Liquid Biopsy Predicts Immunotherapy Response in Breast Cancer and Refines Chemotherapy Decisions in Germ Cell Tumors

Two new studies highlight the expanding role of liquid biopsy in cancer care, demonstrating its potential to predict immunotherapy response in breast cancer and to refine high-dose chemotherapy decisions in relapsed germ cell tumors.

In the first study, led by researchers at the Vanderbilt-Ingram Cancer Center and published April 22 in the journal Science Translational Medicine, repeated blood sampling using liquid biopsy was found to assess and predict the evolving antitumor immune response to therapy in breast cancer. The researchers performed RNA sequencing on 546 peripheral blood samples from 160 patients with high-risk, stages 2 or 3 breast cancers negative for human epidermal growth factor receptor 2 (HER2) during treatment with either chemotherapy alone or in combination with immunotherapy. By sampling the transcriptome — the transcription of genes involved in the clonal expansion and activation of antitumor immune cells called T cells — they found it predicted response to the immunotherapy drug pembrolizumab. The researchers described this minimally invasive and cost-effective alternative to tissue biopsy as "an accessible tool for tailoring treatment strategies in breast cancer." While validation is needed, the new liquid biopsy has the potential to "guide immunotherapy decision-making, tailor treatment regimens, and advance precision oncology, not only in (breast cancer) but potentially in other solid tumors as well," the researchers concluded.

In a separate study published in the Journal of Clinical Oncology, investigators from the Princess Máxima Center for Pediatric Oncology, in collaboration with colleagues in Italy and Slovakia, analyzed circulating tumor DNA (ctDNA) in young adults with relapsed or refractory germ cell tumors. The study evaluated blood samples from 69 patients receiving high-dose chemotherapy and 26 patients receiving standard-dose chemotherapy. Using shallow whole-genome sequencing, the researchers measured tumor fraction (TF) — the proportion of circulating DNA derived from tumor cells — and assessed copy number alterations (CNAs). Tumor fraction exceeded the detection threshold in 75% of patients treated with high-dose chemotherapy. A high tumor fraction was strongly associated with worse outcomes in both the high-dose and standard-dose groups, with patients experiencing significantly shorter progression-free survival and overall survival. This finding positions tumor fraction as a potentially powerful prognostic biomarker. In contrast to miR-371a-3p — which proved highly informative for detecting the presence of disease but not for predicting survival — tumor fraction provided risk stratification relevant to long-term outcomes. The data also suggest that high-dose chemotherapy may be more effective than standard therapy in patients with high tumor fraction, indicating a possible role for ctDNA profiling in therapeutic selection.

Beyond tumor fraction, specific genomic alterations were associated with poor prognosis. Patients with a higher frequency of 3p gain, 9q and 11q gains, and 6q loss showed worse survival outcomes, particularly in the high-dose chemotherapy group. The study further identified associations between histologic subtype and genomic patterns, with tumors having extra-embryonic histology demonstrating distinct CNA profiles linked to inferior survival. The authors concluded that analysis of circulating tumor DNA provides "valuable prognostic information" in germ cell tumors that recur or do not adequately respond to standard chemotherapy. Before clinical implementation, these findings must be validated in larger, prospective cohorts, including adolescents and children with germ cell tumors.