Pearls of Grand Challenge wisdom

This means that annually, at a global scale, hundreds of thousands of individuals carry the burden of intensive treatment without any benefit, compromising their quality of life.

To solve this highly complex issue we must acknowledge that this challenge goes far beyond what a single mind or even a local research group can address. Therefore, only a complementary, focused, multidisciplinary team – with the best experts world-wide – will be able to change current paradigms and transform clinical practice. This is where Cancer Grand Challenges plays such a vital role.

For the PRECISION Cancer Grand Challenge team, we focused on the very commonly found potential precursor of invasive breast cancer: Ductal Carcinoma In Situ (DCIS). The majority of DCIS lesions will never progress to invasive breast cancer, but about one out of five will. As we cannot yet reliably distinguish the progressive, potentially hazardous, high-risk DCIS from the harmless, low-risk ones, almost all women with DCIS are treated by surgery. This is mastectomy or breast-conserving surgery, often supplemented by radiotherapy and, in some countries, hormonal treatment as well. Again, this implies many women carry the burden of intensive treatment without any benefit.

Building a Cancer Grand Challenge team

To address the challenge ‘When cancer is not really cancer’, we built a strong, multidisciplinary team to learn the underlying biology of DCIS, to find and validate features that are different between harmless and potentially hazardous DCIS and to perform studies in which women with low-risk studies are monitored but not treated for their DCIS.

A very important tip I have for future Grand Challenge Teams is to draw expertise from different academic backgrounds together. Our team consists of experts in epidemiology, health economics, quality of life, surgery, radiotherapy, pathology, genetics, and animal modelling.

Along the continuum of the project, we have enriched our team with other experts as well if needed. A great example of this was when we realised how much we could benefit from three-dimensional imaging and single cell sequencing for spatial genomics.

Last but not least, remember patient representatives can, and should, play a central role. First, they are central in keeping a focus for the team and to continually question the patient impact aspects of your work. Secondly, they ‘translate’ the output of our research in plain language summaries, and they can reach out via a variety of options (for example, posters, lectures and the media) to society in general. They can also feed back and interact with the patient advocacy society.

How are we doing?

For the biology, the PRECISION team have generated an impressive series of mouse models that taught us – very unexpectedly – how the growth pattern of DCIS predicts the risk of progression to invasive breast cancer.

These analyses are currently being translated to the human setting to validate whether these findings may help us to distinguish high- from low-risk DCIS.

For features that may distinguish between high- and low-risk DCIS, we developed several pathology, genomic and AI based tests that could be instrumental in distinguishing the two groups. And, excitingly, we have already run trials in which women with low-risk can forego treatment that might not actually benefit them by being monitored on an annual basis.

Overall reflections

Cancer Grand Challenges has offered us an unprecedented opportunity to make substantial impact.

We could do this only with the generous support of Cancer Research UK and the KWF Dutch Cancer Society. We succeeded in many aspects in defining when cancer is not cancer, focusing on DCIS as a very common health issue that was surrounded by way too much uncertainty. Ultimately, this will save many women the harm of needless treatment, preserving their quality of life, and saving substantial costs in health care as well as society.

• Don’t be afraid to take on a bold and unusual design. For Mutographs we wanted to collect and analyze thousands of cancers from more than 30 different countries.
• Allow long enough for the project to evolve and mature: 5-7 years is a reasonable period for a substantial Cancer Grand Challenge to acquire momentum and deliver, whilst still adequately funding multiple groups.
• Be open to evolving the project, perhaps at the halfway stage, with new co-Principal Investigators (PIs) to take advantage of new opportunities.
• Choose the structure of the challenge with respect to co-PIs and work packages thoughtfully. There is no prescribed and optimal design, but ask yourself whether many co-investigators and, hence, many small projects is what is needed or whether a small number of larger work packages, more strategically chosen with higher individual expectations of delivery serves the challenge better.
• Aspire to make the Cancer Grand Challenge work be more than the sum of its parts. Make sure to have presentations of progress and updates from work packages at each steering group meeting and ensure collaborations between work packages. Where there are genuine collaborations, be sure to have joint lab meetings – this can, of course, be virtual. Where you can, have projects designed as pipelines involving multiple groups continuously contributing to the acquisition of samples, data generation, processing, and analysis.
• Always remember to be realistic in assessments of what can be achieved, particularly in logistic and regulatory elements of ethics approval, sample and data acquisition, and recruitment of staff. Being over optimistic in these elements will not help project success.
• Think outside the box. For example, if there are major regulatory obstacles, consider whether employing a lawyer for a period would be helpful. And use the flexibility embodied in the Cancer Grand Challenge spirit and style of management. Bring in new people, incorporate new lines of research. And of course, make the most of the Cancer Grand Challenge administration and oversight teams, they are there to help.
• Be strategic with funding and reallocate if necessary and helpful.
• Leadership for the team is important in defining the spirit of the challenge and in coordinating strategic decisions when necessary. At the beginning, consider a governance structure with authority to make decisions.
• Consider authorship principles from the start.
• Don’t neglect patient advocates. Start thinking with patient advocates early and be sure to invest sufficient time and energy on this. With advocates to establish expectations, define goals and involve advocates in the scientific process.
• Try and establish a mix of PIs at early, middle and later career stages, consider diversity of all kinds.
• Be transparent. With consortia of this size and nature, differences of opinion can arise and are not necessarily resolved. Maintaining transparency will at least bring trust, and trust will be the basis for accepting decisions.
• Keep the frequency of PI meetings regular. Having a 2-hour meeting every 3 months with scientific presentations and administrative issues dealt with will go quite a distance to making the CGC feel like a team.
• In terms of communications, do think about non-standard publications: technical reports, resource reports, tool reports, blogs and others that may not come from the standard sources of post docs, graduate students and PIs.
• Having a programme manager is mandatory and extremely helpful. Give the programme manager a high level of responsibility. They will administer the challenge (which is extremely useful!) but can be considerably more than an administrator. They can be a driving force of a challenge. Moreover, they will know the ins and outs of the Cancer Grand Challenge better than anyone else. They can connect with Co-PIs and sense how the whole enterprise is developing. Encourage their sense of ownership of the challenge and their position as a central spirit, give them the independence to develop their role to the full.