Importance:With increased payer coverage and the advent of antiamyloid therapies, clinical use of amyloid positron emission tomography (PET) is likely to increase to help guide the diagnosis and treatment of patients with cognitive impairment. However, unlike most previous research studies, in clinical practice, scan acquisition is less standardized, interpretation typically relies purely on visual reads rather than scan quantification, and patients have more frequent comorbidities, all of which might compromise test accuracy. Objective:To compare visual interpretation of amyloid-PET in real-world clinical settings to scan interpretation based on central quantification, in order to assess the accuracy of clinical reads. Design, Setting, and Participants:This cross-sectional quality improvement study used data from the Imaging Dementia-Evidence for Amyloid Scanning study, collected between February 2016 and January 2018 and analyzed between December 2021 and April 2023. The setting included 294 imaging facilities in the US. Medicare beneficiaries 65 years or older with cognitive decline for whom Alzheimer disease was a diagnostic consideration were recruited by dementia specialists from their clinical practices. Exposures:Amyloid-PET with [18F]florbetapir, [18F]florbetaben, or [18F]flutemetamol. Main Outcomes and Measures:PET scans were visually interpreted as positive or negative by local radiologists or nuclear medicine physicians following approved guidelines. Independently, scans were centrally processed and quantified using the standardized Centiloid (CL) scale. We applied an a priori autopsy-based threshold of 24.4 CL to quantitatively define scan positivity. Results:Of 18 293 participants included in the parent study, scan images were available for 10 774 (59%), of which Centiloids were successfully calculated for 10 361 (96%). Median (IQR) patient age was 75 (71-80) years; 5245 patients (51%) were female, 6500 (63%) had mild cognitive impairment, and 3861 (37%) had dementia). Participants self-reported the following races and ethnicities: 1 Alaska Native (0%), 23 American Indian (0.2%), 188 Asian (1.8%), 316 Black (3.1%), 449 Hispanic or Latino (4.3%), 8 Native Hawaiian or Other Pacific Islander (0.1%), and 9125 White (88.2%). A total of 6332 scans (61%) were visually read as positive, and 6121 (59%) were quantitatively positive. Agreement between visual reads and quantitative classification was 86.3% (95% CI, 85.7%-87.0%; Cohen κ = 0.72; 95% CI, 0.70-0.73). A total of 5519 (53%) scans were positive visually and quantitatively (V+/Q+), 3416 (33%) were negative by both (V-/Q-), 813 (8%) were V+/Q-, and 602 (6%) were V-/Q+. Female sex (female: 4581/5241 [87.4%]; male: 4354/5109 [85.2%]; P =.001), White race (White race: 7900/9125 [86.6%]; non-White race: 1035/1225 [84.5%]; P =.046), and use of [18F]flutemetamol and [18F]florbetaben ([18F]flutemetamol: 559/628 [89.0%]; [18F]florbetaben: 2664/3032 [87.9%]; [18F]florbetapir: 5712/6690 [85.4%]; P <.001), compared with [18F]florbetapir, were associated with higher visual-quantitative concordance. Scans within a 10- to 40-CL borderline positivity zone were more likely to be discordant. Conclusions and Relevance:This cross-sectional study found high concordance between local visual reads and central quantification of clinical amyloid-PET scans, supporting the validity of amyloid-PET visual reads in real-world clinical practice.

INTRODUCTION:The New Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study (NCT04426539) evaluated the association between amyloid positron emission tomography (PET) and changes in clinical management among ethnoracially diverse, clinically heterogeneous patients. METHODS:We assessed diagnosis and management plan before and 90 ± 30 days after amyloid PET among Medicare beneficiaries who met 2018 National Institute on Aging-Alzheimer's Association criteria for mild cognitive impairment (MCI) or dementia. We aimed to identify ≥ 30% change in a composite patient management endpoint (CPME; i.e., changes in Alzheimer's disease [AD]/non-AD medications, changes in counseling). RESULTS:Among 5757 participants (median age 75 years; 21.7% Black, 20.3% Latinx, 58.1% all other races/ethnicities [AORE]), a change in CPME occurred in 59.0% (95% confidence interval 57.6%-60.5%) of individuals post PET. Change varied by ethnoracial identity and type of clinical presentation: Black (MCI: 55.3%, dementia: 55.8%), Latinx (MCI: 53.7%, dementia: 61.9%), AORE (MCI: 62.0%, dementia: 58.3%), typical (MCI: 64.8%, dementia: 60.9%), atypical (MCI 45.5%, dementia: 53.6%). DISCUSSION:Amyloid PET is associated with clinical management among diverse, clinically heterogeneous populations. HIGHLIGHTS:Changes in management plan occurred in 59% of patients 90 days after amyloid positron emission tomography. Rates of change in management exceeded the pre-specified goal of > 30% across ethnoracial groups. Rates of change in management also exceeded > 30% among amnestic and non-amnestic Alzheimer's disease presentations.

Background: The primary aim of the Tomosynthesis Mammographic Imaging Screening Trial (TMIST) is to determine whether women randomly assigned to be screened through 3-5 rounds with tomosynthesis (TM) have fewer advanced cancers than the population screened with digital mammography (DM) over 3-8 years after entry. In addition, there are 15 secondary aims with data being collected in the areas of imaging assessment, medical physics, breast biology and pathology, long-term follow-up, and health care utilization. Women ages 45 to 74 are eligible to participate. The study will enroll 108,508 women. Participants may also volunteer to contribute blood and/or buccal smears to the TMIST biorepository. Approximately 70% of TMIST participants have agreed to do so. Because of the size of the TMIST study and vast amount of data to be collected, there is an opportunity for investigators to utilize TMIST data to support various research questions not covered in TMIST. Methods:The TMIST study team developed a process where investigators who would like access to the TMIST data can submit a concept while the trial is ongoing for access to data in a protected manner. The process starts with the project investigator reaching out to the TMIST study chair. If the study chair, lead statistician, and ECOG-ACRIN (EA) co-Principal Investigator think the project has promise; a timeline for when the project could take place (either (1) during the TMIST clinical trial or (2) after the end of the trial and publication of the primary paper) is developed. The next steps involve reviews by the TMIST Data Safety and Monitoring Board and the EA Executive Review Committee. All ancillary projects proposed will require an external funding plan and budget before the project moves out of concept review inside of EA. Once the project concept clears all required EA approvals it then goes to the National Cancer Institute (NCI) Division of Cancer Prevention (DCP) for their approval. NCI Central Institutional Review Board (CIRB) approval is also required for the project to start while the trial is still active but is not sought until funding has been received. Two projects have secured external funding, have completed the EA committees’ review processes, and have received NCI approval. One is a case control study assessing short-term breast cancer risk through image-based analysis of screening mammograms (Project PI: Jon Steingrimsson, PhD, Brown University). The second is a case control study to assess the impact of breast compression pressure versus force in screening mammography on the likelihood of developing interval breast cancers (Project PIs: Etta Pisano, MD and Aili Maki, PhD, University of Toronto). Both projects involve analysis of images where software is being applied to TMIST images on computer systems controlled by EA IT personnel. Both projects are expected to be completed in the next year. Two additional projects have been approved for grant submission through the process described above. The PreSCRiB study (PI: Elizabeth Burnside, MD MPH, U of Wisconsin) will utilize Machine Learning applied to TMIST and All of Us data, including genetics, mammograms, social determinates of health and other data to develop individualized screening strategies for women. The second project (PI; Marc Ryser, PhD, Duke University) will utilize TMIST data to validate an algorithm the investigators have developed to assess overdiagnosis. Another project that is in development and will likely be submitted for approval and funding in the next 6-9 months is a collaboration between TMIST and UK-based clinical trial PROSPECTS study teams to compare rates of all cancers and advanced cancers for annual, biennial, and 3-year screening, with analysis by age, race, ethnicity, breast density and other factors. The ongoing TMIST study, as of June 24, 2024, has enrolled 101,394 women. Total enrollment is expected by late 2024 or early 2025. Follow-up on enrolled participants is expected to end in early 2028. Citation Format: Etta Pisano, Constantine Gatsonis, Mitchell Schnall, Melissa Troester, Elodia Cole , Jean Cormack, Jon Steingrimsson, Ilana Gareen, Martin Yaffe, Laura Collins, Amarinthia Curtis, Ruth Carlos, Kathy Miller, Christopher Comstock. Conducting Ancillary Studies during an Active NCTN/NCORP Screening Trial – The TMIST (ECOG-ACRIN EA1151) Experience [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-01-05.

The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study demonstrated that amyloid PET changes patient management in >60% of Medicare beneficiaries with MCI/atypical dementia. IDEAS had limited racial/ethnic diversity and excluded patients with “typical” amnestic clinical presentations. Here we present preliminary results from the New IDEAS study, which evaluates the clinical impact of amyloid PET in a more racially, ethnically and clinically diverse cohort. Launched in December 2020, the New IDEAS study (NCT04426539) is recruiting Medicare beneficiaries with typical (amnestic) and atypical (non-amnestic) MCI/dementia at 142 dementia specialty clinics across the U.S. Multifaceted, community-engaged and culturally-tailored strategies are implemented to enhance the diversity of the cohort. Based on self-identified race/ethnicity, patients are enrolled into 1 of 3 cohorts: Black/African-American (BAA), Latino/Hispanic (LAT), or not BAA or LAT (NBL, all other racial/ethnic identities). Patients undergo amyloid PET using an FDA-approved tracer with local visual read at 127 imaging facilities. Changes in management are measured between the pre-PET visit (intended management, assuming no access to amyloid PET) and 90-day post-PET visit (implemented management, incorporating amyloid PET results). A composite management endpoint captures changes in one or more of the following: AD drug therapy, non-AD drug therapy, counseling about safety and future planning. Out of 5,209 registered participants, 3,328 (63.9%) participants completed amyloid PET, pre- and post-PET visits at time of analysis (median age 74; 55.2% female; 22.6% BAA/17.5% LAT). Demographic and clinical features by cohort are shown in Table 1. Compared to NBL, BAA and LAT cohorts presented with greater clinical impairment, more frequent atypical clinical presentations and lower rates of amyloid PET positivity. Changes in the composite management endpoint occurred in 57.5% of all participants (57.2% MCI, 58.1% dementia), with similar rates across cohorts (Table 2). Following PET, anti-amyloid antibodies were newly recommended in 7.0% of BAA, 7.4% of LAT and 9.0% of NBL. Changes in management were more frequent in typical than atypical clinical presentations (Table 3). These preliminary findings highlight the clinical utility of amyloid PET in a diverse and representative sample of cognitively impaired patients recruited in real-world practice.

CLINICAL TRIAL REGISTRATION:NCT05710328.

The variability in the regional distribution of Aβ-PET signal and its relation to clinical features is debated. We used data-driven approaches to uncover heterogeneity in cortical Aβ-PET signal from a large representative sample collected through the IDEAS study. We analysed cross-sectional Aβ-PET collected from 10,361 patients with MCI or mild dementia scanned in 295 PET facilities using one of the 3 FDA-approved tracers. Central image processing resulted in template-space SUVR images (reference: whole cerebellum) and centiloid (CL) values. Spatial independent component analysis was used to decompose SUVR volumes into 40 independent components. After excluding noise components, participants’ scores were extracted for each of the remaining 11 grey matter (GM) components describing cortical and subcortical binding. K-means clustering was used on these GM component scores to assign each participant to different Aβ-PET clusters based on GM binding (Figure 1). Three informative clusters of PET binding were estimated. Cluster 1: Aβ-(n=4729, CL mean=2±23) with low GM binding, and two Aβ+ clusters; Cluster 2(n=2484, CL mean=76±34) and Cluster 3(n=3148, CL mean=86±32). Subtracting average SUVR of Clusters 2 and 3 showed they differed along a posterior-anterior gradient with Cluster 2 showing an occipital predominant pattern. Principal component analysis conducted on the GM scores confirmed two dominant axes of variation separated the clusters, a Aβ- to Aβ+ axis and, an anterior-posterior axis (Figure 2). Statistically significant but weak differences were observed between the two Aβ+ Clusters (2 vs. 3); Visual Read (positive: 95% vs. 92%); Clinical Stage (dementia: 47% vs. 41%); Age (76.9±6.4 vs. 75.9±6.2), however, most clinical variables showed no differences (Figure 3a). 48 ADNI participants with Aβ-PET and post-mortem neuropathology data (11 Female, Age mean=79.7±7.4, PET-Death mean=2.3±1.7years; Aβ-CL mean=71.2±55.5; APOE4(0/1/2)=22/21/5; Diagnosis(CN/MCI/AD)=6/8/32) were applied to the model fit on IDEAS data. Qualitatively, no differences in neuropathology were observed between the two Aβ+ Clusters (Figure 3b). Data driven classification of Aβ-PET reveals two primary axes reflecting Aβ load and anterior-posterior binding, with the later not clearly related to clinical or pathological variation. Future work will apply new data to this model and investigate if this spatial variation in Aβ-PET is related to longitudinal changes in pathology.

Residence in a disadvantaged neighborhood (e.g., high poverty rate, poor housing, etc.) is associated with greater dementia risk and possibly greater postmortem Alzheimer’s pathology. It remains unknown if neighborhood disadvantage is associated with in vivo beta-amyloid positron emission tomography (PET) for Alzheimer’s. We examined this using data from the Imaging Dementia Evidence for Amyloid Scanning (IDEAS) study. IDEAS captured >18,000 PET scans among cognitively impaired Medicare beneficiaries from 595 US dementia clinics between 2016-2018. We defined neighborhood disadvantage using Area Deprivation Index (ADI), a validated composite of 17 social determinants measures captured in American Community Survey and US Census data. IDEAS participant zip code data was linked to census block group for ADI value calculation through geocoding. Association between visual interpretation of PET in IDEAS (positive/negative) and state-level ADI (1-10; 10 being greatest disadvantage) was examined via logistic regression controlling for covariates (age, sex, education, level of impairment (MCI vs dementia), race/ethnicity, comorbid conditions) with cluster adjusted standard errors by practice location. Among 13,961 cognitively impaired participants, 61.6% were amyloid positive, 56.5% had MCI, and 50.4% were female (Table 1). The majority (90.2%) were non-Latino White with 4.7% Latino, 3.2% Black, and 1.9% Asian representation (Table 1). Participants were highly educated (68.1% beyond high school) and 31.0% (4,333/13,961) resided in neighborhoods of greater disadvantage (ADI ≥ 6) (Figure 1). Greater ADI was associated with lower odds of amyloid positivity (aOR 0.61, 95% CI 0.51-0.73, p<.001 for ADI 10 vs ADI 2 and aOR 0.87, 0.76-1.00, p .051 for ADI 2 vs. ADI 1(ref)). Latino (aOR 0.62, 0.48-0.80, p<.001), Black (aOR 0.58, 0.48-0.72, p<.001), and Asian (aOR 0.42, 0.31-0.58, p<.001) identity was associated with lower odds of amyloid positivity along with multiple comorbidities (Table 2). We observed a relationship between residence in a more disadvantaged neighborhood (higher ADI) and lower rates of amyloid positivity. Given this finding and known association between neighborhood disadvantage and postmortem AD pathology, it is possible non-amyloid pathology also contributes towards cognitive impairment among individuals from disadvantaged neighborhoods and among diverse groups. This has implications for clinical use of novel amyloid lowering therapies.

Previous studies on sex differences in amyloid burden have shown inconsistent findings. We examined the effect of sex on amyloid-PET outcomes in a large, real-world, cohort of individuals with cognitive impairment. The IDEAS study evaluated the clinical utility of amyloid-PET in 18,295 Medicare beneficiaries age ≥65 years with MCI or dementia. All scans were visually interpreted as positive or negative at each site by a local radiologist or nuclear medicine physician. A subset of 10,361 scans were centrally processed and quantified in Centiloids. We used multivariate logistic regression to calculate odds ratios of amyloid-PET positivity (based on visual read) for males and females, adjusting for demographic and clinical risk factors. We used linear regression to assess the association between sex and amyloid burden quantified in Centiloids. Of 10,361 included individuals, 51% were females. Compared to males, females were slightly younger (75 versus 76 median age, p=0.008) and had higher rates of dementia (39.3% versus 35.2%, p<0.001). Rates of vascular risk factors were significantly higher in males than females, whereas females had significantly higher rates of history of depression and family history of AD. Females had higher rates of amyloid-PET positivity than males (63% versus 59%, p<.001) and higher Centiloid values (median=48.7 versus 36.9, p<.01); see Figure 1 and Table 1 model 1. Sex differences remained significant in models adjusted for demographics and clinical risk factors (Table 1, models 2-3). In an analysis that included only individuals with visually positive amyloid-PET, females exhibited higher Centiloid values than males (Table 1 multivariable linear models). In amyloid-positive individuals, we found a significant interaction between sex and age, with greatest sex differences in amyloid burden found in the youngest females (Figure 2A). We also found a significant interaction between sex and race, with greatest differences found in Black females vs. males (Figure 2B). Females with cognitive impairment exhibited a higher frequency of amyloid-PET positivity and higher amyloid burden. Our findings shed light on sex-specific biological and potential sociocultural differences in Alzheimer's disease pathology.

This paper explores the design considerations and hurdles encountered by the CHinA National CancEr Screening (CHANCES) Trial and the Tomosynthesis Mammographic Imaging Screening Trial (TMIST), both aimed at advancing cancer screening research. Before population-based cancer screening programs are launched, it is important to have confidence that the potential benefits of the screening process and resulting interventions outweigh harms, an ethical imperative because the people actively invited into the programs are relatively healthy. Large randomized screening trials provide the strongest, direct evidence regarding the balance of benefits and harms. The implementation of cancer screening programs involves a series of steps, with outcomes influenced by factors such as the prevalence of the disease, availability of effective treatment within the health-care system, and acceptance by the target population—all of which may vary considerably from country to country. This paper examines how these factors shaped the design and statistical approach of the CHANCES Trial for lung and colorectal cancers and the TMIST trial for breast cancer. We discuss the rationale, objectives, endpoint definitions, trial designs, and sample size considerations, highlighting both the challenges and opportunities presented in different settings. Ultimately, the goal is to foster collaboration and develop screening strategies that are scientifically robust and practically effective for diverse populations worldwide.

Real-World data platforms for Alzheimer’s Disease (AD) offer a unique opportunity to improve health equity through better understanding of health disparities and inclusivity in research, which is critical to translatability of research findings. AD research in the US and globally remains largely inaccessible to many individuals due to individual-level, study-level, investigator-level and larger systemic barriers. ALZ-NET, a US-based registry to evaluate longitudinal outcomes of patients being evaluated for or treated with novel FDA-approved AD therapy, and New IDEAS, an observational US-based longitudinal study of amyloid PET clinical utility, both offer opportunities for examining care, inclusivity, and disparities. ALZ-NET (Alzheimer’s Network for Treatment and Diagnostics) is a national, provider-enrolled, patient registry collecting longitudinal regulatory grade clinical data. It also features a diagnostic imaging and biospecimen repository. Providers at clinical sites across the US enroll and longitudinally follow patients being considered for Food and Drug Administration (FDA)-approved AD therapies according to local site practice standards. Clinical practice sites across the US are eligible for ALZ-NET participation, allowing a greater diversity of participating patients. Registry data is maintained using centralized, secure electronic data capture and management systems that will allow for co-enrollment of participants into affiliated clinical trials, merging of data with existing databases, and data sharing to facilitate additional research studies. NEW IDEAS (Imaging Dementia - Evidence for Amyloid Scanning) has enrolled cognitively impaired Medicare beneficiaries at memory clinics across the US since 2020. New IDEAS features a dedicated recruitment and engagement strategy that leverages community partnerships and liaisons in 9 targeted, highly diverse US metro areas to specifically address barriers to participation in traditional research. New IDEAS has identified and developed novel methodology that can inform future studies in successfully increasing representation in AD research on a large scale, with >40% of the current patient population consisting of individuals historically not included in research. New IDEAS also offers insights into rates of amyloid pathology by in vivo biomarkers among diverse populations. Real world data platforms like ALZ-NET and New IDEAS serve an important role in fostering greater understanding of health disparities and inclusivity in research to improve care.

Abstract BACKGROUND. Advanced diagnostics such as magnetic resonance imaging (MRI) and gene-expression profiles are potentially useful to guide treatment in patients with ductal carcinoma in situ (DCIS). To evaluate these tests, we performed a prospective single arm multicenter study. We have previously reported the impact of MRI on surgical management of DCIS patients, and the effect of a 12-gene DCIS Score (DS) on radiotherapy (RT) use after wide local excision (WLE). We now report a pre-planned analysis of ipsilateral breast events (IBE) at 5-years. METHODS. Adult women with a core needle biopsy diagnosis of DCIS and eligible for WLE based on conventional imaging were registered following consent. All registered patients underwent breast MRI. Those still eligible, and willing, to receive WLE after appropriate follow-up biopsies underwent resection to free margins. DCIS sections were submitted to Exact Sciences for DS. Those with a low DS (&lt; 39) were advised to omit RT; those with intermediate/high (inter/hi) DS (≥39) were advised to receive RT. All participants were monitored at 6-month intervals for any breast cancer event, and for survival. An IBE was defined as the first DCIS or invasive recurrence in the ipsilateral breast following the final WLE. Participants without IBE were censored by date of last contact or date of death for those who died. Follow-up was truncated at 5 years from WLE. Using data available as of 07-06-2023, Kaplan-Meier (K-M) curves were constructed to estimate the time-to-event distributions for subjects who received RT and for those who did not. The 5-year IBE rates and 95% confidence intervals (CIs) were estimated from K-M curves for all subjects with a DS (analogue of Intention to Treat [ITT] analysis), and for the subset who were compliant with their DS-based RT recommendation (Per Protocol analysis). The analyses were repeated for subgroups based on age at DCIS diagnosis (&lt; 50 vs. ≥ 50). RESULTS. Of 339 women evaluable for the previously reported primary analysis (PMID 30653209), 171 (50.4%) underwent WLE with free surgical margins and had DS available for RT recommendations (ITT population). Of these, 7/82 low DS patients underwent RT, and 5/89 inter/hi DS patients declined RT; thus, the adherence to DS-based RT recommendations was 93%. At a median of 5 years of follow-up from final WLE, the ITT population experienced a total of eight IBE events (4.8%, 95% CI 2.4, 9.4) with 5-year IBE rates that were similar for participants with a low DS and for those with a inter/hi DS: 5.1% (95% CI: 1.9, 12.9) and 4.5% (95% CI 1.7, 11.7), respectively. Stratification by age did not alter these results: among women aged &lt; 50 years (n=33), the IBE rate was 6.7% (95% CI 1.0, 38.7) for low DS and 5.6% (95% CI 0.8, 33.4) for inter/hi DS. Among women aged ≥ 50 years (n=138), the IBE rate was 4.7% (95% CI 1.5, 13.8) for low DS and 4.3% (95% CI 1.4, 12.7) for inter/hi DS. In the per-protocol analysis (N=159 adherent to RT recommendations), IBE rates were also similar for participants who had a low DS and no RT [5.5% (95% CI 2.1, 14.1)] and for those with inter/hi DS who received RT [4.8% (95% CI: 1.8% to 12.3%)]. Again, there was no discernible influence by age as categorized above. CONCLUSION. We report the first prospective data on use of DCIS Score for RT decisions, and 5-year IBE rates. We find that DS-based recommendations are followed by &gt;90% of patients. Although the sample size is limited, the data are reassuring in that the IBE rate is similar between the low DS group treated with WLE alone and the inter/hi DS group treated with WLE and radiation, whereas prior studies have shown a marked difference in IBE rates by DS with excision alone. Therefore, this prospective trial provides strong evidence to support the omission of RT after surgery in DCIS patients with low DS, and its use in patients with intermediate/high DS. Citation Format: Seema Khan, Justin Romanoff, Constantine Gatsonis, Habib Rahbar, Ruth Carlos, Sunil Badve, Jean Wright, Constance Lehman, Worta McCaskill-Stevens, Ralph Corsetti, Derrick Spell, Kenneth Blankstein, Linda Han, Jennifer Sabol, John Bumberry, Ilana Gareen, Bradley Snyder, Lynne Wagner, Kathy Miller, Joseph Sparano, Christopher Comstock. Magnetic Resonance Imaging and a 12-Gene Expression Assay to Optimize Local Therapy for Ductal Carcinoma In Situ: 5-year clinical outcomes of E4112 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-01.

Importance The National Lung Screening Trial (NLST) found that screening for lung cancer with low-dose computed tomography (CT) reduced lung cancer–specific and all-cause mortality compared with chest radiography. It is uncertain whether these results apply to a nationally representative target population. Objective To extend inferences about the effects of lung cancer screening strategies from the NLST to a nationally representative target population of NLST-eligible US adults. Design, Setting, and Participants This comparative effectiveness study included NLST data from US adults at 33 participating centers enrolled between August 2002 and April 2004 with follow-up through 2009 along with National Health Interview Survey (NHIS) cross-sectional household interview survey data from 2010. Eligible participants were adults aged 55 to 74 years, and were current or former smokers with at least 30 pack-years of smoking (former smokers were required to have quit within the last 15 years). Transportability analyses combined baseline covariate, treatment, and outcome data from the NLST with covariate data from the NHIS and reweighted the trial data to the target population. Data were analyzed from March 2020 to May 2023. Interventions Low-dose CT or chest radiography screening with a screening assessment at baseline, then yearly for 2 more years. Main Outcomes and Measures For the outcomes of lung-cancer specific and all-cause death, mortality rates, rate differences, and ratios were calculated at a median (25th percentile and 75th percentile) follow-up of 5.5 (5.2-5.9) years for lung cancer–specific mortality and 6.5 (6.1-6.9) years for all-cause mortality. Results The transportability analysis included 51 274 NLST participants and 685 NHIS participants representing the target population (of approximately 5 700 000 individuals after survey-weighting). Compared with the target population, NLST participants were younger (median [25th percentile and 75th percentile] age, 60 [57 to 65] years vs 63 [58 to 67] years), had fewer comorbidities (eg, heart disease, 6551 of 51 274 [12.8%] vs 1 025 951 of 5 739 532 [17.9%]), and were more educated (bachelor’s degree or higher, 16 349 of 51 274 [31.9%] vs 859 812 of 5 739 532 [15.0%]). In the target population, for lung cancer–specific mortality, the estimated relative rate reduction was 18% (95% CI, 1% to 33%) and the estimated absolute rate reduction with low-dose CT vs chest radiography was 71 deaths per 100 000 person-years (95% CI, 4 to 138 deaths per 100 000 person-years); for all-cause mortality the estimated relative rate reduction was 6% (95% CI, −2% to 12%). In the NLST, for lung cancer–specific mortality, the estimated relative rate reduction was 21% (95% CI, 9% to 32%) and the estimated absolute rate reduction was 67 deaths per 100 000 person-years (95% CI, 27 to 106 deaths per 100 000 person-years); for all-cause mortality, the estimated relative rate reduction was 7% (95% CI, 0% to 12%). Conclusions and Relevance Estimates of the comparative effectiveness of low-dose CT screening compared with chest radiography in a nationally representative target population were similar to those from unweighted NLST analyses, particularly on the relative scale. Increased uncertainty around effect estimates for the target population reflects large differences in the observed characteristics of trial participants and the target population.

AbstractAmyloid-PET detects fibrillar β-amyloid deposits, a defining feature of Alzheimer’s disease. This technology has been used in research for over 20 years, and is now used in clinical practice to guide patient diagnosis and management. However, the real-world use of amyloid-PET may differ from research settings due to less standardized acquisition protocols, less experienced visual readers, and patients with more comorbidities, potentially compromising test accuracy. We evaluated the performance of amyloid-PET as used in a real-world clinical setting utilizing data collected via the Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study.The study collected clinical amyloid-PET scans of older adults with cognitive decline acquired in 294 imaging facilities using three FDA-approved radiotracers. We centrally processed these scans using a PET-only processing pipeline and derived summary quantification of cerebral radiotracer retention measured on the Centiloid scale. We applied ana prioriautopsy-based threshold of 24.4 Centiloids to quantitatively define scan positivity and compared this quantitative classification with binary visual reads performed by local radiologists or nuclear medicine physicians.10,350/10,774 scans (96%) passed quality control and were successfully quantified. Median patient age was 75 (interquartile range 71, 80) years, 51% were females, 87% self-identified as White, 63% had mild cognitive impairment (vs. 37% with dementia), and 61% of scans were visually positive based on local reads. Centiloid values were higher in visually positive scans (median=74 [46, 99]) compared to scans locally read as negative (−2 [−13, 12]; p<0.001). Patients with dementia had higher Centiloids than those with mild cognitive impairment (57 [8, 91] vs. 34 [−2, 79]; p<0.001), consistent with a higher visual positivity rate (70% vs. 56%, respectively; p<0.001). Agreement between local visual reads and quantitative classification was 86.3% (95%CI: 85.7%, 87.0%), corresponding to Cohen’s Kappa of 0.715 (95%CI: 0.701, 0.729; p<0.001). Overall, 5,519 [53% of total] scans were positive by both visual read and quantification (V+/Q+); 3,416 [33%] were negative by both (V-/Q-), 813 [8%] were V+/Q-, and 602 [6%] were V-/Q+. Female sex, White race, and use of the radiotracers18F-flutemetamol and18F-florbetaben (compared to18F-florbetapir) were associated with higher visual-quantitative concordance.In conclusion, local visual reads showed high concordance with central quantification of clinical amyloid-PET scans, supporting the validity of amyloid-PET as used in the real world and the use of quantification in clinical settings.

We present methods for estimating loss-based measures of the performance of a prediction model in a target population that differs from the source population in which the model was developed, in settings where outcome and covariate data are available from the source population but only covariate data are available on a simple random sample from the target population. Prior work adjusting for differences between the two populations has used various weighting estimators with inverse odds or density ratio weights. Here, we develop more robust estimators for the target population risk (expected loss) that can be used with data-adaptive (e.g., machine learning-based) estimation of nuisance parameters. We examine the large-sample properties of the estimators and evaluate finite sample performance in simulations. Last, we apply the methods to data from lung cancer screening using nationally representative data from the National Health and Nutrition Examination Survey (NHANES) and extend our methods to account for the complex survey design of the NHANES.

Abstract Background: Strategies to optimize treatment decision-making in early stage HER2-positive breast cancer are a current priority for the oncology and patient advocacy community. Recent studies suggest that early metabolic changes on FDG-PET/CT (imaging biomarker) predict response to HER2-directed therapy. The TBCRC026 trial showed that participants not obtaining a 40% reduction in SULmax by cycle 1 day 15 (C1D15) following neoadjuvant trastuzumab/pertuzumab (HP) were unlikely to obtain pCR [negative predictive value (NPV) 91%]. The ECOG-ACRIN EA1211/DIRECT trial aims to validate FDG-PET/CT as a neoadjuvant interim (niFDG-PET/CT) imaging integral biomarker in patients treated with standard HER2-directed regimens (NCT05710328). Design: EA1211/DIRECT is a multicenter, single-arm, primary imaging phase 2 study enrolling patients with stage II/III HER2-positive breast cancer. Patients undergo standard skull base-thigh FDG-PET/CT at baseline and C1D15 and receive standard of care pertuzumab-based neoadjuvant therapy followed by surgery. Eligibility: Age ≥18 years, ECOG performance status 0-2, stage IIa-IIIc, untreated HER2-positive breast cancer with known hormone receptor status, suitable to undergo FDG-PET/CT imaging and neoadjuvant therapy. Methods: ΔSULmaxD15 will be computed as: (D15 SULmax – baseline SULmax)/baseline SULmax. The primary objective is to estimate the NPV of niFDG-PET/CT for pCR using ΔSULmaxD15 of the primary breast cancer at a threshold of 40%, in patients treated with neoadjuvant HER2-directed therapy. NPV is defined as the probability that pCR will not be achieved by participants with ΔSULmaxD15 < 40%. Secondary endpoints include evaluating the sensitivity, specificity, and positive predictive value of ΔSULmaxD15 of the primary breast cancer at a threshold of 40% and the ability of the niFDG-PET/CT biomarker to predict 3-year event free survival (EFS). Sample Size: We expect that 50% of patients will not reach the ΔSULmax threshold of 40% and a pCR rate of 40-60%. The proposed sample size is 210 participants, adjusted to 235 to account for missing data in 10% of cases. Computation of exact, two-sided 95% confidence intervals (CI) for NPV determined the lower limit of the CI is at least 80% when the true NPV is at least 88%. The lower limit is 84% when the true NPV has the value of 91%, which was estimated in the TBCRC026 study. Current Status: EA1211/DIRECT was activated in May 2023 across the NCI National Clinical Trials Network (NCTN), and accrual is anticipated to complete in March 2025. Those interested in the clinical trial can email ea1211team@ecog-acrin.org. Conclusion: The EA1211/DIRECT trial is the first step in implementing a Response-Guided Treatment Strategy by validating the ΔSULmax threshold of 40% as the optimum cut point across standard of care HER2-directed neoadjuvant regimens. If EA1211/DIRECT meets its objectives, the results will be used to design clinical utility studies, and thus hoping to change practice. Citation Format: Heather Jacene, Constantine Gatsonis, Roisin Connolly, Brian Burnette, Erica Stringer-Reasor, Maeve Hennessy, Justin Romanoff, Alexander Taurone, Ciara O'Sullivan, H. T. Carisa Le-Petross, Courtney Lawhn Heath, Vered Stearns, Amy Fowler, Shou-Ching Tang, Karla A Sepulveda, Angela DeMichele, David Mankoff, Antonio Wolff. ECOG-ACRIN EA1211: Interim FDG-PET/CT for predicting response of HER2-positive breast cancer to neoadjuvant therapy (DIRECT Trial) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-01.

Abstract INTRODUCTION Ductal carcinoma in situ (DCIS) is a non-lethal pre-invasive breast cancer that can co-exist with invasive disease. Dynamic contrast-enhanced (DCE) MRI is sensitive for the detection of high-grade DCIS and invasive cancer while Oncotype DCIS Score is a 12-gene assay that can assess recurrence risk. In practice, it is difficult to distinguish low- from high-risk DCIS, which leads to overtreatment for up to half of women diagnosed with DCIS. We hypothesize that radiomic phenotypes of DCIS derived from DCE-MRI data may serve as prognostic markers to improve risk stratification by capturing disease heterogeneity. Here we evaluate the ability of these phenotypes to predict DCIS Score and upstaging of DCIS to invasive disease on wide local excision in a multicenter trial. METHODS Data: DCE-MRI data from the ECOG-ACRIN E4112 trial were retrospectively analyzed. Primary analysis focused on participants with data on disease upstaging (N=295), with secondary analysis in a subset (N=174) of participants with DCIS Scores (dichotomized as >55 and 55) and pure DCIS. Clinical information included patient demographics, lesion morphology on MRI, background parenchymal enhancement, DCIS grade, central necrosis, and hormone receptor status. Data analysis: Radiologist-drawn lesion segmentations and publicly available software, CaPTk, were used to compute 64 radiomic features from first post-contrast images for each participant. Radiomic phenotypes were identified using hierarchical clustering on the extracted features. A Chi-square test was used to evaluate the association between radiomic phenotypes and each outcome. The likelihood ratio test was used to compare two logistic regression models: 1)clinical model using only clinical information as predictors and 2) clinical+phenotypes model using clinical information and phenotype assignment as predictors. Each model was used for the prediction of upstaging to invasive disease and DCIS score. Model performance was evaluated as the 10-fold cross-validated area under the receiver operator characteristic curve (AUC). A p< 0.05 was considered significant. RESULTS A total of 45 (15%) cases upstaged to invasive disease. Two radiomic phenotypes were identified: Phenotype 1 indicated greater lesion signal heterogeneity, while Phenotype 2 indicated lower heterogeneity. Radiomic phenotype was strongly associated with disease upstaging (p=0.0034) – with a higher rate of upstaging for Phenotype 1 – but not with DCIS score (p=0.1174, Table 1). For predicting disease upstaging, the clinical+phenotypes model yielded a higher AUC=0.72 and a significantly better fit to the data (p=0.0022) compared to the clinical model parameterized by clinical information alone (AUC=0.69). For predicting DCIS Score, the clinical+phenotypes model (AUC=0.77) showed similar performance compared to the clinical model (AUC=0.76) and no significant improvement in fit to the data (p=0.2920). CONCLUSION Radiomic phenotypes capturing disease heterogeneity show promise as prognostic predictors for predicting disease upstaging in DCIS compared to clinical information alone and may enable more efficient disease management. We observed that phenotypes did not have independent predictive outcome for DCIS score, suggesting that MRI and DCIS Score offer independent information and could be combined in future models to better predict disease recurrence or progression. Clinical applications of radiomic phenotypes may improve risk stratification and potentially result in decreased overtreatment of women diagnosed with DCIS. Table 1: Association between radiomic phenotypes and DCIS outcomes using a Chi square test. Citation Format: Kalina Slavkova, Ruya Kang, Vivian Belenky, Anum Kazerouni, Debosmita Biswas, Hannah Horng, Rhea Chitalia, Michael Hirano, Jennifer Xiao, Ralph Corsetti, Sarah Javid, Derrick Spell, Antonio Wolff, Joseph Sparano, Seema Khan, Christopher Comstock, Justin Romanoff, Jon Steingrimsson, Constantine Gatsonis, Constance Lehman, Savannah Partridge, Despina Kontos, Habib Rahbar. MRI Radiomic phenotypes derived from the ECOG-ACRIN E4112 Trial to assess high-risk ductal carcinoma in situ [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-10.