Rare cancers: research progresses at a slower pace than in other areas of oncology

Medical knowledge has little value until it is shared and integrated into clinical practice. A recent public debate around rare cancers - which are estimated to currently affect around 4.3 million patients in the European Union (EU) (Eur J Cancer. 2011 Nov; 47(17):2493-2511) - has stressed that inadequate training of the medical workforce is an obstacle, preventing patients and their families from receiving early diagnosis and appropriate treatment. But it is not the only one, as notes Dr Armelle Dufresne from the Centre Léon Bérard, Lyon, France. “The biology itself of rare malignancies, reveals an unexpected heterogeneity of each tumour subtypes,” she says. “The number of rare cancers is still evolving in parallel with our capabilities to detect novel genetic alterations.”

Echoing the theme of the 2025 Rare Disease Day – “More than you can imagine” -, taken together rare cancers occur more frequently than imagined, “equating to around 22% of all cancers (Eur J Cancer. 2011 Nov; 47(17):2493-2511), and as such they are not so 'rare' as a group,” continues Dufresne.
While there is mounting evidence that a shift from the traditional organ-based classification of cancers to a tumour-agnostic approach may deliver future benefits (J Ann Onc. 2024 Nov; 35(11):936-9530), many experts in the field question if time has come to take rare cancers out of their “niche” and consider them as well as other more common malignancies.
For Dufresne, “establishing a specific awareness day for rare cancers would be an interesting initiative to consider,” she adds. “It could be a good way to spread messages and information about rare cancers, and how best to treat them throughout the community, but we would need to establish the clinical objective, the message, and the people we would like to focus on.”

Re-educating the medical workforce

Diagnosis of rare cancers may be challenging. “Medical oncologists are not always involved in the diagnosis approach initially,” says Dr Timothée Olivier, Geneva University Hospital, Switzerland. “About 15% of patients presents with high suspicion of metastases without the identified primary tumours, and often the oncologist is brought in only when there is a confirmation of the diagnosis.” As Olivier highlights, a key step to allow for early diagnosis of rare cancers is a close collaboration with the team directly in charge of the patient, the pathologist – who plays a pivotal role –, medical oncologists, and experts from other specialties like radiology.

Given that diagnosis of rare cancers is a multi-disciplinary process, increasing awareness about less common malignancies among the medical community is paramount to support advances in oncology. For Dufresne, a lack of cooperation is mainly due to difficulties in sharing information about rare cancers with professionals “who have never seen a case”. Olivier adds: “Beyond the oncology community, we also need to inform care-takers in general about when to refer patients to reference centres as advocated by the European Reference Network for rare adult solid tumours (EURACAN), so that to refrain from conducting a biopsy or inappropriate surgery when, for example, a sarcoma is suspected before a multi-disciplinary team is involved. We need to increase the awareness about when to flag those situations.”

Managing rare cancers in a reference centre has consistently been shown to have a positive impact on clinical outcomes in terms of survival (Oncologist. 2019 Jun; 24(6):e338-e346), but their uneven geographic distribution, lack of clinician awareness of the most appropriate nearest centre, inadequate support in terms of resources, and also the bureaucracy and reimbursement issues involved in referring patients to different localities and regions in some countries limit their value.

Pushing the regulatory boundaries

Over the past few years, some advances from research have opened up novel treatment opportunities for patients with rare tumours. “We have recently seen encouraging data from antibody-drug conjugates (ADCs) and a growing interest in tumour-agnostic therapies hitting specific molecular targets,” adds Dufresne. “For example, the approval of an inhibitor of tropomyosin receptor tyrosin kinase, showed some promise also in rare cancer types where neurotrophic tyrosine receptor kinase (NTRK) fusions are nearly ubiquitous.”

Rare cancers constitute a pressing healthcare issue. From a policy perspective, however, a common approach is still lacking in the European Union (EU), something which could help expedite drug approval and access to treatment for rare cancers. Alongside the therapeutic advances, in fact, conducting well-powered randomised clinical studies remains challenging in rare cancers, and sponsoring such studies is also difficult. The result is that research progresses at a slower pace than in other areas of oncology. “Some regulations at a national level, which may vary from country to country, make us struggle to exchange clinical information and biological materials,” explains Dufresne who believes advances in the field would benefit from some incentives. “At both EU and national levels there are grants for research and programmes dedicated to specific diseases, so why not consider rare cancers as an objective and dedicate more grants to the field?”

While randomised controlled trials are the “golden standard” of cancer research, experts in rare malignancies advocate for alternative study design, use of secondary endpoints and the accumulation of lower level of evidence. “Protocols could have a more pragmatic design, such as having fewer exclusion criteria to include more patients, and mirroring the patients we see,” highlights Olivier. “Academic trials are crucial for the advancement of treatment options and improving patient outcomes. Through this route, we can ensure that even smaller patient groups receive the benefits of rigorous research.”

Building research on a solid network of stakeholders in the field is also paramount, concludes Dufresne. “As experts we absolutely need to talk with everyone around the table – scientists, pharmaceutical companies, patient advocacy groups, regulatory authorities - to define strategies to tackle the current challenges in the field. The scientific community around rare cancers is small, but highly collaborative: each of us may have only two or three patients with a specific rare tumour type means that we have to work collaboratively, as nothing can be done on your own in this field. And this may be a major driver to find more effective options of care for our patients together.”