A protocol for remote collection of skeletal muscle mass via D3-creatine dilution in community-dwelling postmenopausal women from the Women's Health Initiative.

BACKGROUND: There is emerging evidence that cancer and its treatments may accelerate the normal aging process, increasing the magnitude and rate of decline in functional capacity. This accelerated aging process is hypothesized to hasten the occurrence of common adverse age-related outcomes in cancer survivors, including loss of muscle mass and decrease in physical function. However, there is no data describing age-related loss of muscle mass and its relation to physical function in the long-term in cancer survivors. METHODS: This study protocol describes the use of a novel method of muscle mass measurement, D3-creatine dilution method (D3Cr), in a large sample (n~6000) of community dwelling postmenopausal women from the Women's Health Initiative (WHI). D3Cr will be used to obtain a direct measure of muscle mass remotely. Participants will be drawn from two sub-cohorts embedded within the WHI that have recently completed an in-home visit. Cancer survivors will be drawn from the Life and Longevity After Cancer (LILAC) cohort, and cancer-free controls will be drawn from the WHI Long Life Study 2. The overall objective of this study is to examine the antecedents and consequences of low muscle mass in cancer survivors. The study aims are to: 1) create age-standardized muscle mass percentile curves and z-scores to characterize the distribution of D3- muscle mass in cancer survivors and non-cancer controls, 2) compare muscle mass, physical function, and functional decline in cancer survivors and non- cancer controls, and 3) use machine learning approaches to generate multivariate risk-prediction algorithms to detect low muscle mass. DISCUSSION: The D3Cr method will transform our ability to measure muscle mass in large-scale epidemiologic research. This study is an opportunity to advance our understanding of a key source of morbidity among older and long-term female cancer survivors. This project will fill knowledge gaps, including the antecedents and consequences of low muscle mass, and use innovative methods to overcome common sources of bias in cancer research. The results of this study will be used to develop interventions to mitigate the harmful effects of low muscle mass in older adults and promote healthy survivorship in cancer survivors in the old (>65) and oldest-old (>85) age groups.

Automated CT Analysis of Body Composition as a Frailty Biomarker in Abdominal Surgery.

Importance: Prior studies demonstrated consistent associations of low skeletal muscle mass assessed on surgical planning scans with postoperative morbidity and mortality. The increasing availability of imaging artificial intelligence enables development of more comprehensive imaging biomarkers to objectively phenotype frailty in surgical patients. Objective: To evaluate the associations of body composition scores derived from multiple skeletal muscle and adipose tissue measurements from automated segmentation of computed tomography (CT) with the Hospital Frailty Risk Score (HFRS) and adverse outcomes after abdominal surgery. Design, Setting, and Participants: This retrospective cohort study used CT imaging and electronic health record data from a random sample of adults who underwent abdominal surgery at 20 medical centers within Kaiser Permanente Northern California from January 1, 2010, to December 31, 2020. Data were analyzed from April 1, 2022, to December 1, 2023. Exposure: Body composition derived from automated analysis of multislice abdominal CT scans. Main Outcomes and Measures: The primary outcome of the study was all-cause 30-day postdischarge readmission or postoperative mortality. The secondary outcome was 30-day postoperative morbidity among patients undergoing abdominal surgery who were sampled for reporting to the National Surgical Quality Improvement Program. Results: The study included 48 444 adults; mean [SD] age at surgery was 61 (17) years, and 51% were female. Using principal component analysis, 3 body composition scores were derived: body size, muscle quantity and quality, and distribution of adiposity. Higher muscle quantity and quality scores were inversely correlated (r = -0.42; 95% CI, -0.43 to -0.41) with the HFRS and associated with a reduced risk of 30-day readmission or mortality (quartile 4 vs quartile 1: relative risk, 0.61; 95% CI, 0.56-0.67) and 30-day postoperative morbidity (quartile 4 vs quartile 1: relative risk, 0.59; 95% CI, 0.52-0.67), independent of sex, age, comorbidities, body mass index, procedure characteristics, and the HFRS. In contrast to the muscle score, scores for body size and greater subcutaneous and intermuscular vs visceral adiposity had inconsistent associations with postsurgical outcomes and were attenuated and only associated with 30-day postoperative morbidity after adjustment for the HFRS. Conclusions and Relevance: In this study, higher muscle quantity and quality scores were correlated with frailty and associated with 30-day readmission and postoperative mortality and morbidity, whereas body size and adipose tissue distribution scores were not correlated with patient frailty and had inconsistent associations with surgical outcomes. The findings suggest that assessment of muscle quantity and quality on CT can provide an objective measure of patient frailty that would not otherwise be clinically apparent and that may complement existing risk stratification tools to identify patients at high risk of mortality, morbidity, and readmission.

A novel body composition risk score (B-Score) and overall survival among patients with nonmetastatic breast cancer.

BACKGROUND & AIMS: Measurements (amount, distribution, and radiodensity) of muscle and adipose tissue were reported to be individually associated with overall survival in patients with breast cancer. However, they were not typically combined to develop an overall risk score, which can identify patients at high risk of death and prioritize patients in need of dietary and lifestyle interventions. Thus, we aimed to develop a novel composite body composition risk score (B-Score). METHODS: We included 3105 patients with stage II or III breast cancer at Kaiser Permanente Northern California and Dana Farber Cancer Institute. From CT scans at diagnosis, we assessed areas and radiodensity of muscle and adipose tissue at the third lumber vertebrae. We considered skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI) and SAT radiodensity as they were independent prognostic factors for overall survival. Each measurement was dichotomized using optimal stratification, with low SMI (<40.1 cm2/m2), high SATI (≥75.7 cm2/m2), and high SAT radiodensity (≥-97.2HU) considered risk factors. We calculated B-Score as the sum of these factors and estimated its association with overall survival using Cox proportional hazards regression with adjustment for clinicopathologic factors. RESULTS: Mean (standard deviation) age was 53.9 (11.8) years, 70.3% were Non-Hispanic White, and 60.5% were stage II. Most patients (60.6%) had only one body composition risk factor (B-Score = 1). Compared to those with no risk factors (B-Score = 0), the risk of death increased with more body composition risk factors: the adjusted hazard ratios were 1.10 (95% CI: 0.85, 1.42), 1.47 (95% CI: 1.12, 1.92), and 2.11 (95% CI: 1.26, 3.53) for B-Scores of 1, 2, and 3, respectively (Ptrend < 0.001). CONCLUSIONS: More unfavorable body composition characteristics were associated with increased risks of overall mortality in a dose-response manner. Considering body composition measurements together as a composite score (B-Score) may improve risk stratification and inform dietary and lifestyle interventions following breast cancer diagnosis.

Postoperative chemotherapy relative dose intensity and overall survival in patients with colon cancer.

PURPOSE: Quantifying the association of chemotherapy relative dose intensity (RDI) with overall survival may enable supportive care interventions that improve chemotherapy RDI to estimate their magnitude of potential clinical benefit. METHODS: This cohort study included 533 patients with stage II-III colon cancer who initiated a planned regimen of 12 cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposure was chemotherapy RDI. The primary outcome was overall survival. Restricted cubic splines estimated hazard ratios (HR). RESULTS: Chemotherapy regimen RDI was associated with overall survival in an L-shaped pattern (linear P = 0.006; nonlinear P = 0.057); the risk of death was flat above 85% but increased linearly below 85%. For example, a decrease in RDI from 85 to 75% was associated with an increased risk of death [HR: 1.20 (95% CI: 1.08, 1.52)], whereas an increase in RDI from 85 to 95% was not associated with the risk of death [HR: 1.06 (95% CI: 0.82, 1.38)]. CONCLUSION: If chemotherapy RDI is considered a potential surrogate of overall survival, supportive care interventions that improve chemotherapy RDI might confer a potential clinical benefit in this population.

Differences in Smoking Behavior by Nativity, Race/Ethnicity, and Education among Women Diagnosed with Breast Cancer.

BACKGROUND: We evaluated smoking differences across nativity and race/ethnicity among women diagnosed with breast cancer. METHODS: In our Northern Californian pooled population of 5,653 [670 Asian, 690 Hispanic, and 4,300 non-Hispanic White (White)] women diagnosed with breast cancer, we evaluated smoking differences across nativity, race/ethnicity, and acculturation and effect modification of nativity by race/ethnicity and education. RESULTS: Foreign-born women currently smoked less than US-born women [odds ratio (OR) = 0.46, 95% confidence limit (CL): 0.29-0.72]. Hispanic (OR = 0.50; 95% CL: 0.32-0.78) women currently smoked less than White women. Among those who ever smoked (n = 2,557), foreign-born women smoked 5.23 fewer pack-years (PY) than US-born women (95% CL: -2.75 to -7.70). Furthermore, Asian (-4.60, 95% CL: -0.81 to -8.39) and Hispanic (-6.79, 95% CL: -4.14 to -9.43) women smoked fewer PY than White women. Associations were generally suggestive of greater smoking with greater acculturation (immigration age, US years, survey language). Finally, associations for nativity differed by education but not race/ethnicity, with a higher likelihood of smoking in US-born women only among those with less than a bachelor's degree (OR = 2.84, 95% CL: 2.15-3.77; current smoking: P = 0.01, PY: P = 0.05). CONCLUSIONS: Asian and Hispanic (vs. White) and foreign-born (vs. US-born) breast cancer survivors reported fewer smoking behaviors. Smoking differences across nativity and education were driven by higher rates of smoking in US-born women with lower educational attainment. IMPACT: Smoking behavioral patterns were similar among breast cancer survivors and the general population, informing potential smoking interventions.

Advances in Adherence Reporting of Resistance Training in a Clinical Trial during Adjuvant Chemotherapy for Colon Cancer.

PURPOSE: Detailed reporting of individually tailored exercise prescriptions (ExR x ) used in clinical trials is essential to describe feasibility, tolerability, and efficacy of the intervention and to inform translation to clinical care. This article outlines the methodology used to develop a resistance training (RT) ExR x for people with colon cancer receiving chemotherapy and reports adherence to the randomized controlled trial testing the impact of RT on relative dose intensity of chemotherapy and patient-reported toxicities. METHODS: Participants randomized to the exercise arm ( n = 90) were included. To promote muscle hypertrophy, the ExR x was twice-weekly, moderate to heavy loads (65%-85% one-repetition maximum), high sets (3-5), and intermediate repetitions (6-10) of five large multijoint movements with adjustable dumbbells. Attendance (achieved frequency) and adherence (achieved volume) were calculated. Group-based trajectory modeling was used to identify clusters of individuals with similar adherence patterns and compared baseline characteristics across adherence groups. RESULTS: The median attendance was 69.1%. Adherence was 60.6% but higher for those receiving 3 versus 6 months of chemotherapy (80.4 vs 47.4%; P < 0.05 ). Participants engaged in a median of 1.4 d of RT each week, lifting 62% of the one-repetition maximum load, for 3.0 sets and 7.5 repetitions per set. Three distinct adherence groups were identified: 13% "nonstarter," 37% "tapered off," and 50% "consistent exercisers." Females were more likely to be in the nonstarter and tapered-off groups. CONCLUSIONS: This article outlines suggested methods for reporting ExR x of RT in oncology clinical trials and provides insight into the tolerance of ExR x of RT during chemotherapy treatment for colon cancer. These findings aim to foster constructive dialogue and offer a premise for designing future research to elucidate the benefits of exercise during chemotherapy.

Skeletal muscle and visceral adipose radiodensities are pre-surgical, non-invasive markers of aggressive kidney cancer.

INTRODUCTION: Most studies on body composition in kidney cancer have been conducted among patients with metastatic disease. Given that aggressive tumours can adversely impact body composition and even non-metastatic tumours can be aggressive, we evaluated associations between pre-surgical body composition features and tumour pathological features in patients with non-metastatic clear cell renal cell cancer (ccRCC). METHODS: The Resolve Cohort consists of 1239 patients with non-metastatic ccRCC who underwent nephrectomy at Memorial Sloan Kettering Cancer Center between 2000 and 2020. The cross-sectional areas and radiodensities of skeletal muscle, visceral adipose, and subcutaneous adipose tissues were determined from pre-surgical computed tomography (CT) scans at the third lumbar vertebrae using Automatica software. Pearson's correlation coefficients describe inter-relationships among BMI and body composition variables, while odds ratios (OR) and 95% confidence intervals (CI) estimate associations between continuous body composition features (per 1-standard deviation) and advanced stage (Stage III vs. Stages I-II) and high Fuhrman grade (Grades 3-4 vs. 1-2) from multivariable logistic regression models that considered the potential impact of biological sex, contrast enhanced CTs, and early age at onset of ccRCC. RESULTS: The cohort was predominantly male (69%), white (89%), and had a median age of 58. The proportion of patients presenting with advanced stage and high-grade disease were 31% and 51%, respectively. In models that adjusted for demographics and all body composition variables simultaneously, decreasing skeletal muscle radiodensity (i.e., more fat infiltration) but increasing visceral adipose tissue radiodensity (i.e., more lipid depletion) were associated with advanced tumour features. Per 8.4 HU decrease in skeletal muscle radiodensity, the odds of presenting with advanced stage was 1.61 (95% CI: 1.34-1.93). Per 7.22 HU increase in visceral adipose tissue radiodensity, the odds of presenting with advanced stage was 1.45 (95% CI: 1.22-1.74). Skeletal muscle index (i.e., sarcopenia) was not associated with either tumour feature. Similar associations were observed for Fuhrman grade, a more direct marker of tumour aggressiveness. Associations did not differ by sex, contrast use, or age at onset of ccRCC. CONCLUSIONS: Lipid infiltrated skeletal muscle, but lipid depleted visceral adipose tissue were independently associated with advanced tumour features in non-metastatic ccRCC. Findings highlight the importance of evaluating the full range of body composition features simultaneously in multivariable models. Interpreting pre-surgical CTs for body composition for patients may be a novel and non-invasive way to identify patients with aggressive renal tumours, which is clinically relevant as renal biopsies are not routinely performed.

Effect of home-based resistance training on chemotherapy relative dose intensity and tolerability in colon cancer: The FORCE randomized control trial.

BACKGROUND: Many patients with colon cancer cannot fully adhere to postoperative chemotherapy due to dose-limiting toxicities, resulting in lower relative dose intensity (RDI) and potentially compromising overall survival. This study examined whether home-based resistance training (RT) during adjuvant chemotherapy improves RDI and patient-reported toxicities versus usual care (UC) in colon cancer patients. METHODS: Multicenter, randomized control trial (RCT) conducted at community and academic practices. Enrollment of patients receiving postoperative chemotherapy for colon cancer occurred between February 23, 2018, and September 29, 2021; final follow-up was March 21, 2022. Participants were randomized to RT (n = 90) or UC (n = 91) for the duration of chemotherapy. Participants in the RT group engaged in twice weekly home-based progressive RT. At the end of the study, UC was given an online exercise program. RESULTS: Among 181 randomized patients (mean age, 55.2 [SD, 12.8] years, 95 [52.5%] were men), there were no differences in the mean RDI among those in RT (79% [SD, 19%]) and those in UC (82% [SD, 19%]); (mean difference -0.04 [95% confidence interval (CI), -0.09 to 0.02]). Assignment to RT did not significantly reduce the number of moderate/severe symptoms per week across follow-up (relative rate: 0.94 [95% CI, 0.72-1.22]). Additionally, time since randomization did not significantly modify the effect of RT on the overall number of symptoms (p = .06). CONCLUSIONS: Among patients with colon cancer, these results do not support home-based RT as an adjunct to chemotherapy specifically to improve planned treatment intensity.

D3-creatine dilution, computed tomography and dual-energy X-ray absorptiometry for assessing myopenia and physical function in colon cancer: A cross-sectional study.

BACKGROUND: Low skeletal muscle mass (myopenia) is common in cancer populations and is associated with functional decline and mortality, but prior oncology studies did not assess total body skeletal muscle mass. Instead, they measured surrogates such as cross-sectional area (CSA) of skeletal muscle at L3 from computed tomography (CT) or appendicular lean mass (ALM) from dual-energy X-ray absorptiometry (DXA). D3-creatine (D3Cr) dilution is a non-invasive method to assess total body skeletal muscle mass, which has been examined in a variety of populations but not in cancer. To compare the associations of D3Cr muscle mass, CT CSA, and DXA ALM with myopenia and physical function, we conducted a cross-sectional study among 119 patients with colon cancer (2018-2022). METHODS: For each technique (D3Cr, CT and DXA), myopenia was defined as the lowest sex-specific quartile of its measurement. Physical function was measured by the short physical performance battery and grip strength. We calculated Pearson correlations (r) among three techniques, computed Cohen's kappa coefficients (κ) to assess the agreement of myopenia, and estimated Pearson correlations (r) of three techniques with physical function. All analyses were sex-specific. RESULTS: Sixty-one (51.3%) participants were male, the mean (standard deviation) age was 56.6 (12.9) years, and most (68.9%) had high physical function (short physical performance battery: ≥11 points). Correlations and myopenia agreement among three techniques were greater in men than women; for example, regarding D3Cr muscle mass versus CT CSA, r was 0.73 (P < 0.001) for men versus 0.45 (P < 0.001) for women, and κ was 0.82 (95% CI: 0.65, 0.99) for men versus 0.24 (95% CI: -0.08, 0.52) for women. Among men, higher D3Cr muscle mass was significantly correlated with faster gait speed (r = 0.43, P < 0.01) and stronger grip strength (r = 0.32, P < 0.05); similar correlations were observed for CT CSA and DXA ALM. However, among women, no measure of muscle or lean mass was significantly associated with physical function. CONCLUSIONS: This is the first study using D3-creatine dilution method to assess muscle mass in a cancer population. Regardless of the techniques used for muscle or lean mass assessment, we observed stronger correlations, greater myopenia agreement, and more significant associations with physical function in men with colon cancer than women. D3Cr, CT and DXA are not interchangeable methods for assessing myopenia and physical function, especially in women with colon cancer. Future studies should consider relative advantages of these techniques and examine the D3-creatine dilution method in other cancer types.

Alcohol consumption and prognosis and survival in breast cancer survivors: The Pathways Study.

BACKGROUND: The impact of alcohol consumption on breast cancer (BC) prognosis remains unclear. METHODS: The authors examined short-term alcohol intake in relation to recurrence and mortality in 3659 women who were diagnosed with stage I-IV BC from 2003 to 2013 in the Pathways Study. Alcohol drinking in the past 6 months was assessed at cohort entry (mean, 2 months postdiagnosis) and 6 months later using a food-frequency questionnaire. Study end points were recurrence and death from BC, cardiovascular disease, and all causes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards models. RESULTS: Over an average follow-up of 11.2 years, 524 recurrences and 834 deaths (369 BC-specific and 314 cardiovascular disease-specific) occurred. Compared with nondrinkers (36.9%), drinkers were more likely younger, more educated, and current or past smokers. Overall, alcohol consumption was not associated with recurrence or mortality. However, women with higher body mass index (BMI ≥ 30 kg/m2 ) had lower risk of overall mortality with increasing alcohol consumption for occasional drinking (HR, 0.71; 95% CI, 0.54-0.94) and regular drinking (HR, 0.77; 95% CI, 0.56-1.08) around the time of diagnosis, along with 6 months later, in a dose-response manner (p < .05). Women with lower BMI (<30 kg/m2 ) were not at higher risk of mortality but were at possibly higher, yet nonsignificant, risk of recurrence for occasional drinking (HR, 1.29; 95% CI, 0.97-1.71) and regular drinking (HR, 1.19; 95% CI, 0.88-1.62). CONCLUSIONS: Alcohol drinking around the time of and up to 6 months after BC diagnosis was associated with lower risk of all-cause mortality in obese women. A possible higher risk of recurrence was observed in nonobese women.

Body Composition, Relative Dose Intensity, and Adverse Events among Patients with Colon Cancer.

BACKGROUND: Despite evidence that low muscle increases the risk of chemotoxicity, most chemotherapies are dosed on body surface area without considering body composition. Among 178 patients with colon cancer, we assessed muscle and adipose tissue with multiple techniques and examined their associations with relative dose intensity (RDI) and adverse events. METHODS: We estimated (i) cross-sectional skeletal muscle area (SMA) and total adipose tissue (TAT) area at L3 from computed tomography (CT); (ii) appendicular lean mass (ALM) and total body fat (TBF) mass from dual-energy X-ray absorptiometry (DXA); and (iii) total body skeletal muscle mass using D3-creatine (D3Cr) dilution. We standardized each measurement by its sex-specific standard deviation (SD). The primary outcome was reduced RDI (RDI <85%). The secondary outcome was the number of moderate and severe adverse events during each cycle of chemotherapy. We estimated the associations of muscle and adipose tissue measurements (per SD increase) with reduced RDI using logistic regression and adverse events using generalized estimating equations for repeated measures. RESULTS: Higher CT SMA and DXA ALM were significantly associated with a lower risk of reduced RDI [odds ratios: 0.56 (0.38-0.81) for CT SMA; 0.56 (0.37-0.84) for DXA ALM]. No measurements of muscle or adipose tissue were associated with adverse events. CONCLUSIONS: More muscle was associated with improved chemotherapy completion among patients with colon cancer, whereas muscle and adipose tissue were not associated with adverse events. IMPACT: Considering body composition may help personalize dosing for colon cancer chemotherapy by identifying patients at risk for poor chemotherapy outcomes.

Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer.

Patients with pancreatic cancer commonly develop weight loss and muscle wasting. Whether adipose tissue and skeletal muscle losses begin before diagnosis and the potential utility of such losses for earlier cancer detection are not well understood. We quantify skeletal muscle and adipose tissue areas from computed tomography (CT) imaging obtained 2 months to 5 years before cancer diagnosis in 714 pancreatic cancer cases and 1748 matched controls. Adipose tissue loss is identified up to 6 months, and skeletal muscle wasting is identified up to 18 months before the clinical diagnosis of pancreatic cancer and is not present in the matched control population. Tissue losses are of similar magnitude in cases diagnosed with localized compared with metastatic disease and are not correlated with at-diagnosis circulating levels of CA19-9. Skeletal muscle wasting occurs in the 1-2 years before pancreatic cancer diagnosis and may signal an upcoming diagnosis of pancreatic cancer.

Pre-diagnosis lipid levels and mortality after obesity-related cancer diagnosis in the Women's Health Initiative cardiovascular disease biomarker cohort.

BACKGROUND: Published studies have demonstrated inconclusive relationships between serum lipid levels and mortality after cancer. METHODS: The primary objective was to evaluate the relationship between fasting lipid levels and mortality after cancer. Data were obtained on baseline lipids and outcomes after cancer from 1263 postmenopausal women diagnosed with 13 obesity-related cancers who were part of the Women's Health Initiative (WHI) lipid biomarkers cohort. Obesity-related cancers included incident invasive cancers of the breast, colorectum, endometrium, esophagus (adenocarcinoma), kidney, liver, gallbladder, pancreas, ovaries, small intestine, thyroid, stomach, as well as multiple myeloma. Baseline lipid measurements included high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and non-HDL-cholesterol. Outcomes were all cause, cancer-specific, and CVD mortality. Multivariable Cox proportional hazards models were used to measure associations between lipid levels and mortality (all cause, cancer, and CVD) after a cancer diagnosis, with lipids analyzed as continuous variables. RESULTS: Among women with obesity-related cancer, there were 707 deaths, of which 379 (54%) were due to cancer and 113 (16%) were due to CVD. Mean time from blood draw to cancer diagnosis was 5.1 years (range: 0.05-10 years). LDL-C values above the 95th percentile were associated with higher risk of all-cause mortality (p < 0.001), and cancer-specific mortality (p < 0.001), but not mortality due to CVD. Non-HDL-C values above the 65th percentile were associated with higher risk of all-cause mortality (p = 0.01) and mortality due to CVD (p = 0.003), but not cancer-specific mortality (p = 0.37). HDL-C values above the 95th percentile were associated with lower all-cause mortality (p = 0.002), and above the 65th percentile with lower cancer-specific mortality (p = 0.003), but no significant relationship with mortality due to CVD was observed. CONCLUSIONS: The relationship between pre-diagnosis fasting lipid levels and mortality after cancer diagnosis is complex. These results suggest that improved lipid control through lifestyle and anti-lipid medications could have a meaningful impact on outcomes after cancer.

Development and testing of a polygenic risk score for breast cancer aggressiveness.

Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature. Using 2363 breast cancers with tumor gene expression data and single nucleotide polymorphism (SNP) genotypes, we examined the associations between ROR-P and known breast cancer susceptibility SNPs using linear regression models. We constructed PRSs based on varying p-value thresholds and selected the optimal PRS based on model r2 in 5-fold cross-validation. We then used Cox proportional hazards regression to test the ROR-P PRS's association with breast cancer-specific survival in two independent cohorts totaling 10,196 breast cancers and 785 events. In meta-analysis of these cohorts, higher ROR-P PRS was associated with worse survival, HR per SD = 1.13 (95% CI 1.06-1.21, p = 4.0 × 10-4). The ROR-P PRS had a similar magnitude of effect on survival as a comparator PRS for estrogen receptor (ER)-negative versus positive cancer risk (PRSER-/ER+). Furthermore, its effect was minimally attenuated when adjusted for PRSER-/ER+, suggesting that the ROR-P PRS provides additional prognostic information beyond ER status. In summary, we used integrated analysis of germline SNP and tumor gene expression data to construct a PRS associated with aggressive tumor biology and worse survival. These findings could potentially enhance risk stratification for breast cancer screening and prevention.

Cachexia: A systemic consequence of progressive, unresolved disease.

Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia.

Long-term Trajectories of Physical Function Decline in Women With and Without Cancer.

Importance: Patients with cancer experience acute declines in physical function, hypothesized to reflect accelerated aging driven by cancer-related symptoms and effects of cancer therapies. No study has examined long-term trajectories of physical function by cancer site, stage, or treatment compared with cancer-free controls. Objective: Examine trajectories of physical function a decade before and after cancer diagnosis among older survivors and cancer-free controls. Design, Setting, and Participants: This prospective cohort study enrolled patients from 1993 to 1998 and followed up until December 2020. The Women's Health Initiative, a diverse cohort of postmenopausal women, included 9203 incident cancers (5989 breast, 1352 colorectal, 960 endometrial, and 902 lung) matched to up to 5 controls (n = 45 358) on age/year of enrollment and study arm. Exposures: Cancer diagnosis (site, stage, and treatment) via Medicare and medical records. Main Outcomes and Measures: Trajectories of self-reported physical function (RAND Short Form 36 [RAND-36] scale; range: 0-100, higher scores indicate superior physical function) estimated from linear mixed effects models with slope changes at diagnosis and 1-year after diagnosis. Results: This study included 9203 women with cancer and 45 358 matched controls. For the women with cancer, the mean (SD) age at diagnosis was 73.0 (7.6) years. Prediagnosis, physical function declines of survivors with local cancers were similar to controls; after diagnosis, survivors experienced accelerated declines relative to controls, whose scores declined 1 to 2 points per year. Short-term declines in the year following diagnosis were most severe in women with regional disease (eg, -5.3 [95% CI, -6.4 to -4.3] points per year in regional vs -2.8 [95% CI, -3.4 to -2.3] for local breast cancer) or who received systemic therapy (eg, for local endometrial cancer, -7.9 [95% CI, -12.2 to -3.6] points per year with any chemotherapy; -3.1 [95% CI, -6.0 to -0.3] with radiation therapy alone; and -2.6 [95% CI, -4.2 to -1.0] with neither, respectively). While rates of physical function decline slowed in the later postdiagnosis period (eg, women with regional colorectal cancer declined -4.3 [95% CI, -5.9 to -2.6] points per year in the year following diagnosis vs -1.4 [95% CI, -1.7 to -1.0] points per year in the decade thereafter), survivors had estimated physical function significantly below that of age-matched controls 5 years after diagnosis. Conclusions and Relevance: In this prospective cohort study, survivors of cancer experienced accelerated declines in physical function after diagnosis, and physical function remained below that of age-matched controls even years later. Patients with cancer may benefit from supportive interventions to preserve physical functioning.

Association of Inflammatory Biomarkers With Survival Among Patients With Stage III Colon Cancer.

Importance: The association of chronic inflammation with colorectal cancer recurrence and death is not well understood, and data from large well-designed prospective cohorts are limited. Objective: To assess the associations of inflammatory biomarkers with survival among patients with stage III colon cancer. Design, Setting, and Participants: This cohort study was derived from a National Cancer Institute-sponsored adjuvant chemotherapy trial Cancer and Leukemia Group B/Southwest Oncology Group 80702 (CALGB/SWOG 80702) conducted between June 22, 2010, and November 20, 2015, with follow-up ending on August 10, 2020. A total of 1494 patients with plasma samples available for inflammatory biomarker assays were included. Data were analyzed from July 29, 2021, to February 27, 2022. Exposures: Plasma inflammatory biomarkers (interleukin 6 [IL-6], soluble tumor necrosis factor α receptor 2 [sTNF-αR2], and high-sensitivity C-reactive protein [hsCRP]; quintiles) that were assayed 3 to 8 weeks after surgery but before chemotherapy randomization. Main Outcomes and Measures: The primary outcome was disease-free survival, defined as time from randomization to colon cancer recurrence or death from any cause. Secondary outcomes were recurrence-free survival and overall survival. Hazard ratios for the associations of inflammatory biomarkers and survival were estimated via Cox proportional hazards regression. Results: Of 1494 patients (median follow-up, 5.9 years [IQR, 4.7-6.1 years]), the median age was 61.3 years (IQR, 54.0-68.8 years), 828 (55.4%) were male, and 327 recurrences, 244 deaths, and 387 events for disease-free survival were observed. Plasma samples were collected at a median of 6.9 weeks (IQR, 5.6-8.1 weeks) after surgery. The median plasma concentration was 3.8 pg/mL (IQR, 2.3-6.2 pg/mL) for IL-6, 2.9 × 103 pg/mL (IQR, 2.3-3.6 × 103 pg/mL) for sTNF-αR2, and 2.6 mg/L (IQR, 1.2-5.6 mg/L) for hsCRP. Compared with patients in the lowest quintile of inflammation, patients in the highest quintile of inflammation had a significantly increased risk of recurrence or death (adjusted hazard ratios for IL-6: 1.52 [95% CI, 1.07-2.14]; P = .01 for trend; for sTNF-αR2: 1.77 [95% CI, 1.23-2.55]; P < .001 for trend; and for hsCRP: 1.65 [95% CI, 1.17-2.34]; P = .006 for trend). Additionally, a significant interaction was not observed between inflammatory biomarkers and celecoxib intervention for disease-free survival. Similar results were observed for recurrence-free survival and overall survival. Conclusions and Relevance: This cohort study found that higher inflammation after diagnosis was significantly associated with worse survival outcomes among patients with stage III colon cancer. This finding warrants further investigation to evaluate whether anti-inflammatory interventions may improve colon cancer outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT01150045.

Association between dietary inflammatory potential and mortality after cancer diagnosis in the Women's Health Initiative.

BACKGROUND: Chronic inflammation is implicated in cancer prognosis and can be modulated by diet. We examined associations between post-diagnosis dietary inflammatory potential and mortality outcomes among post-menopausal women diagnosed with cancer in the Women's Health Initiative (WHI). METHODS: Energy-adjusted dietary inflammatory index scores (E-DII) were calculated from dietary and supplemental intake data collected on the first food frequency questionnaire following the diagnosis of primary invasive cancer for 3434 women in the WHI. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for risk of death from any cause, cancer, cardiovascular disease (CVD) and other causes by post-diagnosis quartiles of E-DII. Subgroup analyses by cancer stage and grade were performed. RESULTS: There were 1156 deaths after a median 13 years of follow-up from the date of a cancer diagnosis. In the multivariable-adjusted analyses, a more anti-inflammatory diet plus supplements after cancer diagnosis was associated with lower all-cause mortality, cancer mortality, CVD mortality and mortality from other causes with HRsQ1vs.Q4 ranging from 0.47 to 0.68 (all P-trends < 0.05). Associations were stronger for cancers diagnosed at more distant stages or moderately differentiated grades. CONCLUSION: A more anti-inflammatory diet plus supplements after a cancer diagnosis may improve survival for post-menopausal cancer survivors.

Association of serum folate levels during pregnancy and prenatal depression.

OBJECTIVE: To evaluate the association between serum folate levels during pregnancy and prenatal depression and the extent to which obesity may modify this relationship. METHODS: This secondary data analysis leveraged data from a previous study of pregnant Kaiser Permanente Northern California participants who completed a survey and provided a serum sample between 2011 and 2013. Serum folate was assessed using the Center for Disease Control's Total Folate Serum/Whole Blood Microbiological Assay Method. A score of 15 or greater on the Center for Epidemiologic Studies Depression Scale was defined as prenatal depression. We used Poisson regression to estimate risk of prenatal depression given prenatal serum folate status (low/medium tertiles vs. high tertile) in the full sample and in subsamples of women with pre-pregnancy body mass index in the (a) normal range and (b) overweight/obese range. RESULTS: Of the sample, 13% had prenatal depression. Combined low/medium folate tertiles was associated with prenatal depression (adjusted relative risk [aRR] = 1.97, 95% confidence interval [CI]: 0.93-4.18), although results did not reach statistical significance. This relationship was stronger among women with overweight/obesity than women with normal weight (aRR: 2.61, 95% CI: 1.01-6.71 and aRR: 1.50, 95% CI: 0.34-6.66, respectively). CONCLUSION: Results suggest an association between lower pregnancy folate levels and prenatal depression that may be stronger among women with overweight or obesity. Future studies need to clarify the temporal sequence of these associations.

Metabolic abnormalities and survival among patients with non-metastatic breast cancer.

BACKGROUND: Research on the impact of metabolic abnormalities on breast cancer prognosis is limited by small samples and assessment of laboratory values at a single time point, often prior to cancer diagnosis and treatment. In this population-based cohort, time-updated laboratory values were adjusted for cancer treatment to assess the association between metabolic risk factors (glucose, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides) and breast cancer survival. METHODS: 13,434 women diagnosed with stage I-III breast cancer from 2005-15 at Kaiser Permanente were included. All outpatient fasting glucose, HDL-C, LDL-C, and triglyceride values from diagnosis through 2019 or death were extracted from electronic medical records. Risk of breast cancer-specific mortality was evaluated with Cox proportional hazards models adjusted for metabolic labs, demographics, body mass index, diabetes, dyslipidemia and anti-hypertensive medications, tumor characteristics (stage, ER and HER2 receptor status) and cancer treatment (use of chemotherapy, tamoxifen, and aromatase inhibitors). RESULTS: Mean (SD) age at diagnosis was 62.3 (11.8) years. Over a median follow-up of 8.6 years, 2,876 patients died; 1,080 of breast cancer. Patients with low HDL-C (≤ 45 vs. > 45 mg/dL) had higher breast cancer-specific mortality (HR, 1.77; 95% CI, 1.53-2.05), as did those with elevated fasting glucose (> 99 vs. 60-99 mg/dL) (HR, 1.19; 95% CI, 1.03-1.37). Elevated levels of triglycerides and LDL-C were not associated with breast cancer-specific mortality. CONCLUSIONS: High fasting glucose and low HDL-C evaluated over time after cancer diagnosis were associated with higher breast cancer mortality independent of cancer treatments and changes in other metabolic risk factors. Future studies should address whether pharmacologic or lifestyle treatment of glucose and lipids after breast cancer diagnosis can optimize survival outcomes.