Harriet E Gee1, Francesca M Buffa2, Adrian L Harris2, Joanne M Toohey3, Susan L Carroll3, Caroline L Cooper4, Jane Beith3, Catriona McNeil5, Hugh Carmalt3, Cindy Mak3, Sanjay Warrier3, Anne Holliday6, Christina Selinger7, Rhiannon Beckers7, Catherine Kennedy8, Peter Graham9, Alexander Swarbrick10, Ewan K A Millar11, Sandra A O'Toole12, Timothy Molloy6. 1. The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia; Central Clinical School, Sydney Medical School, University of Sydney, NSW, Australia. Electronic address: harriet.gee@sydney.edu.au. 2. Department of Medical Oncology, The University of Oxford, Oxford, UK. 3. The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia. 4. Central Clinical School, Sydney Medical School, University of Sydney, NSW, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. 5. The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia. 6. The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. 7. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. 8. Central Clinical School, Sydney Medical School, University of Sydney, NSW, Australia. 9. Department of Radiation Oncology, Cancer Care Centre, St. George Hospital, Kogarah, NSW, Australia. 10. The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Kensington, NSW, Australia. 11. The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Department of Anatomical Pathology, South Eastern Area Laboratory Service, St. George Hospital, Kogarah, NSW, Australia; School of Medicine and Health Sciences, University of Western Sydney, Campbelltown, NSW, Australia; Faculty of Medicine, School of Medical Sciences, University of NSW, Kensington, NSW, Australia. 12. The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Central Clinical School, Sydney Medical School, University of Sydney, NSW, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
Abstract
PURPOSE: Local recurrence and distant failure after adjuvant radiation therapy for breast cancer remain significant clinical problems, incompletely predicted by conventional clinicopathologic markers. We had previously identified microRNA-139-5p and microRNA-1274a as key regulators of breast cancer radiation response in vitro. The purpose of this study was to investigate standard clinicopathologic markers of local recurrence in a contemporary series and to establish whether putative target genes of microRNAs involved in DNA repair and cell cycle control could better predict radiation therapy response in vivo. METHODS AND MATERIALS: With institutional ethics board approval, local recurrence was measured in a contemporary, prospectively collected series of 458 patients treated with radiation therapy after breast-conserving surgery. Additionally, independent publicly available mRNA/microRNA microarray expression datasets totaling >1000 early-stage breast cancer patients, treated with adjuvant radiation therapy, with >10 years of follow-up, were analyzed. The expression of putative microRNA target biomarkers--TOP2A, POLQ, RAD54L, SKP2, PLK2, and RAG1--were correlated with standard clinicopathologic variables using 2-sided nonparametric tests, and to local/distant relapse and survival using Kaplan-Meier and Cox regression analysis. RESULTS: We found a low rate of isolated local recurrence (1.95%) in our modern series, and that few clinicopathologic variables (such as lymphovascular invasion) were significantly predictive. In multiple independent datasets (n>1000), however, high expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence, survival, or both in univariate and multivariate analyses (P<.001). Low RAG1 expression significantly correlated with local recurrence (multivariate, P=.008). Additionally, RAD54L, SKP2, and PLK2 may be predictive, being prognostic in radiation therapy-treated patients but not in untreated matched control individuals (n=107; P<.05). CONCLUSIONS: Biomarkers of DNA repair and cell cycle control can identify patients at high risk of treatment failure in those receiving radiation therapy for early breast cancer in independent cohorts. These should be further investigated prospectively, especially TOP2A and SKP2, for which targeted therapies are available.
PURPOSE: Local recurrence and distant failure after adjuvant radiation therapy for breast cancer remain significant clinical problems, incompletely predicted by conventional clinicopathologic markers. We had previously identified microRNA-139-5p and microRNA-1274a as key regulators of breast cancer radiation response in vitro. The purpose of this study was to investigate standard clinicopathologic markers of local recurrence in a contemporary series and to establish whether putative target genes of microRNAs involved in DNA repair and cell cycle control could better predict radiation therapy response in vivo. METHODS AND MATERIALS: With institutional ethics board approval, local recurrence was measured in a contemporary, prospectively collected series of 458 patients treated with radiation therapy after breast-conserving surgery. Additionally, independent publicly available mRNA/microRNA microarray expression datasets totaling >1000 early-stage breast cancer patients, treated with adjuvant radiation therapy, with >10 years of follow-up, were analyzed. The expression of putative microRNA target biomarkers--TOP2A, POLQ, RAD54L, SKP2, PLK2, and RAG1--were correlated with standard clinicopathologic variables using 2-sided nonparametric tests, and to local/distant relapse and survival using Kaplan-Meier and Cox regression analysis. RESULTS: We found a low rate of isolated local recurrence (1.95%) in our modern series, and that few clinicopathologic variables (such as lymphovascular invasion) were significantly predictive. In multiple independent datasets (n>1000), however, high expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence, survival, or both in univariate and multivariate analyses (P<.001). Low RAG1 expression significantly correlated with local recurrence (multivariate, P=.008). Additionally, RAD54L, SKP2, and PLK2 may be predictive, being prognostic in radiation therapy-treated patients but not in untreated matched control individuals (n=107; P<.05). CONCLUSIONS: Biomarkers of DNA repair and cell cycle control can identify patients at high risk of treatment failure in those receiving radiation therapy for early breast cancer in independent cohorts. These should be further investigated prospectively, especially TOP2A and SKP2, for which targeted therapies are available.
Authors: Timothy J Molloy; David D Ma; Thi Thanh Vu; Friedrich Stölzel; Kristy W Wang; Christoph Röllig; Melinda L Tursky Journal: Leukemia Date: 2020-12-01 Impact factor: 11.528
Authors: Andrew Dhawan; Jacob Scott; Purnima Sundaresan; Michael Veness; Sandro Porceddu; Eric Hau; Adrian L Harris; Francesca M Buffa; Harriet E Gee Journal: Sci Rep Date: 2020-06-23 Impact factor: 4.379