Abstract 241P
Background
We explored the accumulated genomic alterations and their clinical significance through circulating tumor DNA (ctDNA) analysis in patients who were enrolled in the KCSG BR18-14/KM10B trial. This trial investigated the efficacies of trastuzumab biosimilar with cytotoxic chemotherapy in HER2+ MBC patients who had failed 2 or more HER2 directed chemotherapies.
Methods
Ten mL of whole blood was collected for ctDNA preparation before the treatment (n=93), and an additional blood sample was collected at the end of treatment from 6 patients. ctDNA was analyzed by the Axen™ Cancer Panel (Macrogen, Seoul, Korea). Targeted sequencing of tumor tissue was performed using CancerSCAN® (Geninus, Seoul, Korea) in 48 patients. Recurrently reported pathogenic variants were screened as both case of pathogenicity in ClinVar and OncoKB database. ctDNA fractions was estimated based on the maximum somatic mutant allele fraction.
Results
After removing germline and blacklist, 36 genes were identified as a pathogenic somatic alteration from 99 liquid biopsy samples. Among them, TP53 mutation (n = 24), PIK3CA mutation (n = 22) and ERBB2 amplification (n = 11) were most frequently detected. The mutation frequency of homologous recombination deficiency (HRD)-related genes (BRCA1/2, ATM, RAD50, PALB2) in ctDNA was found to be increased compared to that of tumor tissue. Mutations in ERBB2 (2.6 vs 4.7 months, p=0.014), PIK3CA (2.8 vs 5.6 months, p=0.007), or TP53 (3.3 vs 5.9 months, p=0.001) were significantly related with shorter progression free survival (PFS). HRD related gene mutations also tended to be associated with shorter PFS. In addition, patients with a higher ctDNA fraction [> 0.0332 (median)] showed worse PFS (n=45, 3.4 vs 5.8 months, p=0.003). New variants were found in ctDNA at the end of treatment in 6 patients, including BRCA2, VHL, RAD50, RB1, BRIP1, ATM, FANCA, and PIK3CA pathogenic mutations.
Conclusions
ERBB2, TP53 and PIK3CA mutations in ctDNA were associated with worse PFS of trastuzumab biosimilar and cytotoxic chemotherapy in our patients. Enrichment of HRD related gene mutations and newly detected variants in ctDNA may be related with the study drug resistance.
Clinical trial identification
NCT03755141.
Editorial acknowledgement
Legal entity responsible for the study
Korean Cancer Study Group (KCSG).
Funding
K-MASTER- This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C2206) KCSG Celltrion for Herzuma.
Disclosure
All authors have declared no conflicts of interest.