e15072 Background: 18 F-fluoroestradiol positron emission tomography (FES-PET) is a highly specific imaging modality for detecting estrogen receptor-positive (ER+) breast cancer (BC), particularly when biopsy is not feasible or conventional staging is equivocal. Endocrine therapy (ET) resistance often develops during ER+ BC treatment and arises from genomic alterations that promote estrogen-independent signaling and, for some alterations, reduced ER expression. As clinical use of FES-PET expands, understanding the potential impact of these alterations on FES-PET avidity is important. Therefore, we assessed the relationship between tumor genomic profiles and FES-PET positivity in ER+ BC. Methods: We conducted a single-center retrospective study of patients with histologically confirmed ER+ BC at diagnosis who underwent FES-PET/CT or PET/MR between 12/2023-8/2025 and had blood- or tissue-based genomic testing within 6 months of imaging. Human epidermal growth factor receptor 2-positive (HER2+) and negative (HER2-) tumors were included. FES-PET positivity was defined as SUVmax >1.5 in the most avid lesion, assessed by a board-certified nuclear radiologist. Results: Forty-three patients were included (4 local recurrences, 39 metastatic). FES-PET was positive in 22 patients, was non-avid in 9, had mixed ER+ and ER- disease in 2, was indeterminate in 2, and showed no evidence of disease in 8. Of the 9 non-avid FES-PET cases, 3 had ER+ disease on biopsy at metastatic recurrence, 4 had ER- disease, and 2 had mixed ER+ and ER- disease. Genomic profiling was performed via liquid biopsy (n = 33), tissue-based testing (n = 9), or both (n = 1). PIK3CA and TP53 mutations were the most frequent alterations seen in 15 and 11 patients, respectively; 9 patients with PIK3CA mutations and 6 with TP53 alterations had a positive FES-PET. ESR1 mutations were identified in 5 patients, 4 with a positive FES-PET. FGFR1 amplification was seen in 3 patients; one had a strongly positive FES-PET, one had mixed ER+ and ER- lesions, and one had a negative FES-PET despite ER+ disease. KRAS mutations were present in 3 patients; two had a positive FES-PET. The other had ER- disease at recurrence and negative FES-PET. RB1 loss was seen in 2 patients; one had a negative FES-PET in the setting of ER- disease at recurrence, the other had mixed ER+ and ER- lesions. ERBB2 mutations were identified in 2 patients; one had a positive FES-PET, the other had lesions too small to characterize. Conclusions: FES-PET is a valuable imaging tool, though false-negative results can occur and may limit its suitability for initial staging in advanced ER+ BC. In this cohort of ER+ BC patients undergoing FES-PET with concurrent genomic profiling, heterogeneity in FES avidity was seen across multiple genomic alterations associated with resistance to antiestrogen therapies. Further evaluation in a larger cohort is ongoing; updated findings will be presented at the meeting.

Importance:Colorectal cancer (CRC) is the second most common cause of cancer mortality in the US and disproportionately impacts individuals in underresourced settings. Objective:To compare 2 mailed population outreach approaches to increase CRC screening uptake among screening-eligible adults in community health centers (CHCs). Design, Setting, and Participants:This pragmatic cluster randomized clinical trial was conducted in 8 CHCs and an additional site in a nonrandomized parallel protocol. The CHCs were located in the greater Boston area in Massachusetts and Los Angeles County in California (randomized sites), and Rapid City, South Dakota (parallel site). Patients were enrolled in the trial between June 7, 2023, and October 24, 2023. English- or Spanish-speaking primary care patients aged 45 to 75 years, who were due for CRC screening, were eligible to participate. Interventions:Patients received either mailed fecal immunochemical test (FIT) with automated text message outreach from study personnel or mailed FIT-DNA with the manufacturer's outreach protocol. Participants in Boston and Los Angeles (randomized sites) with an abnormal FIT or FIT-DNA result were offered standardized navigation to colonoscopy. Main Outcomes and Measures:The primary outcome was CRC screening participation using any modality (FIT, FIT-DNA, or colonoscopy) within 90 days. Secondary outcomes were screening within 180 days and time to screening participation. The completion of follow-up colonoscopy within 180 days of an abnormal stool test result was also studied. Results:Among 5127 participants in the RCT regions, 2435 (47.5%) were in the FIT group, and 2692 (52.5%) were in the FIT-DNA group. The mean (SD) age was 54.5 (8.1) years; 3018 (58.9%) were female, and 2109 (41.1%) were male. There were 3818 Hispanic individuals (74.5%), 369 non-Hispanic Black individuals (7.2%), 763 non-Hispanic White individuals (14.9%), and 58 individuals of another race (1.1%). A total of 3363 individuals (65.6%) preferred the Spanish language; 2540 (49.5%) were Medicaid insured, and 614 were (12.0%) uninsured. Screening participation was significantly higher in the FIT-DNA group vs the FIT group at 90 days (751 of 2692 [27.9%] vs 550 of 2435 [22.6%], respectively; P = .02) and 180 days (854 of 2692 [31.7%] vs 649 of 2435 [26.7%], respectively). In Boston, screening participation at 90 days was higher (628 of 2208 [28.4%]) than in Los Angeles (673 of 2919 [23.1%]). Findings were similar at 180 days. Among the 100 individuals with an abnormal stool test result, 36 (36.0%) completed a colonoscopy within 180 days. Conclusions and Relevance:In this cluster randomized clinical trial, CRC screening uptake was higher in the FIT-DNA group than in the FIT group and was higher in Boston compared to Los Angeles CHCs. The follow-up colonoscopy rate within 6 months was suboptimal, even with the availability of navigation. Trial Registration:ClinicalTrials.gov Identifier: NCT05714644.

PURPOSE:In TBCRC 022 (NCT01494662), neratinib and ado-trastuzumab emtansine (T-DM1) demonstrated intracranial activity among patients with HER2-positive breast cancer brain metastases. However, gastrointestinal (GI) toxicities-particularly diarrhea-were common, potentially impacting quality of life. Clinician-reported adverse event (CTCAE) grading may underestimate the patient experience. We report GI toxicities using patient-reported outcomes (PROs) in TBCRC's neratinib-T-DM1 cohort. METHODS:Patients received neratinib (160 mg daily) and T-DM1 (3.6 mg/kg IV every 21 days). A pre-planned analysis assessed patient-reported GI toxicities during Cycles 1-4 using the Patient-reported Outcomes Measurement Information System (PROMIS) GI Diarrhea scale, Systemic Therapy-Induced Diarrhea Assessment Tool (STIDAT), and PRO-CTCAE. Descriptive statistics and linear mixed effects models evaluated symptom trajectories over time. We evaluated agreement for PRO and clinician-reported data. RESULTS:Forty-four patients enrolled; all completed ≥1 PRO. GI symptom burden increased over Cycles 1-3. PROMIS scores worsened significantly by Cycle 2, with a peak mean increase of 6.62 (95% confidence interval (CI): 2.67-10.59; p = 0.002) at Cycle 3. STIDAT scores also worsened by Cycle 3 (mean change 0.50; 95%CI: 0.11-0.90; p = 0.015). Based on maximum PRO-CTCAE scores, moderate-to-severe symptoms were reported by 20.5% (diarrhea), 24.4% (appetite loss), and 41.0% (constipation). Agreement between PRO-CTCAE and clinician-reported CTCAE was low (kappa <0.2) with clinicians reporting less toxicity. PROMIS and STIDAT scores were significantly correlated. CONCLUSION:This GI-focused PRO analysis highlights the value of PROs in capturing patient-experienced toxicities that impact quality of life yet are underestimated by clinicians. Incorporating PROs into clinical trials can inform supportive care and prophylactic strategies.

e23373 Background: Multiple biomarker-driven therapies are approved for ER+/HER2- mBC. Oral selective estrogen degraders (SERDs) are approved for ESR1 mut ER+/HER2- mBC, but ESR1 mut may co-occur with other actionable biomarkers, including somatic PIK3CA/AKT1 / PTEN mut , germline BRCA1/2 mut , and HER2-low disease. Optimal timing of matched therapies remains uncertain in patients (pts) with multiple targetable mutations. This study evaluated institutional prescribing patterns, focusing on the first biomarker-matched therapy selected following elacestrant approval, and associated clinical characteristics in pts with ER+/HER2- ESR1 mut mBC with other actionable variants. Methods: Pts with ESR1 mut mBC were included if they had ≥1 additional targetable biomarker and received a matched agent after elacestrant approval (Jan 27, 2023). Genomic and pathology data were assessed for PIK3CA/AKT1/PTEN mut , HER2-low status (IHC 1+ or 2+/FISH negative), and g BRCA1/2 mut . Variants were considered actionable if a matched therapy was available as standard of care or through a clinical trial at treatment selection. Clinical factors annotated included age at therapy start, ECOG, hemoglobin (HgB), HgB A1c, creatinine (Cr), bilirubin, and visceral disease. Comparisons were performed across treatment groups defined by the first matched therapy received (oral SERD vs PI3K/AKTi vs Trastuzumab deruxtecan [T-Dxd]) using Kruskal–Wallis and Chi Square tests. Results: 87 pts with ESR1 mut mBC had ≥1 additional targetable variant at treatment selection (Table 1). Oral SERDs were prescribed first for most pts with concurrent PIK3CA mut , and evenly with T-Dxd for pts with HER2-low mBC. If ≥2 PI3K/AKT pathway mutations were present, a PI3K/AKTi was selected. Median age differed significantly, with older pts more likely to receive oral SERDs (SERD 73, PI3K/AKTi 64, T-Dxd 62 years; p = 0.001). Cr levels differed with lower values in T-Dxd and PI3K/AKTi groups (p = 0.034). In a subanalysis, excluding pts who received a matched agent pre-elacestrant approval (n = 55), median age was higher in oral SERD recipients (75 vs 66 vs 59 years; p < 0.001). All groups had median HgB A1c < 6.5 and no significant difference in Cr. Conclusions: Guidelines for initial biomarker-driven treatment selection in ER+/HER2- ESR1 mut mBC are not well defined. This work shows variability in real-world treatment practices and potential associations with toxicity-related factors. Larger analyses are planned to validate these findings and to evaluate treatment sequencing patterns in this setting. Mutation Profile SERD first (n = 43) PI3K/AKTi first (n = 21) T-Dxd first (n = 23) ESR1 + PIK3CA (n = 28) 20 (71%) 8 (29%) — ESR1 + AKT1 (n = 1) 0 1 (100%) — ESR1 + PTEN (n = 1) 0 1 (100%) — ESR1 + ≥2 PIK3CA/AKT1/PTEN (n = 5) 0 5 (100%) — ESR1 + HER2-low (n = 28) 14 (50%) — 14 (50%) ESR1 + HER2-low + ≥1 PIK3CA/AKT1/PTEN (n = 23) 8 (35%) 6 (26%) 9 (39%) ESR1 + HER2-low + BRCA1/2 + ≥1 PIK3CA/AKT1/PTEN (n = 1) 1 (100%) 0 0

BACKGROUND:PI3K/AKT pathway activation is implicated in CDK4/6 inhibitor resistance. The use of AKT inhibition with continued CDK4/6 blockade after CDK4/6 inhibitor resistance remains unexplored. We evaluated the safety of ipatasertib and an antioestrogen with or without palbociclib in patients with treatment refractory HR+/HER2- metastatic breast cancer. METHODS:This single-centre, open-label, phase 1b trial was conducted at the Massachusetts General Hospital (Boston, MA, USA). Eligible patients were women older than 18 years with biopsy proven HR+/HER2- locally advanced, unresectable, or metastatic breast cancer; an Eastern Cooperative Oncology Group performance status of 0-2; disease progression on at least one previous therapy for metastatic disease; and measurable disease or bone lesions. Patients received 400 mg oral ipatasertib with standard 500 mg intramuscular fulvestrant dosing (ipatasertib and fulvestrant group) or with an aromatase inhibitor (oral anastrozole 1 mg per day, exemestane 25 mg per day, or letrozole 2·5 mg per day; ipatasertib and aromatase inhibitor group) on days 1-28 of each cycle. The ipatasertib and fulvestrant plus palbociclib group included a dose-escalation phase with patients assigned sequentially to escalating doses of ipatasertib and palbociclib using a standard 3 + 3 design starting at the recommended dose of palbociclib (125 mg on days 1-21) and the lowest dose of ipatasertib (200 mg on days 1-21). The primary endpoint was safety and progression-free survival was a key secondary endpoint. Safety was analysed in all patients who received at least one dose of ipatasertib and progression-free survival was assessed in all enrolled participants. This study is registered with ClinicalTrials.gov, NCT03959891 (active, not recruiting). FINDINGS:Between June 5, 2019, and Feb 16, 2022, 77 patients were enrolled (19 assigned to ipatasertib and fulvestrant, 16 to ipatasertib and aromatase inhibitor, and 42 to ipatasertib and fulvestrant plus palbociclib). All patients were female (77 [100%]); 75 were White (97%) and two (3%) were Asian. The median age was 62 years (range 32-88) and 66 (86%) of 77 patients received previous CDK4/6 inhibitor (median number of previous lines was 3 [range 1-13]). The median follow-up was 12·5 months (IQR 7·6-19·7). The recommended phase 2 dose was established at 400 mg ipatasertib on days 1-21 with 100 mg palbociclib on days 8-28 and standard fulvestrant 500 mg. Median progression-free survival was 5·5 months (95% CI 3·8-7·4). Serious adverse events related to study treatment occurred in seven (17%) patients in the ipatasertib and fulvestrant plus palbociclib group and one (5%) in the ipatasertib and fulvestrant group, which were related to neutropenia, leukopenia, thrombocytopenia, and hyperglycaemia. Common grade 3-4 adverse events related to study treatment (occurring in >5% of patients) were neutropenia (30 [39%] of 77), leukopenia (15 [19%]), diarrhoea (14 [18%]), rash (seven [9%]), lymphopenia (three [4%]), and anaemia (four [5%]). Four deaths occurred during the study (one possibly treatment-related due to grade 5 hyperglycaemia in the ipatasertib and fulvestrant group and two due to infectious issues and one due to pulmonary complications in the ipatasertib and fulvestrant plus palbociclib group), deemed unrelated to study treatment. INTERPRETATION:The combination of fulvestrant, ipatasertib, and palbociclib showed preliminary signs of clinical activity and showed expected adverse events in heavily pretreated patients with HR+/HER2- metastatic breast cancer, warranting further evaluation in those with CDK4/6 inhibitor-refractory disease. FUNDING:Genentech, Howard Hughes Medical Institute, National Foundation for Cancer Research, and Breast Cancer Research Foundation.

QuestionWhat is the most effective mailed population outreach approach (fecal immunochemical test [FIT] or FIT-DNA) to increase colorectal cancer screening uptake among screening-eligible adults who receive health care in community health centers (CHCs)?FindingsIn this pragmatic cluster randomized clinical trial of 5127 patients, screening participation was significantly higher in CHCs randomized to FIT-DNA than in CHCs randomized to mailed FIT outreach at 90 days (27.9% vs 22.6%) and at 180 days (31.7% vs 26.7%).MeaningFIT-DNA may be a more advantageous approach to increase colorectal cancer screening uptake compared to mailed FIT outreach in CHCs. ImportanceColorectal cancer (CRC) is the second most common cause of cancer mortality in the US and disproportionately impacts individuals in underresourced settings.ObjectiveTo compare 2 mailed population outreach approaches to increase CRC screening uptake among screening-eligible adults in community health centers (CHCs).Design, Setting, and ParticipantsThis pragmatic cluster randomized clinical trial was conducted in 8 CHCs and an additional site in a nonrandomized parallel protocol. The CHCs were located in the greater Boston area in Massachusetts and Los Angeles County in California (randomized sites), and Rapid City, South Dakota (parallel site). Patients were enrolled in the trial between June 7, 2023, and October 24, 2023. English- or Spanish-speaking primary care patients aged 45 to 75 years, who were due for CRC screening, were eligible to participate.InterventionsPatients received either mailed fecal immunochemical test (FIT) with automated text message outreach from study personnel or mailed FIT-DNA with the manufacturer's outreach protocol. Participants in Boston and Los Angeles (randomized sites) with an abnormal FIT or FIT-DNA result were offered standardized navigation to colonoscopy.Main Outcomes and MeasuresThe primary outcome was CRC screening participation using any modality (FIT, FIT-DNA, or colonoscopy) within 90 days. Secondary outcomes were screening within 180 days and time to screening participation. The completion of follow-up colonoscopy within 180 days of an abnormal stool test result was also studied.ResultsAmong 5127 participants in the RCT regions, 2435 (47.5%) were in the FIT group, and 2692 (52.5%) were in the FIT-DNA group. The mean (SD) age was 54.5 (8.1) years; 3018 (58.9%) were female, and 2109 (41.1%) were male. There were 3818 Hispanic individuals (74.5%), 369 non-Hispanic Black individuals (7.2%), 763 non-Hispanic White individuals (14.9%), and 58 individuals of another race (1.1%). A total of 3363 individuals (65.6%) preferred the Spanish language; 2540 (49.5%) were Medicaid insured, and 614 were (12.0%) uninsured. Screening participation was significantly higher in the FIT-DNA group vs the FIT group at 90 days (751 of 2692 [27.9%] vs 550 of 2435 [22.6%], respectively; P = .02) and 180 days (854 of 2692 [31.7%] vs 649 of 2435 [26.7%], respectively). In Boston, screening participation at 90 days was higher (628 of 2208 [28.4%]) than in Los Angeles (673 of 2919 [23.1%]). Findings were similar at 180 days. Among the 100 individuals with an abnormal stool test result, 36 (36.0%) completed a colonoscopy within 180 days.Conclusions and RelevanceIn this cluster randomized clinical trial, CRC screening uptake was higher in the FIT-DNA group than in the FIT group and was higher in Boston compared to Los Angeles CHCs. The follow-up colonoscopy rate within 6 months was suboptimal, even with the availability of navigation.Trial RegistrationClinicalTrials.gov Identifier: NCT05714644 This cluster randomized clinical trial compares mailed outreach approaches to increase colorectal cancer screening uptake among adults in community health centers who are due for screening.

PURPOSE:Up to 30% of patients with hormone receptor-positive (HR +) breast cancer do not start adjuvant endocrine therapy (AET) as prescribed. AET non-initiation is associated with increased recurrence and decreased survival. We conducted a single-arm, open-pilot study to assess the feasibility and acceptability of a nurse-led, culturally sensitive intervention ('INITIATE') to optimize AET initiation. METHODS:From 9/2022 to 8/2024, we recruited 35 patients with stage I-IIIB, HR + breast cancer who delayed or reported hesitancy to start AET. INITIATE included two virtual sessions delivered in English or Spanish with an oncology nurse. Feasibility was defined by enrollment rates (> 50% eligible patients), intervention attendance (≥ 70% of patients attending one of two sessions), and retention (> 70% completing the 3-month questionnaire). At baseline, 1 month, and 3 months post-baseline, patients self-reported sociodemographics, AET initiation, intervention acceptability (Client Satisfaction Questionnaire-3), and other psychosocial outcomes. We conducted semi-structured, qualitative exit interviews to gather additional feedback. We computed descriptive statistics for the quantitative outcomes and conducted a rapid qualitative analysis of the interview data. RESULTS:We enrolled 45.5% (35/77) of eligible patients; 82.9% (29/35) attended at least one intervention session, and 77.1% (27/35) completed the 3-month assessment. Most patients (68.6%) were White, and 37.1% identified as a racial or ethnic minority. Qualitatively, patients reported that INITIATE helped them understand the importance of taking AET and improved their coping skills. Ninety-six percent reported high acceptability, and 88.9% started their AET by three months post-baseline. CONCLUSION:INITIATE is mostly feasible and acceptable and demonstrates promise for promoting AET initiation among patients with HR + breast cancer.

Background: Treatment of HR+/HER2- MBC often involves an antiestrogen agent and CDK4/6i, and following disease progression, multiple therapies are approved in the second line. Management is increasingly guided by a precision-based approach, including the use of AKTi in tumors harboring an AKT1 or PIK3CA mutation or PTEN loss. However, little is known regarding molecular factors that mediate resistance to AKTi. Results from the TAKTIC trial demonstrated antitumor activity and tolerability of the AKTi ipatasertib with endocrine therapy (ET) +/- palbociclib post-CDK4/6i (Wander et al., 2023). We hypothesize that next-generation sequencing (NGS) of tumors among patients (pts) receiving ipatasertib could inform genomic predictors of response to AKTi. Methods: TAKTIC was a phase Ib open-label trial evaluating ipatasertib in combination with fulvestrant, an aromatase inhibitor, or fulvestrant + palbociclib, in participants with HR+/HER2- MBC who received ≥1 line of prior therapy for MBC and had exposure to CDK4/6i (NCT03959891). An exploratory objective of TAKTIC was to identify genomic biomarkers that correlate with response to an AKTi-based combination regimen. Blood samples for circulating tumor DNA analysis were drawn at routine timepoints and archival tumor tissue was obtained. Mutational profiling was performed using commercially available NGS-based assays (frequently via Guardant360). Progression free survival (PFS) was estimated using the Kaplan-Meier method, and survival analysis was implemented with the Breslow approximation for ties. Univariable and multivariable hazard ratio (HR) and 95% confidence interval (CI) analyses were estimated using a cox proportional hazards model. Results: TAKTIC accrued 77 pts (6/2019 – 2/2022), enrolling 35 on doublet therapy (AKTi + antiestrogen) and 42 on triplet therapy (AKTi, fulvestrant, and palbociclib). Baseline NGS results were available in 58 of 77 pts, and alterations in PI3K/AKT pathway genes were found in PIK3CA (43%), AKT1 (7%), and PTEN (10%). Mutations in ESR1 (29%) were seen at rates consistent with prior studies in MBC post-ET. A subgroup of 20 pts who received the triplet ipatasertib regimen and had baseline NGS data within 60 days of drug start were analyzed. Mutations in PIK3CA (n=7, 35%; n=5 polyclonal) and PTEN (n=4, 20%; n=1 polyclonal) were detected, as were alterations in ESR1 (n=5, 25%), FGFR1 (n=4, 20%), KRAS (n=4, 20%), and ERBB2 (n=3, 15%); no baseline AKT1 mutations were seen in this subgroup. Univariate gene analysis demonstrated that FGFR1 amplification was associated with shorter PFS (HR 5.42, 95% CI 1.3 – 22.1, P=.019), and ERBB2 alteration trended toward worse outcomes (HR 3.38, 95% CI 0.8 – 13.6, P=.086); no significant difference was seen between ESR1 mutant vs. ESR1 wild-type tumors (HR 1.6, 95% CI 0.6 – 4.6, P=.384). Multivariate gene analysis demonstrated that PIK3CA/AKT1/PTEN altered tumors (n=9) had greater response to the AKTi triplet combination compared to tumors without mutations in this pathway (n=11) (median PFS 505 vs. 114 days, HR 0.2, 95% CI 0.1 – 0.7, P=.015). Breast cancers harboring alterations that upregulate RAS pathway signaling (KRAS/NRAS, BRAF, FGFR1/2, ERBB2, EGFR; n=9) showed a trend toward inferior outcomes compared to non-altered disease (n=11) (median PFS 114 vs. 253 days, HR 2.0, 95% CI 0.8 – 5.3, P=.160). Additional analyses at the individual gene and pathway level will be presented at the meeting. Conclusions: Genomic insights using NGS suggest that MBC post-CDK4/6i is more susceptible to an AKTi-based treatment with ipatasertib in the presence of a PI3K/AKT/PTEN pathway mutation, whereas alterations in FGFR1 are associated with worse outcomes. This effort is one of very few studies prospectively evaluating mediators of AKTi response, an area of active interest given changes in the therapeutic landscape. The results presented here are hypothesis-generating; future work is underway to further expand upon these data. Citation Format: Maxwell Lloyd, Geoffrey G. Fell, Elizabeth Scott, Jennifer C. Keenan, Laura M. Spring, Jennifer Shin, Steven J. Isakoff, Lianne Ryan, Sarah Padden, Elizabeth Fisher, Amber Newton, Beverly Moy, Andreas Varkaris, Leif W. Ellisen, Douglas S. Micalizzi, Daniel Haber, Dejan Juric, Aditya Bardia, Seth A. Wander. Genomic predictors of response among patients with hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC) receiving the AKT inhibitor (AKTi) ipatasertib combined w/ endocrine therapy & a CDK4/6 inhibitor (CDK4/6i) in TAKTIC trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-01-17.

1005 Background: Trastuzumab deruxtecan (T-DXd) is FDA-approved for HER2-low, but not HER2-0 metastatic triple negative (TNBC) and hormone positive breast cancer. Therefore, identifying HER2-low status is of great clinical importance. Prior studies have shown HER2-low status in TNBC is dynamic, but the correlation between the number of successive biopsies (Bxs) conducted and the likelihood of a HER2-low result is unknown. Methods: Patients (pts) were identified from an institutional database including all pts with TNBC treated in a single large academic center between 2017-2022. Only pts with TNBC at diagnosis were included. Bxs without known HER2 status were excluded. Pathological, clinical, and demographic data were extracted. HER2-low was defined as HER2 IHC 1+, or 2+ with non-amplified ISH. The type of Bx was categorized as core Bx, surgical Bx, or metastatic Bx based on the timing and method of Bx acquisition. For the early-metastatic matched analysis, the core Bx was considered the early Bx, unless the core Bx was missing and then the surgical bx was used instead. For cases with several metastatic Bxs the first metastatic Bx was used. Results: 529 consecutive pts with TNBC at diagnosis were included. The proportion of pts with HER2-low result increased as the number of successive Bxs increased (60%, 74%, 83%, 87% and 100% when 1 (192 pts), 2 (235 pts), 3 (52 pts), 4 (38 pts), and 5-9 (12 pts) Bxs were conducted, respectively). In women without a prior HER2-low result, about one third converted to HER2-low with each successive additional biopsy (e.g. 322/529 at 1 st biopsy, 44/131 on 2 nd biopsy, 8/25 at 3 rd biopsy, 3/8 at 4 th biopsy). HER2 status distribution did not significantly vary between the different types of Bx (58%, 63%, and 54% of pts had a HER2-low result in their core, surgical or metastatic Bx, respectively; p=0.2). Among 246 women with matched core-surgical biopsies, one quarter changed their HER2 status (55% from low to 0, 44% from 0 to low, and 1% from low to 3+). Core-surgical HER2 status conversion rates did not differ between women who had neoadjuvant therapy with residual disease and women who had surgery as their primary intervention. Among women with both matched early-metastatic (70 pts) or two matched metastatic Bxs (39 pts), nearly half (44%) converted their HER2 status (68%, 26% and 6% or 35%, 59% and 6% were converted from low to 0, 0 to low and low to 3+ in the matched early-metastatic or the two matched metastatic Bxs, respectively). Conclusions: Our findings show that HER2 status is dynamic in pts with TNBC and support the idea that HER2-low is a spectrum, not a specific entity. We further report the novel finding that for pts with TNBC without a prior HER2-low result, repeat Bxs at progression can increase the chance of obtaining a HER2-low result and provide clinically impactful information. Whether the dynamic HER2 result represents underlying biology or analytic variation remains to be determined.

PURPOSE:Antibody-drug conjugates (ADC) harboring topoisomerase I (TOP1) inhibitor payloads have improved survival for patients with metastatic breast cancer. However, knowledge of ADC resistance mechanisms and potential impact on the sequential use of ADCs is limited. In this study, we report the incidence and characterization of TOP1 mutations arising in the setting of ADC resistance in metastatic breast cancer. EXPERIMENTAL DESIGN:Patients with metastatic breast cancer treated with ADCs with available posttreatment plasma-based genotyping were included. TOP1 mutation incidence, mutant allele frequency, and functional characterization were assessed, and incidence was compared with that in patients with metastatic breast cancer not receiving ADC treatment and in The Cancer Genome Atlas. RESULTS:Plasma-based genotyping identified distinct TOP1 mutations (S57C, R364H, W401C, and G359E) in 12.9% of patients (4/31) at the time of disease progression on ADC, compared with 0.7% (3/420) in non-ADC-treated patients with metastatic breast cancer and 0.5% in The Cancer Genome Atlas. The appearance of mutations was associated with clinical cross-resistance, as median duration on the first ADC was 455 versus 52 days for the second ADC. The functional characterization of three novel TOP1-mutant proteins demonstrated that all exhibited reduced enzymatic activity, attenuated covalent DNA binding, and resistance to TOP1 inhibitor ADC payloads SN38 and deruxtecan. CONCLUSIONS:We describe the recurrent emergence of functionally altered, resistance-associated TOP1 mutations in vivo under selective pressure from ADCs and the potential impact on mediating cross-resistance to sequential ADCs. TOP1 mutation may represent a biomarker of resistance in this setting, and additional work is needed to optimize biomarkers and ADC payload design to improve outcomes for the sequential use of ADCs. See related commentary by Gwin and Hurvitz, p. 1824.

PURPOSE:Adjuvant endocrine therapy (AET) is a critical component of hormone receptor-positive (HR+) breast cancer treatment, yet many patients do not start these medications. Patients from racial or ethnic minority communities are less likely to initiate AET and are at greater risk for poor breast cancer outcomes. Interventions are needed to increase AET initiation. The purpose of this study was to adapt an existing AET adherence intervention to enhance cultural sensitivity and target specific barriers that patients from minority communities are likely to experience. METHODS:From 8/2021-6/2022, we developed a brief, behavioral, and culturally sensitive intervention by following two adaptation frameworks: the ADAPT Guidance and the Typology of Adaptation Model. Within these frameworks, we conducted a qualitative study using semi-structured interviews to understand the barriers and facilitators to AET initiation and intervention preferences in a diverse sample of patient stakeholders with HR + breast cancer (N = 10). RESULTS:The finalized intervention ("INITIATE") includes two evidence-based, nurse-led telehealth sessions delivered in the weeks preceding a patient's planned AET start date. Culturally sensitive content includes diverse representation in patient materials and vignettes, tailored psychoeducation regarding AET non-initiation and breast cancer disparities, and the translation and delivery of INITIATE in both English and Spanish. CONCLUSIONS:Tailoring an existing intervention to address culturally relevant barriers to AET initiation is a crucial step in optimizing patient engagement, improving breast cancer outcomes, and reducing breast cancer disparities. We are currently conducting a pilot study to evaluate the feasibility and acceptability of the INITIATE intervention. Clinical Trials Registration # (INITIATE pilot study) - NCT05465408.

Introduction: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in conjunction with endocrine therapies have transformed the treatment landscape for patients with metastatic hormone-receptor positive (HR+)/HER2- breast cancer. Studies exploring the clinical utility of CDK4/6i re-introduction after disease progression on prior CDK4/6i-based therapy have yielded mixed results, including the recent phase III postMONARCH trial (which interrogated the combination of fulvestrant and abemaciclib in the second-line metastatic setting). Here, we explore the clinical outcomes of abemaciclib monotherapy after disease progression on prior combined CDK4/6i and endocrine therapy. Methods: We collected retrospective clinical data at two academic institutions (Massachusetts General Hospital and Barnes-Jewish Hospital) according to site-specific IRB-approved protocols from patients with metastatic HR+/HER2- breast cancer who had received abemaciclib monotherapy after disease progression on another CDK4/6i-based therapy in the metastatic setting. We summarized patient and treatment characteristics and conducted time-to-event analyses. Results: In this preliminary analysis, a total of 16 patients received abemaciclib monotherapy after disease progression on prior CDK4/6i-based therapy. All 16 received prior palbociclib-based therapies. Eleven of these patients continued abemaciclib until disease progression or death, while five patients stopped therapy due to toxicity (three due to gastrointestinal side effects, one due to fatigue, and one due to atrial fibrillation). Patients received palbociclib-based therapy for a median of 16.2 months and abemaciclib for a median of 3.8 months (95% confidence interval, 2.0-7.5 months). Five patients received abemaciclib for >180 days prior to disease progression/death. Conversely, only two patients discontinued abemaciclib prior to 90 days after initiation due to disease progression. Four out of the 16 patients received abemaciclib as the subsequent line of treatment immediately following progression on palbociclib. The median time from progression on palbociclib-based therapies to starting abemaciclib was 10.7 months, with a median number of two intervening lines of therapy. Efforts are underway to combine this cohort with additional patients receiving abemaciclib monotherapy in this setting at other institutions to enhance clinical sample size. Planned analyses will include retrospective review of radiographic images to estimate overall response rate and exploration of genomic sequencing to identify molecular mediators of response and resistance to abemaciclib monotherapy. These ongoing efforts will be presented at the meeting. Conclusions: A subset of patients tolerated abemaciclib monotherapy for > 180 days before progression/death despite progression on prior combination palbociclib and endocrine therapies. This is the first effort to interrogate the utility of abemaciclib monotherapy in this setting and will provide additional insights related to serial CDK4/6-directed therapy in this patient population. These results demonstrate clinical promise in continued CDK4/6 inhibition and raise questions about mechanisms of resistance and the identification of patients that would benefit from abemaciclib monotherapy. Citation Format: Sahar Shahamatdar, Katherine Clifton, Julianna Wu, Annika Putur, Irene Kuter, Aditya Bardia, Dejan Juric, Laura Spring, Katherine Harris, Beverly Moy, Jennifer Shin, Neelima Vidula, Cynthia Ma, Seth A. Wander. Abemaciclib monotherapy after disease progression on prior CDK4/6 inhibitors in patients with metastatic hormone-receptor positive 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 P4-10-12.

6533 Background: A breast biopsy tissue biobank is a valuable resource for studying breast cancer biology and treatment response. However, underrepresentation of patient populations in biobanks limits the generalizability of findings. The aim of this study was to assess potential age and racial/ethnic disparities in the recruitment process for an institutional breast biopsy tissue bank. Methods: Ultrasound-guided (USG) research biopsy cores were collected immediately after routine clinical biopsy from January 2019 to October 2022 at a large academic center. Study eligibility included patients (pts) aged > 18 years undergoing USG clinical breast biopsy with a radiographically evident mass ≥ 0.6 cm in the longest dimension. Eligible pts, identified by a research associate on the day of the biopsy, were invited to participate at the discretion of the radiologist performing the biopsy. Those approached either consented or declined a research biopsy. Demographic and clinical data of eligible pts were extracted from the EMR. Results: 2449 pts underwent USG breast biopsy and 1309 were deemed eligible for a research biopsy. Of the eligible population, 564 (43%) consented to the study, 322 (25%) declined, and 423 (32%) were not approached. Consented pts were younger compared to those who declined or to those not approached (median age 49, 51, and 51 years, respectively; p = .01). Comparison of study groups by age and race categories are shown in the table. Pts > 70 were less likely to be approached compared to pts < 70 (p = .01). However, The likelihood of pts being approached to consent did not differ significantly with age (p=.09 ). Of the eligible pts, 951 (73%) were White, 327 (25%) were non-White (10% Asian, 8% Black, 1% Hispanic, and 7% other race), and race was unknown for 31 (2%) pts. White and non-White pts were equally likely to be approached (p = .3). However, approached non-White pts were significantly less likely to consent compared to White pts (p =.01). Within the non-White population, Black pts were more likely to decline a research biopsy, with only 50% of approached Black pts consenting compared to 66% of White pts, 61% of Asian pts and 55% of pts of other race. Conclusions: We found disparities based on age and race/ethnicity in participation in a breast biopsy tissue biobank. Older pts were less likely to be offered participation but equally likely to consent when invited, while Black pts were equally likely to be offered participation, but less likely to consent when invited, compared to other racial subgroups. Our findings support targeted interventions to increase participation across diverse subgroups of pts. [Table: see text]

PURPOSE:Race/ethnicity may affect outcomes in metastatic breast cancer (MBC) due to biological and social determinants. We evaluated the impact of race/ethnicity on clinical, socioeconomic, and genomic characteristics, clinical trial participation, and receipt of genotype-matched therapy among patients with MBC. EXPERIMENTAL DESIGN:A retrospective study of patients with MBC who underwent cell-free DNA testing (cfDNA, Guardant360, 74 gene panel) between 11/2016 and 11/2020 was conducted. Receipt of genotype-matched therapy targeted at a cfDNA actionable mutation was determined. Pearson χ2 and Wilcoxon rank-sum tests were used to compare categorical and continuous variables between groups. Multivariable logistic regression was used to assess the association of race and receiving matched therapy. RESULTS:A total of 425 patients with MBC and cfDNA results were identified (White: 369, Black: 27, Hispanic: 15, and Asian: 14). White patients traveled further for cancer care than other groups (P < 0.001). White patients had the highest rates of commercial insurance, Black patients had the highest rates of state-supported insurance, and Asian patients had the highest uninsured rates (P < 0.001). Clinical trial enrollment did not differ by race/ethnicity (P = 0.34). The proportion of patients with ≥1 actionable mutation in cfDNA did not vary by race/ethnicity (P = 0.18). The highest rates of matched therapy were observed in White patients (P < 0.001). After multivariable logistic regression adjusting for subtype, commercial versus other insurance, Charlson Comorbidity Index, and distance to center, White patients remained more likely to receive matched therapy (P = 0.024). CONCLUSIONS:Racial/ethnic minority patients were less likely to receive matched therapy. Further research is needed to identify barriers to precision medicine.