attendant data are unable to provide comparative evidence for economic evaluations. This lack of evidence can cause inconsistent and inappropriate reimbursement. Our study defines a core data set to facilitate economic evaluations of precision oncology.

Methods: We conducted a literature review of economic evaluations of next-generation sequencing technologies, a common application of precision oncology, published between 2005 and 2018 and indexed in PubMed (MEDLINE). Based on this review, we developed a preliminary core data set for informal expert feedback. We then used a modified-Delphi approach with individuals involved in implementation and evaluation of precision medicine, including 2 survey rounds followed by a final voting conference to refine the data set.

Results: Two authors determined that variation in published data elements was reached after abstraction of 20 economic evaluations. Expert consultation refined the data set to 83 unique data elements, and a multidisciplinary sample of 46 experts participated in the modified-Delphi process. A total of 68 elements (81%) were selected as required, spanning demographics and clinical characteristics, genomic data, cancer treatment, health and quality of life outcomes, and resource use.

Conclusions: Cost-effectiveness analyses will fail to reflect the real-world impacts of precision oncology without data to accurately characterize patient care trajectories and outcomes. Data collection in accordance with the proposed core data set will promote standardization and enable the generation of decision-grade evidence to inform reimbursement.

PubMed ID: 35216902

doi: 10.1016/j.jval.2022.01.005