Search

Background: The European Society for Medical Oncology Precision Medicine Working Group (ESMO PMWG) was reconvened to update its 2018/19 recommendations on follow-up of putative germline variants detected on tumour-only sequencing, which were based on an analysis of 17 152 cancers., Methods: We analysed an expanded dataset including 49 264 paired tumour-normal samples. We applied filters to tumour-detected variants based on variant allele frequency, predicted pathogenicity and population variant frequency. For 58 cancer-susceptibility genes, we then examined the proportion of filtered tumour-detected variants of true germline origin [germline conversion rate (GCR)]. We conducted subanalyses based on the age of cancer diagnosis, specific tumour types and 'on-tumour' status (established tumour-gene association)., Results: Analysis of 45 472 nonhypermutated solid malignancy tumour samples yielded 21 351 filtered tumour-detected variants of which 3515 were of true germline origin. 3.1% of true germline pathogenic variants were absent from the filtered tumour-detected variants. For genes such as BRCA1, BRCA2 and PALB2, the GCR in filtered tumour-detected variants was >80%; conversely for TP53, APC and STK11 this GCR was <2%., Conclusion: Strategic germline-focused analysis can prioritise a subset of tumour-detected variants for which germline follow-up will produce the highest yield of most actionable true germline variants. We present updated recommendations around germline follow-up of tumour-only sequencing including (i) revision to 5% for the minimum per-gene GCR, (ii) inclusion of actionable intermediate penetrance genes ATM and CHEK2, (iii) definition of a set of seven 'most actionable' cancer-susceptibility genes (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6 and RET) in which germline follow-up is recommended regardless of tumour type., Competing Interests: Disclosure AGe reports receipt of honoraria for participation in advisory board from AstraZeneca, receipt of honoraria as invited speaker from GSK and receipt of honoraria for performing editorial and research review from Roche. HH reports receipt of honoraria for participation in advisory board from AstraZeneca and nonfinancial interest for leadership role as Chair of the UK Cancer Genetics Group. KS reports receipt of honoraria for providing expert testimony from Axa-PPP and receipt of honoraria as invited speaker from Everything Genetic, Merck, Pfizer. AK reports receipt of honoraria as invited speaker from AstraZeneca, receipt of honoraria for professional service agreement with HCA Healthcare and owning stocks/shares in Perci Health. CBW reports receipt of honoraria for participation in advisory board from BMS, Celgene, Rafael, RedHill, Roche, Shire/Baxalta; receipt of honoraria for providing expert testimony from Janssen; receipt of honoraria as invited speaker from Amgen, Bayer, BMS, Celgene, Chugai, Falk, GSK, Janssen, Merck, MSD, Roche, Servier, Sirtex and Taiho; receipt of travel support from Bayer, Celgene, RedHill, Roche, Servier and Taiho; receipt of personal and institutional research grant with no financial interest from Roche and nonfinancial interest as officer in the AIO – Arbeitsgemeinschaft Internistische Onkologie. EC reports receipt of honoraria for participation in advisory board from Astellas, AstraZeneca, Bayer, Janssen, MSD and Pfizer; receipt of honoraria as invited speaker from Astellas, AstraZeneca, Clovis, Janssen and Pfizer; receipt of honoraria for writing engagement from Pfizer; institutional funding from AstraZeneca and Pfizer; research grants to institution from Bayer and Janssen and institutional financial interest as local principal investigator from Janssen and Pfizer. JR reports receipt of honoraria for participation in advisory board from Ellipses Pharma, iOnctura SA, Kelun Pharmaceuticals/KLUS Pharma, Molecular Partners and Peptomyc; receipt of institutional research grant with no financial interest for clinical research from Aadi Bioscience, Amgen, Bicycle Therapeutics, BioMed Valley Discoveries, Cellestia, Curis, Deciphera, ForeBio, Hutchison MediPharma, Ideaya, Linnaeus Therapeutics, Loxo Oncology, Merus, Mirati, Nuvation, Roche Pharmaceuticals, Taiho and Tango Therapeutics; receipt of institutional research grant with no financial interest for research funding/clinical research from Hummingbird and Yingli; receipt of institutional research grant with no financial interest for research funding from Vall d’Hebron Institute of Oncology/Cancer Core Europe; receipt of institutional nonfinancial interest for clinical research from Bayer, BioAtla, CytomX, Genmab, GlaxoSmithKline, Kelun-Biotech, Novartis, Pfizer, Spectrum Pharmaceuticals, Symphogen and Takeda-Millennium; receipt of institutional financial interest for research funding from Black Diamond, Blueprint Medicines, Merck Sharp & Dohme; receipt of consultancy fees from Boxer Capital, LLC and Tang Advisors, LLC; receipt of travel reimbursement from the European Society for Medical Oncology and reports academic collaborations with Chinese University of Hong Kong, VHIO/Ministerio De Empleo Y Seguridad Social. JM reports receipt of honoraria for participation in advisory board from Amgen, AstraZeneca, Clovis Oncology, Janssen and Roche; receipt of honoraria as invited speaker from AstraZeneca, Guardant Health and MSD; no financial interest for serving as a steering committee member from AstraZeneca and Pfizer Oncology; receipt of research grant to institution from AstraZeneca and Pfizer Oncology and nonfinancial interest for receipt of product samples, access to drugs in early development for preclinical testing from AstraZeneca. GJB reports receipt of honoraria as invited speaker from AstraZeneca. MFB reports receipt of honoraria for participation in advisory board from Eli Lilly and PetDx. CT reports receipt of honoraria for participation in advisory board from Roche and receipt of honoraria as invited speaker from AstraZeneca. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The landscape of clinical trials testing risk-adapted modulations of cancer treatments is complex. Multiple trial designs, endpoints, and thresholds for non-inferiority have been used; however, no consensus or convention has ever been agreed to categorise biomarkers useful to inform the treatment intensity modulation of cancer treatments., Methods: An expert subgroup under the European Society for Medical Oncology (ESMO) Precision Medicine Working Group shaped an international collaborative project to develop a classification system for biomarkers used in the cancer treatment de-intensification, based on a tiered approach. A group of disease-oriented clinical, translational, methodology and public health experts, and patients' representatives provided an analysis of the status quo, and scanned the horizon of ongoing clinical trials. The classification was developed through multiple rounds of expert revisions and inputs., Results: The working group agreed on a univocal definition of treatment de-intensification. Evidence of reduction in the dose-density, intensity, or cumulative dose, including intermittent schedules or shorter treatment duration or deletion of segment(s) of the standard regimens, compound(s), or treatment modality must be demonstrated, to define a treatment de-intensification. De-intensified regimens must also portend a positive impact on toxicity, quality of life, health system burden, or financial toxicity. ESMO classification categorises the biomarkers for treatment modulation in three tiers, based on the level of evidence. Tier A includes biomarkers validated in prospective, randomised, non-inferiority clinical trials. The working group agreed that in non-inferiority clinical trials, boundaries are highly dependent upon the disease scenario and endpoint being studied and that the absolute differences in the outcomes are the most relevant measures, rather than relative differences. Biomarkers tested in single-arm studies with a threshold of non-inferiority are classified as Tier B. Tier C is when the validation occurs in prospective-retrospective quality cohort investigations., Conclusions: ESMO classification for the risk-guided intensity modulation of cancer treatments provides a set of evidence-based criteria to categorise biomarkers deemed to inform de-intensification of cancer treatments, in risk-defined patients. The classification aims at harmonising definitions on this matter, therefore offering a common language for all the relevant stakeholders, including clinicians, patients, decision-makers, and for clinical trials., Competing Interests: Disclosure HB reports non-remunerated activities as a principal investigator (PI) within grant for clinical research from the National Cancer Institute, and is a non-remunerated member of Board of Directors in the Alliance for Clinical Trials in Oncology; LC reports receipt of institutional research funding from AbbVie, Immunomedics, NanoString Technologies, Novartis, Seattle Genetics, Syndax, Veracyte, advisory role in Aptitude Health, AstraZeneca/Daiichi Sankyo, Exact Sciences, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, Novartis, and Sanofi; SD reports receipt of honoraria for participation in Advisory Board from AstraZeneca, Cellectis, Isis/Servier, Novartis, Orion, Pierre Fabre, Rappta, Sanofi, receipt of honoraria as invited speaker from AstraZeneca, Exact Sciences, Eli Lilly, Merck Sharp & Dohme (MSD), Pfizer, Seagen, institutional financial interest for research as a Steering Committee Member from AstraZeneca, Bristol Myers Squibb (BMS), Pfizer, Puma, Roche/Genentech, Sanofi, institutional research funding from GE, institutional financial interest for clinical research funding as a coordinating PI from Taiho, institutional financial interest as a local PI from Orion, and a non-remunerated member of Board of Directors of the Société Française de Sénologie et Pathologie Mammaire; NH reports receipt of honoraria for participation in Advisory Board from Aptitude Health, AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Roche, Sandoz-Hexal, Seattle Genetics, receipt of honoraria as invited speaker from Art Tempi, AstraZeneca, Daiichi Sankyo, Eli Lilly, Medscape, MSD, Novartis, Onkowissen, Pierre Fabre, Roche, Seattle Genetics, receipt of honoraria from West German Study Group (WSG) (husband), ownership interest in West German Study Group, institutional research funding from AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Odonate, Palleos, Pierre Fabre, Roche, Seattle Genetics, TRIO, WSG, a member of German AGO Breast Guideline Committee, a member of European School of Oncology/College of the European School of Oncology Breast Cancer Educational Programmes, Editor-in-Chief of Breast Care journal; DH reports receipt of honoraria for consulting in Advisory Board from Agendia, BioVeca, Cellworks, Cepheid, Epic Sciences, Freenome, L-Nutra, OncoCyte, Turnstone Biologics, owns stock shares in Inbiomotion SL, receipt of royalties from an institutional patent on which he is named investigator from Menarini Silicon Biosystems, institutional sponsored laboratory research as a coordinating PI from AstraZeneca, Pfizer, institutional sponsored laboratory and clinical research as a coordinating PI from Menarini Silicon Biosystems, non-remunerated activities as a past president and past member of Board of Directors of ASCO, non-remunerated Chair of Translational Research Advisory Committee in EORTC, and a non-remunerated member of the ESMO Working Group; KK reports receipt of honoraria for participation in Advisory Board from 4D Pharma, AstraZeneca, Cyclacel, Daiichi Sankyo, Eisai, Eli Lilly, Immunomedics, Merck, Novartis, OncoSec, Pfizer, Puma, Seattle Genetics, holding stocks/shares from Grail, spouse employment in Grail, no financial interest to institution as local PI from Acetylon, Amgen, Calithera, CytomX Therapeutics, Eli Lilly, Genentech, Immunomedics, Incyte, Novartis, Pfizer, Seattle Genetics, Zentalis, participation in Steering Committee of Ambrx, AstraZeneca, Genentech, Immunomedics, and support for attending meetings and/or travel from AstraZeneca, Eli Lilly, and Pfizer; LP reports receipt of honoraria for participation in Advisory Board and trial Steering Committee from AstraZeneca, Merck, honoraria for participation in Advisory Board from Novartis, Pfizer, Roche Genentech, no financial interest for clinical trial support to institution as local PI from AstraZeneca, Seagen, no financial interest for clinical trial support to institution as trial chair from Merck, Pfizer, research grant to institution from BMS, and no financial interest for advisory role in Breast Cancer Research Foundation, as a member of the scientific Advisory Board of Pfizer, for product samples, material transfer agreement; MR reports receipt of honoraria for participation in Advisory Board from BMS, Tolmar Pharmaceuticals, honoraria as invited speaker from WebMD, institutional financial interest for investigator-initiated clinical trials supported or drug supply from AstraZeneca, Roche, research grant to institution from Bayer, BMS, institutional financial interest for investigator-initiated clinical trials supported by Ipsen, Novartis, Pfizer, TerSera, and non-financial interest for advisory role from BMS; IS reports receipt of honoraria as invited speaker from Myriad Genetics and Nanostring Technologies; TS reports receipt of honoraria for participation in Advisory Board as a member of Patient Advisory Board from Pfizer and Roche; JS reports receipt of honoraria for participation in Advisory Board from Arvinas, AstraZeneca, Certara, Eisai, GlaxoSmithKline, honoraria as a Data and Safety Monitoring Board member from BMS, Novartis, Roche, and no financial interest to institution as coordinating PI from Merck, Olema, Radius Pharmaceuticals; GC reports receipt of honoraria for participation in Advisory Board from AstraZeneca, BMS, Daiichi Sankyo, Ellipsis, Exact Sciences, Lilly, Merck, Pfizer, Roche, Veracyte, receipt of honoraria as invited speaker from AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Roche, receipt of honoraria for writing engagement from Pfizer, institutional research grant for investigator-initiated clinical trial from Merck, institutional funding for conduct of phase I studies from Astellas, AstraZeneca, Blueprint Medicine, BMS, Daiichi Sankyo, Kymab, Novartis, Philogen, Roche, Sanofi, non-remunerated activities as an officer of the Italian National Health Council, non-remunerated advisory role as a member of the Scientific Council of Europa Donna, non-remunerated advisory role in Fondazione Beretta, and non-remunerated member of Board of Directors of the Lega Italiana Lotta ai Tumori; FA reports receipt of institutional research grants from AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, Roche, and being a founder of Pegacsy. DT has been a past consultant for World Health Organization, noncommunicable diseases, cancer management team. All other authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers. Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could further inform how to optimise the use of this technology., Competing Interests: Disclosure JR: advisory: Merck Sharp & Dohme (MSD), Boehringer, Bristol-Myers Squibb (BMS), AstraZeneca, Roche; speaker's bureau: Pfizer; travel support: OSE Immunotherapeutics SA, BMS, AstraZeneca, Roche. JM: advisory board: Amgen, AstraZeneca, Clovis Oncology, Janssen, MSD and Roche-Foundation Medicine; research funding: AstraZeneca and Pfizer Oncology; principal investigator of several industry sponsored clinical trials. CBW: personal and speakers' fees, reimbursement for travel and accommodation and honoraria for participance in advisory boards from Bayer, Celgene, Ipsen, MedScape, Rafael Pharmaceuticals, RedHill, Roche, Servier, Shire/Baxalta and Taiho; scientific grant support by Roche. FB: personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda. MPL: research grants (to hospital): MSD, Astellas, JnJ, Sanofi; advice: Roche, Bayer, Amgen, JnJ, Sanofi, Servier, Pfizer, Incyte. NN: speaker's fee and/or advisory boards: Amgen, AstraZeneca, Bayer, Biocartis, BMS, Boehringer Ingelheim, Eli Lilly, Ilumina, Incyte, MERCK, MSD, Qiagen, Roche, Thermofisher, Sanofi; institutional financial interests (financial support to research projects): AstraZeneca, Biocartis, BMS, Illumina, Merck, Qiagen, Roche, Sysmex, Thermofisher; non-financial interests: President of the International Quality Network for Pathology (IQN Path); President of the Italian Cancer Society (SIC). ASc: speakers bureau: Ypsen, Astra Zeneca, Amgen, MSD, GSK; consulting: INCYTE Biosciences. MR: consulting or advisory: AstraZeneca (uncompensated), Change Healthcare, Daiichi-Sankyo (uncompensated), Epic Sciences (uncompensated), Merck (uncompensated), Pfizer (uncompensated); research funding: AbbVie (institution), AstraZeneca (Institution), Invitae (Institution, in-kind), Merck (Institution), Pfizer (institution); travel, accommodation, expenses: AstraZeneca, Merck; editorial services: AstraZeneca, Pfizer. FM-B: consulting: Aduro BioTech Inc., Alkermes, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd, Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks; advisory committee: Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; sponsored research: Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd, Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; honoraria: Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey; other (Travel Related): Beth Israel Deaconess Medical Center. NW: research grant from Puma Biotechnology; scientific advisory board and stockholder for Relay Therapeutics; advisor to Eli Lilly. ASt: advisory board/speakers bureau: Astra Zeneca, Eli Lilly, Bayer, BMS, Illumina, Janssen, MSD, Pfizer, Roche, Seattle Genetics, Thermo Fisher; Grants: Bayer, BMS, Chugai. JB: travel support: BMS; consulting fees: BMS, MSD, Astellas. SM: statistical advice: IDDI and Janssen Cilag; Independent Data Monitoring Committee member: Hexal, Steba, IQVIA, Roche, Sensorion, Biophytis, Servier, Yuhan. IB: speaker’s fee: AstraZeneca. ER: board participation: AstraZeneca, BMS, Roche; travel funding: AstraZeneca, BMS. JSR-F: paid consultant: Goldman Sachs, REPARE Therapeutics, and Paige.AI; member of the scientific advisory board: REPARE Therapeutics, Paige.AI, and Volition Rx; member of the Board of Directors: Group Oncoclinicas; ad hoc member of the scientific advisory board: Roche Tissue Diagnostics, Roche, Genentech, Novartis, and Invicro; owns shares: REPARE Therapeutics. RD: advisory: Roche, Boehringer Ingelheim; speaker’s fee: Roche, Ipsen, Amgen, Servier, Sanofi, Merck Sharp & Dohme; research grants: Merck and Pierre Fabre. FA: research grants and talks/advisory boards compensate to the hospital: Roche, Pfizer, Novartis, AstraZeneca, Daiichi Sankyo, Lilly. All remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. All rights reserved.)

It is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focussed analysis' is carried out upon tumour sequencing data and for which variants follow-up analysis of a germline sample is carried out. Here we present analyses of paired sequencing data from 17 152 cancer samples, in which 1494 pathogenic sequence variants were identified across 65 cancer susceptibility genes. From these analyses, the European Society of Medical Oncology Precision Medicine Working Group Germline Subgroup has generated (i) recommendations regarding germline-focussed analyses of tumour-only sequencing data, (ii) indications for germline follow-up testing and (iii) guidance on patient information-giving and consent., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: In order to facilitate implementation of precision medicine in clinical management of cancer, there is a need to harmonise and standardise the reporting and interpretation of clinically relevant genomics data., Methods: The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to propose a classification system for molecular aberrations based on the evidence available supporting their value as clinical targets. A group of experts from several institutions was assembled to review available evidence, reach a consensus on grading criteria and present a classification system. This was then reviewed, amended and finally approved by the ESMO TR and PM WG and the ESMO leadership., Results: This first version of the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) defines six levels of clinical evidence for molecular targets according to the implications for patient management: tier I, targets ready for implementation in routine clinical decisions; tier II, investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed; tier III, clinical benefit previously demonstrated in other tumour types or for similar molecular targets; tier IV, preclinical evidence of actionability; tier V, evidence supporting co-targeting approaches; and tier X, lack of evidence for actionability., Conclusions: The ESCAT defines clinical evidence-based criteria to prioritise genomic alterations as markers to select patients for targeted therapies. This classification system aims to offer a common language for all the relevant stakeholders in cancer medicine and drug development.