Project Funding Details

Title: An empirical ethics study to introduce next-generation DNA sequencing into cancer care in a responsible way.
Alt. Award Code: UU 2014-7469
Funding Organization: KWF Kankerbestrijding / Dutch Cancer Society
Budget Dates: 2015-05-01 to 2018-05-01
Principal Investigator: Bredenoord, A.L.
Institution: University Medical Center Utrecht
Region: Europe & Central Asia
Location: Utrecht, NL

Collaborators

This project funding has either no collaborators or the information is not available.

Technical Abstract

Background and Preliminary results
In the era of personalized cancer treatment the use of large scale genetic analyses of tumors is considered to be key for a better selection of patients for the appropriate therapy. With the rapid advancement of next-generation sequencing (NGS) technologies it is now possible to sequence whole genomes in a short period of time. Although a powerful diagnostic tool, , these tests at the same time generate large amounts of both solicited and unsolicited genetic (risk) information.
In the context of a consortium named the Center for Personalized Cancer Treatment (CPCT), now consisting of NKI-AvL, Erasmus MC and UMC Utrecht, we have taken tumor biopsies and blood samples and performed NGS of over 300 cancer patients in the past two years. By sequencing both tumor and germ-line DNA we encountered several unrelated DNA changes that warranted additional attention. These findings could have medical, psychological, financial and social consequences for patients and a considerable impact on their quality of life. Clearly, NGS raises many ethical and counseling challenges. Should genetic risk information generated by NGS be disclosed to patients and his/her family members (for example postmortem) and if so, what kind of information, and by whom?
We earlier developed a qualified disclosure policy for feedback in the context of large scale genetic testing. In line with our approach, there currently is an international emerging ethical consensus that return of at least some sets of genetic information should be offered to patients. Empirical studies are now necessary to investigate the intentions, needs and preferences of both curable and advanced staged cancer patients and to evaluate our proposed disclosure policy in the context of clinical oncology.

Overall aim and research questions
To develop an ethically sound roadmap to return genetic risk information to patients undergoing NGS within the context of personalized cancer treatment - based on patients&rsquo, own needs and preferences, including both curable and advanced staged patients with any type of cancer. This will result in a flow chart to optimally support clinicians and the starting point for a decision aid for patients who undergo NGS.

I. What are cancer patients&rsquo, intentions, needs and preferences toward receiving genetic (risk) information obtained by NGS and sharing this information with their family members?

II. Whether and to what extent are these results confirmed in a larger group of cancer patients and do differences exist between curable and advanced stage patients?

III. How ,should NGS be introduced into clinical oncology in an ethically sound way?

Study design: mixed methods

I. Qualitative study: semi-structured interviews (N=21)

To address our first research question, a group of patients (both curative and palliative patients with any cancer type) will be invited to participate in in-depth-interviews. The interviews are divided into inventory and evaluative interviews. The results of the interviews will be used to develop and pretest a questionnaire, based on the health related theory of planned behavior.

II. Quantitative study: structured questionnaire (N=700) ,

A quantitative study is performed in which we investigate by means of the developed questionnaire in NGS naive patients, whether the results of the qualitative study are confirmed in a larger group of cancer patients and whether there are differences in certain subgroups.

III. Ethical study

The empirical data obtained in part I and II will be used as input for an ethical analysis. We will focus on the blurring lines between: (1) diagnostics and screening, (2) research and clinical care, (3) individual and family.

Expected outcome

1. Our study will generate empirical data to optimally support and guide patients in making an informed choice to receive information generated by NGS.

2. Our study will generate empirical data to optimally support and guide health care professionals in returning information obtained by NGS to patients and eventually their family members.

3. Our study will result in the development of an ethically robust roadmap for future studies incorporating large scale DNA analyses, containing ethical guidelines for the introduction of NGS in clinical oncology, including an informed consent and disclosure policy for cancer patients undergoing NGS.

4. Our study will result in a flow chart for clinicians and the starting point for a decision aid for patients who undergo NGS.

Public Abstract

Een empirisch-ethische studie om &lsquo,next-generation DNA sequencing&rsquo, op een verantwoorde manier te introduceren in de oncologie.
Met de verbeterde technieken voor het aflezen van DNA (onze genetische code), ook wel Next Generation Sequencing (NGS) genoemd, kan in grote mate worden voorspeld hoe verschillende typen kanker zich zullen ontwikkelen en welke DNA-veranderingen de tumor veroorzaakt. Dit is een belangrijke stap voorwaarts in de behandeling van kanker. Met de informatie waarom kanker is ontstaan en groeit kan namelijk het beste medicijn ingezet worden. Elke patië,nt kan hierdoor een behandelplan &lsquo,op maat&rsquo, aangeboden krijgen en blootstelling aan mogelijk onnodige bijwerkingen is niet meer aan de orde.
Op dit moment wordt NGS nog niet toegepast in de reguliere diagnostiek, maar de verwachting is dat dit binnen enkele jaren ingezet zal gaan worden voor bepaalde vormen van kanker. DNA-onderzoek is nu alleen nog beschikbaar voor mensen met uitgezaaide kanker. Een belangrijk aandachtspunt bij NGS is dat niet alleen informatie wordt verkregen over de ziekte waar onderzoek naar wordt gedaan, maar dat ook per toeval mutaties (genetische afwijkingen) gevonden kunnen worden: &lsquo,bijvangst&rsquo,. Deze mutaties kunnen wijzen op een verhoogd risico op bepaalde aandoeningen of ziektes in de familie, zoals bijvoorbeeld informatie over andere erfelijke vormen van kanker, maar ook neurologische of psychiatrische ziekten. Deze resultaten kunnen medische, psychologische, sociale en financiele consequenties hebben voor de patient en een aanzienlijke impact hebben op diens kwaliteit van leven. Bovendien kunnen de onderzoeksresultaten ook relevant zijn voor directe familieleden.
Het is duidelijk dat met het toenemen van de mogelijkheden van genetische testen ook veel ethische en counseling uitdagingen moeten worden aangepakt. Eerder onderzoek laat zien dat er een opkomende ethische consensus is over het in ieder geval terugrapporteren van enkele sets informatie aan patienten. Op dit moment is er beperkte kennis over behoeften en voorkeuren van patienten ten aanzien van informatie en begeleiding bij de terugrapportage van onderzoeksresultaten voortkomend uit NGS. Verder empirisch onderzoek is daarom nodig om voorgenomen beleid te evalueren en de mening en voorkeuren van kankerpatienten te inventariseren. Ook behoeven enkele ethische vragen opheldering: wat zijn de morele verantwoordelijkheden van artsen en patienten ten opzichte van familieleden? Mag een zorgverlener familieleden waarschuwen, of is dit een onaanvaardbare inbreuk op het beroepsgeheim? Is er een verplichting om hernieuwd contact met patienten op te nemen als er nieuwe informatie aan het licht komt, en wat te doen na overlijden?
Doel van onze beoogde studie is de ontwikkeling van een ethisch verantwoord kader voor het terugrapporteren van informatie over een verhoogd risico op erfelijke aandoeningen aan patienten die in aanmerking komen voor NGS binnen de context van 'personalized cancer treatment'. Het voorgestelde beleid zal gebaseerd zijn op de behoeften en voorkeuren van patienten. De onderzoeksvraag zal beantwoord worden door middel van een combinatie van kwalitatief onderzoek (semi- gestructureerde interviews), kwantitatief onderzoek (een gestructureerde vragenlijst) en een ethische analyse.

Cancer Types

Not Site-Specific Cancer

Common Scientific Outline (CSO) Research Areas

6.4 Cancer Control, Survivorship and Outcomes Research Cost Analyses and Health Care Delivery
6.7 Cancer Control, Survivorship and Outcomes Research Ethics and Confidentiality in Cancer Research

Single-funder organizations
Partner	Caveat
ACS	Dollar amounts found in the ICRP database are different than what is reported in the American Cancer Society's Annual Report. The dollar amounts spent on research reported in audited reports include operating expenses of the Research Department. Additionally, the dollar amounts also exclude all grants that were cancelled after being awarded, but include money that was returned from grants cancelled in the current year that were awarded in previous years. The dollar amounts reported in the database are unaudited and include grants awarded each fiscal year, exclusive of grants that cancelled before activation.
CBCRP	The California Breast Cancer Research Program grants are awarded only to individuals or institutions in California. Grants to the University of California receive only direct funds, while grants to other institutions also receive indirect costs (overhead) at 25% or the federally negotiated rate. Collaborative awards are counted in graphs and tables by the number of co-Principal Investigators rather than the number of projects.
Komen	Dollar amounts found in the ICRP database are different than what is reported on Komen\'s website or in Komen\'s Annual Report for the following reasons: Komen commits all funds necessary to support a research grant in the year it is awarded. Therefore, Komen\'s website reports on the full amount of each grant in the year it is initiated, while the ICRP data is annualized, as described. Komen funds research grants to our Scientific Advisors (Scientific Advisory Board members and Komen Scholars) and also provides discretionary funding of research-related projects that are not traditional research grants (e.g. support of the Komen Tissue Bank, ASCO and AACR meeting support). These are included in the overall Research Program spending, as reported in our Annual Report and on our website, but are not included in the ICRP database.
NIH	NIH projects in NIH Reporter assigned to the Spend Category ‘cancer’ are included in the ICRP database from FY2005 onwards. A small number of projects are excluded if essential information is missing (primarily Project title, Institution). Previous years’ data were drawn from the NFRP and may be incomplete. Starting in FY2007 NCI reports funding supplements, etc., for each grant separately instead of including them in the main project, therefore the number of projects may differ significantly from those of previous years. Projects with a cost of $0 include those that were a no-cost extension of the grant or when funding was provided by another NIH institute or center for that FY. NCI dollars in the ICRP database are drawn from NIH reporter and may not match dollars from other NCI-only databases.
Worldwide Cancer Research	Worldwide Cancer Research is unique in that the majority of our funding is awarded to researchers in countries outside the UK. Like many UK research charities, Worldwide Cancer Research only funds the direct costs of research. This creates significant problems in making quantitative comparisons between our funding and that provided by some of the other agencies in the ICRP, which fund both the direct and indirect costs (often called overheads) of research.

UK Organizations that are part of NCRI
Partner	Caveat
NCRI (GENERIC)	NCRI submits data to ICRP on behalf of all UK NCRI members from its Cancer Research Database (CaRD). The database only includes entries where funding can be directly attributed to a set of clearly defined research objectives. This means that the CaRD only contains information on all direct research funding (project, programme, fellowship, unit and institute) financed by NCRI Member organizations, for which an abstract has been submitted and where the project is active in any given financial year (April - March). Examples of funding that are currently outside the scope of CaRD are infrastructure, meeting grants and research management support."
Breakthrough (UK)	The ICRP database includes all Breakthrough Breast Cancer\'s research spend reported through its Annual Reports & Accounts. There is some variance due to different reporting periods (1 April snapshot versus full financial year) meaning that some research spend that is already committed may not be included in the ICRP figures. Expenditure on non-research charitable activities and management support costs are excluded from the NCRI, and by extension, the ICRP dataset. For further information on Breakthrough\'s research please visit www.breakthroughresearch.org.uk or email research@breakthrough.org.uk
CR-UK (UK)	The ICRP database includes around 70% of Cancer Research UK\'s direct research spend per financial year as reported through its Annual Reports & Accounts. There is some variance due to different reporting periods meaning that some direct research spend that is planned for allocation will not be included in the ICRP figures. Expenditure on vital research services, technology transfer, meeting grants, research management support and infrastructure to support Cancer Research UK\'s activities is excluded from the NCRI, and by extension, the ICRP dataset.
Department of Health (UK)	There will always be some variance between the figures available on ICRP and the figures reported publicly by DH. There are two reasons for this. Firstly, there is variance due to different reporting periods (1 April snapshot of ICRP versus full financial year reporting by DH). Secondly, the Department\'s National Institute for Health Research (NIHR) encompasses various expenditure on NHS infrastructure for research relevant to cancer that is not in a format that it is possible to capture for ICRP.
Macmillan (UK)	The ICRP database represents about 90% of Macmillan Cancer Support\'s direct research spend per financial year. There is some variance due to different reporting periods meaning that some direct research spend that is planned for allocation will not be included in the ICRP figures. Expenditure on research management support and infrastructure to support Macmillan Cancer Support\'s activities is excluded from the NCRI, and by extension, the ICRP dataset.
Scottish Government Health Directorates (UK)	Scottish Government is committed to improve the health of the Scottish population and the Chief Scientist\'s Office (CSO) funds across a broad range of relevant disease areas. Overall, 75% of the CSO spend is committed to research infrastructure in NHS Scotland. This and much other research expenditure is therefore outside the NCRI remit and, by extension, the ICRP dataset.

Canadian organizations who are part of the CCRA
Partner	Caveat
CCRA	Caveats/limitations specific to Canadian Cancer Research Alliance organizations can be accessed here.

Difference	Detail	Impact on investment figures
Not all CCRS participating organizations are included in the ICRP.	For the period 2005–2019, CCRA submitted data to the ICRP for 39 organizations and three now defunct multi-funded initiatives (CBCRA, CPCRI, and CTCRI). Note that the Canadian Breast Cancer Research Foundation merged operations with the Canadian Cancer Society in February 2017 and Prostate Cancer Canada merged in 2020. Projects within the CCRS total 27,239, of which 22,223 were reported to ICRP.	Medium
Not all CCRS projects are included in the ICRP.	“Related support” grants (i.e., travel awards, workshops/symposia, LOIs, etc.) are not submitted to ICRP, but are included in reports released by CCRA. In addition, equipment/infrastructure grants through the Canada Foundation for Innovation and for other funders where the cancer relevance weighting is less than 80% are not reported to the ICRP, but are included in CCRA reports. Any project with cancer relevance of less than 20% is also not reported to the ICRP.	Medium
Co-funded projects are listed by the administering organization.	Projects that are co-funded appear under the administering organization and are not duplicated per funder. Within CCRA reports, however, investments are reported by the actual funders.	Minor
ICRP uses a different approach to calculating annual project investment.	CCRA provides ICRP with the project budget (adjusted for cancer relevance) and start and end dates. A pro-rated calculation is used to derive annual investment. Within the CCRS, prorated calculations on the basis of annual project amounts (where those data are available) are used to calculate the annual investment.	Minor
ICRP uses different site coding conventions.	The cancer site/type codes used within the CCRS are different from ICRP site codes so results by site will vary in some instances.	Minor
ICRP has technical limitations.	ICRP has a technical limit of 12 site codes and 8 CSO codes and this requires truncation for a couple of large-scale projects within the CCRS.	Very minor
CCRA provides less descriptive information about its projects to ICRP.	Lay abstracts are submitted by CCRA to the ICRP in lieu of technical abstracts and in their language of origin. For projects without lay abstracts (and there are a significant number of these), only titles are provided. An English translation is provided alongside all French project titles to facilitate use of the search engine.	No impact on investment figures, but limits full functionality of search engine especially for organizations that do not collect/report lay abstracts.