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Approximately 30% of breast cancer (BC) patients suffer from disease relapse after definitive treatment. Monitoring BC at baseline and disease progression using comprehensive genomic profiling would facilitate the prediction of prognosis. We retrospectively studied 101 BC patients ultimately experiencing relapse and/or metastases. The baseline and circulating tumor DNA-monitoring cohorts included patients with baseline tumor tissue and serial plasma samples, respectively. Samples were analyzed with targeted next-generation sequencing of 425 cancer-relevant genes. Of 35 patients in the baseline cohort, patients with TP53 mutations (P < 0.01), or CTCF/ GNAS mutations (P < 0.01) displayed inferior disease-free survival, and patients harboring TP53 (P = 0.06) or NOTCH1 (P = 0.06) mutations showed relatively poor overall survival (OS), compared to patients with wild-type counterparts. Of the 59 patients with serial plasma samples, 11 patients who were newly detected with TP53 mutations had worse OS than patients whose TP53 mutational status remained negative (P < 0.01). These results indicate that an inferior prognosis of advanced breast cancer was potentially associated with baseline TP53, CTCF, and NOTCH1 alterations. Newly identified TP53 mutations after relapse and/or metastasis was another potential prognostic biomarker of poor prognosis.

Background The potential of circulating tumour DNA (ctDNA) as a reliable biomarker for relapse/metastasis early detection and prognosis in esophageal squamous cell carcinoma (ESCC) after radiotherapy/chemoradiotherapy (RT/CRT) initiation requires comprehensive investigation. Methods Treatment‐naive locally advanced ESCC patients with available baseline plasma samples were prospectively enrolled from November 2018 to January 2020. RT/CRT was delivered with a simultaneous integrated boost of radiation dose. Serial plasma samples were collected at baseline (T0), week 4 of RT/CRT (T1), 1‐3 (T2) and 3‐6 months post‐RT/CRT (T3). ctDNA was analysed using next‐generation sequencing of 474 cancer‐relevant genes. Results A total of 128 plasma samples from 40 eligible patients were analysed (median age: 64 [range: 40‐78], 88% males, 95% stage III/IV), and the median follow‐up time was 20.6 months (range: 12.2‐33.3). During the post‐RT/CRT surveillance including 36 patients, radiological progression was observed in 16 patients, and 69% (11/16) had detectable post‐RT/CRT ctDNA prior to radiological progression, with a median lead time of 4.4 months compared with radiological imaging. ctDNA positivity at T1 (hazard ratio, HR: 3.60, 95% confidence interval, CI: 1.30‐10.01) or T2 (HR: 5.45, 95% CI: 1.72‐17.26) indicated inferior progression‐free survival (PFS). ctDNA clearance between T0‐T1 (HR: 0.31, 95% CI: 0.08‐1.13) or T0‐T2 (HR: 0.11; 95% CI: 0.02‐0.61) was associated with relatively favourable PFS. Similar results were obtained when focusing on patients without esophagectomy after RT/CRT. Notably, detectable ctDNA at T1 was a potential indicator of high local recurrence risks (HR: 4.43, 95% CI: 1.31‐15.04). Conclusions ctDNA was identified as a robust biomarker for early detection of disease progression and post‐RT/CRT prognosis stratification in ESCC. Detectable ctDNA at week 4 of RT/CRT might indicate higher local recurrence risks, implying the potential clinical utility of ctDNA tests in guiding post‐RT/CRT treatments for locoregional control in ESCC.

BackgroundNeoadjuvant chemotherapy (NAC) has been expanded to hormone receptor (HR) positive breast cancer (BC) patients with operable disease, to increase the likelihood of breast-conserving surgery. Genomic profiling at baseline would reveal NAC response relevant genomic features and signaling pathways, guiding clinical NAC utilization based on patients’ genomic characteristics.MethodsWe prospectively studied stage II/III BC patients who were eligible for breast-conserving surgery. Patients received epirubicin and cyclophosphamide for 4 cycles, followed by another 4-cycle docetaxel, and human epidermal growth factor receptor (HER2) positive patients were additionally treated with herceptin when using docetaxel (EC-T(H)). NAC responses were evaluated as pathologic complete response (pCR) or non-pathologic complete response (non-pCR). Genomic features related to NAC responses were identified by profiling baseline tumor tissues sampled one day before NAC, using whole-exome sequencing. Differentially expressed genes and up-/down-regulated pathways were investigated by performing RNA-sequencing.ResultsA total of 25 stage II/III BC patients were enrolled, including 5 patients ultimately evaluated as pCR and 20 patients evaluated as non-pCR. PIK3CA (48%) and TP53 (40%) mutations were enriched in patients not achieving pCR. Mutated phosphatidylinositol-3-kinase-AKT (PI3K-AKT) pathway and homologous recombinational repair pathway were also more frequently observed in patients evaluated as non-pCR. Significant arm-level amplifications (8q24.23 and 17q12) and deletions (1p32.2, 4p14, 7q11.23, 10q21.3, 11q23.3, etc.) were identified among patients not achieving pCR, while patients achieving pCR displayed no significant copy number alterations. Significantly up-regulated expression of PI3K-AKT pathway genes was also detected among patients failed to achieve pCR, compared to patients achieving pCR.ConclusionCompared to BC patients achieving pCR to NAC, aberrant activation of PI3K-AKT pathway genes were more frequently observed in patients not achieving pCR, consistent with the significant up-regulation of PI3K-AKT pathway gene expression in the non-pCR subgroup. Together, these findings indicate that upregulated PI3K-AKT pathway serves as a potential indicator of lack of response to NAC in stage II/III BC patients, and other effective therapeutic options are urgently needed for those resistant patients.

Molecular mechanisms behind potentially inferior prognosis of old cholangiocarcinoma (CCA) patients are unclear. Prevalence of interventional targets and the difference between young and old CCA patients are valuable for promising precision medicine. A total of 188 CCA patients with baseline tumor tissue samples were subgrouped into the young (≤45 years) and old (>45 years) sub-cohorts. Somatic and germline mutation profiles, differentially enriched genetic alterations, and actionable genetic alterations were compared. An external dataset was used for the validation of molecular features and the comparison of overall survival (OS). Compared to young patients, KRAS alterations were more common in old patients ( P = .04), while FGFR2 fusions were less frequent ( P = .05). TERT promoter mutations were exclusively detected in old patients. The external dataset ( N = 392) revealed no significant difference in OS between young and old patients; however, old patient-enriched KRAS (hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.37–2.80) and TERT alterations (HR: 2.03, 95% CI: 1.22–3.38) were associated with inferior OS. Approximately 38.3% of patients were identified of actionable oncogenic mutations indicative of a potential response to targeted therapy or immunotherapy. Actionable FGFR2 fusions ( P = .01) and BRAF V600E ( P = .04) mutations were more frequent in young females than old patients. The enrichment of KRAS / TERT alterations in CCA patients over 45 years resulted in inferior OS. Approximately one-third of CCA patients were eligible for targeted therapy or immunotherapy given the actionable mutations carried, especially young females.