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- 11 March 2019 -

NABCG – a major network of US and Canadian researchers

NABCG – a major network of US and Canadian researchers

Intro text: 

The NABCG is a network of US and Canadian research groups supported by the US National Cancer Institute (NCI), with major funding from the BCRF. For many years, breast cancer clinical trials in the USA were run through 10 different cooperative groups, each with its own breast cancer committee, but researchers decided there was a better way of doing things.

“We recognised that a lot of different groups were doing studies asking the same questions and agreed that it would be better to work together. We talked about it and the NABCG was actually set up on the basis of a handshake in a Toronto cafe,” laughs Dr Larry Norton, Founder and Scientific Director of BCRF.

Since then, the organisation has been further consolidated by the NCI into the National Cancer Trials Network (NCTN), consisting of four adult cancer groups in the USA (NRG, ECOG-ACRIN, SWOG and the Alliance for Clinical Trials in Oncology) and the Canadian Network Group. However, the overall group has kept its ‘legacy’ name of NABCG, through which it collaborates with BIG.

Breast cancer research in Canada: successes and challenges

Within the NABCG network, Canadian breast cancer researchers have consistently ‘punched above their weight’ – leading or making a major contribution to many practicechanging trials of breast cancer treatment, including those on aromatase inhibitors [1,2] and accelerated and partial breast irradiation [3-5]. Uniquely among NABCG members, Canada is also a member of BIG, through the Canadian Cancer Trials Group (CCTG).

He suggests that Canada’s single-payer healthcare system may make it easier for its researchers to participate in some breast cancer research, such as health economic aspects of real world clinical studies, than US researchers whose payer data sources are more fragmented.

“Like Scandinavia, a lot of our provinces have excellent registries with long-term follow up that are linked with health administrative databases. These can allow researchers to look at questions about health care utilisation, such as the drug treatment patients have received, emergency department visits and other contacts with the healthcare system, costs and delivery of care. This is not only useful for clinical trials, it can also show trends that lead to changes in the way local care is delivered,” says Dr Philippe Bedard, a member of BIG’s Executive Board since June 2018 and Associate Professor of Medicine at the University of Toronto.

However, Canada’s vast territory and small population bring both advantages and disadvantages to the country’s research efforts.

Our greatest strength is that breast cancer researchers in Canada are highly collaborative and work well together and with US groups and other academic groups in the rest of the world. However, our relatively small population can make it challenging for us to contribute to large international trials that focus on rare subpopulations of patients with breast cancer,” he says.

Bedard explains that, as in many countries, the rising costs of research are also hampering progress. He estimates that about two-thirds of breast cancer studies in Canada are funded by pharmaceutical companies and one-third investigator initiated.

“Government support for clinical research has decreased, particularly in breast cancer where some studies require long term follow up of patients for 10 years or longer, and it’s a big challenge for cooperative groups to adequately fund practicechanging clinical trials,” he says.

There are also growing concerns that funding challenges will deter young investigators from getting involved in research if they are overwhelmed by administrative and cost hurdles and sustainability issues.

The current focus of national breast cancer research – precision medicine, immunotherapy and treatment de-escalation – is similar to that in other developed countries, though successful recent initiatives to standardise care and bring radiotherapy and chemotherapy closer to patients in remote areas are more specific to Canada.

“Twenty years ago, patients had to be treated in large urban centres and we were sending patients to the US for breast radiotherapy because of resource limitations. Now, that’s all changed because the provinces have really tried to improve care delivery in more rural centres, especially for radiotherapy,” says Bedard.

As in many countries, Canada has a national body, the pan Canadian Oncology Drug Review (pCODR), to assess costeffectiveness and make recommendations for use of cancer medicines, though provinces decide on local availability based on further price negotiations with manufacturers.

Major breast cancer trials currently led by Canadian researchers include MA32, a phase 3, placebo controlled, five-year trial of metformin in patients with high risk, early stage breast cancer, which is expected to report in the next few years, and MA39, a recently initiated radiotherapy de-escalation study in patients with limited node-positive disease, based on genomic risk scores.

Through the Breast Cancer Dream Team initiative, sponsored by StandUpToCancer Canada and the Canadian Cancer Society, research and development of three new biomarker-driven drugs for triple negative breast cancer has been accelerated. These drugs – CFI-400945 (a PLK4 inhibitor), CX5461 (an RNA Pol I inhibitor/GQ binder), and CFI-402257 (a TTK inhibitor) – are undergoing basic/translational development and phase 1/2 trials in patients with advanced breast cancer.

For the future, Bedard hopes that innovative trial designs that enable Canadian patients to take part through electronic follow up and video conferencing will allow greater participation by those living in rural areas – boosting the overall numbers of participants that Canadian researchers can contribute.

“We are proud to have contributed to BIG’s practice-changing breast cancer trials, and we believe we bring a unique perspective in that we are geographically close to the US but, in some aspects of care delivery, we favour a more European approach,” concludes Bedard.

BIG-NABCG: what's next in 2019 and beyond?

During 2019, the BIG-NABCG collaboration aims to consolidate progress in breaking down barriers to clinical trials and simplifying processes for investigators and patients to take part. As demonstrated by the focus of this year’s annual meeting, biomarker-guided treatment de-escalation is another priority as part of efforts to extend precision medicine to more patients with breast cancer.

Piccart points out that there has never been a systematic strategy on the best way to achieve safe de-escalation, so that patients do not lose out in terms of survival. There is also a need to agree the best statistical methodology for de-escalation studies.

The value of treatment de-escalation in women with small HER2+ breast cancers who can be treated with paclitaxel and trastuzumab, without the need for anthracyclines, has now been widely accepted by clinicians and is included in guidelines,explains Piccart. However, it is proving more difficult to act on the results of the MINDACT trial showing that women with high risk, early-stage breast cancer and a favourable MammaPrint® signature may not need chemotherapy [15], because some regulatory organisations have been reluctant to approve or reimburse the test.

At the annual BIG-NABCG meeting, discussions will include patient input about the potential risks and benefits of treatment de-escalation:

“By working together on treatment de-escalation in breast cancer at our annual meeting, we hope to publish a consensus statement from BIG and NABCG which will make a more powerful contribution to the field than either organisation alone,” says Piccart.

Over the next few years, the collaboration will also build on recent evidence supporting the role of immunotherapy for breast cancer, as there is considerable interest in improving understanding about which patients are most likely to benefit from the immune approach.

“We try to be nimble and flexible, and responsive to issues in breast cancer as they arise. We also try to be practical. There are many questions we could tackle but we try to think about the ones that we can potentially control and are particularly pertinent to breast cancer,” says Dr Nancy Davidson, Senior Vice President and Director of the Clinical Research Division at the Fred Hutchinson Cancer Research Center in Seattle, USA, and co-chair of the BIG-NABCG Coordinating Group.

Norton agrees on the importance of maintaining the momentum in building on what has already been achieved and focussing on the most relevant issues. He is also delighted with the way the collaboration is extending to include younger researchers who will be essential for continuing the work of the collaboration in the future: “The ultimate goal is to see a truly international collaboration in which researchers from across the world contribute data from many, many patients in one study to answer one question. In that way, instead of answering questions in years, we will be able to answer them in months.”

References
1. Goss PE, Ingle JN, Martino S et al. A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer. N Engl J Med 2003; 349:1793-1802
2. Goss PE, Ingle JN, Pritchard KI et al. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. N Engl J Med 2016; 375:209-219
3. Whelan TJ, Olivotto IA, Parulekar WR et al. Regional Nodal Irradiation in Early-Stage Breast Cancer N Engl J Med 2015; 373:307-316
4. Whellan TJ, Pignol J-P, Levine MN et al. Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer N Engl J Med 2010; 362:513-520
5. Whelan T, Julian J, Levine M et al. RAPID: A randomized trial of accelerated partial breast irradiation using 3-dimensional conformal radiotherapy (3D-CRT). San Antonio Breast Cancer Symposium 2018. Available at: https://www.abstracts2view.com/sabcs/view.php?nu=SABCS18L_1220&terms
6. Cardoso F, van't Veer LJ, Bogaerts J et al. MINDACT Investigators. 70-gene signature as an aid to treatment secisions in early-stage breast cancer. N Engl J Med. 2016 Aug 25;375(8):717-29.