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Medicina (Kaunas, Lithuania) Oct 2023: Full-thickness trans anal local excision for tumors with favorable response following neoadjuvant therapy for locally advanced rectal cancer (LARC) is a common... (Review)
Review
: Full-thickness trans anal local excision for tumors with favorable response following neoadjuvant therapy for locally advanced rectal cancer (LARC) is a common strategy for organ preservation, but it could be associated with a high rate of postoperative complications. We describe the incidence and pattern of submucosal involvement in surgical specimens following neoadjuvant therapy for LARC and whether limiting local excision of the residual tumor bed to only mucosal/submucosal layers of the rectal wall is sufficient for accurately predicting the ypT status of residual cancer, providing a pathological rationale to replace full-thickness local excision by endoscopic submucosal resection. : This was a single-institution retrospective study conducted at a teaching community hospital. We reviewed clinical and pathological findings with slides of 82 patients diagnosed with LARC treated at our center between 2006 and 2020. Eligibility criteria mirrored our current organ preservation trials. : No tumor was found in surgical specimens in 28 cases (34%). Additionally, 4, 22, 27, and 1 cases were staged as ypT1, ypT2, ypT3, and ypT4, respectively. Residual malignant cells were found in the submucosal layer in 98% of cases with ypT+ stage, with 'skip lesions' in only 2% of cases. : A very high incidence of submucosal involvement is noticed in residual tumors after neoadjuvant therapy, providing pathological rationale to study the role of endoscopic submucosal resection as a restaging tool for tumors with favorable response after neoadjuvant therapy when organ preservation strategy is pursued. This study was limited by its retrospective design and relatively small number of patients.
Topics: Humans; Neoadjuvant Therapy; Retrospective Studies; Neoplasm Staging; Rectal Neoplasms; Rectum; Neoplasm, Residual; Treatment Outcome
PubMed: 37893525
DOI: 10.3390/medicina59101807 -
Breast Cancer Research : BCR Jun 2021Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical...
BACKGROUND
Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes.
METHODS
To identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions following oncogene blockade, and recurrent tumors to analyze gene expression signatures and evaluate tumor-initiating cell properties.
RESULTS
We demonstrate that residual tumor cells surviving oncogenic pathway inhibition at both local and distant sites exist in a state of cellular dormancy, despite adequate vascularization and the absence of adaptive immunity, and retain the ability to re-enter the cell cycle and give rise to recurrent tumors after extended latency periods. Compared to primary or recurrent tumor cells, dormant residual tumor cells possess unique features that are conserved across mouse models for human breast cancer driven by different oncogenes, and express a gene signature that is strongly associated with recurrence-free survival in breast cancer patients and similar to that of tumor cells in which dormancy is induced by the microenvironment. Although residual tumor cells in both the HER2/neu and Wnt1 models are enriched for phenotypic features associated with tumor-initiating cells, limiting dilution experiments revealed that residual tumor cells are not enriched for cells capable of giving rise to primary tumors, but are enriched for cells capable of giving rise to recurrent tumors, suggesting that tumor-initiating populations underlying primary tumorigenesis may be distinct from those that give rise to recurrence following therapy.
CONCLUSIONS
Residual cancer cells surviving targeted therapy reside in a well-vascularized, desmoplastic microenvironment at both local and distant sites. These cells exist in a state of cellular dormancy that bears little resemblance to primary or recurrent tumor cells, but shares similarities with cells in which dormancy is induced by microenvironmental cues. Our observations suggest that dormancy may be a conserved response to targeted therapy independent of the oncogenic pathway inhibited or properties of the primary tumor, that the mechanisms underlying dormancy at local and distant sites may be related, and that the dormant state represents a potential therapeutic target for preventing cancer recurrence.
Topics: Animals; Breast Neoplasms; Disease-Free Survival; Epithelial-Mesenchymal Transition; Female; Humans; Mice; Mice, Transgenic; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplastic Stem Cells; Neovascularization, Pathologic; Receptor, ErbB-2; Wnt1 Protein
PubMed: 34088357
DOI: 10.1186/s13058-021-01416-9 -
Archives of Pathology & Laboratory... Apr 2022Measurable (minimal) residual disease (MRD) is an independent prognostic factor for survival outcomes in patients with lymphoid and plasma cell malignancies and has been... (Review)
Review
CONTEXT.—
Measurable (minimal) residual disease (MRD) is an independent prognostic factor for survival outcomes in patients with lymphoid and plasma cell malignancies and has been incorporated into consensus criteria regarding treatment response, strategy, and clinical trial endpoints. clonoSEQ (a next-generation sequencing [NGS]-MRD assay) uses multiplex polymerase chain reaction and NGS to identify clonotypic rearrangements at the immunoglobulin (Ig) H, IgK, IgL, T-cell receptor (TCR)-β, and TCR-γ loci, as well as translocated B-cell lymphoma 1/IgH and 2/IgH sequences for MRD assessment. Additionally, it can be used to confirm diagnoses of cutaneous T-cell lymphoma (CTCL).
OBJECTIVE.—
To review the technical aspects of our experience using the clonoSEQ Assay in routine clinical practice.
DESIGN.—
In this single-center experience, 390 patients with lymphoid and plasma cell malignancies were assessed with the NGS-MRD Assay at a central laboratory.
RESULTS.—
Median time from arrival of the shipment to initiation of the assay (defined as captured in Adaptive's secure tracking system) was 2.1 hours. Overall, 317 patients had 1 or more samples submitted for sequence identification. Of these, 290 (91.5%) had trackable sequences identified. The median calibration rate of samples by malignancy (where n ≥ 10 samples, excluding CTCL samples) was 88.1%, across a variety of fresh and archived sample sources (177 of 201 samples). TCR-β and/or TCR-γ clonotypes were identified in 40 of 95 samples (42.1%) from 66 patients with suspected CTCL.
CONCLUSIONS.—
This NGS-MRD Assay is a valuable and sensitive tool for monitoring MRD in patients with plasma cell and lymphoid malignancies and assisting in the diagnosis of CTCL.
Topics: Gene Rearrangement; High-Throughput Nucleotide Sequencing; Humans; Neoplasm, Residual; Neoplasms, Plasma Cell; Receptors, Antigen, T-Cell
PubMed: 34343238
DOI: 10.5858/arpa.2020-0457-OA -
Pathology Oncology Research : POR Jan 2018
Topics: Antineoplastic Agents; Humans; Lymph Nodes; Lymphatic Metastasis; Neoplasm, Residual
PubMed: 28432651
DOI: 10.1007/s12253-017-0221-7 -
Molecular Diagnosis & Therapy Nov 2021The detection of circulating tumor DNA via liquid biopsy has become an important diagnostic test for patients with cancer. While certain commercial liquid biopsy... (Review)
Review
The detection of circulating tumor DNA via liquid biopsy has become an important diagnostic test for patients with cancer. While certain commercial liquid biopsy platforms designed to detect circulating tumor DNA have been approved to guide clinical decisions in advanced solid tumors, the clinical utility of these assays for detecting minimal residual disease after curative-intent treatment of nonmetastatic disease is currently limited. Predicting disease response and relapse has considerable potential for increasing the effective implementation of neoadjuvant and adjuvant therapies. As a result, many companies are rapidly investing in the development of liquid biopsy platforms to detect circulating tumor DNA in the minimal residual disease setting. In this review, we discuss the development and clinical implementation of commercial liquid biopsy platforms for circulating tumor DNA minimal residual disease detection of solid tumors. Here, we aim to highlight the technological features that enable highly sensitive detection of tumor-derived genomic alterations, the factors that differentiate these commercial platforms, and the ongoing trials that seek to increase clinical implementation of liquid biopsies using circulating tumor DNA-based minimal residual disease detection.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; Genomics; Humans; Liquid Biopsy; Neoplasm Recurrence, Local; Neoplasm, Residual
PubMed: 34725800
DOI: 10.1007/s40291-021-00559-x -
Cytometry. Part B, Clinical Cytometry Jan 2014Detection of minimal residual disease is recognized as an important post-therapy risk factor in acute myeloid leukemia patients. Two most commonly used methods for... (Review)
Review
Detection of minimal residual disease is recognized as an important post-therapy risk factor in acute myeloid leukemia patients. Two most commonly used methods for residual disease monitoring are real-time quantitative polymerase chain reaction and multiparameter flow cytometry. The results so far are very promising, whereby it is likely that minimal residual disease results will enable to guide future post-remission treatment strategies. However, the leukemic clone may change between diagnosis and relapse due to the instability of the tumor cells. This instability may already be evident at diagnosis if different subpopulations of tumor cells coexist. Such tumor heterogeneity, which may be reflected by immunophenotypic, molecular, and/or cytogenetic changes, can have important consequences for minimal residual disease detection, since false-negative results can be expected to be the result of losses of aberrancies used as minimal residual disease markers. In this review the role of such changes in minimal residual disease monitoring is explored. Furthermore, possible causes of tumor instability are discussed, whereby the concept of clonal selection and expansion of a chemotherapy-resistant subpopulation is highlighted. Accordingly, detailed knowledge of the process of clonal evolution is required to improve both minimal residual disease risk stratification and patient outcome.
Topics: Adult; Biomarkers, Tumor; Clonal Evolution; Drug Resistance, Neoplasm; Flow Cytometry; Genetic Variation; Humans; Immunophenotyping; Leukemia, Myeloid, Acute; Neoplasm Recurrence, Local; Neoplasm, Residual; Real-Time Polymerase Chain Reaction; Treatment Outcome
PubMed: 24151248
DOI: 10.1002/cyto.b.21134 -
Clinical Cancer Research : An Official... Feb 2024Detection of circulating tumor DNA (ctDNA) in patients who have completed treatment for early-stage breast cancer is associated with a high risk of relapse, yet the...
PURPOSE
Detection of circulating tumor DNA (ctDNA) in patients who have completed treatment for early-stage breast cancer is associated with a high risk of relapse, yet the optimal assay for ctDNA detection is unknown.
EXPERIMENTAL DESIGN
The cTRAK-TN clinical trial prospectively used tumor-informed digital PCR (dPCR) assays for ctDNA molecular residual disease (MRD) detection in early-stage triple-negative breast cancer. We compared tumor-informed dPCR assays with tumor-informed personalized multimutation sequencing assays in 141 patients from cTRAK-TN.
RESULTS
MRD was first detected by personalized sequencing in 47.9% of patients, 0% first detected by dPCR, and 52.1% with both assays simultaneously (P < 0.001; Fisher exact test). The median lead time from ctDNA detection to relapse was 6.1 months with personalized sequencing and 3.9 months with dPCR (P = 0.004, mixed-effects Cox model). Detection of MRD at the first time point was associated with a shorter time to relapse compared with detection at subsequent time points (median lead time 4.2 vs. 7.1 months; P = 0.02).
CONCLUSIONS
Personalized multimutation sequencing assays have potential clinically important improvements in clinical outcome in the early detection of MRD.
Topics: Humans; Circulating Tumor DNA; Triple Negative Breast Neoplasms; Neoplasm Recurrence, Local; Recurrence; Biomarkers, Tumor; Neoplasm, Residual
PubMed: 38078899
DOI: 10.1158/1078-0432.CCR-23-2326 -
Clinical Cancer Research : An Official... May 2017Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate... (Randomized Controlled Trial)
Randomized Controlled Trial
Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride (dut) and leuprolide (enza/dut/luteinizing hormone-releasing hormone analogues [LHRHa]). Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enzalutamide or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of PSA and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa. In the enzalutamide arm, none of the 25 patients achieved pCR or MRD. In the enza/dut/LHRHa arm, one of 23 patients (4.3%) achieved pCR and 3 of 23 (13.0%) achieved MRD. Median RCB was higher in the enzalutamide arm than in the enza/dut/LHRHa arm (0.41 cm vs. 0.06 cm, respectively). Tissue testosterone and dihydrotestosterone levels correlated with RCB. No adverse events leading to study drug discontinuation were reported. Combination therapy with enza/dut/LHRHa resulted in pCR and MRD rates comparable with historical controls. Evidence of continued AR activity in residual tumor suggests that AR signaling may contribute to survival. Strategies to more effectively ablate AR activity are warranted to determine whether more substantial antitumor effects are observed. .
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Combined Modality Therapy; Dutasteride; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm, Residual; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Receptors, Androgen
PubMed: 28151719
DOI: 10.1158/1078-0432.CCR-16-1357 -
Breast (Edinburgh, Scotland) Apr 2023In this review, we evaluate the potential and recent advancements in using artificial intelligence techniques to de-escalate loco-regional breast cancer therapy, with a... (Review)
Review
In this review, we evaluate the potential and recent advancements in using artificial intelligence techniques to de-escalate loco-regional breast cancer therapy, with a special focus on surgical treatment after neoadjuvant systemic treatment (NAST). The increasing use and efficacy of NAST make the optimal loco-regional management of patients with pathologic complete response (pCR) a clinically relevant knowledge gap. It is hypothesized that patients with pCR do not benefit from therapeutic surgery because all tumor has already been eradicated by NAST. It is unclear, however, how residual cancer after NAST can be reliably excluded prior to surgery to identify patients eligible for omitting breast cancer surgery. Evidence from clinical trials evaluating the potential of imaging and minimally-invasive biopsies to exclude residual cancer suggests that there is a high risk of missing residual cancer. More recently, AI-based algorithms have shown promising results to reliably exclude residual cancer after NAST. This example illustrates the great potential of AI-based algorithms to further de-escalate and individualize loco-regional breast cancer treatment.
Topics: Humans; Female; Breast Neoplasms; Artificial Intelligence; Neoplasm, Residual; Mastectomy; Breast; Neoadjuvant Therapy
PubMed: 36842193
DOI: 10.1016/j.breast.2023.02.009 -
Nature Reviews. Clinical Oncology Aug 2013Technological advances in the laboratory have led to substantial improvements in clinical decision making through the introduction of pretreatment prognostic risk... (Review)
Review
Technological advances in the laboratory have led to substantial improvements in clinical decision making through the introduction of pretreatment prognostic risk stratification factors in acute myeloid leukaemia (AML). Unfortunately, similar progress has not been made in treatment response criteria, with the definition of 'complete remission' in AML largely unchanged for over half a century. Several clinical trials have demonstrated that high-sensitivity measurements of residual disease burden during or after treatment can be performed, that results are predictive for clinical outcome and can be used to improve outcomes by guiding additional therapeutic intervention to patients in clinical complete remission, but at increased relapse risk. We review these recent trials, the characteristics and challenges of the modalities currently used to detect minimal residual disease (MRD), and outline opportunities to both refine detection and improve clinical use of MRD measurements. MRD measurement is already the standard of care in other myeloid malignancies, such as chronic myelogenous leukaemia and acute promyelocytic leukaemia (APL). It is our belief that response criteria for non-APL AML should be updated to include assessment for molecular complete remission and recommendations for post-consolidation surveillance should include regular monitoring for molecular relapse as standard of care.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Myeloid, Acute; Neoplasm, Residual
PubMed: 23799371
DOI: 10.1038/nrclinonc.2013.100