Liu, Minetta C.

PURPOSE In light of evolving evidence that some patients with node-positive estrogen receptor–positive (ER+) disease may receive less benefit from chemotherapy, this study reports 12-year outcomes of the C9741 trial overall, and by the sensitivity to endocrine therapy (SET2,3) test index, a biomarker measuring endocrine transcriptional activity, to identify patients most likely to benefit from dose-dense chemotherapy. METHODS In all, 1,973 patients were randomly assigned to dose-dense versus conventional chemotherapy. Hazard ratios (HRs) for prognosis and for predictive interaction with chemotherapy schedule were estimated from Cox models of long-term disease-free survival (DFS) and overall survival (OS). SET2,3 was tested on the 682 banked RNA samples from ER+ cancers. RESULTS Dose-dense chemotherapy improved DFS in the overall study population by 23% (HR, 0.77 [95% CI, 0.66 to 0.90]) and OS by 20% (HR, 0.80 [95% CI, 0.67 to 0.95]); the benefits of dose-dense therapy were seen for ER+ and ER-negative subsets, without significant interaction between treatment arm and ER status. Low SET2,3 status was highly prognostic, but also predicted improved outcomes from dose-dense chemotherapy (interaction P = .0998 for DFS; 0.027 for OS), independent of menopausal status. Specifically, low endocrine transcriptional activity predicted benefit from dose-dense chemotherapy, whereas tumor burden and proliferation-driven signatures for molecular subtype classification did not. CONCLUSION At 12-year follow-up, C9741 confirmed the sustained long-term benefit of adjuvant dose-dense chemotherapy for node-positive breast cancer. SET2,3 identified patients with ER+ breast cancer who benefited from dose-dense chemotherapy, and specifically, this benefit was predicted by low endocrine activity in the cancer, rather than tumor burden, molecular subtype, or menopausal status.

PURPOSE Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)–positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. METHODS In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. RESULTS After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. CONCLUSION Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

Abstract INTRODUCTION: The Oncotype DX Breast Recurrence Score® (RS) assay is validated to predict risk of distant recurrence at 10 years and the benefit of adjuvant chemotherapy in patients with estrogen receptor (ER)+, HER2- early breast cancer who receive 5 years of endocrine therapy. The feasibility of Oncotype DX® testing with diagnostic core needle biopsies (CNB) was demonstrated through analysis of a large commercial laboratory experience. The neoadjuvant ADAPT study showed the clinical utility of deriving the Recurrence Score® (RS) result from CNB as well. However, data are limited on concordance of RS results from paired CNB and surgical samples. Our primary objective was to determine the degree of concordance of RS results between paired tissue samples from the same primary breast tumor of patients with early stage, ER+, HER2- invasive breast cancer who had a CNB and subsequent surgical excision (SE; lumpectomy or mastectomy) without intervening systemic therapy. METHODS: Patients with a commercial RS result on either CNB or subsequent SE were identified through medical record and clinical database review. A pathologist reviewed archival tissue samples to confirm eligibility and selected the other paired CNB or SE block most representative of the tumor tissue for subsequent study Oncotype DX testing. Descriptive statistics were used to summarize patient and tumor characteristics. Wilcoxon signed rank, McNemar’s and Cochran-Mantel-Haenszel tests were used to compare RS between SE and CNB paired samples. Cohen’s Kappa and 95% confidence intervals (CIs) were used to compare the agreement of categorical RS (0-25 and 26-100) result between SE and CNB paired samples. Lin’s concordance correlation and 95% CIs were used to compare agreement of continuous RS between paired samples. RESULTS: A total of 134 patients were identified with paired CNB and SE samples with a median time of 34 (range 5-103) days between collections. Of the 134 patients, a commercial RS result was available for 25 (18.7%) with CNB and 109 (81.3%) with SE. A study RS result was then generated on the other paired sample. Median age was 62 years (range 33-99; 23 patients [17%] were age ≤50 vs. 111 [83%] age >50). Cases were predominantly node negative (107/134 node negative vs. 26/134 node positive; 1/134 unknown) invasive ductal carcinomas (104/134 ductal vs. 18/134 classic lobular vs. 12/134 other). Mean RS results were 15.6 (range 0-56) and 16.6 (range 0-59) for CNB and SE, respectively (p = 0.003), with no statistically significant differences in RS category defined as low vs. high risk (119/134 CNB vs. 114/134 SE for RS 0-25 and 15/134 CNB vs 20/134 SE for RS 26-100; p = 0.13) or low vs. intermediate vs. high risk (85/134 CNB vs. 78/134 SE for RS 0-17 and 43/134 CNB vs. 48/134 SE for RS 18-30 and 6/134 CNB vs. 8/134 SE for RS 31-100; p = 0.19). No differences were observed based on age relative to 50 years or nodal status (data not shown). Cohen’s Kappa statistic k = 0.64 (95% CI, 0.44-0.83) supports substantial agreement between the CNB and SE samples. Lin’s concordance correlation coefficient (CCC) demonstrates similar agreement for the continuous RS result between paired samples (CCC = 0.86 [0.80-0.90]). Overall percent agreement was 91.8% (87.1-96.4%). CONCLUSIONS: Studies evaluating the level of concordance of ER, progesterone receptor, and HER2 biomarker status between CNB and SE samples have found high concordance rates, albeit varied. We now provide data demonstrating high concordance of RS results between CNB and SE specimens obtained from the same breast primary tumor without intervening systemic therapy. This supports use of either biopsy source for testing with a genomic predictor to identify those patients who will most likely benefit from chemotherapy and which patients may be spared. Citation Format: Aziza Nassar, Jodi Carter, Paige Innis, Satish Seerapu, Christy Russell, Helena Hanna, Abigail Lochala, Minetta Liu. Concordance analysis of paired breast cancer core needle biopsies and surgical excision samples using the Oncotype DX Breast Recurrence Score® assay [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 PO4-08-09.

Abstract Background: Neoadjuvant immunotherapy (IO) has become standard of care for early-stage triple negative breast cancer (TNBC). I-SPY2 was the first randomized trial to examine the efficacy of IO therapy in high-risk HR+HER2- breast cancer, where most IO arms showed improved efficacy relative to control. We also previously showed immune-gene expression signatures associate with pathologic complete response (pCR) in HR+HER2- treated with IO; and developed a clinically applicable Immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the Response Predictive Subtypes. Here we report the performance of ImPrint in HR+HER2- patients from 5 IO arms. Methods: 204 HR+HER2- (MammaPrint high risk) patients from 5 IO arms (anti-PD1, anti-PDL1/PARPi, anti-PD1/TLR9 dual-IO, and anti-PD1 +/- LAG3 dual-IO) and 191 patients from the control arm were included in this analysis. Patients were classified ImPrint+ (likely sensitive) vs. ImPrint- (likely resistant), by Agendia, Inc, using pre-treatment mRNA. Performance of ImPrint for predicting pCR to IO was characterized and compared to that of MammaPrint (ultra) High2 risk (MP2) and tumor grade (III). Based on the DRFS of pCR vs. non-pCR HR+HER2-/ImPrint+ patients (median follow up ~4.5yr), we predicted the DRFS in the IO vs. control arms using an exponential model as a function of the pCR rates. Results: Overall, the pCR rate over the 5 IO arms was 33%. 28% of HR+HER2- patients were ImPrint+; and pCR rates with IO were 76% in ImPrint+ vs. 16% in ImPrint-, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint-. Based on the pCR rates in the IO vs. control (76% vs. 33%), the predicted DRFS of HR+HER2-/ImPrint+ patients are 91% vs 80% at 5 years, respectively. This translates to a risk reduction of 52% for the IO arm relative to standard chemotherapy in HR+HER2-/ImPrint+ patients. We also compared MP2 and tumor grade (III) to ImPrint+ as pCR predictors, as these markers have been used or proposed as selection markers for neoadjuvant IO trials in HR+HER2-. The pCR rates for MP2, Grade III, at 56%, 45%, respectively, are much smaller than that for ImPrint+ at 75% pCR; thus ImPrint appears to be a more precise predictive biomarker for neoadjuvant IO therapy in the HR+HER2- breast cancers. Conclusion: These results suggest that a subset of high risk HR+HER2- breast cancers is highly sensitive to immunotherapy, and by using a specific and sensitive selection strategy patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (i.e., pCR rate > 65-70%). ImPrint, an FDA IDE-enabled assay currently being further evaluated in I-SPY2, may represent the way to identify patients for IO that best balances likely benefit vs risk of serious immune-related adverse events. Citation Format: Denise M. Wolf, Christina Yau, Lajos Pusztai, Rita Nanda, Jo Chien, Erica Stringer-Reasor, Rebecca Shatsky, Claudine Isaacs, MInetta Liu, Hyo Han, Hatem Soliman, Michael Campbell, Annuska Glas, Andrei Barcaru, Lorenza Mittempergher, Midas Kuilman, Lamorna Brown Swigart, Gillian Hirst, Hongmei Yu, Philip Beineke, Amrita Basu, I-SPY2 Investigators, Douglas Yee, W. Fraser Symmans, Angela DeMichele, Jane Perlmutter, Amy Delson, Laura Huppert, Hope Rugo, Amy Clark, Nola Hylton, Paula Pohlmann, Laura Esserman, Laura van 't Veer. Immune subtyping identifies a subset of HR+HER2- early-stage breast cancer patients with a very high likelihood of response to neoadjuvant immunotherapy (IO): Results from 5 IO arms of the I-SPY2 TRIAL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1207.

Introduction: Nearly 50-60% of the patients withDiffuse large B-cell lymphoma (DLBCL) can be cured by front line chemoimmunotherapy. Current risk stratification modalities include cell-of-origin (germinal center (GCB) or non-GCB (activated B-cell [ABC])) subtyping, use of the revised International Prognostic Index (R-IPI), Ki-67 proliferation index assessment, and cytogenetic aberration detection. However, a novel approach for molecular residual disease (MRD) detection and treatment monitoring is needed to improve patient outcomes. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA in a prospective clinical cohort of patients with DLBCL. Serial ctDNA testing was performed at various time points collected at the treating physician's discretion, including pretreatment (baseline), during first-line therapy, during and post-salvage therapy, at the end of treatment, and during surveillance, up to the last clinical follow-up. ctDNA clearance was defined as change in ctDNA status (positive to negative) from the pre-treatment time point to the subsequent time point. Event-free survival (EFS) was defined as the time elapsed since the initial ctDNA clearance or PET imaging, for those without ctDNA clearance, during which the patient did not experience progression, death or treatment with salvage therapy. EFS was censored at the last date of followup if the patient was alive and without an event. Overall survival (OS) was defined as the elapsed time after primary treatment until death from any cause. Univariate and multivariable models were analyzed using Cox proportional models. Results: In this retrospective evaluation of commercial ctDNA testing in patients with stage I-IV DLBCL, a total of 50 patients (I:3, II:12, III: 4, and IV: 29;median age: 59 years) were analyzed. Patients were followed up for a median of 12.68 months (inter quartile range: 7.9-17.7 months). Of the 50 patients, 41 had pre-treatment (baseline) time points available and ctDNA was detected in 95% (39/41) of patients. Since the majority of the patients had stage IV disease, median ctDNA detection levels were observed to be high (overall median: 534 MTM/ml, range: 0-5957 MTM/ml; I median: 9.6 MTM/mL [range: 0.2-2822 MTM/mL], II median: 53 MTM/mL [range: 0.8-862 MTM/mL], III median: 368 [range: 2-940 MTM/mL], IV median: 1011 MTM/mL [range: 74-5958 MTM/mL]). Clearance of ctDNA at any point during first-line therapy was associated with improved outcomes (EFS, HR: 8.3, 95% CI: 2.56-27.0, p<0.0001 and OS, HR: 15.2, 95% CI: 1.53-149, p=0.0021), compared to patients who remained ctDNA-positive. Furthermore, 48% (13/27) of patients were found to clear their ctDNA upon the completion of the first cycle of treatment. On comparing baseline ctDNA levels with other clinicopathological risk factors, high ctDNA levels were observed to be strongly correlated with higher R-IPI scores (0-2 vs. 3-5; p=0.0008) and higher stage (I-II vs. III-IV; p=0.0007). Additionally, multivariate analysis determined that ctDNA clearance significantly outperformed all other clinicopathologic risk factors associated with EFS (HR: 48.8, 95% CI:1.2-2005, p=0.04). Finally, ctDNA clearance predicted complete response (CR)/no evidence of disease (NED) on average 95 days (range: 0-14.7 months) ahead of PET imaging or biopsy. Conclusions: In this study utilizing a real-world cohort of patients with stage I-IV DLBCL, ctDNA clearance during first-line therapy was prognostic for EFS and OS and preceded clinical response. ctDNA testing in patients with DLBCL may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.

Abstract Cancer is a significant burden worldwide that adversely impacts life expectancy, quality of life, health care costs, and workforce productivity. Although currently recommended screening tests for individual cancers reduce mortality, they detect only a minority of all cancers and sacrifice specificity for high sensitivity, resulting in a high cumulative rate of false positives. Blood-based multicancer early detection tests (MCED) based on next-generation sequencing (NGS) and other technologies hold promise for broadening the number of cancer types detected in screened populations and hope for reducing cancer mortality. The promise of this new technology to improve cancer detection rates and make screening more efficient at the population level demands the development of novel trial designs that accelerate clinical adoption. Carefully designed clinical trials are needed to address these issues.

ImportanceAurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i–resistant MBC is unknown.ObjectiveTo assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC.Design, Setting, and ParticipantsThis phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)–negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (<10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022.InterventionsAlisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2).Main Outcomes and MeasuresImprovement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%.ResultsAll 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]).Conclusions and RelevanceThis randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i–resistant MBC. The overall safety profile was tolerable.Trial RegistrationClinicalTrials.gov Identifier: NCT02860000

Abstract Background: The ATEMPT trial primary analysis found that one year of adjuvant trastuzumab emtansine (T-DM1) achieved a 3-year iDFS of 97.8% for patients with stage I HER2+ breast cancer, but was not associated with fewer clinically relevant toxicities (CRTs) compared with paclitaxel and trastuzumab (TH). In this end-of-study analysis, we report 5-year survival outcomes and correlative analyses from the trial. Methods: Patients with stage I centrally confirmed HER2+ breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for one year or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or paclitaxel 80 mg/m2 IV with weekly trastuzumab IV followed by trastuzumab for 9 months. The co-primary objectives were to compare the incidence of CRTs between the 2 arms and to evaluate iDFS in patients receiving T-DM1. To investigate proteomic correlates of recurrence, spatial proteomic analyses were performed on samples from 13 patients experiencing iDFS events (cases) and 24 matched controls using the NanoString GeoMx Digital Spatial Profiler. The impact of HER2 heterogeneity on outcomes was investigated among 17 cases and 51 matched controls by fluorescence in-situ hybridization (FISH). HER2 genetic heterogeneity was assessed by scrutinizing the whole tumor area and defined as the occurrence of HER2 gene amplification in >5% but < 50% invasive tumor cells. The risk of recurrence was evaluated centrally with the HER2DX genomic assay from 225 primary tumor samples. Germline whole genome sequencing (WGS) was conducted among 55 patients experiencing T-DM1-induced thrombocytopenia and/or bleeding and 55 matched controls to identify genomic correlates for this side effect. Results: A total of 497 patients who initiated protocol therapy were included in this analysis (383 T-DM1 and 114 TH). After a median follow up 5.8 years, among patients receiving T-DM1 there were a total of 11 iDFS events, with 3 distant recurrences. The 5-year iDFS for T-DM1 was 97.0% (95% CI, 95.3-98.8%), the 5-year recurrence-free interval (RFI) was 98.6% (95% CI: 97.4-99.8%) and the 5-year overall survival (OS) for T-DM1 was 97.8 % (95% CI, 96.3-99.3%). Although the study was not powered to evaluate the efficacy of TH, among the 114 patients receiving TH, a total of 9 iDFS events were observed, including 2 distant events; the 5-year iDFS with TH was 91.3% (95% CI: 86.0-96.9%), 5-year RFI was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95% CI: 95.2-100%). A total of 56 samples were evaluable for heterogeneity analyses, among which 14% (n=8) harbored HER2 genetic heterogeneity. Spatial proteomic analyses found that NF1 (adjusted p=0.72 × 10-6) and CTLA-4 (adjusted p=0.15 × 10-3) were significantly upregulated in primary samples from cases, while cleaved caspase 9, CD25, GITR, ICOS, p53 and PD-L2 were significantly upregulated in controls (all with adjusted p< 0.05). Germline WGS found that the top gene associations with thrombocytopenia and thrombocytopenia or bleeding were ALMS1 (p=0,19 × 10-3) and APBA3 (p=0,23 × 10-3), respectively, although none reaching the threshold for genome wide significance. rs62143195 and rs114169776 were the top single nucleotide polymorphisms associated with thrombocytopenia and thrombocytopenia or bleeding, respectively. Data on the impact of HER2 heterogeneity and of HER2DX score on survival outcomes will be presented. Conclusion: With longer follow-up, adjuvant T-DM1 confirmed outstanding long-term outcomes among patients with stage I HER2+ breast cancer, demonstrating a 5-year RFI of 98.6%. Spatial proteomic analyses identified a potential association between NF1 and CTLA-4 expression with recurrence. Details on the impact of HER2 heterogeneity and HER2DX assay on prognosis will be presented. Citation Format: Paolo Tarantino, Nabihah Tayob, Chau T Dang, Denise Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Audrey Merrill Garrett, Paul K. Marcom, Kathy S. Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta C. Liu, Kathryn Ruddy, Yue Zheng, Romualdo Barroso-Sousa, Adrienne Waks, Michelle K. DeMeo, Molly K. DiLullo, Giuseppe Curigliano, Harold Burstein, Ann Partridge, Eric Winer, Giuseppe Viale, Winnie Hui, Elizabeth A. Mittendorf, Bryan P. Schneider, Aleix Prat, Ian Krop, Sara Tolaney. Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-01.

There are four solid tumors with common screening options in the average-risk population aged 21 to 75 years (breast, cervical, colorectal, and, based on personalized risk assessment, prostate), but many cancers lack recommended population screening and are often detected at advanced stages when mortality is high. Blood-based multi-cancer early detection tests have the potential to improve cancer mortality through additional population screening. Reported here is a post-hoc analysis from the third Circulating Cell-free Genome Atlas substudy to examine multi-cancer early detection test performance in solid tumors with and without population screening recommendations and in hematologic malignancies. Participants with cancer in the third Circulating Cell-free Genome Atlas substudy analysis were split into three subgroups: solid screened tumors (breast, cervical, colorectal, prostate), solid unscreened tumors, and hematologic malignancies. In this post hoc analysis, sensitivity is reported for each subgroup across all ages and those aged ⩾50 years overall, by cancer, and by clinical cancer stage. Aggregate sensitivity in the solid screened, solid unscreened, and hematologic malignancy subgroups was 34%, 66%, and 55% across all cancer stages, respectively; restricting to participants aged ⩾50 years showed similar aggregate sensitivity. Aggregate sensitivity was 27%, 53%, and 60% across stages I to III, respectively. Within the solid unscreened subgroup, aggregate sensitivity was >75% in 8/18 cancers (44%) and >50% in 13/18 (72%). This multi-cancer early detection test detected cancer signals at high (>75%) sensitivity for multiple cancers without existing population screening recommendations, suggesting its potential to complement recommended screening programs. Clinical trial identifier: NCT02889978.