601 Background: NCIT improves survival in high-risk eTNBC; however, trial-based data show that most relapses after NCIT are early. Real-world data are lacking. Methods: This retrospective study included pts from the DFCI Multicenter TNBC registry with eTNBC or estrogen receptor (ER)-low (≤10%), HER2-negative breast cancer (BC) treated with NCIT who underwent surgery before 7/1/2025. Aims were to evaluate (1) patterns of relapse; (2) BC–specific event–free survival (BC-EFS) from the first NCIT dose to relapse, contralateral BC, or death; (3) first-line (1L) metastatic systemic treatment patterns, and (4) time to progression (TTP). Results: 220 pts were identified, with median age of 50.1 yrs (IQR: 40.5-60.8). Median follow-up (FU) was 32.7 months (mo) (IQR, 30.4–34.4). At last FU, 29 pts (13.2%) had relapsed (locoregional, n=2; distant, n=27). Among these, 86.2% had not experienced pathologic complete response. Among relapsed pts with PD-L1 assessment (n=16), 43.8% (n=7) had a Combined Positive Score (CPS) <10; 56.2% (n=9) had a CPS ≥10. BC-EFS is shown in the Table. 1L therapy consisted of antibody-drug conjugate (ADC) in 51.7% (n=15), Poly ADP-ribose Polymerase inhibitor (PARPi) in 13.8% (n=4), chemotherapy in 13.8% (n=4), ADC+PARPi in 3.4% (n=1), CIT in 3.4% (n=1), and HER2-directed in 3.4% (n=1); 10.3% (n=3) died before 1L therapy. Median (m)TTP in 1L (n=26) was 7.7 mo (95% CI, 6.0–13.0) and detailed in the Table. Among pts with disease-free interval (DFI) ≤6 mo (n=8), mTTP was 5.1 mos (2.7–NR), with TTP rates of 50.0% (25.0–100.0) at 6 mo and 16.7% (2.9–95.3) at 12 mo. In those with DFI 6–12 mo (n=9), mTTP was 9.7 mo (7.4–NR); TTP rates were 88.9% (70.6–100.0) at 6 mo and 25.4% (7.7–83.8) at 12 mo. For DFI >12 mo (n=9), mTTP was 8.6 mo (5.6–NR), with TTP rates of 71.4% (44.7–100.0) at 6 mo and 28.6% (8.9–92.2) at 12 mo. Among pts treated with 1L ADC (n=16), mTTP was 8.6 mo (7.4–NR); TTP rates were 77.9% (58.4–100.0) at 6 mo and 26.0% (9.9–68.3) at 12 mo. In non-ADC-treated pts (n=10), mTTP was 6.2 mo (3.78–NR), with TTP rates of 60.0% (36.2–99.5) at 6 mo and 20.0% (5.8–69.1) at 12 mo. Median overall survival (from diagnosis) among pts with relapse was 26.3 mo (95% CI, 25.0–NR). Conclusions: Relapse after NCIT was predominantly early with poor metastatic outcomes, underscoring an urgent need for new strategies in this population largely excluded from clinical trials. Any NCIT(n = 216) KEYNOTE-522(n = 176) 1L for metastatic TNBC(n = 26) Time from NCIT start (mo) BC-EFS % (95% CI) Event N BC-EFS % (95% CI) Event N Time from 1L start (mo) TTP survival % (95% CI) Event N 6 100.0(100.0, 100.0) 0 100.0(100.0, 100.0) 0 6 70.8(54.6, 91.7) 7 12 95.4(92.5, 98.4) 9 95.0(91.7, 98.4) 8 12 23.6(11.0, 50.5) 17 18 89.4(84.9, 94.0) 19 89.7(84.9, 94.8) 15 18 14.2(5.0, 40.3) 19 24 86.4(81.3, 91.8) 23 86.0(80.3, 92.2) 19 24 9.4(2.5, 35.2) 20 36 79.9(72.2, 88.3) 27 82.2(74.8, 90.3) 21

e13013 Background: T-DXd is an effective HER2-directed antibody-drug conjugate (ADC) approved for HER2-positive (IHC 3+ or IHC 2+/FISH+), HER2-low (IHC 2+/FISH− or IHC 1+), and hormone receptor-positive (HR+) HER2-ultralow disease (IHC 0). The efficacy of T-DXd is shown to correlate with the degree of HER2 expression. This study evaluates how HER2 expression predicts response to T-DXd in a real-world, racially diverse population. Methods: A retrospective chart review study was conducted for pts with MBC treated with T-DXd at Winship Cancer Institute of Emory University (2020-2024). HER2 IHC/FISH status was recorded from metastatic biopsies performed prior to T-DXd. Results: Of the 230 pts, 45.2% were non-Hispanic White (NHW; n = 104), 42.6% non-Hispanic Black (NHB; n = 98), 8.3% Asian (n = 19), and 3.9% other (n = 9). 8.3% of tumors were IHC 0 (n = 19), 21.3% IHC 1+ (n = 49), 28.3% IHC 2+/FISH− (n = 65), 13.9% IHC 2+/FISH+ (n = 32), and 28.3% IHC 3+ (n = 65). The median duration of T-DXd was 10 cycles. Within the HER2-low subgroup, median overall survival (mOS) was longer for IHC 2+/FISH− compared with IHC 1+ (18.5 vs 10.1 months, p = 0.0203), while median progression free survival (mPFS) was similar (6.6 vs 6.1 months). Compared with IHC 1+ tumors, IHC 0 tumors had a longer mPFS (12.1 vs 6.1 months) and mOS (15.8 vs 10.1 months), although this difference was not statistically significant. Across all IHC/FISH categories, NHB patients had shorter mPFS (8.6 vs 11.4 months; p = 0.0635) and mOS (16.4 vs 18.3 months) compared with NHW patients. Conclusions: OS and PFS generally increased with higher HER2 expression, with notable exceptions. The difference in OS between IHC 1+ and IHC 2+/FISH− tumors indicates heterogeneity within HER2-low disease. Despite a small sample size in the IHC 0 group, the longer PFS and OS suggest deviation from a linear association between HER2 expression and T-DXd response and support further prospective evaluation in HER2-null tumors using high-sensitivity HER2 assays. NHB patients experienced poorer outcomes than NHW patients following ADC therapy, warranting further investigation into the underlying cause of this disparity. Median progression free survival and median overall survival in months by HER2 expression. IHC/FISH status Number of Patients mPFS (months)* mOS (months)** Hazard ratio for mOS IHC 0 19 12.1 [3.2-17.7] 15.8 [4.0-30.9] 2.1 [1.0-4.4] IHC 1+ 49 6.1 [4.7-8.4] 10.1 [7.0-13.0] 3.3 [1.9-5.8] IHC 2+/FISH- 65 6.6 [3.5-10.0] 17.9 [10.8-29.8] 1.7 [1.0-2.9] IHC 2+/FISH+ 32 12.1 [8.3-17.5] 22.0 [16.8-30.1] 1.4 [0.7-2.6] IHC 3+ 65 25.2 [12.3-37.6] 35.5 [18.3-43.8] n/a *p=0.0001, **p=0.0001 indicate significant differences in OS & PFS among HER2 IHC/FISH subgroups. Square brackets = 95% confidence interval. Hazard ratios were generated with multivariable Cox model in comparison to IHC 3+, adjusting for race, BMI, HR+ status, and prior lines of therapy.

520 Background: Oncotype DX Recurrence Score (RS) predicts recurrence risk and potential benefit from chemotherapy (CT) in early-stage ER+ and HER2- breast cancer (BC). However, real-world CT decision patterns remain poorly understood. This work evaluated how socioeconomic, racial and clinical factors influence CT decisions beyond RS-guided recommendations. Methods: We analyzed patients with early-stage ER+/PR+, HER2- BC in SEER OncoDX RS Database (2004-2019). Variables included age, rurality, poverty status, socioeconomic status (SES), RS, histology, tumor grade, nodal status, PR status, and CT receipt. Treatment disparities among patients with similar RS were evaluated using chi-square tests. Multivariable logistic regression model (MVA) identified independent predictors of CT utilization among patients with similar RS. Results: A total of 208,674 patients were included (median age 60). Median follow up was 4.9 years. Among postmenopausal (post-M, ≥50yrs) women with RS≥26 (CT indicated), lowest SES (60.6% vs 66.5% [highest], P<0.001) and Hispanic ethnicity (63.2% vs 63.3% [White], P=0.016) were associated with lower rate of CT. When CT was not indicated in post-M women (RS<26), Black patients were more likely to receive treatment (9.0% vs 7.9% [White], P<0.001). Among premenopausal (pre-M, <50yrs) women with N0 disease and RS>15, highest SES (41.0% vs 44.2% [lowest], P=0.032) and White race (41.2% vs 46.8 [Black], P<0.001) received less CT. Among pre-M women with N1-3 disease, rural residence (42.9% vs 47.1 [urban], P = 0.004) and White race (44.6% vs 50.1% [Black], P = 0.042) were associated with less CT. MVA showed that invasive ductal carcinoma, grade III tumor, PR-negative status and Black race increased the likelihood of CT irrespective of RS (Table 1). Conclusions: CT decisions were frequently influenced by socioeconomic, racial and clinicopathological factors beyond genomic guided recommendations. Our data highlights a gap between clinical guidelines and real-world practice. Future research should focus on understanding the underlying reasons for deviations in treatment selection and examining changes in practice patterns in the post-RxPONDER era. MVA for CT decision by RS (OR, 95%CI). Pre-M, N0, ≤15 Pre-M, N0, >15 Pre-M, N1-3 Post-M, <26 Post-M, ≥26 SES (highest vs lowest) - 0.88 (0.78-0.99) - - 1.34 (1.22-1.49) Race (B vs W) - - - 1.10 (1.01-1.19) 1.14 (1.03-1.26) Histology (IDC vs ILC) - 1.22 (1.11-1.33) 1.16 (1.01-1.32) 0.84 (0.80-0.88) 1.19 (1.09-1.28) Grade (III vs I) 4.89 (3.72-6.42) 7.13 (6.42-7.93) 5.91 (4.96-7.04) 4.07 (3.80-4.36) 2.44 (2.21-2.71) PR (pos vs neg) - 0.49 (0.43-0.56) 0.44 (0.32-0.60) 0.53 (0.50-0.57) 0.82 (0.77-0.87) Not statistically significant.

e13138 Background: HER2-low/ultralow metastatic breast cancer (mBC) is now clinically actionable with HER2-directed antibody–drug conjugates, but expanding HER2 classification beyond a binary model has increased diagnostic complexity and variability in practice. A prior quality improvement (QI) initiative identified diagnostic and therapeutic gaps among community oncologists, including ambiguous results, inconsistent HER2 testing and reporting, limited multidisciplinary communication, and uncertainty in applying HER2 results to treatment decisions. Building on these findings, we surveyed pathologists nationwide to characterize real-world HER2 testing and reporting practices and identify diagnostic and care coordination barriers between specialties. Methods: From May–June 2025, 100 pathologists completed surveys assessing HER2 testing workflows, interpretation, and classification challenges, including barriers to coordinating with oncologists, with key items tethered to the prior oncology survey. Results: The majority of respondents reported practicing in community-based hospitals and clinics (58%). Sixty-three percent of pathologists identified risk of HER2 misclassification as the greatest challenge in identifying HER2-low/ultralow mBC, compared with 21% of oncologists surveyed in the prior QI initiative, whose top challenge was interpreting ambiguous or borderline results. Similar proportions of pathologists and oncologists reported difficulty interpreting ambiguous or borderline results (53% vs 51%) and limited familiarity with the clinical relevance of lower HER2 expression (28% vs 24%), while inconsistencies in testing and reporting were cited by 55% and 24%, respectively. Pre-analytic and analytic barriers included tumor heterogeneity (52%), suboptimal sample conditions (43%), and inadequate clinical information (39%). Evolving HER2 classification was the most common reporting challenge (76%), and only 47% of pathologists felt comfortable distinguishing HER2 IHC 0 from IHC 1+. Fewer than half of pathologists and oncologists reported that HER2-low status was routinely specified in pathology reports 41% and 37%, respectively. Collaboration with oncologists is hindered by understanding of HER2 testing guidelines (58%), pressure to alter or expedite reporting (28%), and communication through intermediaries (26%). To improve identification, nearly two-thirds of pathologists favored workflows to better differentiate IHC 0 versus 1+, and 58% supported standardizing definitions and documentation. Conclusions: Persistent diagnostic variability and inconsistent reporting limit accurate identification of HER2-low and HER2-ultralow mBC, underscoring the need for standardized workflows, clearer reporting, and improved multidisciplinary coordination between pathologists and oncologists.

TPS1131 Background: Endocrine therapy(ET) resistance is a major challenge in treating estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC); estrogen receptor (ESR1) mutations are an important mechanism of resistance. The standard of care (SOC) first-line treatment for ER+, HER2– MBC is ET plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Despite the benefit of ET and CDK4/6i, disease progression and acquired resistance to the combination remain a challenge. Novel, more effective ETs that can overcome resistance are needed to improve outcomes and delay time to chemotherapy. Palazestrant (OP-1250) is a novel oral, complete estrogen receptor antagonist (CERAN) and selective ER degrader (SERD) that acts by blocking both transcriptional activation function domains, AF1 and AF2, regardless of ESR1 mutation status. As monotherapy, palazestrant showed a tolerable safety profile, favorable pharmacokinetics and encouraging antitumor efficacy in heavily-pretreated patients during phase 1/2 studies, regardless of ESR1 mutation status (NCT04505826; Lin et al. ESMO 2023 MO382). Methods: OPERA-01 (NCT06016738) is a multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to SOC ET (fulvestrant, anastrozole, letrozole, or exemestane) in patients with ER+, HER2– MBC that relapsed or progressed on 1-2 prior lines of ET, including a CDK4/6i. Adult patients are eligible with a diagnosis of evaluable ER+, HER2– inoperable locally advanced or MBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior treatments must include 1 or 2 prior lines of ET with the last ET duration of ≥6 months; must have received and have disease progression on CDK4/6i with ET for MBC. Prior chemotherapy for MBC is not allowed. The study included a dose selection phase, where participants were randomized to 90 mg qd or 120 mg qd palazestrant or SOC; enrollment in this phase is complete. After the dose selection of palazestrant, the study will continue with the selected dose compared to SOC ET at a 1:1 randomization. Overall, 510 patients will be randomized to palazestrant or SOC ET during the study. The primary endpoint of progression-free survival will be assessed by blinded independent central review in patients with and without ESR1 mutations (dual primary endpoint). Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, exposure and patient-reported outcomes in patients with and without ESR1 mutations. Study recruitment began in November 2023. Clinical trial information: NCT06016738 .

Purpose: The POSITIVE trial showed that premenopausal women with breast cancer (BC) can safely pause adjuvant endocrine treatment (ET) to attempt conception. 74 % of patients conceived spontaneously or through assisted reproductive technology (ART); Investigating hormonal factors that predict fertility was a key secondary endpoint. Methods: Hormonal factors were assessed in non-pregnant women at months 3, 6, and 12 after ET interruption. The frequency of low ovarian reserve, defined as anti-Mullerian hormone (AMH) < 0.5 ng/mL at month 3, and of premature ovarian insufficiency (POI), defined as follicle stimulating hormone (FSH) > 25 IU/L at month 12, were primary measures. Secondary analyses to predict pregnancy included AMH, FSH, thyroid stimulating hormone (TSH), prolactin and ovulatory status (defined as progesterone >3 ng/mL at month 6), considering covariates such as age, treatment, and ART use. Results: Of 518 women enrolled in POSITIVE, 438 were eligible for low ovarian reserve analysis. Low ovarian reserve was observed in 209 women (47.7 %), more frequently among older women and those with prior chemotherapy, but not in relation to ET type or duration. Overall, low ovarian reserve was associated with reduced odds of pregnancy (OR:0.52; 95 % CI:0.31–0.87). Of 142 patients evaluated for POI, 16.7 % of those who received prior chemotherapy experienced POI. FSH at month 3 was associated with POI, but only modestly with spontaneous pregnancy (OR:0.96; 95 %CI: 0.93–1.00); other factors were not predictive of pregnancy. Conclusion: Hormonal factors are associated with pregnancy in BC patients pausing adjuvant ET to conceive, and their assessment may help to optimize fertility counseling. Trial registration: ClinicalTrials.gov number NCT02308085.

e13127 Background: T-DXd was approved for the treatment of pts with human epidermal growth factor receptor 2 (HER2)-low mBC based on results from the DESTINY-Breast 04 trial in 6/2022. Outcomes in pts with hormone receptor-negative (HR-) and HER2-low mBC are underexplored, as only 58 HR-HER2-low pts were treated on DB-04. We evaluated the efficacy and tolerability of T-DXd in a diverse, real-world cohort of HR- HER2-low mBC pts. Methods: We conducted a single-center retrospective cohort study of HR- HER2-low mBC pts treated with T-DXd between 7/2022 and 8/2024. HR- status was defined as estrogen and progesterone receptor < 1% and HER2-low as IHC 1+ or IHC 2+/FISH negative. Descriptive statistics were used to summarize pt demographics and clinical characteristics. Progression-free survival (PFS) and overall survival (OS) from T-Dxd start were analyzed for the entire cohort and stratified by race using a log rank test in SAS 9.4. Results: Of 38 pts, 25 (65.8%) were Black, 11 (28.9%) were White, and 2 (5.3%) were Asian/other. Median age at diagnosis (dx) of mBC was 59.5 years (range (R) 33–84). 33 pts (86.8%) had recurrent mBC at dx, and 5 pts (13.2%) had de novo mBC. Pts had a median of 2 lines of therapy (R 0–7) prior to T-DXd; 22 (57.9%) received Sacituzumab Govitecan (SG) before T-DXd. The median duration of T-DXd therapy was 4.2 months (mo) (R 0.03-39.88), with a median of six cycles (R 1–32), and did not vary based on prior SG use. 10 pts (26.3%) had brain metastases at the time of T-Dxd start, with a median duration on T-Dxd of 5 mo in this subgroup. Overall, treatment discontinuation occurred due to disease progression in 20 pts (76.9%) and due to drug toxicity in 4 pts (15.4%). Pneumonitis was not observed. Median OS and PFS were 9.6 mo [95% CI (6, 15.6)] and 6 mo [95% CI (4.8, 8.4)], respectively. Differences in outcomes by race are shown in Table. Black pts had shorter PFS and OS than White pts. In a univariate analysis performed to determine the association of clinical variables with race, time from mBC dx to time of T-DXd start (median 15 mo (Black) vs 37 mo (White)) was the only factor (P = 0.04) found to be significant. Liver or brain involvement, # of prior therapies, age, and # of cycles of T-Dxd were not significant. Conclusions: This study highlights real-world outcomes of T-DXd in a diverse pt cohort, including a high proportion of Black pts with HR-HER2-low mBC (65.8%) compared to DB-04 (1.8%). Our cohort as a whole had inferior PFS/OS compared to DB-04, but our White pts had superior outcomes to that cohort and our Black pts fared significantly worse. Our cohort is small and numbers must be interpreted with extreme caution, but they highlight the need for further study of T-DXd in larger, diverse populations of pts with HR-HER2-low mBC. Differences in survival outcomes by race. Black (N=25) White (N=11) P value OS (median, mo, 95%CI) 8.4 (6, 14.4) 15.6 (4.8, NA) 0.053 PFS (median, mo, 95%CI) 6.0 (2.4, 6) 12.0 (4.8, 40.8) 0.005

Background: Despite treatment advances for patients with early-stage triple-negative breast cancer (TNBC) and hormone receptor (HR)-low/human epidermal growth factor receptor 2-negative (HER2−) breast cancer, treatments that improve clinical outcomes while mitigating toxicity are needed. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate consisting of a humanized IgG1 monoclonal antibody attached via a plasma-stable cleavable linker to a topoisomerase-I inhibitor payload, has shown efficacy alone or in combination with durvalumab, a selective, high-affinity anti-programmed cell death ligand 1 antibody, in early-phase clinical studies. Objectives: The primary objective of TROPION-Breast04 is to evaluate the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2− breast cancer. Design: This is an ongoing, international, phase III, open-label, randomized controlled study. Methods and analysis: Approximately 1728 patients (aged ⩾18 years) will be randomized 1:1 to eight cycles of neoadjuvant Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) plus durvalumab (1120 mg IV Q3W) followed by nine cycles of adjuvant durvalumab (1120 mg IV Q3W) with or without chemotherapy versus eight cycles of pembrolizumab (200 mg IV Q3W) plus chemotherapy followed by nine cycles of adjuvant pembrolizumab (200 mg IV Q3W) with or without chemotherapy. Dual primary endpoints are pathological complete response by blinded central review and event-free survival by investigator assessment. Secondary endpoints include overall survival (key), distant disease-free survival, patient-reported outcomes, and safety. Ethics: The study is approved by independent ethics committees and/or institutional review boards at each study site. All patients will provide written informed consent. Discussion: This study will evaluate the potential use of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2− breast cancer. The findings of this trial could lead to promising treatment options for these patients. Trial registration: ClinicalTrials.gov identifier: NCT06112379.

Purpose/Objective(s) Studies examining ctDNA, a blood-based marker of tumor burden, have largely focused on its use as a prognostic and predictive biomarker. While patient reported outcomes are most often associated with treatment-related toxicities, tumor burden may also contribute to these symptoms, including pain. Approximately one third of patients (pts) who receive radiation (RT) to painful bone metastases (mets) do not experience pain relief, but few studies have identified predictors of response to palliative RT. We hypothesize that ctDNA will predict persistent pain in pts with metastatic breast cancer and could be used to predict response to palliative RT. Materials/Methods Plasma was collected before and 3 months (mos) after RT in pts with stage IV HR+, HER2- breast cancer in the context of a multi-institutional Phase II study of palbociclib, hormone therapy (HT), and palliative RT [30 Gy in 10 fractions (fxns) or 20 Gy in 5 fxns] for bone mets. ctDNA was detected using Snapshot, an anchored multiplex assay that detects 28 clinically significant cancer genes. Pts were eligible if treated with HT and palbociclib for at least one cycle and had either painful bone mets or asymptomatic bone mets at risk for a clinical event. Response, the primary endpoint, was prespecified as either a 2-point decrease in maximum pain score on the Brief Pain Inventory in the irradiated site(s) 3 mos post RT or prevention of a clinical event (e.g., cord compression) among pts with asymptomatic disease. The relationship between ctDNA and response to palliative RT was examined. Results 35 pts completed baseline and 3-month post RT assessments. 27 were treated for painful bone mets. With concurrent palbociclib, 61% and 37% of pts received aromatase inhibitors and fulvestrant, respectively. Median age was 60 years (31-83). 25% of pts were non-Hispanic Black. 72% of pts received 5 fxn RT and 69% received RT to one bone region. 29 pts (83%) were responders [95% CI: 66%-93%, p=.003]. Median progression free survival (PFS) was 30.4 mos (1.3 - 44.0). Three-year PFS and overall survival were 45.6% and 67.2%, respectively. 41% and 39% of pts had detectable ctDNA prior to and 3 mos post RT, respectively. 39% of pts had stable or increased ctDNA proportions 3 mos post RT relative to baseline. Six pts, all of whom presented with painful bone mets, did not respond to palliative RT. 100% of pts (n=15) without detectable ctDNA before and after RT responded to palliative RT, while 39% of pts with stable or increased ctDNA 3 mos post RT had no pain relief to RT (p=0.005). Four pts with ctDNA at baseline had no detectable ctDNA after RT, and all responded to RT. Conclusion Our multi-institutional Phase II trial is the first to demonstrate high rates of response to concurrent RT with palbociclib and HT and to evaluate ctDNA as a biomarker of pain and response to palliative RT in pts with metastatic breast cancer. Our novel findings indicate that ctDNA detection correlates with persistent pain, a patient reported symptom, and predicts the efficacy of palliative RT.

11140 Background: In the United States, uterine cancer is the most common gynecologic (GYN) cancer; and ovarian cancer causes more deaths each year than any other GYN cancer. There are currently no recommended population-wide screening tests for ovarian or uterine cancer, which are heavily concentrated in older women. Medicare is the primary health insurer for 97% of Americans aged 65 years and older. This study is the first to examine the association between Medicare enrollment plan – Medicare Advantage (MA) versus fee-for-service (FFS) – and stage at diagnosis among older women newly diagnosed with ovarian or uterine cancer. Methods: Using the linked Surveillance, Epidemiology, and End Results (SEER) registries and Medicare enrollment data, we identified 101,193 women aged 65 years and older with newly diagnosed ovarian or uterine cancer between 2007-2019. We categorized patients into two groups: 1) those continuously enrolled in Medicare MA for six months prior to their diagnosis, through the diagnosis month, and the month following diagnosis; 2) those continuously enrolled in Medicare FFS within the same eight-month window. Late-stage was defined as “Distant” stage (with “Local” and “Regional” stages representing an earlier-stage diagnosis) using the SEER Summary Stage variable. The association between Medicare enrollment plan and stage was examined through multivariable logistic regression modeling that adjusted for sociodemographic characteristics. The influence of each predictor on the difference in the probability of late stage was summarized as an adjusted marginal effect (ME). Results: Among uterine cancer patients, 37% had MA insurance. Compared with Medicare FFS enrollees, the adjusted percentage of late-stage diagnosis was 0.6 percentage points (ppt) lower for MA enrollees (95% CI = -1.1-(-0.1); P<0.05). Notably, patients were more likely to have a late-stage uterine diagnosis if they were: non-Hispanic Black or Hispanic (vs. non-Hispanic White); age 75 and older (vs. between 65 -74); and residing in a lower SES neighborhood. Among ovarian cancer patients, 34% had MA insurance. We found no significant difference between Medicare MA and FFS enrollees in ovarian cancer stage at diagnosis. Of note, Non-Hispanic Black patients were significantly more likely to be diagnosed with late-stage disease compared to Non-Hispanic White, and likewise for patients aged 75 and older (vs. between 65-74). Conclusions: Among Medicare beneficiaries (age 65+) diagnosed with uterine cancer, those enrolled in an MA plan were significantly less likely to be diagnosed at a later stage. In similar analyses for ovarian cancer, there was no such MA - FFS difference in the probability of late-stage. As enrollment in Medicare Advantage plans continues to grow, it becomes increasingly important to identify whether there are significant outcome differences between MA and FFS plans.

Abstract Background Circulating tumor cells (CTCs) are associated with worse survival in metastatic breast cancer (MBC). The PACE study (NCT03147287) enrolled patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) MBC after progression on CDK4/6 inhibitor (CDK4/6i) and endocrine therapy, and randomized pts to fulvestrant (ful) alone; ful with palbociclib; or ful, palbociclib, and avelumab [Mayer et al., SABCS 2022]. Pts with ≥5 CTCs appear to derive benefit from treatment combinations vs ful alone. In this feasibility analysis, we evaluated estrogen receptor (ER) expression on CTCs to further investigate their monitoring/predictive potential.Methods Blood samples were collected from pts enrolled in the PACE study at: baseline (T1), first tumor assessment (T2) and progression (T3). CTCs were enumerated using the CellSearch platform and samples were classified as CTChigh or CTClow (cutoff ≥5 CTCs). CTChigh samples underwent ER expression quantification with the ACCEPT software [Zeune et al. 2017]. ER expression intensity (ERint) was measured through the Marker Characterization function for each CTC; the average was calculated for each sample. Results From the 220 enrolled pts, a total of 409 samples (166, 153 and 90 collected at T1, T2, and T3, respectively) were analyzed for ER. Overall, 236 samples were CTClow (T1 = 91, T2 = 97, T3 = 48) and 173 were CTChigh (T1 =75, T2 =56, T3 =42). ER was quantified on 3928, 1853, and 2209 CTCs collected at T1, T2, and T3, respectively. Overall, 32.2% of CTCs were ER negative (ER-).The samples’ median ERint showed a numerical decrease from T1 to T3 (T1 = 7.27, T2 = 4.58, T3 = 1.31). Similarly, the % of ER positive (ER+) CTCs per sample decreased from baseline to progression: 26.3%, 14.0%, 5.5% at T1, T2, T3, respectively.CTChigh samples were then classified as ER+ or ER- (ER+ = mean ER_int >0). At T1, 91 (54.8%) samples were CTClow, 67 (40.4%) were CTChigh/ER+, and 8 (4.8%) were CTChigh/ER-. At progression, 48 (53.3%) samples were CTClow, 26 (28.9%) were CTChigh/ER+, and 16 (17.8%) samples were CTChigh/ER-. A numerical increase in the proportion of CTChigh/ER- samples was thus observed from baseline to progression (4.8 to 17.8%).Conclusions Herein we demonstrated the feasibility of evaluating and quantify ER expression on CTCs with a software-assisted approach to reduce inter-operator variability. In the PACE study, ER expression on CTCs was decreased at progression compared to baseline, possibly suggesting a mechanism associated with treatment resistance. Future analyses are needed to investigate the correlation between ER expression levels on CTCs with survival and treatment response. This, together with information about the mutational status of ESR1 by ctDNA sequencing, might provide a new perspective on the development of resistance to ful and CDK4/6i in HR+/HER2- MBC. Citation Format: Mara Serena Serafini, Carolina Reduzzi, Lorenzo Gerratana, Rinath Jeselsohn, Reshma L. Mahtani, Cynthia X. Ma, Angela DeMichele, Jane Lowe Meisel, Kathy D. Miller, Yara Abdou, Elizabeth C. Riley, Rubina Qamar, Priyanka Sharma, Sonya Reid, Harold J. Burstein, Sara M. Tolaney, Michelle K. DeMeo, Yuan Liu, Eric Gauthier, Yue Ren, Meredith M. Regan, Huiping Liu, Erica L. Mayer, Massimo Cristofanilli. Characterization of estrogen receptor expression on CTCs during CDK4/6i treatment in HR+/HER2- metastatic breast cancer: Results from the PACE phase II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3707.

TPS5631 Background: Despite advances, ovarian cancer (OC) is the most lethal gynecologic cancer with 5-year survival rates for stage III and IV disease 41% and 21%, respectively. After initial treatment with cytoreductive surgery and chemotherapy, 70% of patients (pts) will relapse. Treatment of relapsed OC is dependent on the amount of time between completion of platinum-based therapy and relapse, known as the platinum-free interval (PFI). Pts with PFI of less than six months are deemed platinum-resistant with low response to further chemotherapy and median progression-free survival (PFS) of 3.6 months. Additional treatment options are needed. Oncogenic signal transduction pathways are a critical component of cancer pathogenesis. In a variety of cancer types, including OC, the transcription factor STAT3 (Signal Transducer and Activator of Transcription 3) has emerged as a key promoter of cellular proliferation and resistance to therapeutic drugs. In OC cells, STAT3 is constitutively activated in over 70% of cells, resulting in enhanced cell survival, angiogenesis, and metastasis. STAT3 also controls innate and adaptive immune response by driving myeloid-derived suppressor cells and regulatory T cells, while hampering CD8+ T cell cytotoxicity. Using the Connectivity Map database to identify drugs that induce gene expression changes contrary to the STAT3 signature, the FDA-approved antimicrobial atovaquone (ATO) was identified as the most active. ATO, a well-tolerated, readily available drug inhibits STAT3 tyrosine phosphorylation by downregulating the cell surface expression of glycoprotein 130, which is necessary for signaling of IL-6 and Janus Kinase, and subsequent phosphorylation of STAT3. Given that the STAT3 pathway is constitutively activated in OC, we hypothesize that ATO, a potent inhibitor of STAT3, could be a repurposed therapeutic agent in OC. Methods: A Phase II, single-arm, investigator-initiated clinical trial is in process at our institution where we are evaluating ATO as targeted therapy in pts with platinum resistant OC whose tumors have progressed despite standard therapies. To date, we have currently enrolled 2 of an anticipated 28 pts. The primary endpoint is PFS, with clinical secondary endpoints to include clinical benefit rate and overall survival. In addition, to confirm the STAT inhibitory effect on OC cells, pre and on-treatment tissue sampling is being obtained to assess changes in STAT3 dependent gene expression via RT-PCR and quantitate changes to the immune profile via flow cytometry. We hypothesize targeting inappropriate activation of STAT3 could be a novel and promising treatment approach in OC. This is the first clinical trial evaluating the clinical efficacy of ATO in OC and could have wide implications on treatment options in the future. Clinical trial information: NCT05998135 .

1059 Background: PACE is a multicenter randomized phase II trial investigating palbociclib (P) in combination with fulvestrant (F) after progression on any CDK4/6 inhibitor (CDK4/6i), with or without the PD-L1 inhibitor avelumab (A), in HR+/HER2- MBC. CTCs are rare cells in the blood stream whose detection is associated with worse outcome and treatment resistance. Methods: Eligible patients (pts) had HR+/HER2- MBC with prior progression after ≥ 6 months (mo) of AI and CDK4/6i for MBC, or during/within 12 mo in the adjuvant setting, with ≤ 1 prior chemotherapy for MBC. Pts were randomized 1:2:1 to F, F+P, or F+P+A. CTC detection and enumeration were performed utilizing CellSearch (Menarini Silicon Biosystems) at baseline (BL), at time of first tumor assessment (TTA1), and at progression. Results were dichotomized using the standard CTC threshold (≥ 5 CTCs/7.5 ml) into a novel prognostic classification: StageIV indolent and StageIV aggressive (Cristofanilli et al 2019). Concurrent ctDNA Sequencing was performed using Guardant360 (Guardant Health). Results: Of the 220 randomized pts, 203 (92%) had sample available for BL CTC enumeration, 155 had detectable CTCs (70.5%), and 99 (48.8%) were StageIV aggressive . De novo disease at initial diagnosis was associated with StageIV aggressive (47.5% vs 30.8% StageIV indolent ), and distribution of visceral versus non-visceral disease was similar across the two CTCs groups. StageIV aggressive represented 38.3%, 54.8%, and 46.2% of the F, F+P and F+P+A treatment groups, respectively. BL CTCs were prognostic in the overall cohort; median PFS was 5.7mo vs 3.5mo for StageIV indolent vs StageIV aggressive (HR: 1.69, 90%CI 1.27,2.24, P<0.001). Median PFS for the F, F+P and F+P+A arms was 1.9mo, 4.6mo and 5.4mo in StageIV aggressive compared to 8.2mo, 5.3mo and 8.3mo in StageIV indolent . Among patients in the StageIV aggressive subgroup, the F+P and F+P+A arms demonstrated improved outcomes compared to F alone. (F+P vs F HR 0.43, 90% CI 0.25-0.71, and F+P+A vs F HR 0.26, 90% CI 0.14-0.49). No benefit of F+P or F+P+A over F was observed in the StageIV indolent subgroup (F+P vs F HR 1.45, 90% CI 0.87 - 2.40 and F+P+A vs F HR 1.06, 90% CI 0.61 - 1.84, each p(interaction)<0.01). Changes in StageIV CTC characterization (indolent vs aggressive) between BL and TTA1 among the subset of 175/203 pts with both timepoints available are reported. Conclusions: Baseline CTC enumeration is prognostic in patients receiving F with or without CDK4/6i. The StageIV aggressive subgroup may derive preferential benefit with combinations of F+P or F+P+A over F alone. Findings should be confirmed in other studies. ctDNA analyses are ongoing. Clinical trial information: NCT03147287 . [Table: see text]

1051 Background: Tucatinib (TUC) is an oral HER2-targeted therapy approved by the FDA in Apr 2020 for use in combination with trastuzumab and capecitabine (TRA+CAP) for patients with previously treated HER2+ metastatic breast cancer (MBC). In the randomized HER2CLIMB trial, median (95% CI) overall survival (mOS) and progression-free survival (PFS) for patients receiving TUC with TRA+CAP were 21.9 (18.3, 31.0) and 7.8 (7.5, 9.6) months, respectively. Median duration of therapy was 7.3 months. HER2CLIMB used a standard of care comparator arm and included patients with active and stable brain metastasis (BM). HER2CLIMB was conducted prior to approval of fam-trastuzumab deruxtecan (T-DXd) so did not assess the impact of TUC-based therapy following T-DXd. Objective: Describe patient characteristics, treatment patterns, and clinical outcomes for TUC-based treatment in the real-world setting. Methods: This retrospective study included patients in the Komodo Health dataset (aggregating data from patient administrative health claims in the United States) diagnosed with MBC between Jan 1, 2017 and Sep 3, 2022 and initiating TUC post- approval in Apr 2020. Patient characteristics were described in the baseline period (≤6 months from TUC initiation). Key outcomes were time to next treatment (TTNT; as a proxy for PFS), time to discontinuation (TTD), and persistence (proportion continuing treatment at each timepoint) in all TUC-treated patients, and in patients receiving TUC immediately following T-DXd. Results: Of 16,990 patients identified with HER2+ MBC, 528 received TUC-based treatment. Of these, 57 (11%), 164 (31%), 154 (29%), and 153 (29%) received TUC in first-line (1L), second-line (2L), third-line (3L), and fourth-line or later (4L+), respectively. Median follow-up from TUC initiation was 9 months. Overall, 400 patients (76%) had BM prior to initiating TUC (43 [75%], 138 [84%], 111 [72%], and 108 [71%] in 1L, 2L, 3L, and 4L+, respectively). Median (95% CI) TTNT was 10.7 (9.4, 13.1) months overall and 11.5 (9.6, 14.4) in patients receiving TUC in 2L or 3L. Median (95% CI) TTD was 8.5 (7.2, 9.3) months overall, and 9.1 (7.7, 9.9) in patients receiving TUC in 2L or 3L. TUC persistence in the overall cohort was 46% (91/200) at 12 months and 35% (40/115) at 18 months. Sixty-one patients (12%) received TUC immediately following T-DXd (median 4L; 12 in 2L/3L, 49 in 4L+); of whom 36 (59%) had BM prior to initiating TUC. TTNT and TTD for patients treated with TUC following T-DXd were 7.5 (5, 13.3) and 7.3 (3.2, 9.5) months, respectively. Conclusions: In the real-world setting, a higher proportion of patients receiving TUC had BM compared with the HER2CLIMB patient population. TUC-based treatment in the real world is used in multiple lines of therapy and is associated with a similar TTNT and TTD to PFS observed in HER2CLIMB, inclusive of a cohort of patients who received TUC following T-DXd therapy.

PURPOSE BMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib. METHODS Patients were categorized at baseline according to WHO BMI categories. Neutropenia rates were assessed with univariable and multivariable logistic regression. Time to early discontinuation of palbociclib was analyzed with Fine and Gray competing risk models. Unstratified Cox models were used to investigate the association between BMI category and time to invasive disease-free survival (iDFS). 95% CIs were derived. RESULTS Of 5,698 patients included in this analysis, 68 (1.2%) were underweight, 2,082 (36.5%) normal weight, 1,818 (31.9%) overweight, and 1,730 (30.4%) obese at baseline. In the palbociclib arm, higher BMI was associated with a significant decrease in neutropenia (unadjusted odds ratio for 1-unit change, 0.93; 95% CI, 0.91 to 0.94; adjusted for age, race ethnicity, region, chemotherapy use, and Eastern Cooperative Oncology Group at baseline, 0.93; 95% CI, 0.92 to 0.95). This translated into a significant decrease in treatment discontinuation rate with higher BMI (adjusted hazard ratio [HR] for 10-unit change, 0.75; 95% CI, 0.67 to 0.83). There was no significant improvement in iDFS with the addition of palbociclib to ET in any weight category (normal weight HR, 0.84; 95% CI, 0.63 to 1.12; overweight HR, 1.10; 95% CI, 0.82 to 1.49; and obese HR, 0.95; 95% CI, 0.69 to 1.30) in this analysis early in follow-up (31 months). CONCLUSION This preplanned analysis of the PALLAS trial demonstrates a significant impact of BMI on side effects, dose reductions, early treatment discontinuation, and relative dose intensity. Additional long-term follow-up will further evaluate whether BMI ultimately affects outcome.

OP-1250 is a small molecule CERAN/SERD with antitumor activity in breast cancer (BC) xenograft models, including ESR1/PIK3CA mutations and brain metastasis. OP-1250 was administered at 30–300 mg daily (qd) in the dose-escalation part of a phase 1 study. Maximum tolerated dose was not reached and no dose-limiting toxicities occurred. OP-1250 at 60 mg and 120 mg was assessed in the dose-expansion part. Based on safety, pharmacokinetics, and preliminary antitumor activity, 120 mg qd was selected as the recommended phase 2 dose. Here we present the phase 1/2 study data (phase 2 is ongoing). Pts with measurable and nonmeasurable disease were included. Eligible women (any menopausal status) and men had received ≤4 lines of endocrine therapy (ET) and ≤1 line of chemotherapy for metastatic disease. Pts with stable brain metastasis had to have ≥1 prior line of ET and ≤3 prior lines of chemotherapy (both for metastatic disease). Tumor assessment (RECIST v1.1) occurred every 8 weeks (NCT04505826). By March 17, 2023, of 86 pts on OP-1250 (120 mg), 66% had ≥2 prior lines of ET, 30% prior chemotherapy, 67% prior fulvestrant, and 98% prior cyclin-dependent kinase 4/6 inhibitors (CDK4/6i); 45% (34/75) of pts with available baseline ctDNA had ESR1 mutations. The most common (≥15% of pts) all-grade treatment-emergent adverse events (AEs) were nausea, vomiting, neutropenia, fatigue, headache, constipation, and diarrhea. The most common grade 3/4 treatment-related AEs were neutropenia (9%), nausea (3%), and vomiting (3%). Neutropenia was reversible; 3 pts with grade 4 neutropenia were rechallenged at a lower dose without recurrence. There were 4 partial responses (3 confirmed) with a clinical benefit rate of 40% (23/57). In pts with an ESR1 mutation, CBR was 50% (11/22). D[NZ1] [NZ2] ata continue to mature and updated data will be presented. OP-1250 (120 mg qd) was well tolerated with promising efficacy in heavily pretreated pts, including pts progressing on fulvestrant and CDK4/6i. A phase 3 monotherapy study in metastatic BC (second/third line) is planned in 2023.

Breast cancer (BC) pioneered precision medicine with immunohistochemistry (IHC) defined subtypes and early advent of targeted therapies. Trastuzumab deruxtecan (T-DXd) has expanded traditional HER2 definitions to include HER2-low (H2L) tumors, defined as HER2 IHC score of 1+ (>10% cells stained), or as 2+ (>10%) and negative in-situ hybridization (ISH) assay. Studies suggest H2L BC is not a separate clinical entity, strongly determined by hormone receptor (HR) status. We sought to understand the impact of H2L on current standards of care (SOC). Retrospective analysis was performed on 24,824 advanced BC with available genomic, transcriptomic, subtyping, and treatment data. Tumors were tested at Caris Life Sciences via NextGen DNA Sequencing (592 gene panel or whole exome) and RNA (whole transcriptome). BC subtypes were defined by IHC/ISH per accepted definitions. PD-L1 was determined by IHC (SP142 immune cells [IC] ≥ 1%). CODEai, a real-world evidence database was used to access clinical outcomes from insurance claims data, with Kaplan–Meier estimates for overall survival (OS) and 95% CI calculated from time of first treatment to last contact. Patients with HR positive (HR+)/H2L tumors treated with CDK4/6 inhibitors (n=1,348) had similar OS compared to pts with HR+/HER2 0 (n=3,027; 1,179 vs 1,105 days; HR=0.89, CI 0.82–0.98, p=0.012). 27.2% of HR+/H2L pts had activating PIK3CA mutations. Among HR+ PIK3CA mutated tumors, H2L pts treated with alpelisib showed no difference in OS (n=27; 342 days) vs. HER2 0 alpelisib treated pts (n=42; 566 days, HR=1.23, CI 0.66 – 2.29, p=0.517), with limited sample size. 13.9% of H2L TNBC pts were PDL-1+. Pts with H2L PD-L1+ TNBC BC treated with immune checkpoint inhibitors (ICI; atezolizumab, pembrolizumab, nivolumab; n=49) showed improved OS vs. HER2 0 (n=233; 991 vs 524 days; HR=0.61, CI 0.37–0.99, p=0.046). HR+/H2L BC pts treated with SOC endocrine therapy demonstrate no difference in OS compared to HER2 0, and thus, should exhaust endocrine therapy options before initiating T-DXd or chemotherapy until indicated by prospective trials. Combinations of T-DXd plus ICI in PDL1+ H2L BC may be promising opportunities for further investigation.