Biomarkers of aging associated with past treatments in breast cancer survivors

Abstract

Radiation and chemotherapy are effective treatments for cancer, but are also toxic to healthy cells. Little is known about whether prior exposure to these treatments is related to markers of cellular aging years later in breast cancer survivors. We examined whether past exposure to chemotherapy and/or radiation treatment was associated with DNA damage, telomerase activity, and telomere length 3-6 years after completion of primary treatments in breast cancer survivors (stage 0-IIIA breast cancer at diagnosis). We also examined the relationship of these cellular aging markers with plasma levels of Interleukin (IL)-6, soluble TNF-receptor-II (sTNF-RII), and C-reactive protein (CRP). Ninety-four women (36.4-69.5 years; 80% white) were evaluated. Analyses adjusting for age, race, BMI, and years from last treatment found that women who had prior exposure to chemotherapy and/or radiation compared to women who had previously received surgery alone were more likely to have higher levels of DNA damage (P = .02) and lower telomerase activity (P = .02), but did not have differences in telomere length. More DNA damage and lower telomerase were each associated with higher levels of sTNF-RII (P's < .05). We found that exposure to chemotherapy and/or radiation 3-6 years prior was associated with markers of cellular aging, including higher DNA damage and lower telomerase activity, in post-treatment breast cancer survivors. Furthermore, these measures were associated with elevated inflammatory activation, as indexed by sTNF-RII. Given that these differences were observed many years after the treatment, the findings suggest a long lasting effect of chemotherapy and/or radiation exposure.

Fig. 1

Percentage of breast cancer survivors with high DNA damage (top quartile) with either past exposure to chemotherapy and/or radiation or surgery alone. OR(95% CI) = 18.49(1.56, 218.9), P = .02

Fig. 2

Estimated marginal mean ± SE of PBMC telomerase enzymatic activity (TPG per 10,000 cells) in breast cancer survivors with either past treatment exposure to chemotherapy and/or radiation or surgery alone, adjusting for age, race, BMI, and years from treatment exposure. B(SE) = −1.93(.83), P = .02. Note: Figure displays mean scores from non-transformed data, while statistical analyses use transformed telomerase activity (deciles) due to non-normal distribution in TPG values

Fig. 3

Mean ± SE of sTNF-RII within higher (top quartile) and lower (three lower quartiles) DNA damage groups adjusting for age, race, BMI, and years from treatment exposure. B(SE) = 349.8(127.5), P = .007