Genomic analysis of plasma circulating tumor DNA in patients with heavily pretreated HER2 + metastatic breast cancer

Abstract

We explored accumulated genomic alterations in patients with heavily treated HER2 + metastatic breast cancer enrolled in the KCSG BR18-14/KM10B trial. Targeted sequencing was performed with circulating tumor DNAs (ctDNAs) collected before the treatment of 92 patients. ctDNAs collected at the time of disease progression from seven patients who had a durable response for > 12 months were also analyzed. Sixty-five genes were identified as pathogenic alterations in 99 samples. The most frequently altered genes were TP53 (n = 48), PIKCA (n = 21) and ERBB3 (n = 19). TP53 and PIK3CA mutations were significantly related with shorter progression free survival (PFS), and patients with a higher ctDNA fraction showed a worse PFS. The frequency of homologous recombination deficiency (HRD)-related gene mutations was higher than that in matched tumor tissues, and these mutations tended to be associated with shorter PFS. New pathogenic variants were found at the end of treatment in all seven patients, including BRCA2, VHL, RAD50, RB1, BRIP1, ATM, FANCA, and PIK3CA mutations. In conclusion, TP53 and PIK3CA mutations, as well as a higher ctDNA fraction, were associated with worse PFS with trastuzumab and cytotoxic chemotherapy. The enrichment of HRD-related gene mutations and newly detected variants in ctDNA may be related to resistance to treatment.

Elucidation of clinical implications Arising from circadian rhythm and insights into the tumor immune landscape in breast cancer

“…Multi-omics mutation analysis based on the CRRS model can identify specific genomic changes related to the circadian rhythm of BC, and could lead to more precise and individualized therapeutic strategies for patients with BC. Previous research has shown that somatic mutations are associated with poor outcomes in BC [ [53] , [54] , [55] , [56] ]. We investigated the differences in the distribution of somatic mutations between populations at different risk levels.…”

Tailoring Potential Natural Compounds for the Treatment of Luminal Breast Cancer

“…In fact, ERα expression may change during disease progression, and conversion of ERα-positive to ERα-negative tumors may occur in approximately 10-20% of patients [164]. Additionally, mutations in ESR1 are described in 20-40% of metastatic cases previously treated with hormone therapy [165,166]. Most of these mutations affect the estrogen-binding domain on the receptor and promote constitutive ERα activity [167].…”