Mahtani, Reshma

1114 Background: While treatment and management of TNBC has improved, there is a need for novel prognostic biomarkers to better inform outcomes and guide therapeutic options. ILF2 is a poorly characterized protein with pleiotropic functions that is highly expressed in TNBC. Here we evaluated the associations of ILF2 with 1) genomic and transcriptomic data, 2) tumor microenvironment (TME), and 3) clinical outcomes in TNBC. Methods: 15,544 breast cancer (BC) samples, including 3,038 TNBC, were tested by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). ILF2 -high (H) and ILF2 -low(L) TNBC were defined by respective quartiles. Immune cell fractions were estimated by WTS deconvolution (Quantiseq). Real world overall survival (OS) was obtained from insurance claims and calculated from tissue collection to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square, Fisher’s exact, and Mann-Whitney U test with p-values adjustments (q < .05). Results: ILF2 expression (median Log2(TPM+1) was higher (all q < .05) in key subgroups: ductal compared to lobular carcinoma (6.4 vs 6.0); primary compared to metastatic BC (6.4 vs 6.3); African American compared to White (6.4 vs 6.3); basal compared to luminal A, luminal B, HER2 PAM50 subtypes (6.9 vs 5.8, 6.3, 6.3); and TNBC compared to HR+HER2+, HR-HER2+, HR+HER2- subtypes (6.7 vs 6.3, 6.4, 6.2). Biopsied tissues from primary TNBC (pTNBC) and metastatic TNBC (mTNBC) patients were stratified into ILF2- H and ILF2- L groups. In both mTNBC and pTNBC, ILF2- H groups had 1) higher percentage of young patients (age < 50) (pTNBC: 35.5% vs 19.8%; mTNBC: 28.1% vs 17.3%; all q < .05); 2) higher mutation frequency of TP53 (pTNBC: 94.5% vs 79.6%; mTNBC: 92.4% vs 74.4%), but lower frequencies for PIK3CA ( pTNBC: 5.1% vs 23.4% , mTNBC: 8.8% vs 27.4%), CDH1 ( pTNBC: 0.8% vs 6.1%; mTNBC: 2.8% vs 12.2%; all q < .05); 3) higher infiltration of NK cells (pTNBC: 3% vs 2.6%; mTNBC: 2.8% vs 2.6%), but lower infiltration of M2 Mφ (pTNBC: 2.5% vs 3.3%; mTNBC: 2.6% vs 3.2%) and Tregs (pTNBC: 1.5% vs 1.9%; mTNBC: 1.4% vs 1.7%; all q < .05); 4) higher expression levels of immune checkpoint ( CD274, PDCD1LG2, CTLA4, LAG3, HAVCR2, FOXP3, IDO1, CD276 , FC: 1.2-3.1; all q < .05), stem cell genes (C D44, NANOG, POU5F1, KLF4, ALDH1A1 , FC: 1.4-2.4; all q < .05), and drug efflux genes ( ABCC3, ABCC11, ABCC2, ABCB1, ABCG2, ABCC1 , FC: 1.1-4.5; all q < .05) compared to ILF2- L group. In pTNBC, ILF2- H had significantly shorter OS vs ILF2- L group (22.3 vs 28.9 months, HR 1.2 [95% CI 1-1.5], p = .03), but no significant differences were observed between mTNBC ILF2 groups (HR 1.1 [95% CI 0.93-1.3], p = .2). Conclusions: ILF2 -H TNBC patients showed differential genomic and transcriptomic alterations that relate to therapy resistance, immune suppressive TME, and shorter OS. Further studies are warranted to validate the effects of ILF2 upregulation on therapeutic efficacy.

1051 Background: Hispanics or Latinos (HL) and African Americans or Black (AA) have a higher prevalence of advanced-stage breast cancer (BC) at diagnosis compared to Non-Hispanic Whites (NHW). To understand the role of immune system, we evaluated the tumor immune microenvironment (TIME) by race/ethnicity among HL, AA, and NHW BC patients. Methods: 15544BC samples were tested by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). Race/ethnicity data is self-reported. Immune cell were estimated using WTS deconvolution (Quantiseq). Gene expression profiles were analyzed for T-cell inflammation score (TIS) and interferon-gamma (IFN-gamma) score. Real-world overall survival (OS) was obtained from insurance claims and calculated from date of tumor biopsy to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square and Mann-Whitney U test with p -values adjusted for multiple comparisons (q < .05). Results: 7170 NHW (35.3%, N = 2528) biopsied (bx) from primary breast cancer (pBC), 64.7% (N = 4642) metastatic bx (mBC), 1,508 AA (pBC 39.3% N = 592, mBC 60.7% N = 916), and 1,754 HL (pBC 44.1% N = 774, mBC 55.9% N = 980) cases were included. By subtype, there were 1,956 (60.4% NHW, 20.7% NHB, 18.9% HL) TNBC, 3425 HR+/HER2- (72.6% NHW, 11.9% NHB, 15.6% HL), and 694 HER2+ (64.6% NHW, 15.7% NHB, 19.7% HL). Across all cases, AA (20.5%) and HL (20.4%) had greater incidence (%) of PD-L1+ cases versus (vs) NHW (17.4%), all q < .05. TMB-High (³10 mut/Mb) was similar in NHW (11.5%), AA (10.8%), and HL (10.9%). AA tumors had lower median % cell infiltration of M2-like macrophages (M2 Mφ), B cells, and neutrophils vs NHW (Table). HL had a lower fraction of M2 Mφ and higher CD8+ T cells (Table). AA had lower TIS (-8 vs 1, p = .02) while HL had lower IFN-gamma (-0.38 vs. -0.35, q < .05) vs NHW. By subtype, AA had lower neutrophils (4% vs 4.3%) and increased DC fractions (3.1% vs 2.8%) in TNBC vs NHW, all q < .05; no significant changes seen in HL vs NHW. AA had worse mOS than NHW overall (31.8 vs 36.8 months (mo)), HR 1.1, 95% CI 1 – 1.2, p = < .01), in pBC (40.3 vs 49.9 mo, HR 1.3, 95% CI 1.1 – 1.5, p = < .01), but not mBC (27.4 vs 29.1 mo, HR 1, p = 0.2). HL had similar mOS vs NHW overall (37.4 vs 36.8 mo, HR 0.9, p = 0.9) and in mBC (29.1 vs 31 mo, HR 0.96, p = 0.4), but worse mOS in pBC (44.7 vs 50.0 mo, HR 1.1, 95% CI 1 – 1.3, p = .01). Conclusions: Our study shows worse mOS in AA and HL pBC cases vs NHW, possibly from a less inflamed TIME in AA and HL and lower fraction of neutrophils and M2 Mφ despite higher % of PD-L1+. Targeting Mφ and CD8+ T cells and converting cold to hot TIME may lessen race/ethnic disparities, especially in early-stage BC. Immune cell fraction of NHW, AA and HL BC. NHW (median %) AA (median %) HL (median %) q-valueNHW vs AA q-value NHW vs HL B cell 5.2 4.8 5.0 <.05 0.7 DC 2.6 2.7 2.6 0.08 0.4 M1 Mφ 2.5 2.4 2.4 0.4 0.9 M2 Mφ 4.6 3.7 4.2 <.05 <.05 Neutrophils 3.7 3.5 3.4 <.05 <.05 NK cell 2.9 2.9 2.9 0.7 0.6 CD8+ T cell 0.1 0.15 0.26 0.8 <.05 Treg 1.5 1.5 1.6 0.6 <.05

1015 Background: T-DXd is an antibody-drug conjugate approved for advanced HER2+/low/ultra-low breast cancer and multiple other solid tumors. T-DXd carries a rare but serious risk of ILD (incidence 12-15%), requiring frequent imaging and symptom evaluation. For > grade (G) 2 ILD, guidelines recommend permanent drug discontinuation. For asymptomatic G1 ILD, drug is held with the option for rechallenge (RC) if imaging findings resolve. Limited data exist on outcomes of RC after ILD in diverse real-world patients (pts). Methods: In this multi-center retrospective study, we analyzed pts with T-DXd related ILD treated from 2017-2024. Pts with ILD were identified via chart/ICD code review. Adjudication of T-DXd related ILD was based on treating providers’ assessment and graded via CTCAE v5. We collected pt demographics, T-DXd and steroid dosing, imaging results, and outcomes after RC. Statistical analysis was performed using Wilcoxon rank sum and Fisher’s exact tests. Results: Four centers treated 712 pts with T-DXd, with a 9.1% rate of any grade ILD (n=65). One other center reported only RC data in 18 pts with ILD. In total, 47 pts were RC; 38 after G1 ILD (81%), 9 after G2. Median (med) time to initial ILD was 145 days (d) after 1st dose (interquartile range [IQR] 78-205). Demographics for pts RC are shown in the table. Among 50 pts with G1 ILD, including pts not RC, 28/50 (56%) received steroids for a med of 36d (IQR 27-79). Radiographic improvement was seen at a med of 24d (IQR 19-63) for pts treated with steroids vs 82d (IQR 48-94) without (p<0.01); and a med of 35d (IQR 22-82) for pts RC vs 81d (IQR 68-105) for pts not RC (p=0.01). Among pts with G1 ILD, 38/50 (76%) were RC at a med of 42d (IQR 36-57) from last dose; 23/38 (61%) were dose reduced. After RC, pts remained on T-DXd for a med of 215d (IQR 60-334); 10/38 (26%) developed recurrent ILD (7-G1, 2-G2, 1-G3) at a med of 211d (IQR 47-273) from RC. No statistically significant differences were seen between ILD onset, time to RC, or demographics for pts with recurrent ILD vs not. Of the 9 pts RC after G2 ILD, T-DXd was continued for a med of 129d (IQR 49-171); 2/9 (22%) developed recurrent ILD (1-G2, 1-G3). No G5 toxicity was seen with RC. Conclusions: In this multi-center study, high RC rates were seen after G1 ILD with long duration of clinical benefit. Pts treated with steroids had faster radiographic ILD improvement, highlighting the importance of early steroid use. Among pts RC after G1 ILD, recurrent ILD rates were low, with the majority G1 and no G5 events. Notably, 9 pts with G2 ILD were RC, with a similar rate of recurrent ILD; this must be interpreted cautiously. Our large cohort data further supports the safety of T-DXd RC in diverse real-world settings. RC Pt Characteristics (n=47) n (%) or Median (IQR) Cancer typeBreastGIGyn 43 (91)3 (6)1 (2) Age (yrs) 57 (52-68) Prior # therapy lines in the advanced/metastatic setting 3 (1-5) Renal impairment (CrCl < 60 mL/min) 8 (17)

TPS1122 Background: Treatment options for patients (pts) with unresectable or metastatic BC have improved with the development of novel targeted therapies including trastuzumab deruxtecan (T-DXd), an ADC directed against HER2 with a cytotoxic topoisomerase I inhibitor as a payload. Currently, there are limited treatment options for pts with HER2+ or HER2-low metastatic BC that has progressed on T-DXd. BB-1701 is an ADC consisting of a monoclonal antibody targeting HER2 with eribulin (microtubule inhibitor) as a payload that is capable of exerting a bystander effect. A first-in-human dose-finding Study 101 of BB-1701 is ongoing. Here we describe Study 205, an open label, multicenter, phase 2 study of BB-1701 in pts with HER2+ or HER2-low unresectable or metastatic BC who have disease progression after treatment with T-DXd. Methods: Study 205 (NCT06188559) includes dose-optimization and dose-expansion parts for BB-1701. Eligible pts must have histologically confirmed HER2+ or HER2-low, unresectable or metastatic BC, with measurable disease per RECIST v1.1. Prior treatment must include 1–3 prior chemotherapy-based regimens for unresectable or metastatic BC, including T-DXd. The primary objectives of the dose-optimization part include determining the recommended dose (RD) and evaluating safety and tolerability of BB-1701. The RD will be assessed by randomly assigning ~50 pts into 1 of 3 dosing cohorts (1.6 mg/kg on day 1 Q3W, 0.8 mg/kg on days 1 and 8 Q3W, and 1.2 mg/kg on day 1 Q3W; IV) in a 2:2:1 ratio. Randomization will be stratified by HER2 status (HER2+ vs. HER2-low) documented prior to T-DXd treatment. The dose-expansion part will enroll ~85 pts at RD; the primary objective includes evaluating the efficacy of BB-1701 at the RD. In both study parts, secondary objectives include assessment of additional efficacy measures (i.e., duration of response [DOR], progression free survival [PFS], overall survival [OS], disease control rate [DCR], clinical benefit rate [CBR], and time to response [TTR]), and pharmacokinetics. Efficacy endpoints will be assessed per RECIST v1.1 by the investigator during the dose-optimization part or by Blinded Independent Central Review during the dose-expansion part. Safety assessments will consist of recording, monitoring, and grading of adverse events (AEs) based on CTCAE v5.0, AEs of special interest, and serious AEs. In both study parts, exploratory objectives will include evaluation of biomarkers of response to BB-1701 and BB-1701 immunogenicity; other efficacy measures (i.e., PFS on the next line of therapy) and population pharmacokinetics will be analyzed in the dose-expansion part only. Pt enrollment is currently open. Clinical trial information: NCT06188559 .

1083 Background: T-DXd and SG are both FDA-approved treatments for patients (pts) with HER2-low MBC, but little data exists on the sequential use of these ADCs. Methods: In this multicenter retrospective cohort study, we identified pts with HER2-low MBC treated sequentially with both T-DXd and SG in either order, with or without intervening therapies (IntTx), at 5 academic centers between 2020-2023. We previously reported real-world progression free survival (rwPFS) and real-world overall survival (rwOS) by HR-status and ADC sequence order. Here we provide updated rwPFS and rwOS data, as well as new subgroup analyses by age, sites of disease, and use of IntTx between ADCs for HR- and HR+ disease. Results: 84 pts with HER2-low MBC treated with both T-DXd and SG were included, including 56 pts with HR+/HER2-low MBC (66.7%) and 28 pts with HR-/HER2-low MBC (33.3%). Prior to the start of ADC1, median age was 58 yrs and 22 pts were >65 yrs (26.2%), 65 pts (77.4%) had visceral disease, and 14 pts (16.7%) had central nervous system (CNS) disease. 36 pts (42.9%) had an IntTx between ADCs. Table 1 shows updated rwPFS and rwOS data by HR-status and ADC sequence order. For pts with HR+ and HR- MBC, there was no difference in ADC1 rwPFS or ADC2 rwPFS by age ≤65 vs. >65 yr or by presence vs. absence of visceral disease. For pts with HR- MBC, ADC1 rwPFS and rwOS was shorter for pts with CNS disease vs. pts without CNS disease (rwPFS 5.4 mo (n=6) vs. 8.5 mo (n=22), p=0.03; rwOS 11.6 mo vs. 21.1 mo, p<0.01 respectively). For pts with HR+ and HR- MBC, there was no difference in ADC2 rwPFS with or without receipt of IntTx. There was no difference in time to treatment failure for first IntTx vs. ADC2 if no InTx was given. Conclusions: This is one of the largest multicenter cohorts of pts treated with sequential ADCs for HER2-low MBC. Median rwPFS was longer for ADC1 than ADC2 in all subgroups, regardless of HR-status, ADC sequence order, age ≤65 or >65 yr, presence of visceral disease, or use of IntTx. Among pts with HR-/HER2-low MBC, pts with CNS disease had shorter ADC1 rwPFS and rwOS than pts without CNS disease. [Table: see text]

Abstract Introduction: Interstitial Lung Disease (ILD) is a known adverse event associated with Antibody Drug Conjugates (ADCs), causing fibrosis of the lung. In the DESTINY-Breast 04, TROPICS-02, and ASCENT trials the rate of ILD/Pneumonitis was 12.1%, 0.4%, and 0% respectively. In these studies, the time to first cross-sectional imaging after initiation of ADC was 6 weeks. However, prior treatment with a topoisomerase-1 inhibitor ADC was not permitted in these studies, so the influence of sequential ADC treatments remains unknown. Here, we aimed to characterize the frequency and management of ILD in sequential use of ADCs in a multi-institution retrospective analysis. Methods: We identified patients (pts) with HR+/HER2-low and HR-/HER2-low MBC who had received both Trastuzumab-deruxtecan (T-DXd) and Sacituzumab govitecan (SG) monotherapy (in either order, with or without intervening therapies) who were treated at five academic centers between 2020-2023. Patients had received treatment with the ADC in either routine clinical treatment or as a prior participant on a clinical trial with ADC monotherapy. Information regarding ILD diagnosis, imaging, timing of onset, peak and resolution along with management information was collected and analyzed. Retrospective assessment of ILD toxicity was graded using CTCAE v5.0, based on available clinical and radiographic reports. Results: 10/60 pts who received ADC therapy in this multi-institutional cohort were diagnosed with ILD (all grades). No differences in age or BMI were observed in those who developed ILD versus those who did not, and 9/10 pts were White, 1 was Asian, with a median age of 59 years (47-79 years). Pertinent history in these pts included 3/10 had a prior smoking history, 8/10 had a prior cardiac or pulmonary comorbidity (including sleep apnea, lung cancer, hypertension, hyperlipidemia, thrombosis, or stroke). Prior to receiving their first ADC, 7/10 patients had metastatic disease to the lung. All 10 patients were diagnosed with ILD during treatment with T-DXd. 4 pts initially received T-DXd, then developed ILD and then upon recovery, subsequently received SG. The remaining 6 pts initially received SG (with no reports of ILD), and then received T-DXd and subsequently developed ILD. In the entire cohort, the median time from ADC initiation to first CT scan was 8 weeks (range 1-22 weeks). Within the cohort that developed ILD, the median time from initiation of T-DXd to first CT scan was also 8 weeks (range 6-13 weeks). The median time to diagnoses of ILD was 3 months after initiation of T-DXd (range 0.4-14.5 months). Dyspnea was the most common presenting symptom in 9/10 pts and at diagnosis of ILD, dyspnea was graded as III in 6/10 pts, II in 3/10 pts, and I in 1/10 pts. Diagnostic evaluation included CT chest (9/10), pulmonary consultation (8/10), pulmonary function testing (2/10), and bronchoscopy (1/10). 4/10 patients presented at their highest-grade toxicity at diagnosis. All patients stopped T-DXd treatment, 7 were hospitalized, 7 required supplemental oxygen, and 8 were prescribed steroids for treatment. Of those receiving steroids, the most common starting dose was prednisone 1 mg/kg and doses ranged from 0.5 mg/kg to 9mg/kg prednisone equivalents. No patient received a secondary immunosuppressive agent. The steroid treatment duration ranged from 1-4 months. None of the 10 pts underwent re-challenge with T-DXd and 3/10 developed grade V ILD (death). Conclusion: We observed a 16.6% incidence of all grade ILD (5% grade V ILD) with T-DXd and 0% with SG. In this small cohort study, we did not observe a clear increased risk for ILD with sequential treatment of ADCs. Practice patterns were consistent with recommended diagnostic evaluation and steroid management. Additional strategies are needed to characterize pts most at risk for developing ILD and to identify situations where re-challenge may be safe. Citation Format: Sarah Premji, Laura Huppert, Reshma Mahtani, Samantha Fisch, Naomi Dempsey, Angelina Raimonde-Taylor, Saya Jacob, Laura Quintal, Jo Chien, Michelle Melisko, Ana Sandoval-Leon, Lauren Carcas, Manmeet Ahluwalia, Natasha Harpalani, Jenna Hoppenworth, Dame Idossa, Ruta Rao, Hope Rugo, Karthik Giridhar. Interstitial Lung Disease (ILD) in Sequential Antibody Drug Conjugate (ADC) use in patients with Metastatic Breast Cancer (MBC): A Multi-Institutional experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-06.

Abstract Introduction. T-DXd is FDA-approved for patients (pts) with hormone receptor positive (HR+) or HR- HER2-low (IHC 1+ or 2+, ISH-) MBC and SG is FDA-approved for pts with HR+/HER2- and triple negative MBC. However, several outstanding questions impact the use of these drugs in clinic, including: 1) what is the efficacy and safety of these agents in real-world populations with diverse pt characteristics not well represented in the pivotal phase III trials, and 2) what is the impact of sequential treatment with ADCs on the efficacy and safety of these agents. Methods. In this multicenter retrospective cohort study, we identified pts with HR+/HER2-low and HR-/HER2-low MBC who had received both T-DXd and SG monotherapy (in either order, with or without intervening therapies) treated at 5 academic centers between 2020-2023. Pts received treatment per standard of care or on a clinical trial with ADC monotherapy. We describe pt demographic and clinical characteristics, treatment history, key safety parameters, and response and survival data by HR+ status and ADC sequence order. Results. Sixty pts with MBC treated sequentially with T-DXd and SG were included in this analysis, including 45 pts with HR+/HER2-low MBC (75.0%) and 15 pts with HR-/HER2-low MBC (25.0%). Most pts were female (n=59; 98.3%), non-Hispanic (n=49, 81.7%), and white (n=43, 71.7%). Median age at start of ADC #1 was 56.6 years (range 23-82). Prior to treatment with ADC #1, most pts had visceral disease (n=45, 75.0%) and 16 (26.7%) had central nervous system metastases. Among pts with HR+/HER2-low MBC, median time from MBC diagnosis to treatment with ADC #1 was 49.0 months, with 4 median lines of prior therapy in the metastatic setting (2 endocrine, 2 chemo). Approximately half of the HR+ pts received T-DXd prior to SG (n=22, 48.9%; median 3.0 prior lines of therapy for MBC, range 1-9) while the other half received SG prior to T-DXd (n=23, 51.1%; median 4.5 prior lines of therapy for MBC, range 1-10). 44% (n=20) received an intervening therapy between ADCs. For HR+ pts who received T-DXd prior to SG, response and survival data is as follows for T-DXd and SG respectively: Overall response rate (ORR) [54.5% and 21.1%], time to next treatment (TTNT) [4.3 mo and 1.6 mo], and real-world overall survival (rwOS) [19.8 mo and 4.9 mo]. For HR+ pts who received SG prior to T-DXd, response and survival data is as follows for SG and T-DXd respectively: ORR [78.3% and 42.9%], TTNT [8.6 mo and 2.8 mo], and rwOS [22.3 mo and 7.3 mo]. Among pts with HR-/HER2-low MBC, median time from MBC diagnosis to treatment with ADC #1 was 8.2 months with 2 median lines of prior therapy in the metastatic setting (2 chemotherapy); 66.7% (n=10) received prior immunotherapy. Most HR- pts received SG prior to T-DXD (n=14, 93.3%) and 40.0% (n=6) received an intervening therapy between ADCs. For HR- pts who received SG prior to T-DXd, response and survival data is as follows for SG and T-DXd respectively: ORR [64.3% and 38.5%], TTNT [6.2 mo and 2.7 mo, and rwOS [15.7 mo and 6.5 mo]. In terms of key safety parameters during treatment with T-DXd, 13.3% of pts (8/60) required a dose reduction. 16.7% (10/60) were diagnosed with interstitial lung disease (ILD)/pneumonitis of any grade including 3 pts with grade 3-4 ILD (5.0%) and 3 pts with grade 5 ILD (5.0%). During treatment with SG, 40.0% of pts (24/60) required a dose reduction. 83.3% (50/60) received growth factor support (24 pts primary prophylaxis; 26 pts secondary prophylaxis); 9 pts (15%) required treatment delay due to neutropenia. Conclusion. This study represents the largest multicenter series to date of pts treated with sequential ADCs for HR+/HER2-low or HR-/HER2-low. ORR was higher and TTNT was longer for ADC #1 than ADC #2 in all subgroups, regardless of HR+ status and ADC sequence order. An additional ~30 pts will be reported at time of final analysis. Future prospective studies are planned to further clarify the efficacy and safety of sequential ADC use and to identify biomarkers of response and resistance. Key demographic, clinical and treatment characteristics in pts with HR+ and HR- HER2-low MBC treated sequentially with T-DXd and SG (in either order, with or without intervening therapies) Abbreviations: T-DXd (trastuzumab deruxtecan), SG (sacituzumab govitecan), MBC (metastatic breast cancer), ADC (antibody drug conjugate), HR (hormone receptor), HER2 (human epidermal growth factor receptor 2), CNS (central nervous system), ET (endocrine therapy), ORR (overall response rate), TTNT (time to next treatment), rwOS (real world overall survival), CI (confidence interval) * Several pts on ADC #2 with ongoing treatment and first scan pending, hence smaller denominator for response assessment Citation Format: Laura Huppert, Reshma Mahtani, Samantha Fisch, Naomi Dempsey, Sarah Premji, Angelina Raimonde-Taylor, Saya Jacob, Laura Quintal, Jo Chien, Michelle Melisko, Ana Sandoval-Leon, Lauren Carcas, Manmeet Ahluwalia, Natasha Harpalani, Jenna Hoppenworth, Dame Idossa, Ruta Rao, Karthik Giridhar, Hope Rugo. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-04.

ImportanceLittle is known about regional nodal irradiation (RNI) practice patterns or rates of locoregional recurrence (LRR) with and without RNI in patients with limited nodal disease and favorable biology treated with modern surgical and systemic therapy, including approaches that de-escalate those latter treatments.ObjectiveTo investigate how often patients with low–recurrence score breast cancer with 1 to 3 nodes involved receive RNI, incidence and predictors of LRR, and associations between locoregional therapy and disease-free survival.Design, Setting, and ParticipantsIn this secondary analysis of the SWOG S1007 trial, patients with hormone receptor-positive, ERBB2-negative breast cancer, and a Oncotype DX 21-gene Breast Recurrence Score assay result of no more than 25, were randomized to endocrine therapy alone vs chemotherapy then endocrine therapy. Prospectively collected radiotherapy information was collected from 4871 patients treated in diverse settings. Data were analyzed June 2022 to April 2023.ExposureReceipt of RNI (targeting at least the supraclavicular region).Main Outcome(s) and Measure(s)Cumulative incidence of LRR was calculated by locoregional treatment received. Analyses were assessed for associations between invasive disease-free survival (IDFS) and locoregional therapy, adjusted for menopausal status, treatment group, recurrence score, tumor size, nodes involved, and axillary surgery. Radiotherapy information was recorded in the first year after randomization, so survival analyses were landmarked as starting at 1 year among those still at risk.ResultsOf 4871 female patients (median [range] age, 57 [18-87] years) with radiotherapy forms, 3947 (81.0%) reported radiotherapy receipt. Of 3852 patients who received radiotherapy and had complete information on targets, 2274 (59.0%) received RNI. With a median follow-up of 6.1 years, the cumulative incidence of LRR by 5 years was 0.85% among patients who received breast-conserving surgery and radiotherapy with RNI; 0.55% after breast-conserving surgery with radiotherapy without RNI; 0.11% after mastectomy with postmastectomy radiotherapy; and 1.7% after mastectomy without radiotherapy. Similarly low LRR was observed within the group assigned to endocrine therapy without chemotherapy. The rate of IDFS did not differ by RNI receipt (premenopausal: hazard ratio [HR], 1.03; 95% CI, 0.74-1.43; P = .87; postmenopausal: HR, 0.85; 95% CI, 0.68-1.07; P = .16).Conclusions and RelevanceIn this secondary analysis of a clinical trial, RNI use was divided in the setting of biologically favorable N1 disease, and rates of LRR were low even in patients who did not receive RNI. Disease-free survival was not associated with RNI receipt; omission of chemotherapy among patients similar to those enrolled in the S1007 trial is not an independent indication for use of RNI.