Circulating Tumor DNA Profiling From Breast Cancer Screening Through to Metastatic Disease.

We investigated the utility of the Oncomine Breast cfDNA Assay for detecting circulating tumor DNA (ctDNA) in women from a breast screening population, including healthy women with no abnormality detected by mammogram, and women on follow-up through to advanced breast cancer. Blood samples were taken from 373 women (127 healthy controls recruited through breast screening, 28 ductal carcinoma in situ, 60 primary breast cancers, 47 primary breast cancer on follow-up, and 111 metastatic breast cancers [MBC]) to recover plasma and germline DNA for analysis with the Oncomine Breast cfDNA Assay on the Ion S5 platform. One hundred sixteen of 373 plasma samples had one or more somatic variants detected across eight of the 10 genes and were called ctDNA-positive; MBC had the highest proportion of ctDNA-positive samples (61; 55%) and healthy controls the lowest (20; 15.7%). ESR1, TP53, and PIK3CA mutations account for 93% of all variants detected and predict poor overall survival in MBC (hazard ratio = 3.461; 95% CI, 1.866 to 6.42; P = .001). Patients with MBC had higher plasma cell-free DNA levels, higher variant allele frequencies, and more polyclonal variants, notably in ESR1 than in all other groups. Only 15 individuals had evidence of potential clonal hematopoiesis of indeterminate potential mutations. We were able detect ctDNA across the breast cancer spectrum, notably in MBC where variants in ESR1, TP53, and PIK3CA predicted poor overall survival. The assay could be used to monitor emergence of resistance mutations such as in ESR1 that herald resistance to aromatase inhibitors to tailor adjuvant therapies. However, we suggest caution is needed when interpreting results from a single plasma sample as variants were also detected in a small proportion of HCs.

Page K ，Martinson LJ ，Fernandez-Garcia D ，Hills A ，Gleason KLT ，Gray MC ，Rushton AJ ，Nteliopoulos G ，Hastings RK ，Goddard K ，Ions C ，Parmar V ，Primrose L ，Openshaw MR ，Guttery DS ，Palmieri C ，Ali S ，Stebbing J ，Coombes RC ，Shaw JA ... -  《JCO Precision Oncology》

Clinical significance of gene mutation in ctDNA analysis for hormone receptor-positive metastatic breast cancer.

Shibayama T ，Low SK ，Ono M ，Kobayashi T ，Kobayashi K ，Fukada I ，Ito Y ，Ueno T ，Ohno S ，Nakamura Y ，Takahashi S ... -  《-》

Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer.

Clatot F ，Perdrix A ，Beaussire L ，Lequesne J ，Lévy C ，Emile G ，Bubenheim M ，Lacaille S ，Calbrix C ，Augusto L ，Guillemet C ，Alexandru C ，Fontanilles M ，Sefrioui D ，Burel L ，Guénot S ，Richard D ，Sarafan-Vasseur N ，Di Fiore F ... -  《-》

ESR1 and PIK3CA mutational status in serum and plasma from metastatic breast cancer patients: A comparative study.

Takeshita T ，Yamamoto Y ，Yamamoto-Ibusuki M ，Tomiguchi M ，Sueta A ，Iwase H ... -  《-》

Identifying Circulating Tumor DNA Mutation Profiles in Metastatic Breast Cancer Patients with Multiline Resistance.

In cancer patients, tumor gene mutations contribute to drug resistance and treatment failure. In patients with metastatic breast cancer (MBC), these mutations increase after multiline treatment, thereby decreasing treatment efficiency. The aim of this study was to evaluate gene mutation patterns in MBC patients to predict drug resistance and disease progression. A total of 68 MBC patients who had received multiline treatment were recruited. Circulating tumor DNA (ctDNA) mutations were evaluated and compared among hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) subgroups. The baseline gene mutation pattern (at the time of recruitment) varied among HR/HER2 subtypes. BRCA1 and MED12 were frequently mutated in triple negative breast cancer (TNBC) patients, PIK3CA and FAT1 mutations were frequent in HR+ patients, and PIK3CA and ERBB2 mutations were frequent in HER2+ patients. Gene mutation patterns also varied in patients who progressed within either 3 months or 3-6 months of chemotherapy treatment. For example, in HR+ patients who progressed within 3 months of treatment, the frequency of TERT mutations significantly increased. Other related mutations included FAT1 and NOTCH4. In HR+ patients who progressed within 3-6 months, PIK3CA, TP53, MLL3, ERBB2, NOTCH2, and ERS1 were the candidate mutations. This suggests that different mechanisms underlie disease progression at different times after treatment initiation. In the COX model, the ctDNA TP53 + PIK3CA gene mutation pattern successfully predicted progression within 6 months. ctDNA gene mutation profiles differed among HR/HER2 subtypes of MBC patients. By identifying mutations associated with treatment resistance, we hope to improve therapy selection for MBC patients who received multiline treatment.

Hu ZY ，Xie N ，Tian C ，Yang X ，Liu L ，Li J ，Xiao H ，Wu H ，Lu J ，Gao J ，Hu X ，Cao M ，Shui Z ，Xiao M ，Tang Y ，He Q ，Chang L ，Xia X ，Yi X ，Liao Q ，Ouyang Q ... -  《EBioMedicine》