Measuring Biologic Resilience in Older Cancer Survivors

INTRODUCTION

Approximately 65% of the 17 million cancer survivors in the United States are over 65 years.¹ By 2040, it is estimated that the number of cancer survivors will increase to 26 million, with 73% age ≥ 65 and almost 50% age ≥ 75. Despite this, only 5% of NIH-funded survivorship research specifically focuses on older adults, leaving us unprepared to meet the needs of this large, growing, and understudied population.²

CONTEXT

• Key Objective

• To highlight the emerging concept of resilience in older cancer survivors, present potential biomarkers of aging that may serve as signatures of resilience, and discuss emerging interventions to promote resilience in this population.

• Knowledge Generated

• Clinically similar older adults with cancer demonstrate variable responses to health stressors. This heterogeneity is attributable to differences in physical or cognitive resilience, defined as the ability to resist or recover function after a health stressor, which diminishes with aging. Measuring age-related biologic processes, such as cellular senescence, epigenetic age acceleration, telomere length, and systemic inflammation, may identify older adults at high risk of functional disability or cognitive decline following cancer therapy. Additionally, interventions targeting these biologic pathways may enhance resilience and promote healthy aging.

• Relevance

• Fundamental biologic aging processes influencing resilience following cancer treatment may be targeted to prevent, delay, and treat the adverse aging-related effects of cancer and its treatment.

A growing body of evidence suggests that cancer and its treatment may be disease drivers of aging.³ Up to 85% of adult survivors suffer from adverse physical or cognitive consequences from cancer and its treatment.⁴ Survivors have a markedly increased risk of developing multimorbidity, frailty, and cognitive impairment earlier than would be expected in the general population,^5,6 in essence, an accelerated aging phenotype.⁷ Despite a growing awareness of these key survivorship issues facing older adults, there is a paucity of interventions to prevent, delay, or treat the short- and long-term aging-related adverse effects in older cancer survivors.⁸

Interventions that target fundamental aging biology have the potential to transform cancer survivorship care. The geroscience hypothesis posits that interventions that target biologic processes of aging can delay age-related dysfunction and disease^9,10 and thus might be applicable to the age-related consequences of cancer and its treatment. The central premise is that aging has a distinct biology that can be targeted and modified.¹¹ Interventions to slow aging have emerged from animal studies^12,13 and several human trials in chronic disease states and frail populations.^14,15 However, translating geroscience-guided interventions developed in animal models to humans is hindered by the decades of follow-up required to measure the extension of healthspan in human trials. An intermediate approach is to test if these interventions can slow the rate of biologic aging as measured by surrogate biomarkers.^16-18

A critical first step to test geroscience-guided interventions in cancer populations is to identify biomarkers that reflect underlying biologic aging in the context of cancer and its treatment. Resilience, originally used to denote the elastic property of materials, is a concept that has been applied to systems, communities, and individuals. The psychosocial literature characterizes resilience as the capacity to maintain or regain psychological well-being during or after adversity.^19,20 Physical and cognitive resilience, defined as the ability to resist or recover function (physical or cognitive) after a health stressor, is especially relevant to the care of older cancer survivors.^21-24 Most older survivors can benefit from cancer therapy in terms of survival; however, such therapies are physiologic stressors. Clinically or chronologically similar older adults demonstrate variable recovery to cancer treatment (Fig 1).^23-25 Some older patients tolerate cancer therapy without significant adverse effects on health (highly resilient). Others experience major toxicities with therapy, with some returning to their prior level of health or functioning (resilient) and others not (nonresilient). Heterogeneity in one's response to cancer therapy (resilience) is thought to be influenced by prestressor determinants and the magnitude of the stressor itself (Fig 2). The capacity to respond to these stressors diminishes with aging, and it is postulated that age-related biologic processes drive one's level of resilience.^26-28 If this is true, then biomarkers of aging may be candidate measures to predict resilience in older survivors undergoing cancer treatment.

FIG 1.

Longitudinal response to cancer therapy is dynamic and variable.

FIG 2.

Conceptual framework of resilience and cancer therapy.

In this review, we highlight the emerging concept of resilience in older cancer survivors, present potential biomarkers of aging that may serve as signatures of resilience, and discuss potential interventions to promote resilience. We summarize the measures of aging biology that are currently available, limiting our focus to measures that can be obtained in humans, and describe their validity, limitations, and potential for further development. The relationship between most biomarkers and resilience requires further discovery, validation, and application. Taken together, this is an exciting—but still nascent—area of cancer and aging research that warrants further development to ensure that older survivors live long and healthy lives well after completing cancer treatment.

RATIONALE FOR STUDYING RESILIENCE IN OLDER CANCER SURVIVORS

Improving or preserving the health and quality of life of older survivors is challenging because of a lack of well‐established clinical guidelines and limited cancer survivorship research focused on older adults.² Clinicians are often forced to engage in cycles of trial and error that are centered on supportive treatment of symptoms rather than the root cause contributors of aging-related dysfunctions that occur months to years following cancer therapy. Indeed, currently available survivorship care for older adults primarily focuses on surveillance, screening of secondary cancers, and some comorbid conditions (eg, cardiovascular disease). However, this focus is often specifically related to the cancer treatment and not necessarily to aging or the impact of cancer treatment on aging.

A deeper understanding of the physiologic and molecular mechanisms underlying an older survivor's recovery response or resilience to cancer treatment may identify novel protective factors and promising strategies to promote lasting health during survivorship. Research to understand the impact of cancer on age-related resilience represents an important opportunity to develop interventions that could prevent or delay the progression of multimorbidity, disability, and cognitive impairment in older survivors. Examples of potential strategies for promoting resiliency include maintenance or recovery of cognitive function following chemotherapy (eg, avoiding cancer-related cognitive decline), recovery of hematopoietic function after chemotherapy, or maintenance of cardiovascular function after bone marrow transplant (Table 1). Studying resilience thus represents an important opportunity to inform strategies to optimize healthy aging of cancer survivors.

TABLE 1.

Health Conditions Observed in Cancer Survivors After Selected Examples of Cancer Treatments, Which Might Be Prevented and/or Mitigated Through Enhancing Specific Resiliencies Before and/or During Cancer Treatment

BIOLOGICAL MEASURES TO ASSESS OR PREDICT RESILIENCE

An important step in advancing this line of research on resilience after cancer therapy is to determine whether measures of aging can identify individuals with impaired resiliency before initiation of therapy and facilitate discovery of preventative interventions.^29,30 Identifying biological measures of resilience²⁷ would be useful in oncology research and practice to: (1) understand biologic mechanisms underlying heterogeneity in recovery after cancer therapy, (2) conduct risk stratification—identify older adults at high risk of functional disability or cognitive decline after cancer therapy to risk stratify patients in well-designed cancer clinical trials and to deliver targeted intervention, and (3) target biological pathways to enhance resilience in older adults before or during cancer therapy (ie, to prevent or mitigate physical or cognitive disability associated with treatment).

Given the increasing frequency of impairments in many types of resilience with aging, it is postulated that aging-related changes in cellular and molecular function could influence changes to a variety of resiliencies.²⁶ If this is true, then biologic aging mechanisms (eg, inflammation, cellular senescence, telomere length, and epigenetic age deceleration) may influence levels of resiliencies. Circulating biomarkers of aging may be candidate measures that could predict or correlate with the degree of specific resilience and identify contributory biologic mechanisms influencing resilience. In the following section, we selected several biological measures of aging (Table 2), given their relationships with cancer treatments and aging-related clinical end points, which may modulate the fundamental aging processes that influence and thus are potential markers for resilience.

TABLE 2.

Selected Examples of Biologic Aging–Related Processes, Biomarkers of Aging, and Contributory Mechanisms of Damage and Resilience, Which Are Relevant in Oncology

CELLULAR SENESCENCE

Cellular senescence represents a state of permanent cellular growth arrest. Senescence limits the proliferation of damaged cells but prevents cell division and tissue repair. Still, senescent cells are metabolically active and are a major source of numerous pro-inflammatory cytokines, chemokines, and Damage-Associated Molecular Patterns that promote inflammation and the previously described inflammaging, impair organ regeneration, and contribute to tissue aging across almost all organ systems.³¹

Biomarkers of senescence include augmented levels of senescence-associated β-galactosidase, p16INK4a, p19ARF, p21CIP1, p17, p53, and PAI-1; upregulation of some microRNAs; and the secretion of growth factors, cytokines, chemokines, and proteases—the senescence-associated secretory phenotype.³² P16^INK4a (hereafter referred to as p16) is to date one of the most promising markers of senescence. P16 is found on chromosome 9p2 and is a CDK 4/6 cyclin-dependent kinase inhibitor that promotes cell senescence by preventing phosphorylation of retinoblastoma proteins leading to G1 cell cycle arrest. Expression of p16 is undetectable in young cells but activated by cellular stress factors,^33-35 which causes permanent cell cycle arrest. Genome-wide association studies have also implicated p16 as a critical factor in human aging and aging-related conditions, including stem-cell aging, cardiovascular disease, decline in physical function, and loss of islet cells.^18,36-42

P16 is increasingly expressed with aging across many types of cells (eg, heart, kidney, lungs, and immune tissue). In humans, the most accessible cell source is immune cells and p16 has high levels of detection in peripheral blood T cells,⁴³ but is also detectable in other blood leukocyte subset. P16 mRNA has a half-life of about 24 hours and is more stable than its derived protein.⁴⁴ In persons of average health, p16 expression in T cells doubles about every 8 years with expression accelerated by a variety of stimuli including cigarette smoking, physical inactivity,⁴³ cytotoxic chemotherapy administration,⁴⁵ irradiation therapy,⁴⁶ chronic HIV infection,⁴⁷ and bone marrow transplantation.⁴⁸

Clinical studies to date have focused on using baseline p16 from T cells to predict patient outcomes and assessing the effects of different therapies, such as chemotherapy, on changes in p16 expression in T cells over time. Studies in multiple myeloma have shown that p16 expression in T cells increases after systemic treatment and dramatically after high-dose chemotherapy or bone marrow transplant regimens and in the latter correlated with up to a 34-year increase in the pace of natural aging.^43,48 A similar study in patients with various hematologic malignancies showed that those undergoing autologous transplant had changes in p16 expression in T cells correlating with 28 years of accelerated aging compared with those with allogeneic stem-cell transplant with an increase in 16 years.⁷⁶

P16 has correlated most convincingly with accelerated aging in studies of childhood, adolescent, and young adult cancer.⁴⁹ The dramatic improvements in survival in this group because of modern treatments have in many patients been accompanied by loss of exercise capacity, cognitive decline, and early development of chronic medical morbidities, especially cardiovascular disease. In a small study of 10 young patients treated with cranial radiation for childhood acute lymphoblastic leukemia, p16 mRNA expression in paired skin biopsies from the scalp and buttock showed a nearly 6-fold increase in p16 expression in the scalp compared with the buttock biopsies.⁴⁶ In a second recent study of childhood, adolescent, and young adult cancer survivors, p16 expression in T cells was higher among survivors than among controls, indicating a 25-year acceleration in age,⁵⁰ remarkably similar to clinical studies of the same group using traditional clinical assessments.⁴⁹ Frailty was also noted in approximately 15% of survivors correlating with a 35-year increase in accelerated aging.⁵⁰

Studies in patients with solid tumor are limited. In early breast cancer, patients with higher baseline p16 expression in T cells were more likely to develop fatigue⁵¹ and there were rapid, marked, and sustained increases in p16 expression from pre- to postchemotherapy, indicating about 15 years of accelerated aging.⁴⁵ A more recent study of women treated with adjuvant and neoadjuvant chemotherapy for early-stage breast cancer confirmed that the largest increases in p16 expression levels post-treatment were associated with anthracycline-based chemotherapy and a lower baseline p16 at the start of treatment.⁵² In a study of 42 heavily treated older patients with stage IV non–small-cell lung cancer treated with nanoparticle albumin-bound-paclitaxel, p16 at baseline was higher than age-matched controls, but there was no convincing change during taxane therapy, suggesting that taxanes may have minimal effects on T-cell senescence, one aspect of biologic aging.⁵³ Measurement of cell senescence with p16 and other biomarkers has clinical promise. Both short- and long-term studies are needed to determine the effects of interventions and treatments on these senescent markers across different tissue and cell sources, and whether this can be used as an indicator of resilience.

EPIGENETIC AGE DECELERATION

Epigenetic age estimates are useful tools to track rates of biologic aging. There are several estimates derived from methylation data that have been proposed to quantify an individual's biologic age as it deviates from chronologic age, allowing an estimate of age acceleration and deceleration. These estimates, colloquially termed epigenetic clocks, are determined from a set number of methylation markers selected based on attributes such as tracking with chronologic age, being related to aging patterns within selected biomarkers indicative of disease risk, or being related to morbidity or mortality. The most well-established to date include the Extrinsic Epigenetic Age Acceleration (EEAA),^54-57 the Phenotypic Epigenetic Age Acceleration (PEAA),^32,58 and the GrimAge estimates of biologic age.⁵⁹ EEAA estimate is partially reflective of immune cell aging and includes percentages of cells in the sample that have reach cellular senescence. PEAA tracks rates of biologic aging that directly correlate with aging-related diseases, frailty, and disability,³² whereas the GrimAge is prognostic of healthspan and lifespan.^59,60 All measures have demonstrated associations with declines in physical and cognitive function.^32,60-62

As these estimates can suggest that the biologic age of a person is older than their chronologic age, it too can suggest that a person is younger than their chronologic age. This inverse interpretation could then infer biologic resilience to aging. Very few studies to date have tested whether a younger epigenetic age is evidence of resistance to physical aging or frailty. A younger epigenetic age (eg, average of 8 years younger than expected for their chronological age) has been reported among individuals with exceptional longevity,^63-66 hinting at the epigenetic clock capturing a resilience phenotype, but considerably more work is needed along this line.

Cancer as an accelerator of epigenetic aging has been observed by only one study to date, showing increased epigenetic age across EEAA, PEAA, and GrimAge measures from pre- to postadjuvant therapy in patients with breast cancer with average acceleration in aging of a few years.³⁴ Interestingly, although the average was increased epigenetic aging, not all women appeared to have accelerations in their epigenetic aging, pointing to some resilience factor(s) that might provide protection.⁶⁷ Future research in this area is critical to understand how some patients undergoing cancer therapy could be protected from the effects of the toxic treatments on their biologic aging rates and how tracking epigenetic age may provide some insights here.

TELOMERE LENGTH

Peripheral blood cell telomere length is one of the most frequently cited biomarkers of aging. Identified as the reason for Hayflick's limit, the telomere gained much attention for its role in limiting the replicative ability of cells. This repeat sequence of DNA at the end of chromosomes is vulnerable to shortening because of the end replication problem where there is a piece of the DNA that does not transfer during replication, and so shortening occurs. This end of the chromosomes serves as protection to the protein encoding DNA and initiates cellular growth arrest when critically short in length, and telomerase enzymes are insufficient within the cell to elongate or serve a capping function.⁶⁸

Although telomere length is involved in the biology of aging and has been identified as one key hallmark of aging as a consequence of damage,⁹ it inconsistently predicts functional outcomes, morbidity, and mortality, which are key aging end points.⁶⁹ However, examples of shorter telomeres as prognostic of risk for comorbidities and mortality have been observed in cancer survivors,^70,71 suggesting that they may yet be useful in the cancer context. To this end, we consider telomere length as a potentially useful indicator of resilience in patients with cancer and recommend future studies consider including this marker, and related telomerase enzyme that rebuilds telomeres, in combination with other indicators of biologic aging to understand which components of the aging biology machinery are affected by which treatments.

In contrast to shortening, maintenance of telomere length may provide clues to biologic resilience in the context of cancer, and further research in this area is warranted. Whether telomere maintenance is related to true biologic resilience is a novel question and is yet to be determined. Being resistant to biologic wear and tear at the level of telomere length could indicate biologic resilience, especially under circumstances, such as with cytotoxic therapy or forced clonal expansion, when telomere length shortening might be expected. To date, telomere length shortening has been observed among a number of populations of patients with cancer, although not all report effects, lending support to the idea that the toxic treatments might have an impact on this particular biologic marker of aging.^{10,45,69,72,73} Patients undergoing cancer therapy but who do not exhibit telomere shortening might provide an example of biologic resilience. The most striking findings to date linking cancer therapy to telomere length shortening come from hematopoietic cancers.^72-75 In particular, post-transplantation proliferative stress may be a cause of telomere shortening rather than direct damage by the cytotoxic drugs.^76,77 Studies of breast cancer have examined telomere length change, reporting mild shortening among some patients,^10,45,69 but not consistently across the studies. This suggests that some element of the patient or exposures might alter risk for telomere length shortening and highlights a place that biologic resilience may help explain diverse responses, but a link between this and resilience is yet to be demonstrated.

SYSTEMIC INFLAMMATION

Immune dysfunction as a consequence of aging is a well-defined phenomenon characterized by a decline in immune function, particularly viral immune defenses, with a concomitant increase in chronic inflammation. This rise in inflammation results from the overstimulation of the innate immune system, stemming from multiple sources including the increasing release of intracellular debris as cells within various tissue, accumulating damage, and becoming necrotic with aging. In addition, immune cells age and reach senescence from both accumulated damage (eg, immune cells are a source of reactive oxygen and nitrogen species, degrading enzymes) and repeated activation from chronic exposure to varying antigens during an individual's lifetime (eg, cytomegalovirus).^78,79 Consequently, even in the absence of an infection (sterile inflammation), older adults often have chronic low-grade systemic inflammation, referred to as inflammaging. Inflammaging is a major contributor to aging-related diseases, and it is clinically characterized by elevated serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β).⁸⁰ As such, inflammation is regarded as a central pillar of aging, driving aging-related syndromes.

Older adults have persistent elevated levels of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β⁷² and known stimulators of CRP production,⁷³ which are shown to exert detrimental effects on physical, functional, and cognitive status.^74,76,81-83 Elevated levels of IL-6 and D-dimer have been shown to be associated with functional decline in community dwelling older adults.⁷⁴ Furthermore, the PolSenior Study, a trial of 3,750 adults of age 65+, found that in addition to the age-dependent increase of IL-6 and CRP, lower levels of both molecules were associated with increased survival and successful aging; fewer aging-related diseases; and better physical performance.⁷⁶ Additionally, elevated serum levels of IL-6, TNF-α, CRP, serum level of vascular cell adhesion molecule,⁸⁴ IL-1β, and IL1-RA have been linked to poor function, physical performance, mobility status, and muscle strength, and other inflammatory markers such as soluble TNF receptor I and II sTNFRI/II have been associated with reduced mobility, fatigue, and chemotherapy induced frailty.^54,85-87 IL-6, CRP, and TNF-α have also been shown to contribute to cognitive decline.^81-83

Blood-based markers of chronic inflammation may be useful to predict or assess resilience in older cancer survivors. They are relatively easy to collect and measure during routinely obtained blood draws during cancer therapy. Given that cancer cells also secrete many of these inflammatory cytokines, one must proceed with caution when exclusively assessing the effect of an individual inflammatory marker on physical, functional, and cognitive decline as well as resilience. However, studies have shown that evaluating the combined effect of multiple markers of inflammation might have better prognostic outcomes. For example, combining IL-6 with TNFR levels to produce a pro-inflammatory score performed better in predicting the risk of mortality and mobility.⁵⁵ Similarly, combining measures of inflammation with reciprocal anti-inflammatory markers might provide additional insight. Given that the exact mechanism linking inflammation to resilience is not yet elucidated, future studies should examine this mechanism.

EMERGING INTERVENTIONS TO PROMOTE RESILIENCE

Senolytics

Cellular senescence provides the focal point linking subcellular changes because of genetic factors and environmental insults with lifespan, and its measurement may help predict health trajectories, such as the onset of comorbid illness and frailty.³² In animal models, transplantation of senescent cells from old to young animals induces aging-related loss of function and shortened lifespan,^59,61 whereas senolytic therapies (pharmacologic v transgenic depletion of senescent cells) can restore function and increase healthspan and lifespan in both normal and aged mice.^61,63 The elimination or lack of accumulation of senescent cells may thus represent biologic resilience. Several clinical trials using senolytic therapies have been completed, and others are now underway, in chronic disease states and frail populations, including adult bone marrow transplant recipients.^15,88,89 Future research is warranted to understand the potential opportunity for enhancing resilience after cancer treatment in older survivors using promising pharmacologic senolytic therapies.

Epigenetic Interventions

Whether the epigenetic clocks are amenable to intervention is also unclear, although two small intervention studies to date show deceleration in epigenetic age through either vitamin D⁹⁰ supplementation or a Thymus rejuvenation protocol.⁹¹ This promising work highlights the potential of biologic age to be modifiable by interventions, and application of the epigenetic clocks in this context provides evidence of intervention efficacy. Future research is needed to investigate how epigenetic interventions can affect biologic resilience in older survivors.

Telomere Protection

To date, interventions looking to reduce attrition or even lengthen telomeres have yielded mixed results but do offer promise. Among these interventions shown to provide telomere protection, exercise⁹² and mindfulness mediation to reduce stress have shown promise,^93,94 although not all interventions to date have documented efficacy. Dietary interventions have yielded similarly mixed effects,⁹⁵ but considerable work remains to be done. One key element to designing effective interventions may be in first characterizing an ideal target population at risk for telomere shortening. Although the majority of these interventions focused on targeting individuals in need of diet modification, stress reduction, or physical activity, the populations were otherwise not exposed to conditions that might accelerate aging. Of noted exception, the mindfulness intervention in patients with breast cancer demonstrated protection from telomere length shortening compared with the control condition,⁹³ suggesting that within this context of cancer therapy, this intervention may be found to provide biologic resilience, but it remains necessary to show links to physical resilience under these circumstances.

Anti-Inflammatory Strategies

The link between inflammation and physical, functional, and cognitive decline suggests that interventions targeting inflammation and activating anti-inflammatory defenses might improve resilience in older adults with cancer. There is robust evidence of behavioral interventions that can effectively alter inflammation to target biologic aging pathways, with the strongest evidence showing modification of inflammation by reducing stress and improving sleep.⁹⁶ Approaches such as the use of physical activity, tai-chi, yoga, meditation, diet modification, and cognitive behavior therapy have been shown to enhance immune function and reduce inflammation.^97-99 Anti-inflammatory signaling through cytokines, glucocorticoids, and the parasympathetic-mediated regulatory pathways works to modulate the pro-inflammatory immune responses as a mechanism to resolve inflammation and prevent damage.¹⁰⁰ Thus, it is plausible that activation of anti-inflammatory pathways might serve as potential strategy to enhance resilience. Understanding the balance of pro- and anti-inflammatory pathways in older adults receiving cancer therapy might help shed light on potential targets for novel interventions to promote resilience after cancer diagnosis.

SUMMARY AND FUTURE DIRECTION

The growing number of older cancer survivors at risk for chronic diseases and disability because of adverse effects of cancer therapy makes it imperative to continue our efforts to investigate the biologic mechanisms of injury resulting from cancer treatments and aging-related recovery or resilience. Trials targeting fundamental aging processes to enhance physical resilience represent an innovative opportunity to transform cancer clinical care. Candidate pharmacologic interventions to slow aging have emerged from studies of animal, and several human trials are underway.⁸⁸ Parallel research showing efficacy of behavioral interventions to target biologic aging pathways is in development.

With regard to pharmacologic interventions, such as senolytics, our limited understanding of the dynamic aging mechanism in human models and the surrogate biomarkers associated with fundamental aging biology represents one of the challenges with translating therapies developed in animal models to help humans. Receipt of cancer treatment is a physiologic stressor and hence can serve as a human model to study resilience and test the geroscience hypothesis. Geroscience leaders (TAME Biomarkers Working Group) have started to identify biomarkers that are important in geroscience trials,⁶⁹ and their framework (Table 3) may be a useful guide to begin identifying the biomarkers that can be incorporated in future clinical trials that test resilience interventions in cancer survivors. These efforts will undoubtedly require high intensity collaboration between basic and clinical scientists across multiple disciplines.

TABLE 3.

Framework for Selecting Biomarkers of Aging for Use in Cancer Clinical Trials to Study Resilience

AUTHOR CONTRIBUTIONS

Conception and design: Mina S. Sedrak, Nikesha J. Gilmore, Judith E. Carroll, Hyman B. Muss, Harvey J. Cohen, William Dale

Financial support: William Dale

Administrative support: William Dale

Collection and assembly of data: Mina S. Sedrak, Nikesha J. Gilmore, Judith E. Carroll, Hyman B. Muss

Data analysis and interpretation: Judith E. Carroll, Hyman B. Muss, Harvey J. Cohen

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Measuring Biologic Resilience in Older Cancer Survivors

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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