ctDNA-guided precision therapy with trastuzumab deruxtecan plus pyrotinib in HER2-positive breast cancer brain metastases: a case report

Background Brain metastases occur in 30-55% of patients with HER2-positive metastatic breast cancer, presenting significant therapeutic challenges. Circulating tumor DNA (ctDNA) monitoring has emerged as a potentially useful tool for earlier molecular detection of disease activity. Case presentation We report a 35-year-old woman with HER2-positive metastatic breast cancer diagnosed during pregnancy who achieved pathological complete response after standard therapy. Given her young age, de novo stage IV disease, and atypical pregnancy-associated presentation, baseline comprehensive genomic profiling was performed at diagnosis. Serial ctDNA monitoring detected positivity approximately three months prior to radiologic evidence of brain metastases. Genomic profiling revealed newly emergent alterations potentially contributory to evolving disease biology, including MET amplification and HER2 V777L mutation. Treatment with trastuzumab deruxtecan plus pyrotinib, informed by ctDNA dynamics and the molecular profile, was associated with intracranial disease control over 17 months of follow-up. Drug-induced hepatotoxicity was managed through dose modifications and supportive care without treatment interruption. Conclusions This case illustrates the feasibility of incorporating ctDNA monitoring into treatment decisions and provides a hypothesis-generating observation regarding combination therapy in managing HER2-positive brain metastases. The temporal relationship between molecular and radiologic findings observed here suggests potential value for earlier detection of disease activity, although whether such lead time translates into improved clinical outcomes requires prospective validation. The findings support prospective evaluation of this approach, including the ongoing TROPHY trial investigating this therapeutic approach.