Personalized Cancer Research Articles

The feasibility of implementing risk stratification into a national breast cancer screening programme: a focus group study investigating the perspectives of healthcare personnel responsible for delivery

BackgroundProviding women with personalized estimates of their risk of developing breast cancer, as part of routine breast cancer screening programmes, allows women at higher risk to be offered more frequent screening or drugs to reduce risk. For this to be feasible, the concept and practicalities have to be acceptable to the healthcare professionals who would put it in to practice. The present research investigated the acceptability to healthcare professionals who were responsible for the implementation of this new approach to screening in the ongoing BC-Predict study.MethodsFour focus groups were conducted with 29 healthcare professionals from a variety of professional backgrounds working within three breast screening services in north-west England. An inductive-manifest thematic analysis was conducted.ResultsOverall, healthcare professionals viewed the implementation of personalised breast cancer risk estimation as a positive step, but discussion focused on concerns. Three major themes are presented. (1) Service constraints highlights the limited capacity within current breast services and concerns about the impact of additional workload. (2) Risk communication concerns the optimal way to convey risk to women within resource constraints. (3) Accentuating inequity discusses how risk stratification could decrease screening uptake for underserved groups.ConclusionsStaff who implemented risk stratification considered it a positive addition to routine screening. They considered it essential to consider improving capacity and demands on healthcare professional time. They highlighted the need for skilled communication of risks and new pathways of care to ensure that stratification could be implemented in financially and time constrained settings without impacting negatively on women.

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Women\u2019s perceptions of PERSPECTIVE: a breast cancer risk stratification e-platform

BackgroundBreast cancer risk stratification categorizes a woman’s potential risk of developing the disease as near-population, intermediate, or high. In accordance, screening and follow up for breast cancer can readily be tailored following risk assessment. Recent efforts have focussed on developing more accessible means to convey this information to women. This study sought to document the relevance of an informational e-platform developed for these purposes.ObjectiveTo begin to assess a newly developed breast cancer risk stratification and decision support e-platform called PERSPECTIVE (PErsonalised Risk Stratification for Prevention and Early deteCTIon of breast cancer) among women who do not know their personal breast cancer risk (Phase 1). Changes (pre- and post- e-platform exposure) in knowledge of breast cancer risk and interest in undergoing genetic testing were assessed in addition to perceptions of platform usability and acceptability.MethodsUsing a pre-post design, women (N = 156) of differing literacy and education levels, aged 30 to 60, with no previous breast cancer diagnosis were recruited from the general population and completed self-report e-questionnaires.ResultsMean e-platform viewing time was 18.67 min (SD 0.65) with the most frequently visited pages being breast cancer-related risk factors and risk assessment. Post-exposure, participants reported significantly higher breast cancer-related knowledge (p < .001). Increases in knowledge relating to obesity, alcohol, breast density, menstruation, and the risk estimation process remained even when sociodemographic variables age and education were controlled. There were no significant changes in genetic testing interest post-exposure. Mean ratings for e-platform acceptability and usability were high: 26.19 out of 30 (SD 0.157) and 42.85 out of 50 (SD 0.267), respectively.ConclusionsAn informative breast cancer risk stratification e-platform targeting healthy women in the general population can significantly increase knowledge as well as support decisions around breast cancer risk and assessment. Currently underway, Phase 2, called PERSPECTIVE, is seeking further content integration and broader implementation .

Abstract P5-15-02: The risk for locoregional breast cancer recurrences: Significant differences in perceptions among health care professionals (HCPs)

Abstract Introduction: Unlike the highly personalized breast cancer treatment, surveillance in the Netherlands is still ‘one-size-fits-all’: annual imaging and physical examination for at least five year after treatment. To identify patients with a low or high risk for locoregional recurrences (LRRs) who might benefit from less or more intensive surveillance, risk prediction models can be used. The INFLUENCE-nomogram is an example of this and is developed using on data of the Netherlands Cancer Registry. It remains unclear to which extent health care professionals (HCPs) are able to accurately estimate the patient individual risk for locoregional recurrences. Objective: To evaluate the current awareness, knowledge and ability to estimate patients individual risks for locoregional recurrences after breast cancer - without using any prediction tools - among HCPs in the Netherlands. Methods: In this study, a cross-sectional survey was performed among general practitioners (GPs) and HCPs working in breast cancer care in six teaching hospitals in the Netherlands. In total, 85 HCPs (25 GPs and 60 hospital HCPs) participated. HCPs received descriptions of eleven breast cancer cases with different patient-, tumor- and treatment characteristics for which they were asked to estimate the risk for LRRs. The estimations were compared among different groups of HCPs and with the estimation calculated using the INFLUENCE-nomogram. Results: HCPs structurally overestimated the risk for LRRs (ranging from an average overestimation from 4% on one case to 26% on another case). In nine out of eleven cases, significant differences in risk estimates were found between groups of HCPs. In five of the eleven cases, GPs had a significantly higher median estimate than medical oncologists (respectively 10 % vs. 2.5 %; 15 % vs. 5 %; 25 % vs. 6.5 %; 25% vs. 6.5 %; 8 % vs. 1 %; and 12 % vs. 2% on these five cases). Conclusion: The structural overestimation of the risks stresses the importance to create more awareness and knowledge of the risk for LRRs after breast cancer. Medical oncologists seem to estimates risks for recurrences more accurately then GPs. This might be due to the fact that medical oncologists have more experience with the use of risk prediction models (such as Predict) in clinical practice. More awareness and knowledge of the risk for LRRs can be generated using objective estimations by prediction models. This will support the implementation of personalized surveillance after breast cancer. Table: Descriptive statistics predicted five-year risks HCPs and risk estimation INFLUENCE-nomogramCaseNMin.Max.MedianMeanStd. DeviationVarianceRisk estimation INFLUENCE-nomogramAverage overestimation HCPs1a850305***5.805.3028.040.96 %4.84 %1b850708***10.6410.07101.312.29 %8.35 %28536015***17.6712.16147.847.17 %10.50 %3a850305***6.956.8046.231.18 %5.77 %3b850.17010***12.5310.70114.482.27 %10.26 %4a8515010***12.598.3769.980.74 %11.85 %4b850.58019***19.0612.86165.441.72 %17.34 %5a851.56020***20.5713.38179.041.57 %19.00 %5b842.59025***29.6818.70349.783.6 %26.08 %6a630305***7.216.1137.310.64 %6.57 %6b620.14010***11.909.1884.272.94 %8.96 %Results of Wilcoxon one-sample signed rank test *** Median is significantly greater than risk estimation INFLUENCE-nomogram at the 0.001 level. ** Median is significantly greater than risk estimation INFLUENCE-nomogram at the 0.01 level. * Median is significantly greater than risk estimation INFLUENCE-nomogram at the 0.05 level. Citation Format: Jet W. Ankersmid, Pauline E.R. Spronk, Anneke M. Zeillemaker, Sabine Siesling. The risk for locoregional breast cancer recurrences: Significant differences in perceptions among health care professionals (HCPs) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-15-02.

Functional nanovesicles displaying anti-PD-L1 antibodies for programmed photoimmunotherapy

BackgroundPhotoimmunotherapy is one of the most promising strategies in tumor immunotherapies, but targeted delivery of photosensitizers and adjuvants to tumors remains a major challenge. Here, as a proof of concept, we describe bone marrow mesenchymal stem cell-derived nanovesicles (NVs) displaying anti-PD-L1 antibodies (aPD-L1) that were genetically engineered for targeted drug delivery.ResultsThe high affinity and specificity between aPD-L1 and tumor cells allow aPD-L1 NVs to selectively deliver photosensitizers to cancer tissues and exert potent directed photothermal ablation. The tumor immune microenvironment was programmed via ablation, and the model antigen ovalbumin (OVA) was designed to fuse with aPD-L1. The corresponding membrane vesicles were then extracted as an antigen–antibody integrator (AAI). AAI can work as a nanovaccine with the immune adjuvant R837 encapsulated. This in turn can directly stimulate dendritic cells (DCs) to boast the body's immune response to residual lesions.ConclusionsaPD-L1 NV-based photoimmunotherapy significantly improves the efficacy of photothermal ablation and synergistically enhances subsequent immune activation. This study describes a promising strategy for developing ligand-targeted and personalized cancer photoimmunotherapy.Graphic

Mammography screening and mortality by risk status in the California teachers study

BackgroundThe debate continues among medical professionals regarding the frequency, starting age, and stopping age for mammography screening. Some experts suggest tailoring recommendations based on individuals’ personal breast cancer risk. Previous studies have not compared the impact of annual versus biennial mammography stratified by age group and risk category. The purpose of this study was to examine the relationship between mammography frequency and mortality by age group and risk category in the California Teachers Study.MethodsUsing data from study questionnaires from 93,438 women between the ages of 40 and 85 and linkages to the California Cancer Registry and other indices, overall and breast cancer-specific mortality by mammography frequency were estimated using multivariable Cox proportional hazards models, stratified by age group and risk category at baseline as determined by the Gail breast cancer risk model.ResultsDuring the follow-up period of 20 years, overall mortality risk was lower in women who had annual or biennial mammography compared to less frequent or no mammography in all age groups. Annual mammography was associated with lower overall mortality risk compared to biennial mammography among women age 50–85. This difference was especially apparent in women age 60–74, regardless of estimated Gail risk category at baseline. Breast cancer-specific mortality was lower among women who had annual mammography compared to biennial or less frequent mammography among women age 60–74, regardless of their baseline risk.ConclusionsOur findings suggest that at least biennial mammography is beneficial to most women age 40–85 and that annual mammography is more beneficial than biennial mammography to most women age 50–85 in terms of overall mortality.

Does Direct-to-Consumer Personal Genetic Testing Improve Gynecological Cancer Screening Uptake among Never-Screened Attendees? A Randomized Controlled Study

The clinical impact of direct-to-consumer genetic testing (DTC-GT) on health behavior change has remained controversial. The aim of this study is to clarify the short-term effects of DTC-GT on gynecological cancer screening uptake among middle-aged never-screened Japanese women in a randomized controlled trial (RCT). A total of 144 women aged 45–50 who had never undergone gynecological cancer screening were randomly selected to receive health education (control group), or health education and DTC-GT (intervention group), at a 1:1 ratio. We compared the gynecological screening uptake during the follow-up period. Furthermore, to estimate the impact of learning of an elevated genetic cancer risk in the intervention group, we conducted an analysis dichotomized by genetic risk category. A total of 139 women completed the one-year follow-up survey (69 in the control group and 70 in the intervention group). The follow-up period did not differ between control and intervention groups (the median follow-up period was 276 days and 279 days, respectively, p = 0.746). There were 7 (9.7%) women in the control group and 10 (13.9%) in the intervention group who attended breast cancer screening (p = 0.606), and 9 (12.5%) women from both groups attended cervical cancer screening (p = 1.000). Likewise, there were no significant differences in cancer screening uptake in the analysis stratified by risk category within the intervention group. In conclusion, there was no significant effect of DTC-GT on gynecological cancer screening uptake in this RCT setting. Increasing cancer screening attendance may require a combination of well-established intervention strategies and DTC-GT. Clinical Trial Registration: UMIN-CTR Identifier, UMIN000031709.

S1235 Disparities in the Incidence of Liver and Bile Duct Cancers in Hispanics at the U.S.-Mexico Border Region

Introduction: Primary liver and bile duct cancers are the fifth most common cause of cancer-related death in men and the seventh most common in women. Both Hispanic men and women are twice as likely to be diagnosed and die from liver cancer as non-Hispanic Whites. Several risk factors may be contributing to this disparity, including higher rates of obesity, diabetes, NAFLD, and alcohol-related liver disease among Hispanics. We investigated the incidence rates of liver and bile duct cancers in persons living near the U.S.-Mexico border, a region where these risk factors appear to be more prevalent. Methods: Average annual incidence rates (cases per 100,000 persons) from 2013 to 2017 of liver and bile duct cancers for counties along the U.S.-Mexico border were obtained from the NIH National Cancer Institute. Data was categorized by ethnicity (Hispanic and non-Hispanic White) and gender. The Wilcoxon matched-pairs signed rank test was used to compare rates among Hispanics versus non-Hispanic Whites. The Mann-Whitney test was used to compare incidence rates between border Hispanics and Hispanics at the national level. Counties/counts were excluded if fewer than 16 cases were reported in a specific area, sex, or ethnicity category (to ensure confidentiality). Results: Incidence rates for border Hispanics were significantly higher than for border non-Hispanic Whites (p < 0.01). When comparing among genders, incidence rates for border Hispanic males were higher than for border non-Hispanic White males (p < 0.01). No statistically significant difference was observed among female groups (p = 0.25); likely attributed to the fact that incidence data for non-Hispanic White females was only available for 3 counties. In addition, the aggregated incidence rate for border Hispanics was significantly higher than the national Hispanic rate (p = 0.0019) (Table 1). Conclusion: To our knowledge, this is the first study comparing incidence rates of liver and bile duct cancers between ethnic groups in the U.S.-Mexico border region. Hispanics are disproportionately affected by liver and bile duct cancers. This disparity is even more evident in the U.S.-Mexico border region, where incidence rates for border Hispanics are higher than the national Hispanic rate. These findings may be related to the higher prevalence of modifiable risk factors in the border region.Table 1.: Incidence rates of liver and bile duct cancers for counties along the U.S.-Mexico border region. Average annual incidence rates per 100,000 persons from 2013 to 2017. 95% confidence intervals in parenthesis. NH = Non-Hispanic * Fewer than 16 cases reported - data suppressed to ensure confidentiality and stability of rate estimates.

Thyroid dose estimates for the genome-wide association study of thyroid cancer in persons exposed in Belarus to 131I after the Chernobyl accident.

The Chernobyl accident on 26 April 1986 led to a sharp increase in thyroid cancer (TC) incidence in the individuals exposed to radiation in childhood. The major risk factor for TC was exposure to Iodine-131 (131I). Here, we estimated the thyroid doses due to 131I intake for 2041 participants of the genome-wide association study of TC in Belarusian people exposed to radioactive fallout from the Chernobyl accident. The following parameter-values specially developed in this study were used to estimate individual thyroid doses: (i) scaling factors for adjustment of the model-based doses, (ii) age and gender diet to characterize 131I intake, and (iii) area-, age- and gender-specific S-values for the thyroid gland per 131I decay in the thyroid. The most reliable doses were calculated for 103 people with measured 131I thyroid activity (the arithmetic mean of 1.2Gy, median 0.52Gy), and 275 individuals with detailed residential history and dietary data (the arithmetic mean of 0.41Gy, median 0.24Gy). The arithmetic mean of thyroid doses among all study participants was 0.23Gy (median 0.082Gy); the highest individual dose was 9.0Gy. Special attention was paid to the reliability and validity of the obtained estimates, in particular for the individuals without 131I thyroid activity measurements and individual data on residential history and diet, by comparing those with the doses from other post-Chernobyl epidemiological studies. Overall, the doses estimated in the current study were in reasonable agreement with previously reported thyroid doses. These doses will be used in the genome-wide association study of TC in people exposed in Belarus to 131I after the Chernobyl accident.

Advanced cancers amongst individuals of African ancestry exhibit an almost five-fold higher prevalence of high-risk HPV types not covered by the current 9-valent vaccine

<h3>Objectives:</h3> Among women with high-risk human papillomavirus (hrHPV) detected in cervical swabs, the distribution of hrHPV types is known to differ by racial/ethnic group, with East and West Africans and North Americans of African ancestry1 showing overrepresentation of hrHPV types that are not covered by the current 9-valent HPV vaccine. Possible downstream consequences in ethno-specific rates of aggressive hrHPV-related cancers, however, have not been systematically examined. Here, we surveyed a large, multiethnic database of aggressive cancers for non-9-valent-vaccine hrHPV types in association with individual ancestry data. <h3>Methods:</h3> Our archive of 290,311 unique advanced cancer samples underwent comprehensive genomic profiling (CGP) using a hybrid-capture-based DNA sequencing platform. We detected hrHPV genomic sequences in 1,690 cervical, 1,196 anogenital, and 1,380 head and neck cancers by <i>de novo</i> assembly of nonhuman reads, followed by alignment to the RefSeq database, which distinguishes hrHPV types. Patient ancestry was determined by classifying specific SNPs by CGP based on their known variation among populations in the 1000 Genomes Project. Quantitative data were analyzed using the Fisher exact test. A two-tailed P value of <.05 was considered statistically significant; the Bonferroni correction was applied for multiple simultaneous comparisons. <h3>Results:</h3> We identified four non-vaccine hrHPV types with >10 cancer cases each: HPV35 (n=71 cases), HPV51 (n=11), HPV59 (n=42), and HPV67 (n=12). Among patients whose cancers harbored hrHPV types that are covered by the 9-valent vaccine (here, HPV16, 18, 31, 33, 45, 52, and 58), 7.5% (308/4,131) were of African ancestry, lower than the overall representation of African ancestry in our database (9.1% [26,471/290,311]). In contrast, among cases with non-9-valent-vaccine hrHPV types, we identified several-fold enrichment for individuals of African ancestry (HPV35: 24% of African ancestry [17/71], HPV51: 27% [3/11], HPV59: 43% [18/42], HPV67: 25% [3/12]). In total, these four non-vaccine hrHPV types accounted for 11.4% (40/350) of all hrHPV-related advanced cancers in persons of African ancestry, but only 2.4% (95/3928) of hrHPV-related advanced cancers in individuals of other ancestries, a difference of nearly five-fold (p<0.00001, Table 1). Genomic alterations and tumor mutational burden showed no significant differences based on hrHPV type or patient ancestry, suggesting similar tumorigenic mechanisms. <h3>Conclusions:</h3> In our pan-hrHPV analysis of advanced cancers, hrHPV types not covered by the current 9-valent vaccine are strikingly increased in individuals of African ancestry. Our data strongly indicate a need to re-evaluate the choice of hrHPV types to include in the vaccine, as well as a need to re-evaluate the underlying process by which hrHPV types are chosen for inclusion.

Secondary Cancer after Meningioma Diagnosis – an Israeli National Study

Background: There are limited data on whether primary diagnosis of meningioma may be associated with development of secondary primary cancer (SPC). Methods: All meningioma cases (ICD-O-3 morphology codes 9530/0-9539/3) diagnosed in Jewish Israelis ages 20 and over between 1990 to 2015 were located in the database of the Israel National Cancer Registry (INCR). All subsequent cancers occurring more than six months after meningioma diagnosis were identified. Risk of secondary cancer (SPC) was compared to cancer risk in the general population through the calculation of standardized incidence ratios (SIRs) and excess absolute risks (EARs). SIRs were stratified by type of second cancer, sex, and age group. Cox regression models were used to estimate hazard ratios of developing SPC. Findings: Overall, 8044 eligible meningioma cases were identified: mean age at diagnosis was 64.0 years (standard deviation=14.1). Of these, 927 (11.5%) were diagnosed with SPC (SIR 1.6, 95% Confidence Interval, CI 1.5–1.7). Secondary cancer risk was found to be elevated in both men (SIR 1.6, 95% CI 1.5–1.9) and women (SIR 1.6, 95%CI 1.5–1.8) diagnosed with meningioma. Cancers most commonly encountered as secondary cancers in persons previously diagnosed with meningioma were breast (17.6%), colorectal (13.4%), lung (8.1%), prostate (5%), and bladder (4.6%) cancer. Interpretation: Meningioma diagnosis is associated with an increased risk for developing secondary cancers. This risk should be discussed with patients treated for meningioma. Funding: There was no funding for this research project. Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Sheba Medical Center ethics committee.

Evaluation and comparison of hereditary Cancer guidelines in the population

BackgroundFamily health history (FHx) is an effective tool for identifying patients at risk of hereditary cancer. Hereditary cancer clinical practice guidelines (CPG) contain criteria used to evaluate FHx and to make recommendations for genetic consultation. Comparing different CPGs used to evaluate a common set of FHx provides insight into how well the CPGs perform, the extent of agreement across guidelines, and how well they identify patients who should consider a cancer genetic consultation.MethodsWe compare the American College of Medical Genetics and Genomics (ACMG) and the National Comprehensive Cancer Networks (NCCN) (2019) CPG criteria for FHx collected by a chatbot and evaluated by ontologies and web services in a previous study. Collected FHx met criteria from seven groups: Gene Mutation, Breast and Ovarian, Li-Fraumeni syndrome (LFS), Colorectal and Endometrial, Relative Meets Criteria, ACMG Only Criteria, and NCCN Testing. CPG Criteria were coded and matched across 12 ACMG sub-guidelines and 6 NCCN sub-guidelines for comparison purposes.ResultsThe dataset contains 4915 records, of which 2221 met either ACMG or NCCN criteria and 2694 did not. There was significant overlap—1179 probands met both ACMG and NCCN criteria. The greatest similarities were for Gene Mutation and Breast and Ovarian criteria and the greatest disparity existed among Colorectal and Endometrial criteria. Only 156 positive gene mutations were reported and of the 2694 probands who did not meet criteria, 90.6% of them reported at least one cancer in their personal or family cancer history.ConclusionHereditary cancer CPGs are useful for identifying patients at risk of developing cancer based on FHx. This comparison shows that with the aid of chatbots, ontologies, and web services, CPGs can be more efficiently applied to identify patients at risk of hereditary cancer. Additionally this comparison examines similarities and differences between ACMG and NCCN and shows the importance of using both guidelines when evaluating hereditary cancer risk.

Association Between Proton Pump Inhibitor Use and Biliary Tract Cancer Risk: A Swedish Population-Based Cohort Study.

Biliary tract cancer is a group of highly aggressive malignant disorders, yet risk factors are poorly understood. In this study, we aim to assess whether prolonged use of proton pump inhibitors (PPIs) increases the risk of incident biliary tract carcinoma in a nation-wide population-based cohort in Sweden. Using nation-wide registries, we identified all adults who received maintenance PPIs (≥180days) according to the Swedish Prescribed Drug Register from 2005 through 2012. Data on incident biliary tract cancer were retrieved from the Swedish Cancer, Death and Outpatient Registers. Risk of biliary tract cancer in persons who received PPI treatment was compared with the general population of the corresponding age, sex, and calendar year yielding standardized incidence ratios (SIRs) with 95% CIs. Of 738,881 PPI users (median follow-up of 5.3years), 206 (0.03%) developed gallbladder cancer and 265 (0.04%) extrahepatic and 131 (0.02%) intrahepatic bile duct cancer corresponding to SIRs of 1.58 (95% CI, 1.37-1.81), 1.77 (95% CI, 1.56-2.00), and 1.88 (95% CI, 1.57-2.23), respectively. In sensitivity analyses restricted to persons without a history of gallstones or chronic liver or pancreatic diseases, SIRs were 1.36 (95% CI, 1.17-1.57) and 1.47 (95% CI, 1.19-1.80) for extra- and intrahepatic duct cancer, respectively. The risk remained higher than the corresponding general population with ≥5years of PPIs use, ruling out confounding by indication. In this study, long-term use of PPIs was associated with an increased risk of gallbladder, intrahepatic, and extrahepatic bile duct cancer compared with the general population.

Abstract 20: Development of International Cancer Research Partnerships Through the NCI US-Latin American-Caribbean HIV/HPV-Cancer Prevention Clinical Trials Network (ULACNet)

Abstract Purpose: Persons living with HIV have elevated risks of HPV-related cervical, anogenital, and oropharyngeal cancers. Yet, research on optimization and implementation of prevention interventions (prophylactic HPV vaccination, cervical and anogenital cancer screening and triage, and precancer therapeutics) for HPV-related cancers among persons living with HIV has been limited. With a goal to expand this evidence, and building on strong academic research partnerships developed for HIV research between institutions in the US and the Latin American and the Caribbean (LAC) region, the US National Cancer Institute (NCI) initiated ULACNet, a new Cooperative Agreement clinical trials network in 2019. Methods: ULACNet comprises of three Partnership Centers each led by US-based institutions (University of California San Francisco, Weill Medical College of Cornell University, and Fred Hutchinson Cancer Research Center), working collaboratively with US and LAC institutions and with the NCI to develop and conduct multicenter prevention clinical trials focused on filling key scientific gaps and evaluating novel interventions. Results: ULACNet encompasses six countries (US, Mexico, Puerto Rico, Brazil, Peru, and Dominican Republic), twenty partner institutions, and over 100 collaborating scientific investigators, clinical and public health practitioners, research staff, and patient advocates. ULACNet will collaboratively conduct nine prevention clinical trials (two prophylactic HPV vaccine trials in adults and perinatally-HIV infected adolescents, three trials for clinical validation of molecular biomarkers and imaging technologies for screening and triage, two candidate HPV therapeutic vaccine trials, and two trials of topical therapeutic agents). Facilitation across network partners is achieved via a Coordinating Committee and three Working Groups (focused on HPV testing and screening, precancer treatment, and recruitment and retention activities). Conclusion: ULACNet seeks to leverage established academic global health partnerships to conduct high quality collaborative clinical trials to inform clinical practice and ultimately reduce the burden of highly preventable HPV-related cancers in persons living with HIV worldwide. Citation Format: Emma Brofsky, Margaret House, Brandy Heckman-Stoddard, Mostafa Nokta, Satish Gopal, Vikrant Sahasrabuddhe. Development of International Cancer Research Partnerships Through the NCI US-Latin American-Caribbean HIV/HPV-Cancer Prevention Clinical Trials Network (ULACNet) [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 20.

Development and pilot of an online, personalized risk assessment tool for a breast cancer precision medicine trial

Breast cancer risk reduction has been validated by large-scale clinical trials, but uptake remains low. A risk communication tool could provide personalized risk-reduction information for high-risk women. A low-literacy-friendly, visual, and personalized tool was designed as part of the Women Informed to Screen Depending On Measures of risk (WISDOM) study. The tool integrates genetic, polygenic, and lifestyle factors, and quantifies the risk-reduction from undertaking medication and lifestyle interventions. The development and design process utilized feedback from clinicians, decision-making scientists, software engineers, and patient advocates. We piloted the tool with 17 study participants, collecting quantitative and qualitative feedback. Overall, participants felt they better understood their personalized breast cancer risk, were motivated to reduce their risk, and considered lifestyle interventions. The tool will be used to evaluate whether risk-based screening leads to more informed decisions and higher uptake of risk-reduction interventions among those most likely to benefit.

Cancer Proteomics: New Horizons and Insights into Therapeutic Applications

A proteome is an efficient rendition of a genome, unswervingly controlling various cancer processes. Molecular mechanisms of several cancer processes have been unraveled by the proteomic approach. Thus far, numerous tumors of diverse status have been investigated by two-dimensional electrophoresis. Numerous biomarkers have been recognized and precise categorization of apparent lesions has led to the timely detection of various cancers in persons at peril. Currently used pioneering approaches and technologies in proteomics have led to highly sensitive assays of cancer biomarkers and improved the early diagnosis of various cancers. The discovery of novel and definite biomarker signatures further widened our perceptive of the disease, and novel potent drugs and aimed therapeutic outcomes in persistent cancers have emerged. However, a major limitation, even today, of proteomics is resolving and quantifying the proteins of low abundance. Despite the rapid development of proteomics technologies and their applications in cancer management, annulling the shortcomings of present proteomic technologies and the development of better methods are still desirable. The main objectives of this review are to discuss the developing aspects, merits and demerits of pharmacoproteomics, redox proteomics, novel approaches and therapies being used for various types of cancer-based on proteome studies.

The associations of CD4 count, CD4/CD8 ratio, and HIV viral load with survival from non-small cell lung cancer in persons living with HIV

ABSTRACT HIV status may influence survival from non-small cell lung cancer (NSCLC). Among NSCLC patients in the Bronx, NY, we assessed (1) associations of CD4 count, CD4/CD8 ratio and HIV viral load (VL) with survival and (2) prognostic factors among persons living with HIV (PLWH). We compared survival from NSCLC diagnosis (2004–2017) between HIV-negative persons (HIV-, n=2,881) and PLWH (n=88) accounting for clinical and sociodemographic factors. HIV-survival was also compared with PLWH, dichotomized by CD4 (<200 vs. ≥200cells/µL), CD4/CD8 (median, <0.43 vs. ≥0.43) and VL (<75 vs. ≥75copies/mL) at NSCLC diagnosis. Among PLWH, we assessed the relationships of CD4, CD4/CD8, and VL with survival, adjusting for age, sex, and cancer stage. PLWH with CD4< 200cells/µL had lower survival than HIV- [hazard ratio, 95% confidence interval [HR(95%CI)]=1.86(0.98–3.55)]. Survival was similar between PLWH with CD4≥ 200cells/µL and HIV- [HR(95%CI) = 0.90(0.61–1.33)]. Results were similar when categorizing PLWH by CD4/CD8 [vs. HIV-: low CD4/CD8: HR(95%CI) = 1.74(1.07–3.89); high CD4/CD8: HR(95%CI) = 0.63(0.37–1.07)] and VL [vs. HIV-: <75copies/mL: HR(95%CI) = 0.74(0.46–1.21), ≥75copies/mL: HR(95%CI) = 1.41(0.88–2.27)]. Among PLWH, CD4< 200cells/µL was associated with worse survival [vs. CD4≥ 200cells/µL: HR(95%CI) = 2.37(1.14–4.92)]. CD4, CD4/CD8, and VL may be prognostic markers for PLWH with NSCLC, suggesting immune status may be important in NSCLC survival among PLWH.

Point of care genetic testing in a breast cancer survivorship clinic.

10580 Background:: Breast cancer survivorship care (BCSC) includes the ongoing assessment of personal and family cancer history and offering genetic education, counseling and testing to survivors who meet NCCN, ASBrS and Medicare guidelines for germline genetic testing. It is reported that approximately 8% of patients with breast cancer (BC) will have a clinically actionable germline mutation. However, lower than expected rates of testing are seen in both the acute and extended phases of BCSC. We sought to identify the number of patients seen in a long-term survivorship clinic who had previously undergone or currently qualified for germline testing, and the prevalence of germline variants in BC survivors. Methods: In a Nurse Practitioner (NP) led clinic, 2,184 non-selected BC survivors were screened to determine if: germline testing was previously completed or if update germline testing or initial germline testing is needed (with a 3-generation review of family history). BC survivors eligible for initial or update germline testing (411 patients) were provided with genetic education, counseling, and offered multigene panel testing. Seven (7) BC survivors declined testing. Results: From May 2019 – January 2021, 2,184 BC survivors were seen in the clinic. The average age of survivors = 60.2 yrs; average time since diagnosis = 10.7 yrs; and average age at diagnosis = 50.1 yrs, gPV were identified in 10.4%. Out of pocket cost on average was $50.00 for 2.0% of those tested. Conclusions: Within a comprehensive Breast Cancer program where genetic testing is common practice, there is an ongoing need to screen breast cancer (BC) survivors for genetic testing eligibility. A significant number of BC survivors will test positive for a pathogenic mutation (10.4%) a decade after an initial diagnosis. Genetic testing is a necessary step to stratify a BC survivors’ risk of developing secondary cancers, appropriate screening and prevention strategies, cascade testing, and for some, treatment planning. This individualized approach to BCSC is often described, but difficult to put into action. Time/access and drop rates with a referral model are barriers. Incorporating a point of care genetic testing model requires additional support (genetic extender), professional development, education, and a commitment to provide patient centric care.[Table: see text]

Clinical and genetic characterization of cancer patients with multiple germline variants.

e22523 Background: Hereditary tumors are generally monogenic diseases with autosomal dominant inheritance. However, we noticed that some individuals may harbor ≥2 germline mutations in one or multiple genes, which remains to be explored. Methods: Genetic mutations were reviewed in more than 50,000 cancer patients who underwent hybridization capture based next-generation sequencing (NGS). Germline variants were interpreted following ACMG guideline, and only pathogenic and likely pathogenic variants were included in this study. Results: Multiple germline variants were identified in 42 individuals with the detection rate of 0.075%. The median age at diagnosis was 48 years (range 31-73). Two thirds of patients were female and 26.2% of patients has cancer family history. Prostate cancer is the most common cancer type (0.6%, 2/332), followed by carcinomas of ovarian or fallopian tube (0.48%, 7/1461), breast (0.24%, 8/3302), pancreas (0.2%, 2/982) and so on. Surprisingly, 7 patients with lung cancer also harbored ≥2 germline mutations (0.02%). Most of these germline variants affected DNA damage repair pathways [75.6% homologous recombination repair (HR), 8.1% mismatch repair (MMR), 1.2% base excision repair (BER)]. Four patients had two germline variants identified on a single gene (2 ATM, 1 BRCA1, 1 BRCA2). Three variants were identified in 2 patients, and 2 variants were identified in the remaining 36 patients. Two or more germline variants in HRR pathway were identified in 64.3% of patients, among which 18.5% patients had BRCA1+ BRCA2 double variants. The efficacy of poly ADP-ribose polymerase inhibitors (PARPi) in this specific population should raise concern. Besides, double variants in HRR and MMR pathway were found in 5 patients, which suggested the potential benefit of immunotherapy and PARPi combination therapy. Conclusions: In addition to identify variants contributing to the personal and family cancer history, NGS can accidentally identify germline variants that may suggest the susceptibility of other hereditary tumors. Multiple variants on HRR or MMR genes may have important implications for the treatment strategy for these patients.

Use of comprehensive next-generation sequencing to identify pathogenic germline variants with therapeutic relevance in metastatic breast cancer.

10527 Background: Among patients with early-stage breast cancer, approximately 6-10% have a pathogenic germline variant (PGV) conferring inherited cancer predisposition. In contrast, few studies have explored the frequency and types of PGVs identified in patients with metastatic breast cancer (MBC); therefore, additional data is needed. Methods: From 2011-2020, 278 patients with MBC underwent fresh tumor biopsy and blood sample collection for paired tumor/normal DNA (targeted exome capture with analysis of 1700 genes) and RNA (tumor transcriptome) sequencing through the Michigan Oncology Sequencing (Mi-ONCOSEQ) program. Somatic and germline alterations were annotated and classified according to degree of clinical actionability with results returned to treating oncologists. Retrospective chart review was performed to determine if: 1) a PGV was identified prior to Mi-ONCOSEQ testing, 2) patients met National Comprehensive Cancer Network (NCCN) guideline criteria for genetic testing on the basis of personal or family cancer history and 3) patients received subsequent therapy informed by a PGV. Results: Forty-eight of the 278 patients (17.3%) had at least one PGV identified, with a total of 50 PGVs identified in this cohort. Only twelve of these PGVs (24%) had been identified prior to Mi-ONCOSEQ testing. The most frequent PGVs identified were in CHEK 2 (n = 9, 18%), MUTYH (n = 6, 12%), BRCA 1 (n = 5, 10%), BRCA2 (n = 5, 10%), ATM (n = 4, 8%) and PALB2 (n = 4, 8%). Somatic loss of heterozygosity events (LOH) occurred in 30 of the 50 cases with PGVs identified (60%). LOH events were observed in 83.3% of BRCA1, BRCA2, ATM and PALB2 PGVs, but were less frequently observed with CHEK2 (33.3%) and MUTYH (66.7%). Two hundred sixteen out of 278 patients (77.7%) in this cohort met NCCN criteria for genetic testing, although six patients with a PGV identified (CHEK2: n = 5; MUTYH: n = 1) did not meet NCCN criteria. Twenty-nine PGVs identified (58%) had potential therapeutic relevance and 11 patients (22.9%) received targeted therapy based on the PGV. Conclusions: The frequency of PGVs identified in this cohort is nearly double the frequency reported for patients with early-stage disease, suggesting that certain PGVs may confer worse prognosis. CHEK2, the most frequently identified PGV, was less likely to have an identifiable LOH event. The direct role of CHEK2 PGVs in tumor pathogenesis is uncertain, but other mechanisms of silencing the wild type allele must be considered. Despite the majority of patients meeting NCCN criteria for genetic testing, those with PGVs in CHEK2 were less reliably identified by this mechanism. The majority of PGVs identified were of potential therapeutic relevance, supporting the recommendation for genetic testing in all patients with MBC.