Breast cancer is the most common cancer among women worldwide, and early detection and treatment have significantly boosted survival rates. With five-year survival at 91% and ten-year survival at 85%, millions of women are now living as breast cancer survivors. However, new research published in Aging reveals that surviving breast cancer comes with a hidden cost: accelerated biological aging. This study, which introduces the concept of Phenotypic Age Acceleration (PAA), examines how both the characteristics of the tumor and the treatments administered may contribute to an increased rate of aging among survivors.
Understanding Phenotypic Age Acceleration (PAA)
PAA is a novel metric that combines a person’s chronological age with levels of C-reactive protein (CRP) and eight routine blood biomarkers to assess biological aging. Unlike traditional measures, PAA offers a cost-effective and accessible way to predict mortality risk by estimating how much older a person’s body appears to be compared to their actual age. In breast cancer survivors, this measure can help determine whether the disease and its treatments have long-lasting impacts on health beyond the immediate challenges of cancer.
Study Participants: A Comprehensive Cohort
The study analyzed data from 1,264 breast cancer patients and compared them with 429 cancer-free controls. On average, the breast cancer patients were five years older than the controls, and during a median follow-up period of nine years, their mortality rate was double that of the control group (8% versus 4%). At the time of diagnosis, 68% of the patients were in stage I or II, while 17% had stage III/IV disease. Tumor grade varied, with 35% of cases being high-grade and 39% intermediate-grade. In terms of cancer subtypes, 45% were hormone receptor-positive but HER2-negative (HR+/HER2-), 13% were HER2-positive, and 14% had triple-negative breast cancer (TNBC).
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The treatment regimens were diverse: nearly 90% of patients underwent surgery; 60% received chemotherapy; 51% were treated with radiation; and 66% received hormone therapy. Only 17% underwent targeted therapy, and a mere 3% received immunotherapy. Over the follow-up period, 2% developed a second breast cancer, while 20% experienced metastasis or recurrence.
Key Findings: Accelerated Aging at Diagnosis and Beyond
At diagnosis, breast cancer patients had a phenotypic age that was, on average, four years older than their chronological age. This initial gap in biological aging provides a stark indicator of how the disease and its aggressive nature might impact the body. Interestingly, the gap narrowed over time: one year post-diagnosis, the difference reduced to two years, and by ten years, it had further diminished to one year. However, these trends varied significantly depending on several factors, including the patient’s age at diagnosis, tumor stage, and grade.
Patients diagnosed at age 65 or older initially appeared phenotypically younger than their chronological age, but over the course of the follow-up, they aged faster, eventually surpassing their chronological age by an average of 1.5 years at two, five, and ten years. Those with stage III/IV breast cancer exhibited a pronounced acceleration, with a five-year gap at diagnosis that persisted even after ten years. High-grade tumors were linked to sustained accelerated aging, peaking at a three-year difference at one year and remaining two years higher at ten years.
The impact of cancer subtype was also notable. Patients with HER2-positive disease aged faster than those with HR+/HER2- tumors, with a two-year PAA at one year post-diagnosis and 1.5 years at five years. TNBC patients experienced an even more dramatic acceleration—3.5 years at one year and two years at two years—although by ten years, their phenotypic age was reportedly two years lower than their chronological age, suggesting a complex, time-dependent effect.
Treatment Impact: The Double-Edged Sword
Different treatment modalities for breast cancer were found to have varying effects on biological aging. Surgery appeared to offer a protective effect; patients who underwent surgery exhibited a phenotypic age that was seven years younger than their chronological age at ten years post-diagnosis. Radiation therapy alone also showed a beneficial effect, resulting in a two-year reduction in phenotypic age. When surgery and radiation were combined, the impact was similar to surgery alone, highlighting the potential long-term benefits of these interventions.
In contrast, the effects of chemotherapy and targeted therapy were more complex. When administered alone, these treatments did not significantly impact PAA. However, combination regimens that included chemotherapy led to an accelerated aging of about four years at one year post-diagnosis. Hormone therapy, whether used alone or in combination with other treatments, was associated with an almost three-year acceleration in phenotypic age at both one and ten years. Notably, among chemotherapy agents, alkylating agents and anthracyclines initially increased PAA by two years at one year, but this effect reversed over time, resulting in a reduction of 2 to 2.5 years at five and ten years. Conversely, antimetabolites initially reduced phenotypic age by one year at two years but ultimately accelerated aging by seven years at ten years, while aromatase inhibitors added two years to the phenotypic age over the same period.
Mechanisms of Accelerated Aging
The study posits that accelerated aging in breast cancer survivors may result from a combination of the disease itself and the cytotoxic effects of various treatments. Cytotoxic chemotherapy can induce cellular senescence, accelerate telomere shortening, provoke chronic inflammation, and lead to mitochondrial dysfunction, genomic instability, and epigenetic alterations. These factors can collectively speed up the aging process, even years after treatment has ended.
Hormone therapy, while effective in managing certain types of breast cancer, may also disrupt normal hormonal adaptation and genomic stability, contributing to increased biological aging. The observed differences in phenotypic age among patients based on tumor characteristics and treatment regimens underscore the need for a nuanced approach to survivorship care.
Conclusions: Implications for Survivorship Care
“This study provides evidence of accelerated aging among breast cancer survivors and identifies high-risk populations based on tumor characteristics and treatments,” the authors state. The application of PAA—calculated from routine biochemical markers—offers a new lens through which to assess the long-term impact of cancer and its treatments on the body.
While the findings highlight significant associations between certain treatments and accelerated aging, they must be interpreted with caution. Selection and survival biases may influence the results, as patients with more aggressive tumors or those undergoing intensive treatments may inherently have higher PAA and greater mortality risks. Moreover, tumor characteristics seem to primarily influence aging at diagnosis, with less impact during the follow-up period.
Further research is needed to explore the interplay between demographic and lifestyle factors and aging outcomes in breast cancer survivors, particularly as new treatment regimens emerge. These insights could be invaluable in refining long-term care strategies and improving the quality of life for survivors. By understanding the mechanisms that drive accelerated aging, clinicians can develop targeted interventions to mitigate these effects and help survivors maintain their health and vitality long after their cancer treatment has ended.
Looking Forward
As the number of breast cancer survivors continues to grow—over four million in the United States alone—addressing accelerated aging becomes increasingly critical. Future studies will ideally lead to more personalized care approaches, where treatment decisions are informed not only by cancer subtype and stage but also by the potential long-term impact on a patient’s biological aging. Integrating these insights into survivorship care plans could help ensure that survivors not only live longer but also maintain a higher quality of life.
