Worse Progression-free Survival Research Articles

Abstract PO1-14-01: Clonal Architecture of circulating tumor DNA predicts Early Progression on Tamoxifen With or Without Palbociclib in Hormone Receptor-Positive Advanced Breast Cancer: NCCH1607/PATHWAY trial

Abstract Objective: Some patients with poor prognosis hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) experience early disease progression on the combination of CDK4/6 inhibitors and endocrine therapy. We aimed to determine whether clonal architecture assessed by circulating tumor DNA (ctDNA) could identify patients at higher risk of early progression on tamoxifen therapy with or without palbociclib. Methods: PATHWAY trial is a randomized, placebo-controlled, Asian international, double-blind, phase 3 study evaluating palbociclib plus tamoxifen (PAL+TAM) versus placebo plus tamoxifen (PLB+TAM) in pre/perimenopausal and postmenopausal women with HR+/HER2- ABC (NCT03423199). The study was conducted as a Clinical Research Collaboration with the National Cancer Center Hospital as the regulatory study sponsor and Pfizer providing drug and financial support. The primary endpoint was investigator assessed progression-free survival (PFS). Genomic profiling by next-generation sequencing was an exploratory endpoint to characterize molecular alterations in ctDNA and correlate these with clinical outcomes. Plasma samples were collected at cycle 1-day 1 (pre-treatment) and cycle 2-day 15 and sequenced with the Guardant360 assay (Guardant Health). Patients were included if they had a minimum of 14 days of treatment in the first cycle. The variant allele frequency (VAF) was defined as number of mutant molecules at a specific nucleotide location over the total number of molecules present in the background at a specific given genomic location. We assessed the gene with highest VAF as the dominant clone allele frequency (DCAF). The association of changes in ctDNA alterations with PFS was evaluated to identify biomarkers of early progression. Results: Pre-treatment plasma was successfully sequenced in 177 of the 184 patients; 88 patients treated with PAL+TAM, and 89 with PLB+TAM. ctDNA was detected in 144 (81.4%) patients; the median number of genetic abnormalities was 2 (range, 0-19). PIK3CA, TP53, ERBB2, ESR1, AKT1, EGFR and PTEN were the genes with highest VAF as the dominant clone (24.3%, 11.9%, 4.5%, 4.5%, 3.4%, 3.4%, 3.4%, respectively). The median DCAF was 1.79 (range, 0.1-81.23); PAL+TAM, 2.53 (range, 0.1-63.5) and PLB+TAM, 1.65 (range, 0.08-81.23). Patients with ≥ 2 detectable genomic alterations and DCAF ≥ 1.8% had worse PFS (hazard ratio (HR) 1.93 [95% confidence interval (CI): 1.375 to 2.721], p = 0.0003 and HR 1.95 [95% CI: 1.345 to 2.834], p < 0.0001, respectively) compared to all other patients. In addition, we evaluated whether changes of clonal architecture in ctDNA at early treatment time point (ie. Cycle 2 Day 15) are associated with PFS. Patients with increased DCAF had worse PFS on both PAL+TAM (HR 2.80 [95% CI: 0.552 to 14.15], p = 0.04) and PLB+TAM (HR 2.02 [95% CI: 1.022 to 3.990], p = 0.01). All patients with high pretreatment DCAF (≥ 1.8%) and increase in DCAF progressed within 1 year (n=5, 2 patients treated with PAL+TAM, and 3 with PLB+TAM). Conclusion: Evaluation of clonal architecture in ctDNA could support identification of HR+/HER2- ABC patients with poorer prognosis, who may be at higher risk of early progression, regardless of CDK4/6 inhibitor use. Citation Format: Yoon-Sim Yap, Yuki Kojima, Akinobu Hamada, Hirofumi Mukai, Yen-Shen Lu, Joo Hyuk Sohn, Yoshiko Umeyama, Emi Noguchi, Kazuki Sudo, Tomomi Hata, Aya Kuchiba, Taro Shibata, Shigehiro Yagishita, Masayuki Yoshida, Shinji Kohsaka, Kouya Shiraishi, Kenichi Nakamura, Kenji Tamura, Kan Yonemori. Clonal Architecture of circulating tumor DNA predicts Early Progression on Tamoxifen With or Without Palbociclib in Hormone Receptor-Positive Advanced Breast Cancer: NCCH1607/PATHWAY trial [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 PO1-14-01.

Abstract PO4-04-13: Impact of dose reduction of CDK4/6 inhibitors on progression-free survival in Mexican patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a retrospective single-center study

Abstract Background Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been demonstrated to prolong survival in women with hormone receptor-positive, HER-2 negative, metastatic breast cancer. However, these treatments often require dose adjustments due to adverse effects, resulting in a reduction in 30-50% of cases. There is evidence suggesting a relationship between dose intensity and progression-free survival (PFS), but data in the Hispanic population are limited. Therefore, the objective of the study was to explore the association between dose reduction of CDK4/6/i inhibitors and PFS in patients with metastatic breast cancer. Methods We conducted a retrospective single-center study involving patients diagnosed with hormone receptor-positive, HER-2 negative metastatic breast cancer (MBC) between 2020 and 2023. Eligible patients were those who received at least one cycle of palbociclib, abemaciclib, or ribociclib and had a follow-up period of more than three months since the initiation of CDK4/6 inhibitor (CDK4/6i) treatment. Patient data were collected from electronic medical records. We analyzed demographic and clinicopathological characteristics and estimated the PFS in patients who had any dose reduction within the first 12 weeks compared to those who did not, using Kaplan-Meier plots and compared the differences in survival using the log-rank test. A Cox regression analysis was performed to estimate survival hazard ratios (HR). Results Among 41 patients, the mean age at CDK4/6i initiation was 61.0 years (SD 12.9), 22 (53.7%) were postmenopausal at diagnosis, 25 (61%) had recurrent disease, and 22 (53.7%) were receiving CDK4/6i in the first-line setting. Bone metastases were present in 30 (73.2%), and visceral metastases in 22 (53.7%). Regarding type of CDK4/6i, 33 (80.5%) received palbociclib, 7 (17.1%) ribociclib, and 1 (2.4%) abemaciclib. At 12 weeks, 12 patients (29.3%) had a dose reduction (Table 1). With a median follow-up since CDK4/6i initiation of 407 days (95% confidence interval (CI) 272-542), 19 events were recorded, with a median PFS of 12.6 months (95% CI 8.0-17.3) for the overall population. Median PFS was 9.7 months (95% CI 0.6-18.8) in patients who had a dose reduction at 12 weeks and 35.2 months (95% CI 0-72.2) in those who did not (p=0.014). The univariate Cox proportional hazard model showed that dose reduction was associated with a worse PFS (hazard ratio 3.1; 95% CI: 1.20–7.80, p = 0.0019) Conclusion In this cohort of Mexican patients with hormone receptor-positive, HER2-negative metastatic breast cancer we found that dose reduction of CDK4/6 inhibitors within the first 12 weeks of treatment was associated with worse PFS. Given the retrospective nature of this analysis, we believe that these findings should be replicated in prospective studies. Table. Patient characteristics Citation Format: Andres Meraz-Brenez, Alejandro Aranda-Gutierrez, Hector Raul Gonzalez-Sanchez, Bertha Alejandra Martinez-Cannon, Leonardo Verduzco-Rodriguez, Haydee Cristina Verduzco-Aguirre. Impact of dose reduction of CDK4/6 inhibitors on progression-free survival in Mexican patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a retrospective single-center study [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 PO4-04-13.

Abstract PO1-05-10: Clinical effectiveness of CDK4/6 inhibitors in HER2-low metastatic breast cancer

Abstract Introduction: There is growing evidence indicating that human epidermal growth factor 2 (HER2)-low is a unique subtype of breast cancer that comprises a substantial share of patients historically classified as HER2 negative. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are important in the treatment of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC). Whether HER2-low status or the level of HER2 gene amplification have prognostic significance for HR+/HER2-negative MBC patients treated with ET and CDK4/6i remains an area of active investigation. Methods: Patients diagnosed with HR+/HER2-negative MBC and who were treated with palbociclib, ribociclib, or abemaciclib from 6/10/2015 to 12/28/2022 were selected from the Montefiore Health system database and followed until 3/24/2023. HER2-0 was defined as immunohistochemistry (IHC) 0, and HER2-low was defined as IHC 1+ or IHC 2+/in situ hybridization negative by 2018 ASCO/CAP guidelines. Median values were used to establish cutoffs for HER2/CEP17 ratio and HER2 gene copy number (GCN). Characteristics of the patients and tumors in the subgroups were compared using chi-squared/Fisher’s exact test for categorical data and Kruskal-Wallis/Wilcox signed rank tests for continuous data. Kaplan-Meier and Cox proportional hazards analysis were used to compare overall survival (OS) and progression free survival (PFS). Results: 239 patients received CDK4/6i, with 46 HER2-0 and 193 HER2-low patients. There was no statistically significant difference in clinicopathological characteristics between both cohorts. No significant differences were observed in median OS (36 vs 34 months, P > 0.9) and median PFS (44 vs 35 months, P = 0.4) between HER2-0 and HER2-low patients. Adjusting for HER2 status, multivariable analysis showed no statistically significant association between HER2-low status and worse OS (HR: 1.03, P = 0.9) or worse PFS (HR: 1.37, P = 0.4). The median HER2/CEP17 ratio was 1.25 (Interquartile range (IQR): 1.18-1.39), and the median HER2 GCN was 2.58 (IQR: 2.10-3.18). Median OS (25 vs 37, P = 0.15) and median PFS (35 vs 37, P = 0.15) showed no significant differences between ratio-below vs above-median patients. However, patients with GCN-below-median had significantly worse OS (25 vs 37 months, P = 0.026), with no significant difference in median PFS (38 vs 35 months, P = 0.3). Multivariate analysis revealed a significant effect of GCN-below-median on OS (HR: 0.50, P = 0.022) but not on PFS. Conclusion: The clinical effectiveness of CDK4/6i is not influenced by HER2-low status; however, the extent of HER2 gene amplification may have a substantial impact on therapy responsiveness in MBC patients undergoing CDK4/6i treatment. Table 1. Baseline characteristics of patients with MBC comparing HER2-0 vs HER2-low, above/below median HER2/CEP17 ratio, and above/below median HER2 GCN. Table 2. Median OS and PFS in patients with MBC comparing HER2-0 vs HER2-low, above/below median HER2/CEP17 ratio, and above/below median HER2 GCN. Table 3. Multivariable analysis of OS and PFS for patients with MBC comparing HER2-0 vs HER2-low, above/below median HER2/CEP17 ratio, and above/below median HER2 GCN. Citation Format: Frank Zhang, Jesus Anampa Mesias. Clinical effectiveness of CDK4/6 inhibitors in HER2-low metastatic 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 PO1-05-10.

Abstract PO3-05-09: The impact of body mass index on CDK4/6 inhibitor treatment survival outcomes in metastatic breast cancer

Abstract Introduction: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are important in the treatment of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC). Previous studies have shown that CDK4/6is affect metabolic processes and cell metabolism, including adipogenesis, lipid synthesis, and glucose regulation. Obesity has been associated with worse survival in breast cancer. We aimed to assess the effect of body mass index (BMI) on survival outcomes in patients treated with CDK4/6is for MBC. Methods: Patients diagnosed with metastatic HR+/HER2-negative BC and who were treated with palbociclib, ribociclib, or abemaciclib from 6/10/2015 to 12/28/2022 were selected from the Montefiore Health system database and followed until 3/24/2023. The patients were divided into three groups according to BMI level as follows; normal: 18.5-24.9 kg/m2, overweight: 25-29.9 kg/m2 and obese: ≥ 30 kg/m2. Patients were also stratified by BMI measured after 3 months of therapy. Characteristics of the patients and tumors in the subgroups were compared using chi-squared/Fisher’s exact test for categorical data and Kruskal-Wallis/Wilcox signed rank tests for continuous data. Kaplan-Meier and Cox proportional hazards analysis were used to compare overall survival (OS) and progression free survival (PFS). Results: Among 221 patients, 66 were normal weight, 78 were overweight, and 77 were obese. There was no statistically significant difference in clinicopathological characteristics among the cohorts. Neither BMI measured at baseline nor after 3 months of therapy had any association with OS (P = 0.8 at baseline and P = 0.1 after 3 months) or PFS (P = 0.4 at baseline and P = 0.6 after 3 months). Multivariable analysis showed no statistically significant association between BMI and worse OS (HR: 1.1 for overweight, P = 0.7; and 0.96 for obese, P = 0.9) or worse PFS (HR: 0.9 for overweight, P = 0.8; and 0.76 for obese, P = 0.5). Multivariate analysis revealed a significant effect of obese BMI after 3 months of treatment on OS (HR: 0.48, P = 0.035) but not on PFS (HR: 0.88, P = 0.8). Overweight BMI after 3 months of treatment was not found to have a significant effect on OS (HR: 0.49, P = 0.063) or PFS (HR: 0.89, P = 0.9). Conclusion: The clinical effectiveness of CDK4/6is was not found to be influenced by BMI measured prior to therapy; however, there may be an association between improved OS and obese BMI after 3 months of treatment. Median OS and PFS in patients with MBC comparing different BMI groups (normal, overweight, and obese) at baseline prior to therapy and after 3 months of therapy. Table 1 Baseline characteristics of patients with MBC comparing different BMI groups (normal, overweight, and obese) at baseline prior to therapy and after 3 months of therapy. Table 2 Table 3 Multivariable analysis of OS and PFS for patients with MBC comparing different BMI groups (normal, overweight, and obese) at baseline prior to therapy and after 3 months of therapy. Citation Format: Frank Zhang, Jesus Anampa Mesias. The impact of body mass index on CDK4/6 inhibitor treatment survival outcomes in metastatic 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 PO3-05-09.

Abstract PO3-05-04: Characteristics and clinical outcome of patients with HR positive HER2 low metastatic breast cancer treated with CDK 4/6 inhibitors

Abstract Introduction Breast cancer (BC) is a disease characterized by significant intra- and intertumoral heterogeneity. Hence, it is not surprising that new subtypes with distinct biological features are being discovered, even among previously well-defined BC groups. Recently, HER2-low BC emerged as a new entity with specific clinical behavior, response to treatment and prognosis. HER2-low is a subset of HER2-negative BC, with HER2 immunohistochemical (IHC) score of 1+ or 2+, without HER2 gene amplification measured by in situ hybridization (ISH). As new therapeutic options become available for HER2-low patients, the best treatment sequence is yet to be determined. Furthermore, it is important to distinguish whether there is a difference in the response to standard treatment lines, such as CDK 4/6 inhibitors in metastatic HR positive BC patients, depending on HER2-low status. Methods A retrospective study of 369 metastatic BC (mBC) cases who started CDK 4/6 inhibitor therapy from January 2018 through December 2022 at University Hospital Centre Zagreb was conducted, with prior Ethics Committee approval. All patients with HR positive HER2 negative mBC, determined by standard IHC and ISH, were included in the research. Patient demographics and clinical presentation, tumor characteristics and treatment information were collected. Progression-free survival (PFS) analysis was done with the final data cut-off date being June 1st, 2023. Type 1 right censoring was performed. The data was analyzed using the Kaplan-Meier method and Cox proportional-hazards regression for clinically relevant covariates (age, line of treatment, de novo metastatic disease, endocrine resistance, liver metastases, and detected PIK3CA mutation). Results Median follow-up was 23 months. Of the 283 patients included, 146 (51.59%) had HER2-low disease. A change in HER2 expression between primary tumor and metastasis was found in 16.96% (N=48) patients. Of them,10.25% (N=29) who were initially HER2-low, were found to be HER2-0 in metastatic disease. Meanwhile, 6.71% (N=19) of patients had a change in HER2 expression from 0 to low upon becoming metastatic. In the HER2-low group, 47.06% (N=45) patients had a PIK3CA mutation as opposed to 33.33% (N=30) in the HER2-0 group. Odds ratio for a PIK3CA mutation in HER2-low patients was 1.86 (95% confidence interval (CI): 1.01-3.43, p-value 0.046). Median PFS in the HER2-low group was 18 months (95% confidence interval (CI): 14-24) versus 23 (95% CI: 18-30) in the HER2-0 group. Using multivariable analysis an adjusted hazard ratio of 1.15 (95% CI:0.84-1.57; p-value 0.389) was calculated. Covariates associated with a statistically significant increased risk of disease progression were a higher line of therapy (HR 1.39, 95% CI 1.36-1.71, p-value 0.002) and the presence of liver metastases (HR 2.17, 95% CI 1.42-3.32, p-value 0.0004). A covariate associated with a statistically significant longer PFS was de novo metastatic disease (HR 0.63, 95% CI 0.41-0.97, p-value 0.034). Conclusion There was a trend toward worse PFS in HER2-low mBC that did not reach statistical significance. HER2-low patients were more likely to harbor PIK3CA mutations than HER2-0 patient group. Longer follow-up and a larger cohort are needed in order to make definitive conclusions. Citation Format: Katarina Čular, Kristina Kanceljak, Ana Magdalena Glas, Dora Gudelj, Marija Križić, Marina Popović, Natalija Dedić Plavetić, Maja Sirotković-Skerlev, Stjepko Pleština, Tajana Silovski. Characteristics and clinical outcome of patients with HR positive HER2 low metastatic breast cancer treated with CDK 4/6 inhibitors [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 PO3-05-04.

Abstract PO1-06-02: Solti-1716 TATEN phase II trial: Targeting non-Luminal disease by PAM50 with pembrolizumab and paclitaxel in Hormone Receptor-positive/HER2-negative advanced breast cancer (ABC)

Abstract Background Within HR+/HER2-negative breast cancer, PAM50 non-luminal tumors (HER2-enriched [HER2-E] and Basal-like) have higher expression of proliferation and immune-related genes and tumor infiltrating lymphocytes and might benefit from immunotherapy. Here, we report the efficacy, safety, and correlative analysis data of the TATEN trial, the first study designed to evaluate pembrolizumab and paclitaxel in HR+/HER2-negative, PAM50 non-luminal, ABC. Methods TATEN trial (NCT04251169) is a single-arm, multicenter, phase II study evaluating pembrolizumab in combination with paclitaxel in patients with HR+/HER2-, PAM50 non-luminal ABC. Key inclusion criteria include progression to prior CDK4/6 inhibitors (CDK4/6i), presence of measurable disease, no prior chemotherapy for ABC, ECOG 0-1, and non-luminal metastatic disease by PAM50. Included patients received pembrolizumab at 200 mg every 3 weeks (beginning at cycle 1) in combination with weekly paclitaxel at 80 mg/m2 beginning at cycle 2. The primary endpoint was overall response rate (ORR) according to RECIST V1.1. in patients who received at least one dose of combination treatment and had a first, post-baseline tumor assessment (evaluable population). Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), safety, and predictive biomarkers. The study was based on a Simon two-stage design. Stage I of the trial would be considered successful if at least 6 of 15 patients achieved a partial response and/or complete response. In that case, the trial would recruit up to 46 evaluable patients for a target ORR ≥ 41%. Metastatic biopsies from patients enrolled in pre-screening were also evaluated for tumor infiltrating lymphocytes (TILs) and were further analyzed with an expression panel of 192 genes, including PDL1 and PD1. Results From July 2020 to December 2021, 132 tumors were screened, and 27 PAM50 non-luminal tumors were identified (20%). Non-luminal tumors trended to have higher PDL1 expression (p=0.090) and TILs (p=0.084) compared to luminal tumors, while no difference was observed for PD1 (p=0.850). Of 20 recruited patients in the study (stage I+II), 18 were evaluable for the primary endpoint. Baseline characteristics were as follows: median age 55 years, ECOG 0 55%, de novo MBC 22%, and visceral disease 72.2%. Eleven patients had received paclitaxel treatment in the adjuvant setting. Regarding PAM50 subtype, 2 patients had basal-like and 16 HER2-E tumors. At the time of data cut-off (June 2023), 13 patients (72.2%) had stopped their treatment because of progressive disease and 3 (16.6%) due to toxicity. Two patients (11.1%) were still on treatment. The ORR was 61.1 % (11 of 18, 95% CI 35.7-82.7). CBR was 88.9% (16 of 18, 95% CI 65.3-98.6), and median PFS was 8.3 months (95% CI 7.3 – 14.1). Treatment-related adverse events (TRAEs) of any grade (G) occurred in 19 patients (95%), while 45% of patients experienced G3 TRAEs. No G4 or G5 TRAEs were reported in the evaluable population. Gene expression analysis was successful for all recruited patients (n=20). High expression of the PAM50 luminal A signature (p=0.049), and the luminal genes PGR (p=0.028) and RRAGA (p=0.038) were associated with worse PFS (univariate analyses). The pan-leucocyte receptor CD84 (p=0.028) was associated with better PFS (univariate analysis). Conclusions Pembrolizumab in combination with paclitaxel is safe and exhibits promising efficacy outcomes in patients with CDK4/6i resistant HR+/HER2- ABC with a PAM50 non-luminal subtype. Although meeting the criteria for stage II, the enrollment was stopped prematurely due to the lack of funding and pembrolizumab supply. More correlative analyses will be presented at the conference. This study was funded in part by MSD. Citation Format: Aleix Prat, Benedetta Conte, Fara Brasó-Maristany, Nuria Chic, Montserrat Muñoz, Cristina Hernando, Manuel Alva, Silvia Vazquez, Salvador Blanch, Mafalda Oliveira, Esther Fernández, Oleguer Castillo, Patricia Galván, Ángela Aguirre, Esther Sanfeliu, Lorea Villanueva, Tomás Pascual, Eva Ciruelos. Solti-1716 TATEN phase II trial: Targeting non-Luminal disease by PAM50 with pembrolizumab and paclitaxel in Hormone Receptor-positive/HER2-negative advanced breast cancer (ABC) [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 PO1-06-02.

Grade Heterogeneity in High-Grade Urothelial Carcinomas: Does It Have an Impact on the Survival of Patients With Intermediate/High-Risk Nonmuscle-Invasive Bladder Cancer Who Received Adequate Adjuvant Bacillus Calmette-Guérin Therapy?

We aimed to compare recurrence-free survival (RFS) and progression-free survival (PFS) of the patients with pure high-grade (HG) vs mixed-grade (MG) nonmuscle-invasive bladder cancer who received adequate bacillus Calmette-Guérin therapy. We conducted a retrospective cohort analysis using data from an institutional database. The study included patients diagnosed with HG nonmuscle-invasive bladder cancer at the initial transurethral resection specimen between 2010 and 2020. The initial transurethral resection specimens of all patients were reevaluated by a dedicated uropathologist. The percentage of low-grade tumor areas accompanying HG areas was determined for each case. Time-to-event analysis was performed using the Kaplan-Meier method. RFS and PFS rates were compared between groups. Of the 203 patients enrolled in the study, 69 (34%) had MG tumors. Recurrence was observed in 41 out of 134 patients (30.6%) in the HG group and in 19 out of 69 patients (27.5%) in the MG group. The 36-month RFS rates were 69% (CI: 62-77) and 72% (CI: 62-83) for the HG-urothelial carcinoma (UC) and MG-UC groups, respectively. The RFS rates were similar between groups (log-rank, P = .58). Progression was observed in 22 out of 134 patients (16.4%) in the HG group and in 4 out of 69 patients (5.8%) in the MG group. The 36-month PFS rates were 84% (CI: 77-90) and 94% (CI: 89-100) for the HG-UC and MG-UC groups, respectively. The pure HG-UC group had a worse PFS than the MG-UC group (log-rank, P = .042). Multivariate analysis demonstrated that age and tumor grade were significant risk factors for the development of progression. The indication of MG-UC category separately from pure HG carcinomas in the pathology report seems to be an important issue that can guide patient management. In this way, both more accurate risk classification and more accurate patient counseling can be performed. More importantly, the treatment plan can be made more accurately. For more precise conclusions, our results should be supported by prospective studies with larger sample size.

Predicting Trabectedin Efficacy in Soft Tissue Sarcoma: Inflammatory Biomarker Analysis.

Trabectedin is used as a treatment for advanced-stage soft tissue sarcomas (STSs), particularly liposarcoma and leiomyosarcoma. Aside from its direct effect on tumor cells, trabectedin can affect the immune system in the tumor microenvironment. This study aimed to evaluate whether inflammatory biomarkers predict trabectedin efficacy in STSs. We retrospectively reviewed the clinical features and outcomes of patients with STS treated with trabectedin at our institution between 2016 and 2020. The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation response index (SIRI=neutrophil × monocyte/lymphocyte) were calculated based on the blood samples obtained prior to trabectedin treatment initiation. Analyses of overall survival (OS) and progression-free survival (PFS) were performed according to various factors. Of the 101 patients identified, 54 had L-sarcoma (leiomyosarcoma: 30; liposarcoma: 24), and 47 had other types of STSs. Elevated SIRI, NLR, PLR, LMR, and C-reactive protein (CRP) were associated with worse PFS (p<0.001, p=0.008, p=0.027, p=0.013, and p<0.001, respectively) according to the results of the univariate analysis. Multivariate analysis showed that elevated SIRI, other histology, and CRP were associated with poor PFS (p=0.007, p=0.008, and p=0.029, respectively). In addition, the multivariate analysis of OS showed that SIRI was an independent prognostic factor (hazard ratio=2.16, p=0.006). Pretreatment SIRI can be considered a biomarker for the prognostic prediction of patients with STS treated with trabectedin.

Cell-free human papillomavirus (HPV) DNA is a sensitive biomarker for prognosis and for early detection of relapse in locally advanced cervical cancer.

Human papillomavirus (HPV) is the cause of the majority of cervical cancers and has been showed to be released as cell-free tumour DNA (ctHPV DNA) into the circulation. We here analyse if ctHPV DNA could be used as a prognostic biomarker and/or to detect relapse earlier than traditional methods in locally advanced cervical cancer (LACC). 74 patients with LACC were included, 66/74 were positive for 13 high-risk HPV-types using a bead-based assay on tumour biopsies. HPV-type-specific droplet digital PCR (ddPCR) assays were developed. Longitudinal plasma samples were then analysed for the biopsy-verified HPV-type for each patient. 418 plasma samples were analysed. Patients were followed for a median of 37 months. Results were correlated to tumour- and clinical characteristics. 92.4% of pre-treatment plasma samples were positive for ctHPV DNA. Persistent ctHPV DNA in end-of-treatment, early follow-up (1-2 months after end-of-treatment) or tumour evaluation (3-4 months after end-of-treatment) plasma was correlated with worse progression-free survival (p < 0.001) compared to if ctHPV DNA was not found. The positive predictive value of ctHPV-status at early follow-up for predicting disease progression was 87.5% and the negative predictive value was 89.3%. ctHPV DNA was found in plasma before relapse was diagnosed on radiology in all patients (n=10) who experienced relapse after complete clinical response to treatment with a median 315 days lead time. ctHPV DNA in follow-up plasma is a promising prognostic biomarker in patients with LACC, useful for analysis of response to therapy and for early detection of relapse.

Circulating tumor DNA as a biomarker for predicting progression-free survival and overall survival in patients with epithelial ovarian cancer: a systematic review and meta-analysis.

Circulating tumor DNA (ctDNA) is emerging as a potential prognostic biomarker in multiple tumor types. However, despite the many studies available on small series of patients with ovarian cancer, a recent systematic review and meta-analysis is lacking. The objective of this study was to determine the association of ctDNA with progression-free-survival and overall survival in patients with epithelial ovarian cancer. An electronic search was conducted using PubMed (MEDLINE), Embase, CENTRAL (Cochrane Library), and CINAHL-Complete from January 2000 to September 15, 2023. To be included in the analysis the studies had to meet the following pre-specified inclusion criteria: (1) evaluable ctDNA; (2) progression-free-survival and overall survival reported as hazard ratio (HR); and (3) the patient population had epithelial ovarian cancer at the time of ctDNA detection. We evaluated the association of ctDNA with progression-free survival and overall survival. Secondary outcomes focused on sub-group analysis of genomic alterations and international Federation of Gynecology and Obstetrics (FIGO) stage. A total of 26 studies reporting on 1696 patients with epithelial ovarian cancer were included. The overall concordance rate between plasma-based and tissue-based analyses was approximately 62%. We found that a high level of ctDNA in epithelial ovarian cancer was associated with worse progression-free survival (HR 5.31, 95% CI 2.14 to 13.17, p<0.001) and overall survival (HR 2.98, 95% CI 1.86 to 4.76, p<0.0001). The sub-group analysis showed a greater than threefold increase in the risk of relapse in patients with positive HOXA9 meth-ctDNA (HR 3.84, 95% CI 1.57 to 9.41, p=0.003). ctDNA was significantly associated with worse progression-free survival and overall survival in patients with epithelial ovarian cancer. Further prospective studies are needed. CRD42023469390.

NTRK3 exhibits a pro-oncogenic function in upper tract urothelial carcinomas.

Neurotrophic receptor tyrosine kinase 3 (NTRK3) has pleiotropic functions: it acts not only as an oncogene in breast and gastric cancers but also as a dependence receptor in tumor suppressor genes in colon cancer and neuroblastomas. However, the role of NTRK3 in upper tract urothelial carcinoma (UTUC) is not well documented. This study investigated the association between NTRK3 expression and outcomes in UTUC patients and validated the results in tests on UTUC cell lines. A total of 118 UTUC cancer tissue samples were examined to evaluate the expression of NTRK3. Survival curves were generated using Kaplan-Meier estimates, and Cox regression models were used for investigating survival outcomes. Higher NTRK3 expression was correlated with worse progression-free survival, cancer-specific survival, and overall survival. Moreover, the results of an Ingenuity Pathway Analysis suggested that NTRK3 may interact with the PI3K-AKT-mTOR signaling pathway to promote cancer. NTRK3 downregulation in BFTC909 cells through shRNA reduced cellular migration, invasion, and activity in the AKT-mTOR pathway. Furthermore, the overexpression of NTRK3 in UM-UC-14 cells promoted AKT-mTOR pathway activity, cellular migration, and cell invasion. From these observations, we concluded that NTRK3 may contribute to aggressive behaviors in UTUC by facilitating cell migration and invasion through its interaction with the AKT-mTOR pathway and the expression of NTRK3 is a potential predictor of clinical outcomes in cases of UTUC.

Evaluation of histological variants of upper tract urothelial carcinoma as prognostic factor after radical nephroureterectomy

PurposeTo evaluate the impact of variant histology on patients with upper tract urothelial carcinoma (UTUC) survival outcomes.Materials and methodsA total of 519 patients underwent radical nephroureterectomy without neoadjuvant therapy for UTUC at a single institution between May 2003 and December 2019. Multivariate Cox regression analysis evaluated the impact of variant histology on progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS).ResultsAmong 84 patients (16.2%) with variant histology, the most frequent variant type was squamous cell differentiation (64.3%), followed by glandular differentiation (25.0%) and sarcomatoid variant (2.4%). They showed pathologically advanced T stage (for ≥ T3, 59.5% vs 33.3%, p < 0.001), higher tumor grade (96.4% vs 85.7%, p = 0.025), and higher rates of lymph node metastasis (17.9% vs 7.8%, p = 0.015), angiolymphatic invasion (41.7% vs 25.7%, p = 0.003), tumor necrosis (57.1% vs 29.0%, p < 0.001) and positive surgical margin (13.1% vs 5.7%, p = 0.015). On multivariate Cox regression analyses, variant histology was significantly associated with worse PFS (hazard ratio [HR] 2.23; 95% confidence interval [CI] 1.55–3.21; p < 0.001), CSS (HR 2.67; 95% CI 1.35–5.30; p = 0.005) and OS (HR 2.22; 95% CI 1.27–3.88; p = 0.005). In subgroup analysis, no significant survival gains of adjuvant chemotherapy occurred in patients with variant histology.ConclusionsVariant histology was associated with adverse pathologic features and poor survival outcomes. Our results suggest that patients with variant histology may require a close follow-up schedule and novel adjuvant therapy other than chemotherapy postoperatively.

304 NF2 Loss-of-Function and Hypoxia Together Drive Radioresistance in Grade 2 Meningiomas

INTRODUCTION: Grade 2 meningiomas (G2Ms) are associated with an aggressive natural history characterized by recurrence and resistance to radiation therapy. Histopathological necrosis is associated with worse progression-free survival (PFS) following radiation therapy in G2Ms. We seek to understand the molecular pathophysiology of radiation resistance and to identify molecular biomarkers and therapeutic targets for radioresistant G2M. METHODS: We performed genetic sequencing and histopathological analysis of 121 G2Ms. Using the IOMM-Lee meningioma cell line, we investigated the role of tumor hypoxia and genes of interest in radio-resistance through lentivirally targeted gene knockdown and clonogenic survival assays following exposure to ionizing radiation. Transcriptional profiling of cells in in vitro and in 38 patient G2Ms was performed using RNA sequencing. RESULTS: NF2 loss of function mutations were significantly associated with tumor necrosis in G2Ms (p = 0.0026). Patients with NF2mutation and spontaneous necrosis had worse post-radiation PFS compared to NF2 wildtype patients without necrosis (p = 0.035). In the setting of hypoxia, NF2 knockdown significantly increased radio-resistance in vitro (p &lt; 0.001). Gene set enrichment analysis on in vivo and in vitro data and functional assays revealed downregulation of apoptosis and upregulation of cell proliferation in NF2-deficient and necrotic group compared to control. Integration of differentially expressed genes in both NF2-deficient cells in vitro and human necrotic tumors identified shared upregulation of HES1, XDH, NOG, IGFBP3, ALOXE3, THSB1, and TRIML2, suggesting these genes may represent targets for radio-sensitization or biomarkers of radio-resistance. CONCLUSIONS: NF2 loss-of-function in the setting of hypoxia confers radiation resistance through a transcriptional program that promotes proliferation and DNA repair. Targeting molecular pathways identified by transcriptional profiling may improve local control in patients with radioresistant G2M.

379 Meningioma Molecular Groups Predict Response to Adjuvant Radiotherapy Following Surgery

INTRODUCTION: Aside from surgery, radiotherapy (RT) remains the only treatment for meningiomas. However, patient selection for adjuvant RT remains controversial. METHODS: We utilized publicly available molecular datasets of meningiomas and generated de novo DNA-methylation and RNA-sequencing data. Meningiomas were classified into different molecular and methylation groups based on the methodologies of their original publications (Nassiri et al. [2021], Bayley et al. [2022], Choudhury et al. [2022], Sahm et al.[2017]) and progression-free survival (PFS) following surgery with and without adjuvant RT were analyzed. RESULTS: A total of 2029 meningiomas from 11 different institutions with adjuvant RT data were included. Adjuvant RT was associated with improved PFS in WHO grade 1 meningiomas following subtotal resection (STR), WHO grade 2 meningiomas following gross total resection (GTR) or STR, and immunogenic (COCA1) and NF2-wildtype (COCA2) meningiomas following STR. Multivariable analysis using Cox proportional hazards regression models showed that having a meningioma belonging to a hypermetabolic (COCA3) (HR 2.49, 95% CI 1.71-3.62), or proliferative (COCA4) (HR 3.77, 95% CI 2.78-5.10) group were associated with worse PFS when controlling for age, gender, extent of resection, and receipt of adjuvant RT. Meningiomas belonging to DKFZ MC-intermediate, MC-malignant, MenGC, and UCSF hypermitotic groups were also associated with worse outcomes. These relationships held true even in subgroup analysis with only WHO grade 2 meningiomas and following propensity score matching for the same clinical covariates above. Nearly all molecular and methylation classifications predicted 5-year PFS following surgery and adjuvant RT (area under the curve [AUC] 0.61-0.72) better than WHO grade (AUC 0.51). CONCLUSIONS: Molecular classification improves outcome prediction for meningiomas following surgery and adjuvant radiotherapy, supporting the rationale for molecularly informed treatment decisions and clinical trial stratification.

Salvage Stereotactic Radiosurgery for Recurrent WHO Grade 2 and 3 Meningiomas: A Multicenter Study (STORM)

PurposeThe role of stereotactic radiosurgery (SRS) in the management of grade 2 and 3 meningiomas is not well elucidated. Unfortunately, local recurrence rates are high, and guidelines for management of recurrent disease are lacking. To address this knowledge gap, we conducted STORM, a multicenter retrospective cohort study of patients treated with primary SRS for recurrent grade 2 and 3 meningiomas. Methods and MaterialsData on patients with recurrent grade 2 and 3 meningioma treated with SRS at first recurrence were retrospectively collected from eight academic centers in the United States. Patients with multiple lesions at the time of initial diagnosis or more than two lesions at the time of first recurrence were excluded from this analysis. Patient demographics and treatment parameters were extracted at time of diagnosis, first recurrence, and second recurrence. Oncologic outcomes including progression-free survival (PFS) and overall survival (OS) as well as toxicity outcomes were reported at the patient level. ResultsFrom 2000-2022, 108 patients were identified (94% grade 2, 6.0% grade 3). 106 patients (98%) had upfront surgical resection (60% gross-total resection) with 18% receiving adjuvant radiotherapy (RT). Median time to first progression was 2.5 years (IQR 1.34-4.30). At first recurrence, patients were treated with single or fractionated SRS to a median marginal dose of 16 Gy to a maximum of two lesions (87% received single fraction SRS). Median follow-up time after SRS was 2.6 years. 1-, 2-, and 3-year PFS was 90%, 75%, and 57%, respectively after treatment with SRS. 1-, 2-, and 3-year OS was 97%, 94%, and 92%, respectively. On multivariable analysis, grade 3 disease (HR 6.80; 95% CI 1.61-28.6), male sex (HR 3.48; 95% CI 1.47-8.26), and receipt of prior RT (HR 2.69; 95% CI 1.23-5.86) were associated with worse PFS. SRS dose and tumor volume were not correlated with progression. Treatment was well-tolerated, with a 3.0% incidence of grade 2+ radiation necrosis. ConclusionsThis is the largest multi-center study to evaluate salvage SRS in recurrent grade 2 and 3 meningiomas. In this select cohort of patients with primarily grade 2 meningioma with potentially more favorable natural history of delayed, localized first recurrence amenable to salvage SRS, local control rates and toxicity profiles were favorable, warranting further prospective validation.

International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Abstract 5208: Dynamic changes in circulating tumor DNA and T cell receptor repertoire predict disease progression in patients with unresectable esophageal squamous cell carcinoma

Abstract Background: Patients with unresectable esophageal squamous cell carcinoma (ESCC) showed variations in their response to treatments and experienced inevitable disease progression. The development of non-invasive and clinically viable biomarkers is urgently needed. Therefore, this study aimed to investigate prognostic value of circulating tumor DNA (ctDNA) and T cell receptor (TCR) repertoire in these patients. Methods: A total of 21 ESCC patients who underwent definitive chemoradiotherapy, radiotherapy, or immune checkpoint inhibitor (ICI)-combined therapy from October 2020 to March 2022 were retrospectively evaluated. Baseline tumor samples were collected for genomic profiling using targeted NGS. Baseline and post-therapy plasma were collected for genomic and TCR profiling. Results: We found that ctDNA detection rates were significantly reduced after treatment (P&amp;lt;0.001). Post-treatment ctDNA positivity were associated with worse local recurrence-free survival (P=0.001) and progression-free survival (P=0.001), but not overall survival. Moreover, TCR clonality was significantly increased after treatment, including CDR3 diversity (P=0.003), TCR clonotype (P=0.004), and VJ pairs (P=0.010), indicating an increased T cell expansion and complexity. Specifically, we identified two increased and four reduced VJ rearrangements after treatment, and the four reduced VJ rearrangements (Vβ12-2Jβ2-4, Vβ6-9Jβ1-5, Vβ6-7Jβ1-5, and Vβ6-9Jβ1-1) were significantly associated with worse progression-free survival. Conclusion: Our findings suggest the prognostic implication of plasma ctDNA and TCR profiles in patients with unresectable ESCC receiving definitive therapy, supporting the future development of non-invasive monitoring of disease progression in these patients. Citation Format: Baidong Zhang, Xiang Zhan, Qiang Li, Chenxuan Wang, Jiaohui Pang, Yaru Zhang, Song Wang, Qiuxiang Ou, Haimeng Tang, Alei Feng, Zhe Yang. Dynamic changes in circulating tumor DNA and T cell receptor repertoire predict disease progression in patients with unresectable esophageal 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 5208.

Abstract 2425: Pairwise analysis of plasma cell-free DNA before and after paclitaxel plus ramucirumab treatment in patients with metastatic gastric cancer

Abstract Background: Plasma cell-free DNA (cfDNA) analysis has emerged as an appealing alternative to detect somatic mutations. This study compared cfDNA at baseline (baseline-cfDNA) and progressive disease (PD-cfDNA) and tumor tissue DNA (ttDNA) in patients with metastatic gastric cancer who underwent palliative second-line paclitaxel+ramucirumab treatment. Methods: We conducted targeted sequencing of 106 cancer-related genes using germline DNA, baseline-cfDNA, and PD-cfDNA samples. The results were then compared with conventional cancer panel results using ttDNA. Results: Of 76 consecutively enrolled patients who received paclitaxel+ramucirumab treatment, 46 patients (27 males; median age 57.5 [range, 32-73] years) with access to all three samples were analyzed along with their ttDNA data. A total of 138, 145, and 80 mutations were detected in baseline-cfDNA, PD-cfDNA, and ttDNA respectively. Combined analysis of baseline-cfDNA and ttDNA revealed that TP53 (56.5%) was the most frequently mutated gene, followed by CDH1 (26.1%), KRAS (21.7%), and APC (13.5%). For the top four genes, the sensitivity and positive predictive value of baseline-cfDNA compared with ttDNA were 71.8% and 51.9%, respectively. Compared with ttDNA alone, 32 patients (70.0%) benefited from baseline-cfDNA in detecting novel mutations. When combined with baseline-cfDNA and PD-cfDNA, novel mutations were discovered in 34 patients (73.9%). Of note, PD-cfDNA analysis detected 9 novel pathogenic mutations in TP53, APC, PIK3CA, CDH1, RNF43, CTNNB1, and BRCA2 genes in 8 patients (17.4%) after treatment. In baseline-cfDNA, patients with a circulating ttDNA fraction concentration at 110-160 bp of &amp;gt;4.3777 ng/µL had significantly shorter progression-free survival (PFS) (median 3.5 vs. 5.3 months, P=0.016). In addition, maximal variant allele frequency (VAF) values of &amp;gt;0.1045 (median 3.4 vs. 5.2 months, P=0.022) and the sum of VAF values of &amp;gt;0.2071 (median 3.4 vs. 5.2 months, P=0.028) were significantly associated with shorter PFS. In patients with TP53 mutations, those with TP53 VAF values of &amp;gt;0.1014 significantly had worse PFS (median 4.6 vs. 6.4 months, P=0.022). Conclusions: Although cfDNA could not entirely take over the role of ttDNA, cfDNA analysis identified additional somatic mutations that were otherwise missed by ttDNA alone. Moreover, PD-cfDNA analysis detected novel pathogenic mutations that developed during treatment, implicating the clonal evolution of cancer. In addition, baseline cfDNA predicted PFS of patients receiving paclitaxel+ramucirumab therapy. Citation Format: Ji-Won Kim, Dong Soo Kyung, Won Yeong Ko, Hwang-Phill Kim, Sung-Hyun Hwang, Kui-Jin Kim, Ju Hyun Lee, Jeongmin Seo, Minsu Kang, Eun Hee Jung, Koung Jin Suh, Se Hyun Kim, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Keun-Wook Lee. Pairwise analysis of plasma cell-free DNA before and after paclitaxel plus ramucirumab treatment in patients with metastatic gastric cancer [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 2425.

Abstract 6438: Subcutaneous fat mass predicts progression-free survival in patients treated with antibody-drug-conjugates in early-phase clinical trials

Abstract Background: Antibody drug conjugates (ADCs) have revolutionized the treatment of many solid tumours and hematological diseases. Little is known about the influence of body composition on efficacy and safety of ADCs. Methods: All patients treated with ADCs in early phase clinical trials between 03/2015 and 03/2023 at the Drug Development Department at Gustave Roussy were retrospectively included in the analysis. A deep learning software (Anthropometer3DNet) automatically measured anthropometric parameters in 3D on pretreatment scans, allowing multi-slice measurements of muscle body mass (MBM), fat body mass (FBM), subcutaneous fat mass (SFM) and visceral fat mass (VFM). Other clinical and biological parameters were also retrieved and evaluated. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival analysis was performed using Cox regression models and Kaplan-Meier (KM) estimator. Cut-offs were determined using the maxstat method. Anthropometric parameters’ effect on toxicity was also evaluated using a ROC analysis. Results: A total of 136 patients were treated with ADCs. The most frequent tumor types were non-small cell lung cancer (56 patients, 41%) and colorectal cancer (31 patients, 23%). Median age, ECOG PS, albumin and number of previous lines of treatment were 60.8 years (30 to 85), 1, 42 g/L and 3 respectively. In the overall cohort, median PFS and OS were 2.8 and 8.6 months respectively, 90 (66%) patients had experienced toxicity, of which 46 were grade 3-4. The Royal Marsden Hospital (RMH) prognostic score of 2 or more was significantly associated with worse PFS (HR=2.13, p=0.007) and OS (HR=2.12, p=0.008). The number of treatment lines was significantly associated with worse OS (HR=1.21, p&amp;lt;0.001). For the anthropometric parameters, SFM (HR=0.89, p=0.013) and FBM (HR=0.89, p=0.02) were significantly associated to PFS. Higher SFM (cutoff: 3.3 kg/m2) and FBM (cutoff: 3.6 kg/m2) were significantly associated with longer PFS (mPFS=3.8 vs 2.3 months and 3.7 vs 1.9 respectively). Patients with higher SFM and FBM had numerically but non-significantly longer (mOS=8.5 vs 7.7 months and 8.6 vs 6.4 months respectively). All anthropometric parameters were significantly associated with all-grade toxicity in the univariate but not in the multivariate analysis. None of the parameters were associated with grade 3-4 toxicity. Conclusions: In this large monocenter cohort, 3D measured high SFM and FBM were significantly associated with PFS. Automatic extraction of body composition parameters using AI may help in anticipating the benefits of ADCs in patients included in early-phase clinical trials. Citation Format: Matthieu Delaye, Littisha Lawrance, Younes Belkouchi, Felix Wirth, Pierre Decazes, Alexandre Bône, Kaïssa Ouali, Antoine Hollebecque, Cristina Smolenschi, Rastislav Bahleda, Anas Gazzah, Stéphane Champiat, François-Xavier Danlos, Clémence Hénon, Kristi Beshiri, Madona Sakkal, Aurélien Marabelle, Jean-Marie Michot, Vincent Ribrag, Claudia Parisi, Christophe Massard, Vincent Goldschmidt, Pierre Vera, Santiago Ponce-Aix, Nathalie Lassau, Samy Ammari, Capucine Baldini. Subcutaneous fat mass predicts progression-free survival in patients treated with antibody-drug-conjugates in early-phase clinical trials [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 6438.

Abstract 6881: Investigating the role of post-transplant bone marrow immune dysregulation in multiple myeloma

Abstract Multiple myeloma (MM) is a cancer of bone marrow plasma cells (BMPCs), which to date remains incurable. Standard of care for qualifying patients involves high-dose chemotherapy followed by autologous stem cell transplant (ASCT), after which minimal residual disease (MRD) testing is used to assess the degree of tumor clearance. Though strongly associated with better survival, MRD-negativity is an imperfect predictor for patient outcomes and fails to account for the pro-tumorigenic BM dysregulation often found in MM patients. As the post-transplant BM milieu in MM is not well understood, we conducted 3' single-cell RNA sequencing (scRNAseq) of 49 newly diagnosed (NDMM) and 79 day-100 post-ASCT whole-BM aspirates to investigate how immunosuppressive microenvironmental signatures may persist or develop following ASCT to influence patient outcomes. 68 of 79 post-ASCT samples come from uniformly-treated clinical trial enrollees with progression-free survival (PFS) ranging from 10 months to over 7 years, with both MRD- and MRD+ cases at either PFS extreme. We observe that although post-ASCT samples have uniformly lower PC count than NDMM samples, only erythroblasts and B cells appear relatively depleted in NDMM samples to compensate for higher PC proportions. T/NK cells and myeloid lineages, though similar in percentage across samples, exhibit clear subtype bias between the two timepoints. Post-ASCT samples are significantly enriched for GZMH+ CD8+ T and NK cells, HIF1A+ hypoxia-responsive monocytes, and depleted for S100A8/9-high CD14+ monocytes. NDMM samples are also enriched for SPINK2+, CDK6+, and AVP+ neutrophils, which are rare in post-ASCT samples. Notably, higher HIF1A expression in myeloid cells post-ASCT is further associated with longer PFS. Regardless of MRD status, NFKBIA, FOS, and GNLY upregulation and GZMK downregulation in post-ASCT T cells are associated with worse PFS. Conversely, enrichment of CD16+ IFN-responsive monocytes and depletion of ARG1+/FUT4+/CEACAM8+ myeloid-derived suppressor cells (MDSCs) are associated with longer PFS. Beyond such general trends, we observe MRD-dependent PFS-association of several CD8+ T cell subsets. Overall, this study enhances our understanding of how post-transplant BM repopulation and immune interaction may impact treatment response in MM. Citation Format: Julia T. Wang, Mark Fiala, Kazuhito Sato, Julie Fortier, Ravi Vij, Li Ding. Investigating the role of post-transplant bone marrow immune dysregulation in multiple myeloma [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 6881.