An article by David Segarnick, PhD, Chief Medical Officer/Executive Vice President of Medical Analytics & Innovation/Specialized Services, MEDiSTRAVA
The landscape of precision medicine in cancer treatment has dramatically evolved, with biomarkers playing a pivotal role. Biomarkers—molecular signatures indicative of pathogenic processes—are now integral to diagnosing, prognosticating, and personalizing treatment strategies, particularly for treatment-resistant and refractory cancers. These cancers, which do not respond to standard therapies or relapse after initial treatment, present significant clinical challenges. This overview explores the current state and future prospects of biomarker utilization in managing these challenging cancer types. Inizio Medical is on the forefront of biomarker identification, utilization, product differentiation and clinician education in this rapidly evolving area. Recent data presented at ASCO 2024 further expands our understanding of resistance mechanisms and how biomarkers can help improve targeted therapeutic approaches.
Biomarkers in Treatment-Resistant Cancers
Identification of Resistance Mechanisms: Biomarkers enable the identification of genetic and molecular mechanisms underlying resistance. For instance, mutations in the EGFR gene and ALK rearrangements in non-small cell lung cancer (NSCLC) have been pivotal in understanding resistance to tyrosine kinase inhibitors (TKIs). Late-stage clinical trial data presented at ASCO explores different treatment regimens including osimertinib and mefatinib in patients with EGFR mutation-positive NSCLC. Secondary mutations such as T790M in EGFR further delineate resistance pathways, guiding the development of third-generation inhibitors.
Predictive Biomarkers: Predictive biomarkers forecast the likelihood of response to specific therapies. In breast cancer, the HER2 receptor status predicts response to trastuzumab. Similarly, PD-L1 expression serves as a predictive biomarker and key study design segmentation criterion for the efficacy of immune checkpoint inhibitors in various cancers, including melanoma and NSCLC. Additional biomarkers are under current investigation to determine their predictive accuracy across a wide range of hematologic and solid tumor types across tumor stage and treatment history.
Monitoring and Early Detection of Relapse: Circulating tumor DNA (ctDNA) and other liquid biopsy techniques offer non-invasive methods to monitor disease progression and detect minimal residual disease or early relapse during continued therapy or post-surgery. Recent data presented at ASCO describes ultra-sensitive mutation-tracking techniques currently being implemented to monitor tumor progression in breast, lung, pancreatic and gynecologic cancers among others. These approaches provide real-time insights into tumor dynamics and genetics, enabling timely intervention.
Biomarkers in Refractory Cancer Management
Genomic Profiling for Personalized Therapy: Comprehensive genomic profiling (CGP) using next-generation sequencing (NGS) can uncover actionable mutations in refractory cancers. Personalized therapy can improve outcomes by matching therapy choice to the genomic profile. For example, NTRK fusions across various cancers can be targeted with larotrectinib or entrectinib, offering new therapeutic avenues for otherwise refractory cases. Emerging data from ASCO show great promise for use of CGP to treat an individual patient’s cancer more specifically.
Immunotherapy Biomarkers: In the context of immune-resistant cancers, biomarkers such as tumor mutational burden (TMB) and mismatch repair deficiency (dMMR) guide the use of immunotherapies. High TMB and dMMR are associated with better responses to immune checkpoint inhibitors, expanding treatment options for refractory cancers. Emerging data from ASCO support use of these biomarkers to more effectively choose a treatment approach. Several investigational drugs have shown benefits in lung, colorectal and endometrial dMMR tumors, including dostarlimab, vibostolimab and atezolizumab.
Epigenetic and Proteomic Biomarkers: Epigenetic changes, such as DNA methylation patterns, and proteomic alterations are emerging as significant biomarkers. These can provide insights into resistance mechanisms and identify novel therapeutic targets. For example, aberrant methylation of the methylguanine-DNA-methyltransferase gene (MGMT) in glioblastoma can predict response to alkylating agents. New drugs are in development for these MGMT-unmethylated glioblastomas. In addition, recent data presented at ASCO highlights the importance of mapping methylation patterns across the genome in multiple myeloma, early breast cancer and colorectal cancer.
Future Directions and Challenges
Integrative Biomarker Approaches: The future of biomarker research lies in integrative approaches combining genomic, transcriptomic, proteomic, and metabolomic data. This holistic view can unravel complex resistance mechanisms and guide multifaceted therapeutic strategies potentially leading to more personalized treatment approaches.
Overcoming Tumor Heterogeneity: Tumor heterogeneity remains a major challenge. Intratumoral and intertumoral heterogeneity can lead to differential biomarker expression, complicating treatment decisions. Single cell sequencing and spatial transcriptomics are promising technologies to address this issue by providing detailed maps of tumor heterogeneity and informing treatments to include more focal therapy when possible.
Standardization and Validation: The clinical implementation of biomarkers requires rigorous validation and standardization. Reproducibility and accuracy are paramount to ensure biomarkers’ reliability in guiding treatment decisions. Collaborative efforts, such as those by the National Cancer Institute’s (NCI) Biomarker, Imaging, and Quality of Life Studies Funding Program, are crucial in this regard (https://www.cancer.gov/about-nci/organization/ccct/funding/biqsfp). Ongoing clinical research continues to test biomarker sensitivity and effectiveness with the goal of more robust understanding of individual tumors and therefore more effective treatment approaches.
Conclusion
Biomarkers are revolutionizing the management of treatment-resistant and refractory cancers, offering hope for more effective and targeted therapies. The continued advancement in biomarker research and technology promises to unravel the complexities of cancer resistance and tailor interventions to improve patient outcomes. However, achieving this potential requires overcoming significant challenges in standardization, tumor heterogeneity, and equitable access. Collaborative efforts across the scientific, medical, and regulatory communities highlighted at ASCO are essential to realize the full promise of biomarkers in combating these formidable challenges. Inizio Medical continues to research, evaluate and bring forward novel biomarker strategies across the spectrum of treatment-resistant and refractory cancers to the benefit of patients, providers and industry.
