The incidence of breast cancer, the most frequent tumor occurring in women, increases with age. While adequate treatment can improve outcome and survival in the elderly, concerns over side effects or the idea of futility results in a lower use of adjuvant chemotherapy in this patient population. This might be one of the reasons why cancer-related mortality is higher in older patients. In addition, long-term impact of chemotherapy on the patient’s global health condition may be more pronounced and, at the same time, less predictable in older individuals.
Body ageing is a complex phenomenon involving several, partly overlapping, molecular mechanisms. Among others, these include the accumulation of oxidative stress and DNA damage, the shortening of telomeres, and neuroendocrine and immunologic changes. It is generally assumed that chemotherapy may accelerate the ageing process through interference at the level of one or several of these ageing driving forces.
MicroRNAs (miRNAs) are important regulators of cellular function and have been associated with both ageing and cancer, while the impact of chemotherapy on miRNAs has barely been studied. To examine whether chemotherapy accelerates the ageing process, Dalmasso and colleagues monitored age-related circulating miRNAs in 89 older breast cancer patients (>70 years), receiving adjuvant chemotherapy (N= 46; chemo-group) or no chemotherapy (N= 43; control-group). All patients underwent geriatric assessment at inclusion, after 3 months and 1 year.
At each timepoint the investigators analysed the serum expression of nine age-related miRNAs (miR-20a, miR-30b, miR-34a, miR-106b, miR-191, miR-301a, miR320b, miR374a, miR-378a). The primary aim of the study was to assess miRNA changes during the study period, including differences between groups. Secondary endpoints included association of microRNAs with: chronological age, clinical geriatric assessment parameters and ageing biomarkers assessed in the above-mentioned study. Also clustering of patients according to specific miRNA signatures was performed. Finally, the predictive role of miRNAs at time of inclusion on decline in functionality and quality of life and on toxicity and unexpected hospitalization during or after chemotherapy was evaluated.
Except for miR-106b, which appeared to behave slightly different in the chemo-group compared to the control-group, all other miRNAs underwent moderate fluctuations during the study course with no significant differences between both groups. Also within the older cohort, several age-related miRNAs significantly (p<0.05) correlated with clinical ageing/frailty (miR-106b, miR-191, miR-301a, miR-320b, miR-374a), as well as with other biomarkers of ageing. In particular, miR-106b, miR-374a and miR-378a were associated with the age-related biomarker IL-6 (slope= -0.34, -0.30 and 0.30 respectively, p<0.05), whereas miR-301a and miR-378a showed a relevant correlation with another age-related biomarker: MCP-1 (slope= -0.18 and 0.27 respectively, p< 0.05).
Moreover, based on their ageing miRNA profiles, patients clustered into two distinct groups, cluster A and cluster B, exhibiting significantly different results for several biological/clinical ageing parameters. Cluster A (N=43, miR-20a, miR-30b, miR-191, miR-301a and miR-374a underexpressed, miR-378a overexpressed) was characterized by older age, higher geriatric risk profile, as well as elevated IL-6, TNFα and MCP-1 levels compared to cluster B (N=45, inverse expression pattern). Moreover, 31.9% of cluster A-patients but only 7.4% of cluster B-patients experienced decline in quality of life after chemotherapy (p=0.051).
In summary: these results further corroborate recent findings1, stating that adjuvant chemotherapy does not significantly boost ageing progression in elderly breast cancer patients. The data presented at the San Antonio Breast Cancer Conference 2016 also endorsed specific age-related miRNAs as promising ageing/frailty biomarkers in oncogeriatric populations.
- Brouwers B, Hatse S, Dal Lago L, et al. The impact of adjuvant chemotherapy in older breast cancer patients on clinical and biological ageing parameters. Oncotarget. 2016; 7: 29977-29788.
- Dalmasso B, Hatse S, Brouwers B, et al. Age-related microRNAs and their biomarker potential in chemotherapy-treated older breast cancer patients. Poster presentation at the San Antonia Breast Cancer Congress 2016. Abstract P4-07-08.