Global DNA methylation is altered by neoadjuvant chemoradiotherapy in rectal cancer and may predict response to treatment – A pilot study

Tsang, Julia Y. S.; Vencken, Sebastian; Sharaf, Osama; Leen, Eamonn; Kay, Elaine W.; McNamara, Deborah A.; Deasy, Joseph; Mulligan, ED

doi:10.1016/j.ejso.2014.06.008

Cited by 19 publications

(17 citation statements)

References 36 publications

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“…This variation could be ascribed to the use of different methodologies. Some studies also examined genetic/epigenetic changes or protein expression levels, although research is still at an early stage. Nevertheless, large‐scale validation studies of predictive markers are necessary before incorporating such methodologies into future clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Predictive immunohistochemical features for tumour response to chemoradiotherapy in rectal cancer

et al. 2020

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Background Reduced expression of cluster of differentiation (CD) 133 and cyclo‐oxygenase (COX) 2, and increased density of CD8+ tumour‐infiltrating lymphocytes, are associated with a favourable tumour response to preoperative chemoradiotherapy (CRT). This study aimed to evaluate these markers in relation to tumour response after preoperative CRT in two rectal cancer cohorts. Methods Patients with low rectal cancer who underwent radical resection and preoperative short‐term CRT in 2001–2007 (retrospective cohort) and long‐term CRT in 2011–2017 (prospective cohort) were analysed. Pretreatment biopsies were stained immunohistochemically using antibodies to determine CD133 and COX‐2 expression, and increased CD8+ density. Outcome measures were tumour regression grade (TRG), tumour downstaging and survival. Results For 95 patients in the retrospective cohort, the incidence of TRG 3–4 was 67 per cent when two or three immunohistochemistry (IHC) features were present, but only 20 per cent when there were fewer features (P < 0·001). The incidence of tumour downstaging was higher in patients with at least two IHC features (43 versus 22 per cent with fewer features; P = 0·029). The 49 patients in the prospective cohort had similar rates to those in the retrospective cohort (TRG 3–4: 76 per cent for two or more IHC features versus 25 per cent with fewer features, P < 0·001; tumour downstaging: 57 versus 25 per cent respectively, P = 0·022). Local recurrence‐free survival rates in patients with more or fewer IHC features were similar in the retrospective and prospective cohort (P = 0·058 and P = 0·387 respectively). Conclusion Assessment of CD133, COX‐2 and CD8 could be useful in predicting a good response to preoperative CRT in patients with lower rectal cancer undergoing neoadjuvant therapy. Further studies are needed to validate the results in larger cohorts and investigate a survival benefit.

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Section: Discussionmentioning

confidence: 99%

Predictive immunohistochemical features for tumour response to chemoradiotherapy in rectal cancer

et al. 2020

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“…Breast cancer “CpG island methylator phenotype” (CIMP), revealed by genome-wide methylation analysis of metastatic breast cancers where a large number of genes are hypermethylated, and has been suggested to be informative for metastatic potential [47]. A significant correlation between pre-treatment global DNA methylation with neoadjuvant chemotherapy response in rectal cancer has been reported [48]. Though DNA hypomethylation was the first epigenetic alteration identified in cancer, its molecular process and effects are not well understood yet [49].…”

Section: Discussionmentioning

confidence: 99%

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours

Selli

Turnbull

Pearce

et al. 2018

Preprint

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BackgroundThe risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate, previous efforts have been limited to in vitro or in vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant endocrine treatment were characterised as a novel clinical model.MethodsConsecutive tumour samples from 62 patients undergoing extended (4-45 months) neoadjuvant aromatase inhibitor, letrozole, therapy were subjected to transcriptomic and proteomic analysis, representing before (≤0), early-on (13-120 days) and long-term (>120 days) neoadjuvant letrozole treatment. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as “dormant”, and the remaining 20 patients as “acquired resistant”.ResultsChanges in gene expression in dormant tumours begin early and become more pronounced at later timepoints. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared to dormant tissues after extended letrozole treatment.ConclusionsThis is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients supporting a potential role for therapy targeted at these epigenetic alterations in the management of endocrine resistant breast cancer.

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“…42,43 Although patients receiving neoadjuvant therapy were excluded in our study, the relationship between methylation and response to CRT (neoadjuvant and adjuvant) is likely to be significant, as has been identified in previous studies. 37,44 The benefits of neoadjuvant therapy in rectal cancer are clear, but it is acknowledged that a tumour's response to neoadjuvant therapy is currently not predictable, 45 and identifying significant factors that affect response may be beneficial in managing patients. Currently, cNC status, mucinous tumours, and poorly differentiated tumours have all been associated with poor response to neoadjuvant therapy, 46 but the prognostic values of these measures is limited and has no clinical utility in restricting access to pre-surgical therapies.…”

Section: Discussionmentioning

confidence: 99%

DNA hypermethylation as a predictor of extramural vascular invasion (EMVI) in rectal cancer

Kokelaar

Jones

Williamson

et al. 2018

Cancer Biology & Therapy

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Given the association between CIMP-intermediate epigenotype and EMVI-positivity, and the subsequent disadvantage in pathological stage, requirement for adjuvant therapy and worse survival, tumour epigenotyping could potentially play an important role in personalising patients' cancer care. Further work is required to understand the mechanisms that underlie the observed effect, with the hope that they may provide novel opportunities for intervention and inform treatment decisions in rectal cancer.

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Global DNA methylation is altered by neoadjuvant chemoradiotherapy in rectal cancer and may predict response to treatment – A pilot study

Cited by 19 publications

References 36 publications

Predictive immunohistochemical features for tumour response to chemoradiotherapy in rectal cancer

Predictive immunohistochemical features for tumour response to chemoradiotherapy in rectal cancer

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours

DNA hypermethylation as a predictor of extramural vascular invasion (EMVI) in rectal cancer

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