This article is more than 5 years old. Information may no longer be current.
Adjuvant chemotherapy induced cellular aging in patients with breast cancer
Click Here to Manage Email Alerts
Concomitant chemotherapy for breast cancer may expedite the process of molecular aging in the hematopoietic tissue of survivors, according to recent findings.
In the prospective cohort study, researchers evaluated 33 women with newly diagnosed stage I to III breast cancer slated to undergo neoadjuvant or adjuvant anthracycline-based chemotherapy. The investigators collected clinical and hematologic data from these participants before anthracycline-based chemotherapy, immediately after the chemotherapy, 3 months after chemotherapy, and 12 months after anthracycline-based chemotherapy.
Researchers used quantitative reverse-transcription polymerase chain reaction to assess the expression of aging markers p16INK4aand ARF mRNA in CD3+ T cells, and Southern analysis was used to measure telomere length. Cytokines related to aging were detected via enzyme-linked immunosorbent assay.
The researchers also evaluated a separate, cross-sectional cohort of breast cancer survivors (n=176), who had undergone surgical resection for stage I to III disease. These participants were enrolled in the study a median of 3.4 years post-treatment. Of these participants, 39% underwent chemotherapy.
The investigators found that in the cohort of patients with newly diagnosed breast cancer, there was an immediate increase in the expression of log2 p16INK4aand ARF mRNA after chemotherapy, and this increase remained consistent for the following 12 months.
There was a median increase in log2 p16INK4aof 0.81 (interquartile range=0.28-1.62; Wilcoxon signed-rank P<.001), which represented a 75% absolute increase in expression and equaled the increase seen in the course of 14.7 years of chronological aging. There also was a significant increase in ARF(P<.001). Dose-dense therapy and toxicity in the blood were implicated in the increased expression of p16INK4aand ARF.
Adjuvant chemotherapy also was found to cause a lasting increase the expression of two aging-related cytokines, VEGFA and MCP1. Chemotherapy did not have an apparent effect on telomere length.
In the survivor cohort, previous chemotherapy exposure was independently linked to a log2 increase of 0.57 (repeated measures model, P<.001) in the expression of log2 p16INK4a, which was equal to 10.4 years of chronological aging.
“We have shown that cytotoxic chemotherapy potently induces the expression of markers of cellular senescence in the hematologic compartment in vivo, comparable with the effects of 10 to 15 years of chronologic aging in independent cohorts of healthy donors,” the researchers wrote.
Disclosure: Two of the researchers are co-inventors on a University of North Carolina-owned patent related to this work (US PCT/US2005/034542 “Determination of Molecular Age by Detection of INK4a/ARF Expression”).
Click Here to Manage Email Alerts