Clinical trial NCT04002570: Adjuvant Radiotherapy on Circulating Cells in Breast Cancer Patients
Official title: Effects of Adjuvant Radiotherapy on Bone-marrow Derived and Immune Cells in Breast Cancer Patients
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Breast Cancer
Keywords: breast cancer
circulating bone marrow-derived cells
circulating immune cells
radiotherapy
conservative treatment
disease control
Lead sponsor: Clinica Luganese Moncucco
Sponsor class: OTHER
Collaborators: name: Curzio Rüegg, MD, Head of Department, University of Fribourg
name: Swiss National Science Foundation
name: Tsoutsou Pelagia MD, Head of Radation Therapy Department
First posted: 2019-06-28
Enrollment: 13
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: patients performing treatments for breast cancer

Brief summary: Radiation applied to the preserved breast during radiotherapy treatment activates numerous molecular cascades in tumor bed adjacent cells causing an inflammatory state. During this process, pre-clinical studies demonstrated CD11b + and CD11b+cKit+cells mobilization in the blood. These cells are involved in numerous processes during tumor progression/control and metastases development. The expected results in clinical setting allow us to investigate the development of innovative therapeutic and monitoring strategies. The clinical repercussions would consist in identifying new predictive and prognostic targets in breast cancer.

Detailed description: Every year, around one million women are newly diagnosed with breast cancer. Early screening and adjuvant treatments with curative intent such as radiotherapy, hormone therapy, chemotherapy, immunotherapy, have reduced the incidence of breast cancer specific mortality. Despite this, breast cancer remains the main cause of cancer mortality in Europe. The primary cause is due to metastases development in different organs, such as lung, liver, bones and brain. A significant decrease in mortality in breast cancer patients is likely to be achieved by preventing the formation of metastases or by implementing the efficacy of their treatment. Radiotherapy is one of the pillars of breast cancer adjuvant treatments with important survival benefits.

Mutual and dynamic communications between tumor cells and the tumor microenvironment (TME) influence the development and evolution of the tumor as well as the appearance of distant metastases. The mediators of the immune and inflammatory response that constitute TME, as well as mediators of tumor progression, are also considered "targets" of future therapeutic strategies.

Radiation applied to the preserved breast during radiotherapy treatment activates numerous molecular cascades in tumor bed adjacent cells causing an inflammatory state. During this process, pre-clinical studies demonstrated CD11b + and CD11b+cKit+cells mobilization in the blood. These cells are involved in numerous processes during tumor progression/control and metastases development. The results allow us to investigate the development of innovative therapeutic and monitoring strategies. The clinical repercussions would consist in identifying new predictive and prognostic targets in breast cancer.

Eligibility criteria: Inclusion Criteria:

* breast cancer diagnosis bioptically proven with pre-operative clinical stage cT1-4, N0-1, M0;
* patients who are candidates for conservative surgery (tumorectomy / quadrantectomy +/- lymphadenectomy or sentinel lymph node) or patients already undergoing conservative surgery;
* patients who are candidates for an adjuvant mammary radiotherapy treatment +/- adjuvant or neoadjuvant chemotherapy due to a triple negative or a high ki67 value that has indicated it;
* understanding of the Italian language for the Coordinating Center, understanding of the French language for the satellite center.

Exclusion Criteria:

* previous mastectomy surgery;
* concomitant cancer diseases;
* previous chemo / radiotherapy treatments in the last three years.

Primary outcomes:
measure: the frequency of CD11b⁺cKit⁺ cells in peripheral blood and/or gene expression in circulating CD11b⁺ cells
timeFrame: pre surgery
measure: the frequency of CD11b⁺cKit⁺ cells in peripheral blood and/or gene expression in circulating CD11b⁺ cells
timeFrame: pre radiotherapy
measure: the frequency of CD11b⁺cKit⁺ cells in peripheral blood and/or gene expression in circulating CD11b⁺ cells
timeFrame: week 6 of radiotherapy
Secondary outcomes:
measure: radiotherapy alters in a potentially predictive way the frequency of CD11b⁺cKit⁺ cells in peripheral blood
timeFrame: week 12-14 (fu)
Other outcomes:
Locations:
city: Lugano
country: Switzerland
facility: Clinica Luganese Moncucco
state: Ticino
Study officials:
affiliation: Clinica Luganese Moncucco
name: Alessandra Franzetti Pellanda, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ruegg CR, Chiquet-Ehrismann R, Alkan SS. Tenascin, an extracellular matrix protein, exerts immunomodulatory activities. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7437-41. doi: 10.1073/pnas.86.19.7437.
citation: Lorusso G, Ruegg C. The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem Cell Biol. 2008 Dec;130(6):1091-103. doi: 10.1007/s00418-008-0530-8. Epub 2008 Nov 6.
citation: Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012 Mar 20;21(3):309-22. doi: 10.1016/j.ccr.2012.02.022.
citation: Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002 Dec 19-26;420(6917):860-7. doi: 10.1038/nature01322.
citation: Schlaeppi M, Ruegg C, Tran-Thang C, Chapuis G, Tevaearai H, Lahm H, Sordat B. Role of integrins and evidence for two distinct mechanisms mediating human colorectal carcinoma cell interaction with peritoneal mesothelial cells and extracellular matrix. Cell Adhes Commun. 1997 Mar;4(6):439-55. doi: 10.3109/15419069709004460.
citation: Boylan AM, Ruegg C, Kim KJ, Hebert CA, Hoeffel JM, Pytela R, Sheppard D, Goldstein IM, Broaddus VC. Evidence of a role for mesothelial cell-derived interleukin 8 in the pathogenesis of asbestos-induced pleurisy in rabbits. J Clin Invest. 1992 Apr;89(4):1257-67. doi: 10.1172/JCI115710.
citation: Ruegg C, Pytela R, Erle DJ. Characterization of the leukocyte integrin subunit beta 7. Chest. 1993 Feb;103(2 Suppl):86S. doi: 10.1378/chest.103.2_supplement.86s. No abstract available.
citation: Sharma P, Sahni NS, Tibshirani R, Skaane P, Urdal P, Berghagen H, Jensen M, Kristiansen L, Moen C, Sharma P, Zaka A, Arnes J, Sauer T, Akslen LA, Schlichting E, Borresen-Dale AL, Lonneborg A. Early detection of breast cancer based on gene-expression patterns in peripheral blood cells. Breast Cancer Res. 2005;7(5):R634-44. doi: 10.1186/bcr1203. Epub 2005 Jun 14.
citation: Kuonen F, Secondini C, Ruegg C. Molecular pathways: emerging pathways mediating growth, invasion, and metastasis of tumors progressing in an irradiated microenvironment. Clin Cancer Res. 2012 Oct 1;18(19):5196-202. doi: 10.1158/1078-0432.CCR-11-1758. Epub 2012 Jun 22.
citation: Drooger JC, Hooning MJ, Seynaeve CM, Baaijens MH, Obdeijn IM, Sleijfer S, Jager A. Diagnostic and therapeutic ionizing radiation and the risk of a first and second primary breast cancer, with special attention for BRCA1 and BRCA2 mutation carriers: a critical review of the literature. Cancer Treat Rev. 2015 Feb;41(2):187-96. doi: 10.1016/j.ctrv.2014.12.002. Epub 2014 Dec 8.
citation: Ruegg C, Yilmaz A, Bieler G, Bamat J, Chaubert P, Lejeune FJ. Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med. 1998 Apr;4(4):408-14. doi: 10.1038/nm0498-408.
citation: Han M, Liew CT, Zhang HW, Chao S, Zheng R, Yip KT, Song ZY, Li HM, Geng XP, Zhu LX, Lin JJ, Marshall KW, Liew CC. Novel blood-based, five-gene biomarker set for the detection of colorectal cancer. Clin Cancer Res. 2008 Jan 15;14(2):455-60. doi: 10.1158/1078-0432.CCR-07-1801. Epub 2008 Jan 18.
citation: Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thurlimann B, Senn HJ; Panel Members. Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015 Aug;26(8):1533-46. doi: 10.1093/annonc/mdv221. Epub 2015 May 4.
citation: Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Med Etika Bioet. 2002 Spring-Summer;9(1-2):12-9. No abstract available.
citation: Dixon JR Jr. The International Conference on Harmonization Good Clinical Practice guideline. Qual Assur. 1998 Apr-Jun;6(2):65-74. doi: 10.1080/105294199277860.
citation: [The Helsinki Declaration of the World Medical Association (WMA). Ethical principles of medical research involving human subjects]. Pol Merkur Lekarski. 2014 May;36(215):298-301. No abstract available. Polish.