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Cancer Research Mar 2019Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that...
Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients ( = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35; = 0.007 and HR 6.91; 95% CI, 1.37-34.97; = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer ( = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies. Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer..
Topics: Antineoplastic Agents, Immunological; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; Cohort Studies; DNA, Neoplasm; Follow-Up Studies; Humans; Lung Neoplasms; Neoplasm, Residual; Nivolumab; Prognosis; Survival Rate
PubMed: 30541742
DOI: 10.1158/0008-5472.CAN-18-1127 -
Journal of Cellular and Molecular... Aug 2021Major advances in the field of genomic technologies have led to an improvement in cancer diagnosis, classification and prognostication. However, many cancers remain... (Review)
Review
Major advances in the field of genomic technologies have led to an improvement in cancer diagnosis, classification and prognostication. However, many cancers remain incurable due to the development of drug resistance, minimal residual disease (MRD) and disease relapse, highlighting an incomplete understanding of the mechanisms underlying these processes. In recent years, the impact of non-genetic factors on neoplastic transformations has increasingly been acknowledged, and growing evidence suggests that low oxygen (O ) levels (ie hypoxia) in the tumour microenvironment play a critical role in the development and treatment of cancer. As a result, there is a growing need to develop research tools capable of reproducing physiologically relevant O conditions encountered by cancer cells in their natural environments in order to gain in-depth insight into tumour cell metabolism and function. In this review, the authors highlight the importance of hypoxia in the pathogenesis of malignant diseases and provide an overview of novel engineering tools that have the potential to further drive this evolving, yet technically challenging, field of cancer research.
Topics: Bioengineering; Humans; Hypoxia; Neoplasm, Residual; Neoplasms; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 34213838
DOI: 10.1111/jcmm.16759 -
Seminars in Hematology Jan 2018Circulating tumor DNA faithfully recapitulates somatic mutations detected in bone marrow aspirates from patients with newly diagnosed or relapsed or recurrent myeloma.... (Review)
Review
Circulating tumor DNA faithfully recapitulates somatic mutations detected in bone marrow aspirates from patients with newly diagnosed or relapsed or recurrent myeloma. Extending these methods to enable detection of minimal residual disease will require increased sensitivity and breadth of genomic assays to maximize information content from small quantities of cell-free DNA; as well as definition of a clinically meaningful ctDNA concentration in comparison with conventional bone marrow cell-count thresholds. This review describes the use of cell-free DNA sequencing in myeloma to date, identifies challenges associated with pushing limit of detection of these assays into the realm of detecting minimal residual disease, and describes potential strategies to overcome these challenges.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; Humans; Multiple Myeloma; Neoplasm, Residual
PubMed: 29759151
DOI: 10.1053/j.seminhematol.2018.03.002 -
Cancer Medicine Aug 2023Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising...
BACKGROUND
Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising performance. The objective of this study was to develop and validate OriMIRACLE S (Minimal Residual Circulating Nucleic Acid Longitudinal Detection in Solid Tumor), a highly sensitive and specific tumor-informed assay for MRD detection.
METHODS
Tumor-specific somatic single nucleotide variants (SNVs) were identified via whole exome sequencing of tumor tissue and matched germline DNA. Clonal SNVs were selected using the OriSelector algorithm for patient-specific, multiplex PCR-based NGS assays in MRD detection. Plasma-free DNA from patients with gastrointestinal tumors prior to and following an operation, and during monitoring, were ultradeep sequenced.
RESULTS
The detection of three positive sites was sufficient to achieve nearly 100% overall sample level sensitivity and specificity and was determined by calculating binomial probability based on customized panels containing 21 to 30 variants. A total of 127 patients with gastrointestinal tumors were enrolled in our study. Preoperatively, MRD was positive in 18 of 26 patients (69.23%). Following surgery, MRD was positive in 24 of 82 patients (29.27%). The positivity rate for MRD was 33.33% (n = 18) for gastric adenocarcinoma and 32.26% (n = 62) for colorectal cancer. Twenty (20) of 59 patients (34.48%) experienced a change in MRD status over the monitoring period. Patients 8 and 31 responded to 3 cycles of systemic therapy, after which levels for all ctDNA dropped below the detection limit. Patient 53 was an example of using MRD to predict tumor metastasis. Patient 55 showed a weak response to treatments first and respond to new systemic therapy after tumor progression.
CONCLUSION
Our study identified a sensitive and specific clinical detection method for low frequency ctDNA, and explored the detection performance of this technology in gastrointestinal tumors.
Topics: Humans; Circulating Tumor DNA; Neoplasm, Residual; Neoplasm Recurrence, Local; Gastrointestinal Neoplasms; Carcinoma
PubMed: 37602656
DOI: 10.1002/cam4.6286 -
Archives of Gynecology and Obstetrics May 2023Several international studies reported relatively high re-excision rates due to residual tumor in breast conserving surgery (BCS). Cavity shaving (CS) is a surgical...
BACKGROUND
Several international studies reported relatively high re-excision rates due to residual tumor in breast conserving surgery (BCS). Cavity shaving (CS) is a surgical strategy to reduce re-excision rates. This study aimed to investigate the effect of circumferential cavity shaving during BCS to reduce residual tumor.
MATERIAL AND METHODS
A total of 591 patients with early invasive carcinoma or carcinoma in situ of the breast (ICD-10, C50 or D05) who were diagnosed between 01/01/2017 and 31/12/2019 and underwent BCS in a certified breast cancer center of the University Regensburg were analyzed regarding surgical excision methods. Patients with CS during BCS and patients with targeted re-excision in a specific direction depending on the result of intraoperative mammography or sonography during BCS were compared. The risk of pathologic residual tumor (R1) was compared between both groups by means of a multivariable binary logistic regression model to determine if there is a benefit of a certain surgical method to avoid a second intervention for re-excision. We adjusted for age, tumor size, nodal status, histologic type, surgeon, breast side, and neoadjuvant chemotherapy.
RESULTS
80 (n = 13.54%) patients had CS and 511 (n = 86.46%) had a targeted re-excision in a specific direction during BCS according to intraoperative mammography or sonography. After comparing both techniques in a multivariable regression model, there was no significant difference regarding risk of residual tumor (p = 0.738) in the total cohort. However, CS showed a tendency to be favorable regarding rates of residual tumor in patients with invasive breast cancer between 60 and 70 years (p = 0.072) and smaller T1-tumors (p = 0.057) compared to targeted intraoperative re-excision following mammographic or sonographic assessment.
CONCLUSION
CS showed a tendency to reduce residual tumor compared to the standard technique of intraoperative re-excision in specific subgroups, although no statistical significance was reached. Further studies are needed to overcome potential limitations like surgeon-based bias and missing standardized definitions of CS to reduce residual tumor rates.
Topics: Humans; Female; Mastectomy, Segmental; Carcinoma, Ductal, Breast; Neoplasm, Residual; Reoperation; Breast Neoplasms; Carcinoma in Situ; Retrospective Studies
PubMed: 36282347
DOI: 10.1007/s00404-022-06803-x -
Cancer Research Sep 2021Optical imaging (OI) provides real-time clinical imaging capability and simultaneous molecular, morphological, and functional information of disease processes. In this...
Optical imaging (OI) provides real-time clinical imaging capability and simultaneous molecular, morphological, and functional information of disease processes. In this study, we present a new interventional OI technique, which enables visualization of three distinct pathologic zones of ablated tumor periphery for immediate detection of residual tumors during a radiofrequency ablation (RFA) session. Rabbits with orthotopic hepatic tumors were divided into two groups ( = 8/group): incomplete RFA and complete RFA. Indocyanine green-based interventional OI was used to differentiate three pathological zones: ablated tumor, transition margin, and residual tumor or surrounding normal liver-with quantitative comparison of signal-to-background ratios among the three zones and between incompletely and completely ablated tumors. Subsequent OI and pathologic correlation were performed to confirm the findings of interventional OI. Interventional OI could differentiate incompletely or completely ablated tumor peripheries, thus permitting identification of residual tumor. This technique may open new avenues for immediate assessment of tumor eradication during a single interventional ablation session. SIGNIFICANCE: Interventional optical imaging can instantly visualize pathologic zones of ablated tumor peripheries to detect residual tumors, which could revolutionize current image-guided interventional oncologic ablation techniques.
Topics: Animals; Cell Differentiation; Cell Line, Tumor; Female; Hepatocytes; Humans; In Vitro Techniques; Indocyanine Green; Liver; Liver Neoplasms; Neoplasm, Residual; Optical Imaging; Rabbits
PubMed: 34244237
DOI: 10.1158/0008-5472.CAN-21-1040 -
Recent Results in Cancer Research.... 2012The mechanisms driving dormancy of disseminated tumor cells (DTCs) remain largely unknown. Here, we discuss experimental evidence and theoretical frameworks that support... (Review)
Review
The mechanisms driving dormancy of disseminated tumor cells (DTCs) remain largely unknown. Here, we discuss experimental evidence and theoretical frameworks that support three potential scenarios contributing to tumor cell dormancy. The first scenario proposes that DTCs from invasive cancers activate stress signals in response to the dissemination process and/or a growth suppressive target organ microenvironment inducing dormancy. The second scenario asks whether therapy and/or micro-environmental stress conditions (e.g. hypoxia) acting on primary tumor cells carrying specific gene signatures prime new DTCs to enter dormancy in a matching target organ microenvironment that can also control the timing of DTC dormancy. The third and final scenario proposes that early dissemination contributes a population of DTCs that are unfit for immediate expansion and survive mostly in an arrested state well after primary tumor surgery, until genetic and/or epigenetic mechanisms activate their proliferation. We propose that DTC dormancy is ultimately a survival strategy that when targeted will eradicate dormant DTCs preventing metastasis. For these non-mutually exclusive scenarios we review experimental and clinical evidence in their support.
Topics: Humans; Neoplasm, Residual; Neoplasms; Tumor Microenvironment
PubMed: 22527492
DOI: 10.1007/978-3-642-28160-0_3 -
Indian Journal of Cancer 2022Neoadjuvant chemotherapy (NACT) is the standard of care for the treatment of locally advanced or non-metastatic breast cancer, which may increase the chances of breast...
Accuracy of digital mammography, ultrasound and MRI in predicting the pathological complete response and residual tumor size of breast cancer after completion of neoadjuvant chemotherapy.
BACKGROUND
Neoadjuvant chemotherapy (NACT) is the standard of care for the treatment of locally advanced or non-metastatic breast cancer, which may increase the chances of breast conservative surgery (BCS) in place of radical mastectomy without compromising on the overall survival. The aim of this study was to evaluate the accuracy of mammography (MG), ultrasound (US), and magnetic resonance imaging (MRI) in predicting the complete response and to assess the extent of residual breast cancer in women treated with NACT.
MATERIALS AND METHODS
Fifty-six consecutive patients with stage II or III breast cancer, who underwent imaging evaluation of breast with digital mammogram, US, and MRI after NACT and before the breast surgery, were included in the study. For each patient, pathologic complete response (pCR) or residual tumor (non-pCR) was predicted and the maximum extent of the residual tumor was measured on each imaging modality. These measurements were subsequently compared with the final histopathology results.
RESULTS
Of 56 patients, 22 showed pCR with MRI having better accuracy for predicting complete response than the MG and US (area under the receiver operating characteristic curve: 0.86, 0.68, and 0.65, respectively; p = 0.0001 for MRI; p = 0.06 for MG, and p = 0.02 for US). The sensitivity of MRI for detecting pCR was 72.7%; specificity and positive predictive value were 100%. For pathological residual tumor, the size measured on MRI showed significantly higher correlation with the pathologic size (correlation coefficient, r = 0.786), than the MG (r = 0.293) and US (r = 0.508) with P < 0.05.
CONCLUSIONS
Accuracy of MRI for predicting pathological complete response was significantly higher than the MG and US. Pathologic residual tumor size was also more precisely reflected by the longest tumor dimension on MRI with the strong positive correlation coefficient.
Topics: Humans; Female; Neoadjuvant Therapy; Breast Neoplasms; Neoplasm, Residual; Ultrasonography, Mammary; Mastectomy; Mammography; Magnetic Resonance Imaging; Chemotherapy, Adjuvant; Treatment Outcome
PubMed: 33753611
DOI: 10.4103/ijc.IJC_795_19 -
Journal of Biomedical Optics Jul 2015Surgery is the most effective method to cure patients with solid tumors, and 50% of all cancer patients undergo resection. Local recurrences are due to tumor cells...
Surgery is the most effective method to cure patients with solid tumors, and 50% of all cancer patients undergo resection. Local recurrences are due to tumor cells remaining in the wound, thus we explore near-infrared (NIR) fluorescence spectroscopy and imaging to identify residual cancer cells after surgery. Fifteen canines and two human patients with spontaneously occurring sarcomas underwent intraoperative imaging. During the operation, the wounds were interrogated with NIR fluorescence imaging and spectroscopy. NIR monitoring identified the presence or absence of residual tumor cells after surgery in 14/15 canines with a mean fluorescence signal-to-background ratio (SBR) of ∼16 . Ten animals showed no residual tumor cells in the wound bed (mean SBR<2 , P<0.001 ). None had a local recurrence at >1-year follow-up. In five animals, the mean SBR of the wound was >15 , and histopathology confirmed tumor cells in the postsurgical wound in four/five canines. In the human pilot study, neither patient had residual tumor cells in the wound bed, and both remain disease free at >1.5-year follow up. Intraoperative NIR fluorescence imaging and spectroscopy identifies residual tumor cells in surgical wounds. These observations suggest that NIR imaging techniques may improve tumor resection during cancer operations.
Topics: Adult; Animals; Dogs; Humans; Image Processing, Computer-Assisted; Indocyanine Green; Male; Middle Aged; Neoplasm, Residual; Optical Imaging; Pilot Projects; Sarcoma; Spectroscopy, Near-Infrared
PubMed: 26160347
DOI: 10.1117/1.JBO.20.7.076002 -
Archives of Pathology & Laboratory... Aug 2013Cancer stem cells (CSCs) comprise a minor cell population in a tumor; however, they possess self-renewal capacity and are responsible for tumor recurrence and the... (Review)
Review
CONTEXT
Cancer stem cells (CSCs) comprise a minor cell population in a tumor; however, they possess self-renewal capacity and are responsible for tumor recurrence and the emerging issue of tumor resistance. Despite recent advances in the study of pathogenesis and mechanisms of CSC-mediated disease recurrence and multidrug resistance, many questions remain unanswered.
OBJECTIVES
To provide an overview of CSC theory and to describe major methods of CSC detection and isolation, with the emphasis on those techniques that are potentially relevant in clinical laboratory practice. Particular attention is given to CSC markers, such as cancer testis antigens, which could become promising targets in the development of immunotherapy in settings of minimal residual disease.
DATA SOURCES
The review is based on analysis of peer-reviewed literature cited in PubMed, as well as preliminary results of studies conducted in our laboratory.
CONCLUSIONS
Despite a lack of consensus in the scientific community on research methodology, CSCs have demonstrated significant potential as therapeutic targets in the treatment of cancer. Further research of CSC biology and markers will eventually lead to the development of novel therapeutic approaches for targeting these cells to treat resistant and recurrent tumors and minimal residual disease.
Topics: Animals; Antigens, Neoplasm; Biomarkers, Tumor; Female; Humans; Immunotherapy; Male; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplasms; Neoplastic Stem Cells; Prognosis
PubMed: 23153183
DOI: 10.5858/arpa.2012-0494-RA