Allometric versus traditional body-shape indices and risk of colorectal cancer: a Mendelian randomization analysis.

BACKGROUND: Traditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing. METHODS: We used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank and the GIANT consortium, and from GECCO, CORECT and CCFR consortia. RESULTS: WHI was positively associated with CRC in men (OR per SD: 1.20, 95% CI: 1.03-1.39) and in women (1.15, 1.06-1.24), and similarly for colon and rectal cancer. ABSI was positively associated with colon and rectal cancer in men (1.27, 1.03-1.57; and 1.40, 1.10-1.77, respectively), and with colon cancer in women (1.20, 1.07-1.35). There was little evidence for association between HI and colon or rectal cancer. The BMI-adjusted WHR and HC showed similar associations to WHI and HI, whereas WC showed similar associations to ABSI only in women. CONCLUSIONS: This large MR study provides strong evidence for a potential causal positive association of the allometric indices ABSI and WHI with CRC in both sexes, thus establishing the association between abdominal fat and CRC without the limitations of the traditional waist size indices and independently of BMI. Among the BMI-adjusted traditional indices, WHR and HC provided equivalent associations with WHI and HI, while differences were observed between WC and ABSI.

Aspirin vs Placebo as Adjuvant Therapy for Breast Cancer: The Alliance A011502 Randomized Trial.

Importance: Observational studies of survivors of breast cancer and prospective trials of aspirin for cardiovascular disease suggest improved breast cancer survival among aspirin users, but prospective studies of aspirin to prevent breast cancer recurrence are lacking. Objective: To determine whether aspirin decreases the risk of invasive cancer events among survivors of breast cancer. Design, Setting, and Participants: A011502, a phase 3, randomized, placebo-controlled, double-blind trial conducted in the United States and Canada with 3020 participants who had high-risk nonmetastatic breast cancer, enrolled participants from 534 sites from January 6, 2017, through December 4, 2020, with follow-up to March 4, 2023. Interventions: Participants were randomized (stratified for hormone receptor status [positive vs negative], body mass index [≤30 vs >30], stage II vs III, and time since diagnosis [<18 vs ≥18 months]) to receive 300 mg of aspirin (n = 1510) or placebo once daily (n = 1510) for 5 years. Main Outcomes and Measures: The primary outcome was invasive disease-free survival. Overall survival was a key secondary outcome. Results: A total of 3020 participants were randomized when the data and safety monitoring committee recommended suspending the study at the first interim analysis because the hazard ratio had crossed the prespecified futility bound. By median follow-up of 33.8 months (range, 0.1-72.6 months), 253 invasive disease-free survival events were observed (141 in the aspirin group and 112 in the placebo group), yielding a hazard ratio of 1.27 (95% CI, 0.99-1.63; P = .06). All invasive disease-free survival events, including death, invasive progression (both distant and locoregional), and new primary events, were numerically higher in the aspirin group, although the differences were not statistically significant. There was no difference in overall survival (hazard ratio, 1.19; 95% CI, 0.82-1.72). Rates of grades 3 and 4 adverse events were similar in both groups. Conclusion and Relevance: Among participants with high-risk nonmetastatic breast cancer, daily aspirin therapy did not improve risk of breast cancer recurrence or survival in early follow-up. Despite its promise and wide availability, aspirin should not be recommended as an adjuvant breast cancer treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02927249.

Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis.

Although prediagnostic circulating concentrations of the immune activation markers soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) have been associated with non-Hodgkin lymphoma (NHL) risk, studies have been limited by sample size in associations with NHL subtypes. We pooled data from eight nested case-control studies to investigate subtype-specific relationships for these analytes. Using polytomous regression, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific analyte tertiles to selected subtypes vs controls (n = 3310): chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 623), diffuse large B cell lymphoma (DLBCL; n = 621), follicular lymphoma (FL; n = 398), marginal zone lymphoma (MZL; n = 138), mantle cell lymphoma (MCL; n = 82) and T cell lymphoma (TCL; n = 92). We observed associations with DLBCL for elevated sCD27 [OR for third vs first tertile (ORT3 ) = 2.2, 95% CI = 1.6-3.1], sCD30 (ORT3  = 2.0, 95% CI = 1.6-2.5) and CXCL13 (ORT3  = 2.3, 95% CI = 1.8-3.0). We also observed associations with sCD27 for CLL/SLL (ORT3  = 3.3, 95% CI = 2.4-4.6), MZL (ORT3  = 7.7, 95% CI = 3.0-20.1) and TCL (ORT3  = 3.4, 95% CI = 1.5-7.7), and between sCD30 and FL (ORT3  = 2.7, 95% CI = 2.0-3.5). In analyses stratified by time from phlebotomy to case diagnosis, the sCD27-TCL and all three DLBCL associations were equivalent across both follow-up periods (<7.5, ≥7.5 years). For other analyte-subtype comparisons, associations were stronger for the follow-up period closer to phlebotomy, particularly for indolent subtypes. In conclusion, we found robust evidence of an association between these immune markers and DLBCL, consistent with hypotheses that mechanisms related to immune activation are important in its pathogenesis. Our other findings, particularly for the rarer subtypes MZL and TCL, require further investigation.

Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.

Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study.

BACKGROUND: Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. METHODS: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. RESULTS: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98-1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00-1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04-1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77-1.22) and colon cancer (OR: 0.97, 95% CI: 0.76-1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90-1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). CONCLUSIONS: Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.

NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.

Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts.

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100- < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

Trends in breast cancer incidence rates by race/ethnicity: Patterns by stage, socioeconomic position, and geography in the United States, 1999-2017.

BACKGROUND: The incidence rate of breast cancer has been increasing over time across race/ethnicity in the United States. It is unclear whether these trends differ among stage, poverty, and geography subgroups. METHODS: Using data from the North American Association of Central Cancer Registries, this study estimated trends in age-adjusted breast cancer incidence rates among women aged 50 to 84 years from 1999 to 2017 by race/ethnicity (non-Hispanic Black, non-Hispanic White, and Hispanic) and across subgroups (stage, county-level poverty, county urban/rural status, and geographic region [West, Midwest, South, and Northeast]). RESULTS: From 2004 to 2017, breast cancer incidence rates increased across race/ethnicity and subgroups, with the greatest average annual percent increases observed for non-Hispanic Black women, overall (0.9%) and those living in lower poverty areas (0.8%), rural areas (1.2%), and all regions except the West (0.8%-1.0%). Stronger increases among non-Hispanic Black women were observed for local-stage disease and for some subgroups of distant-stage disease. Non-Hispanic Black women had the smallest decrease in regional-stage disease across most subgroups. Similarly, Hispanic women had the strongest increases in some subgroups, including areas with higher poverty (0.6%-1.2%) and in the West (0.8%), for local- and distant-stage disease. CONCLUSIONS: These trends highlight concerns for an increasing burden of breast cancer among subpopulations, with some already experiencing disparate breast cancer mortality rates, and they highlight the need for targeted breast cancer prevention and efforts to reduce mortality disparities in areas with increasing incidence.

Racial and ethnic differences in the adoption of opportunistic salpingectomy for ovarian cancer prevention in the United States.

BACKGROUND: Clinicians in the United States have rapidly adopted opportunistic salpingectomy for ovarian cancer prevention. However, little is known about racial and ethnic differences in opportunistic salpingectomy adoption. Surgical innovations in gynecology may be adopted differentially across racial and ethnic groups, exacerbating current disparities in quality of care. OBJECTIVE: This study aimed to evaluate racial and ethnic differences in opportunistic salpingectomy adoption across inpatient and outpatient settings and assess the effect of national guidelines supporting opportunistic salpingectomy use on these differences. STUDY DESIGN: A sample of 650,905 women aged 18 to 50 years undergoing hysterectomy with ovarian conservation or surgical sterilization from 2011 to 2018 was identified using the Premier Healthcare Database, an all-payer hospital administrative database, including more than 700 hospitals across the United States. The association between race and ethnicity and opportunistic salpingectomy use was examined using multivariable-adjusted mixed-effects log-binomial regression models accounting for hospital-level clustering. Models included race and ethnicity by year of surgery (2011-2013 [before guideline] and 2014-2018 [after guideline]) interaction term to test whether racial and ethnic differences in opportunistic salpingectomy adoption changed with the release of national guidelines supporting opportunistic salpingectomy use. RESULTS: From 2011 to 2018, 82,792 women underwent hysterectomy and opportunistic salpingectomy (non-Hispanic White, 60.3%; non-Hispanic Black, 18.8%; Hispanic, 12.2%; non-Hispanic other race, 8.7%) and 23,398 women underwent opportunistic salpingectomy for sterilization (non-Hispanic White, 64.7%; non-Hispanic Black, 10.8%; Hispanic, 16.7%; non-Hispanic other race, 7.8%). The proportion of hysterectomy procedures involving an opportunistic salpingectomy increased from 6.3% in 2011 to 59.7% in 2018 (9.5-fold increase), and the proportion of sterilization procedures involving an opportunistic salpingectomy increased from 0.7% in 2011 to 19.4% in 2018 (27.7-fold increase). In multivariable-adjusted models, non-Hispanic Black (risk ratio, 0.94; 95% confidence interval, 0.92-0.97), Hispanic (risk ratio, 0.98; 95% confidence interval, 0.95-1.00), and non-Hispanic other race women (risk ratio, 0.93; 95% confidence interval, 0.90-0.96) were less likely to undergo hysterectomy and opportunistic salpingectomy than non-Hispanic White women. A significant interaction between race and ethnicity and year of surgery was noted in non-Hispanic Black compared with non-Hispanic White women (P<.001), with a reduction in differences in hysterectomy and opportunistic salpingectomy use after national guideline release (risk ratio2011-2013, 0.80 [95% confidence interval, 0.73-0.88]; risk ratio2014-2018, 0.98 [95% confidence interval, 0.95-1.01]). Moreover, non-Hispanic Black women were less likely to undergo an opportunistic salpingectomy for sterilization than non-Hispanic White women (risk ratio, 0.91; 95% confidence interval, 0.88-0.95), with no difference by year of surgery (P=.62). Stratified analyses by hysterectomy route and age at surgery revealed similar results. CONCLUSION: Although opportunistic salpingectomy for ovarian cancer prevention has been rapidly adopted in the United States, our findings suggested that its adoption has not been equitable across racial and ethnic groups. Non-Hispanic Black, Hispanic, and non-Hispanic other race women were less likely to undergo opportunistic salpingectomy than non-Hispanic White women even after adjusting for sociodemographic, clinical, procedural, hospital, and provider characteristics. These differences persisted after the release of national guidelines supporting opportunistic salpingectomy use. Future research should focus on understanding the reasons for these differences to inform interventions that promote equity in opportunistic salpingectomy use.

Comorbidities and the risk of cardiovascular disease mortality among racially diverse patients with breast cancer.

BACKGROUND: Women who have coexisting comorbidities at the time of breast cancer diagnosis have an increased risk of breast cancer and overall mortality. However, the associations between newly diagnosed comorbidities and the risk of cardiovascular disease (CVD) mortality among these patients have not been examined. METHODS: The authors compared the associations between coexisting and newly diagnosed CVD, type 2 diabetes, and hypertension and the risk of CVD mortality among patients with breast cancer identified in the Missouri Cancer Registry. In total, 33,099 women who had incident invasive breast cancer with inpatient and outpatient hospital discharge data within 2 years after breast cancer diagnosis were included: 9.3% were Black. Subdistribution hazard ratios (sdHRs) and 95% CIs were calculated for the risk of CVD-related mortality using adjusted Cox proportional hazards regression models, accounting for a competing risk of breast cancer deaths. RESULTS: Within the first 2 years after breast cancer, the most reported newly diagnosed comorbidity was hypertension (9%), followed by CVD (4%), and type 2 diabetes (2%). CVD mortality was increased in women who had newly diagnosed CVD (sdHR, 2.49; 95% CI, 2.09-2.99), diabetes (sdHR, 2.16; 95% CI, 1.68-2.77), or hypertension (sdHR, 2.06; 95% CI, 1.71-2.48) compared with women who did not have these conditions. Associations were similar by race. The strongest association was among women who received chemotherapy and then developed CVD (sdHR, 3.82; 95% CI, 2.69-5.43). CONCLUSIONS: Monitoring for diabetes, hypertension, and CVD from the time of breast diagnosis may reduce CVD mortality.

Fitness and prostate cancer screening, incidence, and mortality: Results from the Henry Ford Exercise Testing (FIT) Project.

BACKGROUND: The relation between cardiorespiratory fitness (CRF) and prostate cancer is not well established. The objective of this study was to determine whether CRF is associated with prostate cancer screening, incidence, or mortality. METHODS: The Henry Ford Exercise Testing Project is a retrospective cohort study of men aged 40 to 70 years without cancer who underwent physician-referred exercise stress testing from 1995 to 2009. CRF was quantified in metabolic equivalents of task (METs) (<6 [reference], 6-9, 10-11, and ≥12 METs), estimated from the peak workload achieved during a symptom-limited, maximal exercise stress test. Prostate-specific antigen (PSA) testing, incident prostate cancer, and all-cause mortality were analyzed with multivariable adjusted Poisson regression and Cox proportional hazard models. RESULTS: In total, 22,827 men were included, of whom 739 developed prostate cancer, with a median follow-up of 7.5 years. Men who had high fitness (≥12 METs) had an 28% higher risk of PSA screening (95% CI, 1.2-1.3) compared with those who had low fitness (<6 METs. After adjusting for PSA screening, fitness was associated with higher prostate cancer incidence (men aged <55 years, P = .02; men aged >55 years, P ≤ .01), but not with advanced prostate cancer. Among the men who were diagnosed with prostate cancer, high fitness was associated with a 60% lower risk of all-cause mortality (95% CI, 0.2-0.9). CONCLUSIONS: Although men with high fitness are more likely to undergo PSA screening, this does not fully account for the increased incidence of prostate cancer seen among these individuals. However, men with high fitness have a lower risk of death after a prostate cancer diagnosis, suggesting that the cancers identified may be low-risk with little impact on long-term outcomes.

Relationship of circulating immune cells with lifestyle factors and cancer recurrence in early-stage breast cancer.

PURPOSE: To evaluate the relationship of circulating immune cells with recurrence and metabolic/lifestyle factors in patients with early-stage breast cancer. METHODS: Patients with early-stage breast cancer were identified from the electronic record and institutional registry. Lymphocyte and monocyte counts were obtained from blood samples at time of diagnosis prior to any chemotherapy. Correlations between lymphocyte and monocyte and recurrence were assessed in the entire cohort and among obese patients, those reporting alcohol consumption and smoking. Competing risk regression was used to analyze time to recurrence. RESULTS: A total of 950 patients with ≥ 5 years of follow-up were identified; 433 had complete data and were eligible for analysis. 293 (68%) had hormone receptor-positive breast cancer, 82 (19%) HER2 positive, and 53 (13%) triple negative. Patients in the highest quintile of lymphocytes compared to the lowest quintile had lower risk of recurrence (subhazard ratio (SHR) = 0.17, 95% CI [0.03-0.93], p = 0.041) while patients in the highest quintile of monocytes had lower risk for recurrence (SHR = 0.19, 95% CI [0.04, 0.92], p = 0.039). Higher monocytes were more strongly associated with lower recurrence among those reporting alcohol consumption (HR = 0.10, 95% CI [0.01, 0.91], p = 0.04). In obese patients, higher lymphocytes were associated with lower risk of recurrence (p = 0.046); in non-obese patients, higher monocytes were associated with lower risk of recurrence (p = 0.02). There were no correlations among patients who reported tobacco use. CONCLUSIONS: High lymphocyte and monocyte counts are associated with lower recurrence rate in early-stage breast cancer, particularly in obese patients and those reporting alcohol consumption.

Association between pre-diagnostic circulating adipokines and colorectal cancer and adenoma in the CLUE II cohort.

OBJECTIVE: Obesity is a known risk factor for colorectal cancer (CRC) and adenoma. Obese individuals have higher circulating concentrations of certain endocrine and immune factors produced by adipocytes thought to partially underlie the association between obesity and colorectal neoplasia. Thus, we evaluated the association of plasma concentrations of adiponectin, leptin, and soluble tumor necrosis factor receptor-2 (sTNFR2) with CRC and adenoma. METHODS: We ascertained 193 CRC cases and 193 matched controls, and 131 colorectal adenoma cases and 131 matched controls who had had an endoscopy nested in the CLUE II cohort of Washington County, MD. Plasma markers were measured using ELISA. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression for quartiles of the plasma markers separately for CRC and adenoma. RESULTS: Adjusting for leptin and adiponectin, sTNFR2 was positively associated with CRC only in men (Q4 vs. Q1: OR = 3.14, 95% CI 1.11-8.86), which was unchanged adjusting for BMI (3.46, 95% CI 1.19-10.06). Leptin and adiponectin were not associated with CRC risk overall or in men or women. Adiponectin, leptin, and sTNFR2 were not associated with adenoma risk overall or in men or women. CONCLUSION: In this study, leptin and adiponectin were not associated with colorectal carcinogenesis and thus do not appear to underlie the association between obesity and colorectal carcinogenesis. sTNFR2, which we measured as a correlate of TNF-α, was positively associated with CRC in men adjusting for BMI, suggesting that TNF-α may influence colorectal carcinogenesis independent of adipocyte production.

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies.

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.

Disparities in the uptake of digital breast tomosynthesis for breast cancer screening: A retrospective cohort study.

We present a retrospective cohort study evaluating the utilization and effectiveness of digital breast tomosynthesis (DBT) for breast cancer screening with a focus on racial differences. 46,236 females underwent screening mammography between 4/1/2013 and 3/30/2020, during which there was an increase in DBT utilization from 18.8% in year 1 to 89.6% in year 7. Black and Asian women were significantly less likely to have a screening study with DBT compared to White women. Overall, the DBT group had a lower recall rate (9.1% versus 11.2%, p < 0.001) and higher cancer detection rate (6.0 vs 4.1, p < 0.001) compared to the FFDM group.

Adult weight change and premenopausal breast cancer risk: A prospective pooled analysis of data from 628,463 women.

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g., HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors.

Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3).

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

Serologic Response to Helicobacter pylori Proteins Associated With Risk of Colorectal Cancer Among Diverse Populations in the United States.

BACKGROUND & AIMS: Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States. METHODS: We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression. RESULTS: Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007). CONCLUSIONS: In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.

A comparison of cancer stage at diagnosis and treatment initiation between enrollees in an urban HIV clinic and SEER.

PURPOSE: A comparison of stage at cancer diagnosis and cancer treatment rates between people with HIV (PWH) and the general US population is needed to identify any disparities by HIV status. METHODS: We compared 236 PWH in clinical care diagnosed with cancer from 1997 to 2014 to a sample from NCI's Surveillance, Epidemiology and End Results (SEER) Program, presumed to be HIV negative. We performed G-computation using random forest methods to estimate stage and treatment percent differences (PD) by HIV. We conducted sensitivity analyses among non-AIDS-defining cancers (NADC), by sex and by CD4 ≤ 200 or > 200 cells/mm3. RESULTS: PWH were less likely to be diagnosed at localized stage (PD = - 16%; 95% CI - 21, - 11) and more likely to be diagnosed at regional stage (PD = 14%; 95% CI 8, 19) than those in SEER. Cancer treatment rates were 13% lower among PWH as compared to SEER (95% CI - 18, - 8). The difference in percent receiving cancer treatment was more pronounced for those with lower CD4 at cancer diagnosis (PD -15%; 95% CI - 27, - 6). Lower treatment rates were observed among NADC, males, and women with CD4 ≤ 200. CONCLUSION: Cancer care for PWH could be improved by diagnosis at earlier stages and increasing rates of cancer treatment.