Citations

TPS650 Background: The TAILORx and RxPONDER trials showed that recurrence score (RS) identifies many postmenopausal pts who do not benefit from addition of ACT to endocrine therapy (ET); however, RS also identifies subsets who do benefit (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25). Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2– BC in SOFT/TEXT, we question whether the ACT benefit in TAILORx/RxPONDER was due to chemotherapy-induced OFS. To address this, we developed OFSET, a phase III clinical trial comparing OFS+ET to ACT+OFS+ET. Methods: We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal pts with early-stage HR+/HER2– tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25; pN1 RS 0-15; pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39; ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI) per physician discretion; or tamoxifen if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per protocol guidelines. An HRQOL sub-study will assess severe menopausal symptoms (measured by FACT ESS-19) and pain severity (PROMIS) between arms. Blood and tumor specimens will be collected for future research. We anticipate accrual of 3,960 pts in 7 yrs, 7 mos. Per NSABP B-28/RxPONDER data, 5-yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Per TAILORx data, 5-yr IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with 1-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur ~11 yrs after study initiation. Accrual is 496/3,960 (from 8/2023 to 1/2026). NCT #: NCT05879926. Clinical trial information: NCT05879926 .

Abstract As shown by the TAILORx and RxPONDER trials, recurrence score (RS) identifies many postmenopausal pts who do not benefit from addition of ACT to endocrine therapy (ET); however, it also identifies certain subsets of premenopausal pts who do benefit (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25). Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, we question whether the noted ACT benefit in TAILORx/RxPONDER may have been the result of chemotherapy-induced OFS. To address this, we developed OFSET, a phase III clinical trial comparing OFS+ET v ACT+OFS+ET. We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI) per physician discretion; or tamoxifen if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per protocol guidelines. The HRQOL substudy will assess differences between arms in severe menopausal symptoms (measured by FACT ESS-19) and pain severity (PROMIS). Blood and tumor specimens will be collected for future research. We anticipate accrual of 3,960 pts in 7 yrs, 7 mos. Per NSABP B-28/RxPONDER data, 5-yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5-yr IBCFS of pN0 pts on the ACT arm is ∼95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with 1-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur ∼11 yrs after study initiation. Accrual is 292/3,960 (from 8/2023 to 5/2025). Among 148 pts with OFS data available, 79 (53.4%) were prescribed goserelin and 69 (46.6%) leuprolide. A monthly dosing schedule was prescribed for 86.1% of pts receiving goserelin and 73.5% of those receiving leuprolide; the remaining received a 3-monthly schedule. NCT05879926 Support: U10 CA180868, -80822, UG1 CA189867, U24 CA196067 Citation Format: S. Swain, G. Tang, S. L. Puhalla, P. A. Ganz, N. L. Henry, R. S. Cecchini, S. A. Reid, P. Rastogi, C. E. Geyer, Jr., J. R. White, A. S. Clark, T. C. Haddad, G. A. Vidal, N. Wolmark, E. P. Mamounas. NRG-BR009: A phase III trial evaluating addition of adjuvant chemotherapy to Ovarian Function Suppression + Endocrine Therapy in premenopausal women with pN0-1, HR+/HER2- breast cancer and recurrence score ≤25 (OFSET) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-04.

Abstract Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX® have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy (ET), freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after breast-conserving surgery (BCS) and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for IBR and breast preservation in women intending ET for stage 1 invasive breast cancer (ER and/or PR-positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (≤11, >11-18/MammaPrint Low). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (moderate or ultra hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER and/or PR-positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS ≤18 (diagnostic core biopsy or resected specimen). A “low risk” MammaPrint is permissible if completed as part of usual care prior to screening. Primary endpoint is IBR (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% v 91.6% for the omission-of-RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1%/yr. Some T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. As of July 9, 2025, 1,490 pts have been screened and 1,349 randomly assigned. NCT #: NCT04852887 Support: U10 CA180868, -180822, U24 CA196067, UG1 CA189867 Citation Format: J. R. White, R. S. Cecchini, E. E. Harris, E. P. Mamounas, J. G. Bazan, D. G. Stover, P. A. Ganz, R. Jagsi, S. J. Anderson, C. Bergom, V. Théberge, M. B. El-Tamer, R. C. Zellars, D. A. Shumway, G. Chen, T. B. Julian, N. Wolmark. A phase III trial evaluating De-escalation of Breast Radiation (DEBRA) following breast-conserving surgery of stage 1, HR+, HER2-, RS ≤18 breast cancer: NRG-BR007 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-20.

Abstract Approximately 17% of people aged 65 years and older are anemic, and 10% of death certificates report anemia as a secondary cause of death in the United States. Nonetheless, anemia remains unexplained in 30%-50% of older adults. This unexplained anemia of aging (UAA) is a diagnosis of exclusion. The mechanism, impact, and progression of UAA remain unknown. At older ages, anemia adds to pre-existing co-morbidities with significant adverse health consequences, representing a compelling unmet clinical concern. The National Institute on Aging held a workshop in 2024 to discuss current knowledge and research opportunities. Topics included the epidemiology of anemia at older age and its clinical implications; probable mechanism(s) underlying UAA, that is, low-grade inflammation’s effects on erythropoiesis; the role of microbiota in iron regulation in bone marrow; the importance of ruling out a diagnosis of leukemic clonal hematopoiesis (CH), which is more prevalent in older age; the role of senescence and aging governing hematopoiesis; and the effects of sex hormones on hematopoietic stem cell aging. Understanding the roles of these factors could reduce the proportion of the older anemic population whose anemia remains unexplained and offer insights into new potential diagnostic and intervention strategies. Speakers reviewed previous clinical trials in patients with UAA and CH. They discussed lessons learned and future research priorities, including efforts to develop new diagnostic algorithms and potential uses of machine learning.

Abstract Rationale High-attenuation area (HAA) is a computed tomography (CT) tool that correlates with lung inflammation and fibrosis. Systemic molecular correlates of HAA (e.g., plasma proteins) may inform biological processes involved in interstitial lung disease. Objectives To identify plasma proteins that associate with HAA and correlate with a higher probability of developing new-onset fibrotic or subpleural interstitial lung abnormalities (ILAs). Methods Plasma protein levels were measured using a semiquantitative aptamer-based platform in MESA (the Multi-Ethnic Study of Atherosclerosis; N = 5,486) and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study; N = 1,781). Linear regression models identified HAA-associated proteins after adjustment for demographic and socioeconomic factors, CT scanner parameters, study center, and batch. Associations of HAA-related proteins with new-onset fibrotic or subpleural ILAs were examined in MESA participants with ILA assessments on full-lung CT 10 years later. Immunohistochemical staining of select proteins was performed in lung tissue from pulmonary fibrosis cases. Measurements and Main Results There were 75 proteins detected that were significantly associated with HAA in MESA and SPIROMICS. Gene Ontology analysis of these proteins identified processes involved in immune cell chemotaxis and cellular growth and apoptosis. Seven proteins were associated with a higher probability of new-onset fibrotic or subpleural ILAs in MESA, and two of these, junctional adhesion molecule-like protein and GTP cyclohydrolase 1 feedback regulatory protein, stained in areas of fibrosis in lung tissue from patients with interstitial lung disease. Conclusions Plasma proteins associated with more HAA are involved in immune and cellular processes and associate with new-onset fibrotic-subpleural ILA.

TPS625 Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy (ET), freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after breast-conserving surgery (BCS) and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for IBR and breast preservation in women intending ET for stage 1 invasive breast cancer (ER and/or PR-positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (≤11, >11-18/MammaPrint Low). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (moderate or ultra hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER and/or PR-positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS ≤18 (diagnostic core biopsy or resected specimen). A “low risk” MammaPrint is permissible if completed as part of usual care prior to screening. Primary endpoint is IBR (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% v 91.6% for the omission-of-RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1%/yr. Some T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. As of 1-6-2025: 1,168/1,670 pts have been randomly assigned, and 1,294 screened. Support: U10 CA180868, -180822, UG1 CA189867. Clinical trial information: NCT04852887 .

TPS615 Background: The TAILORx and RxPONDER trials demonstrated that RS identifies many postmenopausal pts with node-neg and node-pos BC and RS ≤25, who do not benefit from addition of ACT to endocrine therapy (ET). Both trials also showed that certain subsets of premenopausal pts (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25) benefited from adding ACT to ET. Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, many questioned whether all or part of the observed ACT benefit in the TAILORx/RxPONDER trials may have been the result of chemotherapy-induced OFS. To address this question, we developed OFSET, a phase III, multicenter clinical trial comparing OFS+ET v ACT+OFS+ET. Methods: We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET v ET is an aromatase inhibitor (AI). Choice is per investigator discretion; tamoxifen is allowed if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per investigator discretion per protocol guidelines. The HRQOL sub-study will assess differences in severe menopausal symptoms, measured by the FACT ESS-19 score between arms, as well as increased pain severity (PROMIS). Blood and tumor specimens will be collected for future research. Accrual of 3,960 pts is anticipated to be completed in 7 yrs, 7 mos. Per NSABP B-28 and RxPONDER data, 5yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5yr IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with one-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur~11 yrs after study initiation. OFSETwas activated Aug 2023. As of 1-6-25, accrual is: 188/3,960. NCT #: NCT05879926. Support: U10CA180868, -80822, UG1CA189867, U24CA196067. Clinical trial information: NCT05879926 .

Abstract Chronic obstructive pulmonary disease (COPD) and pulmonary emphysema were the third-leading cause of death globally in 2019. Besides alpha-1 antitrypsin deficiency, emphysema lacks disease-modifying medications due to its heterogeneity and there remains a need to further investigate emphysema subtypes to advance its diagnosis and treatment. Recent unsupervised machine learning of the texture and anatomical location of emphysema on computed tomography (CT) images of the lung defined six quantitative CT emphysema subtypes uniquely associated with specific gene variants, environmental exposures, symptoms, physiology and clinical events. We aim to identify associations of plasma proteins with each CT emphysema subtype cross-sectionally in a multi-ethnic general population sample. MESA is a prospective cohort study that recruited 6,814 participants from six communities who self-identified as White, Black, Hispanic, or Asian race/ethnicity, ages 45-84 years old and free of clinical cardiovascular disease in 2000-02. The MESA Lung Study performed CT scans among 3,137 participants in 2010-12, which were labeled with previously described (PMID: 37268414) CT emphysema subtypes. Proteomics was assessed using SomaScan version 4.1 assay (7,596 plasma proteins). Linear regression models were adjusted for age, height, weight, sex, race, educational attainment, smoking status, pack years, urine cotinine level, body-mass index (BMI), estimated glomerular filtration rate (eGFR), CT scanner manufacturer and other CT emphysema subtypes. Results were adjusted to reflect a False Discovery Rate (FDR) p-value of less than 5% using the Benjamini-Hochberg method. Among 2,343 participants with both CT and proteomic data (mean age 69.5 years, 52.3% women, 23.7% with COPD), we identified statistically significant associations of proteins with the vanishing lung subtype (42 proteins; top hit Natural cytotoxicity triggering receptor 3 ligand 1, q = 2.9[asterisk]10-9), restrictive combined pulmonary fibrosis/emphysema (CPFE) subtype (11 proteins; top hit Integrin alpha-2/b1, q=1.0[asterisk]10-5), the combined bronchitis-apical emphysema subtype (9 proteins; top hit Desmoglein-2, q=8.8[asterisk]10-13), and the diffuse emphysema subtype (4 proteins; top hit Pulmonary surfactant-associated protein D, q=5.7[asterisk]10-3). No significant proteins were associated with the obstructive CPFE or senile subtypes after FDR correction. Most proteins were uniquely associated with one CT emphysema subtype, while a few proteins were associated with more than one subtype. This study identified specific proteins for different CT emphysema subtypes, many of which have been related less specifically to emphysema, including pulmonary surfactant production, anti-inflammatory pathways, and mitochondrial deregulation, amongst others. Validation of these proteomic associations can provide insight into further pathway assessment, clinical biomarker discovery, and targeted prevention of emphysema in the general population.

TPS311 Background: Approximately 45% of dMMR/MSI-H metastatic colorectal cancer (mCRC) in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Within the AtezoTRIBE 8-pt dMMR CRC subgroup treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first progression event at ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up has been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues at U.S. sites. Current accrual (as of 9-20-2024): 100/120. Clinical trial information: NCT02997228 .