Shifting the Paradigm: Challenges, Opportunities and Methodologies in Studying Rare Cancers
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The study of rare cancers has undergone a paradigm shift, transitioning from a singular disease entity approach to a more nuanced understanding of biomarker-defined subtypes.
Nicholas Robert, MD, chief medical officer, Ontada
Driven by advancements in genomic profiling and molecular diagnostics, the study of rare cancers has undergone a significant transformation. Traditional views of cancer as singular disease entities have evolved into a more intricate understanding that recognizes that cancer includes a collection of rare, biomarker-defined subtypes. This paradigm shift is evident in cancers like lung cancer, which is no longer categorized simply as small cell or non–small cell lung cancers, but rather as a group of biomarker-defined cancers, each requiring different treatment strategies.
The advent of actionable biomarkers has fundamentally altered the landscape of oncology, enabling the development of targeted therapies that have significantly improved overall survival (OS) rates. For example, studies have shown that targeted therapies can extend median OS by more than 1 year compared with nontargeted therapies.1
Rare cancers now account for up to 25% of all cancer cases, underscoring the importance of understanding their natural history, clinical course, and treatment outcomes.2 There is increased interest in real-world research which can provide insights that can inform future clinical trials and therapeutic strategies in clinical practice.
For instance, a recent FDA-awarded study aims to investigate the natural history of 10 rare cancers treated in the US community oncology setting, evaluating patient and clinical characteristics, treatment patterns, and long-term outcomes.3
The shift to biomarker-defined cancer subtypes has opened new avenues for targeted therapies but also presents significant research challenges. Addressing these challenges through the use of real-world data and real-world evidence can help improve patient outcomes in this complex field of oncology.
Challenges and Opportunities Associated With Studying Rare Cancers
The challenges and opportunities presented by studying rare cancers, especially in the context of precision medicine and biomarker-driven oncology, can be categorized into the following 4 key areas:4
Amy O’Sullivan, PhD, senior vice president & chief research officer, Ontada
Clinical Development
Finding patients with specific biomarkers for clinical trials is both challenging and time-consuming due to the small size of these patient populations. This limits the scope and progress of clinical trials. Small sample sizes may reduce the generalizability of findings and the statistical power of studies, making it difficult to draw reliable conclusions. Privacy, data sharing, and informed consent are significant legal and ethical concerns, especially when comprehensive genomic data is involved.
A major opportunity lies in the identification of specific genetic biomarkers, which enables the development of targeted therapies designed for individuals with those biomarkers. This can lead to more effective treatments and improved patient outcomes. Clinical trials can become more precise, by including patients who are more likely to respond to specific treatments, thereby improving the chances of success. Developing efficient solutions to these challenges can potentially shorten the time to market for new therapies.
Cancer Screening and Early Diagnosis
Access to comprehensive genomic testing is not uniformly available, which can lead to disparities in cancer diagnosis and treatment. Certain geographic areas and subpopulations may have limited access to advanced genomic testing, affecting early diagnosis and intervention efforts.
An opportunity associated with the identification of germline alterations can facilitate early detection of cancers, allowing for timely intervention. Targeted screening strategies can assess an individual’s genetic predisposition to certain types of cancer. Advancements in precision medicine have the potential with liquid biopsies, a noninvasive and repeatable method for cancer screening to detect early cancers. Although liquid biopsies are not currently standard in this setting, this technology holds promise for improving early detection.
Treatment Selection
Targeted treatment selection is only possible if the patient has been tested for specific biomarkers. Precision medicine allows physicians to select therapies that are more likely to be effective for a particular patient, leading to better outcomes. It also enables the identification of specific subgroups who are more likely to respond to a particular treatment, thereby avoiding unnecessary treatments.
It is anticipated that the number of cancers with identifiable biomarkers will increase in this area.
Zhaohui Su, PhD, vice president, biostatistics, Ontada
Treatment Outcomes
Tumors can be genetically heterogeneous, meaning that targeting a single mutation may not be sufficient to eradicate all tumor cells. Despite initial responses, many cancers develop resistance to targeted therapies over time, necessitating ongoing research to identify new therapeutic targets and combination treatments.
The advancement of precision medicine provides the opportunity to develop combination therapies that target multiple pathways simultaneously, potentially improving treatment outcomes. Given that precision medicine has been shown to improve overall patient outcomes relative to standard care, there is a compelling case for its continued development and integration into oncology practice. Liquid biopsies also have the potential of assessing treatment efficacy.
Statistical Considerations
Statistically analyzing rare cancers poses unique challenges due to their small patient populations. Nonetheless, with meticulous planning, robust evidence can be obtained. Key considerations include ensuring appropriate statistical power, enhancing data completeness, and selecting suitable study designs and end points.
An underpowered study may fail to detect significant associations, while an overpowered study can be unnecessarily costly. It is essential to determine the appropriate statistical power or precision for estimating the outcomes of interest. To help increase the statistical power, a study may: (1) leverage a large data source or link multiple data sources to increase the sample size, (2) extend follow-up periods, thereby gathering more data points, (3) select appropriate surrogate end points, such as pathologic complete response serving as early indicators of long-term outcomes,5 and (4) choose a study design and analysis methods that are tailored for small sample sizes, eg, exact tests.
Missing data can reduce statistical power and lead to biased results. To mitigate this, it's crucial to assess data completeness and fitness for purpose. Employing machine learning, natural language processing and expert chart abstraction can significantly enhance data extraction and completeness.6 Small sample sizes often elevate the risk of bias and confounding, limiting the generalizability of findings. Data representativeness should be evaluated, and sensitivity analyses are highly recommended.
In conclusion, while the study of rare cancers poses significant challenges, it also offers numerous opportunities that can lead to significant advancements in oncology treatment and outcomes. By addressing these challenges through strategic planning and methodological rigor, researchers can generate robust real-world evidence that informs clinical practice and improves patient outcomes.
