Tissue rebiopsy identified triple-negative transformation in two patients with metastatic breast cancer whose circulating tumor DNA (ctDNA) results alone could have led to inappropriate treatment selection. The results point to the diagnostic value of combining tissue and liquid biopsy at disease progression.
The case series, published in JCO Precision Oncology, examined two patients whose cancers were initially hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative. Both experienced metastatic progression despite endocrine-based therapy and underwent serial ctDNA testing alongside image-guided tissue biopsy.
In the first case, ctDNA detected ESR1 and PIK3CA mutations associated with endocrine resistance. These findings could have supported further targeted endocrine-based treatment. However, a concurrent tissue biopsy showed that the progressing tumor had become estrogen receptor-negative, progesterone receptor-negative, and HER2-negative – a triple-negative phenotype. The tissue sample also revealed a different genomic profile, suggesting that ctDNA was detecting smaller tumor populations rather than the dominant clone driving progression.
A similar discrepancy occurred in the second case. Serial ctDNA testing detected emerging ESR1, PIK3CA, and FGFR1 alterations, again pointing toward endocrine resistance and potential targeted treatment options. When imaging subsequently demonstrated progression in the liver and bone, however, liver biopsy confirmed high-grade triple-negative disease that could not be identified from ctDNA alone.
The findings illustrate an important limitation of liquid biopsy. Although ctDNA can identify actionable mutations and monitor tumor evolution without an invasive procedure, it provides a pooled signal from DNA shed by different tumor sites. It also generally cannot establish receptor expression, proliferation markers such as Ki-67, or PD-L1 status – all of which can influence treatment selection.
The cases support retaining tissue assessment when metastatic disease progresses unexpectedly or clinical behavior does not match ctDNA findings. Image-guided biopsy can establish the phenotype and molecular characteristics of a specific progressing lesion, complementing the broader information available from blood.
The authors caution that the evidence comes from only two selected cases and cannot establish how frequently clinically important discordance occurs. Nevertheless, they conclude that tissue and ctDNA profiling provide complementary information and that rebiopsy remains important when treatment failure raises the possibility that tumor biology has changed.
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