gms | German Medical Science

Background: Radiotherapy (RT) is routinely applied after breast conserving surgery (BCS) in breast cancer patients to decrease the risk of local recurrences. However, late adverse effects of tissue such as skin alterations (e.g. telangiectasia) and fibrosis can occur as a consequence of radiotherapy years after treatment. We investigated the influence of potential risk factors such as radiation dose, BMI, and genetic variants on the occurrence of RT-induced late adverse effects.

Methods: A subgroup of 414 breast cancer patients from the study region Rhein-Neckar-Karlsruhe of the German MARIE study, who underwent RT after BCS between 2002 and 2005 but did not receive chemotherapy, participated in this subproject (participation rate: 84%). Exclusion criteria were bilateral disease, previous cancer(s) or metastases at time of diagnosis. The occurrence of late adverse effects was evaluated by an experienced study physician according to standardized EORTC/RTOG scoring, ranging from 0=no late toxicities to 4=severe adverse effects. The non-irradiated breast was used as reference. Associations of risk factors with skin alterations and with fibrosis, respectively, were assessed by logistic regression in 387 patients, excluding individuals who received intraoperative or interstitial boost to achieve a homogeneously exposed population. Genotype association was tested in up to 363 individuals with genotype information. An independent study of 390 breast cancer patients from the same study region (RT after BCS: 1998-2001) was used for replication (iPlex application).

Results: A total of 46 of 414 patients (11%) presented with skin alterations grade 2 or 3 after a median follow-up time of 67 months. 43 patients developed fibrosis (10%), of whom 23 experienced skin alterations as well. No grade 4 toxicities occurred. In a model adjusted for age at end of RT, follow-up time, and normalized total radiation dose, BMI (25+ vs. <25: OR 2.4, 95% CI 1.1-5.4) and boost energy type (p<0.001) were significantly associated with skin alterations. Two SNPs in the oxidative stress-related gene NQO1 were found to decrease the risk for telangiectasia (OR 0.3, 95% 0.1-0.9). This finding was replicated in an independent study. Risk for developing fibrosis was significantly associated with heavy smoking (≥ 20 pack years) (OR 3.97, 95% CI 1.2-13.6) and non-significantly with hypertension (OR 2.2, 95% CI 0.9-5.0).

Conclusion: We confirmed previous findings that, in addition to therapy-related factors, modifiable patient-related factors may alter the risk for late adverse effects and identified possible modifying genetic variants.