TP53 mutations in circulating tumor DNA for response monitoring in patients with high grade serous carcinoma of ovary

Background. The analysis of circulating tumor DNA provides wide opportunities for monitoring the results of cancer treatment. Somatic mutations in TP53 gene are present in almost all breast carcinomas developing in hereditary BRCA1 mutation carriers, as well as in the majority of high-grade serous ovarian tumors, which makes it possible to use them for effective monitoring of these diseases. The aim of the study was to analyze the content of tumor-specific TP53 mutations in plasma of patients with high-grade serous ovarian cancer (OC) and BRCA1-associated breast cancer (BC). Materials and methods. At least one plasma sample was obtained from 10 patients with OC and 7 patients with BRCA1-associated BC. The primary intratumoral status of TP53 gene was determined in the archival tumor material by targeted next generation sequencing. Digital droplet PCR was applied for testing of plasma samples for the presence of tumor-specific TP53 mutations, and in one case, BRAF V600E mutation. Results. All 8 plasma samples obtained from OC patients at the time of disease progression, before or during neoadjuvant chemotherapy, were positive for TP53 mutations. In contrast, 8 OC plasma samples obtained during remission, after surgery, or after neoadjuvant chemotherapy did not contain tumor-specific mutations. In breast cancer, circulating tumor DNA was detected in 2 of 4 samples obtained before treatment, and was not detected after the end of therapy or in remission. Conclusion. There is a good correlation between the presence of tumor-specific TP53 mutations in circulating DNA and the disease status in OC patients, therefore TP53 is a promising marker for clinical monitoring of ovarian cancer. In breast cancer, circulating tumor DNA is less abundant, therefore TP53 mutations cannot be reliably detected by digital droplet PCR in the plasma of patients with moderate disease burden.

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Feasibility of monitoring response to the PARP inhibitor rucaparib with targeted deep sequencing of circulating tumor DNA (ctDNA) in women with high-grade serous carcinoma on the ARIEL2 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.5549 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. 5549-5549 ◽

Cited By ~ 4

Author(s):

Anna Piskorz ◽

Kevin K. Lin ◽

James Anthony Morris ◽

Elaina Mann ◽

Amit M. Oza ◽

...

Keyword(s):

Deep Sequencing ◽

Parp Inhibitor ◽

Circulating Tumor Dna ◽

Serous Carcinoma ◽

High Grade ◽

Targeted Deep Sequencing ◽

Tumor Dna ◽

Monitoring Response

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TP53 mutations in circulating tumor DNA in advanced epidermal growth factor receptor-mutant lung adenocarcinoma patients treated with gefitinib

Translational Oncology ◽

10.1016/j.tranon.2021.101163 ◽

2021 ◽

Vol 14 (9) ◽

pp. 101163

Author(s):

Ruofei Yu ◽

Hua Bai ◽

Tangai Li ◽

Bingyu Gao ◽

Jiefei Han ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Lung Adenocarcinoma ◽

Growth Factor Receptor ◽

Circulating Tumor Dna ◽

Tp53 Mutations ◽

Epidermal Growth ◽

Receptor Mutant ◽

Tumor Dna

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Patient-Specific Circulating Tumor DNA Detection during Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

Clinical Chemistry ◽

10.1373/clinchem.2016.262337 ◽

2017 ◽

Vol 63 (3) ◽

pp. 691-699 ◽

Cited By ~ 72

Author(s):

Francesca Riva ◽

Francois-Clement Bidard ◽

Alexandre Houy ◽

Adrien Saliou ◽

Jordan Madic ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Minimal Residual Disease ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Residual Disease ◽

Circulating Tumor Dna ◽

Tp53 Mutations ◽

Tumor Dna ◽

Minimal Residual

Abstract BACKGROUND In nonmetastatic triple-negative breast cancer (TNBC) patients, we investigated whether circulating tumor DNA (ctDNA) detection can reflect the tumor response to neoadjuvant chemotherapy (NCT) and detect minimal residual disease after surgery. METHODS Ten milliliters of plasma were collected at 4 time points: before NCT; after 1 cycle; before surgery; after surgery. Customized droplet digital PCR (ddPCR) assays were used to track tumor protein p53 (TP53) mutations previously characterized in tumor tissue by massively parallel sequencing (MPS). RESULTS Forty-six patients with nonmetastatic TNBC were enrolled. TP53 mutations were identified in 40 of them. Customized ddPCR probes were validated for 38 patients, with excellent correlation with MPS (r = 0.99), specificity (≥2 droplets/assay), and sensitivity (at least 0.1%). At baseline, ctDNA was detected in 27/36 patients (75%). Its detection was associated with mitotic index (P = 0.003), tumor grade (P = 0.003), and stage (P = 0.03). During treatment, we observed a drop of ctDNA levels in all patients but 1. No patient had detectable ctDNA after surgery. The patient with rising ctDNA levels experienced tumor progression during NCT. Pathological complete response (16/38 patients) was not correlated with ctDNA detection at any time point. ctDNA positivity after 1 cycle of NCT was correlated with shorter disease-free (P < 0.001) and overall (P = 0.006) survival. CONCLUSIONS Customized ctDNA detection by ddPCR achieved a 75% detection rate at baseline. During NCT, ctDNA levels decreased quickly and minimal residual disease was not detected after surgery. However, a slow decrease of ctDNA level during NCT was strongly associated with shorter survival.

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BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

Cancer Discovery ◽

10.1158/2159-8290.cd-18-0715 ◽

2018 ◽

Vol 9 (2) ◽

pp. 210-219 ◽

Cited By ~ 69

Author(s):

Kevin K. Lin ◽

Maria I. Harrell ◽

Amit M. Oza ◽

Ana Oaknin ◽

Isabelle Ray-Coquard ◽

...

Keyword(s):

Ovarian Carcinoma ◽

Parp Inhibitor ◽

Acquired Resistance ◽

Circulating Tumor Dna ◽

High Grade ◽

Tumor Dna

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Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance

International Journal of Gynecological Cancer ◽

10.1111/j.1525-1438.2007.01039.x ◽

2008 ◽

Vol 18 (3) ◽

pp. 487-491 ◽

Cited By ~ 88

Author(s):

R. SALANI ◽

R. J. KURMAN ◽

R. GIUNTOLI ◽

G. GARDNER ◽

R. BRISTOW ◽

...

Keyword(s):

Drug Resistance ◽

Mutation Frequency ◽

Clinical Stage ◽

Serous Carcinoma ◽

Low Grade ◽

High Grade ◽

Mutation Status ◽

Tumor Dna ◽

Serous Tumors

The TP53 mutation frequency in ovarian serous carcinomas has been reported to range between 50% and 80%, but a stringent analysis of TP53 using purified epithelial samples has not yet been performed to accurately assess the mutation frequency and to correlate it with the histologic grade. The purpose of this study was to assess the TP53 mutational profile in a relatively large series of high-grade (53 primary and 18 recurrent) and 13 low-grade ovarian serous tumors using DNA isolated from affinity-purified tumor cells and to correlate it with in vitro drug resistance. All samples were affinity purified, and the tumor DNA was analyzed for TP53 mutations in exons 4–9. In vitro drug resistance assays to carboplatin, cisplatin, paclitaxel, and taxotere were performed on the same tumor samples and correlated with the TP53 mutation status. TP53 mutations were detected in 57 (80.3%) of 71 high-grade carcinomas and in one (7.8%) of 13 low-grade serous tumors (an invasive low-grade serous carcinoma). The mutations were predominantly missense mutations (59.6%). TP53 mutations were associated with high-grade serous carcinomas and recurrent disease (P < 0.0001). There was no statistically significant correlation between TP53 mutation status and drug resistance assays or clinical stage (P > 0.25). The frequency of TP53 mutations using purified tumor DNA from ovarian serous carcinomas was 80.3%, which is much higher than previously reported. Furthermore, we found that TP53 is not directly involved in the development of drug resistance in high-grade ovarian serous carcinomas.

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