BACKGROUND:The phase III RxPONDER trial has affected treatment for node-positive (1-3), hormone receptor-positive, HER2-negative breast cancer with a 21-gene recurrence score (RS) less than 26. We investigated how these findings apply to different racial and ethnic groups within the trial. METHODS:The trial randomly assigned women to endocrine therapy (ET) or to chemotherapy plus ET. The primary clinical outcome was invasive disease-free survival (IDFS), with distant relapse-free survival (DRFS) as a secondary outcome. Multivariable Cox models were used to evaluate the association between race/ethnicity and survival outcomes, adjusting for clinicopathological characteristics, RS, and treatment. RESULTS:A total of 4048 women with self-reported race/ethnicity were included: Hispanic (15.1%), non-Hispanic Black (NHB) (6.1%), Native American/Pacific Islander (0.8%), Asian (8.0%), and non-Hispanic White (NHW) (70%). No differences in RS distribution, tumor size, or number of positive nodes were observed by race/ethnicity. Relative to NHWs, IDFS was worse for NHB participants (5-year IDFS 91.6% vs 87.1%, HR = 1.37; 95% CI = 1.03 to 1.81) and better for Asians (91.6% vs 93.9%, HR = 0.64; 95% CI = 0.46 to 0.91). Relative to NHW, DRFS was worse for NHB participants (5-year DRFS 95.8% vs 91.0%, HR = 1.65; 95% CI = 1.17 to 2.32) and better for Asians (95.8% vs 96.7%, HR = 0.59; 95% CI = 0.37 to 0.95). Adjusting for clinical characteristics, particularly body mass index, diminished the effect of race on outcomes. Chemotherapy treatment efficacy did not differ by race/ethnicity. CONCLUSIONS:NHB women had worse clinical outcomes compared with NHWs in the RxPONDER trial despite similar RS and comparable treatment. Our study emphasizes the persistent racial disparities in breast cancer outcomes while highlighting complex interactions among contributing factors. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01272037.

Supplementary Table 3. Patient Characteristics for those with and without assay results

Background: Poor compliance with medications has been linked to inferior health outcomes. Inability to complete therapy is often attributed to adverse effects from the treatment or its financial burden. However, other less easily measurable factors (e.g. trust in the recommendation, fear of future adverse events, nocebo effect, misinformation, convenience, competing life priorities, etc.) can also influence patients’ willingness and ability to follow medical recommendations. In this study, we compared the survival of patients who completed versus not the everolimus placebo pill assigned in the control arm of the S1207 randomized trial. Methods: The S1207 trial compared 1 year of adjuvant everolimus versus 1 year of placebo added to standard of care adjuvant endocrine therapy. No benefit of everolimus was seen for invasive disease-free (IDFS) or overall survival (OS1. Treatment completion rates were 48% in the everolimus arm and 73% in the placebo arm. In this exploratory analysis, we assessed in the control arm if iDFS and OS differed between patients who could complete 1 year of placebo versus those who could not. The Kaplan-Meier method was used to estimate survival from 1 year (i.e. end of treatment period) and the log rank test to compare the groups. Multivariable Cox regression model included age, performance status, and prognostic risk group1 as covariates. Results: This 1-year OS landmark analysis included 823 patients in the placebo arm. Median age was 54 years, 86% were White, 32% premenopausal, and 80% were in prognostic risk groups 3 (i.e. ≥ 4 positive nodes at diagnosis) and 4 (≥ 1 positive nodes after neoadjuvant chemotherapy). Two hundred and twenty-one patients (18%) did not complete placebo defined as taking < 75% of total planned placebo pills. Grade 1-2 adverse events (AE) were reported in 77% (515 out of 670) of the patients in the completer cohort and in 63% (133 out of 211) (p < 0.0001) of the non-completer cohort. Grade ≥3 AEs were reported in 5% and 13% (p < 0.0001) respectively. After placebo discontinuation, endocrine therapy continued for 89% of patients in the completer and 85% of patients in the non-completer cohort (p=0.30). The 1-year iDFS landmark analysis included 782 patients in the placebo arm. The estimated 5-year iDFS rates from 1-year were similar, 76.4% and 78.2% respectively (HR=0.95, 95% CI: 0.64 –1.41, p=0.81). At median follow-up of 74 months, the 5-year OS rate from 1-year among placebo completers and non-completers was 88.6% and 67.4%, respectively (HR=0.32, 95%CI: 0.22-0.44, p<0.0001). In multivariable analysis, only completer status was associated with improved OS (HR=0.31, 95%CI 0.22-0.44, p<0.0001). Conclusion: Patients who were not able to complete the assigned placebo drug in the control arm of the randomized S1207 trial had significantly lower OS compared to those who completed the assigned placebo treatment. Reference: 1. Chavez-MacGregor, M., et al. Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy±1 Year of Everolimus in Patients With High-Risk, Hormone Receptor–Positive, Early-Stage Breast Cancer. J. Clin Oncol, JCO.23.02344 DOI:10.1200/JCO.23.02344. Citation Format: Tara Sanft, Jieling Miao, Allison Meisner, Shay Bellasea, William E. Barlow, Mariana Chavez-MacGregor, Lajos Pusztai. Ability to comply with placebo predicts overall survival in randomized 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 PS15-06.

Supplementary Table 2. Representativeness of Study Participants

Supplementary Figure 1. Progression-Free Survival and Overall Survival in patients with cancers with TP53 co-mutations, and STK11 co-mutations.

Background: While the landscape of metastatic breast cancer treatment has evolved over the years with incorporation of targeted agents and antibody drug conjugates, chemotherapy continues to be the mainstay of adjuvant treatment for high-risk early breast cancer. S0221 was a previously reported phase III randomized trial performed by the North American Breast Cancer Intergroup (now known as the National Clinical Trials Network [NCTN]) investigating alternative dosing schedules of chemotherapy for early breast cancer. Methods: S0221 investigated weekly (arms 2 and 4) doxorubicin (A)/cyclophosphamide (C) + granulocyte colony stimulating factor (GCSF; filgrastim or pegfilgrastim) versus (vs.) every 2 weeks (Q2W) (arms 1 and 3) schedule AC, followed by paclitaxel (P) given Q2W or weekly for 12 weeks as post-operative adjuvant therapy in node-positive or high-risk node-negative breast cancer. Weekly AC was given as doxorubicin 24mg/m2 IV once per week and cyclophosphamide 60mg/m2 orally once per day with GCSF. Between December 2003 and November 2010, 2716 patients were randomized in a 2x2 factorial design to: 1) 15 weeks of weekly AC vs. 6 cycles of Q2W AC and 2) P weekly vs. P Q2W with GCSF support and this accounted for arms 1-4. After enrollment of 2716 patients, randomization to the two AC arms was stopped for futility and the trial was modified to study only the P schedules. Between January 2011 and January 2012, an additional 578 patients were assigned to 4 cycles of Q2W AC and randomized to P weekly vs. Q2W accounting for arms 5-6. Here, we present updated survival outcomes of four arms on the original protocol and report, for the first time, analysis of 578 patients from two additional arms on the revised protocol. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 12.1 years, among the patients treated in the original protocol, there were no significant differences among the four treatment arms for disease free survival [DFS] (p=0.91) or overall survival [OS] (p=0.34). When stratified by disease subtype, the human epidermal receptor-2 (HER2) positive cohort had the highest 10-year DFS rate (77.7%) compared to HR-positive/HER2-negative (70.6%) or HR-negative/HER2-negative (70.3%) cohorts (p value = 0.0005). The HER2-positive cohort also had a superior 10-year OS rate of 82.3% compared to HR-positive/HER2-negative (78.1%) or HR-negative/HER2-negative (74.9%) cohorts (p=0.0044). Among the 578 patients assigned AC for 4 cycles and randomized to P weekly vs. Q2W P, there were no overall differences in DFS (p=0.32) or OS (p=0.42). There was no difference in 10-year DFS rate between original (71.3%) or revised (74.4%) protocol (HR 0.80; 95% CI 0.75-1.05). Patients were also stratified in terms of sex (23 men enrolled) and race (379 Blacks enrolled). While women have superior DFS and OS compared to men, due to small number of men and wide CI, these data should be interpreted with caution. Black patients had worse DFS and OS (10-year DFS rate of 64.2% vs. 72.8%; 10-year OS rate of 70.4% vs. 79.0%) compared to non-Blacks. In terms of toxicity, cardiac toxicity profile was more favorable in arms 2 and 4 (0.5-0.7%) that used weekly AC compared to the other four arms that incorporated AC Q2W (1.1-3.3%). There was more skin toxicity with weekly AC schedule with 15.7-16.1% events compared to 2.4-4.0% events in the other four arms. There was no difference in infectious risk or changes in metabolic profile but there were more neurological AEs, and more pain with arms that used Q2W paclitaxel compared to weekly paclitaxel. Conclusion: As there were no significant outcome differences in DFS or OS between the studied schedules with extended follow-up in the original cohort or in the additional 578 patients treated on the revised protocol, either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference rather than efficacy. Citation Format: Azka Ali, William E Barlow, Halle CF Moore, Timothy J Hobday, Claudine Isaacs, Muhammad Salim, Jonathan K Cho, Kristine J Rinn, Kathy S Albain, Helen K Chew, Gary V Burton, Timothy D Moore, Gordan Srkalovic, Bradley A McGregor, Lawrence E Flaherty, Danika. Long-Term Follow-up and updated analysis from S0221, Comparing Alternative Dose-Schedules of Adjuvant Anthracycline/Taxane Therapy in High-Risk Early 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 RF1-04.

Supplementary Table 1. Dose Modifications for Docetaxel and Trametinib

8003 Background: Stereotactic body radiation therapy (SBRT) is the standard of care (SoC) for early stage, medically inoperable non-small cell lung cancer (NSCLC). While rates of in-field control exceed 90%, regional and distant control after SBRT remain suboptimal. A prior phase II randomized trial suggested a benefit to adding immunotherapy (PMID 37478883). SWOG/NRG S1914 (NCT#04214262) is a randomized phase III trial evaluating neoadjuvant, concurrent and adjuvant atezolizumab plus SBRT for early-stage NSCLC vs SoC. Methods: Eligible patients (pts) had T1-3N0M0 NSCLC ≤7cm, were medically inoperable or declined surgery, and had ≥1 risk factor for increased recurrence: tumor diameter ≥2 cm, ≥6.2, moderately/poorly/undifferentiated histology. Randomization was to SoC SBRT (S [3-8 fractions, biologically effective dose ≥100 Gy]) or neoadjuvant, concurrent and adjuvant atezolizumab (AS [1200 mg IV Q3 week, 8 cycles]) with SBRT initiated with cycle 3, stratifying by tumor location (central vs peripheral), size (<4 cm vs ≥4cm) and ECOG performance status (PS, 0-1 vs 2). The primary objective was to compare overall survival (OS) between the arms. Secondary objectives included comparisons of progression free survival (PFS), failure patterns, toxicity and quality of life (QoL). OS and PFS were compared using a 1-sided stratified log-rank test at the 2.5% level, confidence intervals (CI) are 95%. The accrual goal was 432 eligible pts. Results: From 8/13/20 - 9/6/24, 417 pts were randomized, 403 met eligibility [201 to S, 202 to AS]. Accrual closed at the first interim analysis for futility based on OS and PFS per design. Median follow-up for pts still alive was 12 (range: 0.03-49) months. Median age was 73 (41-91) years and 89% had PS 0-1. Median tumor diameter was 2.3 cm. No protocol treatment was received for 6 pts on S and 8 on AS. With 49 deaths, OS was not different between the arms (HR (CI): 1.15(0.65-2.01), p=0.63; 2-year OS: 82% S vs 80% AS). With 88 events, PFS was not better with AS (HR (CI): 1.35(0.89-2.06), p=0.16); 2-year PFS was 71% on S vs 60% on AS. Regional (2% vs 3%) and distant (4% vs 5%) failures were not different; there were more local failures with AS (13% vs 7%). Among former (53%)/never (3%) smokers, AS had worse OS and PFS than S (HR(CI): 2.50 (1.11-5.59), p=0.03); HR(CI): 2.16(1.15-4.04), p=0.01), respectively. Grade (G) ≥3 adverse event (AE) rates were 12% on AS (N=21 G3, 1 G4, 1 G5 respiratory failure) vs 2% on S (N=3 G3, 1 G4). Conclusions: In the first reported phase III trial to assess immunotherapy (IO) added to SBRT in early-stage NSCLC, IO failed to improve survival. More G ≥3 adverse events were reported with AS. Central review of local recurrence events is ongoing. Additional investigation into subgroups, PD-L1 status, QoL and blood/tissue are pending to determine whether there are subsets who can benefit from this combination and shed further insights into these findings. Clinical trial information: NCT04214262 .

PURPOSEPhosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy.METHODSPatients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC.RESULTSOne thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%).CONCLUSIONOne year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

8504 Background: In unselected patients (pts) with extensive-stage small cell lung cancer (ES-SCLC), the addition of immune checkpoint inhibitors (ICI) to chemotherapy resulted in a modest improvement in OS. In a retrospective analysis of a study with veliparib (PARP inhibitor [PARPi]) and temozolomide in patients with SCLC, Schlafen-11 (SLFN11) predicted PFS and OS benefit for the addition of PARPi. We evaluated whether the addition of PARPi (talazoparib) to standard-of-care maintenance ICI (atezolizumab) following frontline chemoimmunotherapy improved outcomes in pts with SLFN11-positive ES-SCLC. Methods: Participants with ES-SCLC expressing SLFN11 (H-score ≥ 1, evaluated centrally at MDACC) were randomized to maintenance atezolizumab (A) versus atezolizumab plus talazoparib (AT) following frontline chemotherapy and A. Randomization was stratified by Zebrod PS (0-1 vs 2) and use of consolidation thoracic radiation. The primary endpoint was PFS, and secondary endpoints included ORR, OS, and toxicity. The primary analysis was done using a 1-sided 10% level stratified log-rank test. Target sample size was 94 pts. Results: From June 2020 to December 2022, 309 pts were screened, of which 204 of 259 (79%) with evaluable tissue were SLFN11 positive, and 106 were randomized (52 A, 54 AT). Median follow up time is 5 months. Median age was 67 (45-84); 51 (48%) were females; 94 (89%) were white,102 (96%) were PS 0-1, and 26 (25%) had radiation prior to randomization. With 80 PFS events reported, PFS was significantly improved with AT (hazard ratio [80% CI]: 0.70 [0.52-0.94]; p = 0.056). Median PFS was 2.8 months (80% CI 2.0-2.9) for A and 4.2 months (80% CI 2.8-4.7) for AT. OS was not different (hazard ratio [80% CI]: 1.17 [0.80-1.71]; p = 0.30). Median OS was 8.5 months (80 % CI 7.4-12.7) for A and 9.4 months (80% CI 8.1-14.2) for AT. ORR was 16% (5/32, 80% CI 8-27%) for A and 12% (4/34, 80% CI 5-22%) for AT. Grade 3 or greater treatment related non-hematological adverse events (AEs) occurred in 13% pts in A and 15% in AT. Hematological AEs occurred 4% in A compared to 50% pts in AT (Expected for T) (p < 0.001). There were no treatment related grade 5 events. One participant on AT experienced grade 3 febrile neutropenia. The majority of grade 3 AEs were due to anemia (2% in A and 37% in AT). Only three pts discontinued treatment due to toxicity (2 in A and 1 in AT). Conclusions: This study met its primary endpoint demonstrating that maintenance AT improved PFS in SLFN11-selected patients with ES-SCLC. Hematologic toxicity was increased with AT as expected, with majority being grade 3 anemia. This study demonstrates the feasibility of conducting biomarker selected trials in SCLC, paving the way for future evaluation of novel therapies in selected SCLC populations. Clinical trial information: NCT04334941 .

PURPOSE To evaluate whether the addition of a poly (ADP-ribose) polymerase inhibitor (PARPi) talazoparib to maintenance immune checkpoint inhibitor (ICI) atezolizumab following frontline chemoimmunotherapy improved outcomes in patients with Schlafen 11 (SLFN11)-positive extensive stage small cell lung cancer (ES-SCLC). METHODS Patients with newly diagnosed SLFN11 expressing (H-score ≥ 1, evaluated centrally) ES-SCLC were randomized to maintenance atezolizumab (A) versus atezolizumab plus talazoparib (AT) following frontline chemotherapy plus atezolizumab. The primary objective was to compare progression-free survival (PFS) using a 1-sided 10% level stratified log-rank test. Secondary endpoints included objective response rate (ORR), overall survival (OS), and toxicity. Target sample size was 84 eligible patients. RESULTS From June 15, 2020 to December 15, 2022, 106 eligible patients were randomized (54 to AT and 52 to A). PFS was improved with AT versus A (hazard ratio [HR], 0.66; 80% confidence interval [CI]: 0.50-0.86; 1-sided P = 0.019) with a median PFS of 2.9 and 2.4 months; OS was not different between groups (HR, 0.98; 80% CI: 0.71-1.36; 1-sided P = 0.47). Grade ≥ 3 non-hematologic treatment-related adverse events (TRAEs) occurred in 17% of patients with AT and 14% of patients with A. Grade ≥ 3 hematological TRAEs were more common in AT (50%) than in A (4%) (P < 0.001). CONCLUSION Maintenance AT improved PFS in patients with SLFN11-positive ES-SCLC that did not progress following initial chemo-immunotherapy. Hematologic toxicity, primarily grade 3 anemia, was increased with AT, as expected. Prospective biomarker-selection was demonstrated, paving the way for future evaluation of novel therapies in molecularly defined SCLC populations.

11019 Background: Studies show that <10% of patients with cancer participate in clinical trials. Pragmatica – Lung (SWOG S2302) utilizes a pragmatic approach for a registrational (FDA) trial that allows less data collection and broader eligibility, thus decreasing barriers to diverse enrollment. S2302 aims to improve overall and diverse accrual by using a novel trial design and multilevel community engagement. Methods: S2302 is a real-world randomized phase III registrational study comparing pembrolizumab + ramucirumab vs investigator-chosen standard therapy in 2nd line advanced/metastatic NSCLC. A multi-stakeholder recruitment plan was developed to improve diverse accrual (with initial focus on recruiting Black patients). The plan was vetted through SWOG communications and SWOG Lung Committee’s Working Group, DEI champion, patient advocate, and community engagement subcommittee. The DEI champion identified sites in the Southeast with high minority accrual in prior trials and completed directed informational visits. An external firm created culturally and linguistically appropriate patient education material, engaged sites with historically high accrual of Black and/or LatinX patients, leveraged advocacy partners to improve community awareness, and monitored enrollment by site. A monthly accrual report with demographic summaries (including age, sex, race, ethnicity) and site enrollment information is generated from SWOG Statistics and Data Management Center to monitor accrual rate and diversity. Results: From March through December 2023 (Table), the study accrued 37% of its goal and is enrolling above its target rate of 25 pts/mo averaging 36/mo over the last 5 months. Of enrolled pts, 58% are male, 13% are Black, and 3% are LatinX; from 59 academic, 67 community (13% rural), and 2 VA sites. Comparatively, LungMAP S1800A (the phase II precursor to S2302) accrued 7% Black and 1.5% LatinX pts with an average accrual of 9.2 pts/mo. Through November, the external firm contacted 24 site PIs (63% community-based), whose sites had collectively enrolled 16 pts, for a normalized pre-call rate of 0.1340 pts/mo. After contact and through November, these sites enrolled 23 pts, a rate of 0.3835 pts/mo – a 186% increase. Conclusions: The intentional, multi-pronged recruitment plan has exceeded historical overall, Black, and LatinX patient accrual rates. The data highlight novel approaches to trial design, recruitment strategies, and increased internal and external collaboration resulting in improved diversity of clinical trial enrollment and may be a potential toolkit for future trials. Support: NIH/NCI grants U10CA180888 and U10CA180819; and in part by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Eli Lilly and Company. Clinical trial information: NCT05633602 . [Table: see text]

TPS8657 Background: Most patients (pts) with advanced non-small cell lung cancer (NSCLC) will receive treatment with immunotherapy and develop tumor resistance. Several trials investigating combination therapy have not shown benefit over chemotherapy. Additional therapeutic options are needed. Complex clinical trials increase barriers to enrollment. Pragmatic trial designs may overcome challenges with accrual and representativeness in the appropriate setting. S1800A was a randomized phase II trial within Lung-MAP that showed a statistically significant improvement in overall survival (OS) with PR versus SOC for pts with advanced NSCLC who had tumor progression on prior chemotherapy and immunotherapy (JCO 2023). As a follow-on, we designed a pragmatic, randomized, registration intent trial to validate OS results and enhance representative accrual reflecting real-world practice. Methods: S2302 is a registration-intent randomized trial for pts who previously received PD-(L)1 inhibitor therapy for at least 84 days and platinum-based therapy, stratified by immediate prior line of therapy including PD-(L)1 inhibition (yes/no) and PS (0/1 v. 2). Pts are randomized to PR or investigator’s choice SOC (recommended to be based on NCCN guidelines). The primary objective is to compare OS between the arms. The only secondary objective is to summarize serious and unexpected high-grade (Grade 3-4) treatment-related adverse events and all Grade 5 adverse events. The accrual goal is 700 pts based on a design with 85% power to detect a hazard ratio of 0.77, using a 1-sided 2.5% level log-rank test. Estimated accrual duration is 24 months. As of January 2024, 286 pts were randomized, and enrollment is ongoing. S2302 Pragmatica-Lung presents a novel and potentially practice-changing paradigm to conduct a study with a combination of FDA approved drugs with well-known safety profiles and limited toxicity overlap. There are no onerous radiology or specimen requirements, and SOC treatment is provided as per FDA-approved package inserts and institutional policies. The goal is to empower practicing clinicians to enroll pts they see every day by reducing the study barriers and burden of clinical trial participation. The resulting pts enrolled will be more representative than other registration-intent trials. This approach allows the trial to reach more patients and holds the potential to better inform the field across a more representative set of pts with broader impact. Clinical trial information: NCT05633602 .

Introduction: Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the differential effect of endocrine therapy (ET) vs chemotherapy followed by endocrine therapy (CET), including the impact of menopausal status, on CRCI is not well understood. Methods: Participants (pts) with hormone receptor positive, HER2 negative breast cancer with 1-3 positive lymph nodes and an Oncotype DX recurrence score of 0-25 enrolled in the RxPONDER trial were randomly assigned to ET alone versus CET. Until the health-related quality of life (HRQoL) accrual goal was reached, English speaking pts in the US were invited to complete HRQoL questionnaires including the 8-item PROMIS Perceived Cognitive Function Concerns (PCF) Short Form questionnaire shortly after randomization (baseline), as well as 6, 12, and 36 months after baseline. Analysis of measures of anxiety and fatigue is presented separately. Standardized T scores (mean 50; SD 10) for PCF were computed with higher scores indicating less cognitive impairment. The primary endpoint of this exploratory analysis was to compare mean PCF T scores by treatment arm and menopausal status. Separately by menopausal status, a generalized estimating equations (GEE) model was fit to the three timepoints adjusting for baseline to estimate the difference between treatment arms and whether there was a time trend over the three follow-up measures. Results: The HRQoL accrual exceeded the goal of 500 patients, with 74% of pts participating voluntarily until the QOL invitation was removed from the protocol (Dec 1, 2012). A total of 139 pre and 429 postmenopausal pts completed the questionnaires at baseline. T scores were similar between ET and CET arms at baseline [Table 1]. In the ET arm, T scores decreased from baseline to 6 and 12 months but recovered to baseline at 36 months. In the CET arm, T scores decreased from baseline to 6 months and 12 months but did not return to baseline at 36 months. The mean score difference between CET and ET over time was -3.02 (p=0.01) and -2.36 (p=0.003) for pre and postmenopausal pts, respectively. Adjusting for baseline, there was no significant time trend over the three follow-up periods for either premenopausal (p=0.12) or postmenopausal (p=0.49) pts. Dropoff occurred over time with 79%, 76%, 60% of pts at baseline participating at 6, 12, and 36 months. Complete endocrine treatment adherence data are not yet available at each timepoint. Conclusion: Chemoendocrine therapy has a greater negative effect on patient-reported CRCI compared to ET alone in both pre- and post-menopausal pts and it is sustained over 36 months. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of patients treated with CET. Table 1. Comparisons of mean Cognitive Function score by treatment arm and menopausal status. Citation Format: Irene Kang, Jamie K. Forschmiedt, Michelle M. Loch, William E. Barlow, Danika L. Lew, Julie R. Gralow, Funda Meric-Bernstam, Kathy S. Albain, Daniel F. Hayes, Nancy U. Lin, Edith A. Perez, Lori J. Goldstein, Priya Rastogi, Anne F. Schott, Steven Shak, Priyanka Sharma, Jieling Miao, Debu Tripathy, Lajos Pusztai, Gabriel N. Hortobagyi, Kevin Kalinsky, N. Lynn Henry. Patient-reported cognitive impairment in women participating in the RxPONDER trial (SWOG S1007) by menopausal status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-04.

Introduction: Racial disparities in breast cancer (BC) outcomes continues to be a major health care challenge. The 21-gene recurrence score (RS) is an important tool to guide treatment (tx) decisions among women with early-stage BC. We report an analysis of clinical characteristics, survival outcomes and race in association with RS in participants (pts) in the RxPONDER trial. Methods: We analyzed clinical outcomes with respect to race and ethnicity. Unreported race excluded 18.7% of the pts, with most due to privacy rules. The primary outcome was invasive disease-free survival (IDFS). Distant relapse-free survival (DRFS) was also evaluated. Analyses adjusted for assigned tx arm, RS, and grade were performed. There were too few events to include Native American/Pacific Islander (NAPI) women in the survival analyses. Results: A total of 4,048 trial women with Hormone Receptor positive, HER2 negative (HR+/HER2-) BC, 1-3 involved axillary lymph nodes (LNs), RS ≤ 25 and known race/ethnicity were included in this analysis including the following: 2,833 non-Hispanic (NH) White pts (70%), 248 NH Black pts (6.1%), 610 Hispanic pts (15.1%), 324 Asian pts (8.0%), and 33 NAPI pts (0.8%). Asian and Hispanic women were younger than NH Whites (by 7.1 and 2.4 years, respectively) but NH Blacks did not differ in age. RS distribution did not differ among all racial subgroups (p=0.49). There were also no significant differences in tumor size (p=0.10) or number of positive LNs (p=0.26) across all racial groups. However, tumor grade was found to be significantly different with grade 3 tumors higher for NH Blacks (18.0%), NH NAPI (21.1%), and Hispanics (14.5%) vs. NH Whites (10.4%) and Asians (6.5%) (p< 0.001). Overall five-year IDFS was lower for NH Blacks (87.0%) compared to that for Asians (93.9%), NH Whites (91.5%), and Hispanics (91.4%) (Table 1). A multivariable Cox model adjusting for RS and tx arm showed worse IDFS for NH Blacks compared to NH Whites (HR=1.38; 95% CI 1.00-1.90; p=0.048), although Asian pts had better IDFS than NH Whites (HR=0.65; 95% CI 0.44-0.97; p=0.034). In a separate analysis by menopausal status the magnitude of the IDFS hazard ratios (HRs) for NH Blacks was similar, although no longer statistically significant (premenopausal HR=1.37; 95% CI 0.69-2.72; postmenopausal HR=1.38; 95% CI 0.96-1.98). While there was no statistically significant interaction between NH Blacks vs. NH Whites and tx arm for either premenopausal (p=0.99) or postmenopausal women (p=0.44), adjusting for RS, the small number of events in the NH Black cohort, particularly in premenopausal women (n = 9 IDFS events), limit power and inference about differences in chemotherapy benefit. Among postmenopausal women, NH Blacks had worse DRFS compared to NH Whites (HR=1.69; 95% CI 1.12-2.53; p=0.01), adjusting for tx and RS. A similar trend was seen among premenopausal women (HR=1.74; 95% CI 0.79-3.82; p=0.17), although not statistically significant. Data on tx adherence over 5 years was not mature, although NH Blacks were more likely to accept tx assignment compared to NH Whites at randomization (93% vs. 86%, p=0.004). Conclusion: Black women with HR+/HER2- BC, 1-3 involved LNs and RS ≤ 25 have worse outcomes compared to White women despite similar RS results. There was no significant interaction between NH Blacks vs. NH Whites and tx arm, although this analysis was limited due to sample size. There remains an important need for novel approaches to improve clinical outcomes particularly for NH Black Women. Table 1. IDFS by Race and Ethnicity. Citation Format: Yara Abdou, William E. Barlow, Julie R. Gralow, Funda Meric-Bernstam, Kathy S. Albain, Daniel F. Hayes, Nancy U. Lin, Edith A. Perez, Lori J. Goldstein, Stephen K. Chia, Sukhbinder Dhesy-Thind, Priya Rastogi, Emilio Alba, Suzette Delaloge, Anne F. Schott, Steven Shak, Priyanka Sharma, Danika L. Lew, Jieling Miao, Joseph M. Unger, Debu Tripathy, Lajos Pusztai, Gabriel N. Hortobagyi, Kevin Kalinsky. Race and clinical outcomes in the RxPONDER Trial (SWOG S1007) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-01.

Supplementary Figure from Circulating Tumor DNA Kinetics Predict Progression-Free and Overall Survival in EGFR TKI–Treated Patients with EGFR-Mutant NSCLC (SWOG S1403)

Introduction: Anxiety and fatigue have been reported by women undergoing cytotoxic and endocrine treatment (tx) for breast cancer and can have lasting effects on quality of life (QoL). The differential effects of menopausal (meno) status, tx allocation and duration of symptoms are not well established. Methods: Participants (pts) with hormone receptor positive, HER2 negative breast cancer with 1-3 positive lymph nodes and an Oncotype DX recurrence score of 0-25 enrolled in the RxPONDER trial were randomly assigned to endocrine therapy (ET) alone vs chemotherapy followed by ET (CET). A subset of English speaking pts in the US at the start of the trial were invited to complete health-related QoL (HRQoL) questionnaires shortly after randomization (baseline; BL) and 6, 12, and 36 months after BL until accrual goal reached. BL surveys were completed in clinic; cognitive function results presented separately. Standardized T scores (mean 50; SD 10) were computed for anxiety (PROMIS Emotional Distress – Anxiety Short Form 7a) and fatigue (PROMIS Fatigue Short Form 7a). Higher T scores indicate more anxiety or fatigue. The primary endpoint of this exploratory analysis was to compare mean anxiety and fatigue T score by tx arm by meno status. Separately by meno status, a GEE model was fit to the three follow-up timepoints adjusting for BL to estimate the difference between tx arms and whether there was a time trend over the three follow-up measures. Results: The accrual exceeded the goal of 500 pts with 74% of pts participating voluntarily until the QOL invitation was removed from the protocol (12/1/12). A total of 139 pre and 432 postmenopausal pts completed the anxiety questionnaire at BL. There was no difference in anxiety between tx arms [Table 1]. Mean anxiety score difference between CET and ET over time in the premenopausal cohort was -0.63 (p=0.63) and in the postmenopausal cohort was 0.59 (p=0.45). Although anxiety scores decreased over the three follow-up times, the change was not statistically significant. A total of 139 pre and 429 postmenopausal pts completed the fatigue questionnaire at BL. Fatigue mean T scores in both the pre and postmenopausal cohorts were higher over time in the CET vs ET arm [Table 2]. Fatigue scores were 2.85 points higher for CET vs. ET over time in the premenopausal cohort (p=0.02) and 1.82 points higher in the postmenopausal cohort (p=0.007). Fatigue scores decreased over time for premenopausal (p=0.01), but not for postmenopausal (p=0.62) pts. Dropoff occurred over time with 79%, 76%, 60% of pts at BL participating at 6, 12, and 36 months. Endocrine treatment adherence data are not yet available at each timepoint. Conclusions: CET had a clinically significant negative effect on mean fatigue scores compared to ET alone in both pre and postmenopausal pts over time. Scores improved over time but did not return to BL. Pts had lower mean anxiety scores during tx compared to BL, but differences in scores between CET and ET groups out to 3 years did not significantly differ. Future therapeutic studies must continue to include HRQoL assessments to broaden our understanding of the full impact of chemotherapy and for the development of preventative and therapeutic strategies to manage these toxicities. Table 1. Comparisons of mean Anxiety score by treatment arm and menopausal status. Table 2. Comparisons of mean Fatigue score by treatment arm and menopausal status. Citation Format: Michelle M. Loch, Jamie K. Forschmiedt, Irene M. Kang, Julie R. Gralow, Funda Meric-Bernstam, Kathy S. Albain, Daniel F. Hayes, Nancy U. Lin, Edith A. Perez, Lori J. Goldstein, Priya Rastogi, Anne F. Schott, Steven Shak, Priyanka Sharma, Danika L. Lew, Jieling Miao, William E. Barlow, Debu Tripathy, Lajos Pusztai, Gabriel N. Hortobagyi, Kevin Kalinsky, N. Lynn Henry. Patient-reported anxiety and fatigue in women enrolled in the RxPONDER trial (SWOG S1007) by menopausal status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-06.