tbuckley/cabot-search huggingface dataset:
Association of polygenic-based breast cancer risk prediction with patient management.
Authors: Katie Johansen Taber, Elisha Hughes, Alexander Gutin, Brady DeHart, Laura Becker, Jeff Jasper, Sarah Ratzel, Claire Miller, Devika Chawla, Pamela Morin, Julia M Certa, Allison W. Kurian
Journal: Journal of Clinical Oncology (2024)

10527 Background: Guidelines recommend individuals with ≥20% lifetime risk of breast cancer (BC) undergo enhanced management, including annual screening mammography (SM) as early as age 30, annual breast MRI, and genetic counseling (GC). Lifetime BC risk can be estimated using a validated risk model, such as Tyrer-Cuzick (TC). A risk predictor that combines TC with a polygenic risk score (“combined risk score” or CRS) significantly improves risk prediction over TC alone. Little is known about how clinicians manage patients based on CRS. Here, we describe management following receipt of CRS results. Methods: De-identified administrative claims data from the Optum Labs Data Warehouse were linked with de-identified TC and CRS results originally provided to ordering clinicians. Patients were divided into four subgroups based on their lifetime risk predicted by CRS and by TC alone (high risk: ≥20%, average risk: &lt;20%): A (CRS-high/TC-high), B (CRS-high/TC-avg), C (CRS-avg/TC-high), and D (CRS-avg/TC-avg). Patient management claims were compared 360 days before and after the CRS test date and differences evaluated with McNemar’s test. Differences in post-test management were analyzed using multivariable logistic regression with adjustment for clinical factors. Results: Before receiving risk results, 11.9%, 7.7%, 8.8%, and 5.0% of patients in A, B, C, and D received a SM before age 40, respectively; 3.4%, 2.6%, 2.3%, and 0.9% received an MRI, respectively; and 4.3%, 4.7%, 6.0%, and 3.6% received GC, respectively. After receiving risk results, SM in those under age 40 significantly increased 1.6-2.2-fold in A, B, and C; MRI significantly increased 4.7-5.6-fold in A, B, and C; and GC significantly increased 1.9-2.3-fold in A and B. SM, MRI, and GC did not increase in D. Prophylactic mastectomy occurred in only 0.17% of all patients after receiving results. After adjustment for confounders, those in A, B, and C were 3.8-5.2 times more likely to undergo SM; 11.6-23.1 times more likely to undergo MRI; and 2.0-2.9 times more likely to undergo GC, compared to those in Group D (all p&lt;0.001). Conclusions: Patients with a ≥20% lifetime risk for BC were more likely to undergo enhanced management compared to those with a lifetime risk &lt;20%, regardless of whether their risk was based on the CRS or on TC. These results suggest that clinicians recommended management aligned with guidelines for those with ≥20% lifetime risk, even when such risk was predicted by the CRS. [Table: see text]
Blood type as a risk factor for pancreatic ductal adenocarcinoma.
Authors: Navid Rahimi Larki, Melissa Skanderson, Janet Tate, Rachel Levinson, Ronald G Hauser, Cynthia Brandt, Yu-Xiao Yang, Amy C. Justice, Louise Wang
Journal: Journal of Clinical Oncology (2024)

10559 Background: Non-O blood type has been associated with increased risk of pancreatic ductal adenocarcinoma (PDAC), the third leading cause of cancer death in the United States (US), in largely white populations. We aimed to explore PDAC risk across blood types in the racially diverse Veteran’s Health Administration (VA), the largest integrated healthcare system in the US. Methods: We included all individuals in the VA from 2002 - 2022 with at least one inpatient or outpatient encounter and a non-missing race. We defined the index date as 1.5 years after the initial VA encounter and excluded individuals with prior PDAC. We defined the exposure by non-O (A, B, AB) or type O blood type. We defined PDAC based on a previously validated algorithm of ≥2 sources (cancer registry, hospitalizations, or outpatient oncology encounters) with 95% positive predictive value. Using time to PDAC as the outcome in a multivariable Cox regression, we evaluated the association between blood type and PDAC risk, adjusting for age, sex, BMI, smoking, alcohol use, Hepatitis C (HCV) and diabetes. We censored at time of death, 1.5 years after the last VA encounter, or the end of the study period. We performed a subgroup analysis to evaluate the association of blood type by race. Results: Of the 2.5 million individuals with an available blood type, 1.35 million (52.6%) had a non-O blood type (Table) and over a quarter of our cohort (28.2%, 725,878) were over baseline age 50. Median time to PDAC diagnosis was 8.6 years. There were 877 PDAC cases (0.03%), with 530 (60.4%) of those having a non-O blood type. Compared to those with type O blood, risk of PDAC for individuals with non-O blood type was higher overall [adjusted HR = 1.37 (95% CI 1.20-1.57)], and higher among Whites (n=1,689,092, HR 1.52, 95% CI 1.27-1.82) than Black patients (n=525,666, HR 1.15, 95% CI 0.90-1.48), though this was limited by smaller sample size. Conclusions: Non-O blood type was associated with higher risk of PDAC in a diverse population. Given the potential differences between races, we will further explore the impact of neighborhood-level socioeconomic data on PDAC risk. [Table: see text]
Improving a polygenic risk score (PRS) for breast cancer (BC) risk assessment in diverse ancestries.
Authors: Timothy Simmons, Elisha Hughes, Dmitry Pruss, Matthew Kucera, Benjamin Roa, Thaddeus Judkins, Adib Younus, Shelly Ann Cummings, Srikanth Jammulapati, Kirsten Timms, Allison W. Kurian, Holly Jane Pederson, Pat W. Whitworth, Susanne Wagner, Dale Muzzey, Jerry S. Lanchbury, Alexander Gutin
Journal: Journal of Clinical Oncology (2024)

10533 Background: Accurate BC risk assessment is essential to identify women for whom screening and preventive interventions may be lifesaving. Incorporation of PRS into clinical models can improve risk prediction, but most PRS have shown suboptimal performance among non-Europeans. We previously described a multiple-ancestry PRS (MA-149) based on 56 ancestry-informative and 93 BC-associated single-nucleotide polymorphisms (SNPs). MA-149 achieved accuracy for diverse populations by characterizing genetic ancestry at each SNP in terms of fractions attributable to reference ancestries (African, East Asian, European) and applying ancestry-specific risks and frequencies. MA-149 significantly outperformed the Tyrer-Cuzick (TC) model, and integration of MA-149 with TC improved predictive accuracy by roughly two-fold over TC alone. Here, we aimed to improve MA-149 by expanding the set of BC SNPs and refining ancestry-specific risks. Methods: We developed a novel stepwise regression methodology accounting for linkage disequilibrium to select an optimal set of BC SNPs. Women referred for hereditary cancer testing and negative for pathogenic variants in BC genes were divided into consecutive cohorts to (1) refine ancestry-specific SNP risks ( N=58,191 Black/African; N=27,160 East Asian), (2) develop the PRS ( N=184,322), and (3) conduct independent validation ( N=146,110). Predictive accuracy and calibration of the new PRS were evaluated in the full cohort and subpopulations of different ancestries. Odds ratios (OR) from multivariable regression are reported per standard deviation. Results: A set of 385 SNPs (56 ancestry, 329 BC) was selected for the new PRS (MA-385). MA-385 improved upon clinical factors and outperformed MA-149 within each ancestry (Table). Among non-Europeans, MA-385 was a better BC risk predictor (OR=1.47, 95% CI: 1.42-1.52) than MA-149 (OR=1.40, 95% CI: 1.35-1.45). The strongest associations were observed in Ashkenazi Jewish and Hispanic women (Table). MA-385 identified more women at &gt;2-fold increased risk than MA-149 (6.5 % vs 2%). Goodness-of-fit tests showed that MA-385 was well-calibrated while a 385-SNP PRS with European weights was miscalibrated for non-Europeans. Conclusions: MA-385 was well-calibrated, improved upon clinical factors, and outperformed existing PRS in all tested ancestries. Incorporation of MA-385 into risk assessment could improve the early detection and prevention of BC. [Table: see text]
Significant results from a major multi-year, multi-cancer follow-up study with an enrollment of over 19,000 individuals.
Authors: Chris Chang Yu, Xuedong Du, Yue Lin, Xing Tang
Journal: Journal of Clinical Oncology (2024)

10539 Background: Multi-cancer screening has become a major approach for early stage cancer screening and prevention. However, there has been very few reported multi-year, multi-cancer follow-up studies to validate the effectiveness of multi-cancer screening. We report a number of significant, major findings from what we believe the first large scale, multi-year, multi-cancer follow-up study. Methods: In this study, cancer differentiation analysis (CDA) technology, a bio-physics based detection platform, has been used to screen over 200,000 individuals in a general population. Based on the CDA test values, individuals have been classified into high risk, medium risk and low risk (for cancer) groups. Up to January 31, 2024, a total of 19,141 individuals have been enrolled, with 1,122 in high risk, 15,784 in medium risk, and 2,235 in low risk group. In this follow-up study, enrolled individuals were initially contacted within 6 months (high risk individuals were contacted within 15 days after the test report became available) and subsequently on an annual basis, and their health conditions were recorded. Results: Up to January 31, 2024, 256 individuals have been confirmed with cancer, 1,607 confirmed with pre-cancer diseases and benign tumors, and finally, 1,378 confirmed with diseases. When enrollment is normalized (number of individuals enrolled into each group is equal), for confirmed cancer group, 91.4% is in high risk group, 7.5% in medium risk group and only 1.1% in low risk group. The above result is very significant, indicating that multi-cancer screening using CDA technology is very effective. As shown, there are 23 types of cancer (Table). There are close to 30 types of pre-cancer diseases and benign tumors confirmed. Above results showed that CDA technology is indeed very effective in screening out multiple cancer types (including some cancer types which do not yet have other effective IVD tests such as thyroid cancer and esophageal cancer). The results also show that this approach is very helpful for cancer prevention as it screened out large number of pre-cancer diseases and benign tumor types. Conclusions: A large scale, multi-year, multi-cancer follow-up study has been carried out. Results showed that CDA technology is effective for multi-cancer screening in a general population.[Table: see text]
Patterns of cancer screening practice and mutational status of cancer-predisposing genes among individuals at high risk for cancer.
Authors: Jincong Q. Freeman, Achille Van Christ Manirakiza, Fangyuan Zhao, Emma Keel, Christine Drogan, Robin Bradley, Dezheng Huo, Olufunmilayo I. Olopade
Journal: Journal of Clinical Oncology (2024)

10557 Background: Research on cancer screening practice and prevention strategies among individuals at high risk for cancer is limited. We explored the patterns of screening practice of seven cancer types in high-risk patients (pts) at a single institution. Methods: Between June-September 2023, we conducted a follow-up survey on pts enrolled in the University of Chicago Cancer Prone Study, a longitudinal cohort of high-risk families initiated in 1992. We assessed breast, cervical, colorectal, prostate (PSA), ovarian, skin (full-body skin exam [FBSE]), and lung cancer screening by mutational status. Results: Of 912 respondents, 80.4% were female. 81.6% were White, followed by 10.6% Black, 4.0% other/multi-racial, and 3.8% Hispanic. Overall, 35.2% reported having cancer-predisposing gene mutations. Mutation carriers were younger than those non-carriers (54.8 [SD 13.7] vs 60.3 [SD 12.8] years). After adjusting for age, carriers were more likely than non-carriers to have had breast MRI ( p&lt;.001), colorectal cancer screening ( p=.039), ovarian cancer screening ( p=.043), and an FBSE ( p=.007) (Table). No statistically significant differences in mammogram (OR=1.50, 95% CI=0.55-2.30; p=.13), cervical cancer (OR=0.92, 95% CI=0.54-1.59; p=.77), PSA (OR=0.70, 95% CI: 0.26-1.88; p=.48), or lung cancer (OR=1.18, 95% CI=0.72-1.92; p=.51) screening between carriers and non-carriers. By race/ethnicity, cervical cancer screening (Hispanic 92%, White 90.6%, other/multiracial 80.7% and Black 76%; p=.002) and colorectal cancer screening (White 83.3%, other/multiracial 71.8%, Black 71.4% and Hispanic 66.6%; p=.004) differed significantly. Conclusions: In this diverse cohort of individuals at high risk for cancer, findings highlight an increased awareness and uptake of cancer screening, though varying by race/ethnicity. Cancer risk assessment clinics can be great avenues to provide comprehensive cancer screening and prevention strategies while addressing racial/ethnic screening disparities. [Table: see text]
The utility of HPV16 E6 as a potential biomarker for HPV-related cancers in HIV-infected men who have sex with men.
Authors: Naokatsu Ando, Daisuke Mizushima, Haru Hoshino, Misao Takano, Takahiro Aoki, Koji Watanabe, Takato Nakamoto, Akira Kawashima, Seitaro Abe, Birgitta E Michels, Tim Waterboer, Hiroyuki Gatanaga
Journal: Journal of Clinical Oncology (2024)

10526 Background: The burden of HPV-related cancers, including oropharyngeal and anal cancers, poses a significant challenge. Although recent advancements in screening for anal cancer have been made for HIV-infected men who have sex with men (HIV-MSM), establishing effective screening protocols for oropharyngeal cancer remains ongoing. The early oncoprotein HPV16 E6 presents as a promising biomarker for the detection of HPV-associated cancers in this population as well. We investigated the utility of HPV16 E6 in HIV-MSM. Methods: We conducted a retrospective study using an HIV cohort at the AIDS Clinical Center of the National Center for Global Health and Medicine. Participants were all HIV-MSM and included those with HPV-related cancers or precancerous lesions such as oropharyngeal cancer, anal cancer, anal high-grade squamous intraepithelial lesions (aHSIL), and anal low-grade squamous intraepithelial lesions (aLSIL). All cancers and precancerous lesions were histologically confirmed. Frozen plasma samples taken at the time of diagnosis were evaluated. Additionally, when available, samples were retrospectively analyzed up to four years pre- and post-diagnosis. These specimens were sent to the German Cancer Research Center (DKFZ, Heidelberg, Germany) for analysis of antibodies against the early oncoproteins of carcinogenic mucosal HPV types, particularly HPV16 and other high-risk HPVs. Results: One hundred thirty-seven patients living with HIV (PWH) were included in the analysis. The distribution of PWH diagnosed with oropharyngeal cancer, anal cancer, aHSIL, and aLSIL was 6, 14, 96, and 9 respectively. Regarding HPV16 E6 seropositivity, 100% of patients with oropharyngeal cancer tested positive (6/6). Seropositivity rates for anal cancer, aHSIL, and aLSIL were 28.6% (4/14), 12.5% (12/96), and 11.1% (1/9) respectively (Table). Patients with oropharyngeal cancer exhibited the highest titer of HPV16 E6. Among the six patients with oropharyngeal cancer, one demonstrated persistent positivity from four years prior, and four showed positivity from one year prior. Two patients were not assessed as they were newly diagnosed at the time of the study. After chemoradiation treatment, their titers decreased but did not fall below the cutoff level during the follow-up period. In two cases of relapse, the titers, which had initially decreased with chemoradiation, increased again at least one year before the relapse diagnosis. Conclusions: The study demonstrated that screening for HPV16 E6 seropositivity is highly effective for the detection of oropharyngeal cancer in HIV-MSM. This could potentially contribute to early diagnosis and treatment of HPV-related cancers. [Table: see text]
Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma
Authors: Thierry Facon, Meletios-Athanasios Dimopoulos, Xavier P Leleu, Meral Beksac, Ludek Pour, Roman Hájek, Zhuogang Liu, Jiri Minarik, Philippe Moreau, Joanna Romejko-Jarosinska, Ivan Spicka, Vladimir I Vorobyev, Britta Besemer, Tadao Ishida, Wojciech Janowski, Sevgi Kalayoglu-Besisik, Gurdeep Parmar, Pawel Robak, Elena Zamagni, Hartmut Goldschmidt, Thomas G Martin, Salomon Manier, Mohamad Mohty, Corina Oprea, Marie-France Brégeault, Sandrine Macé, Christelle Berthou, David Bregman, Zandra Klippel, Robert Z Orlowski
Journal: New England Journal of Medicine (2024)

BackgroundBortezomib, lenalidomide, and dexamethasone (VRd) is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear.MethodsIn an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)–negative status in patients with a complete response.ResultsA total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P=0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P=0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups.ConclusionsIsatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. (Funded by Sanofi and a Cancer Center Support Grant; IMROZ ClinicalTrials.gov number, NCT03319667.)
Association of neighborhood-level superfund sites with atmospheric toxic exposures and increasing cancer risk in the United States: A proof-of-concept geospatial study.
Authors: S. M. Qasim Hussaini, Azar Mohammad Abadi Kamarei
Journal: Journal of Clinical Oncology (2024)

10577 Background: Decades of underinvestment have disproportionately exposed several neighborhoods in the US to hazardous conditions. Superfund is the name given to the environmental program established by the US Congress in 1980, to address abandoned hazardous waste sites. The extent to which Superfund sites have contributed to differences in cancer risk remains unknown. We investigated atmospheric toxic exposures increasing cancer risk by proximity to Superfund sites at the neighborhood level. Methods: In this cross-sectional study of US neighborhoods, census-tract level air toxic cancer risk data from the Environmental Protection Agency for 2019 were linked with census-tract level geolocation data of ~1300 Superfund sites from the Superfund Enterprise Management System database. Linear regression models were utilized to explore association between cancer risk and proximity to Superfunds. Geographically Weighted Regression models explored spatial non-stationarity by modeling spatial relationships that vary across the study area. Bivariate Local Indicators of Spatial Association (LISA) cluster maps were created for superfund site proximity and cancer risk (high-high, low-low, low-high, high-low). Kruskal-Wallis testing compared the distributions of different variables across the four LISA cluster types. Results: Study explored 82,770 census tracts nationwide. For every 10 percentile increase in Superfund proximity, there was an increase of 4% in cancer risk (p &lt; 0.001). This association was strongest in the Intermountain West, South-Southeast, and Northeast regions. High-high clusters (high proximity to Superfund, high cancer risk) had higher percentage of non-White, low-income, unemployed and lower education attainment populations compared to low-low clusters (all p &lt; 0.001). Within high-high clusters, non-White population had the strongest correlation with proximity to Superfunds. Cancer risk was much higher for the top 10% than the bottom 10% of proximity to Superfunds (Table). Conclusions: Our study highlights higher clustering of cancer risk around neighborhoods with existing Superfund sites. Further, we demonstrate the closer a neighborhood is to a Superfund site, the greater the cancer risk is with associated sociodemographic changes. Using a novel approach to geospatial analytics, the results demonstrate the first clear evidence of a dangerous association between Superfunds and healthcare, and encourage the urgent prioritization of Congressional policies that optimize investment in Superfund site clean up for public health. [Table: see text]
Health equity in multi-cancer early detection (MCEDs): A literature review and content analysis.
Authors: Rosa Negash, Chyke Doubeni, John F.P. Bridges, Norah L Crossnohere
Journal: Journal of Clinical Oncology (2024)

10549 Background: Multi-cancer early detection tests (MCEDs) are an emerging screening technology to identify biomarkers of up to 50 different types of cancer using a single blood sample. While there is potential for MCEDs to advance health equity in cancer screening, considerations for how to do so are not established. We sought to identify emerging health equity themes related to MCEDs, and to explore where along the MCED evaluation process they have been considered. Methods: We conducted a targeted review of white and grey literature to identify references discussing health equity and MCEDs. We searched PubMed and Google Scholar from 2015-2024, using key search terms including “MCEDs,” “health equity,” and “diversity, equity and inclusion.” We used thematic analysis to identify health-equity related themes raised across included records. We then used content analysis to describe where these themes arose along the phases of cancer screening evaluation described by the CanTest Framework (product design, test performance, clinical feasibility, clinical effectiveness, and screening implementation). Results: We identified 22 records for inclusion, which varied in their content and depth when exploring health equity considerations for MCEDs. Thematic analysis of the records revealed five overarching health equity themes: access, acceptability, affordability, bias, and disparities. Acceptability, which included topics such as patient preference and measuring benefit/harms, and disparities, such as racial/ethnic differences in cancer deaths, were the most discussed themes (55% of records; Table). Bias, including provider discrimination, was the least discussed theme (32% of records). Content analysis revealed that health equity themes mostly arose across cancer screening evaluation phases of clinical feasibility, effectiveness, and implementation (82%, 73%, 64% of records respectively). No records explored health equity themes of acceptability, access, or bias in the product design phase (0%). Conclusions: Current literature considering health equity for MCEDs consistently address equity aspects related to clinical feasibility, clinical effectiveness, and implementation, but generally fails to consider health equity in early phase evaluation. Increasing consideration of health equity across all phases of the screening lifecycle is crucial if MCEDs are to advance health equity.[Table: see text]