Background/Objectives: Apparent diffusion coefficient (ADC) calculated from diffusion-weighted MRI (DWI) can predict tumor response to neoadjuvant chemotherapy for breast cancer. However, obtaining consistently adequate image quality in breast DWI can be challenging, and the effect of image quality on ADC’s predictive performance is unclear. The objective of this study was to evaluate inter-reader variability in image quality assessment and the effect of DWI image quality on the predictive performance of ADC. Methods: This multi-institutional study included 428 patients. Two readers assessed three DWI image quality factors—fat suppression, artifacts, and signal-to-noise ratio (SNR). Inter-reader agreement was estimated using Fleiss’ Kappa. The percent change in tumor ADC from pretreatment (T0) to early treatment (T1) was used to predict pathologic complete response (pCR), assessed at surgery. Results: Out of 428 patients, 134 were excluded (missing pCR [n = 17]; missing/incorrect DWI [n = 23]; inability to define region-of-interest [ROI, n = 94]) and 294 were included in the analysis. Kappa coefficients were estimated as: 0.47 (95% confidence interval [CI]: 0.42, 0.52) for fat suppression, 0.54 (0.50, 0.59) for artifact, and 0.38 (0.32, 0.44) for SNR. The AUC of ADC calculated from DWI with adequate (high or medium at both time points) image quality was 0.61 (95% CI: 0.52, 0.702), while it was 0.68 (95% CI: 0.53, 0.83) from DWI with inadequate image quality at either T0 or T1. The p-value for the difference in AUCs was 0.45. Conclusions: The inter-reader agreement was moderate to fair across all three quality categories. When a manually delineated tumor ROI was possible, no statistically significant difference in ADC predictive performance was observed between the quality-adequate and quality-inadequate cohorts; still, both were predictive of pCR. Furthermore, no statistically significant differences were observed in inter-reader agreement or ADC predictive performance between 1.5T and 3T scanners. These findings are clinically relevant to the use of ADC as an imaging biomarker in real-world conditions.

Abstract Purpose Invasive lobular carcinoma (ILC) of the breast presents challenges in monitoring response to neoadjuvant endocrine therapy (NET). Dedicated breast positron emission tomography with 18F-fluoroestradiol (FES-dbPET), a molecular imaging technique targeting the estrogen receptor (ER), may offer insight into treatment response. This study evaluated whether changes in FES-dbPET uptake before and after NET in patients with ILC correlate with treatment response indicators, and whether these associations differ by endocrine therapy type. Methods This prospective pilot study included patients with stage I-III ER positive, human epidermal growth factor 2 (HER2) negative ILC undergoing NET between 2017 and 2021. FES-dbPET was performed pre- and post-NET. Patients were stratified by type of NET received – aromatase inhibitor (AI) therapy or selective estrogen receptor modulator/degrader (SERM/SERD) therapy. The primary goal was to assess correlation between FES-dbPET parameters and change in tumor Ki-67 staining (%), a validated prognostic endpoint after NET. Results We enrolled 19 patients with ER + HER2- ILC, of whom 12 underwent both pre- and post-NET FES-dbPET. Among the AI cohort, changes in SUVpk and SULpk from pre- to post-NET each positively correlated with changes in Ki-67, though these associations did not reach statistical significance (r = 0.74, p = 0.256; and r = 0.75, p = 0.254, respectively). Conversely, among the SERM/SERD cohort, changes in SUVpk and SULpk strongly and positively correlated with changes in Ki-67 (r = 0.92, p = 0.027; and r = 0.92, p = 0.028, respectively). Conclusion In this pilot study of 19 ER + ILC patients, change in FES uptake on dbPET showed some correlations with tumor response to NET. These findings suggest potential for FES-dbPET to capture tumor biology beyond that of standard imaging tools in predicting therapy response for patients with ILC. Further research with larger samples is needed to refine the role of FES-dbPET in improving neoadjuvant treatment monitoring and surgical planning in ILC patients.

Purpose To develop a fully automated method for measuring apparent diffusion coefficient (ADC) for breast tumors in diffusion-weighted MRI that is objective, repeatable, and reproducible for assessing early response to neoadjuvant chemotherapy. Materials and Methods This study was a retrospective analysis of American College of Radiology Imaging Network 6698 trial data (August 2012-January 2015). Regions of interest (ROIs) were automatically derived by transferring the tumor ROI from dynamic contrast-enhanced MRI to diffusion-weighted MRI via image registration, and the ΔADC were calculated from baseline to early treatment. The ΔADC performance was assessed for predicting a pathologic complete response (pCR) using receiver operating characteristic curve analysis. The analysis was performed in all participants and in subgroups defined by tumor human epidermal growth factor receptor 2 (HER2) status. The reproducibility of automated tumor ADC measurements was assessed in a test-retest subcohort. Results The analysis cohort included 226 participants with breast cancer (mean age, 48 years ± 10 [SD]). Automated ADC measurements were reproducible in the test-retest subcohort (n = 71; estimated agreement index, 0.82 [95% CI: 0.77, 0.85]). The ΔADC from the automated ROI predicted pCR, with an area under the receiver operating characteristic curve (AUC) of 0.61 (95% CI: 0.53, 0.69; P = .008). The AUC in the HER2-positive subcohort (0.69 [95% CI: 0.54, 0.93]) was higher than that in the HER2-negative subcohort (0.52 [95% CI: 0.41, 0.62]; P = .06). Conclusion The automated ADC measurement method was reproducible, and tumor ΔADC could predict pCR early. External validation will be included in future work. Keywords: Breast, MRI, DWI, Diffusion-weighted Imaging, Tumor Response, DCE, Dynamic Contrast-enhanced, MR Imaging, MR-Diffusion-weighted Imaging, MR-Dynamic Contrast-enhanced Clinical trial registration no. NCT01564368

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.

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.

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.

ImportanceIntratumoral immunotherapy that leverages the biological characteristics of high-risk ductal carcinoma in situ (DCIS) may be able to reduce the extent of surgical treatment and provide an alternative approach to improve patient outcomes.ObjectiveTo determine if combination intratumoral immunotherapy can activate immune cells to shrink or eliminate high-risk DCIS.Design, Setting, and ParticipantsThis phase 1 open-label nonrandomized clinical trial at a single academic center tested the safety and efficacy of intratumoral immunotherapy in patients with high-risk DCIS, defined as at least 2 of the following present: younger than 45 years, tumor size greater than 5 cm, high-grade, palpable mass, hormone receptor (HR)–negative, or ERBB2-positive. Patients were enrolled between June 8, 2021, and December 13, 2022.InterventionPembrolizumab (anti–programmed cell death protein 1), dose ranging from 2 mg to 8 mg, and mRNA-2752 (a combination of interleukin [IL]-23, IL-36γ, and OX40L mRNAs), dose ranging from 1 mg to 4 mg, delivered intratumorally, with 2 to 4 doses given 2 to 3 weeks apart.Main Outcomes and MeasuresThe primary objective was to evaluate the safety and tolerability of intratumoral injections of pembrolizumab and mRNA-2752. The secondary objectives were to assess radiologic and pathological responses and immunological and histological differences in the posttreatment tumor microenvironment.ResultsTen female patients with high-risk DCIS (median [range] age, 46 [35-80] years) were enrolled. The median (range) tumor size was 5.3 (1.0-10.0) cm. Five tumors were HR-negative ERBB2-positive; 2 HR-negative ERBB2-negative; 2 HR-positive ERBB2-negative; and 1 HR-positive ERBB2-positive. Of all treated patients, 8 of 10 responded to treatment, and all 8 patients had ERBB2-positive or HR-negative DCIS. Three patients had complete responses. Three patients with negative posttreatment core biopsy results declined surgery and remained disease-free after 1 to 2 years. Multiplex immunofluorescence staining demonstrated that high baseline levels of tumor-infiltrating lymphocytes and programmed cell death ligand 1–positive cells (immune or tumor) were associated with a better treatment response. All patients experienced up to 1 week of fever, malaise, flulike symptoms, axillary adenopathy, erythema, injection site swelling, and swelling in the breast. One patient had intermittent urticaria for 3 months. The dose was serially reduced from 8 mg to 2 mg for pembrolizumab and 4 mg to 1 mg for mRNA-2752 to improve tolerability. The final recommended combination dose is pembrolizumab, 4 mg, with mRNA-2752, 1 mg.Conclusions and RelevanceIn this phase 1 nonrandomized clinical trial, the results suggest that intratumoral injections of pembrolizumab and mRNA-2752 are safe and may induce rapid regression of high-risk DCIS with high immune infiltrates. These findings warrant additional investigation, and studies are ongoing.Trial RegistrationClinicalTrials.gov Identifier: NCT02872025

Motivation: Functional tumor volume (FTV) and background parenchymal enhancement (BPE) are potentially useful MRI markers for assessing HR+/HER2- breast cancer undergoing neoadjuvant endocrine treatment (NET). Goal(s): We aimed to investigate the combined ability of FTV and BPE as early markers of treatment response to NET, defined by pre-surgery FTV. Approach: We tested the performance of FTV and BPE available up to 3 weeks of treatment in predicting whether pre-surgery FTV is more than or less than 1.1 cc. Results: Both early changes in FTV and BPE predicted pre-surgery FTV and may be more effective when used in combination. Impact: Functional tumor volume (FTV) and background parenchymal enhancement (BPE) derived from baseline and 3-week MRI predicted the final FTV after neoadjuvant endocrine treatment (NET) for patients with HR+/HER2- breast cancer. These metrics may be non-invasive early markers for NET.

Motivation: Previously, we developed MRI-based models for the prediction of pathologic complete response (pCR) using an initial cohort of 990 patients enrolled in I-SPY. The purpose of this study is to validate the performance of the MRI model using an independent patient cohort from I-SPY 2. Goal(s): The goal is to test the robustness of the MRI-based models. Approach: Area under the receiver operating characteristic curve (AUC), PPV, and sensitivity for pCR prediction was used to evaluate performance in the subsequent cohort. Results: Overall, the sensitivity and PPV were 72% and 57%, slightly higher than the values evaluated in the initial 990 cohort. Impact: This is the first study of MRI-based predictive models that were developed and validated using two separate large cohorts from a multicenter neoadjuvant chemotherapy clinical trial.

IMPORTANCE Intratumoral immunotherapy that leverages the biological characteristics of high-risk ductal carcinoma in situ (DCIS) may be able to reduce the extent of surgical treatment and provide an alternative approach to improve patient outcomes. OBJECTIVE To determine if combination intratumoral immunotherapy can activate immune cells to shrink or eliminate high-risk DCIS. DESIGN, SETTING, AND PARTICIPANTS This phase 1 open-label nonrandomized clinical trial at a single academic center tested the safety and efficacy of intratumoral immunotherapy in patients with high-risk DCIS, defined as at least 2 of the following present: younger than 45 years, tumor size greater than 5 cm, high-grade, palpable mass, hormone receptor (HR)-negative, or ERBB2-positive. Patients were enrolled between June 8, 2021, and December 13, 2022. INTERVENTION Pembrolizumab (anti-programmed cell death protein 1), dose ranging from 2 mg to 8 mg, and mRNA-2752 (a combination of interleukin [IL]-23, IL-36 gamma, and OX40L mRNAs), dose ranging from 1 mg to 4 mg, delivered intratumorally, with 2 to 4 doses given 2 to 3 weeks apart. MAIN OUTCOMES AND MEASURES The primary objective was to evaluate the safety and tolerability of intratumoral injections of pembrolizumab and mRNA-2752. The secondary objectives were to assess radiologic and pathological responses and immunological and histological differences in the posttreatment tumor microenvironment. RESULTS Ten female patients with high-risk DCIS (median [range] age, 46 [35-80] years) were enrolled. The median (range) tumor size was 5.3 (1.0-10.0) cm. Five tumors were HR-negative ERBB2-positive; 2 HR-negative ERBB2-negative; 2 HR-positive ERBB2-negative; and 1 HR-positive ERBB2-positive. Of all treated patients, 8 of 10 responded to treatment, and all 8 patients had ERBB2-positive or HR-negative DCIS. Three patients had complete responses. Three patients with negative posttreatment core biopsy results declined surgery and remained disease-free after 1 to 2 years. Multiplex immunofluorescence staining demonstrated that high baseline levels of tumor-infiltrating lymphocytes and programmed cell death ligand 1-positive cells (immune or tumor) were associated with a better treatment response. All patients experienced up to 1 week of fever, malaise, flulike symptoms, axillary adenopathy, erythema, injection site swelling, and swelling in the breast. One patient had intermittent urticaria for 3 months. The dose was serially reduced from 8 mg to 2 mg for pembrolizumab and 4 mg to 1 mg for mRNA-2752 to improve tolerability. The final recommended combination dose is pembrolizumab, 4 mg, with mRNA-2752, 1 mg. CONCLUSIONS AND RELEVANCE In this phase 1 nonrandomized clinical trial, the results suggest that intratumoral injections of pembrolizumab and mRNA-2752 are safe and may induce rapid regression of high-risk DCIS with high immune infiltrates. These findings warrant additional investigation, and studies are ongoing.

Background: Functional tumor volume (FTV), measured from dynamic contrast-enhanced MRI, is an imaging biomarker that can predict treatment response in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). The FTV-based predictive model, combined with core biopsy, informed treatment decisions of recommending patients with excellent responses to proceed to surgery early in a large NAC clinical trial. Methods: In this retrospective study, we constructed models using FTV measurements. We analyzed performance tradeoffs when a probability threshold was used to identify excellent responders through the prediction of pathology complete response (pCR). Individual models were developed within cohorts defined by the hormone receptor and human epidermal growth factor receptor 2 (HR/HER2) subtype. Results: A total of 814 patients enrolled in the I-SPY 2 trial between 2010 and 2016 were included with a mean age of 49 years (range: 24 to 77). Among these patients, 289 (36%) achieved pCR. The area under the ROC curve (AUC) ranged from 0.68 to 0.74 for individual HR/HER2 subtypes. When probability thresholds were chosen based on minimum positive predictive value (PPV) levels of 50%, 70%, and 90%, the PPV-sensitivity tradeoff varied among subtypes. The highest sensitivities (100%, 87%, 45%) were found in the HR−/HER2+ sub-cohort for probability thresholds of 0, 0.62, and 0.72; followed by the triple-negative sub-cohort (98%, 52%, 4%) at thresholds of 0.13, 0.58, and 0.67; and HR+/HER2+ (78%, 16%, 8%) at thresholds of 0.34, 0.57, and 0.60. The lowest sensitivities (20%, 0%, 0%) occurred in the HR+/HER2− sub-cohort. Conclusions: Predictive models developed using imaging biomarkers, alongside clinically validated probability thresholds, can be incorporated into decision-making for precision oncology.

612 Background: EOP, an I-SPY2 sub-study, evaluates the tolerability and activity of novel endocrine strategies in stage 2/3 breast cancer (BC) patients (pts) predicted to have lower chemotherapy benefit. Laso, a selective estrogen receptor modulator (SERM), has shown favorable toxicity profile and activity in HR+/HER2- endocrine-resistant metastatic BC. Methods: Pts with Stage 2/3 HR+/HER2-, MammaPrint (MP) low risk BC were enrolled. Pts with MP High1 BC were included if clinically node-negative. Pts received oral laso 5 mg daily for six 28-day cycles. Laso was continued until the day prior to surgery. Premenopausal pts received ovarian function suppression (OFS) starting C2D1. The primary endpoint was feasibility (>75% of patients completing >75% study therapy). Baseline (T0), 3-wk (T1) biopsies, and the surgical specimen (T3) was assessed centrally for Ki-67. Breast MRI functional tumor volume (FTV) was performed at T0, T1, 12 weeks (T2), and pre-operatively (T3). Blood was collected for tumor informed ctDNA at T0, T1, T2, T3. Advance event (AE) was assessed using CTCAE V5. Results: From 3/2023 to 5/2024, 20 pts were enrolled. Median age 50.5 years, 50% premenopausal, and 1 male pt. 60% cN0, 80% MP low-risk signature. 18 (90%) pts completed >75% study therapy. Two pts discontinued treatment due to pt preference. Median Ki67 at T0 was 14.7%. At T1, 87.5% of pts remained or suppressed Ki67 to <10% and 37.5% suppressed to <2.7%. Ki67 at T1 was similar between pre-and postmenopausal pts despite OFS (Table). The median MRI FTV was 8.4 cc at T0, and 3.4 cc at T3. Median % FTV reduction from T0 to T3 was -47.5%. 2/20 pts (10%) achieved a modified PEPI score of 0. No patients achieved completed pathological response. Of the 16 pts with RCB results, 2 (12.5%) RCB-1, 6 (37.5%) RCB-2, 8 (50%) RCB-3 disease. 14 pts had ctDNA available at T0. 4/14 were ctDNA+ at T0, 2 of whom became ctDNA negative, and 2 remained ctDNA+. 10/14 pts were ctDNA negative at T0, 8 of whom remained negative, 2 became positive at T1 then cleared. All AEs were grade(G) 1 except 1 pt with G2 hot flashes. Most common AEs include hot flashes (85%), constipation (50%), fatigue (50%), and nausea (35%). One pt had G3 hypersensitivity and hypertension, both unrelated to therapy. Conclusions: Neoadjuvant laso demonstrates a favorable AE profile and promising anti-tumor activity in suppressing 3-wk Ki67 and MRI FTV change in pts with HR+ HER2-negative early BC. Ki67 suppression in premenopausal pts was seen in the absence of OFS. Clinical trial information: NCT01042379 . Ki67 expression at pre-treatment, and 3-wk time point. All Patients(n=20) Premenopausal (n=10) Postmenopausal (n=9) Median Ki67 expression Baseline 10.0% 12.5% 10.0% 3-wk 5.1% 3.0% 6.0% Number of pts with Ki67 expression <10% at 3-wk 87.5% 1 87.5% 85.7% Number of pts with Ki67 expression <2.7% at 3-wk 37.5% 50% 28.6% 1 Include the one male pt.

Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab-deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin-cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2-Immune-DNA repair deficiency- subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2-Immune-DNA repair deficiency- signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379. In the I-SPY2.2 trial, patients with high-risk stage 2/3 breast cancer received neoadjuvant datopotamab-deruxtecan, followed by sequential chemotherapy with or without targeted therapy, with the option of early surgical resection after each block of therapy. In a subgroup of patients, the sequential treatment strategy was superior to standard of care.

Background: This multicenter and retrospective study investigated the additive value of tumor morphologic features derived from the functional tumor volume (FTV) tumor mask at pre-treatment (T0) and the early treatment time point (T1) in the prediction of pathologic outcomes for breast cancer patients undergoing neoadjuvant chemotherapy. Methods: A total of 910 patients enrolled in the multicenter I-SPY 2 trial were included. FTV and tumor morphologic features were calculated from the dynamic contrast-enhanced (DCE) MRI. A poor response was defined as a residual cancer burden (RCB) class III (RCB-III) at surgical excision. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive performance. The analysis was performed in the full cohort and in individual sub-cohorts stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Results: In the full cohort, the AUCs for the use of the FTV ratio and clinicopathologic data were 0.64 ± 0.03 (mean ± SD [standard deviation]). With morphologic features, the AUC increased significantly to 0.76 ± 0.04 (p < 0.001). The ratio of the surface area to volume ratio between T0 and T1 was found to be the most contributing feature. All top contributing features were from T1. An improvement was also observed in the HR+/HER2- and triple-negative sub-cohorts. The AUC increased significantly from 0.56 ± 0.05 to 0.70 ± 0.06 (p < 0.001) and from 0.65 ± 0.06 to 0.73 ± 0.06 (p < 0.001), respectively, when adding morphologic features. Conclusion: Tumor morphologic features can improve the prediction of RCB-III compared to using FTV only at the early treatment time point.