BackgroundTumor-infiltrating lymphocytes (TILs), assessed by visual examination, are prognostic and predictive in early-stage triple-negative breast cancer. Computational assessment may provide a complementary approach. We evaluated the prognostic value of TILs by visual examination and computational assessment.MethodsCisplatin vs Paclitaxel for Triple Negative Breast Cancer (TBCRC030; ClinicalTrials.gov identifier NCT01982448) was a randomized phase 2 trial enrolling patients with BRCA1/2-proficient stage I to III triple-negative breast cancer to receive preoperative cisplatin or paclitaxel. The primary endpoint was pathological response at surgery. The TILs were visually scored on digitized pretreatment biopsies per International TILS Working Group recommendations. Computational assessment used the 4D Path QPOR platform to generate TILs, an immune heterogeneity index, and a combined immune/cell cycle biomarker (CmbI). Predictive performance for residual cancer burden 0/1 was assessed using receiver operating characteristic curves and odds ratios (ORs) with 95% CIs; all statistical tests were 2-sided.ResultsOf 139 response-evaluable patients, 121 had matched visual examination and computational assessment data (59 on cisplatin, 62 on paclitaxel). Median visual examination TILs were higher in responders (40.0% vs. 10.0%; P = .002) and predicted response (OR = 1.86, 95% CI = 1.24 to 2.87; area under the curve = 0.69, 95% CI = 0.57 to 0.80). Computational assessment CmbI differed by response group and predicted residual cancer burden 0/1 (OR = 3.20, 95% CI = 1.05 to 11.07; area under the curve = 0.62, 95% CI = 0.51 to 0.73). Computational assessment TILs and immune heterogeneity index were not predictive. Visual examination TILs and computational assessment CmbI predicted response to paclitaxel (OR = 2.91, 95% CI = 1.56 to 6.14; OR = 9.17, 95% CI = 2.01 to 66.39, respectively) but not to cisplatin.ConclusionVisual examination TILs and computational assessment CmbI were each associated with response to neoadjuvant chemotherapy in triple-negative breast cancer in the overall cohort and the paclitaxel arm. Computational assessment CmbI did not outperform visual assessment. Further validation is needed before clinical implementation of computational approaches.

BackgroundEmerging blood tests may improve colorectal cancer (CRC) screening uptake and outcomes but are less sensitive for advanced precancerous lesions than some currently recommended tests. We examine whether these tests meet expectations for the US Preventive Services Task Force (USPSTF) recommendation.MethodsA decision-analytic model that informed USPSTF was replicated and used to estimate the lifetime benefits (averted CRC cases and deaths, life-years gained [LYG]), burdens (required screening tests and colonoscopies), and harms (colonoscopy-related complications) for annual, biennial, or triennial blood testing through age 45-75 years vs a benchmark of recommended and contemporary stool-based strategies, with colonoscopy screening as the reference. Base-case analyses assumed 100% adherence. Sensitivity analyses evaluated more realistic scenarios.ResultsAmong benchmark strategies, colonoscopy screening had the most benefit, with an estimated 30 CRC deaths averted, 356 LYG, 4270 colonoscopies required, and 15 complications per 1000 adults; stool-based strategies resulted in 81% to 88% of LYG for colonoscopy, 6829-19 476 screening tests, 1523-1880 colonoscopies, and 9-10 complications. By comparison, annual blood testing resulted in 85% to 87% of LYG for colonoscopy and an intermediate number of screenings, colonoscopies, and complications. Biennial and triennial blood testing provided 57% to 72% of LYG for colonoscopy but resulted in net population benefit under plausible scenarios for increased utilization vs existing strategies.ConclusionsThe estimated benefits, burdens, and harms of annual blood testing are within the range of current CRC screening strategies. Biennial and triennial testing should also be considered for recommendation given the potential for increased utilization and net population benefit.

BackgroundRecommended noninvasive strategies for average-risk colorectal cancer (CRC) screening include multitarget stool DNA and fecal immunochemical test from ages 45 to 75 years. With new clinical trials, performance data for next-generation multitarget stool DNA, multitarget stool RNA, and blood-based screening tests are now available. This decision analytical model study evaluated the estimated benefit-to-burden ratio by means of efficient frontiers for noninvasive established and emerging CRC screening strategies.MethodsOutcomes were estimated using the Colorectal Cancer and Adenoma Incidence and Mortality microsimulation model for average-risk individuals in the United States. Screening strategies were next-generation multitarget stool DNA (an updated marker panel), fecal immunochemical tests, multitarget stool RNA, or blood-based tests every 1-3 years, over various age ranges. Test performance inputs were derived from recent large clinical trials. A strategy was deemed efficient if no other strategy provided more life-years gained with equivalent or fewer lifetime colonoscopies and near-efficient if within 3 days of life-years gained of the efficient frontier.ResultsAll modeled screening strategies resulted in life-years gained vs no screening. No strategy using blood-based tests was efficient or near-efficient. Overall, 10 strategies were efficient (6 next-generation multitarget stool DNA and 4 fecal immunochemical tests), including 2 strategies among those ages 45-75 years (biennial and triennial next-generation multitarget stool DNA). Overall, 22 strategies were near-efficient, including 4 strategies among those ages 45-75 years (annual, biennial, or triennial fecal immunochemical test; annual next-generation multitarget stool DNA).ConclusionBased on this modeling study, next-generation multitarget stool DNA was the only noninvasive screening test at guideline-endorsed interval and age-recommended ranges that was deemed efficient. Blood-based and multitarget stool RNA strategies were deemed not efficient for primary screening.

IntroductionThere is convincing evidence that overall adiposity increases the risks of several cancers. Whether the distribution of adiposity plays a similar role is unclear.MethodsWe used 2-sample Mendelian randomization (MR) to examine causal relationships of 5 adiposity distribution traits (abdominal subcutaneous adipose tissue (ASAT); visceral adipose tissue (VAT); gluteofemoral adipose tissue (GFAT); liver fat; and pancreas fat) with the risks of 12 obesity-related cancers (endometrial, ovarian, breast, colorectal, pancreas, multiple myeloma, liver, kidney (renal cell), thyroid, gallbladder, esophageal adenocarcinoma, and meningioma).ResultsSample size across all genome-wide association studies (GWAS) ranged from 8407 to 728 896 (median: 57 249). We found evidence that higher genetically predicted ASAT increased the risks of endometrial cancer, liver cancer, and esophageal adenocarcinoma (odds ratios (OR) and 95% confidence intervals (CI) per standard deviation (SD) higher ASAT = 1.79 (1.18 to 2.71), 3.83 (1.39 to 10.53), and 2.34 (1.15 to 4.78), respectively). Conversely, we found evidence that higher genetically predicted GFAT decreased the risks of breast cancer and meningioma (ORs and 95% CIs per SD higher genetically predicted GFAT = 0.77 (0.62 to 0.97) and 0.53 (0.32 to 0.90), respectively). We also found evidence for an effect of higher genetically predicted VAT and liver fat on increased liver cancer risk (ORs and 95% CIs per SD higher genetically predicted adiposity trait = 4.29 (1.41 to 13.07) and 4.09 (2.29 to 7.28), respectively).DiscussionOur analyses provide novel insights into the relationship between adiposity distribution and cancer risk. These insights highlight the potential importance of adipose tissue distribution alongside maintaining a healthy weight for cancer prevention.

BackgroundCancer-related fatigue (fatigue) is a common and persistent symptom after cancer treatment, yet the role of genetic susceptibility remains unclear.MethodsWe used data from a prospective cohort study called the ColoCare Study, conducted over 5 US sites and Germany. Fatigue was assessed at 5 time points using the European Organisation for the Research and Treatment of Cancer Core Quality of Life Questionnaire fatigue subscale and analyzed as (1) a binary summary measure of the trajectory from diagnosis into survivorship (defined as severe: yes/no), (2) a mean score across all time points, and (3) the highest (ie, worst) score across all time points. We genotyped samples using the Illumina Infinium Global Diversity Array kit with imputation using the National Institutes of Health TOPMed reference panel to conduct a genome-wide association study. The Sum of Single Effects was used to identify independent secondary signals. Transcriptome-wide association studies using the S-PrediXcan and MultiXcan methods were conducted to examine genetic regulation of gene expression. The COLOC package assessed whether variants identified in the genome-wide association study influence gene expression through colocalization analysis.ResultsAmong 1219 participants, 31.0% experienced severe fatigue over the course of their disease. A locus near LINC02505 on chromosome 4 was associated with severe fatigue (rs6531463; odds ratio = 3.25, P = 3.88 × 10−8). When modeling mean fatigue levels, strongly associated variants were identified in or near NEK10 and SLC4A7. Integrative analyses linked the predicted expression of NEK10 in liver tissue to risk of fatigue (P < 4.36 × 10−6). Colocalization analysis identified genetic loci and gene expression near NEK10 (posterior probabilities >0.9).ConclusionsThis study identified novel genetic loci associated with fatigue in patients with colorectal cancer and may be useful for identifying high-risk individuals for preventative strategies.

Background20% of patients with cancer are estimated to be ineligible for phase III trials because of restrictive eligibility criteria. Ineligibility rates for earlier phase trials are even greater. In response, several groups, including the US Food and Drug Administration, have advocated for more inclusive study designs. We examined Kirsten rat sarcoma virus (KRAS) G12C inhibitor trials to determine if inclusivity has shifted in the development of molecularly targeted therapies.MethodsWe evaluated phase I-III studies of KRAS G12C inhibitors in non–small cell lung cancer (NSCLC) by applying criteria from 15 US trials to a multi-institutional real-world cohort of patients with metastatic NSCLC and universal KRAS testing (n = 2383). Eligibility analysis, multivariate logistic regression for ineligibility, and a Cox proportional hazards model were used on patients with KRAS G12C–mutated NSCLC (n = 185) to compare trial enrollment and overall survival under various eligibility modifications.ResultsOf patients with metastatic KRAS G12C-mutated NSCLC, 60%-70% were ineligible for any KRAS inhibitor clinical trial, including studies aiming to establish first-line standard of care. Eligibility criteria remained unchanged from phase I to phase III. Performance status, renal function, and active brain metastases were the main causes of trial ineligibility. Liberalizing criteria for renal function and brain metastases increased enrollment by 25% without affecting overall survival (P = .49), whereas allowing worse performance status reduced study effect sizes (P = .001 in second-line and P = .04 in first-line).ConclusionsMost patients with metastatic KRAS G12C-mutated NSCLC are excluded from trials. There is substantial potential to refine trial entry criteria to better balance generalizability, safety, speed, and success.

BackgroundTattooing can deliver carcinogens directly into the skin and cause immunological responses, and yet the relationship between tattooing and melanoma risk is unknown.MethodsIn a population-based case-control study with 1167 melanoma cases (566 in situ; 601 invasive) and 5835 frequency-matched controls, we examined tattooing and melanoma risk using multivariable logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs).ResultsAlthough ever receiving a tattoo was not strongly associated with melanoma risk, heavier tattooing exposure was associated with decreased risk. Overall melanoma risk was decreased among individuals who had received 4 or more tattoo sessions (OR = 0.44, 95% CI = 0.27 to 0.67) and individuals who had 3 or more large tattoos (OR = 0.26, 95% CI = 0.10 to 0.54) compared with those who were never tattooed. Invasive melanoma risk was also decreased among individuals who received their first tattoo before age 20 (OR = 0.48, 95% CI = 0.29 to 0.82) compared with never tattooed individuals.ConclusionsOur findings suggest that more tattoo exposure is associated with reduced melanoma risk, which does not support previously hypothesized associations between tattooing and increased melanoma risk. Unmeasured confounding is likely to contribute to our findings because we were not able to control for important melanoma risk factors. Potential causes of these associations could include sun exposure-related behaviors or immune responses to tattooing. Further investigation is warranted to clarify these relationships.

BackgroundThe incidence and worsening of financial difficulty among patients with cancer participating in clinical trials and their relationship with mortality, quality of life, and toxicity outcomes have been understudied. The objective of this study was to understand the incidence of financial difficulty among Canadian patients participating in systemic therapy trials at baseline and after trial participation and to assess the relationship between financial difficulty and clinical outcomes.MethodsThis retrospective cohort study included patients participating in 14 systemic therapy trials conducted by the Canadian Cancer Trials Group for adult patients with advanced cancer. Incidence of financial toxicity at baseline and after trial participation were measured using the European Organisation for Research and Treatment of Cancer QLQ Core Questionnaire. The association of financial difficulty with trial characteristics and patient outcomes (mortality, quality of life, and toxicity) was studied.ResultsOverall, 2766 patients from 14 trials were included, of whom 37% had financial difficulty at baseline and 25% experienced worsening of financial difficulty after trial enrollment compared with their baseline status. Baseline financial difficulty but not the worsening of financial difficulty was associated with worse mortality outcomes. Worsening of financial difficulty was, however, associated with poor global quality of life outcomes and increased odds of clinical toxicities.ConclusionsEven in the setting of a public health system in Canada, one-third of patients experience financial difficulty, with one-quarter of them experiencing worsening of financial difficulty with trial participation, and both were related to worse patient outcomes. Targeted policy-level interventions are needed to understand and address the cause of financial difficulty in patients with cancer.

BackgroundThe ability to predict ovarian function loss after anticancer treatment is important for appropriate oncofertility counseling and to aid in therapy decision-making for young women with early breast cancer (eBC).MethodsThis biomarker analysis of the BETH (NCT00625898) and KAITLIN (NCT01966471) randomized trials investigated anti-Müllerian hormone (AMH) use, alone and combined with follicle stimulating hormone (FSH) and estradiol (E2), for predicting ovarian function loss following currently adopted chemotherapy and anti-HER2 therapy in premenopausal women with HER2-positive eBC. Serum samples were centrally tested measuring AMH, FSH, and E2 using Roche Elecsys assays.ResultsAmong 194 included patients (BETH: n = 62; KAITLIN: n = 132), AMH values declined from baseline median 8.44 pmol L−1 to undetectable levels (<0.07 pmol L−1) at the end of therapy, with partial recovery at 36 months (median 0.14 pmol L−1). AMH measured at baseline was predictive of ovarian loss (area under the ROC curve [AUC] = 0.784). Addition of age to AMH slightly improved AUC to 0.800. AMH measured at the end of therapy had AUC 0.741, which increased to 0.785 with addition of age. The combination of AMH at baseline and end of therapy increased prediction to 0.808 and with addition of age to 0.820. Addition of baseline FSH and E2 did not improve prediction in any analysis.ConclusionsThese results support the use of pretreatment measurement of AMH in predicting ovarian function loss in premenopausal women with HER2-positive eBC receiving chemotherapy and anti-HER2 therapy. Measurement of AMH at the end of treatment had reduced accuracy than pretreatment but in combination added slightly to the value of pretreatment sampling.