Abstract
Purpose
Identifying patients who are at risk of relapse is a key challenge of primary breast cancer. The current study investigates the utility of urinary DNA in breast cancer management and as a predictor of relapse. This work also compares the sensitivity of plasma DNA with urinary DNA.
Methods
Blood plasma and urine specimens were collected concurrently from 200 breast cancer patients receiving neoadjuvant chemotherapy. Comparison of both plasma and urinary DNA was performed at baseline to determine assay significance. Serial measurements of urinary DNA were conducted to gauge DNA variations after surgery. Correlations to disease relapse were performed to affirm the clinical utility of urinary DNA.
Results
Molecular analysis showed patients were successfully identified with mutant PIK3CA using urinary DNA. A strong correlation was affirmed from urinary and plasma DNA at baseline with the correlation coefficient r = 0.859. We analyzed post-surgery measurements of urinary DNA for disease-relapse predictions. In subsequent serial followup of urinary DNA samples, we confirmed increased sensitivity in predicting relapse of these patients. The hazard ratio determined at the 9-month was 1.51 that identified patients at greater risk of disease relapse.
Conclusion
Urinary DNA offers a unique opportunity to glimpse upon dynamic changes in early breast cancer. Our results demonstrated good correlation to plasma DNA and post monitoring of cancer patients to identify individuals susceptible to a high risk of relapse. This potentially allows for early intervention such as adjuvant chemotherapy to be administered to better manage these patients.
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References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.
Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LAG et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. JNCI. 2014;106(5):dju55.
Brackstone M, Townson JL, Chambers AF. Tumour dormancy in breast cancer: an update. Breast Cancer Res. 2007;9(3):208.
Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32(6):579–86.
Niekel MC, Bipat S, Stoker J. Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment. Radiology. 2010;257(3):674–84.
Weissleder R, Pittet MJ. Imaging in the era of molecular oncology. Nature. 2008;452(7187):580.
Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early-and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24.
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;2004(351):781–91.
Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch R-D, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Can Res. 2001;61(4):1659–65.
Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10(20):6897–904.
Maheswaran S, Haber DA. Circulating tumor cells: a window into cancer biology and metastasis. Curr Opin Genet Dev. 2010;20(1):96–9.
Li J, Gregory SG, Garcia-Blanco MA, Armstrong AJ. Using circulating tumor cells to inform on prostate cancer biology and clinical utility. Crit Rev Clin Lab Sci. 2015;52(4):191–210.
Krishnamurthy N, Spencer E, Torkamani A, Nicholson L. Liquid biopsies for cancer: coming to a patient near you. J Clin Med. 2017;6(1):3.
Smerage JB, Hayes DF. The measurement and therapeutic implications of circulating tumour cells in breast cancer. Br J Cancer. 2006;94(1):8.
Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MHE, et al. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med. 2015;7(8):1034–47.
Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 2007;450(7173):1235–9.
Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627.
Cidado J, Park BH. Targeting the PI3K/Akt/mTOR pathway for breast cancer therapy. J Mammary Gland Biol Neoplas. 2012;17(3–4):205–16.
Ma CX. The PI3K pathway as a therapeutic target in breast cancer. Am J Hematol Oncol®. 2015;11(3):23–29.
Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, Inao T, Sueta A, Fujiwara S, et al. Prognostic role of PIK3CA mutations of cell-free DNA in early-stage triple negative breast cancer. Cancer Sci. 2015;106(11):1582–9.
Singletary SE, Greene FL, editors. Revision of breast cancer staging: the 6th edition of the TNM classification 2003: Wiley Online Library.
Yokota M, Tatsumi N, Tsuda I, Takubo T, Hiyoshi M. DNA extraction from human urinary sediment. J Clin Lab Anal. 1998;12(2):88–91.
Brinkmann B, Rand S, Bajanowski T. Forensic identification of urine samples. Int J Legal Med. 1992;105(1):59–61.
Botezatu I, Og Serdyuk, Potapova G, Shelepov V, Alechina R, Molyaka Y, et al. Genetic analysis of DNA excreted in urine: a new approach for detecting specific genomic DNA sequences from cells dying in an organism. Clin Chem. 2000;46(8):1078–84.
Reckamp KL, Melnikova VO, Karlovich C, Sequist LV, Camidge DR, Wakelee H, et al. A highly sensitive and quantitative test platform for detection of NSCLC EGFR mutations in urine and plasma. J Thoracic Oncol. 2016;11(10):1690–700.
Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015;7(302):302ra133.
Tachtsidis A, McInnes LM, Jacobsen N, Thompson EW, Saunders CM. Minimal residual disease in breast cancer: an overview of circulating and disseminated tumour cells. Clin Exp Metas. 2016;33(6):521–50.
Guttery DS, Blighe K, Page K, Marchese SD, Hills A, Coombes RC, et al. Hide and seek: tell-tale signs of breast cancer lurking in the blood. Cancer Metastasis Rev. 2013;32(1–2):289–302.
Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–90.
Gedvilaitė V, Schveigert D, Cicėnas S. Cell-free DNA in non-small cell lung cancer. Acta medica Lituanica. 2017;24(2):138.
Acknowledgements
This work was supported by research grants provided by Jingzhou First People’s Hospital.
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All human and animal studies have been approved by the appropriate ethics committee and have, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
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Informed consent was obtained from all individual participants included in the study.
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Liu, Z., Liu, W. Association of urinary and plasma DNA in early breast cancer patients and its links to disease relapse. Clin Transl Oncol 20, 1053–1060 (2018). https://doi.org/10.1007/s12094-017-1825-9
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DOI: https://doi.org/10.1007/s12094-017-1825-9