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Molecular analysis of circulating tumor DNA from breast cancer patients before and after surgery and following adjuvant chemotherapy.

ABSTRACT: The primary aim of the present study is to provide a complex molecular profile of tumors using liquid biopsy and to monitor profile changes over time in association with surgery and administered adjuvant therapy. Our secondary aim was to compare the liquid biopsy profile with the tissue biopsy and assess concordance. A total of 27 samples of circulating tumor DNA (ctDNA) collected from 9 breast cancer patients at three different time points and their matched formalin-fixed and paraffin-embedded (FFPE) samples of primary tumor were analyzed with targeted next-generation sequencing. Somatic pathogenic variants were detected before surgery in samples from 5 patients (55.6%). The most frequently mutated genes were phosphatase and tensin homolog (4/9, 44.4%) and tumor protein 53 (4/9, 44.4%). Serial sampling of ctDNA enabled the detection of more variants compared with single-time tissue primary tumor biopsy. There were 17 ctDNA variants across all samples, but only 6 FFPE variants across all patients. In addition, the concordance between ctDNA and FFPE DNA was determined in only 1 patient, and this was connected with higher variant allele frequency. The findings of the present study suggest that liquid biopsy and tissue biopsy may be used as complementary analyses to adequately capture all tumor variants.

SUBMITTER: Zelinova K

PROVIDER: S-EPMC7403808 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Molecular analysis of circulating tumor DNA from breast cancer patients before and after surgery and following adjuvant chemotherapy.

Zelinova Katarina K Jagelkova Marianna M Laucekova Zuzana Z Bobrovska Martina M Dankova Zuzana Z Grendar Marian M Dokus Karol K

Molecular and clinical oncology 20200720 4

The primary aim of the present study is to provide a complex molecular profile of tumors using liquid biopsy and to monitor profile changes over time in association with surgery and administered adjuvant therapy. Our secondary aim was to compare the liquid biopsy profile with the tissue biopsy and assess concordance. A total of 27 samples of circulating tumor DNA (ctDNA) collected from 9 breast cancer patients at three different time points and their matched formalin-fixed and paraffin-embedded ...[more]

PMID: 32765873

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Project description:BACKGROUND:In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS:Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS:Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N?=?42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4?months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P?=?0.002)] and OS (HR 4.1; P?=?0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P?<?0.0001) and OS (HR 4.0; P?=?0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION:ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

Project description:Postoperative monitoring for patients with colorectal cancer (CRC) requires sensitive biomarkers that are associated with medical response and adjuvant therapy following surgery. Conventional tumor biomarkers [including carcinoembryonic antigen (CEA), CA19-9 and CA125] are widely used, but none of the markers provide high sensitivity or specificity. Previous studies indicated that circulating tumor DNA (ctDNA) is useful for postoperative monitoring of patients with cancer. However, the majority of previous studies involved patients with lung cancer, and therefore further studies are required which investigate patients with CRC. The present study enrolled 11 patients with CRC. All patients underwent surgery, and a number of patients were treated with postoperative chemotherapy. Tumor tissues and serial blood samples were collected from each patient, and somatic mutations of each sample were obtained using next-generation sequencing. The mutation landscape and dynamic changes in mutations for each patient were analyzed, and these results were compared with the changes of CEA levels. A number of driver genes were selected, including tumor protein P53 (TP53), APC and KRAS, to monitor the postoperative outcome of the 11 patients with CRC. Driver mutations were detected in preoperative plasma in 7 patients, with markedly decreased mutation rates detected in postoperative plasma compared with preoperative plasma. Driver mutations were not detected in 4 patients in the preoperative or postoperative plasma. In 1 patient with metastatic rectal cancer, the rate of TP53 mutation increased from 8.95 (preoperative) to 71.4% (postoperative), and a new phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α mutation emerged. This patient succumbed to mortality six months following surgery, however there were no marked changes in CEA levels during periodic detection of CEA levels. In summary, ctDNA has a high sensitivity and specificity in prediction of the prognosis of patients with CRC.

Project description:BackgroundCirculating tumor DNA (ctDNA) has emerged as a biomarker that can define the risk of recurrence after curative-intent surgery for patients with colorectal cancer (CRC). However, beyond the predictive power of postoperative ctDNA detection, the efficacy and potential limitations of ctDNA detection urgently need to be fully elucidated in a large cohort of CRC.ObjectivesTo define potentially cured CRC patients through ctDNA monitoring following surgery.DesignA prospective, multicenter, observational study.MethodsWe enrolled 309 patients with stages I-IV CRC who underwent definitive surgery. Tumor tissues were sequenced by a custom-designed next-generation sequencing panel to identify somatic mutations. Plasma was analyzed using a ctDNA-based molecular residual disease (MRD) assay which integrated tumor-genotype-informed and tumor-genotype-naïve ctDNA analysis. The turnaround time of the assay was 10-14 days.ResultsPostoperative ctDNA was detected in 5.4%, 13.8%, 15%, and 30% of patients with stage I, II, III, and IV disease, respectively, and in 17.5% of all longitudinal samples. Patients with positive postsurgery MRD had a higher recurrence rate than those with negative postsurgery MRD [hazard ratio (HR), 13.17; p < 0.0001], producing a sensitivity of 64.6%, a specificity of 94.8%, a positive predictive value (PPV) of 75.6%, and a negative predictive value (NPV) of 91.5%. Furthermore, patients with positive longitudinal MRD also had a significantly higher recurrence rate (HR, 14.44; p < 0.0001), with increased sensitivity (75.0%), specificity (94.9%), PPV (79.6%), and NPV (93.4%). Subgroup analyses revealed that adjuvant therapy did not confer superior survival for patients with undetectable or detectable MRD. In addition, MRD detection was less effective in identifying lung-only and peritoneal metastases.ConclusionPostoperative ctDNA status is a strong predictor of recurrence independent of stage and microsatellite instability status. Longitudinal undetectable MRD could be used to define the potentially cured population in CRC patients undergoing curative-intent surgery.

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Molecular analysis of circulating tumor DNA from breast cancer patients before and after surgery and following adjuvant chemotherapy.

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Molecular analysis of circulating tumor DNA from breast cancer patients before and after surgery and following adjuvant chemotherapy.

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