2524 Background: IMC-002 is a novel therapeutic agent with a distinct mechanism of action. In a phase 1a dose-escalation study, IMC-002 demonstrated favorable safety and tolerability, and clinical activity was observed in patients with hepatocellular carcinoma (HCC) in a subsequent phase 1b trial. Here, we present results from the phase 1b expansion cohort in patients with triple-negative breast cancer (TNBC), focusing on safety, efficacy, and analyses of soluble biomarkers. Methods: Eligible pts had advanced TNBC with progression after ≥1 prior systemic therapy and ECOG PS ≤1. IMC-002 (20 mg/kg Q3W) was administered in combination with gemcitabine plus carboplatin or paclitaxel and continued until disease progression. Tumor response was assessed every 6 weeks per RECIST 1.1 and iRECIST. Baseline ctDNA was analyzed using the AlphaLiquid 1000 platform (1,023 -gene panel). To exclude germline and clonal hematopoiesis of indeterminate potential (CHIP) variants, paired PBMC sequencing was performed. The assay detected single nucleotide variants (SNVs), small insertions and deletions (INDELs), fusions, copy number alterations (CNAs), microsatellite instability (MSI), and blood-based tumor mutational burden (bTMB). Results: A total of 12 pts with advanced TNBC received IMC-002 in combination with gemcitabine plus carboplatin (n=9) or paclitaxel (n=3). Most pts had received ≥2 prior systemic therapy (n=11), and ECOG PS 1 was observed in 10 pts. TRAEs reported in > 1 pt included grade 3 hematologic events, namely anemia (n=6) and hemolytic anemia (n=5). Non-hematologic TRAEs were limited to grade 1–2 and included skin rash (n=9), vitreous floaters (n=4), photopsia (n=3), and IRR (n=2). Among 12 efficacy-evaluable pts, the ORR was 25%, the DCR was 75%, and the CBR (disease control ≥ 6 months) was 42%. Exploratory ctDNA analyses identified no MSI-H tumors. One patient with a partial response was BRCA-positive. Patients achieving clinical benefit showed a higher median maximum somatic allele frequency (MSAF) than those without clinical benefit (32.65 vs 1.00; p=0.19). No clear association between bTMB and clinical activity was observed. Conclusions: IMC-002 in combination with gemcitabine plus carboplatin or paclitaxel demonstrated encouraging antitumor activity with a manageable safety profile in heavily pretreated patients with advanced TNBC. Exploratory baseline ctDNA analyses did not identify molecular features clearly associated with clinical benefit. Clinical trial information: NCT05276310 .

BACKGROUND:Avoiding unnecessary dose reductions is important for patients with advanced breast cancer (ABC) receiving trastuzumab deruxtecan (T-DXd). Nausea and vomiting, the most common adverse events of T-DXd, frequently necessitate dose reductions, which may impact treatment benefit. METHODS:This retrospective exploratory study investigated the impact of triple antiemetic regimen (TAR) prophylaxis on T-DXd dose preservation over time. Data from 143 human epidermal growth factor receptor 2 (HER2)-positive or HER2-low ABC patients who received ≥2 T-DXd cycles were stratified based on TAR use in the first cycle. TAR included an NK1 receptor antagonist, a 5-HT3 receptor antagonist (or fixed netupitant/palonosetron combination), and dexamethasone. RESULTS:Patients receiving TAR in the first cycle were significantly less likely to require T-DXd dose reductions in subsequent cycles than the non-TAR group (31.3% vs. 66.7%, P = 0.033). The lowest T-DXd dose relative to initial dose for each patient was significantly higher in the TAR group than in the non-TAR group (100% vs. 80.6%, P = 0.001). There was a trend toward a longer median time to T-DXd dose reduction in the TAR group (15.7 vs. 3.9 months; P = 0.183). CONCLUSION:These findings suggest that upfront TAR may help maintain the dosing of T-DXd in patients with HER2-positive or HER2-low ABC.

Circulating tumor DNA (ctDNA) enables non-invasive monitoring in solid tumors. This study evaluates the prognostic and predictive value of minimal residual disease (MRD) detection using a personalized ctDNA assay during neoadjuvant chemotherapy (NAC) and post-surgical follow-up in triple-negative breast cancer (TNBC) or HER2-positive breast cancer (BC) patients. Patients with stage IA-IIIC TNBC or HER2-positive BC scheduled for NAC followed by curative surgery were prospectively enrolled. Peripheral blood samples (20 mL) were collected at three time points: before NAC (P0), perioperatively (pre- or one month post-operatively, P1), and one year post-operatively (P2). The CancerDetect™ assay (IMBdx, Inc.), a tumor-informed MRD test, identified patient-specific mutations (up to 100) through whole exome sequencing (WES) of tumor tissue and peripheral blood mononuclear cells. CtDNA positivity was defined as the presence of more than two tumor-derived mutations in plasma. Of 145 patients analyzed (68 TNBC, 77 HER2-positive, median age 49 years), stages included stage I (2.1%), stage II (64.1%), and stage III (33.8%). The median number of mutations identified through WES was 59 (range 9-234), higher in TNBC (71 vs. 50, P = 0.002) but not by stage (P = 0.668). Baseline ctDNA positivity (P0) was 86.9% (median 20 mutations; range 0-97), significantly higher in TNBC (100% vs. 75.3%, P < 0.001) and stage III (95.9% vs. 82.3%, P = 0.021).After NAC, ctDNA clearance occurred in 86.5% of P1-positive patients, with overall ctDNA positivity at P1 dropping to 11.7%, slightly higher in TNBC (14.7% vs. 9.1%, P = 0.314). Pathologic complete response (pCR) rates post-NAC were 55.6%, similar across subtypes and stages. P1 positivity tended to be higher in non-pCR patients (15.6% vs. 7.5%, P = 0.202). CtDNA clearance was associated with higher pCR (60.6%) compared to persistent positive (37.5%, P = 0.106) or persistent negative (42.1%, P = 0.207). For TNBC, P1 positivity was associated with non-pCR (22.6% vs. 5.6%, P = 0.070), unlike HER2-positive BC (9.1% for both).At P2, 90.4% were ctDNA-negative, with positivity in 8.2% (6/73; 4 persistent positives, 2 conversions). At 23 months’ median follow-up, 5 patients developed distant metastases. Persistent positivity at P0-P1 (23.5% vs. 0.8%, P < 0.001) or P1-P2 (75.0% vs. 0%, P < 0.001) was linked to higher recurrence rates. The personalized ctDNA assay detected BC effectively and correlated with subtypes and stages. Post-NAC ctDNA monitoring predicted treatment response and recurrence risk. We are planning longer-term follow-up in the enrolled cohort to better validate its power in recurrence prediction. Yongjun Cha, Junghoon Shin, Jongseong Ahn, Sunghoon Heo, Hwang-Phill Kim, Duhee Bang, Sang-Hyun Song, Young-Hyuck Im, Ji-Yeon Kim, Tae-You Kim. Perioperative tumor-informed ctDNA monitoring for minimal residual disease in triple-negative and HER2-positive breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3260.

Purpose Neoadjuvant pembrolizumab has shown efficacy in improving pathologic complete response (pCR) rates and survival outcomes in triple-negative breast cancer (TNBC). However, real-world data on its clinical efficacy, safety, and surgical outcomes remain limited. Materials and methods This retrospective observational study included 331 TNBC patients treated at a single institution from July 2022 to December 2023. Patients received weekly paclitaxel with carboplatin followed by doxorubicin and cyclophosphamide (AC), with or without pembrolizumab. Primary outcomes included pCR rates and surgical de-escalation in the breast and axilla. Secondary outcomes included event-free survival (EFS), overall survival (OS), surgical complications, and persistent immune-related adverse events (irAEs). Results The pCR rate was higher in the pembrolizumab group (57.7 %) compared to the control group (49.1 %), with an estimated difference of 8.5 % (p = 0.120). Pembrolizumab enabled 32.7 % of patients initially planned for mastectomy to undergo breast-conserving surgery (BCS). Axillary lymph node dissection (ALND) was avoided in 91 % of pembrolizumab-treated patients versus 86.9 % in the control group. Persistent irAEs were observed in 10.9 % of the pembrolizumab group, with thyroid dysfunction being the most common. Surgical complications were similar between groups. Short-term oncologic outcomes, including EFS and OS, did not differ significantly after a median follow-up of 21 months. Conclusion Pembrolizumab demonstrated potential benefits in increasing pCR rates and facilitating surgical de-escalation while maintaining comparable safety to conventional regimens. Persistent irAEs underscore the need for preoperative management and vigilant monitoring. Future studies should identify predictive biomarkers to optimize pembrolizumab's use and assess its long-term impact on survival outcomes.

Abstract Background: Programmed cell death ligand 1 (PD-L1) expression alone has limited predictive value for pembrolizumab plus 5-fluorouracil and platinum (PFP) therapy in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). An artificial intelligence (AI)-powered spatial tumor-infiltrating lymphocyte (TIL) analyzer may provide independent prognostic information. Methods: This study included 63 patients with locally incurable HNSCC who received first-line PFP at Samsung Medical Center. Patients were classified into inflamed phenotype (IP) or non-inflamed phenotype (NIP) based on the 5% proportion threshold of inflamed 1 mm2-sized grids over total grids within hematoxylin and eosin-stained whole-slide images (WSIs) analyzed using Lunit SCOPE IO. We evaluated the prognostic value of inflamed status and densities of intratumoral TILs (iTILs), stromal TILs (sTILs), and tumor microenvironment TILs (tTILs). Results: Patients were predominantly male (78%). The median age at PFP initiation was 57 years. The most common primary tumor site was oral cavity (49.2%), followed by oropharynx (16%) and hypopharynx (10%). Of the 37 patients with available PD-L1 combined positive score (CPS), 2 (5%), 23 (62%), and 12 (32%) had CPS values of <1, 1-19, and ≥20, respectively. The overall response rate was 54%, with 67% in the CPS ≥20 subgroup and 48% in the CPS <20 subgroup. The median progression-free survival (PFS) was 7.2 months, with 10.8 months for patients with CPS ≥20 and 5.5 months for patients with CPS <20. The median overall survival (OS) was 18.6 months. Among 62 patients with available WSIs, 47 (74%) and 15 (26%) patients were categorized as having an IP and NIP, respectively. Oral cavity cancer was enriched with IP (57.4% of all IP cases vs 26.7% of all NIP cases), while all four paranasal sinus tumors had NIP. The overall response rate was 57% in the IP group and 44% in the NIP group. Patients with IP had significantly longer PFS and OS than patients with NIP, both in unadjusted (hazard ratio [HR] for PFS, 0.4; 95% confidence interval [CI], 0.21-0.78; P = 0.007; HR for OS, 0.43; 95% CI, 0.2-0.95; P = 0.036) and PD-L1 CPS-adjusted analyses (HR for PFS, 0.41; 95% CI, 0.21-0.79; P = 0.008; HR for OS, 0.4; 95% CI, 0.18-0.89; P = 0.025). High densities (≥25th percentile) of iTILs, sTILs, and tTILs were all significantly associated with prolonged PFS after CPS adjustment (P = 0.001, 0.001, and 0.012). High density of iTILs was also significantly associated with improved OS (P = 0.001 after CPS adjustment), while there was no significant association between OS and high density of sTILs or tTILs (0.077 and 0.085, respectively, after CPS adjustment). Conclusion: An AI-driven spatial TIL analyzer might serve as a simple and independent prognostic biomarker in HNSCC patients receiving pembrolizumab plus chemotherapy. Citation Format: Sehhoon Park, Junghoon Shin, Chan-Young Ock, Chang Ho Ahn, Hyun Ae Jung, Se-Hoon Lee, Myung-Ju Ahn. Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as a prognostic biomarker for pembrolizumab plus chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7658.

Abstract Background: Neoadjuvant pertuzumab and trastuzumab in combination with chemotherapy can achieve pathological complete response (pCR, defined as ypT0/is ypN0) in approximately 40–60% of patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). Patients who achieve pCR have significantly improved survival. Therefore, the prediction of pCR is crucial for optimizing neoadjuvant therapy. Methods: To identify a gene expression signature that could predict pCR in patients with HER2+ BC, we used the nCounter Breast Cancer 360TM V2 panel to quantify the expression of 758 genes in 104 HER2+ BC samples from patients who received neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) chemotherapy and subsequent curative breast surgery. Data normalization, differentially expressed gene (DEG) analysis, and gene set enrichment analysis (GSEA) were performed using the NanoTube Bioconductor package. Using the elastic net logistic regression model with optimal hyperparameters determined by 5-fold cross-validation (5-CV), we developed a chemosensitivity score based on the expression of significant DEGs (genes with absolute log2-fold-change ≥0.5 and q-value < 0.1). We tested its predictive value for pCR using multivariable logistic regression analysis. Results: The median age at diagnosis was 49.5 years. The clinical stage was II in 53 (51%) patients and III in 51 (49%) patients at diagnosis. Ninety (86.5%) patients had a HER2 immunohistochemistry (IHC) score of 3+, while the remaining 14 (13.5%) patients had HER2 IHC 2+ but HER2 amplification detected by in situ hybridization. Pathological evaluation of surgical specimens revealed that 55 (52.9%) patients achieved pCR. Menopausal status (p = 0.01), PAM50 intrinsic subtype (p = 0.002), hormone receptor (HR) status (p < 0.001), and HER2 IHC score (p = 0.019) were significantly correlated with the pCR rate. DEG analysis using the PAM50 intrinsic subtype, HR status, and HER2 IHC score as covariates revealed 6 downregulated DEGs and 33 upregulated DEGs in patients who achieved pCR compared to patients who did not (Table 1). The 39 DEGs were significantly enriched in nine preselected MSigDB hallmark gene sets representing immunological processes (p < 0.001). The optimal elastic net logistic regression model containing 39 DEGs achieved the mean 5-CV area under the receiver operating characteristic curve of 0.81. The chemosensitivity score calculated using the optimal model parameters was significantly correlated with pCR after adjustment for the PAM50 intrinsic subtype, HR status, and HER2 IHC score (p < 0.001). GSEA revealed eight hallmark gene sets that were significantly up- or downregulated in samples with pCR, including epithelial-mesenchymal transition (normalized enrichment score [NES] = -2.16; q < 0.001), late estrogen response (NES = -2.01; q = 0.004), early estrogen response (NES = -1.972; q = 0.005), and inflammatory response (NES = 1.53; q = 0.06). Conclusion: Our findings demonstrate that gene expression patterns can predict the response to neoadjuvant TCHP chemotherapy in HER2+ BC. The functional characterization of 39 DEGs suggests that the tumor microenvironment, including adjacent immune cells, plays a significant role in modulating the response to neoadjuvant chemotherapy in HER2+ BC. Table 1. Significant DEGs Citation Format: Junghoon Shin, Ji-Yeon Kim, Eun Yoon Cho, Seok Won Kim, Jeong Eon Lee, Hyunwoo Lee, Yeon Hee Park, Jin Seok Ahn, Young-Hyuck Im. Gene expression signature as a predictor of pathological complete response to neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab treatment in locally advanced HER2-positive breast cancer [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 PO1-15-05.

BACKGROUND:Hematopoietic stem cell transplantation (HSCT) is a complex, high-risk procedure with significant morbidity and mortality. The positive impact of higher institutional case volume on survival has been reported in various high-risk procedures. The association between annual institutional HSCT case volume and mortality was analyzed using the National Health Insurance Service database. METHODS:Data on 16,213 HSCTs performed in 46 Korean centers between 2007 and 2018 were extracted. Centers were divided into low- or high-volume centers using an average of 25 annual cases as the cut-off. Adjusted odds ratios (OR) for 1-year mortality after allogeneic and autologous HSCT were estimated using multivariable logistic regression. RESULTS:For allogeneic HSCT, low-volume centers (≤25 cases/y) were associated with higher 1-year mortality (adjusted OR 1.17, 95% CI 1.04-1.31, P = .008). However, low-volume centers did not show higher 1-year mortality (adjusted OR 1.03, 95% CI 0.89-1.19, P = .709) for autologous HSCT. Long-term mortality after HSCT was significantly worse in low-volume centers (adjusted hazard ratio [HR] 1.17, 95% CI, 1.09-1.25, P < .001 and adjusted HR 1.09, 95% CI, 1.01-1.17, P = .024, allogeneic and autologous HSCT, respectively) compared with high-volume centers. CONCLUSION:Our data suggest that higher institutional HSCT case volume seems to be associated with better short- and long-term survival.