Implementation of human papillomavirus circulating tumor DNA to identify recurrence during treatment de-escalation.
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ABSTRACT:
SUBMITTER: Haring CT
PROVIDER: S-EPMC8448944 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The limitation of circulating tumor DNA (ctDNA) is its inability to detect cancer cell subpopulations with few or no dying cells. Lung cancer patients subjected to the EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured. The first data set (21 patients) consisting of samples collected in the period from before initiation of EGFR-TKI to at least 2 weeks after initiation: the ctDNA dynamics generally exhibited a rapid decrease and/or a transient increase. In 4 patients, we detected a transient increase of ctDNA bearing activating mutations not identified in biopsy samples. ctDNA with the same genotypical pattern was identified in 7 out of the 39 patients of the second data set intended to include samples until the onset of disease progression. In 6 of the 7 patients, this unique ctDNA appeared in the early period after treatment initiation, and did not reappear even after disease progression or chemotherapy. In another patient, similar ctDNA appeared upon radiation therapy. The identification of ctDNA with a unique genotype indicates the presence of cancer cell subpopulations that normally contain few or no dying cells, but generate dead cells because of the treatment.
| S-EPMC5146655 | biostudies-literature
Project description:The prevalence and dynamics of circulating tumor DNA (ctDNA) in patients with breast cancer recurrence or de novo metastatic cancer were examined in a retrospective analysis of a prospective observational cohort. Twenty-three recurrent/metastatic breast cancer cases (8 locoregional, 15 distant metastasis) were enrolled, and sequential plasma samples were obtained. Anchor mutations were selected from the target sequencing of each patient's primary and/or metastatic tumor. An in-house developed assay (UHS assay) was employed for a tumor-informed ctDNA assay during treatment and follow-up. A median of three (range 1-5) anchor mutations per case were applied for ctDNA detection. ctDNA was detected in 14 (63.6%, 14/22) cases at the time of enrollment and 18 (78.5%, 18/23) cases during follow-up. More anchor mutations and higher tumor burden were significantly related to higher ctDNA positive rates (p-value 0.036, 0.043, respectively). The mean enriched variant allele frequency (eVAF) at each time point was significantly higher for stable or progressive disease responses (ANOVA test p-value < 0.001). Eight patients showed an increase in their ctDNA eVAF prior to clinical progression with a mean lead time of 6.2 months (range 1.5-11 months). ctDNA dynamics measured using personalized assay reflected the clinical course of breast cancer recurrence.
| S-EPMC11364657 | biostudies-literature
Project description:Patients with high-risk non-metastatic breast cancer are recommended for chemotherapy, preferably in the neoadjuvant setting. Beyond advantages such as a better operability and an improved assessment of individual prognosis, the preoperative administration of systemic treatment offers the unique possibility of selecting postoperative therapies according to tumor response. In patients with HER2-positive disease, both the escalation of therapy in the case of high-risk features and the de-escalation in patients with a low tumor load are currently discussed. Patients with small node-negative tumors receive primary surgery and, upon confirmation of pathological T1 N0 status, de-escalated adjuvant therapy with paclitaxel and trastuzumab. For those with a large tumor and/or nodal involvement, neoadjuvant polychemotherapy with a dual antibody blockade is recommended. Patients with invasive residual disease benefit from switching postoperative therapy to the antibody-drug-conjugate trastuzumab emtansine (T-DM1). In this review, we discuss current evidence and controversies regarding post-neoadjuvant treatment strategies in HER2-positive breast cancer.
| S-EPMC9221124 | biostudies-literature
Project description:Circulating tumor DNA (ctDNA) can be a prognostic biomarker for non-muscle-invasive bladder cancer (NMIBC); however, targeted sequencing has not been performed to detect ctDNA in NMIBC. We applied targeted sequencing based on an 861-gene panel to determine mutations in tumor tissue DNA and plasma ctDNA in 82 NMIBC patients receiving transurethral resection (TUR) of bladder followed by immunotherapy. We detected 476 and 165 somatic variants in tumor DNA from 82 NMIBC patients (100%) and ctDNA from 54 patients (65.85%), respectively. Patients with high heterogeneity in tumor DNA had a significantly shorter disease-free survival than those with low heterogeneity. Tumor-derived alterations were detectable in plasma of 43 patients (52.44%). The concordance of somatic variants between tumor DNA and plasma ctDNA were higher in patients with T1 stage (p < 0.0001) and tumor size ≥3 cm (p = 0.0002). Molecular tumor burden index (mTBI) in ctDNA positively correlated with larger tumor size (p = 0.0020). A higher mTBI was an independent predictor of recurrence after TUR of bladder followed by immunotherapy. Analysis of ctDNA based on targeted sequencing is a promising approach to predict disease recurrence for NMIBC patients receiving TUR of bladder followed by immunotherapy.
| S-EPMC8114939 | biostudies-literature
Project description:IntroductionIn most cases of cervical cancers, HPV DNA is integrated into the genome of carcinoma cells. This mutational insertion constitutes a highly specific molecular marker of tumor DNA for every patient. Circulating tumor DNA (ctDNA) is an emerging marker of tumor dynamics which detection requires specific molecular motif. To determine whether the sequence of the cell-viral junction could be used in clinical practice as a specific marker of ctDNA, we analyzed a series of cervical cancer patient serums.Methods and findingsSerum specimens of 16 patients diagnosed with HPV16/18-associated cervical cancer, and for which the viral integration locus had been previously localized, were analyzed. Sequential serum specimens, taken at different times during the course of the disease, were also available for two of these cases. ctDNA was found in 11 out of 13 patients with tumor size greater than 20 mm at diagnosis, and analysis of sequential serum specimens showed that ctDNA concentration in patients serum was related to tumor dynamics.ConclusionsWe report that HPV mutational insertion constitutes a highly specific molecular marker of ctDNA in HPV-associated tumor patients. Using this original approach, ctDNA was detected in most cervical cancer patients over stage I and ctDNA concentration was found to reflect tumor burden. In addition to its potential prognostic and predictive value, HPV mutation insertion is likely to constitute a new molecular surrogate of minimal residual disease and of subclinical relapse in HPV-associated tumor. This is of major importance in the perspective of specific anti-HPV therapy.
| S-EPMC3427328 | biostudies-literature
Project description:Uterine serous carcinoma (USC) and carcinosarcomas (CSs) are rare, highly aggressive variants of endometrial cancer. No reliable tumor biomarkers are currently available to guide response to treatment or detection of early recurrence in USC/CS patients. Circulating tumor DNA (ctDNA) identified using ultrasensitive technology such as droplet digital polymerase chain reaction (ddPCR) may represent a novel platform for the identification of occult disease. We explored the use of personalized ctDNA markers for monitoring USC and CS patients. Tumor and plasma samples from USC/CS patients were collected at the time of surgery and/or during the treatment course for assessment of tumor-specific somatic structural variants (SSVs) by a clinical-grade next-generation sequencing (NGS) platform (i.e., Foundation Medicine) and a droplet digital PCR instrument (Raindance, ddPCR). The level of ctDNA was quantified by droplet digital PCR in plasma samples and correlated to clinical findings, including CA-125 serum and/or computed tomography (CT) scanning results. The genomic-profiling-based assay identified mutated "driver" target genes for ctDNA analysis in all USC/CS patients. In multiple patients, longitudinal ctDNA testing was able to detect the presence of cancer cells before the recurrent tumor was clinically detectable by either CA-125 or CT scanning. Persistent undetectable levels of ctDNA following initial treatment were associated with prolonged progression-free and overall survival. In a USC patient, CA-125 and TP53 mutations but not PIK3CA mutations become undetectable in the plasma at the time of recurrence, suggesting that more than one customized probe should be used for monitoring ctDNA. Longitudinal ctDNA testing using tumor-informed assays may identify the presence of residual tumors, predict responses to treatment, and identify early recurrences in USC/CS patients. Recognition of disease persistence and/or recurrence through ctDNA surveillance may allow earlier treatment of recurrent disease and has the potential to change clinical practice in the management of USC and CS patients. CtDNA validation studies in USC/CS patients prospectively enrolled in treatment trials are warranted.
| S-EPMC10219151 | biostudies-literature
Project description:BackgroundSurgery is the treatment of choice for patients with non-small cell lung cancer (NSCLC) stages I-IIIA. However, more than 20% of these patients develop recurrence and die due to their disease. The release of tumor cells into peripheral blood (CTCs) is one of the main causes of recurrence of cancer. The objectives of this study are to identify the prognostic value of the presence and characterization of CTCs in peripheral blood in patients undergoing radical resection for NSCLC.Patients and methods56 patients who underwent radical surgery for previously untreated NSCLC were enrolled in this prospective study. Peripheral blood samples for CTC analysis were obtained before and one month after surgery. In addition CTCs were phenotypically characterized by epidermal growth factor receptor (EGFR) expression.Results51.8% of the patients evaluated were positive with the presence of CTCs at baseline. A decrease in the detection rate of CTCs was observed in these patients one month after surgery (32.1%) (p = 0.035). The mean number of CTCs was 3.16 per 10 ml (range 0-84) preoperatively and 0.66 (range 0-3) in postoperative determination. EGFR expression was found in 89.7% of the patients at baseline and in 38.9% patients one month after surgery. The presence of CTCs after surgery was significantly associated with early recurrence (p = 0.018) and a shorter disease free survival (DFS) (p = .008). In multivariate analysis CTC presence after surgery (HR = 5.750, 95% CI: 1.50-21.946, p = 0.010) and N status (HR = 0.296, 95% CI: 0.091-0.961, p = 0.043) were independent prognostic factors for DFS.ConclusionCTCs can be detected and characterized in patients undergoing radical resection for non-small cell lung cancer. Their presence might be used to identify patients with increased risk of early recurrence.
| S-EPMC4767413 | biostudies-literature
Project description:This article outlines the ways that transoral robotic surgery and transoral laser microsurgery relate to treatment de-escalation in the treatment of head and neck cancer. Treatment de-escalation has particular importance in context of human papillomavirus-related oropharynx squamous cell carcinoma, which responds well to therapy but leaves many survivors with decades of treatment-related sequelae. We compare these less invasive transoral approaches with previously used open approaches to the oropharynx. We discuss the topic of treatment de-escalation in human papillomavirus-related disease and outline completed and ongoing clinical trials investigating the choice of primary treatment modality and de-escalation of adjuvant therapy.
| S-EPMC8060871 | biostudies-literature
Project description:PurposeReal-time detection and intervention can be used as potential measures to markedly decrease breast cancer mortality. Assessment of circulating tumor DNA (ctDNA) may offer great benefits for the management of breast cancer over time. However, the use of ctDNA to predict the effectiveness of neoadjuvant treatment and recurrence of breast cancer has rarely been studied.MethodsWe prospectively recruited 31 breast cancer patients with 4 subtypes. Three time points were set in this study, including before any therapy (C1), during surgery (T), and six months after surgery (C2). We collected peripheral blood samples from all 31 patients at C1, tumor tissue from all 31 patients at T, and peripheral blood samples from 25 patients at C2. Targeted 727-gene panel sequencing was performed on ctDNA from all blood samples and tissue DNA from all tissue samples. Somatic mutations were detected and analyzed using a reference standard pipeline. Statistical analysis was performed to identify possible associations between ctDNA profiles and clinical outcomes.ResultsIn total, we detected 159, 271, and 70 somatic mutations in 30 C1 samples, 31 T samples, and 12 C2 samples, respectively. We identified specific genes, such as PIK3CA, TP53, and KMT2C, which were highly mutated in the tissue samples. Furthermore, mutated KMT2C observed in ctDNA of the C2 samples may be an indicator of breast cancer recurrence.ConclusionOur study highlights the potential of ctDNA analysis at different timepoints for assessing tumor progression and treatment effectiveness, as well as prediction of breast cancer recurrence.
| S-EPMC7462818 | biostudies-literature
Project description:The prevalence of oropharyngeal squamous cell carcinoma has been increasing in North America due to human papillomavirus-associated disease. It is molecularly distinct and differs from other head and neck cancers due to the young population and high survival rate. The treatment regimens currently in place cause significant long-term toxicities. Studies have transitioned from mortality-based outcomes to patient-reported outcomes assessing quality of life. There are many completed and ongoing trials investigating alternative therapy regimens or de-escalation strategies to minimize the negative secondary effects while maintaining overall survival and disease-free survival. The goal of this review is to discuss the most recent advancements within the field while summarizing and reviewing the available evidence.
| S-EPMC9139371 | biostudies-literature