Accelerated Aging in Breast Cancer Survivors: The Impact of Tumors and Treatment
Introduction
Breast cancer is the most prevalent cancer among women worldwide. While advancements in early detection and treatment have significantly increased survival rates—91% at five years and 85% at ten years—many survivors experience premature aging. Currently, an estimated four million women in the United States alone live as breast cancer (BC) survivors.
Despite extended lifespans, BC survivors often face accelerated cognitive decline and physical frailty compared to their cancer-free counterparts. A recent study published in Aging investigated the association between Phenotypic Age Acceleration (PAA) and various BC characteristics and treatments. This novel method combines chronological age (CA) with multiple biomarkers, including C-reactive protein (CRP), to assess biological aging and predict mortality risk.
Study Participants
The study analyzed data from 1,264 BC patients and 429 cancer-free controls. On average, BC patients were five years older than controls and exhibited a higher mortality rate (8% vs. 4%) over a median follow-up period of nine years. At the time of diagnosis, 68% had early-stage cancer (stage I/II), while 17% were diagnosed with stage III/IV disease. Tumor grading varied, with 35% classified as high-grade and 39% as intermediate-grade.
Breast cancer subtypes were distributed as follows:
- 45% HR+/HER2- (hormone receptor-positive, HER2-negative)
- 13% HER2-positive
- 14% triple-negative BC (TNBC)
Treatment strategies varied, with surgery being the most common (90%). Chemotherapy was administered to 60% of patients, 51% received radiation therapy, and 66% underwent hormone therapy. Targeted therapy was used in 17% of cases, whereas immunotherapy was administered to only 3%. During follow-up, 2% of patients developed a second BC, and 20% experienced metastasis or recurrence.
Study Findings
BC patients demonstrated significantly higher PAA than controls. At diagnosis, their phenotypic age (PA) exceeded their chronological age by an average of four years. Over time, this gap narrowed:
- One-year post-diagnosis: PA exceeded CA by two years
- Ten-year mark: PA exceeded CA by one year
- No significant differences were observed at two or five years
Aging patterns varied based on patient characteristics:
- Age at diagnosis: Patients diagnosed at 65+ initially appeared biologically younger but aged faster over time, surpassing their CA by 1.5 years at two, five, and ten years.
- Cancer stage: Stage III/IV patients had a persistent five-year PAA that lasted throughout the ten-year follow-up.
- Tumor grade: High-grade tumors correlated with sustained accelerated aging, peaking at a three-year difference at one year and remaining two years higher at year ten.
- Cancer subtype: HER2+ patients aged faster than HR+/HER2- patients, showing a PAA of two years at year one and 1.5 years at year five. TNBC patients aged 3.5 years faster at year one but displayed a reversal by year ten, appearing two years younger than their CA.
Impact of Treatment on Aging
Different treatments influenced aging differently:
- Surgery had a protective effect, leading to a phenotypic age seven years younger than CA by year ten.
- Radiation therapy alone resulted in a two-year reduction in aging.
- Chemotherapy had no significant effect on PAA when administered alone but, when combined with other therapies, accelerated aging by four years at one year post-diagnosis.
- Hormone therapy increased aging by nearly three years at both one and ten years post-diagnosis.
- Specific chemotherapy agents:
- Alkylating agents and anthracyclines initially increased PAA by two years at year one but later reversed this effect, leading to a two- to 2.5-year reduction at years five and ten.
- Antimetabolites, selective estrogen receptor modulators (SERMs), and aromatase inhibitors (AIs) initially slowed aging but eventually accelerated it. Antimetabolites increased aging by seven years at year ten, while AIs added two years to CA at the same time point.
These findings suggest that while some treatments slow aging temporarily, hormone therapy and chemotherapy combinations may contribute to long-term accelerated aging.
Mechanisms Behind Accelerated Aging
Several biological mechanisms may explain accelerated aging in BC survivors. Cytotoxic chemotherapy can induce cellular senescence, telomere shortening, chronic inflammation, mitochondrial dysfunction, genomic instability, and epigenetic changes—effects that may persist for a decade. Hormone therapy may also disrupt normal hormonal regulation, genomic stability, and mitochondrial function, leading to stem cell depletion and increased biological aging.
