Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Prevalence of healthy behaviors among cancer survivors in the United States: How far have we come?

Background: The 16.9 million cancer survivors in the United States are at increased risk for comorbidities and recurrence. However, this risk may be attenuated by a healthy lifestyle. This study describes health behaviors by cancer history to inform behavior change priorities. Methods: We analyzed 2013–2017 data from the National Health Interview Survey. There were 164,692 adults, of whom 12,648 reported a cancer history. We calculated prevalence of smoking, physical activity, alcohol consumption, body mass index (BMI), and sleep duration by cancer history, age, and cancer site. We conducted logistic regression to determine odds of meeting lifestyle recommendations by cancer history. Results: Overall, those with a cancer history were less likely to report current smoking (14.1% vs. 16.8%) and moderate/heavy drinking (18.8% vs. 21.9%) than those without a cancer history. However, a lower percentage of cancer survivors met physical activity guidelines (14.2% vs. 21.1%) or reported a healthy BMI (31.6% vs. 34.7%) compared with those without a cancer history. Cancer survivors were more likely to report excessive sleep (6.8% vs. 3.6%). In adjusted logistic regression, survivors were more likely to meet recommendations on smoking, physical activity, and BMI but were less likely to meet alcohol recommendations; meeting sleep recommendations did not differ by cancer history. Conclusions: While cancer survivors had lower prevalence of smoking and moderate/heavy drinking, they also had lower prevalence of physical activity and healthy BMI, and reported longer sleep duration. Regression analyses suggested survivors only showed poorer behaviors for alcohol. Impact: Targeted health promotion interventions among cancer survivors are needed

Disparities in HRQOL of cancer survivors and non-cancer managed care enrollees.

Health plan member survey and cancer registry data were analyzed to understand differences in health-related quality of life (HRQOL) among cancer survivors and those without a cancer diagnosis enrolled in Medicare managed care. HRQOL was measured by the physical component summary score (PCS) and mental component summary score (MCS) of the Medical Outcomes Study SF-36, version 1.0. Cancer survivors enrolled in Medicare managed care have lower PCS and MCS scores than those enrollees who have never been diagnosed with cancer. PCS scores are worse than the MCS scores, and lowest for cancer survivors who are Hispanic, Medicaid enrollees, and those who have low income or education. HRQOL disparities are greatest among cancer survivors diagnosed with lung cancer and those with multiple primary cancer diagnoses. The influence of these variables persists when controlling for multiple variables including comorbidity status. Health plans should focus on addressing these disparities

Double Jeopardy? Age, Race, and HRQOL in Older Adults with Cancer

Understanding the post-treatment physical and mental function of older adults from ethnic/racial minority backgrounds with cancer is a critical step to determine the services required to serve this growing population. The double jeopardy hypothesis suggests being a minority and old could have compounding effects on health. This population-based study examined the physical and mental function of older adults by age (mean age = 75.7, SD = 6.1), ethnicity/race, and cancer (breast, prostate, colorectal, and gynecologic) as well as interaction effects between age, ethnicity/race and HRQOL. There was evidence of a significant age by ethnicity/race interaction in physical function for breast, prostate and all sites combined, but the interaction became non-significant (for breast and all sites combined) when comorbidity was entered into the model. The interaction persisted in the prostate cancer group after controlling for comorbidity, such that African Americans and Asian Americans in the 75–79 age group report lower physical health than non-Hispanic Whites and Hispanic Whites in this age group. The presence of double jeopardy in the breast and all sites combined group can be explained by a differential comorbid burden among the older (75–79) minority group, but the interaction found in prostate cancer survivors does not reflect this differential comorbid burden

Cancer, comorbidities, and health-related quality of life of older adults.

This study examined the physical and mental health of 126,685 males and females age 65 or over, with and without cancer that completed a Medicare Health Outcomes Survey (MHOS) between 1998-2002. Cancer information was ascertained through the National Cancer Institute's (NCI's) Surveillance, Epidemiology and End Results (SEER) program and linked to MHOS data. Results indicated that across most cancer types, cancer patients reported significantly more comorbid conditions and poorer physical and mental health compared with patients without cancer. Negative associations were most pronounced in those with two or more comorbidities and in those diagnosed with cancer within the past year

Cancer-related information needs and cancer's impact on control over life influence health-related quality of life among adolescents and young adults with cancer.

ObjectiveAdolescents and young adults (AYAs) diagnosed with cancer between 15 and 39 years of age often report need for greater amounts of cancer-related information and perceive that cancer has had a negative impact on control over their life. We examined whether unmet information need and perceived control over life are associated with health-related quality of life (HRQOL).MethodsWe examined data from 484 AYA cancer survivors recruited from population-based cancer registries in 2007-2008. Participants completed surveys a median of 11 months after diagnosis. Multivariable linear regression analyses estimated associations of unmet cancer-related information needs and impact of cancer on control over life on HRQOL (SF-12).ResultsTwo-thirds of AYAs reported an intermediate or high level of unmet information need, and half (47%) reported a negative impact of cancer on control. Greater unmet information need was associated with lower overall mental and physical HRQOL and lower levels of all HRQOL subscales except vitality. A negative impact on control over life was associated with lower overall mental HRQOL as well as lower HRQOL across all subscales except general health perceptions (all p <0.05). In multivariable analyses, perceived control and unmet information need were independently associated with HRQOL (p-values for interaction >0.1).ConclusionsAdolescent and young adult patients with cancer have high levels of unmet cancer-related information needs and perceived negative impact of cancer on control over life; both were independently associated with lower HRQOL. Addressing unmet information needs among AYA cancer survivors and finding ways to increase their sense of control may help improve HRQOL in this understudied population