Impact of sensitive circulating tumor DNA monitoring on CT scan intervals during postoperative colorectal cancer surveillance
Tomoko SasakiTakeshi IwayaMizunori YaegashiMasashi IdogawaHayato HirakiMasakazu AbeYuka KoizumiNoriyuki SasakiAkiko Yashima‐AboRyosuke FujisawaFumitaka EndoShoichiro TangeTomomi HiranoKoki OtsukaAkira SasakiMari MasudaMasashi FujitaHidewaki NakagawaFumiaki TakahashiYasushi SasakiTakashi TokinoSatoshi Nishizuka
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Objective This study investigated whether digital PCR (dPCR)-based circulating tumor DNA (ctDNA) monitoringcan allow longer intervals between computed tomography (CT) scans during postoperative surveillance of colorectal cancer (CRC). Design The longitudinal dynamics of ctDNA for 52 patients with CRC as measured by dPCR using probes targeting 87 individual tumor-specific mutations (1-5 per patient) were compared with results from conventional (i.e., clinical) surveillance using serum tumor markers and CT. A total of 382 CT procedures were carried out for the patient cohort (3.3/year per patient) and the median lead time from ctDNA relapse to clinical relapse was 182 days (range 0-376 days). If the CT interval was annual, potential delays in detection of clinical relapse would have occurred for 7 of the 10 patients who experienced clinical relapse (9 of 13 events), with a median delay of 164 days (range, 0-267 days). If annual CT surveillance was performed together with ctDNA monitoring, 218 (57.1%) CTs would not have been needed to detect the first clinical relapse. Nonetheless, ctDNA monitoring would still have provided a lead time of 339 days for detection of clinical relapse (range, 42-533 days). Conclusion Our findings suggest that the ctDNA monitoring as part of post-operative surveillance and clinical relapse detection for patients with CRC could allow the CT interval to be lengthened.Keywords:
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Abstract Currently, oncologists use prior clinical trials data to recommend therapies based upon features of the tumor and clinical stage of the patient. A limitation with this approach is that these data are averaged from large groups of patients that are then applied to each individual. This creates uncertainty as there is currently no reliable method to identify whether an individual patient truly is at risk for an unfavorable outcome and would benefit from a specific intervention. Recently, we and others have demonstrated the feasibility of detecting circulating plasma tumor DNA in metastatic breast cancer patients using digital PCR. We have now extended these studies to include early stage breast cancer patients using the second generation platform of droplet digital PCR (ddPCR). In this study the feasibility and accuracy of circulating plasma tumor DNA (ptDNA) detection was prospectively assessed by screening for the presence of tumor PIK3CA mutations in patients' plasma prior to and after breast surgery using ddPCR. We observed in early stage breast cancer patients that ddPCR could detect PIK3CA mutations preoperatively with 93.3% sensitivity (14 of 15 mutations detected) and 100% specificity (no false positives in 30 tumors). Moreover, 5 of 10 patients with PIK3CA mutation positive tumors continued to have mutant PIK3CA detected in their postoperative blood sample despite having no clinical evidence of disease. This work demonstrates that droplet digital PCR (ddPCR) can be used to accurately detect cancer DNA mutations in the blood of early stage breast cancer patients including those with minimal, clinically undetectable disease. Our results suggest that ddPCR provides an accurate and relatively non-invasive method for measuring residual disease and could be developed as a biomarker to identify early stage breast cancer patients at higher risk for recurrence to help make informed decisions regarding adjuvant therapies. Ongoing studies assessing mutational profiles from ptDNA from metastatic patients as well as patients undergoing neoadjuvant therapies will be discussed. Citation Format: Ben Ho Park. Circulating plasma tumor DNA as biomarkers for breast cancer therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES8-2.
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Minimal Residual Disease
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Circulating tumor DNA (ctDNA) is a component of the "naked" DNA found in blood. It can be isolated from plasma and represents combined genetic material from the primary tumor and metastases. Quantitative and qualitative information about a cancer, including mutations, can be derived using digital polymerase chain reaction and other technologies. This "liquid biopsy" is quicker and more easily repeated than tissue biopsy, yields real-time information about the cancer, and may suggest therapeutic options. All stages of cancer therapy have the ability to benefit from ctDNA, starting with screening for cancer before it is clinically apparent. During treatment of metastatic disease, it is useful to predict response and monitor disease progression. Currently, ctDNA is used in the clinic to select patients who may benefit from epidermal growth factor receptor-targeted therapy in non-small cell lung cancer. In the future, ctDNA technology promises useful applications in every part of clinical oncology care.
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Circulating tumor DNA(ctDNA) is the DNA fragment released into blood by tumor cells.Wheather it presents or not and its plasma concentration are closely related to the prognosis of patients. The common detection methods of ctDNA include digital polymerase chain reaction,second-generation sequencing,methylation detection technology and so on. Detecting specific point mutations or methylation of ctDNA can not only assist in the diagnosis of pancreatic cancer,but also be expected to identify pancreatic cancer at an early stage. Detecting ctDNA after operation can help predicting tumor recurrence and metastasis effectively,so that patients with high recurrence and metastasis risks can be intervened in advance. Accordingly,this article intends to review detection technology of ctDNA and its clinical applications in the early diagnosis of pancreatic cancer,the prediction of tumor recurrence and metastasis after surgery,and the evaluation of patient prognosis.循环肿瘤DNA（ctDNA）是肿瘤细胞释放入血的DNA片段，其存在与否、血浆浓度的高低与患者预后息息相关。常见的检测方法有数字聚合酶链式反应技术、二代测序、甲基化检测等。针对ctDNA的特异性点突变或甲基化进行检测，不但能辅助诊断胰腺癌，还有望在早期阶段识别胰腺癌。针对术后ctDNA的检测能有效预测肿瘤复发转移，对患者进行风险分层，从而得以对高复发转移风险患者提前进行干预。据此，本文对ctDNA检测技术及ctDNA在胰腺癌早期诊断、手术后复发转移的预测和患者预后评估等方面的临床应用研究进行综述。.
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The use of liquid biopsy is of potential high importance for children with high grade (HGG) and diffuse midline gliomas (DMG), particularly where surgical procedures are limited, and invasive biopsy sampling not without risk. To date, however, the evidence that detection of cell-free DNA (cfDNA) or circulating tumor DNA (ctDNA) could provide useful information for these patients has been limited, or contradictory.
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PURPOSE Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a potential minimally invasive biomarker and monitoring tool in other cancers; however, it remains underexplored in RMS. We aimed to determine the feasibility of identifying and quantifying ctDNA in plasma as a marker of disease burden and/or treatment response using blood samples from RMS mouse models and patients. METHODS We established mouse models of RMS and applied quantitative polymerase chain reaction (PCR) and droplet digital PCR (ddPCR) to detect ctDNA within the mouse plasma. Potential driver mutations, copy-number alterations, and DNA breakpoints associated with PAX3/ 7-FOXO1 gene fusions were identified in the RMS samples collected at diagnosis. Patient-matched plasma samples collected from 28 patients with RMS before, during, and after treatment were analyzed for the presence of ctDNA via ddPCR, panel sequencing, and/or whole-exome sequencing. RESULTS Human tumor-derived DNA was detectable in plasma samples from mouse models of RMS and correlated with tumor burden. In patients, ctDNA was detected in 14/18 pretreatment plasma samples with ddPCR and 7/7 cases assessed by sequencing. Levels of ctDNA at diagnosis were significantly higher in patients with unfavorable tumor sites, positive nodal status, and metastasis. In patients with serial plasma samples (n = 18), fluctuations in ctDNA levels corresponded to treatment response. CONCLUSION Comprehensive ctDNA analysis combining high sensitivity and throughput can identify key molecular drivers in RMS models and patients, suggesting potential as a minimally invasive biomarker. Preclinical assessment of treatments using mouse models and further patient testing through prospective clinical trials are now warranted.
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Abstract Background: A common challenge in treating patients with metastatic breast cancer (MBC) is ensuring adequate therapeutic efficacy, maintenance of quality of life, and avoidance of drug toxicity by preventing exposure to ineffective treatment. Critical to balancing these goals is the ability to quickly identify progression in order to minimize exposure to ineffective therapies. Imaging is the current standard-of-care for disease response evaluation, but high cost, relative low sensitivity, and tumor flare phenomenon remain significant issues. Circulating tumor DNA (ctDNA) testing based on next generation sequencing (NGS) is emerging as an alternative to imaging-based response assessment, but remains an expensive proposition. Here we evaluate a hybrid monitoring strategy using an initial baseline NGS-based ctDNA analysis to identify mutant alleles, followed by response monitoring with a low-cost, personalized digital droplet PCR (ddPCR) assay. Methods: Blood for ddPCR ctDNA analysis was collected at the same timepoint as a sample for commercial ctDNA analysis by NGS. PCR primer and probe sets were designed against clinically relevant mutations identified from each patient’s commercial ctDNA NGS report. ddPCR was then performed. Variant allele fractions (VAFs) detected by ddPCR were compared to allelic fractions reported by commercial NGS using Bland-Altman analysis and significance was determined by paired t-test. To demonstrate the potential for longitudinal ddPCR-based ctDNA monitoring, serial samples from the same patient were analyzed. Results: In our pilot validation set, 10 paired patient samples were analyzed by NGS and ddPCR. NGS-reported VAFs ranged from 0.30% to 16.20%. High comparative performance was observed between NGS and ddPCR platforms over expected mutant fractional abundance ranges. There was no significant quantitative difference between the two approaches (p=0.45). Longitudinal monitoring of ctDNA by ddPCR was performed on a metastatic hormone-positive breast cancer patient and revealed a significant rise in the clinically-relevant PIK3CA H1047L mutation that preceded imaging-based documentation of progression by 3 months. A final timepoint was taken several months before the patient’s death with a further significant increase in ctDNA burden. Conclusions: Here we demonstrate that highly-sensitive ddPCR-based ctDNA assays provide comparable results to next generation sequencing, but at considerably lower cost. These results indicate that bespoke tracking of select alleles by ddPCR offers an inexpensive and rapid approach to serial ctDNA monitoring in metastatic breast cancer patients. A larger prospective study has been designed and is underway. Citation Format: Nicole Higashiyama, LaTerrica Williams, Bryant McCue, Alphi Kuriakose, Tiffaney Tran, Stephanie Gonzalez, Mayra Licerio, Carol Chenault, Heidi Dowst, Susan Hilsenbeck, Matthew Ellis, Bora Lim, George Miles. Longitudinal circulating tumor DNA (ctDNA) monitoring by digital droplet PCR (ddPCR) in metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-13.
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Introduction: Early detection of cancers through the analysis of ctDNA could have a significant impact on morbidity and mortality of cancer patients. However, using ctDNA for early cancer diagnosis is challenging partly due to the low amount of tumor DNA released in the circulation and its dilution within DNA originating from non-tumor cells. Development of new technologies such as droplet-based digital PCR (ddPCR) or optimized next generation sequencing (NGS) has greatly improved the sensitivity, specificity and precision for the detection of rare sequences.Areas covered: This paper will focus on the potential application of ddPCR and optimized NGS to detect ctDNA for detection of cancer recurrence and minimal residual disease as well as early diagnosis of cancer patients.Expert commentary: Compared to tumor tissue biopsies, blood-based ctDNA analyses are minimally invasive and accessible for regular follow-up of cancer patients. They are also described as a better picture of patients' pathology allowing to highlight both tumor heterogeneity and multiple tumor sites. After a brief introduction on the application of the follow-up of ctDNA using genetic or epigenetic biomarkers for prognosis and surveillance of cancer patients, potential perspectives of using ctDNA for early diagnosis of cancers will be presented.
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