Abstract
In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer’s mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.
Highlights
In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer’s mutational profile when analyzing a single tumor biopsy
Recognizing that mutation cancer cell fraction (CCF) in tumor-derived cell-free DNA (cfDNA) was correlated with the number of tissue lesions harboring a mutation, we evaluate the possibility of using cfDNA to distinguish between truncal and non-truncal alterations in a patient, and identify a CCF threshold to classify truncal and non-truncal driver mutations with a specificity of ~0.80
We selected lesions representative of the overall spread of metastatic disease based on radiological imaging in each patient, in order to capture the full extent of spatial heterogeneity in these cancers (Fig. 1A and Supplementary Table 1)
Summary
In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer’s mutational profile when analyzing a single tumor biopsy. Spatial heterogeneity between metastases can confound the evaluation of genetic and transcriptomic biomarkers in patients presenting with pretreated metastatic disease, as these may be present in only a subset of lesions[1,2,3]. In these cases, analysis of just a single tissue biopsy from a patient may mask spatial heterogeneity in actionable and resistance-associated mutations[4]. Some driver mutations, including those implicated in drug resistance, are found in only subsets of lesions in a patient, and a single tissue sample is inadequate for profiling the entire genetic landscape of metastatic disease. Recognizing that mutation cancer cell fraction (CCF) in tumor-derived cfDNA was correlated with the number of tissue lesions harboring a mutation, we evaluate the possibility of using cfDNA to distinguish between truncal and non-truncal alterations in a patient, and identify a CCF threshold to classify truncal and non-truncal driver mutations with a specificity of ~0.80
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