Background: Tumor genomic testing (TGT) has become standard-of-care for all patients with metastatic breast cancer (MBC). Guidelines for patient education prior to TGT from the American Society of Clinical Oncology (ASCO) and the American College of Medical Genetics (ACMG) are not widely followed. We have previously demonstrated disparities in general genomic knowledge across race and income. The purpose of this study was to evaluate the impact of a concise (3-4 minute) video for patient education prior to TGT in a prospective interventional trial. We report the results of the MBC cohort (ClinicalTrials.gov NCT05215769). Methods: We created a base animated video incorporating culturally diverse images, available in English and Spanish, applicable to any cancer type, with MBC-specific content included for patients with MBC. From March 2022 to June 2024, a total of 54 patients with MBC were enrolled at a single tertiary academic institution, and three community cancer centers. Participants completed validated survey instruments immediately prior to video viewing (T1), immediately post-viewing (T2) and after receipt of their own TGT results (T3). Instruments included: 1) 10-question objective genomic knowledge/understanding (GKU); 2) 10-question video message-specific knowledge/recall (VMSK); 3) 11-question Trust in Physician/Provider (TIPP); 4) attitudes around TGT. The primary objective was to assess change in VMSK between T1 and T2. A cohort of fifty patients provided 90% power to detect an effect size of 0.47 in change of recall accuracy from pre- to post-video using two-sided Wilcoxon signed-rank test with alpha of 0.05. The associations of VMSK, GKU, and TIPP with categorical demographic variables were explored with Kruskal-Wallis test. Results: To date 50 of the 54 patients with MBC enrolled have completed surveys at all timepoints. The MBC cohort had a median age of 57; all were female; most were Caucasian (49/54, 91%); most were married/in domestic partnership (41/54, 76%). For the primary endpoint, there was a significant increase in VMSK (p<0.001) but there was no significant change in GKU (p=0.89) or TIPP (p=0.59). Improvement of VMSK was consistent across demographic groups, including race/ethnicity, age, income, and education. Of the 10-questions in the VMSK survey, results for four questions significantly improved after viewing the video, including questions informing the likelihood of TGT impact on treatment decision, incidental germline findings, and cost of testing. However, the improvement seen was not consistently sustained at T3 in seven of ten questions. Higher baseline genomic knowledge was significantly associated with higher participant income. Conclusions: A single viewing of our concise, 3-4 minute, broadly applicable video incorporating culturally diverse images administered prior to TGT significantly improved VMSK across all demographic groups. While video content recall regressed over time, patient’s perception of the merits of TGT and their TIPP remained unchanged. This approach can be a valuable tool for empowering patients and educating them on the risks, benefits, and limitations of TGT in alignment with ASCO and ACMG guidelines. Citation Format: Deloris Veney, Lai Wei, Amanda E. Toland, Carolyn J. Presley, Tasleem J. Padamsee, Clara N. Lee, Heather Hampel, William J. Irvin, James Kim, Michael J. Bishop, Shelly R. Hovick, Leigha Senter, Daniel G. Stover. A Video Intervention to Improve Patient Understanding of Tumor Genomic Testing in Patients with Metastatic Breast Cancer: Primary Results of a Prospective Intervention Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-12-21.

LBA509 Background: NRG-BR003 is a phase III, randomized trial evaluating whether the addition of carboplatin (carbo) to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide (AC) followed by paclitaxel (P) will improve invasive disease-free survival (IDFS) compared to AC followed by P when administered to patients (pts) with operable node-positive or high-risk node-negative triple-negative breast cancer (TNBC). Methods: Eligible pts had operable node-positive or high-risk node-negative TNBC and were randomized to receive dose-dense (DD) AC every 2 weeks for 4 cycles followed by weekly P (80 mg/m2) for 12 doses or the same regimen with carbo AUC of 5 IV every 3 weeks for 4 cycles. Stratification factors were number of positive nodes (0, 1-3, 4-9, 10+) and BRCA mutation status (positive; negative; or unknown). The study was designed to detect a hazard ratio (HR) in IDFS at 0.67 with the addition of carbo. The stratified log-rank test was used for the primary analysis. Secondary endpoints include DRFI, OS, BCFS, and RFI. Results: 769 pts were randomized to control arm (n=385) and carbo arm (n=384) from June 2015 to May 2022. Patient characteristics include age >50 (66%), primary tumors >2 cm (70%), node-positive (69%), and g BRCA pathogenic variants (9%). Delivery of AC was balanced between arms and P delivery was not compromised by co-administration of carbo with a mean of 11.3 doses (sd=2.1) of P with a relative total dose intensity (RTDI) at 0.97 in the control arm and 11.0 doses (sd=2.3) and a RTDI at 0.95 in the carbo arm. At data cutoff (2/28/25), median follow-up was 79.4 mos. IDFS events were reported in 92 pts (23.9%) in the control group and 76 (19.8%) in the carbo group. The stratified log-rank test p-value was 0.097, not meeting the prespecified significance of 0.049; the HR was 0.77 (95% CI, 0.57-1.05). The 5-year IDFS (95% CI) was 77.8% (73.7%-82.2%) vs 82.9% (79.2%-86.9%), respectively. HR was similar across patient subgroups, including germline BRCA and nodal status. Grade ≥3 treatment-related AE rates were 51.1% in the control group and 72.9% in the carbo group. Grade 5 events were 0.8% vs 0.8%, respectively. Conclusions: The addition of carbo to P following DD AC for adjuvant therapy of node-positive or high-risk node-negative TNBC did not result in a statistically significant improvement in IDFS, DRFI, or OS. However, it increased grade ≥3 treatment-related AE rates. Although not meeting criteria for efficacy across the entire study population, results support planned translational research to identify subsets of pts who may benefit from carbo. Clinical trial information: NCT02488967 . Secondary efficacy results of DRFI and OS. End Points Treatment 5-year Event-free Rate (95% CI) HR (95% CI) DRFI AC → P 84.4% (80.7-88.2) 1 AC → P+Carbo 88.7% (85.5-92.0) 0.74 (0.50-1.10) OS AC → P 84.4% (80.8-88.3) 1 AC → P+Carbo 87.7% (84.4-91.2) 0.81 (0.56-1.16)

Tamoxifen undergoes metabolic activation by cytochrome P450 (CYP) enzymes to metabolites with more potent anti-estrogenic effects. Numerous studies demonstrate decreased tamoxifen efficacy associated with reduced CYP2D6 activity or lower Z-endoxifen concentrations. Women taking tamoxifen frequently experience vasomotor symptoms (VMS) that may require medical treatment. Many medications used for VMS or depression are CYP substrates that may reduce Z-endoxifen concentrations. While the drug-drug interactions (DDI) from potent CYP2D6 inhibitors (CYPi) on tamoxifen metabolism has been studied, the impact of less potent CYPi including drugs used to treat VMS remains largely unknown. We performed a prospective trial to evaluate the impact of gabapentin or non-potent CYPi (venlafaxine citalopram) on plasma concentrations of tamoxifen and its metabolites (Z-endoxifen, N-desmethyl-tamoxifen (NDMT) and 4-hydroxy-tamoxifen (4HT). Patients enrolled were intermediate to extensive metabolizers by CYP2D6 genotyping. While tamoxifen and NDMT plasma concentrations were not significantly altered, the percent decrease in plasma Z-endoxifen concentration was statistically significant with the addition of venlafaxine (n = 22) or citalopram (n = 18) (median − 14.7 and − 14.4

Background: The CLEOPATRA trial established trastuzumab, pertuzumab, and docetaxel (THP) as a standard of care for first-line metastatic, HER2-positive breast cancer with median progression-free survival (PFS) of 18.7 months and median overall survival (OS) of 57 months. NRG-BR004 was a phase III, placebo-controlled trial designed to determine whether the addition of the PD-L1 inhibitor atezolizumab to THP would improve PFS, relative to THP/placebo in patients with newly documented HER2-positive measurable metastatic breast cancer. Methods: In this double-blinded phase III trial, patients with newly documented HER2-positive measurable metastatic breast cancer were randomly assigned (in a 1:1 ratio) to receive atezolizumab (1200 mg IV) or placebo on days 1 and 22 every six weeks until progression or for two years, combined with 1) a taxane regimen selected by investigator (weekly paclitaxel 80 mg/m2 IV on days 1, 8, 15, 22, 29, and 36, or docetaxel 75 mg/m2 IV on days 1 and 22 every six weeks) administered until progression or toxicity required discontinuation and 2) trastuzumab with pertuzumab on days 1 and 22 every six weeks until progression or toxicity required discontinuation. The primary endpoint, PFS, was assessed by investigators using RECIST 1.1 criteria. Results: One hundred ninety out of the planned 600 patients were randomized over 37 months from May 1, 2019, to May 20, 2022. An imbalance in Grade 5 AEs coupled with continued poor accrual and the changing landscape in HER2+ metastatic breast cancer resulted in the permanent closure to further enrollment in May of 2022. A decision was made to discontinue atezolizumab/placebo in patients receiving the investigational component of the trial therapy and to unblind investigators and patients. Treatment with the standard components of therapy continued at investigator discretion. The study continued to collect information on PFS events, deaths, and late immune adverse events through April of 2024. The primary analyses were performed in September 2024. Median follow-up for PFS was 31.1 months and 35.6 months for OS. Characteristics for the randomly assigned patient population included median age of 52 years, 66% had estrogen-receptor positive disease, 79% had visceral metastases, 4% had brain metastases, 82% had presented with de novo metastatic disease, and only 14% were PD-L1 positive. Characteristics were balanced between the two arms. The mean and median number of cycles of trastuzumab, pertuzumab, and taxanes were similar in the atezolizumab and placebo arms. Total grade 2, 3, and 4 adverse events were similar across both arms. Grade 5 events totaled 6 in the atezolizumab arm and 0 in the placebo arm at the time of closure of the study and discontinuation of atezolizumab/placebo. Two-year PFS was 54.0% and 45.6% in the atezolizumab-THP arm and placebo-THP arm (hazard ratio 0.73 [0.49, 1.09]), respectively. Three-year OS was 86.4% and 81.7% in the atezolizumab-THP arm and placebo-THP arm (hazard ratio 0.8 [0.39, 1.63]), respectively. Stratified log-rank test was used to compare the distribution of PFS and OS between the two treatment arms with estrogen receptor status and prior neoadjuvant or adjuvant trastuzumab as the stratification factors. Conclusions: Accrual to BR004 was closed to further enrollment in May 2022 and atezolizumab/placebo was discontinued due to poor accrual and the imbalance in Grade 5 events between the two arms, 6 deaths in the atezolizumab-THP arm versus 0 in the placebo-THP arm. The results suggest checkpoint inhibitors may have activity in metastatic HER2+ breast cancer, but further studies would be necessary to establish efficacy and improve safety. NCT #: NCT03199885 Support: U10 CA180868, U10 CA180822, UG1 CA189867, U24 CA196067, Genentech/Roche Citation Format: Vicente Valero, Gong Tang, Charles E. Geyer, Jr, Priya Rastogi, Shannon L. Puhalla, Jiahe Li, Stephen K.L. Chia, Erin F. Cobain, Elias Obeid, David B. Page, Andrew S. Poklepovic, William J. Irvin, Jr, Adam M. Brufsky, Irene L. Wapnir, J. Marie Suga, Eleftherios P. Mamounas, Norman Wolmark. NRG-BR004: A Randomized, Double-blind, Phase III Trial of Taxane/Trastuzumab/Pertuzumab with Atezolizumab or Placebo in First-line HER2-positive Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr RF3-04.

BACKGROUND:The PRO-CTCAE Measurement System was designed to enhance the quality of the standard toxicity evaluation in clinical trials. We developed a substudy within NRG-BR004, a phase III clinical trial in patients with newly documented HER2-positive metastatic breast cancer (MBC), to examine the added value and feasibility of frequent PRO-CTCAE data collection. METHODS:Patients were asked to complete 23 PRO-CTCAE items assessing 12 symptoms. Electronic PRO (ePRO) reporting was preferred; however, paper administration was allowed. The data on items assessed before treatment initiation, then weekly during Cycles 1-2 (12 weeks), are presented herein. Feasibility of frequent assessment with ePRO reporting was assessed using these data and was predefined as ≥25% of patients being compliant (submitted ≥75% of scheduled assessments). We also examined PRO-CTCAE and clinician-reported CTCAE data for key symptoms using maximum toxicity grade and the toxicity index (TI). RESULTS:Overall, 80% of patients (82 of 103) were compliant with expected weekly assessments (90% CI = 0.72 to 0.86). For all symptoms, the median maximum grade (TI value) of clinician-reported CTCAE was lower than the median maximum score (TI value) of patient-reported PRO-CTCAE. The differences in the data trend for weekly vs less frequent assessment were more apparent when data were evaluated using the TI vs the maximum score. CONCLUSIONS:Weekly assessments within the first two chemotherapy cycles were feasible in this trial of MBC patients. As expected, patients reported greater severity of symptoms than clinicians. Demonstrating the feasibility of frequent assessment could have implications for future research and clinical practice. CLINICALTRIALS.GOV:NCT03199885 (https://clinicaltrials.gov/study/NCT03199885).

Background The benefit of regional nodal irradiation in the treatment of breast cancer is well established for patients with pathologically positive axillary nodes, but whether it is also beneficial for patients whose nodes become pathologically tumor free (ypN0) after neoadjuvant chemotherapy remains unclear. Methods We evaluated whether regional nodal irradiation improves outcomes in patients with biopsy-proven, node-positive breast cancer who reach ypN0 status after neoadjuvant chemotherapy. Patients with breast cancer with a clinical stage of T1 to T3 (tumor size, <= 2 cm to >5 cm), N1, and M0 (indicating spread to one to three axillary lymph nodes but no distant metastasis) who had ypN0 status after neoadjuvant chemotherapy were randomly assigned to receive regional nodal irradiation or no regional nodal irradiation. The primary end point was the interval of freedom from invasive breast cancer recurrence or death from breast cancer (invasive breast cancer recurrence-free interval). Secondary end points included the locoregional recurrence-free interval, the distant recurrence-free interval, disease-free survival, and overall survival. Safety was also assessed. Results A total of 1641 patients were enrolled in the trial; 1556 were included in the primary-event analysis: 772 in the irradiation group and 784 in the no-irradiation group. After a median follow-up of 59.5 months, 109 primary end-point events (50 in the irradiation group and 59 in the no-irradiation group) had occurred. Regional nodal irradiation did not significantly increase the invasive breast cancer recurrence-free interval (hazard ratio, 0.88; 95% confidence interval, 0.60 to 1.28; P=0.51). Point estimates of survival free from the primary end-point events were 92.7% in the irradiation group and 91.8% in the no-irradiation group. Regional nodal irradiation did not increase the locoregional recurrence-free interval, the distant recurrence-free interval, disease-free survival, or overall survival. No deaths related to the protocol-specified therapy were reported, and no unexpected adverse events were observed. Grade 4 adverse events occurred in 0.5% of patients in the irradiation group and 0.1% of those in the no-irradiation group. Conclusions The addition of adjuvant regional nodal irradiation did not decrease the risk of invasive breast cancer recurrence or death from breast cancer in patients who had negative axillary nodes after neoadjuvant chemotherapy.

Background: The benefit of adjuvant regional nodal irradiation including the chest wall after mastectomy (CWI+RNI) and with whole breast irradiation (WBI+RNI) after breast conserving surgery (BCS) is well established in pts with pathologically positive axillary nodes (pN+). Pts who present with axillary node involvement (cN+), receive neoadjuvant chemotherapy (NC), and are found to be pathologically node-negative at surgery (ypN0), have lower loco-regional recurrence (LRR) rates compared to those who remain pathologically node-positive (ypN+). This phase III, randomized trial aimed to evaluate whether CWI+RNI after mastectomy or addition of RNI to WBI after BCS significantly improves invasive breast cancer recurrence-free interval (IBC-RFI) in cN+ pts found to be ypN0 after NC. Methods: Eligible pts had clinical cT1-3, N1, M0 invasive breast cancer (biopsy-proven N+ by FNA/core needle bx), completed ≥8 wks of NC (and anti-HER2 therapy if HER2+), and were ypN0 after mastectomy or BCS and sentinel node biopsy (SLNB, ≥2 nodes), axillary lymph node dissection (ALND), or both. Pts were randomized to “No RNI” (i.e., observation after mastectomy or WBI after BCS) vs. “RNI” (i.e., CWI+RNI after mastectomy or WBI+RNI after BCS). Primary endpoint was IBC-RFI. Secondary endpoints reported here: LRR-free interval (LRRFI), distant recurrence-free interval (DRFI), disease-free survival (DFS), and overall survival (OS). Study was designed to have 80% power to detect 35% reduction in annual rate of IBC-RFI for an absolute risk reduction of 4.6% (5-yr cumulative rate). Per protocol, final analysis was to occur after 172 events or 10 yrs after study initiation.Here we report the time-driven analysis prespecified in the protocol. Results: From 9/13-12/20, 1,641 pts were enrolled; 1,556 pts were available for primary event analysis; median f/u time 59.5 mos (IQR 40.7-74.1). Pt/tumor characteristics were well balanced between groups. Median age 52 yrs (range 21-84); 31% non-white; 21% cT1, 60% cT2, 19% cT3; 23% triple-negative, 21% HR+/HER2-, 56% HER2+; 58% BCS; 55% SLNB, 45% ALND+/-SLNB; and 78% had breast pathologic complete response. At the time of the analysis, 109 IBC-RFI events (63% of the planned 172) were confirmed (“No RNI”: 59, “RNI”: 50). There was no statistically significant difference between groups for IBC-RFI (HR=0.88, 95%CI 0.60-1.29; p=0.51), 5-yr point estimates: 91.8% for “No RNI” and 92.7% for “RNI.” There were no statistically significant differences between the treatment groups for secondary endpoints. There were no study-related deaths and no unexpected toxicities.Grade 4 toxicity was rare (0.1% with “No RNI”, 0.5% with “RNI”); 6.5% of pts developed grade 3 toxicity in “No RNI” and 10% in “RNI” group. Most common grade 3 toxicity was radiation dermatitis (3.3% in “No RNI,” 5.7% in “RNI”). Conclusion: In pts who present with biopsy-proven axillary node involvement and convert their axillary nodes to ypN0 after NC, CWI+RNI after mastectomy, or WBI+RNI after BCS, did not significantly improve IBC-RFI, LRRFI, DRFI, DFS, or OS. These findings suggest that downstaging involved axillary nodes with NC can result in optimization of adjuvant radiotherapy without adversely affecting oncologic outcomes. Follow-up of pts for long-term outcomes continues. NCT01872975 *EPM and JW are co-first authors. Table 1 Citation Format: Eleftherios Mamounas, Hanna Bandos, Julia White, Thomas Julian, Atif Khan, Simona Shaitelman, Mylin Torres, Frank Vicini, Patricia Ganz, Susan McCloskey, Nilendu Gupta, X. Allen Li, Peter Lucas, Nadeem Abu-Rustum, Saumil Gandhi, Rahul Tendulkar, Robert Coleman, Keiichi Fujiwara, Samantha Seaward, William Irvin, Kristin Higgins, Robert Mutter, Jean-Francois Boileau, Andrew Muskovitz, Reshma Jagsi, Anna Weiss, Curran Walter Jr., Norman Wolmark. Loco-Regional Irradiation in Patients with Biopsy-proven Axillary Node Involvement at Presentation Who Become Pathologically Node-negative After Neoadjuvant Chemotherapy: Primary Outcomes of NRG Oncology/NSABP B-51/RTOG 1304 [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 GS02-07.

Importance Observational studies of survivors of breast cancer and prospective trials of aspirin for cardiovascular disease suggest improved breast cancer survival among aspirin users, but prospective studies of aspirin to prevent breast cancer recurrence are lacking. Objective To determine whether aspirin decreases the risk of invasive cancer events among survivors of breast cancer. Design, Setting, and Participants A011502, a phase 3, randomized, placebo-controlled, double-blind trial conducted in the United States and Canada with 3020 participants who had high-risk nonmetastatic breast cancer, enrolled participants from 534 sites from January 6, 2017, through December 4, 2020, with follow-up to March 4, 2023. Interventions Participants were randomized (stratified for hormone receptor status [positive vs negative], body mass index [<= 30 vs >30], stage II vs III, and time since diagnosis [<18 vs >= 18 months]) to receive 300 mg of aspirin (n = 1510) or placebo once daily (n = 1510) for 5 years. Main Outcomes and Measures The primary outcome was invasive disease-free survival. Overall survival was a key secondary outcome. Results A total of 3020 participants were randomized when the data and safety monitoring committee recommended suspending the study at the first interim analysis because the hazard ratio had crossed the prespecified futility bound. By median follow-up of 33.8 months (range, 0.1-72.6 months), 253 invasive disease-free survival events were observed (141 in the aspirin group and 112 in the placebo group), yielding a hazard ratio of 1.27 (95% CI, 0.99-1.63; P = .06). All invasive disease-free survival events, including death, invasive progression (both distant and locoregional), and new primary events, were numerically higher in the aspirin group, although the differences were not statistically significant. There was no difference in overall survival (hazard ratio, 1.19; 95% CI, 0.82-1.72). Rates of grades 3 and 4 adverse events were similar in both groups. Conclusion and Relevance Among participants with high-risk nonmetastatic breast cancer, daily aspirin therapy did not improve risk of breast cancer recurrence or survival in early follow-up. Despite its promise and wide availability, aspirin should not be recommended as an adjuvant breast cancer treatment.

BACKGROUND:FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity. METHODS:In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS). RESULTS:One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia. CONCLUSIONS:A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting.

Importance:Observational studies of survivors of breast cancer and prospective trials of aspirin for cardiovascular disease suggest improved breast cancer survival among aspirin users, but prospective studies of aspirin to prevent breast cancer recurrence are lacking. Objective:To determine whether aspirin decreases the risk of invasive cancer events among survivors of breast cancer. Design, Setting, and Participants:A011502, a phase 3, randomized, placebo-controlled, double-blind trial conducted in the United States and Canada with 3020 participants who had high-risk nonmetastatic breast cancer, enrolled participants from 534 sites from January 6, 2017, through December 4, 2020, with follow-up to March 4, 2023. Interventions:Participants were randomized (stratified for hormone receptor status [positive vs negative], body mass index [≤30 vs >30], stage II vs III, and time since diagnosis [<18 vs ≥18 months]) to receive 300 mg of aspirin (n = 1510) or placebo once daily (n = 1510) for 5 years. Main Outcomes and Measures:The primary outcome was invasive disease-free survival. Overall survival was a key secondary outcome. Results:A total of 3020 participants were randomized when the data and safety monitoring committee recommended suspending the study at the first interim analysis because the hazard ratio had crossed the prespecified futility bound. By median follow-up of 33.8 months (range, 0.1-72.6 months), 253 invasive disease-free survival events were observed (141 in the aspirin group and 112 in the placebo group), yielding a hazard ratio of 1.27 (95% CI, 0.99-1.63; P = .06). All invasive disease-free survival events, including death, invasive progression (both distant and locoregional), and new primary events, were numerically higher in the aspirin group, although the differences were not statistically significant. There was no difference in overall survival (hazard ratio, 1.19; 95% CI, 0.82-1.72). Rates of grades 3 and 4 adverse events were similar in both groups. Conclusion and Relevance:Among participants with high-risk nonmetastatic breast cancer, daily aspirin therapy did not improve risk of breast cancer recurrence or survival in early follow-up. Despite its promise and wide availability, aspirin should not be recommended as an adjuvant breast cancer treatment. Trial Registration:ClinicalTrials.gov Identifier: NCT02927249.

INTRODUCTION:Standard investigator-based adverse events (AE) assessment is via CTCAE for clinical trials. However, including the patient perspective through PRO (patient-reported outcomes) enhances clinicians' understanding of patient toxicity and fosters early detection of AEs. We assessed longitudinal integration of PRO-CTCAE within clinical workflow in a phase II trial. MATERIALS AND METHODS:As a sub-study in a phase II trial of genotype-directed irinotecan dosing evaluating efficacy in patients with metastatic colorectal cancer receiving FOLFIRI and bevacizumab, patients reported on 13 AEs generating a PRO-CTCAE form. The primary objective was to estimate forms completed by patients and clinicians at least 80% of time. Secondary objectives were estimating concordance and time to first score of specific symptoms between patient and clinician pairs. RESULTS:Feasibility of longitudinal PRO-CTCAE integration was met as 96% of patients and clinician-patient pairs completed at least 80% of PRO-CTCAE forms available to them with 79% achieving 100% completion. Concordance between patient and clinician reporting a severe symptom was 73% with 24 disconcordant pairs, 21 involved patients who reported a severe symptom that the clinician did not. Although protocol-mandated dose reductions were guided by CTCAE not PRO-CTCAE responses, the median time to dose reduction of 2.53 months, and the time-to-event curve closely approximated time to patient-reported toxicity. CONCLUSION:Longitudinal integration of PRO-CTCAE paired CTCAE proved feasible. Compared to clinicians, patients reported severe symptoms more frequently and earlier. Patient-reported toxicity more closely aligned with dose decreases indicating incorporation into routine clinical practice may enhance early detection of toxicity improving patient safety and quality of life.

This report describes the rationale, purpose and design of A011801 (CompassHER2 RD), an ongoing prospective, multicenter, Phase III randomized trial. Eligible patients in the United States (US) and Canada with high-risk (defined as ER-negative and/or node-positive) HER2-positive (HER2+) residual disease (RD) after a predefined course of neoadjuvant chemotherapy and HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 and placebo, versus T-DM1 and tucatinib. Patients have also received adjuvant radiotherapy and/or endocrine therapy, if indicated per standard of care guidelines. The primary objective of the trial is to determine if the invasive disease-free survival (iDFS) with T-DM1 plus tucatinib is superior to iDFS with T-DM1 plus placebo; other outcomes of interest include overall survival (OS), breast cancer-free survival (BCFS), distant recurrence-free survival (DRFS), brain metastases-free survival (BMFS) and disease-free survival (DFS). Correlative biomarker, quality of life (QoL) and pharmacokinetic (PK) end points are also evaluated.

PurposeNeither the United States nor the European oncology guidelines include details for appropriate management of hyperglycemia in cancer patients. The aim was to identify fasting and random blood glucose thresholds, and hemoglobin A1c (HbA1c) targets used by oncologists in clinical practice when managing hyperglycemia in patients with cancer undergoing chemotherapy.MethodsThis national, cross sectional study utilized a questionnaire to collect oncologists' perceptions about optimal blood glucose thresholds and HbA1c targets in patients with cancer undergoing chemotherapy. Descriptive statistics were calculated to summarize glucose thresholds, HbA1c targets, and sample characteristics. Responses to an open-ended question about oncologists' approach to hyperglycemia management were analyzed via thematic analysis using an inductive approach.ResultsRespondents (n = 229) were on average 52.1 years of age, 67.7% men, and 91.3% White. For patients without diabetes but experiencing hyperglycemia, oncologists targeted lower and upper fasting blood glucose levels between 75-121 mg/dL and 105-135 mg/dL, respectively. For patients with diabetes, the targets for lower and upper fasting blood glucose levels ranged between 100-130 mg/dL and 128-150 mg/dL, respectively. Fasting blood glucose (95.6%) and HbA1c (78.6%) were the most commonly used clinical indicators to consider chemotherapy dose reduction, delay, or discontinuation due to hyperglycemia in patients receiving chemotherapy with curative intent. Among those receiving palliative intent chemotherapy, the preferred clinical parameters were random blood glucose (90.0%), patient-reported blood glucose readings (70.7%), continuous glucose monitoring readings (65.1%), and patient-reported symptoms of hyperglycemia (65.1%). Three main themes emerged about oncologists' approach to hyperglycemia management: 1) identification of high-risk patients; 2) need for early identification, screening, and diagnosis of hyperglycemia; and 3) multiple hyperglycemia management strategies.ConclusionOncologists reported a wide variation of target blood glucose ranges considered appropriate in patients undergoing chemotherapy. Lack of clear guidance for hyperglycemia management during chemotherapy in the United States may be contributing to a lack of consistency in clinical practice.

Abstract Background: Patients with HER2+ early breast cancer (EBC) and invasive residual disease (RD) after neoadjuvant therapy (NAT) have a higher risk of relapse than patients who have a pathologic complete response (pCR). Escalation of therapy in patients with RD using post-neoadjuvant T-DM1 has become the new standard of care, leading to improved invasive disease-free survival (iDFS), but patients with estrogen receptor (ER)-negative or nodal RD have suboptimal outcomes, and central nervous system recurrences are a challenge. More effective treatment strategies are urgently needed. Alliance A011801 (CompassHER2 RD) is an escalation trial for patients with high-risk HER2+ RD after neoadjuvant systemic therapy, evaluating the addition of the HER2 selective tyrosine kinase inhibitor (TKI) tucatinib to post-neoadjuvant T-DM1. Methods: Eligibility and Intervention: Patients with high-risk HER2+ RD (i.e., ER-, node-positive, or both) after a predefined course of neoadjuvant HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 + placebo, vs. T-DM1 and tucatinib with adjuvant RT +/- ET. Eligibility criteria include completion of ≥ 6 cycles of NAT, including ≥ 9 weeks of paclitaxel and trastuzumab +/- pertuzumab. All chemotherapy (CT) must be completed preoperatively unless participating in EA1181 (~15-30% will be participants in the CompassHER2 pCR de-escalation companion trial [NCT04266249]; these patients must receive postoperative CT to complete ≥ 6 cycles prior to enrollment on A011801). Patients who received prior HER2-targeted TKIs or antibody-drug conjugates are ineligible. Objectives: The primary objective is to determine if iDFS is improved with addition of tucatinib to T-DM1 in patients with HER2+ EBC with RD after neoadjuvant systemic therapy; secondary endpoints include overall survival, breast cancer free survival, distant recurrence-free survival, brain metastases-free survival and disease-free survival. Correlative objectives include the association of i) tumor infiltrating lymphocyte (TILs) levels in the primary tumor and RD with iDFS, ii) TILs with tucatinib benefit, iii) iDFS and circulating tumor cells (CTC) at serial timepoints and iv) the magnitude of benefit of tucatinib (iDFS) in patients with/without detectable pretreatment CTCs. Quality of life and pharmacokinetic endpoints are also being evaluated. Statistics: A011801 is a prospective, double-blind, randomized, phase III superiority trial; stratified by i) receipt of postoperative CT (Y/N), ii) hormone receptor-status (+/-), and iii) pathologic lymph node status (+/-). The study targets an absolute difference of 5% in iDFS (control vs. experimental arm 82% & 87%, HR = 0.7), with a two-sided alpha of 0.05 and power of 80%. The sample size is 981; target accrual = 1031 patients; activation and estimated completion dates are 01/6/21 and ~ 01/2028. Accrual as of 7/10/2023: 438 patients. Support: U10CA180821, U10CA180882; Seagen Inc; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT04457596 Citation Format: Ciara O'Sullivan, Karla Ballman, Linda McCall, Tyler Zemla, Anna Weiss, Melissa Mitchell, Victoria Blinder, Nadine Tung, William Irvin, Myounghee Lee, Sailaja Kamaraju, Matthew Goetz, W. Fraser Symmans, Virginia Borges, Ian Krop, Ann Partridge, Lisa Carey. A011801 (CompassHER2 RD): Postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-11.

Abstract Background: The benefit of adjuvant regional nodal irradiation including the chest wall after mastectomy (CWI+RNI) and with whole breast irradiation (WBI+RNI) after breast conserving surgery (BCS) is well established in pts with pathologically positive axillary nodes (pN+). Pts who present with axillary node involvement (cN+), receive neoadjuvant chemotherapy (NC), and are found to be pathologically node-negative at surgery (ypN0), have lower loco-regional recurrence (LRR) rates compared to those who remain pathologically node-positive (ypN+). This phase III, randomized trial aimed to evaluate whether CWI+RNI after mastectomy or addition of RNI to WBI after BCS significantly improves invasive breast cancer recurrence-free interval (IBC-RFI) in cN+ pts found to be ypN0 after NC. Methods: Eligible pts had clinical cT1-3, N1, M0 invasive breast cancer (biopsy-proven N+ by FNA/core needle bx), completed ≥8 wks of NC (and anti-HER2 therapy if HER2+), and were ypN0 after mastectomy or BCS and sentinel node biopsy (SLNB, ≥2 nodes), axillary lymph node dissection (ALND), or both. Pts were randomized to “No RNI” (i.e., observation after mastectomy or WBI after BCS) vs. “RNI” (i.e., CWI+RNI after mastectomy or WBI+RNI after BCS). Primary endpoint was IBC-RFI. Secondary endpoints reported here: LRR-free interval (LRRFI), distant recurrence-free interval (DRFI), disease-free survival (DFS), and overall survival (OS). Study was designed to have 80% power to detect 35% reduction in annual rate of IBC-RFI for an absolute risk reduction of 4.6% (5-yr cumulative rate). Per protocol, final analysis was to occur after 172 events or 10 yrs after study initiation.Here we report the time-driven analysis prespecified in the protocol. Results: From 9/13-12/20, 1,641 pts were enrolled; 1,556 pts were available for primary event analysis; median f/u time 59.5 mos (IQR 40.7-74.1). Pt/tumor characteristics were well balanced between groups. Median age 52 yrs (range 21-84); 31% non-white; 21% cT1, 60% cT2, 19% cT3; 23% triple-negative, 21% HR+/HER2-, 56% HER2+; 58% BCS; 55% SLNB, 45% ALND+/-SLNB; and 78% had breast pathologic complete response. At the time of the analysis, 109 IBC-RFI events (63% of the planned 172) were confirmed (“No RNI”: 59, “RNI”: 50). There was no statistically significant difference between groups for IBC-RFI (HR=0.88, 95%CI 0.60-1.29; p=0.51), 5-yr point estimates: 91.8% for “No RNI” and 92.7% for “RNI.” There were no statistically significant differences between the treatment groups for secondary endpoints. There were no study-related deaths and no unexpected toxicities.Grade 4 toxicity was rare (0.1% with “No RNI”, 0.5% with “RNI”); 6.5% of pts developed grade 3 toxicity in “No RNI” and 10% in “RNI” group. Most common grade 3 toxicity was radiation dermatitis (3.3% in “No RNI,” 5.7% in “RNI”). Conclusion: In pts who present with biopsy-proven axillary node involvement and convert their axillary nodes to ypN0 after NC, CWI+RNI after mastectomy, or WBI+RNI after BCS, did not significantly improve IBC-RFI, LRRFI, DRFI, DFS, or OS. These findings suggest that downstaging involved axillary nodes with NC can result in optimization of adjuvant radiotherapy without adversely affecting oncologic outcomes. Follow-up of pts for long-term outcomes continues. NCT01872975 *EPM and JW are co-first authors. Table 1 Citation Format: Eleftherios Mamounas, Hanna Bandos, Julia White, Thomas Julian, Atif Khan, Simona Shaitelman, Mylin Torres, Frank Vicini, Patricia Ganz, Susan McCloskey, Nilendu Gupta, X. Allen Li, Peter Lucas, Nadeem Abu-Rustum, Saumil Gandhi, Rahul Tendulkar, Robert Coleman, Keiichi Fujiwara, Samantha Seaward, William Irvin, Kristin Higgins, Robert Mutter, Jean-Francois Boileau, Andrew Muskovitz, Reshma Jagsi, Anna Weiss, Curran Walter Jr., Norman Wolmark. Loco-Regional Irradiation in Patients with Biopsy-proven Axillary Node Involvement at Presentation Who Become Pathologically Node-negative After Neoadjuvant Chemotherapy: Primary Outcomes of NRG Oncology/NSABP B-51/RTOG 1304 [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 GS02-07.

Abstract Background: Tumor genomic testing (TGT) has become standard-of-care for all patients with metastatic breast cancer (MBC). American Society of Clinical Oncology (ASCO) and American College of Medical Genetics (ACMG) guidelines for patient education prior to TGT are not widely followed. We have previously demonstrated disparities in general genomic knowledge across race and income. The purpose of this study was to develop a concise (3-4 minute) video for patient education prior to TGT and evaluate the video’s impact in a prospective interventional trial. We report the results of the primary endpoint of the MBC cohort (ClinicalTrials.gov NCT05215769). Methods: We previously published our internal quality improvement cycle involving provider surveys, patient focus groups, and adult learning theory-based content development for TGT educational videos. An animated video incorporating culturally diverse images available in English and Spanish was created to be applicable to any cancer type, with MBC-specific content included for patients with breast cancer. A total of 150 participants were enrolled at a single tertiary academic institution, of whom 53 were diagnosed with MBC. Participants completed validated survey instruments immediately prior to video viewing (T1), immediately post-viewing (T2) and 60-90 days later, after TGT results were documented (T3). Instruments included: 1) 10-question objective genomic knowledge/understanding (GKU); 2) 10-question video message-specific knowledge/recall (VMSK); 3) 11-question Trust in Physician/Provider (TIPP); 4) attitudes regarding TGT. The primary objective was to assess change in VMSK between T1 and T2 and a cohort of 50 participants provided 90% power to detect an effect size of 0.47 from pre- to post-video using two-sided Wilcoxon signed-rank test with alpha of 0.05. Associations of VMSK, GKU, and TIPP with categorical demographic variables were explored with Kruskal-Wallis test. Results: From April 2022 to May2023, a total of 150 participants were enrolled (MBC n=53, lung cancer n=38, metastatic cancer of any type n=59). The MBC cohort analysis is presented. The MBC cohort had a median age of 59; all were female; majority Caucasian (48/53, 91%); most were married/in domestic partnership (35/53, 66%). For the primary endpoint, there was a significant increase in video message-specific knowledge (Wilcoxon signed rank p< 0.0001) but there was no significant change in general genomic knowledge (p=0.89) or trust in provider (p=0.59). Improvement of video message-specific knowledge was consistent across demographic groups, including age, income, and education. Of the 10-questions in the VMSK survey, results for four questions significantly improved after viewing the video, including questions informing the likelihood of TGT impact on treatment decision, incidental germline findings, and cost of testing (Table 1). Baseline genomic knowledge was significantly associated with income (nominal p=0.028), with higher income associated with higher baseline knowledge. Conclusions: A concise, 3-4 minute, broadly applicable video incorporating culturally diverse images administered prior to TGT significantly improved video message-specific knowledge across all demographic groups. Ongoing work includes analysis of additional cohorts (lung, any type) and evaluation in community oncology setting with a goal to provide a paradigm to efficiently educate and empower patients while addressing ASCO/ACMG guidelines within the flow of clinical practice. Table 1. Response to video message-specific questions before versus after tumor genomic testing educational video intervention Citation Format: Daniel Stover, Deloris Veney, Lai Wei, Amanda Toland, Carolyn Presley, Tasleem Padamsee, Clara Lee, Heather Hampel, William Irvin, Jawad Francis, Michael Bishop, Shelly Hovick, Leigha Senter. A Video Intervention to Improve Patient Understanding of Tumor Genomic Testing in Patients with Metastatic Breast Cancer: Primary Results of a Prospective Intervention Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-10-07.

Supplementary Table S4 shows the characteristics of the patients used in the case cross-over analysis

Supplementary Figure S4 shows a validation of the predictive nature of Immunotherapy Response Score