Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study

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Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study

Conclusions

In this retrospective study, we demonstrated that ctDNA is correlated with volume of disease at the start of treatment in women with HGSOC and that a decrease of ≤60% in TP53MAF after one cycle of chemotherapy was associated with shorter TTP. These results provide evidence that ctDNA has the potential to be a highly specific early molecular response marker in HGSOC and warrants further investigation in larger cohorts receiving uniform treatment.

Author Summary

Why Was This Study Done?

• The standard clinical blood test for measuring response in women receiving chemotherapy for high-grade serous ovarian cancer (HGSOC) is the serum protein cancer antigen 125 (CA-125).
• CA-125 is sensitive but it lacks specificity for detection of ovarian cancer, and in response to chemotherapy, CA-125 level does not change rapidly enough to suggest change in treatment after one or two cycles if chemotherapy treatment is ineffective.
• Better tumour markers are required, and circulating tumour DNA (ctDNA) is a promising candidate.
• ctDNA is cell-free DNA derived from tumour cells that can be detected in the bloodstream; ctDNA can be used as a highly specific marker because it carries mutations unique to the cancer.

What Did the Researchers Do and Find?

• HGSOC is an ideal cancer to test ctDNA as a biomarker because 99% of patients have a mutation in the TP53 gene.
• We designed patient-specific TP53 assays for a retrospective study of 40 patients with HGSOC, and these were used to quantify the amount of ctDNA in 318 plasma samples collected before, during, and after chemotherapy.
• We asked if ctDNA level was correlated with the amount of disease present before chemotherapy treatment measured using 3-D volume reconstruction from CT images taken as part of routine care.
• We also asked if the decrease in TP53 ctDNA after one cycle of chemotherapy treatment could predict which patients would have progression of their cancer within six months.
• ctDNA level, but not CA-125 level, was strongly correlated with the total volume of disease.
• Patients whose ctDNA level exhibited a decrease of >60% after one cycle of chemotherapy had a significantly longer time to progression than those whose ctDNA level decreased by 60% or less.

What Do These Findings Mean?

• TP53 ctDNA has the potential to be a clinically useful blood test to assess prognosis and response to treatment in women with HGSOC.
• The response findings from this retrospective study should be confirmed in larger, prospective studies with uniform treatment. If these findings are confirmed, TP53 ctDNA could be used in HGSOC clinical trials and routine practice to identify earlier whether treatment is effective.