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LOH (Loss of Heterozygosity) scores offer a functional assessment of a tumor's DNA repair capability. They are computationally derived to detect a 'scar' of characteristic genomic changes, like copy number alterations, that accumulate when a tumor cannot repair DNA double-strand breaks, going beyond single-gene mutation analysis.
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When a colorectal tumor loses HER2 protein expression (IHC 0) but retains HER2 gene amplification via NGS, the decision to continue HER2-targeted therapy is guided by the amplification copy number. A low copy number argues against continuing the targeted regimen.
DNA-based NGS can fail to detect clinically actionable fusions in NSCLC due to assay design limitations (low sensitivity). It can also report fusions of unclear significance (low specificity). Integrating RNA-based NGS is critical to reliably identify true driver fusions and clarify ambiguous DNA findings.
An individual tumor can have hundreds of unique mutations, making it impossible to predict treatment response from a single genetic marker. This molecular chaos necessitates functional tests that measure a drug's actual effect on the patient's cells to determine the best therapy.
For post-progression biopsies, which are often small and contain necrotic tissue, institutions may prioritize DNA-based NGS panels. This strategy is based on the rationale that most resistance mechanisms are genetic mutations detectable by DNA sequencing, reserving RNA panels primarily for identifying less common fusion events.
Not all DNA damage repair gene alterations create PARP inhibitor sensitivity. Clinical data from multiple trials (TRITON, PROfound, TALAPRO-2) consistently shows that while BRCA1/2 mutations confer significant benefit, alterations in genes like ATM and CHEK2, which are not core to homologous recombination repair (HRR), do not.
The RSClin tool integrates a patient's Oncotype DX score with their unique clinical-pathologic features, such as tumor size and grade. This provides a more accurate and personalized risk assessment, as the same genomic score can represent significantly different prognoses for patients who have low versus high clinical risk factors.
The success of Next-Generation Sequencing (NGS) is highly dependent on sample quality. Samples older than three years have degraded DNA. Furthermore, low tumor content, common in prostate cancer bone biopsies or plasma samples, makes it difficult to reliably detect the copy number changes required for analyses like LOH scores.
Oncotype DX risk scores are more influenced by estrogen-related genes, while other assays like MammaPrint are driven more by genes related to cell proliferation. This fundamental difference in their underlying biology can inform an oncologist's choice of which genomic test is most appropriate for a given patient's tumor.
ctDNA testing does more than identify targetable mutations. The mutant allele fraction provides a quasi-volumetric measure of tumor burden, and its early clearance on therapy (as seen in MONALEESA-3) is a strong prognostic indicator for survival, adding value beyond standard radiographic assessment.
Hematologic cancers often have a single, common genetic marker per disease, enabling MRD detection with simple PCR for decades. Solid tumors are genetically diverse, lacking a universal marker. This required developing personalized, multi-probe assays like Signatera to track unique mutations, explaining the field's more recent progress.
