Molecular Profile Interpretation 101 with Nurse Practicioner Lauren Welch
Conference:
2024 West Oncology Virtual Conference for Advanced Patient Practicioners (APP)
Presenter:
Lauren Welch, MSN, NP-C, AOCNP
At the 2024 West Oncology Virtual Conference for Advanced Patient Practicioners (APP) Nurse Practicioner Lauren Welch provided an overview of cancer genomics and molecular profiling. Given the current complexities of molecular diagnostics in cancer care, Ms Welch outlined the relevance of genomic testing in cancer care, current methodologies, interpretation of results, and clinical applications, and the transformative role of molecular profiling in precision medicine.
Cancer Genomics: The Foundation
Ms Welch noted that cancer is fundamentally a disease of the genome, explaining how mutations in DNA—the instruction manual of cellular growth and function—can drive tumorigenesis. DNA encodes proteins via transcription and translation of proteins, which, in turn orchestrate all essential cellular functions. As such, mutations in the DNA can fundamentally disrupt this process and impair the regulation of critical functions such as cell growth.
Some of the key types of cancer-related mutations include:
Oncogenes ("Gas Pedal"): In their normal state, these genes promote controlled cell division. Mutations in some genes such as RAS and EGFR can cause them to become permanently activated, thereby resulting in unregulated cell proliferation.
Tumor Suppressor Genes ("Brakes"): Genes such as TP53 and BRCA, on the other hand, function to halt cell division and prevent overgrowth. As such, mutations can cause them to be inactivated thereby eliminating critical growth regulatory checkpoints.
DNA mutations can either be:
Germline Mutations: Meaning inherited, and present in all cells of the individual, predisposing them to certain cancers (e.g., BRCA mutations in breast cancer), or
Somatic Mutations: Meaning acquired mutations which are localized to tumor cells, such as PIK3CAmutations in breast cancer.
By disrupting the delicate balance of cell growth and/or growth inhibition, mutations in oncogenes and tumor suppressor genes can contribute to unchecked proliferation and tumor progression.
What is Molecular Profiling?
Molecular profiling, or biomarker testing, identifies alterations in genes, proteins, and other molecules that can impact biological behavior of the tumor. The National Cancer Institute defines molecular profiling as a laboratory method that uses tissue or liquid samples to detect molecular markers indicative of cancer, with applications for prognosis, treatment planning, and monitoring. Tumor profiling is a related process focused on specific genetic changes in tumor DNA.
Molecular profiling has two primary clinical roles:
Initial Treatment Planning: This type of profiling identifies actionable biomarkers to guide therapeutic decisions, such as whether the patient is a candidate for targeted therapies or immunotherapies.
Management of Progressive Disease: This type of profiling can help determine potential tumors resistance mechanisms when patients stop responding to initial therapies, and can help define a more appropriate second-line treatment.
Ms Welch highlighted the increasing availability of biomarker-associated therapies across different cancer types, which has helped to individualize therapy, beyond more traditional treatment paradigms (e.g., wherein all lung cancer patients were treated the same way).
Cancer Biomarkers: Predictive and Prognostic
Ms Welch also distinguished between the two types of biomarkers:
Predictive Biomarkers: These are biomarkers that indicate how a patient will respond to therapy (e.g., PDL1 expression for immunotherapy efficacy).
Prognostic Biomarkers: These are biomarkers that provide insight into overall disease trajectory and outcomes (e.g., circulating tumor DNA correlating with poor prognosis).
The integration of predictive biomarkers has revolutionized precision medicine, such that treatments can now be tailored based upon the tumor's specific molecular signature, rather than its anatomical origin. For example, patients with HER2-positive breast cancer can be expected to benefit from HER2-targeted therapies, while those with positive PDL1 expression respond to immunotherapy with immune checkpoint inhibitors.
Tumor-Agnostic Approvals: A New Frontier
Ms Welch emphasized tumor-agnostic drug approvals as a significant milestone in oncology. These are drugs target a specific biomarker or molecular alteration irrespective of cancer type, and can offer additional treatment options for patients with rare mutations. Some examples of tumor agnostic targeted therapy approvals include:
NTRK Fusion Inhibitors: Larotrectinib and entrectinib.
RET Inhibitors: Selpercatinib.
BRAF Inhibitors: Dabrafenib combined with trametinib.
Some other more recent examples include drugs like trastuzumab deruxtecan (T-DXd) for tumors with HER2 overexpression. Tumor-agnostic approvals demonstrate how clinical trial designs have evolved so as to enroll patients based on their targetable biomarkers rather than just on tumor type, which helps expedite drug development and approvals.
Techniques in Molecular Profiling
Ms Welch provided an overview of molecular profiling modalities, explaining their overall applications and limitations.
1. Tissue Biopsy
Advantages: Tissue biopsies can enable more comprehensive testing such as histopathological analysis, and assessment of protein biomarkers (e.g., PDL1, Ki67).
Limitations: Biopsies are more invasive, time-consuming, and can be potentially impacted by tumor heterogeneity. For example, tissue from one tumor site may not reflect molecular changes in distant metastatic sites.
2. Liquid Biopsy
Advantages: This kind of biopsy evaluates circulating tumor DNA (ctDNA) from all disease sites, offering a dynamic and minimally invasive ‘snapshot’ of the tumor's molecular landscape. Results are typically faster, with turnaround times generally under one week.
Limitations: False negatives can occur if the tumor does not shed sufficient quantities of ctDNA for detection.
Ms Welch underscored the importance of selecting the appropriate modality based on the specific clinical scenario (e.g., accessibility of the tumor for a biopsy), and emphasized their complementary roles in the treatment plan.
Common Molecular Profiling Techniques
Some of the key techniques for molecular profiling include:
Immunohistochemistry (IHC): Measures protein expression in tissues (e.g., HER2 overexpression, PDL1 expression).
Fluorescence In Situ Hybridization (FISH): Detects chromosomal abnormalities and gene amplifications (e.g., ALK fusions).
Polymerase Chain Reaction (PCR): Amplifies specific DNA sequences to detect specific mutations (e.g., EGFR mutations).
Next-Generation Sequencing (NGS): Currently the most comprehensive method for molecular profiling, capable of analyzing multiple genes in a single test to identify mutations, fusions, and other alterations.
Ms Welch explained that while IHC and PCR remain important for single biomarkers, NGS has emerged as the preferred approach, as it enables a much broader genomic profile for the tumor.
How to Interpret Molecular Profiling Results
Ms Welch outlined a stepwise approach in order to effectively interpret molecular profiling reports:
Step 1: Sample Quality
Adequate sample quantity and tumor cell content are critical to avoid false negatives. Reports indicating "Quantity Not Sufficient (QNS)" or "Test Failure" often reflect sample issues, rather than the absence of mutations.
Tumor cellularity below 20% poses challenges for comprehensive profiling.
Step 2: Testing Methodology
Clinicians must identify whether the test involved single-gene methods (e.g., IHC, FISH) or broader NGS panels.
Ms Welch emphasized the importance of understanding panel design, as broader panels require higher DNA input and may have variable sensitivity for certain mutations.
Step 3: Results Annotation
Actionable mutations with clinical significance (for example, the patient is a candidate for a targeted treatment) should be prominently displayed, while variants of unknown significance (VUS) should be annotated separately so as to avoid confusion.
Reports often include therapeutic evidence levels, such as ONCO KB or ESCAT classifications, to prioritize actionable findings.
Step 4: Clinical Decision-Making
Molecular tumor boards are increasingly utilized to interpret complex reports. These multidisciplinary discussions typically include oncologists, pathologists, and geneticists, to foster collaborative decision-making.
Applications of Molecular Profiling
Ms Welch described several clinical scenarios where molecular profiling can be transformative:
Early Diagnosis and Therapy Selection: Identifying biomarkers like EGFR mutations or HER2 overexpression can enable targeted treatments with improved outcomes and lower toxicities.
Monitoring Resistance Mechanisms: Molecular profiling at disease progression can help to identify resistance mutations, and guide second-line therapy selection.
Minimal Residual Disease (MRD) Detection: Liquid biopsies and ctDNA monitoring can help detect MRD, enabling earlier intervention, and/or helping to monitor treatment efficacy.
Challenges and Considerations
Ms Welch acknowledged some of the current challenges in molecular profiling, including:
Tumor Heterogeneity: Spatial and temporal variations in mutations can complicate interpretation of results.
False Negatives: Particularly in liquid biopsies, insufficient ctDNA shedding can result in undetected mutations.
Annotation Variability: A lack of standardization in molecular testing report formats and therapeutic evidence levels can complicate interpretation of results.
Summary
Molecular profiling is being increasingly recognized as a cornerstone of modern oncology. By providing insights into tumor biology and identifying actionable targets, profiling enables precision medicine approaches that can in many cases improve patient outcomes with less toxicity than conventional treatments. As a final thought, Ms Welch emphasized that clinicians should review molecular profiling reports meticulously, engage with molecular tumor boards, and remain vigilant about the limitations of testing results.
Speaker Disclosure Information: Lauren Welch is an employee and stockholder of Guardant Health, but has no relevant disclosures for this unbranded CME presentation.
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You can see the full presentation on molecular profile interpretation 101 by Lauren Welch, MSN, NP-C, AOCNP here.