Two Basic Scientists Walk into a Translational Space.

When John Schiller first joined Douglas Lowy's lab at the National Cancer Institute of the NIH, he could have not predicted that their common interest in the molecular biology of oncogenes would set them in path for discoveries that ultimately enabled the development of a vaccine for the human papillomavirus, which causes the majority of cervical cancers worldwide. John and Doug, the recipients of the 2017 Lasker-DeBakey Clinical Award, have joined Cell editor João Monteiro in a Conversation about science, public health, and the joys and challenges of being basic scientists in a translational space. Annotated excerpts from this conversation are presented below.

A Prize for Cancer Prevention.

This year's Lasker-DeBakey Prize for Clinical Research to Douglas Lowy and John Schiller celebrates the science behind one of the greatest advances in the history of cancer research: the development of vaccines that prevent infection and thus prevent tumor induction by pathogenic strains of human papilloma virus (HPV).

Evolution of community outreach and engagement at National Cancer Institute-Designated Cancer Centers, an evolving journey.

Cancer mortality rates have declined during the last 28 years, but that process is not equitably shared. Disparities in cancer outcomes by race, ethnicity, socioeconomic status, sexual orientation and gender identity, and geographic location persist across the cancer care continuum. Consequently, community outreach and engagement (COE) efforts within National Cancer Institute-Designated Cancer Center (NCI-DCC) catchment areas have intensified during the last 10 years as has the emphasis on COE and catchment areas in NCI's Cancer Center Support Grant applications. This review article attempts to provide a historic perspective of COE within NCI-DCCs. Improving COE has long been an important initiative for the NCI, but it was not until 2012 and 2016 that NCI-DCCs were required to define their catchment areas rigorously and to provide specific descriptions of COE interventions, respectively. NCI-DCCs had previously lacked adequate focus on the inclusion of historically marginalized patients in cancer innovation efforts. Integrating COE efforts throughout the research and operational aspects of the cancer centers, at both the patient and community levels, will expand the footprint of COE efforts within NCI-DCCs. Achieving this change requires sustained commitment by the centers to adjust their activities and improve access and outcomes for historically marginalized communities.

Genomic Classification of Cutaneous Melanoma.

We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.

Cancer treatment and survivorship statistics, 2022.

The number of cancer survivors continues to increase in the United States due to the growth and aging of the population as well as advances in early detection and treatment. To assist the public health community in better serving these individuals, the American Cancer Society and the National Cancer Institute collaborate triennially to estimate cancer prevalence in the United States using incidence and survival data from the Surveillance, Epidemiology, and End Results cancer registries, vital statistics from the Centers for Disease Control and Prevention's National Center for Health Statistics, and population projections from the US Census Bureau. Current treatment patterns based on information in the National Cancer Database are presented for the most prevalent cancer types by race, and cancer-related and treatment-related side-effects are also briefly described. More than 18 million Americans (8.3 million males and 9.7 million females) with a history of cancer were alive on January 1, 2022. The 3 most prevalent cancers are prostate (3,523,230), melanoma of the skin (760,640), and colon and rectum (726,450) among males and breast (4,055,770), uterine corpus (891,560), and thyroid (823,800) among females. More than one-half (53%) of survivors were diagnosed within the past 10 years, and two-thirds (67%) were aged 65 years or older. One of the largest racial disparities in treatment is for rectal cancer, for which 41% of Black patients with stage I disease receive proctectomy or proctocolectomy compared to 66% of White patients. Surgical receipt is also substantially lower among Black patients with non-small cell lung cancer, 49% for stages I-II and 16% for stage III versus 55% and 22% for White patients, respectively. These treatment disparities are exacerbated by the fact that Black patients continue to be less likely to be diagnosed with stage I disease than White patients for most cancers, with some of the largest disparities for female breast (53% vs 68%) and endometrial (59% vs 73%). Although there are a growing number of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based strategies and equitable access to available resources are needed to mitigate disparities for communities of color and optimize care for people with a history of cancer. CA Cancer J Clin. 2022;72:409-436.

Cancer statistics for African American/Black People 2022.

African American/Black individuals have a disproportionate cancer burden, including the highest mortality and the lowest survival of any racial/ethnic group for most cancers. Every 3 years, the American Cancer Society estimates the number of new cancer cases and deaths for Black people in the United States and compiles the most recent data on cancer incidence (herein through 2018), mortality (through 2019), survival, screening, and risk factors using population-based data from the National Cancer Institute and the Centers for Disease Control and Prevention. In 2022, there will be approximately 224,080 new cancer cases and 73,680 cancer deaths among Black people in the United States. During the most recent 5-year period, Black men had a 6% higher incidence rate but 19% higher mortality than White men overall, including an approximately 2-fold higher risk of death from myeloma, stomach cancer, and prostate cancer. The overall cancer mortality disparity is narrowing between Black and White men because of a steeper drop in Black men for lung and prostate cancers. However, the decline in prostate cancer mortality in Black men slowed from 5% annually during 2010 through 2014 to 1.3% during 2015 through 2019, likely reflecting the 5% annual increase in advanced-stage diagnoses since 2012. Black women have an 8% lower incidence rate than White women but a 12% higher mortality; further, mortality rates are 2-fold higher for endometrial cancer and 41% higher for breast cancer despite similar or lower incidence rates. The wide breast cancer disparity reflects both later stage diagnosis (57% localized stage vs 67% in White women) and lower 5-year survival overall (82% vs 92%, respectively) and for every stage of disease (eg, 20% vs 30%, respectively, for distant stage). Breast cancer surpassed lung cancer as the leading cause of cancer death among Black women in 2019. Targeted interventions are needed to reduce stark cancer inequalities in the Black community.

Cancer treatment and survivorship statistics, 2019.

The number of cancer survivors continues to increase in the United States because of the growth and aging of the population as well as advances in early detection and treatment. To assist the public health community in better serving these individuals, the American Cancer Society and the National Cancer Institute collaborate every 3 years to estimate cancer prevalence in the United States using incidence and survival data from the Surveillance, Epidemiology, and End Results cancer registries; vital statistics from the Centers for Disease Control and Prevention's National Center for Health Statistics; and population projections from the US Census Bureau. Current treatment patterns based on information in the National Cancer Data Base are presented for the most prevalent cancer types. Cancer-related and treatment-related short-term, long-term, and late health effects are also briefly described. More than 16.9 million Americans (8.1 million males and 8.8 million females) with a history of cancer were alive on January 1, 2019; this number is projected to reach more than 22.1 million by January 1, 2030 based on the growth and aging of the population alone. The 3 most prevalent cancers in 2019 are prostate (3,650,030), colon and rectum (776,120), and melanoma of the skin (684,470) among males, and breast (3,861,520), uterine corpus (807,860), and colon and rectum (768,650) among females. More than one-half (56%) of survivors were diagnosed within the past 10 years, and almost two-thirds (64%) are aged 65 years or older. People with a history of cancer have unique medical and psychosocial needs that require proactive assessment and management by follow-up care providers. Although there are growing numbers of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based resources are needed to optimize care.

State of the science and future directions for research on HIV and cancer: Summary of a joint workshop sponsored by IARC and NCI.

An estimated 38 million people live with human immunodeficiency virus (HIV) worldwide and are at excess risk for multiple cancer types. Elevated cancer risks in people living with HIV (PLWH) are driven primarily by increased exposure to carcinogens, most notably oncogenic viruses acquired through shared transmission routes, plus acceleration of viral carcinogenesis by HIV-related immunosuppression. In the era of widespread antiretroviral therapy (ART), life expectancy of PLWH has increased, with cancer now a leading cause of co-morbidity and death. Furthermore, the types of cancers occurring among PLWH are shifting over time and vary in their relative burden in different parts of the world. In this context, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) convened a meeting in September 2022 of multinational and multidisciplinary experts to focus on cancer in PLWH. This report summarizes the proceedings, including a review of the state of the science of cancer descriptive epidemiology, etiology, molecular tumor characterization, primary and secondary prevention, treatment disparities and survival in PLWH around the world. A consensus of key research priorities and recommendations in these domains is also presented.

The role of community outreach and engagement in evaluation of NCI Cancer Center Support Grants.

PURPOSE: National Cancer Institute (NCI)-designated cancer centers are required to consider their impact on the catchment area they serve. These activities are facilitated by community outreach and engagement (COE) activities as specified in the Cancer Center Support Grant (CCSG) request for applications. While the critical importance of COE activities to NCI-designated cancer centers is well known, it is less clear what impact the COE component has on the overall CCSG merit descriptor and score. METHODS: We undertook an online survey of all 62 NCI-designated Comprehensive and Clinical centers who reported their COE merit descriptor and overall CCSG priority score as of Fall 2021. RESULTS: Of 48 (77%) of responding centers, we identified a strong correlation between the COE merit descriptor and the overall numerical CCSG score received by the center (Spearman's rank correlation coefficient r = 0.360, p = 0.0053). When stratifying this relationship by center type, we observed a very strong correlation between COE and CCSG ratings for comprehensive cancer centers (n = 40; r = 0.544; p = 0.0003) but not for non-comprehensive cancer centers (n = 8; r = 0.073; p = 0.864). CONCLUSION: COE component merit descriptors for comprehensive cancer center CCSG evaluations are strongly correlated with the overall cancer center review score.

Payer-Negotiated Price Variation and Relationship to Surgical Outcomes for the Most Common Cancers at NCI-Designated Cancer Centers.

BACKGROUND: Federal rules mandate that hospitals publish payer-specific negotiated prices for all services. Little is known about variation in payer-negotiated prices for surgical oncology services or their relationship to clinical outcomes. We assessed variation in payer-negotiated prices associated with surgical care for common cancers at National Cancer Institute (NCI)-designated cancer centers and determined the effect of increasing payer-negotiated prices on the odds of morbidity and mortality. MATERIALS AND METHODS: A cross-sectional analysis of 63 NCI-designated cancer center websites was employed to assess variation in payer-negotiated prices. A retrospective cohort study of 15,013 Medicare beneficiaries undergoing surgery for colon, pancreas, or lung cancers at an NCI-designated cancer center between 2014 and 2018 was conducted to determine the relationship between payer-negotiated prices and clinical outcomes. The primary outcome was the effect of median payer-negotiated price on odds of a composite outcome of 30 days mortality and serious postoperative complications for each cancer cohort. RESULTS: Within-center prices differed by up to 48.8-fold, and between-center prices differed by up to 675-fold after accounting for geographic variation in costs of providing care. Among the 15,013 patients discharged from 20 different NCI-designated cancer centers, the effect of normalized median payer-negotiated price on the composite outcome was clinically negligible, but statistically significantly positive for colon [aOR 1.0094 (95% CI 1.0051-1.0138)], lung [aOR 1.0145 (1.0083-1.0206)], and pancreas [aOR 1.0080 (1.0040-1.0120)] cancer cohorts. CONCLUSIONS: Payer-negotiated prices are statistically significantly but not clinically meaningfully related to morbidity and mortality for the surgical treatment of common cancers. Higher payer-negotiated prices are likely due to factors other than clinical quality.

Evaluating implementation of a community-focused patient navigation intervention at an NCI-designated cancer center using RE-AIM.

BACKGROUND: Patient navigation is an evidence-based intervention that reduces cancer health disparities by directly addressing the barriers to care for underserved patients with cancer. Variability in design and integration of patient navigation programs within cancer care settings has limited this intervention's utility. The implementation science evaluation framework, RE-AIM, allows quantitative and qualitative examination of effective implementation of patient navigation programs into cancer care settings. METHODS: The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework was used to evaluate implementation of a community-focused patient navigation intervention at an NCI-designated cancer center between June 2018 and October 2021. Using a 3-month longitudinal, non-comparative measurement period, univariate and bivariate analyses were conducted to examine associations between participant-level demographics and primary (i.e., barrier reduction) and secondary (i.e., patient-reported outcomes) effectiveness outcomes. Mixed methods analyses were used to examine adoption and delivery of the intervention into the cancer center setting. Process-level analyses were used to evaluate maintenance of the intervention. RESULTS: Participants (n = 311) represented a largely underserved population, as defined by the National Cancer Institute, with the majority identifying as Hispanic/Latino, having a household income of $35,000 or less, and being enrolled in Medicaid. Participants were diagnosed with a variety of cancer types and most had advanced staged cancers. Pre-post-intervention analyses indicated significant reduction from pre-intervention assessments in the average number of reported barriers, F(1, 207) = 117.62, p < .001, as well as significant increases in patient-reported physical health, t(205) = - 6.004, p < .001, mental health, t(205) = - 3.810, p < .001, self-efficacy, t(205) = - 5.321, p < .001, and satisfaction with medical team communication, t(206) = - 2.03, p = .029. Referral patterns and qualitative data supported increased adoption and integration of the intervention into the target setting, and consistent intervention delivery metrics suggested high fidelity to intervention delivery over time. Process-level data outlined a successful transition from a grant-funded community-focused patient navigation intervention to an institution-funded program. CONCLUSIONS: This study utilized the implementation science evaluation framework, RE-AIM, to evaluate implementation of a community-focused patient navigation program. Our analyses indicate successful implementation within a cancer care setting and provide a potential guide for other oncology settings who may be interested in implementing community-focused patient navigation programs.

Rationale, Procedures, and Response Rates for a Pilot Study to Sample Cancer Survivors for NCI's Health Information National Trends Survey: HINTS-SEER 2021.

The National Cancer Institute's (NCI) Health Information National Trends Survey (HINTS) is a nationally representative survey of U.S. adults in which 12-17% of respondents report a cancer history. To increase representation from adult cancer survivors, in 2021, NCI sampled survivors from three Surveillance, Epidemiology, and End Results (SEER) program cancer registries: Iowa, New Mexico, and the Greater Bay Area. Sampling frames were stratified by time since diagnosis and race/ethnicity, with nonmalignant tumors and non-melanoma skin cancers excluded. Participants completed a self-administered postal questionnaire. The overall response rate for HINTS-SEER (N = 1,234) was 12.6%; a non-response bias analysis indicated few demographic differences between respondents and the pool of sampled patients in each registry. Most of the sample was 10+ years since diagnosis (n = 722; 60.2%); 392 respondents were 5 to < 10 years since diagnosis (29.6%); and 120 were < 5 years since diagnosis (10.2%). Common cancers included male reproductive (n = 304; 24.6%), female breast (n = 284; 23.0%), melanoma (n = 119; 9.6%), and gastrointestinal (n = 106; 8.6%). Tumors were mostly localized (67.8%; n = 833), with 22.4% (n = 282) regional, 6.2% (n = 72) distant, and 3.7% (n = 47) unknown. HINTS-SEER data are available by request and may be used for secondary analyses to examine a range of social, behavioral, and healthcare outcomes among cancer survivors.

Employment-related Education and Support for Cancer Survivors: a Content Analysis of Employment Resources Offered on National Cancer Institute-Designated Cancer Center Websites.

High rates of employment changes and associated concerns among cancer survivors following diagnosis and treatment suggest a need to examine what employment-related educational resources and support are currently being offered to cancer survivors and what gaps exist in those resources. In 2023, we conducted a content analysis of employment resources described on the websites of the NCI-Designated Cancer Centers that provide clinical care (N = 64) through a systematic review procedure using predetermined search terms and a standardized process to examine the availability and accessibility of such resources. Descriptive analyses were conducted to characterize the employment resources identified. In total, 175 employment resources were identified across 49 cancer center websites; 102 (58%) provided patient-facing education/information, 58 (33%) offered a consultation, 14 (8%) offered support groups/classes, and 1 (1%) was classified as "Other." Most (76%) resources were provided internally by the cancer center, and often, more than one discipline was involved, most commonly social work and medicine. These findings are encouraging as they suggest that most (77%) NCI-Designated Cancer Centers recognize employment support as a component of survivorship care. The multidisciplinary nature of the resources identified is supported by moderate evidence that multidisciplinary interventions appear to have the greatest potential to foster a return to work for cancer survivors and align with suggestions made by recent expert groups and guidelines regarding employment support for cancer survivors. Ongoing work is needed to assess the utilization, impact, and equity of available employment resources to optimize work outcomes among cancer survivors.

Harnessing imaging tools to guide immunotherapy trials: summary from the National Cancer Institute Cancer Imaging Steering Committee workshop.

As the immuno-oncology field continues the rapid growth witnessed over the past decade, optimising patient outcomes requires an evolution in the current response-assessment guidelines for phase 2 and 3 immunotherapy clinical trials and clinical care. Additionally, investigational tools-including image analysis of standard-of-care scans (such as CT, magnetic resonance, and PET) with analytics, such as radiomics, functional magnetic resonance agents, and novel molecular-imaging PET agents-offer promising advancements for assessment of immunotherapy. To document current challenges and opportunities and identify next steps in immunotherapy diagnostic imaging, the National Cancer Institute Clinical Imaging Steering Committee convened a meeting with diverse representation among imaging experts and oncologists to generate a comprehensive review of the state of the field.

National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

Global oncology research and training at US National Cancer Institute-designated cancer centres: results of the 2021 Global Oncology Survey.

Global oncology research and training are crucial to address the growing global burden of cancer, which largely and increasingly occurs in low-income and middle-income countries. To better understand global oncology activities at the 71 National Cancer Institute (NCI)-designated cancer centres, the US NCI Centre for Global Health regularly surveys cancer centre directors, global oncology leads, and principal investigators in 36 US states and the District of Columbia. The survey results complement internal and publicly available data about global oncology research funded directly by the US National Institutes of Health to provide a comprehensive catalogue of global oncology research, training, and activities led by NCI-designated cancer centres. 91% (61 of 67) of responding cancer centres reported global oncology activities not directly funded by the National Institutes of Health. The survey results indicate that global oncology is an important priority at cancer centres and provide a valuable resource for these centres, researchers, collaborators, trainees, and the NCI and other funders.

Early drug development in solid tumours: analysis of National Cancer Institute-sponsored phase 1 trials.

BACKGROUND: The low expectation of clinical benefit from phase 1 cancer therapeutics trials might negatively affect patient and physician participation, study reimbursement, and slow the progress of oncology research. Advances in cancer drug development, meanwhile, might have favourably improved treatment responses; however, little comprehensive data exist describing the response and toxicity associated with phase 1 trials across solid tumours. The aim of the study is to evaluate the trend of toxicity and response in phase 1 trials for solid tumours over time. METHODS: We analysed patient-level data from the Cancer Therapy Evaluation Program of the National Cancer Institute-sponsored investigator-initiated phase 1 trials for solid tumours, from Jan 1, 2000, to May 31, 2019. We assessed risks of treatment-related death (grade 5 toxicity ratings possibly, probably, or definitely attributable to treatment), all on-treatment deaths (deaths during protocol treatment regardless of attribution), grade 3-4 toxicity, and proportion of overall response (complete response and partial response) and complete response rate in the study periods of 2000-05, 2006-12, and 2013-2019, and evaluated their trends over time. We also analysed cancer type-specific and investigational agent-specific response, and analysed the trend of response in each cancer type over time. Univariate associations of overall response rates with patients' baseline characteristics (age, sex, performance status, BMI, albumin concentration, and haemoglobin concentration), enrolment period, investigational agents, and trial design were assessed using risk ratio based on the modified Poisson regression model. FINDINGS: We analysed 465 protocols that enrolled 13 847 patients using 261 agents. 144 (31%) trials used a monotherapy and 321 (69%) used combination therapies. The overall treatment-related death rate was 0·7% (95% CI 0·5-0·8) across all periods. Risks of treatment-related deaths did not change over time (p=0·52). All on-treatment death risk during the study period was 8·0% (95% CI 7·6-8·5). The most common grade 3-4 adverse events were haematological; grade 3-4 neutropenia occurred in 2336 (16·9%) of 13 847 patients, lymphopenia in 1230 (8·9%), anaemia in 894 (6·5%), and thrombocytopenia in 979 (7·1%). The overall response rate for all trials during the study period was 12·2% (95% CI 11·5-12·8; 1133 of 9325 patients) and complete response rate was 2·7% (2·4-3·0; 249 of 9325). Overall response increased from 9·6% (95% CI 8·7-10·6) in 2000-05 to 18·0% (15·7-20·5) in 2013-19, and complete response rates from 2·5% (2·0-3·0) to 4·3% (3·2-5·7). Overall response rates for combination therapy were substantially higher than for monotherapy (15·8% [15·0-16·8] vs 3·5% [2·8-4·2]). The overall response by class of agents differed across diseases. Anti-angiogenesis agents were associated with higher overall response rate for bladder, colon, kidney and ovarian cancer. DNA repair inhibitors were associated with higher overall response rate in ovarian and pancreatic cancer. The rates of overall response over time differed markedly by disease; there were notable improvements in bladder, breast, and kidney cancer and melanoma, but no change in the low response of pancreatic and colon cancer. INTERPRETATION: During the past 20 years, the response rate in phase 1 trials nearly doubled without an increase in the treatment-related death rate. However, there is significant heterogeneity in overall response by various factors such as cancer type, investigational agent, and trial design. Therefore, informed decision making is crucial for patients before participating in phase 1 trials. This study provides updated encouraging outcomes of modern phase 1 trials in solid tumours. FUNDING: National Cancer Institute.

Shifting Sociodemographic Characteristics of a Phase I Clinical Trial Population at an NCI-Designated Comprehensive Cancer Center in the Southeast.

Racial and ethnic minority populations are consistently under-represented in oncology clinical trials despite comprising a disproportionate share of a cancer burden. Phase I oncology clinical trials pose a unique challenge and opportunity for minority inclusion. Here we compared the sociodemographic characteristics of patients participating in phase 1 clinical trials a National Cancer Institute ( NCI)-designated comprehensive center to all patients at the center, patients with new cancer diagnosis in metropolitan Atlanta and patients with new cancer diagnoses in the state of Georgia. From 2015 to 2020, 2325 patients (43.4% female, 56.6% male) consented to participate in a phase I trial. Grouped self-reported race distribution was 70.3% White, 26.2% Black, and 3.5% other. Of new patient registrations at Winship Cancer Institute (N = 107 497) (50% F, 50% M), grouped race distribution was 63.3% White, 32.0% Black, and 4.7% other. Patients with new cancer diagnoses in metro Atlanta from 2015 to 2016 (N = 31101) were 58.4% White, 37.2% Black, and 4.3% other. Race and sex distribution of phase I patients was significantly different than Winship patients (P < .001). Over time, percent of White patients decreased in both phase I and Winship groups (P = .009 and P < .001, respectively); percentage of females did not change in either group (P = .54 phase I, P = .063 Winship). Although phase I patients were more likely to be White, male, and privately ensured than the Winship cohort, from 2015 to 2020 the percentage of White patients in phase I trials and among all new patients treated at Winship decreased. The intent of characterizing existing disparities is to improve the representation of patients from racial and ethnic minority backgrounds in phase I clinical trials.

PLCOjs, a FAIR GWAS web SDK for the NCI Prostate, Lung, Colorectal and Ovarian Cancer Genetic Atlas project.

MOTIVATION: The Division of Cancer Epidemiology and Genetics (DCEG) and the Division of Cancer Prevention (DCP) at the National Cancer Institute (NCI) have recently generated genome-wide association study (GWAS) data for multiple traits in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Genomic Atlas project. The GWAS included 110 000 participants. The dissemination of the genetic association data through a data portal called GWAS Explorer, in a manner that addresses the modern expectations of FAIR reusability by data scientists and engineers, is the main motivation for the development of the open-source JavaScript software development kit (SDK) reported here. RESULTS: The PLCO GWAS Explorer resource relies on a public stateless HTTP application programming interface (API) deployed as the sole backend service for both the landing page's web application and third-party analytical workflows. The core PLCOjs SDK is mapped to each of the API methods, and also to each of the reference graphic visualizations in the GWAS Explorer. A few additional visualization methods extend it. As is the norm with web SDKs, no download or installation is needed and modularization supports targeted code injection for web applications, reactive notebooks (Observable) and node-based web services. AVAILABILITY AND IMPLEMENTATION: code at https://github.com/episphere/plco; project page at https://episphere.github.io/plco.

The Molecular Tumor Board of the Regina Elena National Cancer Institute: from accrual to treatment in real-world.

BACKGROUND: Molecular Tumor Boards (MTB) operating in real-world have generated limited consensus on good practices for accrual, actionable alteration mapping, and outcome metrics. These topics are addressed herein in 124 MTB patients, all real-world accrued at progression, and lacking approved therapy options. METHODS: Actionable genomic alterations identified by tumor DNA (tDNA) and circulating tumor DNA (ctDNA) profiling were mapped by customized OncoKB criteria to reflect diagnostic/therapeutic indications as approved in Europe. Alterations were considered non-SoC when mapped at either OncoKB level 3, regardless of tDNA/ctDNA origin, or at OncoKB levels 1/2, provided they were undetectable in matched tDNA, and had not been exploited in previous therapy lines. RESULTS: Altogether, actionable alterations were detected in 54/124 (43.5%) MTB patients, but only in 39 cases (31%) were these alterations (25 from tDNA, 14 from ctDNA) actionable/unexploited, e.g. they had not resulted in the assignment of pre-MTB treatments. Interestingly, actionable and actionable/unexploited alterations both decreased (37.5% and 22.7% respectively) in a subset of 88 MTB patients profiled by tDNA-only, but increased considerably (77.7% and 66.7%) in 18 distinct patients undergoing combined tDNA/ctDNA testing, approaching the potential treatment opportunities (76.9%) in 147 treatment-naïve patients undergoing routine tDNA profiling for the first time. Non-SoC therapy was MTB-recommended to all 39 patients with actionable/unexploited alterations, but only 22 (56%) accessed the applicable drug, mainly due to clinical deterioration, lengthy drug-gathering procedures, and geographical distance from recruiting clinical trials. Partial response and stable disease were recorded in 8 and 7 of 19 evaluable patients, respectively. The time to progression (TTP) ratio (MTB-recommended treatment vs last pre-MTB treatment) exceeded the conventional Von Hoff 1.3 cut-off in 9/19 cases, high absolute TTP and Von Hoff values coinciding in 3 cases. Retrospectively, 8 patients receiving post-MTB treatment(s) as per physician's choice were noted to have a much longer overall survival from MTB accrual than 11 patients who had received no further treatment (35.09 vs 6.67 months, p = 0.006). CONCLUSIONS: MTB-recommended/non-SoC treatments are effective, including those assigned by ctDNA-only alterations. However, real-world MTBs may inadvertently recruit patients electively susceptible to diverse and/or multiple treatments.