William J. Gradishar, MD
Some data suggest that adjuvant chemotherapy may cause an aging effect.
“What are the long-term side effects of chemotherapy?” That is a frequent question from patients preparing to embark on a course of adjuvant therapy. Depending on the regimen of chemotherapy chosen, potential long-term adverse effects include premature menopause, cognitive impairment, cardiovascular and neuromuscular toxicity, and secondary malignancies. Now, two groups of investigators have studied whether premature aging is also a possible effect.
Sanoff and colleagues cite evidence that adjuvant therapy may confer effects consistent with molecular aging of 10 to 15 years in breast cancer patients. Cellular senescence has been associated with activation of INK4/ARF locus on chromosome 9p21.3, which codes for the tumor-suppressor proteins p16INK41 and ARF in peripheral blood T cells. Other markers of aging include decreased leukocyte telomere length (LTL) and expression of senescence-associated cytokines such as interleukin 6.
Blood and clinical information was obtained prospectively from 33 patients with stage I–III breast cancer prior to adjuvant anthracycline-based chemotherapy as well as at completion and 3 and 12 months after completion of chemotherapy. Markers of senescence in the study group were independently assessed in a cross-sectional cohort of 176 breast cancer survivors, of whom 39% had received adjuvant chemotherapy; these patients were enrolled a median of 3.4 years after treatment. Patients in both groups received standard-of-care chemotherapy or treatment outlined in clinical trials. Anthracycline-based chemotherapy with or without a taxane was administered to >85% of patients receiving chemotherapy.
Expression of p16INK4a and ARF increased immediately after chemotherapy and remained elevated 12 months later. This finding corresponds to an almost 15-year chronological aging in the hematologic compartment, specifically CD3+ lymphocytes. A similar effect was observed with ARF expression. The senescence-associated cytokines VEGFA (vascular endothelial growth factor A) and monocyte chemotactic protein-1 were also persistently elevated with adjuvant chemotherapy, whereas LTL did not appear to be affected. The increased expression of p16INK4a was validated in the survivor cohort with findings consistent with a 10.4-year aging effect.
Duggan and colleagues also studied the impact of LTL shortening in breast cancer survivors. A cohort of 1183 women with stage 0–III breast cancer was recruited from Surveillance, Epidemiology, and End Results (SEER) registries. Patients with ductal carcinoma in situ were excluded due to the low expectation of disease-related mortality. Ultimately, 478 patients were able to provide LTL measurements at baseline and 30 months. The findings were correlated with breast cancer-specific and all-cause mortality.
As in the Sanoff study, neither baseline nor 30-month LTL was significantly associated with disease-specific or all-cause mortality. Patients whose telomeres shortened between baseline and 30 months had a 2.3-fold higher risk for all-cause mortality and a 3-fold higher risk for breast cancer mortality than women whose telomeres lengthened. Unlike in the Sanoff study, treatment with chemotherapy or endocrine therapy (and other clinical-pathologic variables besides stage) did not enhance the correlation between LTL and all-cause or breast cancer mortality. Nevertheless, measures of aging may portend prognosis in patients with early-stage breast cancer.
Citation(s):
Sanoff HK et al. Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer. J Natl Cancer Inst 2014 Mar 28; [e-pub ahead of print].
Duggan C.Change in peripheral blood leukocyte telomere length and mortality in breast cancer survivors. J Natl Cancer Inst 2014 Mar 13; [e-pub ahead of print].
