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Supplementary Figures S1 - S10, Tables S1 - S2

BACKGROUND: Skeletal muscle loss, commonly known as sarcopenia, is highly prevalent and prognostic of adverse outcomes in oncology. However, there is limited information on adults with early breast cancer and examination of other skeletal muscle indices, despite the potential prognostic importance. This study characterizes and examines age-related changes in body composition of adults with early breast cancer and describes the creation of a novel integrated muscle measure. METHODS: Female patients diagnosed with stage I-III breast cancer with abdominal computerized tomography (CT) scans within 12 weeks from diagnosis were identified from local tumor registry (N=241). Skeletal muscle index (muscle area per height [cm(2)/m(2)]), skeletal muscle density, and subcutaneous and visceral adipose tissue areas, were determined from CT L3 lumbar segments. We calculated a novel integrated skeletal measure, skeletal muscle gauge, which combines skeletal muscle index and density (SMI × SMD). RESULTS: 241 patients were identified with available CT imaging. Median age 52 years and range of 23-87. Skeletal muscle index and density significantly decreased with age. Using literature based cut-points, older adults (≥65 years) had significantly higher proportions of sarcopenia (63 vs 28%) and myosteatosis (90 vs 11%) compared to younger adults (

Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments. Significance: Many genotoxic chemotherapies have debilitating side effects and also induce cellular senescence in normal tissues. The senescent cells remain chronically present where they can promote local and systemic inflammation that causes or exacerbates many side effects of the chemotherapy. Cancer Discov; 7(2); 165–76. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 115

Background. Geriatric assessment (GA) is an important tool for management of older cancer patients; however, GA research has been performed primarily in the outpatient setting. The primary objective of this study was to determine feasibility of GA during an unplanned hospital stay. Secondary objectives were to describe deficits found with GA, to assess whether clinicians recognized and addressed deficits, and to determine 30-day readmission rates. Materials and Methods. The study was designed as an extension of an existing registry, “Carolina Senior: Registry for Older Patients.” Inclusion criteria were age 70 and older and biopsy-proven solid tumor, myeloma, or lymphoma. Patients had to complete the GA within 7 days of nonelective admission to University of North Carolina Hospital. Results. A total of 142 patients were approached, and 90 (63%) consented to participation. All sections of GA had at least an 83% completion rate. Overall, 53% of patients reported problems with physical function, 63% had deficits in instrumental activities of daily living, 34% reported falls, 12% reported depression, 31% had ≥10% weight loss, and 12% had abnormalities in cognition. Physician documentation of each deficit ranged from 20% to 46%. Rates of referrals to allied health professionals were not significantly different between patients with and without deficits. The 30-day readmission rate was 29%. Conclusion. GA was feasible in this population. Hospitalized older cancer patients have high levels of functional and psychosocial deficits; however, clinician recognition and management of deficits were poor. The use of GA instruments to guide referrals to appropriate services is a way to potentially improve outcomes in this vulnerable population. Implications for Practice: Geriatric assessment (GA) is an important tool in the management of older cancer patients; however, its primary clinical use has been in the outpatient setting. During an unplanned hospitalization, patients are extremely frail and are most likely to benefit from GA. This study demonstrates that hospitalized older adults with cancer have high levels of functional deficits on GA. These deficits are under-recognized and poorly managed by hospital-based clinicians in a tertiary care setting. Incorporation of GA measures during a hospital stay is a way to improve outcomes in this population.

Background. We investigated whether a brief geriatric assessment (GA) would identify important patient deficits that could affect treatment tolerance and care outcomes within a sample of older cancer patients rated as functionally normal (80%–100%) on the Karnofsky performance status (KPS) scale. Methods. Cancer patients aged ≥65 years were assessed using a brief GA that included both professionally and patient-scored KPS and measures of comorbidity, polypharmacy, cognition, function, nutrition, and psychosocial status. Data were analyzed using descriptive statistics and multivariable logistic regression. Results. The sample included 984 patients: mean age was 73 years (range: 65–99 years), 74% were female, and 89% were white. GA was conducted before (23%), during (41%), or after (36%) treatment. Overall, 54% had a breast cancer diagnosis (n = 528), and 46% (n = 456) had cancers at other sites. Moreover, 81% of participants (n = 796) had both professionally and self-rated KPS ≥80, defined as functionally normal, and those patients are the focus of analysis. In this subsample, 550 (69%) had at least 1 GA-identified deficit, 222 (28%) had 1 deficit, 140 (18%) had 2 deficits, and 188 (24%) had ≥3 deficits. Specifically, 43% reported taking ≥9 medications daily, 28% had decreased social activity, 25% had ≥4 comorbidities, 23% had ≥1 impairment in instrumental activities of daily living, 18% had a Timed Up and Go time ≥14 seconds, 18% had ≥5% unintentional weight loss, and 12% had a Mental Health Index score ≤76. Conclusion. Within this sample of older cancer patients who were rated as functionally normal by KPS, GA identified important deficits that could affect treatment tolerance and outcomes.

Background: Increased expression of p16INK4a, a molecular marker of aging, is a hallmark of increased cellular senescence in most mammalian tissues. In human peripheral blood T-lymphocytes, expression of p16INK4a increases 10-fold between 20 and 80 years of age (Liu et al, Aging Cell, 2009). We hypothesized that higher "molecular age," as evidenced by increased T-cell expression of p16INK4a at the time of initiation of breast cancer (BC) chemotherapy (CRx), predicts increased treatment-related toxicity. Methods: Patients (pts) with early breast cancer scheduled to receive neoadjuvant (NA) or adjuvant (Adj) chemotherapy (CRx) had p16INK4a evaluation performed prior to treatment. Expression of p16INK4a mRNA in CD3+ T-lymphocytes was determined using TaqMan real time quantitative reverse transcription polymerase chain reaction. Grade 3 and 4 (G3/4) hematologic (H) and non-hematologic (NH) toxicities (NCI CTCAE version 4) were assessed during and within 4 weeks of completion of CRx. Wilcoxon Rank Sum tests compared p16INK4a between groups. Results: 93 pts with Stage I-III BC and complete toxicity data during and within 4 weeks after completion of CRx have been accrued. Median age (range) was 52 (25-76). 48 (52%) of pts were hormone receptor (HR) positive, 21 (23%) HER-2 positive, and 24 (26%) triple-negative. 39 (42%) received NA and 54 (58%) received Adj CRx. 57 pts (61%) received an anthracycline containing combination and 21 (23%) cyclophosphamide/docetaxel (TC). 85 pts (91%) received pegfilgrastim. Overall, 69 pts (74%) had a G3/4 toxicity during or ≤4 wks of CRx, 54% NH and 40% H. 22 pts (24%) were hospitalized for CRx related toxicity and 11 (12%) of these admissions were for neutropenic fever (NF). 23 (25%) reported G3/4 fatigue during CRx and had significantly higher p16INK4a values at baseline than those without fatigue (p=0.03). There was no significant association of baseline p16INK4a and other NH or H toxicity or hospitalization in this cohort. Conclusion: In this small sample of pts treated with anthracycline and non-anthracycline containing NA and Adj CRx regimens, there was a significant association of baseline p16INK4a and G3/4 fatigue. The heterogeneity of treatment and use of pegfilgrastim in almost all pts limits the power of this study to find significant relationships between p16INK4a and other toxicities. The cohort for this study is being expanded to further explore p16INK4a as a predictor for G3/4 toxicity. Support: Breast Cancer Treatment Foundation, New York, NY; University Cancer Research Fund, University of North Carolina, Chapel Hill. Citation Format: Hyman Muss, Allison Deal, Arti Hurria, Natalia Mitin, Chad Torrice, Krishnamurthy Janakiraman, Trevor Jolly, Grant Williams, Shani Alston, Jerard West, Laura Zavala, Vani Katheria, Norman Sharpless. p16INK4a expression and chemotherapy toxicity in women with early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-34.

Background New highly efficacious direct-acting antiviral (DAA) therapies are available to treat chronic hepatitis C viral (HCV) infection. Real-world, patient-centered data on harms and benefits associated with these therapies are needed. Methods PROP UP is a multi-center prospective observational study that plans to enroll 1600 patients starting treatment with recently-approved DAA regimens. Informed by extensive input from a HCV patient engagement group who prioritized outcomes most important to them, patient-reported outcomes will be characterized using surveys at five time points: Baseline (T1), treatment week 4 (T2), end of treatment (T3), 12 weeks post-treatment (T4), 12 months post-treatment (T5). Outcomes (1) Changes in side effects, functioning, pre-existing conditions, and out-of-pocket costs during therapy (T1 vs T2/T3); (2) Medication adherence in relation to a history of mental health/substance abuse, treatment regimens, pill burden, reasons for missed doses, and cure rates; (3) Short term impact of cure on functioning and amelioration of symptoms (T1 vs T4); (4) Long-term treatment harms or benefits of cure on symptoms, side effects, pre-existing conditions, and functioning (T1 vs T5). Similarities between regimens will be examined where comparisons are appropriate and meaningful. Conclusion PROP UP complements previous clinical trials by focusing on patient-reported outcomes in a representative sample of patients treated in clinical practice, by collaborating with a patient engagement group, by characterizing the experiences of vulnerable subgroups, and by investigating long-term harms and benefits of treatments. PROP UP is designed to provide novel and detailed information to support informed decision-making for patients and providers contemplating HCV treatment (PCORI CER-1408-20,660; NCT02601820 ).

Objective Sarcopenia is the age-related loss of muscle mass, strength, and function. It is a common finding in older patients and is associated with decreased life expectancy and potentially higher susceptibility to chemotherapy toxicity. This study describes the prevalence of sarcopenia in older adults with early stage colorectal cancer. Materials and Methods Patients ≥ 70 years old who underwent surgical resection for stage I–III colorectal cancer between 2008 and 2013 were identified from the medical record. Sarcopenia was assessed by measuring the total muscle area on computerized tomography (CT) images obtained prior to surgery. Total muscle area was measured at the level of L3 and normalized using each patient’s height to produce a skeletal muscle index (SMI). Sarcopenia was defined using sex- and body mass index (BMI)–specific threshold values of SMI. Results Eighty-seven patients were included, with a median age of 77 years (70–96). Twenty-five men (60% of 42) and 25 women (56% of 45) had sarcopenia. Sarcopenic patients had significantly lower BMI ( p = 0.03) compared to non-sarcopenic patients. There was a positive correlation between BMI and SMI for both men ( r = 0.44) and women ( r = 0.16). Conclusion Sarcopenia is highly prevalent among older patients with early stage colorectal cancer. BMI alone is a poor indicator of lean body mass and improved methods of screening for sarcopenia are necessary. CT scans are a viable option for identifying sarcopenic patients in whom timely interventions may improve survival, quality of life, and functional outcomes.

With the aging of the American population, the incidence of new cancer diagnoses is projected to increase 45% from 2010 to 2030 (1). Coupled with the growing proportion of cancer patients who are cured (2), we face a new challenge: a large population of aging cancer survivors (3). Long-term survivors of childhood and adult cancer can exhibit substantial late sequelae, including endocrine dysfunction, cognitive impairment, cardiovascular morbidity, secondary neoplasms, and neuromuscular impairment (4–8). Little is known about how chemotherapy causes long-term adverse effects and whether it alters the pace of physiologic aging. Human aging is characterized by a steady decline in organ function, which leads to loss of physiologic reserve and frailty (9). This loss of function is characterized by a decline in the replicative capacity of certain self-renewing cells and the accumulation of cells that have undergone cellular senescence (10,11). Cellular senescence is triggered by the activation of tumor-suppressor mechanisms in response to varied cellular stresses such as oncogene activation, tissue injury, telomere dysfunction, and persistent DNA damage. Senescence is strongly associated with activation of the INK4/ARF (CDKN2a) locus on human chromosome 9p21.3, which encodes the p16INK4a and ARF tumor suppressor proteins. Several lines of evidence suggest senescence influences mammalian aging: 1) expression of p16 INK4a increases exponentially with chronological aging (12–14) and causes reduced replicative capacity of some cell types (15–19); 2) regulatory polymorphisms of senescence regulators (eg, CDKN2a and TERT) have been linked through unbiased genome-wide studies with many age-associated conditions such as cancer, pulmonary fibrosis, atherosclerosis, and type II diabetes (20); and 3) therapies to decrease the production of or increase the clearance of senescent cells in mice ameliorate certain age-associated phenotypes (21–23). Because of the intimate links between senescence and aging, markers of cellular senescence, including leukocyte telomere length (LTL), expression of senescence-associated (SA) cytokines such as interleukin 6 (IL-6), and expression of INK4a/ARF transcripts, have been tested as potential biomarkers of molecular aging. Decreased LTL has been linked with chronological age and age-promoting stressors such as cigarette smoking in several studies in human populations (24–26). Senescent cells elaborate a host of potent cytokines (ie, the senescence-associated secretory phenotype) (27), which promote a proinflammatory tissue microenvironment. Expression of SA-cytokines, such as IL-6, has been reported to increase with aging and to predict age-associated morbidities and mortality (28–32). More recently, expression of p16 INK4a, and to a lesser extent ARF, in defined tissues such as peripheral blood T cells (PBTLs) have been described as biomarkers of aging. Using the p16 INK4a assay, we have shown that smoking, physical inactivity, and chronic human immunodeficiency virus infection accelerate expression of this biomarker of molecular age in the PBTL compartment (14,33). Given the apparent long-term toxicities of DNA-damaging agents, we sought to determine whether cytotoxic chemotherapy given with curative intent accelerates molecular aging in humans.

Objective Emerging results support the value of geriatric assessment (GA) in determining the risk and benefits of cancer treatment in older adults. A brief GA tool consisting of valid and reliable measures has been developed; however, little data exist on the ability to perform the GA in community oncology clinics. The objective of this study was to determine the feasibility of performing the GA in the community. Materials and Methods Patients aged ≥ 65 were eligible. The GA included a health care provider assessment of performance status, cognitive function, a Timed Up and Go test, and a self-administered patient questionnaire that evaluated measures of functional status, comorbidity, psychological state, social support, and nutritional status. Results From 2009 to 2013, 1088 patients were assessed including 339 (31%) from seven community clinics across North Carolina. The median amount of time to complete the patient-report portion of the GA was 19 min in the academic center versus 22 min in the community. The median amount of time to complete the entire GA was 23 min in the academic center and 30 min in community settings. Significantly more patients in the community required assistance completing the questionnaire (24% vs. 14%); however, most patients required no assistance (76%). Conclusion A brief GA can be performed in community oncology clinics. The time to complete the professional assessments and patient self-assessments were similar in both settings. Future studies are planned to determine if such assessments can improve cancer care for older patients.

9543 Background: National guidelines recommend 150 minutes a week of moderate-intensity physical activity for adults with a cancer diagnosis. Our study investigated the feasibility of a self-direct...

e20537 Background: Hospital readmission is a major healthcare concern. We aimed to investigate whether GA-identified deficits are associated with subsequent readmission in non-electively admitted o...

9543 Background: Physical inactivity (PI), alcohol (A) and tobacco (T) abuse are associated with poor health outcomes in older adults, however, little is known about the prevalence of these HB and their associations with GA domains in older cancer patients (pts). This study explores the relationship between HB and GA in older BC pts. Methods: Between 03/2010-01/2013, 111 pts ≥65 yrs completed a predominantly self-administered GA (Hurria et al. Cancer 2005) comprising measures of comorbidity, polypharmacy, cognitive, functional, psychosocial and nutritional status as well as a nine-item HB questionnaire based on the 2006/7 National Health Interview Survey ( www.cdc.gov/nchs/nhis.htm ) assessing PI, A and T use. Fisher’s Exact and Wilcoxon Rank sum test were used to evaluate associations with GA measures. Results: Median age was 72 (range 65-94). Most pts were white (89%), married (61%), retired (86%) and at least high school graduates (96%). 51% never smoked while 45% were former and 4% current smokers. Former/current smokers were more likely than never smokers to have slower gait speeds (Timed “up and go” >14 second; 32 vs 14%; p=.04) and took more daily prescription medications (mean 5 vs. 4; p=.04). 52% of pts consumed at least one alcoholic drink per week (median 3.5). Modest alcohol consumption was associated with less activity of daily living (ADL) impairment (p=.03), lower mean BMI (29 vs. 26 kg/m2 p=.03) and greater non-prescription medication use (p=.04). 48% never performed vigorous activity and these pts were more likely than those exercising to have one or more functionally impairing comorbidities (p=.03); mainly arthritis. PI correlated with more impairment in both ADL (p

e20582 Background: Smoking, alcohol use, and exercise among cancer patients (pts) are important health concerns due to their effects on treatment outcomes. Few studies have focused on health behaviors (HB) in this group. The goal of this study was to assess HB in cancer pts seen at an academic medical center. Methods: The Health Behavior Questionnaire (HBQ) is a nine-item survey that assesses smoking, alcohol and exercise behaviors based on the 2006/7 National Health Interview Survey (http://www.cdc.gov/nchs/nhis.htm). Pts completed the HBQ from 2010 to present as part of two breast cancer (BC) trials and a geriatric assessment trial. The Jonckheere-Terpstra test compared differences among groups as age increased (Jonckheere, Biometrika 41:1/2, 1954). Results: Of 371 pts, 66% were age ≥60 (median 66), 81% white, 16% black and 95% were female. BC was most common (92%). 5% were current and 40% former smokers. 43% reported having ≥1 drinks per week (dpw). Alcohol users averaged 5 dpw (range of 1-18). 40% never exercised vigorously (≥10 minutes that causes heavy sweating or large increases in heart rate/breathing). Older pts were less likely to exercise (p

9002 Background: Breast cancer (BC) is a disease of aging. In healthy humans, p16INK4a expression increases markedly in peripheral blood T-lymphocytes with chronologic age and exposure to mutagens ...

e19546 Background: Although the majority of cancer incidence and death occur in adults age 65 and older they are seldom offered entry into clinical trials (CT). Some decisions to not offer CT are b...