Autotaxin (ATX) as a Marker for Breast Cancer

Breast Cancer Clinical Trial

Official title:

Autotaxin (ATX) as a Marker for Breast Cancer

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04328194
• Other study ID #: medicin
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 1, 2021
• Est. completion date: November 1, 2022

Study information

• Verified date: March 2020
• Source: Assiut University
• Contact: Hanan Hareth, MD
• Phone: 01002954322
• Email: abdlatif[@]aun.edu.eg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Breast cancer is the leading cause of cancer death in women worldwide. According to the GLOBOCAN 2018 worldwide estimates of cancer incidence and mortality, in 2018, about 2,088,849 new cases were diagnosed and approximately 626,679 women were predicted to die from the disease . It is the leading cause of cancer related mortality, representing15% of deaths per year worldwide .

Description:

Breast cancer is the most common malignancy in females in Egypt. It accounts for 32 % of cancer in women . Breast cancer in Egypt carries an unfavorable prognosis with 29% mortality and 3.7:1 incidence to mortality ratio .

Despite the rising incidence of breast cancer, the survival rates have improved in recent years due to the deep research in biological behavior of breast cancer . Although the current 5-year survival for primary breast cancer is relatively high (ranging from 80% to 92% in different populations) survival rates decrease to less than 25% when the disease becomes metastatic .These data support the need to develop more efficient strategies for preventive, intervention, evaluation of therapy, and prediction of prognosis .

Autotaxin (ATX) is a glycoprotein encoded by the ENPP2 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 2) gene located on chromosome 8. Identical to lysophospholipase D, ATX plays a role in the synthesis of the bioactive lipid mediator lysophosphatidate (LPA) from lysophosphatidylcholine (LPC) .

LPA acts through specific G protein-coupled receptors (GPCRs) to promote cellular proliferation, migration, and survival . ATX expression was also reported higher in poorly differentiated tumors and, in independent studies, is correlated with invasiveness of cancer cells suggesting a higher metastatic potential of ATX-expressing tumors . ATX is generated from platelets, endothelial cells, fibroblasts, and adipocytes and specifically, ATX from adipocytes has an impact on plasma LPA level . Thus, adipocytes could be an important origin of ATX in tumors. Breast cancer is a human cancer that has adipocyte-rich stroma. Adipose tissue comprises 56% of non-lactating breast tissue, and 35% of lactating breast tissue . ATX-LPA signaling has been reported to be involved in angiogenesis, tumor cell invasion, and migration in breast cancer .

Increased ATX expression has also been reported in various forms of cancer, such as glioblastoma, hepatocellular and thyroid carcinomas, pancreatic and hematological cancers. A large number of evidence indicate that ATX-LPA is associated with chemotherapy resistance of cancer, and in breast cancer, ATX can reverse cell apoptosis.

In a mouse model, α-bromomethylene phosphonate LPA (BrP-LPA), a dual ATX and pan-LPAR( Lysophosphatidic acid receptor ) inhibitor, inhibited migration and invasion of breast cancer cell lines and suppressed primary tumor and angiogenesis in a mouse xenograft study . Since tumor and stromal cells in breast cancer express ATX-LPA signaling-related proteins, inhibition of the ATX-LPA axis could be of therapeutic importance .Therefore, further study ATX as a tumor marker in breast cancer is required.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: November 1, 2022
• Est. primary completion date: May 1, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 19 Years to 69 Years

Eligibility

Inclusion Criteria:

• The study will be conducted on one hundred female individuals; 80 newly diagnosed breast cancer patients before any treatment or surgical intervention and 20 apparently normal female individuals.

Exclusion Criteria:

• Patients with any other type of malignant or benign tumors, renal failure, cardiovascular diseases and liver cirrhosis were excluded from our study.

• Past history of chemotherapy or surgical treatment of any malignancy.

• Inflammatory diseases (e.g.bronchitis) or autoimmune diseases (e.g.rheumatoid arthritis).

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Diagnostic Test:
• Serum Autotaxin
Marker

Radiation:
• chest x-ray
chest x- ray will be done for the study group

Diagnostic Test:
• Breast ultrasound or mammography
Breast ultrasound or mammography will be done for the study group to diagnosis of breast cancer
• Histopathological examination of breast mass specimens
by True cut or fine needle aspiration cytology

Radiation:
• Magnetic Resonance Imaging ( MRI) and Bone scan
will be done for the study group

Diagnostic Test:
• Peripheral haemogram
blood sample will be taken from the patients
• Renal and liver functions
to exclude any other morbidity
• Prothrombin time and concentration
blood sample will be taken from the patients
• Cancer Antigen 15-3 (CA15-3).
will be done for the 2 groups

Other:
• Full medical history
full medical history will be taken from all patients
• Full clinical examination
full clinical examination will be done for the patients

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Assiut University

References & Publications (24)

Boucharaba A, Serre CM, Grès S, Saulnier-Blache JS, Bordet JC, Guglielmi J, Clézardin P, Peyruchaud O. Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest. 2004 Dec;114(12):1714-25. — View Citation

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epu — View Citation

Choi JW, Herr DR, Noguchi K, Yung YC, Lee CW, Mutoh T, Lin ME, Teo ST, Park KE, Mosley AN, Chun J. LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol. 2010;50:157-86. doi: 10.1146/annurev.pharmtox.010909.105753. Review. — View Citation

Dusaulcy R, Rancoule C, Grès S, Wanecq E, Colom A, Guigné C, van Meeteren LA, Moolenaar WH, Valet P, Saulnier-Blache JS. Adipose-specific disruption of autotaxin enhances nutritional fattening and reduces plasma lysophosphatidic acid. J Lipid Res. 2011 Ju — View Citation

Ferry G, Tellier E, Try A, Grés S, Naime I, Simon MF, Rodriguez M, Boucher J, Tack I, Gesta S, Chomarat P, Dieu M, Raes M, Galizzi JP, Valet P, Boutin JA, Saulnier-Blache JS. Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis — View Citation

Hinestrosa MC, Dickersin K, Klein P, Mayer M, Noss K, Slamon D, Sledge G, Visco FM. Shaping the future of biomarker research in breast cancer to ensure clinical relevance. Nat Rev Cancer. 2007 Apr;7(4):309-15. doi: 10.1038/nrc2113. Review. Erratum in: Nat — View Citation

Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971. doi: 10.1155/2014/437971. Epub 2014 Sep 21. — View Citation

Jansen S, Stefan C, Creemers JW, Waelkens E, Van Eynde A, Stalmans W, Bollen M. Proteolytic maturation and activation of autotaxin (NPP2), a secreted metastasis-enhancing lysophospholipase D. J Cell Sci. 2005 Jul 15;118(Pt 14):3081-9. Epub 2005 Jun 28. — View Citation

Kazama S, Kitayama J, Aoki J, Mori K, Nagawa H. Immunohistochemical detection of autotaxin (ATX)/lysophospholipase D (lysoPLD) in submucosal invasive colorectal cancer. J Gastrointest Cancer. 2011 Dec;42(4):204-11. doi: 10.1007/s12029-010-9186-4. — View Citation

Leblanc R, Peyruchaud O. New insights into the autotaxin/LPA axis in cancer development and metastasis. Exp Cell Res. 2015 May 1;333(2):183-9. doi: 10.1016/j.yexcr.2014.11.010. Epub 2014 Nov 25. Review. — View Citation

Lønning PE. Breast cancer prognostication and prediction: are we making progress? Ann Oncol. 2007 Sep;18 Suppl 8:viii3-7. Review. — View Citation

Mao Y, Keller ET, Garfield DH, Shen K, Wang J. Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev. 2013 Jun;32(1-2):303-15. doi: 10.1007/s10555-012-9415-3. Review. — View Citation

Nikitopoulou I, Oikonomou N, Karouzakis E, Sevastou I, Nikolaidou-Katsaridou N, Zhao Z, Mersinias V, Armaka M, Xu Y, Masu M, Mills GB, Gay S, Kollias G, Aidinis V. Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled — View Citation

Ramsay DT, Kent JC, Hartmann RA, Hartmann PE. Anatomy of the lactating human breast redefined with ultrasound imaging. J Anat. 2005 Jun;206(6):525-34. — View Citation

Reis-Filho JS, Pusztai L. Gene expression profiling in breast cancer: classification, prognostication, and prediction. Lancet. 2011 Nov 19;378(9805):1812-23. doi: 10.1016/S0140-6736(11)61539-0. Review. — View Citation

Samadi N, Gaetano C, Goping IS, Brindley DN. Autotaxin protects MCF-7 breast cancer and MDA-MB-435 melanoma cells against Taxol-induced apoptosis. Oncogene. 2009 Feb 19;28(7):1028-39. doi: 10.1038/onc.2008.442. Epub 2008 Dec 15. — View Citation

Shao Y, Yu Y, He Y, Chen Q, Liu H. Serum ATX as a novel biomarker for breast cancer. Medicine (Baltimore). 2019 Mar;98(13):e14973. doi: 10.1097/MD.0000000000014973. — View Citation

Teo K, Brunton VG. The role and therapeutic potential of the autotaxin-lysophosphatidate signalling axis in breast cancer. Biochem J. 2014 Oct 1;463(1):157-65. doi: 10.1042/BJ20140680. Review. — View Citation

van Meeteren LA, Moolenaar WH. Regulation and biological activities of the autotaxin-LPA axis. Prog Lipid Res. 2007 Mar;46(2):145-60. Epub 2007 Mar 16. Review. — View Citation

Vandeweyer E, Hertens D. Quantification of glands and fat in breast tissue: an experimental determination. Ann Anat. 2002 Mar;184(2):181-4. — View Citation

Windrichova J, Fuchsova R, Kucera R, Topolcan O, Fiala O, Finek J, Slipkova D, Karlikova M, Svobodova J. Testing of a Novel Cancer Metastatic Multiplex Panel for the Detection of Bone-metastatic Disease - a Pilot Study. Anticancer Res. 2016 Apr;36(4):1973 — View Citation

Xia Q, Deng AM, Wu SS, Zheng M. Cholera toxin inhibits human hepatocarcinoma cell proliferation in vitro via suppressing ATX/LPA axis. Acta Pharmacol Sin. 2011 Aug;32(8):1055-62. doi: 10.1038/aps.2011.31. Epub 2011 Jul 18. — View Citation

Zhang H, Xu X, Gajewiak J, Tsukahara R, Fujiwara Y, Liu J, Fells JI, Perygin D, Parrill AL, Tigyi G, Prestwich GD. Dual activity lysophosphatidic acid receptor pan-antagonist/autotaxin inhibitor reduces breast cancer cell migration in vitro and causes tum — View Citation

Zhang S, Li L, Wang T, Bian L, Hu H, Xu C, Liu B, Liu Y, Cristofanilli M, Jiang Z. Real-time HER2 status detected on circulating tumor cells predicts different outcomes of anti-HER2 therapy in histologically HER2-positive metastatic breast cancer patients — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To estimate the level of serum ATX as a diagnostic marker for breast cancer.	blood sample will be taken from the patients for measure of serum ATX	Baseline (before any treatment)
Secondary	To establish a cut off for serum ATX as a marker for breast cancer	blood sample will be taken from the patients for measure of serum ATX	Baseline (before any treatment)