RISE UP (Revolutionizing Investigations to StEp Up Prevention) for breast cancer brought together leading cancer specialists, women’s health providers, basic and population scientists, regulators, politicians, industry leaders, patient advocates, and more from around the world to discuss and chart a radical rethinking of breast cancer prevention and risk reduction through a lens of hormonal management across a woman’s life course. The presentations at RISE UP were organized to outline a path forward by leveraging what we know about breast cancer biology, early detection, treatment, and endocrine therapy toward a better and sustainable approach for breast cancer prevention. Important conference considerations were to expand our thinking about prevention by broadly considering how the hormonal environment during different life phases or common benign conditions could be better managed to minimize breast cancer risk. This set the stage for transitioning to advances in risk prediction, promising risk-reducing agents, and biomarker-driven trials to test them. Biomarker-based trials discussed focused on 1) lower or intermittent doses of standard prevention agents, 2) drugs already approved for other health purposes, and 3) maximizing benefits from lifestyle interventions alone or in combination. Throughout RISE UP, there was a strong focus on promoting health equity, including comprehensive reproductive health access, equitable representation in clinical trials, and strategies to educate women, providers, and advocates about disparities in care and how to successfully reduce them. The meeting concluded with a competition for innovative approaches to breast cancer prevention that could be integrated into hormonal and women’s health interventions. RISE UP was an innovative conference that provided a forum for cross-cutting topics in women’s health that do not currently exist. The insights shared at RISE UP will be paradigm shifting in breast cancer prevention and women’s health space in the years to come.

610 Background: The adverse event (AE) landscape in oncology is changing due to the introduction of immunotherapy and antibody drug conjugates. These AEs come with both short and long-term symptoms that significantly impact patient quality of life. Monitoring for early onset of symptoms could optimize therapy for a particular patient, maximizing potential efficacy while mitigating toxicity. It is also possible that some toxicities are directly associated with drug sensitivity. We sought to identify symptoms associated with pathologic complete response (pCR) using patient-reported outcomes (PROs) in early-stage high-risk breast cancer patients. Methods: Our study population included 288 stage II/III high-risk breast cancer patients enrolled on the I-SPY2 trial from 2021-2024, who received novel neoadjuvant therapies ± standard paclitaxel. pCR was assigned if tumor was absent in breast and nodes at surgery following neoadjuvant treatment. Patients (n = 288, pCR rate = 29%, 89% administered immunotherapy) were sent electronic PROs. 33 patient-reported AEs were measured using NCI's Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE). Each symptom was evaluated using severity, frequency, and interference on a Likert Scale. Presence of early PRO symptoms (cycles 1-3 of treatment) were binarized (at least one of moderate or greater), and odds ratios were computed with pCR as outcome. To assess whether higher grade AEs were enriched in patients that achieved a pCR, we also performed the Wilcoxan rank sum test using maximum (worst) symptom severity. Results: Of 288 patients included in our analysis (median age = 48 years, range = 20-78), 203 (70.5%) were White, 17 (5.9%) were Asian, 33 (11.5%) were Black or African American, and 35 (12.2%) were Hispanic. PRO analysis revealed that patients that had moderate to severe muscle pain (27% vs 10% OR = 3.15, p < 0.05), joint pain (22% vs 8% OR = 3.23, p < 0.05), headache (27% vs 12.5% OR = 2.59, p < 0.05), or mouth/throat sores (16% vs 5% OR = 3.56, p < 0.05) within weeks 1-3 had higher odds of achieving a pCR. When we looked at maximum severity between weeks 1-3, patients that achieved a PCR had higher grade muscle pain (p = 0.04), heart palpitations (p = 0.035), and significantly lower grade numbness and tingling (p = 0.002). Beyond 6 weeks, associations were weaker or insignificant. Conclusions: Our study utilizes an analysis framework that was able to determine sentinel symptoms such as muscle and joint pain, mouth/throat sores and palpitations as early as weeks 1-3 associated with increased efficacy. This may suggest an early immune reaction in patients that eventually respond favorably to treatment. Our work can help provide earlier proactive monitoring to mitigate toxicities, treatment redirection if needed, and a potential symptom-based early understanding to personalize treatment efficacy. A similar analysis is underway to predict immune related AEs. Clinical trial information: NCT01042379 .

Importance:Molecular analyses of biospecimens collected from study participants are essential for identifying biomarkers that can tailor treatments to specific subsets of patients who are most likely to benefit. Sharing of data and biospecimens from clinical trials enables personalized, patient-centric use of cancer therapies and accelerates the development of new treatments. Objective:To describe obstacles to sharing data and biospecimens and to propose strategies to enhance access and collaboration. Evidence Review:This is a Special Communication authored by 53 academic investigators and patient representatives from the breast cancer community with extensive experience in conducting clinical and translational research. The article also evaluates the impact of biomarker research on specifying responsive subpopulations in the 29 registrational clinical trials that have led to approval of a new drug for treatment of breast cancer between 2017 and 2024. Findings:Clinical trial participants are increasingly asked to provide tissue and/or body fluid biospecimens for biomarker research that is typically controlled by the sponsoring pharmaceutical company, but published biomarker studies are rare. Among 29 breast cancer registrational studies reported in the past 8 years, none resulted in biomarker research that restricted a drug's approved indication. Herein, strategies to maximize the value of clinical data and biospecimens contributed by participants are proposed, thereby supporting the shared goals of the pharmaceutical industry and academia to improve patient care. These strategies include (1) establishing coleadership structures involving academia and patients in clinical trial design and conduct, (2) ensuring that informed consent forms state that data and biospecimens will be shared with academia for future research, (3) requiring the sharing of clinical data as a condition for regulatory approval, and (4) enabling access to biospecimens and translational research data for independent studies on biomarkers that may indicate drug efficacy and toxicity. Conclusions and Relevance:Data and biospecimen sharing from registrational trials has been suboptimal. Improving clinical data, biospecimens, and biospecimens' related data sharing requires concrete actions and a multidimensional stakeholder approach to accelerate the impact of clinical cancer research on the quality of patient care.

625 Background: I-SPY 2 is a multicenter phase II adaptive platform trial evaluating novel agents for stage II-III high-risk breast cancer using response-predictive subtypes (RPS) and a sequential neoadjuvant treatment design of up to three blocks (A/B/C). Investigational regimens are given in Block A, followed by response-guided escalation to standard-of-care (SOC) therapy (tx) in subsequent blocks or early surgery for responders. Topoisomerase I (TOPO1) inhibition plus PARP inhibition may enhance DNA damage and tumor response. DAN-222 is a tumor-targeted polymeric camptothecin conjugate designed to improve the therapeutic index of TOPO1 inhibition. Based on favorable phase 1 safety and preliminary activity in metastatic breast cancer, DAN-222 plus niraparib was evaluated as Block A tx in HER2− disease. Notably, the neoadjuvant regimen used a higher dose of niraparib (200 mg daily) than the prior phase 1 metastatic study. Methods: Patients (pts) with HER2− breast cancer were randomized to DAN-222 plus niraparib for up to 12 weeks in Block A. Response was assessed by serial MRI and biopsy. Inadequate responders escalated early to SOC tx in Blocks B/C. Primary endpoint was pathologic complete response (pCR). Secondary endpoints included residual cancer burden, safety, early discontinuation, and treatment-strategy performance versus subtype-specific SOC tx controls. Given established PARPi sensitivity in BRCA mut disease, the key objective was to assess clinically meaningful activity of DAN-222 plus niraparib in BRCA wt pts. Accordingly, a prespecified Bayesian interim futility analysis focused on BRCA wt and tested the probability of the true pCR rate after Block A alone exceeded 15% after 50 pts. Results: Fifty pts enrolled from Sep to Dec 2024. In BRCA wt (n=47), estimated Block A pCR was 3%, with posterior probability of 0.02 that that true pCR exceeded 15%, meeting futility criteria and prompting arm closure. Across all blocks, pCR rate was 57% (8/14) for HR-HER2−; 11% (4/36) for HR+ HER2−, largely after SOC tx. 2/3 BRCA mut pts achieved pCR. Treatment strategies initiating with DAN-222 plus niraparib underperformed subtype-specific controls. 68% discontinued Block A early, mainly due to toxicity. Grade ≥3 cytopenias were common: neutropenia (n=25; 50%), anemia (24%), and thrombocytopenia (18%). Cystitis occurred in 36% (1 grade ≥3). Conclusions: Neoadjuvant DAN-222 plus niraparib showed insufficient activity and no treatment-strategy benefit in BRCA wt HER2− breast cancer, underscoring challenges for TOPO1–PARP inhibitor combinations. Although not supported for further development in this setting, these results highlight the strength of I-SPY 2 in rapidly enrolling patients and quickly distinguishing ineffective from promising therapeutic strategies to accelerate progress toward improved outcomes for patients with curable breast cancer. Clinical trial information: NCT01042379 .

Background Immune checkpoint inhibitors can result in serious, long-lasting immune-related adverse events (irAEs). Early identification of symptoms predictive of irAEs could enhance monitoring and timely intervention. This study assessed whether symptoms within the first 8 weeks of treatment could predict subsequent development of immune-related adrenal insufficiency(AI) or hypothyroidism. Methods This retrospective cohort study analyzed prospectively collected data from the I-SPY2 trial, a phase 2 platform trial for high-risk stage II/III breast cancer across 30 U.S. sites. The cohort included 482 women treated with experimental immunotherapy agents concurrent with weekly paclitaxel neoadjuvant chemotherapy. The primary outcomes were grade ≥ 1 hypothyroidism or AI, adjudicated by an independent safety group, up to 1-year post-treatment. Symptoms and irAEs were assessed using the Common Terminology Criteria for Adverse Events. Symptom burden was quantified as area under the curve (AUC) based on symptom grade and duration. Predictive modeling was performed using logistic regression and ROC analysis; symptom enrichment between cases and controls was evaluated using Fisher’s exact tests. Results Among 482 participants, 107 (22.2%) developed irAEs, with hypothyroidism (n = 61, 12.7%) occurring more frequently than AI (n = 38, 7.9%) at medians of 99 and 105 days from treatment initiation, respectively. Symptom enrichment analysis identified early predictive symptoms. Fatigue (17.2% vs 6.8%, p = 0.011) and rash (20.7% vs 7.8%, p = 0.0037) were predictive of hypothyroidism, while diarrhea (45.9% vs 31%, p = 0.048), constipation (5.4% vs 0.2%, p = 0.018), and taste changes (5.4% vs 0.5%, p = 0.034) were associated with AI. A predictive model demonstrated moderate performance (AUC 0.65 for AI, p < 0.0001; AUC 0.61 for hypothyroidism, p = 0.012). Model accuracy in an external validation cohort was 72.8% for AI and 74.7% for hypothyroidism. Conclusions This study presents a predictive framework to identify patients at risk for adrenal insufficiency and hypothyroidism as irAEs, enabling personalized care and proactive intervention to improve treatment outcomes and safety.

e12755 Background: Pathologic complete response (pCR) is an early endpoint in neoadjuvant breast cancer considered in accelerated approval decisions by the FDA. However trial-level odds ratios of pCR and mature hazard ratios of disease free survival are only weakly associated in meta-analyses, resulting in approvals being delayed until survival evidence becomes available. We used data from the I-SPY 2 trial to develop early endpoints with better trial level correlations to support accelerated approvals. Methods: The I-SPY 2 trial treated 2117 patients with early stage high-risk breast cancer across 26 regimens between 2010 and 2022. When we separate the regimens into groups by subtype, there were 47 total experimental groups (19 HR+HER2-, 19 HR-HER2- and 9 HER2+). Each group is matched to concurrent control group enrolled within 90 days of the enrollment period, forming a experimental/control comparison. Treatment groups with less than 10 patients or insufficient follow-up were excluded, leaving 27 comparisons across 1577 patients. Hazard ratios for event free survival and negative log odds ratios for various early endpoints (e,g, pCR, RCB Class 0 or1) are computed for each experimental/control comparison. Novel early endpoints, including a binary subtype-specific RCB cutoffs, were developed on a training subset, with 5 comparisons held out for validation. The weighted trial-level correlation (R) was calculated overall and in HRHER2 subgroups. Subtype specific RCB cutoffs were chosen to optimize the overall and within subgroup weighted correlation, while maintaining C indices > .70 for individual survival association. More sophisticated models with RCB index as a continuous variable that incorporated baseline T stage, nodal status and response predictive subtypes were also explored. Results: Overall weighted correlations (R) for PCR, RCB 0/1 and Subtype Specific RCB cutoffs are shown in Table 1. Optimal cutoffs of RCB of 1.1 for HER2+, 1.7 for HR-HER2-, and 2.6 for HR+HER2- were identified giving a correlation of .70 overall in the training set and .54 in training and validation combined. The C index (C) was greater than 0.8 for all endpoints indicating good individual association. Preliminary results using more sophisticated models will be presented. Conclusions: Subtype-specific RCB cutoffs show a modest but clear improvement as an early endpoint over RCB-0/1 and pCR while maintaining a strong patient-level association with survival. External validation efforts are underway. Integrative approaches using continuous RCB improve trial level correlation and will be presented. Trial-level weighted correlation and individual C indices across all 3 subtypes and within each HRHER2 subtype separately. Measure OverallR,C HER2+R,C HR+HER2-R,C HR-HER2-R,C PCR .23, .84 .31, .80 .13, .84 .18, .87 RCB 0-1 .31, .83 .37, .80 .38, .85 .16, .85 Subtype Specific Cutpoint .54, .80 .37, .77 .40, .75 .54, .87 R = correlation; C = C index.

592 Background: Historically, young women with early-stage breast cancer (EBC) have had worse outcomes than older women. This is based largely on population-based or adjuvant studies, with limited neoadjuvant data. Methods: Patients (pts) with Stage 2-3 EBC treated with neoadjuvant chemotherapy +/- immunotherapy (Cx-IT) on the I-SPY2 trial between 2010-2022 were included (data cutoff 07/2025). Pts were stratified by age at trial screening (<40 vs ≥40 yrs), and clinical/molecular subtypes, including ImPrint, an immune signature predictive of Cx-IT response. Pathologic complete response (pCR), residual cancer burden (RCB), and event-free survival (EFS) were evaluated by age and disease subtypes using Kaplan-Meier methods and Cox proportional hazard ratios (HR). Results: Among 2117 evaluable pts, 510 (24%) were <40 yrs and 1607 (76%) were ≥ 40 yrs. Overall, 43% of tumors were HR+/HER2-, 35% HR-/HER2- (TN), 22% HER2+. 34% / 66% were ImPrint +/- (27% / 73% for HR+; 44% / 56% for HR-), with similar rates of ImPrint+/- between age groups. Rates of pCR (31% vs 35 %) and RCB 0/1 (48% vs 51%) were similar between pts <40 and ≥40. Overall, pts < 40 had worse EFS (p < 0.01) vs pts ≥ 40; however, in pts who achieved pCR, there was no difference in EFS in all biologic subgroups (HR 0.90, p=0.77). In contrast, in pts with residual disease, those <40 had worse EFS than pts ≥40 (HR 0.72, p<0.01). The worse EFS in pts<40 with residual disease was limited to pts with ImPrint- disease, in both HR+/HER2- (HR 0.64, p=0.02) and TN (HR 0.62, p=0.04) subtypes, where response rates were lower. In ImPrint+ pts, no differences in EFS by age were observed (HR 1.01, p=0.98). Similar results were seen for pts with HR+/HER2- disease when stratifying by RCB (RCB 0/I vs 2/3). There was no difference in EFS by age for pts with RCB 0/1 disease in any subtype (HR 0.66, p=0.09). For ImPrint-, pts<40 with RCB 2/3 disease had worse EFS than pts ≥40 (HR 0.61, p=0.01). For HR+/HER2-, 64% of tumors were MammaPrint (MP) High 1 vs 36% MP High 2, and 74% were Luminal. When stratifying by pCR or RCB 0/1, similar age-related EFS differences were observed in HR+/HER2- Luminal or MP High 1 tumors, as in ImPrint- tumors. Conclusions: Overall, young pts <40 yrs with high-risk EBC in the I-SPY2 trial had worse 5-yr EFS than pts ≥40; however, when taking response into account, there were no age-related EFS differences for pts who had an excellent response to neoadjuvant Cx-IT (i.e. pCR or RCB 1). The EFS difference was driven by pts with residual disease, specifically in the subset with ImPrint- disease, which is associated with less response to Cx-IT. Whereas, for pts with ImPrint+ disease, there was no difference in EFS by age, regardless of pCR or RCB. This highlights the unmet need for more effective therapies for immune-negative tumors. Our results reinforce the importance and prognostic value of neoadjuvant therapy, particularly in our youngest pts, to better risk-stratify and optimize treatment based on tumor biology and response to therapy. Clinical trial information: NCT01042379 .

The Women Informed to Screen Depending on Measures of risk (WISDOM) Study (clinicaltrials.gov NCT02620852, 2016-08-31) is pragmatic randomized controlled trial evaluating risk assessment to inform the age to start, frequency and modality of breast cancer screening and risk reduction. The WISDOM Study uses a preference-tolerant design, enabling women who decline randomization to self-select their screening arm. The risk-based arm included comprehensive breast cancer risk assessment using the Breast Cancer Surveillance Consortium (BCSC) model and genetics. From August 2016 to February 2023, WISDOM enrolled a large, diverse, nationwide cohort of 46,403 participants - 77% non-Hispanic (NH) White, 9% Hispanic, 6% (NH) Black, and 5% (NH) Asian; demographic diversity increased over time. Mean age at baseline was 54 years. 28,372 (61%) were randomized, while 89% of those who self-selected their screening arm chose risk-based screening. The preference-tolerant design captured real-world screening preferences while maintaining scientific rigor and demonstrated strong preference for risk-based screening.

10512 Background: The relative contributions of pathogenic variants (PV) in breast cancer (BC) genes, polygenic risk scores (PRS), and clinical risk factors to inform risk-stratified screening have not been well-studied on the population level. The WISDOM Study, a study of risk-based screening, used panel-based testing for PVs in 9 BC genes and the Breast Cancer Surveillance Consortium risk model modified by PRS (BCSC-PRS) to generate screening recommendations for > 30,000 participants undergoing risk-based screening. Women with PVs in high-penetrance genes were assigned q6 month screening (alternating MRI and mammogram). Those with PVs in moderate-penetrance genes were assigned q6 screening or yearly mammogram depending on family history. To determine the impact of PV detection on screening assignments, we examined the concordance between screening strategies informed by PV status vs. BCSC-PRS only. Methods: We analyzed participants with high-penetrance ( BRCA1, BRCA2, TP53, PALB2, STK11, CDH1 ), moderate-penetrance ( CHEK2, ATM ), or CHEK2 low-penetrance (I157T, S428T) PVs. We performed cross-tabulations of hypothetical (based on BCSC-PRS only) vs. actual (which considers PV) screening recommendation. To generate hypothetical screening recommendations, we calculated individual BCSC-PRS 5-year risk and applied the trial’s risk-based screening algorithm as if there were no PV. We considered initial (Year 1) screening recommendations to reflect that PV testing occurred at time of enrollment. We stratified analyses by PV category and age. Results: Our analysis included 714 women with a PV, of which 32% were high-penetrance, 39% were moderate-penetrance, and 29% were CHEK2 low-penetrance. Median age was 53 (IQR 45-62) years and 86% self-reported as non-Hispanic White. We found little overlap between screening recommendations based on PV status vs. BCSC-PRS. In women with a high-penetrance PV, 1.3% (3/234) would have received a q6 screening recommendation based on BCSC-PRS. In women with a moderate-penetrance PV, 33% (92/278) were assigned to q6 screening, of whom 6.5% (6/92) would have received the same assignment under BCSC-PRS. Additionally, 65% (182/278) were assigned to yearly mammogram, of whom 2.2% (4/182) would have received the same assignment under BCSC-PRS. In women with PVs aged 40-49, 67% (187/280) would have been recommended no screening until age 50 based on BCSC-PRS. In women with PVs aged 50-74, 90% (390/432) would have been recommended biennial screening. Conclusions: Most women with PVs in BC genes would not have otherwise been recommended for enhanced screening based on clinical and PRS risk. Our results highlight the importance of testing for PVs as a cornerstone of risk-based screening on the population level. Future studies will examine opportunities for risk reduction as we integrate genetic and non-genetic risk factors. Clinical trial information: NCT02620852 .

Determine the association between the Breast Cancer Surveillance Consortium v2 model (BCSC) risk score and advanced and non-advanced invasive breast cancer (IBC). We estimated BCSC 5-year invasive breast cancer risk for 11,915 participants in a prospective screening cohort with median follow-up of 6.9 years prior to breast cancer diagnosis. Individuals in the top 25

From extrachromosomal DNA to neo-peptides, reprogramming of cancer genomes leads to the emergence of cancer state-specific molecules. Here, we systematically identify and characterize a large repertoire of orphan non-coding RNAs (oncRNAs), a class of cancer-emergent small RNAs, across 32 tumor types. We show that oncRNA binary presence-absence patterns represent a digital molecular barcode that captures cancer type and subtype identities. Importantly, this barcode is partially accessible from the cell-free space as cancer cells secrete a subset of oncRNAs. Leveraging large-scale in vivo genetic screens in xenografted mice, we functionally identify driver oncRNAs in multiple tumor types. In a retrospective study across 192 breast cancer patients, we show that oncRNAs are reliably detected in blood and that changes in cell-free oncRNA burden predict both short-term and long-term clinical outcomes. Together, we establish that oncRNAs have potential roles in tumor progression and clinical utility in liquid biopsies for tumor-naive minimum residual disease monitoring.

e23224 Background: The WISDOM randomized clinical trial demonstrated that risk-based breast cancer screening incorporating population-based genetic testing safely stratified screening intensity and was noninferior to annual screening for stage ≥IIB cancers while reducing mammography utilization. Breast cancer screening also represents a substantial national expenditure, estimated at approximately US$11B annually in recent years.The environmental consequences of screening guideline intensity and downstream diagnostic cascades—relevant to population health and environmental justice—remain under-characterized. Methods: We conducted a pathway-based life cycle assessment (LCA) to quantify environmental impacts of hypothetical breast cancer screening–diagnostic cascades under (1) population-based annual screening and (2) WISDOM-aligned risk-stratified screening pathways. The modeled clinical sequence included screening mammography, recall, diagnostic imaging, biopsy, and pathology. Pathways were parameterized for four clinically defined risk groups (low, average, elevated, high), with procedure volumes and intensities informed by WISDOM trial screening assignments and supporting empirical evidence. A cradle-to-grave boundary captured energy use, consumables, equipment manufacturing, and waste. Primary data inputs were derived from audit and process inventories across three US academic centers. Environmental outcomes were expressed as kg CO₂-equivalents (CO₂e) per patient pathway and summarized across risk strata. Results: Compared with population-based annual screening, risk-stratified pathways were associated with an approximate 30% reduction in total greenhouse gas emissions. Emissions were dominated by routine mammography (approximately 65% of total pathway emissions) and downstream diagnostic imaging and biopsy (approximately 20%). Per-patient emissions increased with escalating risk intensity: +30%, +163%, and +400% for average-, elevated-, and high-risk pathways, respectively, relative to low-risk pathways. The average-risk group accounted for approximately 52% of total pathway emissions due to its prevalence. Conclusions: WISDOM-aligned risk-based screening may offer clinically safe screening intensity while reducing the environmental footprint of breast cancer screening pathways by approximately 30%, largely through decreased routine mammography volume and associated downstream diagnostic cascades. Incorporating environmental impact metrics into screening policy evaluations could strengthen value-based, equitable guideline modernization by jointly considering outcomes, costs, and environmental externalities.

LBA514 Background: Preclinical and clinical data show that antibody-drug conjugates (ADCs) such as T-DXd may synergize with immunotherapy. Rilvegostomig (R) is a monovalent, Fc-reduced, dual checkpoint bispecific IgG1 monoclonal antibody against PD-1 and TIGIT receptors. R + T-DXd was evaluated as neoadjuvant therapy for up to 4 cycles. Methods: I-SPY2.2 is a phase II neoadjuvant trial with three neoadjuvant sequences (Blocks A/B/C). All HER2-negative subtypes were eligible for R + T-DXd in Block A. Predicted responders at the end of Block A or B could undergo surgery; otherwise, they continued to Block B +/- C. Block B pts received paclitaxel +/- carboplatin +/- pembrolizumab and Block C pts doxorubicin + cyclophosphamide (AC) +/- pembrolizumab, HR+ immune+ received IO in Blocks B/C. Results are analyzed by receptor and response predictive subtypes (RPS), that include expression-based immune, and luminal signatures with hormone receptor (HR) and HER2 status. Some pts were randomized to a control regimen (skipping R + T-DXd in block A and starting in block B). To minimize risk of interstitial lung disease (ILD) that could lead to treatment discontinuation, pts underwent pulmonary function tests and high-resolution chest CTs every 6 weeks. Abnormalities were reviewed in real time. The primary endpoint was pathologic complete response (pCR), within each RPS and HR/HER2 signature, with estimated pCR (EpCR) rates compared to subtype-specific block A goal rates and control pts in those groups. Other endpoints included safety and treatment discontinuation. Results: 105 pts were treated with R + T-DXd in block A, while 31 pts were randomized to the control regimen. Block A EpCR rate was 57% in the 12 HR+Immune+ pts vs a pre-specified goal of 15% (posterior probability, PP > .99). In 35 HR-Immune+ pts EpCR was 52% vs a pre-specified goal of 40% (PP = .87). No other groups (Immune-) had a PP > .85 for their respective pCR goal rate. HER2-IHC was 0 (27.6%), 1+ (49.5%) and 2+ (22.9%) in the treatment arm vs. 37.7%, 37.7%, and 24.7% in the control arm, with no difference in distribution between arms in immune subtypes. The most common adverse events in Block A were fatigue (84.8%), nausea (81.0%) and alopecia (58.1%). ILD was the most common adverse event of special interest in Block A and overall, occurring in 12 pts (11.4%; 7G1, 4G2, 1G3) during Block A and in 3 pts (G1, 2.9%) in other Blocks. 8 pts discontinued T-DXd + R due to ILD and proceeded to the next Block. Conclusions: When considering the full treatment strategy including block B and C regimens, experimental strategies had similar EpCR rates vs. controls in immune+ subtypes but block A rates exceeded pre-defined goal thresholds. This infers that treatment beginning with R + T-DXd has equivalent efficacy to standard of care for immune+ pts, but 64% pts with pCR skip chemotherapy (Block B) and 97% avoid AC (Block C). R + T-DXd participants avoided persistent ILD. Clinical trial information: NCT01042379 .

618 Background: In neoadjuvant cancer trials, early endpoints that predict treatment effect on survival identify promising agents early and support accelerated regulatory approval. However, binary endpoints like pathologic complete response inadequately characterize the full distribution of residual disease in breast cancer, while promising continuous biomarkers like MRI derived functional tumor volume (FTV) are associated with survival outcomes but not widely collected. Using a Bayesian hierarchical model, long-term treatment effects on distant recurrence free survival (DRFS) can be predicted from continuous MRI-derived functional tumor volume (FTV) in the I-SPY 2 platform trial. Methods: I-SPY 2 treated 2117 patients from 2010-2022 (12 weeks of paclitaxel ± experimental agent followed by 4 cycles of doxorubicin + cyclophosphamide), and 1,859 underwent dynamic contrast-enhanced MRI at baseline and after 12 weeks of neoadjuvant therapy. MRI-derived functional tumor volume provided volumetric quantification of dynamic tissue enhancement. ΔFTV was defined as the ratio of 12-week to baseline FTV. A Bayesian joint hierarchical model (brms) fit treatment effects on ΔFTV and DRFS for each treatment regimen by HR/HER2 subtype, controlling for clinical nodal status, clinical T stage, grade, and calendar year. Arms with < 8 subjects are excluded. Performance was assessed using cross-validation, predicting DRFS treatment effects in one held out fold at a time from the learned ΔFTV-DRFS association in the remaining data, then comparing predicted to actual DRFS treatment effect. Sensitivity analyses on priors will be presented. Results: Across 1753 patients and 45 treatment–subtype combinations, the estimated treatment effects on ΔFTV and DRFS were highly correlated (posterior correlation -0.91; 95% CrI -1.00 to -0.23). Predicted DRFS treatment effect from ΔFTV demonstrated strong concordance with actual DRFS treatment effects (Pearson r = 0.94 in TNBC; 0.97 HER2+; 0.80 HR+HER2-). The top 5 treatment-subtype regimens ranked by predicted and actual DRFS were identical. 20 regimens predicted to have > 70% probability of DRFS benefit over subtype specific controls showed DRFS improvement, yielding 100% specificity and 69% sensitivity at this decision threshold. Conclusions: We demonstrate internally validated prediction of neoadjuvant treatment effect on DRFS from MRI-derived change in functional tumor volume in the I-SPY 2 trial of high-risk early breast cancer. This suggests continuous imaging measures capture a range of response to therapy while Bayesian approaches can be effective for predicting treatment effects. This encourages collecting MRI biomarkers in trials to facilitate validation as early endpoints supporting decisions in screening platform trials as well as regulatory accelerated approval.

This Viewpoint details the potential impacts that the 2024 Alabama Supreme Court decision defining cryopreserved embryos as “children” and restricting in vitro fertilization could have on patients with cancer and surgeons.

3008 Background: Numerous studies have demonstrated the prognostic value of ctDNA analysis after neoadjuvant chemotherapy for early-stage high-risk breast cancer. Few studies have characterized ctDNA in pts receiving NET for early-stage hormone receptor positive (HR+)/HER2- BC that is predicted to benefit less from chemotherapy. Methods: Cell-free DNA (cfDNA) was isolated from 432 plasma samples from 108 pts enrolled in the I-SPY2 EOP trial. Pts had Stage 2/3 HR+/HER2-, MammaPrint low or high risk 1 BC. Pts were randomized to one of 7 neoadjuvant-based treatment arms including arms containing AI, Z-endoxifen, Lasofoxifene, vepdegestrant (ARV-471), and Abemaciclib. Pts were treated for 6 months prior to surgery. Blood was collected at baseline (T0), 3 weeks (T1), 12 weeks (T2), and 6 months (T3). A personalized ctDNA test (Signatera) was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The chi-square test was used to assess associations between categorical variables, and the Wilcoxon rank-sum test was used to evaluate differences in medians. Results: ctDNA information was available for 101 patients at baseline (T0) (Table 1). At T0, 36 (35.6%) patients were ctDNA-positive. 23/36 (63.9%) became ctDNA-negative and 13/36 (36.1%) remained ctDNA-positive. At T0, 65/101 patients (64.4%) were ctDNA-negative. Of these, 57 (87.7%) remained negative, while 8 (12.3%) became ctDNA-positive at T1 before reverting to ctDNA-negative. A higher percentage of ctDNA-positive patients at T0 were cN+ compared to ctDNA-negative pts (p = 0.036, 64% vs. 40%). Additionally, ctDNA-positivity at T0 was strongly associated with higher Ki67 (p = 0.03) and larger functional tumor volume by MRI at baseline (p = 0.03). T3/T4 and high-grade tumors at baseline were also associated with having ctDNA positivity at baseline, though this was not statistically significant (p = 0.34 and 0.058, respectively). Conclusions: In this study of pts with Stage 2/3 HR+ HER2- BC with largely MammaPrint low risk signatures, over one-third of pts had detectable ctDNA at baseline. Detectable ctDNA at baseline was associated with cN+ disease, larger FTV, and high baseline Ki67. The majority of pts with positive ctDNA at baseline cleared the ctDNA on NET. Clinical trial information: NCT01042379 . Clinicopathologic characteristics of EOP patients. All Patients(N=101) Age at screening 55 (27-80) years* Clinical N Stage Node+ (cN+) 49 (48.5%) Node- (cN-) 52 (51.5%) SET status High 84 (83.2%) Low 14 (13.9%) Missing 3 (2.97%) MammaPrint (MP) risk** High risk 1 (H1) 15 (14.9%) Low risk 86 (85.1%) *Mean(min-max). **H1: MP score between 0 and -0.57; low: MP score between 0 and 0.355.

CHFR, which encodes an E3 ubiquitin ligase previously implicated in regulating the premitotic checkpoint and response to taxanes, is silenced in a subset of breast cancers. Here we assessed the impact of differences in CHFR expression on sensitivity to various antimitotic agents in vitro and on response to neoadjuvant taxane treatment in the clinical setting. Colony forming assays as well as live cell imaging in human breast cancer cell lines indicated that CHFR downregulation is associated with increased sensitivity to PLK1 inhibitors as well as paclitaxel in vitro that reflects premature mitotic exit and increased multinucleation. To assess the relationship between CHFR expression and neoadjuvant taxane response, we utilized immunohistochemistry to examine CHFR expression in the inter-regimen biopsy from 81 patients on the I-SPY neoadjuvant breast cancer trial (NCT01042379) who had dynamic contrast-enhanced breast MRIs before and after paclitaxel monotherapy. CHFRLow cancers had indistinguishable volumes before taxane therapy but smaller MRI tumor volumes after paclitaxel [median 0.07 cm3 (interquartile range 0–1.1) in CHFRLow versus 1.1 cm3 (0.02–5.0) in CHFRHigh cancers, p = 0.03 by rank sum test]. Moreover, there was a strong association between higher CHFR expression and lower relapse-free survival in estrogen receptor (ER) positive, HER2 negative cancers (HR 7.8, p = 0.024). These observations identify CHFR as a potential predictive marker of sensitivity in ER positive breast cancer that warrants further investigation and suggest that CHFR might also be associated with response to certain other mitotic inhibitors.