Rare Cancer: Unmet Needs & Implications for Community Practice

May 31, 2022

ORION by VieCure

Volume 3, Issue 5

Fredrick Ashbury, PhD and Pradip De, MSc PhD

More than 1.9 million Americans will be diagnosed with some form of cancer in 2022 and over 600,000 people will die of cancer. With the increased technology of advanced genomics, molecularly driven precision medicine, and immunotherapy, mortality due to cancer is starting to decline toward a goal that one day, hopefully soon, a cancer diagnosis is no longer the death verdict it once was. In the context of rare cancers, which the National Institutes of Health defines as cancers that impact fewer than 40,000 people per year in the U.S, omics-guided medicine has increased our optimism to see reductions in death. As a group, rare cancers make up just over a quarter of all cancers. Because rates of cancer in children are very low, all children’s cancers are considered rare. In this article, we are considering only the rare solid tumors (namely appendiceal cancer, cholangiocarcinoma, ocular (uveal) melanoma, soft tissue sarcoma, ameloblastoma, penile cancer, etc.) and the scope of precision medicine. Fred Ashbury (FA): What are the challenges in treating and managing patients with rare malignancies?


Pradip De (PD): Although rare tumors are infrequent by definition, when all subtypes of rare cancers are combined, they account for approximately 25% of adult malignancies (Kato S et al. Oncologists 2018; 23: 171-178). Henceforth the overall burden of rare tumors is significant. Clinical management of rare malignancies is often challenging due to lack of information, as well as a shortage of therapeutic options that are approved by the U.S. Food and Drug Administration (FDA) and limited experimental options of large scale clinical trials as well as very few cancer centers, have dedicated rare tumor clinic. A quarter of all cancer deaths each year are due to rare cancers. Although new treatments are always being developed, finding new treatments for rare cancers is very hard for many reasons, particularly the absence of data from the randomized clinical trials. Patients with rare tumors may lack approved treatments and clinical trial access. Thus, patients with rare cancers tend to lack novel therapeutic approaches such as those with genomically-driven targeted therapies.


Conceivably due to these limitations, patients with rare tumors are reported to have lower 5-year overall survival when compared with those with common tumors (47% vs.66%) (Eur J Cancer 2011; 47: 2493–2511). Based on the unmet need for novel treatments for patients with rare cancers and due to lack of initiating the randomized clinical trial, all cancer centers (including community cancer centers) should have initiated “Rare Tumor Clinic” that emphasized a precision medicine strategy utilizing the genomic and phospho-proteomic analysis to guide individualized therapy. Here is some NGS-based genomically-driven treatment approach with rare tumors and its success/encouraging results:

  1. UCSD had recently published an article with rare tumors and matched therapies. Among 40 patients with rare tumors, 33 patients underwent tissue NGS. Among 21 patients who underwent genomically-matched targeted therapy, 14.3% (3/21) attained SD (stable disease) for >6 months, 28.6% (6/21) had a partial response (PR), and 9.5% (2/21) achieved complete response (CR), for a total of 52.4% of patients with SD > 6 months, PR, or CR. Median PFS with matched therapy was 19.6 months (range 0.991 to 26.11 months) (Please see details in the article by Kato S et al. Oncologists 2018; 23: 171-178).

  2. This is a basket study with copanlisib (PI3K inhibitor) in patients with PIK3CA mutation from MD Anderson (Damodaran S et al. JCO 2022). One ameloblastoma patient in their cohort showed an exceptional response (more than 24 months and still on the treatment when the M.S. was published) with copanlisib. This patient with mandibular ameloblastoma, in addition to PIK3CA, BRAF, and MED12 mutations, was also observed.

  3. In the last couple of years, the FDA approved three targeted drugs for advanced or metastatic cholangiocarcinoma. Ivosidenib and pemigatinib/infigratinib were approved for IDH1 R132X mutation and FGFR2 fusion/rearrangement cholangiocarcinoma, respectively.

  4. Very recently the FDA also approved tebentafusp-tebn (a bi-specific fusion protein) for unresectable or metastatic uveal melanoma with HLA*02.01 positive adult patients. Tebentafusp binds to one molecule (gp100) on melanoma cells and another on T cells (activates T cells), which are a type of immune cell. gp100 that tends to be produced in abundance in melanoma cells, including uveal melanoma cells. Cells must also express a specific type of human leukocyte antigen (HLA), known as HLA-A*02:01. HLAs, which are present on the surfaces of most cells in the body, plays an important part in the body’s immune response to foreign substances. HLA-A*02:01 is present in approximately half of all Whites, which is the population most affected by uveal melanoma.


Hence comprehensive molecular analysis has identified a relatively high incidence of potentially targetable genomic alterations in rare tumors, predictive of response to targeted and immunotherapies. Recently, the Target Cancer Foundation initiated a clinical trial Called TRACK (Target Rare Cancer Knowledge, TCF-001, NCT04504604). TRACK provides participating rare cancer patients and their physicians with personalized, actionable information to potentially inform treatment, as well as recommendations for on-label, off-label, or clinical trial treatments from an expert panel of rare cancer clinicians and scientists.

We know cancer has a genetic basis, we can be agnostic with respect to its cause. In the era of precision cancer medicine (including rare tumors), biomarkers are increasingly appreciated for selecting patients in the clinical cancer research and practice therapeutic settings. Biomarkers with the potential to inform treatment, including but not narrowed to pathogenic genomic alterations that alter actionable signaling cascades and/or cause specific immune deregulation, are identifiable by testing approaches such as next-generation sequencing (NGS).


In this aspect NGS/biomarker driven treatment approach clinicians (including community oncologists) may prepare for oncology world influenced by artificial intelligence (AI). In the near future AI and machine learning (ML) are poised to convert the way health care is provided. AI is the use of computers to simulate intelligent tasks classically performed by human beings. Ml is a domain of AI that involves computers automatically learning from data without prior programming (JAMA 2022; 327: 1333). AI represents entering a new era of potentially practice changing technology. The pursuit of diagnostic/treatment excellence involves AI which is an evidence-based medicine (also include functional genomics) which have the capacity to create the user guidelines to equip oncologists (including community oncologists) with the skill to read and appropriately apply research into their day to day clinical practice. This is a challenging but manageable task that can be accomplished through adaptation and standardization of the treatment paradigm in oncology.



Fredrick D. Ashbury, PhD

Chief Scientific Officer, VieCure Professor (Adj), Department of Oncology University of Calgary Professor (Adj), DLSPH, University of Toronto



Pradip De, PhD

Signal Transduction Pathway Consultant, VieCure, Assistant Professor, Department of Internal Medicine at the University of South Dakota, South Dakota, USA