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Radiotherapy plays an important role in the treatment of breast cancer. Some women (approximately 5-10%) experience severe radiation-related side effects of the skin and connective tissue. There is evidence that various factors, such as individual genetic susceptibility or smoking status, may be related to an increased risk for adverse effects after radiotherapy.

With this in mind, we carried out a research project on individual radiation sensitivity. The ISE study aimed to find factors that are suitable for predicting radiotherapy-related side effects. Among other things, cellular features that limit the effectiveness of radiotherapy or trigger an overreaction of normal cells were examined. If such features are taken into account for radiotherapy treatment planning, it could lead to better treatment success and fewer side effects.

In the first part of the ISE study (1998–2001), clinical data on anamnesis and course of treatment was collected from 478 breast cancer patients from the Rhine-Neckar-Karlsruhe region in Germany. The patients received radiotherapy after breast-conserving surgery without chemotherapy. Blood samples were collected to obtain genetic data. The clinical acute radiation sensitivity documented by physicians was compared with changes in the reparability of lymphocytes. It was found that the acute skin reactions after radiotherapy were independent of the reparability of the lymphocytes.
In the second part of the study (2003–2005) risk factors for late side effects were examined. 416 patients took part in the follow-up survey to analyse long-term effects. Late radiation effects such as enlarged veins of the irradiated skin (telangiectasia) and hardening of the connective tissue (breast fibrosis) depend not only on the radiation dose but also on the age of the patient and her smoking status. In addition, patients with allergies or high blood pressure had an increased risk of radiotherapy-induced skin changes compared to women without these diseases. In patients with telangiectasia, certain genetic traits were associated with an increased risk of late side effects.
In the third part of the study (2011), 295 study patients were examined about 10 years after radiotherapy for the identification of biomarkers for long-term effects. Like in the first part of the study, quality of life data were also collected. Increased hardening of the connective tissue outside the surgical area, likely to be related to the radiotherapy, was found in 8% of the patients. Almost 5% of the patients had pain that required treatment. In a radiation-induced lymphocyte assay (RILA), low levels of CD4+ T lymphocytes were associated with an increased risk of breast fibrosis and telangiectasia after 10 years.

 

Further Evaluations

In order to enlarge the study sample and to achieve more reliable results, the genetic studies were extended to about 400 selected radiotherapy-treated patients of the MARIE study (MARIErad) and also to other cohorts within the framework of the Radiogenomics consortium . It was found that certain genotypes (e.g. XRCC1, TNFalpha) can also influence the risk of late side effects after radiotherapy.
The technical advancement of radiotherapy have reduced the side effects and allows a more targeted treatment while sparing normal tissue, so that serious late effects are now rare. To investigate the occurrence of late effects of modern radiotherapy and their influencing factors, the international REQUITE project with a large patient cohort and its follow-up studies such as RADprecise followed.

Collaboration partners of the ISE Study:

Unit of DNA repair and Epigenomics (P. Schmezer and O. Popanda).
Universitätsklinikum Heidelberg
Städtisches Klinikum Karlsruhe
St. Vincentius-Kliniken gAG Karlsruhe
Universitätsklinikum Mannheim
Roswell Park Cancer Institute, Buffalo, New York

Funding:

Bundesamt für Strahlenschutz (BfS, Federal Office for Radiation Protection)
Dietmar Hopp Stiftung (Dietmar Hopp Foundation)
Department of Defense, USA

Selected publications:

Association of CD4+ radiation-induced lymphocyte apoptosis with fibrosis and telangiectasia after radiotherapy in 272 breast cancer patients with >10-year follow-up, Veldwijk MR, Seibold P, Botma A, Helmbold I, Sperk E, Giordano FA, Gürth N, Kirchner A, Behrens S, Wenz F, Chang-Claude J, Herskind C. (2018), Clin Cancer Res, doi: 10.1158/1078-0432.CCR-18-0777

A replicated association between polymorphisms near TNFa and risk for adverse reactions to radiotherapy. Talbot CJ, Tanteles GA, Barnett GC, Burnet NG, Chang-Claude J, Coles CE, Davidson S, Dunning AM, Mills J, Murray RJS, Popanda O, Seibold P, West CML, Yarnold JR; Symonds RP. Br J Cancer (2012), 1–6.

Polymorphisms in oxidative stress-related genes and postmenopausal breast cancer risk, Seibold P, Hein R, Schmezer P, Hall P, Liu J, Dahmen N, Flesch-Janys D, Popanda O, Chang-Claude J. Int J Cancer 2011; 129(6): 1467-76.

Predictive factors for late normal tissue complications following radiotherapy for breast cancer, Lilla C, Ambrosone CB, Kropp S, Helmbold I, Schmezer P, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Chang-Claude J (2007), Breast Cancer Res Treat, 106 (1), 143-150.

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