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e19531 Background: Effective treatment and elimination of clonal plasma cells (PC) in multiple myeloma (MM) are typically associated with recovery of polyclonal (normal) plasma cells (PPC). Studies suggest that robust PPC recovery is associated with better outcomes. However, it is unclear if this remains valid in the context of monoclonal antibodies, such as Daratumumab, that selectively target plasma cells, and in turn, may adversely impact PPC recovery. Methods: We identified patients with MM who underwent MRD testing using Euroflow method at 6-12 months after treatment initiation. Eight patients had disease progression prior to MRD testing and were excluded from further analysis. PPC was quantitated by the proportion of total events acquired during flow examination. Patients were considered MRD-negative if they had <1 clonal PCs in 10 5 cells, as detected in the marrow. We first examined the impact of initial therapy (Daratumumab vs. non-Daratumumab based regimens) and MRD status on PPC recovery. Subsequently, we analyzed impact of PPC recovery on patient outcomes in terms of progression-free survival (PFS) and overall survival (OS). Results: We identified 572 patients who had MRD testing by flow at a median of 9 months (range 6-12) after treatment initiation. The median age was 63 years, 58% were male. Daratumumab was part of initial therapy in 17% of patients; the most common induction therapies were PI-IMiD triplets (73%), and dara-PI-IMiD quads (15%). In our cohort, 74% of patients were MRD-negative. In our practice, only samples with no monotypic PCs identified on initial low-sensitivity flow proceed to MRD testing, hence, the proportion of MRD-negative patients appears higher in our study than previously reported. Median PPC was 0.02% and was similar between MRD-negative and -positive patients. We found the median PPC was significantly low in patients who received Daratumumab compared to the non-Daratumumab treated cohort (0.011% vs. 0.023%; p<0.01). There was a trend towards lower PFS and OS among the lowest PPC quartile group compared to the upper 3 quartiles, although this was not significant (p=0.07 for PFS and OS, Wilcoxon). This trend was more evident among patients who did not receive Daratumumab. Conclusions: Our study demonstrates negative impact of anti-CD38 therapy with Daratumumab on recovery of PPCs after initial treatment, consistent with the persistent hypogammaglobulinemia seen in clinical practice among these patients. However, unlike the observation with the non-Daratumumab treated cohort, the low proportion of PPCs does not significantly impact patient outcomes among patients who received Daratumumab.

e19545 Background: Cytogenetic abnormalities (CA) at diagnosis are important prognostic factors in multiple myeloma (MM), but there is limited information on how these abnormalities evolve at first relapse and their significance. Methods: This retrospective study included patients aged ≥18 years, with a confirmed diagnosis of MM who experienced at least one disease relapse and had fluorescence in situ hybridization analysis within six months of both diagnosis and relapse. Data on CA and clinical outcomes were collected. High-risk (HR) secondary CA were defined as the presence of deletion of chromosome 17p (del17p) or gain or amplification of chromosome 1q. The primary objective was to evaluate changes in HR secondary CA at first relapse, while the secondary objective was to assess the impact of the cytogenetic changes on overall survival (OS) from diagnosis. Based on the presence or absence of HR secondary CA, patients who were tested for HR secondary CA at both time points were classified into four groups: 1) persistent absence of HR secondary CA, 2) emergence of HR secondary CA at relapse, 3) persistent presence of HR secondary CA, and 4) loss of HR secondary CA at relapse. Results: A total of 233 patients diagnosed between 2004 and 2023 were included. HR secondary CA were tested in 98.7% (n= 230) of patients at diagnosis, with 24.8% (n=57) testing positive. At first relapse, testing for HR secondary CA was performed in 97.4% (n=227) of patients, of whom 23.8% (n=54) tested positive. Del17p was evaluated in 98.3% (n=229) of patients at baseline and 95.7% (n=223) at relapse, with positivity increasing from 10.9% (n=25) to 15.3% (n=34). Gain or amplification of chromosome 1q was evaluated in 49.4% (n=115) at baseline and 25.5% (n=60) at relapse, with positivity rate rising from 28.7% (n=33) to 38.3% (n=23). There were no differences in overall response rate or very-good-partial-response-or-better rates to the initial therapy at diagnosis between the groups. (Table) Emergence/persistence of HR CA were associated with lower OS from diagnosis. Conclusions: Emergence of HR secondary CA at first relapse in MM has prognostic significance. These findings highlight the importance of serial cytogenetic testing for risk stratification. Response rate to initial line of therapy and overall survival from diagnosis among patients tested for HR secondary CA both at diagnosis and first relapse (n=224). Outcome Persistent absence of HR secondary CA(n=142) Emergence of HR secondary CA at relapse (n=25) Persistent presence of HR secondary CA (n=27) Loss of HR secondary CA at relapse(n=30) p-value Overall response rate a 75% (106) 76% (19) 63% (17) 67% (20) 0.5 b Very-good-partial response or better response rate 43% (61) 36% (9) 44% (12) 40% (12) >0.9 b Median (95% CI) OS from diagnosis in years 11.3 (9.7-13.4) 7.5 (5.1-12.1) 6.1 (4.2-9.4) 10.1 (6.5-14.1) <0.0001 c a Partial response or better; b Chi-square test; c Log-rank test.

e19503 Background: The uptake of BCMA directed ADCs in MM has been hindered by ocular toxicity. Belantamab mafodotin (BM) and MEDI2228 (MEDI) are BCMA directed monoclonal antibodies conjugated to the microtubule inhibitor, monomethyl auristatin F and the alkylator, pyrrolobenzodiazepine, respectively. Differences in the ADCs payload, antibody specificity and linker stability influence ocular toxicity. We investigated the patterns of ocular toxicity and tolerability of BCMA directed ADC therapy. Methods: Retrospective study of MM patients who commenced treatment with a commercial or investigational BCMA directed ADC at the Mayo Clinic between 2019-22. Results: 111 patients were included, the median age was 69 and median follow up 40 months. The median number of prior treatments was 6, 87% of patients were triple class refractory, 50% penta class refractory, 14% had prior BCMA directed therapy and 24% had extraosseous disease. Treatments included BM (n=56, 50%), BM in combination with other MM therapy (n=12, 11%) and MEDI (n=43, 39%). The overall response rate was 30% for BM and 44% for MEDI. The median OS and PFS for BM was 8 and 2 months, the median OS and PFS for MEDI was 11 and 5 months. The median number of ADC cycles was 2.5. Ocular toxicity is summarized in the table 1. Keratopathy was more common with BM (p=0.004). Only 4 MEDI patients developed keratopathy, all grade 1 and associated with dry eyes and/or photophobia. In contrast, 60% of BM patients developed keratopathy (13% grade 3-4 keratopathy). The median time to keratopathy onset was 1 month with BM, and 2.8 with MEDI. The median time until keratopathy was 4.6 months for BM. Loss of best-corrected visual acuity (VA) was significantly more common with BM (p<0.001). The median time to any decline in VA was 1.5 months for BM and 2.3 for MEDI. The median time until VA returned to baseline was 2.4 months for BM and 2.3 for MEDI. The frequency of dose delays for ocular toxicity was comparable between ADCs, as was the number of dose reductions (16% BM vs. 12% MEDI, p=0.5). The most common reasons for treatment discontinuation were progression or death (BM=69%, MEDI=44%) and ocular toxicity (BM=18%, MEDI=30%). Conclusions: Treatment interruptions, dose reductions and drug discontinuation are common with BCMA directed ADC therapy. Further research to optimize the administration schedule of these agents is warranted. BM and MEDI produce distinct patterns of ocular side effects, namely keratopathy and reduced VA with the former, and photophobia and dry eyes with the latter. BM N = 68 MEDI N = 43 p-value 2 Prophylactic steroid eye drops 4 (6%) 28 (68%) <0.001 Prophylactic lubricant eye drops 42 (63%) 33 (80%) 0.051 Max grade keratopathy 0.004 1-2 29 (47%) 4 (19%) 3-4 8 (13%) 0 (0%) VA equal or worse than 20/40 26 (68%) 6 (20%) <0.001 Days of ADC treatment 59 (33, 167) 68 (41, 105) 0.9 Dose delay for ocular toxicity 19 (28%) 8 (19%) 0.2 n (%); Median (IQR); 2 Chisq test; Wilcoxon rank sum.

526 Background: The PALLAS trial (NCT02513394) investigated the efficacy of the addition of palbociclib (palbo) to standard adjuvant endocrine therapy (ET) to reduce breast cancer recurrence. Previous analyses of this trial have not shown significant benefit of combination palbo+ET over ET alone. Given prior data showing that extent of neutropenia is associated with response to palbo and other cell cycle-specific therapies, we evaluated whether extent of neutropenia could identify responders to palbo in the adjuvant setting. Methods: PALLAS is a global, open-label, phase III trial that randomized patients (pts) with stage II-III hormone-receptor positive, HER2-negative breast cancer to receive ET for ≥5 years with or without standard-dose palbo for 2 years in 28-day cycles. The primary endpoint is invasive disease-free survival (iDFS). For this exploratory analysis, the palbo population was classified into pts with treatment-emergent high-grade neutropenia (HGN) with maximum grade ≥3 (absolute neutrophil count <1000), or low-grade/no neutropenia (LGN) with maximum grade <2; these groups were compared to each other and to the ET alone group for 5-year iDFS outcomes. Logistic regression examined individual baseline characteristics associated with HGN during the first 3 cycles within the palbo group. Impact of HGN during the first 3, 6, and 12 cycles on iDFS was tested using univariate and multivariable landmark Cox regression. Results: The safety population included 5736 pts, 2840 allocated to palbo+ET, 2896 to ET alone. Prior publications reported no new safety signals, low rates of serious infection, and no grade 5 treatment-related events. The palbo+ET group consisted of 1006 (35.4%) LGN and 1834 (64.6%) HGN. 5-year iDFS results are shown in the table. Pts who received palbo+ET and developed HGN by the end of cycle 6 had significantly improved 5-year iDFS compared to those who received ET alone (p=0.04), which remained statistically significant when adjusting for body mass index (BMI), prior chemotherapy, and race. Multivariable logistic regression showed lower BMI, prior chemotherapy, Asian race, and prior mastectomy were significantly associated with HGN (all p<0.05). Conclusions: In this exploratory analysis of the phase III PALLAS adjuvant trial, addition of palbo to ET appeared to be superior to ET alone in pts who developed HGN in the first 6 cycles of treatment but not in those who had LGN. These findings are consistent with observations in the metastatic setting suggesting that neutropenia could be a useful biomarker for palbo concentration and efficacy. Clinical trial information: NCT02513394 . Maximum grade neutropenia measured at end of cycle: 5-year iDFS Palbo+ET HGN (%) Palbo+ET LGN (%) ET alone (%) Hazard Ratio p-value 3 84.9 84.4 1.06 0.54 84.9 82.9 1.17 0.06 6 85.6 84.9 1.08 0.44 85.6 83.4 1.19 0.04 12 86.3 85.9 1.06 0.57 86.3 85.0 1.12 0.20

TPS1657 Background: Cancer treatments are traditionally administered in clinical settings, which can isolate patients from their familiar environments and exacerbate physical, psychosocial, and financial burdens. Travel requirements further amplify these challenges, particularly for underserved populations. Studies indicate that patients prefer receiving care at home, and international models have demonstrated the safety of home-delivered chemotherapy since the 1990s; however, no U.S. clinical trial data exists. In response, Mayo Clinic has developed the Cancer CARE (Connected Access and Remote Expertise) Beyond Walls (CCBW) program, a distributed cancer care delivery model that expands access to quality cancer care by bringing it to the home environment, providing in-home cancer treatment, lab testing, telemedicine, and community paramedic support. This trial evaluates the safety, acceptability, and impact of home-based subcutaneous (SC) nivolumab (Nivo) administration compared to in-clinic treatment within the CCBW initiative. Methods: This open-label, single-arm trial evaluates the impact of SC Nivo administration location—home versus infusion center—on patient reported cancer care experience, patient-preferred treatment location, acceptability, safety, and patient-reported outcomes. Eligible adult patients (ECOG 0-1) receiving IV Nivo for an FDA-approved indication and residing within 75 miles of Mayo Clinic Florida will transition to SC Nivo, receiving two initial in-clinic cycles. If tolerated without injection reactions, four cycles will be administered at home before resuming in-clinic treatment. Exclusion criteria include concurrent investigational/standard treatments or contraindications to immunotherapy. Fifty patients will be enrolled, with an estimated 75% (n=38) providing cancer care ratings after 8 weeks in-clinic and 8 weeks at-home, offering 85% power to detect a mean difference in ratings of 0.50 standard deviations. The primary endpoint is within-patient change in cancer care rating (0–10 scale, CAHPS Cancer Care Survey) comparing 8 weeks of in-clinic vs. at-home care. Secondary endpoints include patient-preferred treatment location, comfort with home injections, safety (grade 3+ adverse events), function (EORTC QLQ-F17), symptoms (PRO-CTCAE), side effect impact (GP5), and healthcare utilization (ER visits, hospitalizations). Cost will be assessed as a tertiary endpoint. The trial has FDA approval (IND #170079), Mayo Clinic IRB approval (#23009663), and ClinicalTrials.gov registration (NCT06265285). Enrollment began in April 2024, with an expected accrual period of 24 months. To date, 10 patients have been enrolled, and final analysis is expected 2.5 years after trial activation. Clinical trial information: NCT06265285 .

610 Background: The adverse event (AE) landscape in oncology is changing due to the introduction of immunotherapy and antibody drug conjugates. These AEs come with both short and long-term symptoms that significantly impact patient quality of life. Monitoring for early onset of symptoms could optimize therapy for a particular patient, maximizing potential efficacy while mitigating toxicity. It is also possible that some toxicities are directly associated with drug sensitivity. We sought to identify symptoms associated with pathologic complete response (pCR) using patient-reported outcomes (PROs) in early-stage high-risk breast cancer patients. Methods: Our study population included 288 stage II/III high-risk breast cancer patients enrolled on the I-SPY2 trial from 2021-2024, who received novel neoadjuvant therapies ± standard paclitaxel. pCR was assigned if tumor was absent in breast and nodes at surgery following neoadjuvant treatment. Patients (n = 288, pCR rate = 29%, 89% administered immunotherapy) were sent electronic PROs. 33 patient-reported AEs were measured using NCI's Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE). Each symptom was evaluated using severity, frequency, and interference on a Likert Scale. Presence of early PRO symptoms (cycles 1-3 of treatment) were binarized (at least one of moderate or greater), and odds ratios were computed with pCR as outcome. To assess whether higher grade AEs were enriched in patients that achieved a pCR, we also performed the Wilcoxan rank sum test using maximum (worst) symptom severity. Results: Of 288 patients included in our analysis (median age = 48 years, range = 20-78), 203 (70.5%) were White, 17 (5.9%) were Asian, 33 (11.5%) were Black or African American, and 35 (12.2%) were Hispanic. PRO analysis revealed that patients that had moderate to severe muscle pain (27% vs 10% OR = 3.15, p < 0.05), joint pain (22% vs 8% OR = 3.23, p < 0.05), headache (27% vs 12.5% OR = 2.59, p < 0.05), or mouth/throat sores (16% vs 5% OR = 3.56, p < 0.05) within weeks 1-3 had higher odds of achieving a pCR. When we looked at maximum severity between weeks 1-3, patients that achieved a PCR had higher grade muscle pain (p = 0.04), heart palpitations (p = 0.035), and significantly lower grade numbness and tingling (p = 0.002). Beyond 6 weeks, associations were weaker or insignificant. Conclusions: Our study utilizes an analysis framework that was able to determine sentinel symptoms such as muscle and joint pain, mouth/throat sores and palpitations as early as weeks 1-3 associated with increased efficacy. This may suggest an early immune reaction in patients that eventually respond favorably to treatment. Our work can help provide earlier proactive monitoring to mitigate toxicities, treatment redirection if needed, and a potential symptom-based early understanding to personalize treatment efficacy. A similar analysis is underway to predict immune related AEs. Clinical trial information: NCT01042379 .

7541 Background: Multiple myeloma (MM) is characterized by recurrent cytogenetic abnormalities, including translocations involving the immunoglobulin heavy chain locus on chromosome 14 and trisomies, which are considered primary and clonal. Throughout disease progression, MM cells may acquire additional abnormalities, which include chromosome 1 abnormalities (gain or amplification of 1q or deletion of 1p) and chromosome 17 abnormalities (del 17p or monosomy 17p). All these factors are considered high-risk markers that predict below-average outcomes. While outcomes related to 1q have been documented, their relationship with other abnormalities and clinical characteristics is less clearly defined. Methods: We created a cohort of newly diagnosed MM (NDMM) patients from April 1996 to December 2023 for whom FISH testing was performed using a panel that included 1q findings. Data on clinical and laboratory characteristics, other FISH abnormalities, and survival outcomes were collected from existing databases and the electronic medical record (EMR). Results: The cohort included 875 patients, with a median age of 65. Of these patients, 60% were male and 91% identified as white. A 1q abnormality was observed in 443 patients (51%); 87% exhibited a gain of 1q, while 13% showed amplification of 1q. Among those tested, other abnormalities included del13 (58%), t(11;14) (25%), t(4;14) (17%), t(14;16) (6%), del 17p (13%), and trisomies (51%). The distribution of abnormalities concerning the presence of 1q is presented in the table. Patients with 1q abnormalities were more likely to present with additional high-risk cytogenetic abnormalities. The median overall survival (OS) for those with a 1q abnormality was 73 months, compared to 105 months for those without it. Among these, patients with 1q amplification tended to have worse outcomes than those with a 1q gain, though this observation did not reach statistical significance. Conclusions: Abnormalities of chromosome 1, including 1q gain and amplification, can be seen in nearly 50% of patients with NDMM who are tested. 1q abnormalities are associated with other high-risk cytogenetic abnormalities. Measures of disease burden are higher among those with a 1q abnormality. Interestingly, we observed a higher proportion of patients with lambda light chain and those with IgA among those with a 1q abnormality. The presence of a 1q abnormality was associated with inferior survival, with a trend towards worse outcomes among those with 1q amplification compared to 1q gain. Clinical characteristics and cytogenetic associations of multiple myeloma patients with and without 1q abnormalities. 1q abnormality present 1q abnormality absent P del13 78% 39% <0.01 t(4;14) 25% 8% <0.01 t(11;14) 22% 27% NS t(14;16) 15% 3% <0.01 Trisomies 48% 53% NS 17p del 24% 12% <0.01 Lambda light chain 45% 26% <0.01 IgA 32% 16% <0.01 Hemoglobin 10.3 g/dL 11.2 g/dL <0.01

504 Background: Axillary surgery in breast cancer is used for staging and therapeutic purposes, but axillary lymph node dissection (ALND) confers high risk of complications including lymphedema. Accordingly, trials have focused on right-sizing axillary surgery, with options ranging from complete omission of surgery, sentinel lymph node (SLN) surgery, targeted axillary dissection (TAD), or ALND. Identifying a biomarker to reliably predict nodal burden would facilitate accurate selection of surgical management. We evaluated whether the presence or absence of ctDNA in the blood pre and post NAC is associated with residual nodal burden. Methods: I-SPY2 is a prospective, multicenter NAC trial for patients with clinical stage II-III high-risk breast cancer. Patients are randomized to novel NAC agents, with pathologic complete response being the primary endpoint. As part of the trial, serial ctDNA is assessed with a highly sensitive tumor-informed assay using up to 16 patient-specific tumor mutations (Signatera) at baseline, 3 weeks, 12 weeks, and post-NAC. We determined whether ctDNA positivity or negativity post-NAC, and the change in ctDNA status baseline/post-NAC (-/-, -/+, +/+, +/-) are associated with ypN category (N0, N1, N2). Results: ctDNA status was available post-NAC in 495 patients and change in ctDNA status from baseline was available in 493. At baseline, ctDNA was detected in 160/220 (72.3%) cN0 patients and 227/273 (83.2%) cN+ patients (p=0.006). Post-NAC, ctDNA was detected in 11/220 (5%) cN0 patients and 34/273 (12.5%) cN+ patients (p=0.004). While baseline ctDNA status was not associated with ypN category, there was a significant association between post-NAC ctDNA status and ypN category. For ctDNA + patients post-NAC, 33.3% were ypN0, 31.1% were ypN1, and 35.6% were ypN2 at surgery; in contrast, for ctDNA - patients post-NAC, 67.1% were ypN0, 23.1% were ypN1, and 9.8% were ypN2 (p<0.0001). Dynamic ctDNA changes were also associated with ypN category, with significantly more ypN0 patients among ctDNA -/- or ctDNA +/- cases, and more ypN2 patients in those who did not clear ctDNA (+/+) (p=0.0001, Table). Conclusions: To our knowledge this is the first study to demonstrate a significant relationship between ctDNA and ypN category, which has important surgical implications. CtDNA negativity was associated with low likelihood of ypN2 disease, making these patients excellent candidates for SLN surgery or TAD. Ongoing analyses will incorporate receptor subtype and timing of clearance of ctDNA. CtDNA in breast cancer may help tailor surgical management of the axilla, potentially reducing patient morbidity without compromising prognostic information. ctDNA baseline/post-NAC ypN0 (n=317) ypN1 (n=116) ypN2 (n=60) ctDNA -/- (n=105) 72.4% 19.1% 8.6% ctDNA -/+ (n=1) 0.0% 100.0% 0.0% ctDNA +/+ (n=44) 34.1% 29.6% 36.4% ctDNA +/- (n=343) 65.9% 23.9% 10.2%

TPS2092 Background: Glioblastoma (GBM) is the most common primary brain malignancy in adults. GBM is universally recurrent and associated with dismal outcomes. Re-irradiation (reRT) is ideal for evaluating combination therapy for recurrent GBM (rGBM) due to its multifactorial mechanism of action, including downstream immunomodulatory activity. RT (especially multi-fraction) increases immunogenicity in preclinical models by promoting immune activation, immune migration, and antigen uptake. Additionally, a recent study demonstrated enhanced PD-L1 expression in the glioma tumor microenvironment (TME) following RT, and combining stereotactic RT with a PD-1 inhibitor improved survival in murine models. Retifanlimab is a humanized monoclonal anti-PD1 IgG4 antibody that received FDA approval for adults with metastatic or recurrent locally advanced Merkel cell carcinoma. Bevacizumab, an anti-VEGF antibody, is a treatment for radiation necrosis/cerebral edema with less immune suppression than corticosteroids. In a previous Phase 2 study, hypofractionated RT (HFRT), retifanlimab, and bevacizumab was associated with a 9-month overall survival (OS) rate of 71.4%. To demonstrate the efficacy of this regimen compared to HFRT and bevacizumab, we have designed a new randomized controlled Phase 2 trial. We hypothesize that combination reRT with retifanlimab will produce a more robust anti-tumor immune response and improve OS compared to reRT without retifanlimab. Methods: This is a multicenter, open-label, randomized, controlled Phase 2 study of retifanlimab, bevacizumab, and HFRT for adult patients with rGBM. Patients are randomized 1:1 to the experimental (bevacizumab + retifanlimab + HFRT) or control cohort (bevacizumab + HFRT). Key eligibility criteria include age ≥ 18 years, Karnofsky performance status ≥ 60, ≥ 4 months since administration of any prior bevacizumab, and dexamethasone dose ≤ 4 mg at the time of randomization. The primary endpoint is 9-month OS. Secondary endpoints include OS, progression-free survival, objective response rate, neurologic assessment by NANO criteria, and adverse events profile. Protocol treatment will continue up to two years, or until progression or intolerable toxicity. Survival follow up will continue every two months, up to four years. Seven of the planned 94 patients have been enrolled as of submission on 1/28/25. Clinical trial #: NCT06160206. Funding provided by Incyte. Clinical trial information: NCT06160206 .

501 Background: EA1181 (NCT04266249) is a single-arm trial of neoadjuvant THP for patients with clinical anatomic stage II/III HER2+ breast cancer; patients with cT4 or cN3 disease were excluded . Assessing the primary endpoint, 3-year recurrence-free survival in patients with a pCR (ypT0/Tis, ypN0), requires longer follow-up. Here, we present results for the secondary objective of pCR rate and its relation to clinicopathologic factors and the HER2DX pCR likelihood score (Reveal Genomics) derived from gene expression and clinical features. Methods: Patients received 4 cycles of trastuzumab and pertuzumab (HP) with weekly paclitaxel (12 weeks) or docetaxel (q3w x 4), followed by surgery. Clinicopathologic features were assessed for all patients and HER2DX pCR score (stratified by ER status) was determined using the diagnostic biopsy in a representative subset of study participants. Results: 2175 patients were enrolled. Median age was 55 years (range 22-88 years); 58% had clinical stage IIA, 33% stage IIB, and 9% stage III. 45% had nodal involvement (mostly cN1). 781 tumors were HER2+/ER- and 1394 HER2+/ER+ (locally tested ). 2141 patients started THP, for whom the pCR rate was 44% overall, 63.7% in HER2+/ER- and 32.4% in HER2+/ER+ tumors. Disease progressed during THP in 16 patients (0.7%). The pCR rate varied inversely to the proportion of cells staining for ER among patients with HER2+/ER+ breast cancer: 1-10%+, 62.5%; 11-69%, 51.6%; ≥70%, 22.5% (p <0.001). The pCR rate was significantly associated with higher grade, especially in HER2+/ER+ disease. T and N stage did not significantly affect pCR rate. Among 569 patients assessed for the HER2DX pCR score, the pCR rate was significantly greater for patients with a higher vs lower score, regardless of ER status (Table). Further correlations and interactions will be presented. Conclusions: Neoadjuvant THP resulted in pCR in nearly two-thirds of pts with clinical stage II/III HER2+/ER- and in one-third with HER2+/ER+ breast cancer. There was no association with clinical stage. Lower ER expression and higher grade were associated with higher pCR rates. The HER2DX pCR score was a significant predictor of pCR, regardless of ER status. Clinical trial information: NCT04266249 . All Participants HER2+/ER- HER2+/ER+ # patients enrolled pCR rate (95% CI) # patients enrolled pCR rate (95% CI) # patients enrolled pCR rate (95% CI) Evaluable Cohort 2141 44%(42-46%) 774 64%(60-67%) 1367 32%(30-35%) HER2DX Cohort 569 48%(44- 52%) 230 69% (63-75%) 339 34%(29-39%) HER2DX pCR-high score 182 (32%) 68%(60-74%) 147 (64%) 70% (62-77%) 36 (11%) 58%(41-74%) HER2DX pCR-medium score 161 (28%) 67% (59- 74%) 70 (30%) 74%(62- 84%) 89 (26%) 61%(50-71%) HER2DX pCR-low score 226 (40%) 19%(14- 25%) 13 (6%) 31%(9-61%) 214 (63%) 18%(13-24%) P-value HER2DX score <0.001 0.010 <0.001