Abstract IA007: Precision oncology and the N-of-1 revolution: Rare cancers as a paradigm

Abstract

Rare cancers have challenged conventional drug development because patient populations are too small for traditional disease-specific trials. Yet rare cancers may provide the paradigm for the future of oncology. Cancer classification has evolved from organ-of-origin taxonomy to molecular stratification and then to tumor-agnostic therapies targeting single biomarkers across histologies. However, comprehensive molecular profiling reveals that most tumors harbor not a single driver, but complex, unique molecular architectures. Thus, every cancer may be considered ultra-rare—a biologically distinct N-of-1. Rare cancers expose a fundamental limitation of traditional treatment models. While tissue-specific and single-biomarker approaches have produced important advances, they do not capture the molecular complexity and heterogeneity observed within and across cancer types. Even tumors sharing histology or genomic alterations often differ substantially in co-occurring abnormalities, immune contexture, and evolutionary trajectories. Rare cancers therefore exemplify a broader principle: the individual patient, rather than the disease category, is the relevant unit of analysis. Precision oncology must move beyond matching one alteration to one drug and instead address the totality of a tumor/patient molecular profile. Because multiple dysregulated pathways commonly coexist, optimal therapy may require customized combinations of gene- and immune-targeted agents, cytotoxics, endocrine therapies, and repurposed drugs selected to address the unique molecular ecosystem of each tumor. The I-PREDICT study provided a blueprint for this transformative model. Patients received individualized therapies matched to their molecular alterations, and a Matching Score quantified the degree to which treatment addressed the tumor's molecular abnormalities. Clinical outcomes correlated linearly/significantly/independently with Matching Score, demonstrating that greater molecular matching was associated with greater benefit. Therefore, matching complexity matters, and individualized combination strategies can be safely implemented and evaluated. The N-of-1 (r)evolution carries major implications for clinical research. If each patient's cancer is molecularly unique, the question becomes whether molecular matching algorithms can effectively translate complex biological data into personalized treatment regimens. In this model, the algorithm—not the tumor type or individual drug—becomes the principal object of investigation. Rare cancers foreshadow the future of precision oncology. As molecular characterization becomes increasingly comprehensive, classification based on tissue of origin or single biomarkers gives way to recognition that each tumor possesses a unique and complex molecular identity. The N-of-1 paradigm reframes cancer as requiring customized therapeutic solutions. Future advances will depend not only on new drugs but also on validating sophisticated matching algorithms capable of delivering truly personalized cancer care. Razelle Kurzrock. Precision oncology and the N-of-1 revolution: Rare cancers as a paradigm [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr IA007.