Advancing Precision Oncology: From Molecular Diagnostics to Biomarker-Driven Treatment

Cancer remains one of the most significant global health challenges, with incidence and mortality expected to rise substantially in the coming decades. By 2040, the worldwide cancer burden is projected to reach 28.4 million cases, reflecting demographic aging and increasing prevalence of metastatic disease. For most of these individuals, cure is no longer feasible, and systemic therapy is primarily palliative, offering modest response rates and considerable toxicity. This underscores the urgent need for biomarkers that can guide more effective and less harmful treatment strategies.
The evolution of cancer treatment has been shaped by centuries of scientific progress. From early descriptions in ancient Egyptian texts to the radical surgical approaches of the 19th century, cancer therapy long relied on local interventions such as surgery and radiotherapy. The mid‑20th century marked a turning point with the advent of combination chemotherapy, which demonstrated curative potential in diseases such as childhood leukemia and Hodgkin lymphoma. Parallel to these clinical advances, fundamental biological insights established cancer as a genetic disease driven by hallmark biological capabilities.
The Human Genome Project and subsequent technological breakthroughs in sequencing catalyzed the modern era of precision oncology. Rapid, affordable next‑generation sequencing enabled the identification of actionable genomic alterations across tumor types, leading to the development of targeted therapies such as imatinib and trastuzumab. Increasingly, treatment decisions are guided not by tumor histology but by molecular characteristics, with studies suggesting that 30–80% of metastatic cancers harbor potentially actionable genomic variants. However, many targeted therapies are approved only for specific indications, limiting access for patients whose tumors share the relevant molecular features.
To address this gap, the Drug Rediscovery Protocol (DRUP) was launched in 2016 as a prospective, adaptive, pan‑cancer clinical trial providing patients with treatment refractory cancers access to FDA/EMA‑approved targeted and immunotherapies based on their tumor’s molecular profile. Early DRUP results demonstrated a clinical benefit rate of 34% across treatment classes, with particularly strong outcomes in patients with mismatch repair deficient tumors treated with nivolumab. DRUP also highlighted the importance of publishing negative results, as illustrated by cohorts in which molecularly matched therapies failed to demonstrate efficacy.
The thesis further explores key challenges in precision oncology, including optimal timing of molecular diagnostics, the role of Molecular Tumor Boards in interpreting increasingly complex data, and the stability of actionable genomic alterations over time. Whole‑genome sequencing appears sufficient in most metastatic cases, although exceptions exist, particularly in tumors treated with targeted inhibitors where resistance mutations emerge. Additional chapters examine the management of dMMR/MSI metastatic colorectal cancer, the potential role of surgery following immunotherapy, and the reorganization of cancer care during the COVID‑19 pandemic.
Looking ahead, the promise of precision oncology will depend on equitable access to advanced diagnostics, integration of multi‑omic and patient‑specific factors, and continued international collaboration. As targeted therapies, immunotherapies, and combination strategies evolve, a more personalized, effective, and less toxic approach to cancer treatment becomes increasingly attainable.