Chanan‐Khan, Asher

Introduction BCL-2 inhibition with venetoclax (ven) was a major advance in CLL treatment, but the 5-week dose ramp-up to mitigate the risk of tumor lysis syndrome and drug-drug interactions (DDIs) challenge treatment optimization. Lisaftoclax is an investigational, oral BCL-2i with a short half-life, allowing it to be ramped-up on a daily schedule. We present updated results of a phase 1b/2 study of lisaftoclax alone or combined with acalabrutinib or rituximab in pts with treatment-naïve (TN; lisaftoclax-acalabrutinib arm), relapsed/refractory, or prior ven-treated CLL/SLL (NCT04215809). Methods Pts were treated with a rapid 4- to 6-day daily ramp-up of lisaftoclax from 20 mg to a target dose of 400, 600, or 800 mg, receiving daily oral lisaftoclax alone or, plus continuous acalabrutinib or 6 cycles of rituximab in 28-day cycles, starting on Cycle 1 Day 8 (C1D8) until disease progression, complete response by C24, or unacceptable toxicity. Intensive blood samples were collected for pharmacokinetic (PK) and exposure-response (E-R) analyses. Results From March 20, 2020, to June 27, 2024, 176 pts were enrolled: 46 in monotherapy and 39 and 91 in rituximab and acalabrutinib combination cohorts, respectively; 154/176 (87.5%) were R/R and 22/176 (12.5%) TN. The median (range) age was 63 (34-80) years; 67% were male; 25.6% had del(17p) and/or TP53 mutation; and 70.6% had unmutated IGHV. Median (range) duration of treatment with lisaftoclax was 16.5 (1-54; monotherapy), 24 (3-39; rituximab), and 27 (1-43; acalabrutinib) months. In R/R pts, the median (range) number of prior lines of therapy was 2 (1-15), and 14 (9%) pts had been treated with ven. Prior ven pts had a median (range) age of 65 (51-78); 79% were male; of evaluable pts, 50% had del(17p), 36% TP53 mut, 64% del(11q), 38% complex karyotype (≥ 3 abnormalities), and 92% unmutated IGHV; 57% were BTKi naïve; and the median (range) number of prior therapies was 3 (1-6). Incidence and severity of TEAEs were similar across cohorts. Common (>10%) any-grade TEAEs in all cohorts combined were neutropenia (59 [33.5%]), diarrhea (38 [21.6%]), anemia (27 [15.3%]), and thrombocytopenia (26 [14.8%]). Grade ≥ 3 TEAEs were neutropenia in 15 (32.6%), 10 (25.6%), and 22 (24%) pts and anemia in 10 (21.7%), 5 (12.8%), and 12 (13.2%) pts in monotherapy, rituximab, and acalabrutinib combination cohorts, respectively. Comprehensive E-R analyses indicated that lisaftoclax had similar systemic exposure as monotherapy or when combined with acalabrutinib or rituximab; lisaftoclax had no DDI when combined with acalabrutinib or rituximab. No discontinuations were attributed to lisaftoclax TRAEs. Forty-four (95.7%) pts in monotherapy discontinued treatment. Most discontinuations were due to progressive disease (n = 41 [23.3%]) and 13 (7.4%), AEs; 9 (5.1%) pts withdrew consent; 7 (4%) achieved complete response or MRD negativity after ≥ 24 cycles; 5 (2.8%) died; and 18 (10.2%) discontinued for other reasons. Clinical (n = 2) and laboratory (n = 3) TLS was observed in 5 (2.8%) pts on lisaftoclax (by Howard/Cairo-Bishop criteria), with cases rapidly resolving to resume lisaftoclax safely. ORR for lisaftoclax plus acalabrutinib in 87 pts was 96.6%, and the median DOR (95% CI, 23-NR) and median PFS (95% CI, 34-NR) were not reached. The 12- and 18-month PFS rates were 89% and 86%, respectively. Fourteen R/R CLL ven-exposed pts received lisaftoclax plus acalabrutinib, of whom 9 had progressed on ven, 3 relapsed after completing ven, and 2 discontinued due to ven intolerance. Median (range) duration of treatment was 16 (3-25) months. Safety profile was similar to that of other study cohorts. ORR was 85.7% (12/14), 100% (8/8), and 66.7% (4/6) in the ven-exposed, ven-exposed but BTKi-naïve, and ven- and BTKi-exposed pts, respectively. The median duration of response (DOR) and progression-free survival (PFS) were not reached. The 12- and 18-month PFS rates were 84% and 73%, respectively. Conclusions Our data suggest that lisaftoclax combined with acalabrutinib is effective for pts with prior ven exposure, including those with progression on ven. In this updated analysis with longer follow-up, no DDIs or new safety findings were observed in TN or R/R CLL/SLL pts treated with lisaftoclax monotherapy/combinations. We continue to accrue pts with prior ven exposure to further evaluate this promising signal. A global registrational phase 3 study GLORA (NCT06104566) is recruiting.

Introduction: Overall outcomes have improved significantly for MM with a 5-year relative survival rate currently of >60%. With effective treatments, patients from all clinical strata and age groups are expected to have meaningful benefit, but despite excellent therapeutic advancements, some patients continue to have early mortality. We conducted this study to investigate factors associated with early mortality. Methods: The National Cancer Database (NCDB) was queried for adult patients with NDMM between 2004 and 2021. We excluded patients with multiple primary malignancies or lost to follow-up (unknown vital status or last contact). Early mortality was defined as death within 6 months from MM diagnosis. Patient demographics and socioeconomic factors available in NCDB were collected. Kaplan-Meier and multivariate Cox regression were used to evaluate the likelihood of early mortality in this large cohort of MM patients using multi-variate analysis. Results: Out of 255,579 eligible patients with MM, 35,302 (13.8%) died within the first 6 months of diagnosis and 108,534 (42.5%) died after the first 6 months of MM diagnosis. The early mortality cohort had significantly higher mean age at MM diagnosis (73.9 vs. 68.5 years, p<0.001) but no significant differences were noted for gender distribution. There was a statistically significant difference for racial/ethnic distribution (p=0.019), but the percentages were very similar among non-Hispanic White (69% vs 68.1%), non-Hispanic African American (18% vs 18.7%) and Hispanic patients (4.7% vs 4.8%). Patients in the early mortality cohort were less likely to be treated at academic institutions (28.4% vs 37.8%, p<0.001) and have significantly different distribution by insurance type (less likely to have private insurance; 17.3% vs. 30%, more likely to have Medicare; 72.1% vs. 58.7%, p<0.001) although overall insurance access was similar between the two groups (95.3% vs 95.2%, p=0.283). Early mortality was associated with higher morbidity scores as per the Charlson-Comorbidity Index (CCI) (p<0.001) and were more likely to have not received any treatment for MM (53.2% in early mortality group vs. 28.4% in late mortality, p<0.001). Early mortality was also associated with a lower literacy rate (high school graduation rate 21.2% vs. 19.7%, p<0.001) and lower household income (<$46,277; 19.1% vs. 17.7%, p<0.001). Conclusion: This large real-world analysis shows that despite therapeutic advances in recent years, there is a significant percentage of patients with NDMM in the U.S. who suffer from early mortality. There are several sociodemographic and economic factors that were found to be associated with early mortality, with some showing clear trends (older age, treatment facility type, insurance type, income, education, CCI), while others like racial differences were significant but somewhat ambiguous. Identifying and addressing these factors at diagnosis will help provide personalized care plans and minimize early mortality.

Introduction MYD88 L265P mutations (MUT) are found in 90% of patients with Waldenstrom macroglobulinemia (WM) and lead to the activation of pro-survival signaling. Limited literature has demonstrated that patients with MYD88 wild-type (WT) WM have poorer responses to conventional therapies and a higher likelihood of histological transformation. Increasingly the role of non-coding genomics in lymphomagenesis has demonstrated importance and currently, the epigenetic landscape of MYD88 WT WM remains underexplored. This study utilized a multi-omics approach to assess DNA methylation in MYD88 WT WM compared to MYD88 MUT patients and controls. Methods Bone marrow samples were prospectively collected from 20 subjects [3 MYD88 WT/CXCR4 WT WM, 12 MYD88 MUT WM and 5 normal controls] and positive selection for CD19+ and/or CD138+ B cells was performed. The analysis focused on the comparison between MYD88 WT WM to normal controls and MYD88-WT to MUT WM. Genome-wide DNA methylation analysis was performed, and CpG methylation ratios were segmented into 200-bp regions. Differentially methylated regions (DMRs) were determined using a Q-value <0.05 and absolute methylation difference ≥10%. Next, RNA-seq data was interrogated and differentially expressed genes (log2fold change>0.5 or <-0.5, false discovery rate<0.05) with corresponding promoter hypo- or hypermethylation were assessed. Ingenuity Pathway Analysis was used to determine potentially epigenetically regulated pathways using a corrected p<0.05. Results Comparing MYD88 WT WM samples to controls, a statistically greater number of hypermethylated DMRs were observed across genomic regions (hyper- vs hypomethylated): promoter (29129 vs 6300), 3'untranslated region (UTR) (2068 vs 1551), 5'UTR (10169 vs 735), intron (30344 vs 24511), exon (2224 vs 6855), CpG island (30372 vs 1240) and CpG shore (14477 vs 5872) (all p<0.001). Next, mRNA analysis demonstrated that 214 genes were differentially up-/downregulated with concordant promoter hypo-/hypermethylation. On the assessment of promoter-methylation-based pathways, multiple pathways involved in cell signaling, proliferation, gene regulation, cytokine and immune signaling and metabolism were found to be deregulated. Most pathways were found to be negatively enriched in MYD88 WT patients compared to controls including several members of interleukin (IL) signaling (IL-2, IL-3, IL,7) and regulators of cell proliferation and signaling including mTOR, PI3K/AKT, and p53. Positive enrichment of the PTEN, FGFR3 and ERK/MAPK pathways were observed. Underlying multiple pathways was promoter hypermethylation with corresponding mRNA downregulation of AKT3 and PIK3CA. Furthermore, promoter hypomethylation with transcript upregulation of PTEN was observed. Next, in comparison of MYD88 WT to MUT samples, a statistically greater number of hypermethylated DMRs were observed across genomic regions (hyper- vs hypomethylated): promoter (24829 vs 2544), 3'UTR (3534 vs 378), 5'UTR (6111 vs 605), intron (52292 vs 5360), exon (21066 vs 2187), CpG island (18334 vs 1551) and CpG shore (16351 vs 1957) (all p<0.001). Assessing mRNA expression, 354 genes were up-/downregulated with concordant promoter hypo-/hypermethylation. Pathway analysis revealed positive enrichment of the mitotic G1 phase to G1/S transition pathway with upregulation of the CDK4, LYN, and PSMA6 transcripts in MYD88 WT compared to MUT samples. Further, negative enrichment of cell signaling regulators including the RHO GTPase family, IL pathways (IL-4, IL-8, IL-13, IL-17) and integrin signaling were found in MYD88 WT compared to MUT samples. Underlying multiple pathways were downregulation with promoter hypermethylation of BCL2, an important regulator of apoptosis. Conclusion Genome-wide methylation analysis of MYD88 WT WM revealed a unique DNA methylation profile, with potential epigenetic alteration of key oncogenic transcripts and pathways. The negative enrichment of cell signaling and cytokine/inflammatory pathways in MYD88 WT samples compared to controls and MYD88 MUT WM suggests an epigenetic mechanism for immune evasion and potentially underlies the reduced response to conventional WM-directed therapies. Overall, this study reveals that MYD88 WT WM is epigenetically distinct from MYD88 MUT WM and regulators such as methylation may underlie the unique clinical and phenotypic properties observed.

7078 Background: Lisaftoclax is a novel, oral, highly selective, potent BCL-2 inhibitor in development. In an ibrutinib-resistant patient-derived WM xenograft/preclinical model, lisaftoclax + ibrutinib has a strong synergistic effect. This report provides updated efficacy and safety data of lisaftoclax-based therapies (including combinations with ibrutinib) in pts with WM. Methods: In this global, open-label, phase 1b/2 multicenter study, pts with WM were enrolled in 3 arms: Arm A (lisaftoclax) included BTKi-resistant/intolerant pts; Arm B (lisaftoclax + ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax + rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high risk of tumor lysis syndrome (TLS). Objectives were efficacy, safety, and pharmacokinetics (PK) assessments (responses assessed per IWWM criteria). Results: As of January 25, 2024, 46 pts were enrolled and treated at doses of up to 1,000 (Arm A), 1,200 (Arm B), and 800 mg (Arm C; Table). The median (range) treatment duration was 11 (1-28; Arm A), 23.5 (1-34; B), and 11.5 (5-33; C) months. Objective response rates (PR, VGFR, CR) were: 41.7% (Arm A), 90.9% (B), and 37.5% (C). In Arm A, pts with wild-type CXCR4 (n = 7) had better overall response to lisaftoclax than the CXCR4mut group (n = 3). No significant difference was observed between pts with/without CXCR4mut in Arms B and C. In Arm B, 1 DLT (grade 3 clinical TLS due to preexisting renal impairment) was reported at 1,200 mg; 1 grade 3 laboratory TLS, primarily attributed to dehydration and concomitant symptomatic therapies, occurred at 1,000 mg; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (15.2%), thrombocytopenia (4.3%), decreased leukocytes (4.3%), TLS (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmia was not observed. One pt required dose reduction because of neutropenia. The MTD was not reached. Lisaftoclax + ibrutinib showed a PK exposure comparable to lisaftoclax or ibrutinib alone, indicating no potential drug-drug interactions. Conclusions: Lisaftoclax alone and combined with ibrutinib or rituximab was well tolerated and demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. (CT.gov: NCT04260217; Internal ID: APG2575WU101) *Co-first authors: ML and SA. Clinical trial information: NCT04260217 . [Table: see text]

7072 Background: LG-NHL is mostly incurable, imposing a prolong impact of cancer care burden for pts. This study aimed to quantify the burden of MH conditions in pts with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), or marginal cell lymphoma (MZL). Methods: A retrospective study was conducted using Optum Clinformatics Data Mart to identify pts ≥18 years with ≥1 new diagnosis for CLL, FL, MCL, WM, or MZL from 6/2016-6/2022 (index period). Pts were required to be continuously enrolled for 60 days pre- and 365 days post-index date, defined as the date of first cancer diagnosis. Incidence and prevalence of MH conditions of interest (anxiety, depression, stress reaction/adjustment disorder, insomnia, post-traumatic stress disorder [PTSD]) were categorized based on if diagnoses were post- or pre-index date. All-cause healthcare resource utilization (HCRU) and costs were measured during the 1-yr follow-up period. Results: Approximately half of newly diagnosed 36,054 LG-NHL pts (CLL/SLL=48.0%; FL=52.7%; MCL=57.2%; WM=50.5%; MZL=52.5%) had either an incident (19.4-25.7%) or prevalent (28.6-32.1%) MH condition diagnosis following their cancer diagnosis (Table). There were no significant demographic differences in pts with and without MH conditions. LG-NHL pts suffered most from anxiety (30.9-38.2%) and depression (27.5-31.9%), followed by insomnia (16-23.1%), stress (10.3-13.5%), and PTSD (1.4-1.9%). Median time from cancer diagnosis to onset of a MH condition was 334 days for CLL/SLL, 301 for FL, 248 for MCL, 351 for WM, and 328 for MZL. LG-NHL pts with an identifiable MH diagnosis had significantly higher costs and HCRU compared to those without; for example, in CLL/SLL pts with MH diagnosis, outpatient visits were 1.4 times higher, inpatient admissions 3.0 times higher, and costs 2.1 times higher than those without (all P=0.0001). HCRU and cost increases were also observed in MCL, FL, WM, and MZL pts with MH diagnosis. Conclusions: This real-world study uncovered a high proportion of LG-NHL patients suffer from MH conditions, incurring higher financial burden than those without. With advancements in new treatments, there remains unmet need of MH burden in these pts. [Table: see text]

Abstract Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and characterized by poor outcomes with a lack of targeted therapies. A comprehensive analysis of the molecular and immune landscape of invasive ductal TNBC can help improve our understanding of TNBC biology and identify novel targets and/or pathways for better management of this disease. Here, we characterized the molecular and immune signature of invasive ductal (ID) TNBC. Methods: 13,036 BC samples (ID TNBC, n=392; ID non-TNBC, n=927) were analyzed by NGS (592, NextSeq; WES, NovaSeq), WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). A total of 10 pro-apoptotic (BAX, BAK1, BID, BAD, BIK, BCL2L11, BMF, HRK, PMAIP1, BBC3) and 6 anti-apoptotic (BCL2, BCL2L1, BCL2L2, MCL1, BCL2A1, BCL2L10) BCL2 family genes were analyzed. Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. Real world overall survival (OS) and treatment-associated survival was extracted from insurance claims and calculated from tissue collection or treatment start to last contact using Kaplan-Meier estimates. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q < 0.05). Results: ID TNBC had a higher frequency of TP53, RB1, NF1, PIK3R1, NOTCH1, CREBBP, BRCA1, FANCI, and HRAS mutations (Table 1), NOTCH2 (4.3% vs 0.47%), EGFR (3.4% vs 0%), NFIB (4% vs 0.6%), MYB (3.5% vs 0.5%), CCNE1 (4.4% vs 1.1%) and AKT2 (2.4% vs 0.3%) copy number alterations, and NOTCH2 (1.6% VS 0.2%) fusion (all p < 0.05) compared to invasive ductal non-TNBC. Analysis of inferred immune cell infiltrates showed that ID TNBC had increased infiltration of Tregs (2% vs 1.7%), DC (3.2% vs 2.4%), CD8 T cells (0.5% vs 0.1%), and M1 macrophages (M) (3.4% vs 2.9%), but decreased infiltration of B cells (4.5% vs 6%) and M2M (2.9% vs 4.5%) (all p < 0.05). ID TNBC had increased T cell inflamed score (23 vs -9, p < 0.05), IFNy score (-0.24 vs -0.34, p < 0.05), MHC class I genes (HLA-A, HLA-B, TAP1, TAP2, FC: 1.1-1.5, all p < 0.05), immune checkpoint genes (CD274, PDCD1, CTLA4, PD-L2, FOXP3, IDO, FC: 1.1-2, all p < 0.05) and PD-L1 protein expression (SP142: 49.8% vs. 28.4%; 22c3: 41.7% vs. 16.8%, all p < 0.05). ID TNBC had differential expression of BCL2 family genes (upregulation: BAK1, BID, MCL1, BCL2A1, BCL2L10, FC: 1.1-2.0; downregulation: BAD, BIK, BBC3, BCL2, BCL2L1, BCL2L2, FC: 1.2-2.8, all p < 0.05) compared to invasive ductal non-TNBC. ID TNBC was associated with worse OS compared to ID non-TNBC (mOS: 24.5 vs 54.6 months; HR: 0.5, 95% CI 0.47-0.57; p < 0.00001) but trend towards better survival with pembrolizumab (mOS: 29.4 vs 8.8 month; HR: 0.67, 95% CI 0.28-1.5; p=0.3) treatment. No significant OS difference was noted for by high vs. low pro and anti-apoptotic BCL2 genes except for anti-apoptotic BCL2A1 (higher expression associated with better OS (mOS: 5.7 months, HR: 0.78, 95% CI 0.6-0.99; p=0.047). Conclusion: These data indicate that ID TNBC is associated with distinct mutational profile compared to non-TNBC, has increased T cell inflamed score, IFNy score, MHC class I and immune checkpoint gene expression, and differential immune cell infiltration. Interestingly, TNBC was associated with increased M1 and decreased M2M. There is evidence to suggest that transcriptomically defined M1 high tumors are clinically aggressive and have worse OS in TNBC. BCL2 family genes are not prognostic for TNBC outcomes except BCL2A1, which needs further prospective validation. Table 1: Mutation frequency in invasive ductal TNBC and invasive ductal non-TNBC Citation Format: Pooja Advani, Sachin Deshmukh, Sharon Wu, Jacob Andring, Joanne Xiu, Alex Farrell, Jose Leone, Priya Jayachandran, Stephanie Graff, Matthew Oberley, George Sledge Jr, Asher Chanan-Khan. Comprehensive Molecular and Immunological Characterization of Invasive Ductal Triple-Negative 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 PO4-24-01.

Abstract Background: Metaplastic Breast Cancer (MBC) is rare (0.2-5%), aggressive form of BC characterized by chemotherapy resistance and has worse outcomes in comparison to other BC subtypes. Resistance to chemotherapeutic agents is related to defects in intact intrinsic apoptosis pathway and the BCL2 family of proteins are the central regulators of this pathway. Majority of MBC have triple-negative receptor status and have no standard therapeutic approach and validated prognostic markers. Here, we examine the association of BCL2 family pro-apoptotic and anti-apoptotic genes expression with metaplastic TNBC (MTNBC) patient survival. Methods: 13,036 BC samples (MTNBC, n=102; metaplastic non-TNBC, n=20) were analyzed by next-generation sequencing (592, NextSeq; WES, NovaSeq), Whole Transcriptome Sequencing (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). A total of 10 pro-apoptotic (BAX, BAK1, BID, BAD, BIK, BCL2L11, BMF, HRK, PMAIP1, BBC3) and 6 anti-apoptotic (BCL2, BCL2L1, BCL2L2, MCL1, BCL2A1, BCL2L10) BCL2 family genes were analyzed. MTNBC with PMAIP1-high(H) and -low(L) expression was classified by top and bottom quartile, respectively. Pathway enrichment was determined by GSEA (Broad Inst). Real world overall survival (OS) was extracted from insurance claims and calculated from tissue collection to last contact using Kaplan-Meier estimates. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q < 0.05). Results: MTNBC had enrichment of apoptosis (NES: 1.4, FDR: 0.05), glycolysis (NES: 1.48, FDR: 0.03), PI3K/AKT/mTOR signaling (NES: 1.43, FDR: 0.05), P53 (NES: 1.51, FDR: 0.06), NOTCH signaling (NES: 1.39, FDR: 0.05), TGFβ signaling (NES: 1.41, FDR: 0.05), WNTβ catenin signaling (NES: 1.41, FDR: 0.05) and IL2/STAT5 signaling (NES: 1.33, FDR: 0.09) pathways compared to metaplastic non-TNBC. MTNBC had higher expression of BCL2 pro-apoptotic genes BAX (Fold Change (FC): 1.6), BAK1 (FC: 1.3), BID (FC: 2), BAD (FC: 1.6), BCL2L11 (FC: 2.5) and BBC3 (FC: 1.5), and anti-apoptotic genes BCL2L1 (FC: 1.6) and BCL2L2 (FC: 1.3) (all p < 0.05) compared to metaplastic non-TNBC. Higher PMAIP1 gene expression was associated with worse MTNBC patient survival (mOS: 14.3 month; HR: 0.37; 95% CI 0.19-1.41; p=0.002) (Table 1), but not in metaplastic non-TNBC (mOS: Inf; HR: 1.96; 95% CI 0.64-6.02; p=0.23). PMAIP1-H MTNBC had higher expression of immune checkpoint genes CD274 (FC: 2.8), PDCD1 (FC: 2.2), TIM3 (FC: 1.8), LAG3 (FC: 2.1) and IDO1 (FC: 5.7) (all p < 0.05), compared to PMAIP1-L MTNBC. PMAIP1-H MTNBC had higher frequency of IHC-PD-L1 positivity (68.4% vs 14.3%, p < 0.05). PMAIP1-H MTNBC had higher expression of stem cell related genes CD44 (FC: 1.7), ALDH1A2 (FC: 2.2), ALDH1A3 (FC: 2.6), SOX2 (FC: 5.21) and NANOG (FC: 2.13) (all p < 0.05) compared to PMAIP1-L MTNBC. Conclusion: This is the first comprehensive analysis of expression and prognostic role of BCL2 family proteins in MBC. Our data suggest a strong association of higher expression of PMAIP1 with worse MTNBC patient survival, potentially attributed to higher immune checkpoint, stem cell-related genes expression, and higher frequency of PD-L1 positivity in PMAIP1-H tumors. These findings indicate PMAIP1 as a potential prognostic biomarker candidate in MTNBC but needs further validation in large prospective studies Table 1. Overall survival of metaplastic TNBC patient based on BCL2 family gene expression. Citation Format: Pooja Advani, Sachin Deshmukh, Sharon Wu, Jacob Andring, Joanne Xiu, Alex Farrell, Milan Radovich, George Sledge Jr, Dario Trapani, Evanthia Roussos Torres, Stephanie Graff, Asher Chanan-Khan. Comprehensive Characterization of BCL2 Family Genes in Metaplastic Triple Negative 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 PO4-24-02.

Abstract Background: Triple-negative invasive lobular carcinoma (TN-ILC) is a rare (0.1-1.4%) breast cancer with prognosis worse than ER positive ILC. Currently there are no targeted therapies or clinical trials specifically for TN-ILC. A comprehensive analysis of the molecular and immune landscape can help identify novel targets and pathways for TN-ILC to improve patient outcomes. Here, we characterized the molecular and immune signature of TN-ILC. Methods: 11,760 breast cancer samples (Invasive ductal (ID) TNBC, n=364; TN-ILC, n=31) were analyzed (592, NextSeq; WES, NovaSeq), (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) totaled somatic mutations per tumor (high ≥10 mt/MB) was tested by NGS. Microsatellite-instability (MSI) was tested by NGS. Immune cell fractions were calculated by deconvolution of WTS. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q < 0.05). Results: TN-ILC had higher frequency of CDH1 (0.83% vs. 66.67%), ERBB2 (0.84% vs.28.57%), ARID1A (1.65% vs. 23.33%), CBFB (0.55% vs.16.67%), AKT1 (2.22% vs.16.13%) and KMT2C (3.83% vs.13.79%), but lower frequency of TP53 (89.7%5 vs. 38.71%) mutations (all p<0.05) compared to ID-TNBC. TN-ILC had higher frequency of TMB high (23.3% vs. 5.2%, p<0.05) but there was no difference in dMMR/MSI-H (0% vs 1.1%, p=1). TN-ILC had higher AR RNA (FC: 14.2), protein expression (80.6% vs. 24.8%) and higher frequency of fusion variant-AR (16.1% vs 4.9%) (all p < 0.05) compared to ID-TNBC. Analysis of inferred immune cell infiltrates showed that TN-ILC had higher infiltration of M2 macrophages (5.34% vs. 2.94%) and neutrophils (4.83% vs. 2.65%) but lower infiltration of M1 macrophages (3.46% vs 2.17%) and CD8 T cells (0.58% vs. 0.11%) (all p<0.05). TN-ILC had lower T cell inflamed signature (16.1% vs 35.7%, p<0.05), decreased immune checkpoint genes (CD274, CTLA4, FOXP3, LAG3, IDO, FC: 1.2-2.7, all p < 0.05), PD-L1 protein expression (SP142: 30.4% vs. 50.2%, p=0.06; 22c3: 15.4% vs. 42.6%, p = 0.05) and differential expression of BCL2 family genes (upregulation: BIK, FC: 2.2; downregulation: BAX, BAK1, BID, PMAIP1, MCL1, BCL2A1, BCL2L10, FC: 1.0-6.3, all p < 0.05) compared to ID-TNBC. Conclusion: These data suggest that TN-ILC had higher frequency of CDH1, ERBB2, AKT1, ARID1A mutations, higher M2 macrophages and neutrophils and lower M1 macrophages and CD8 T cells infiltration and, lower T cell inflamed signature. High TMB and AR expression can translate into use of immunotherapy (ICI) and AR antagonists in these patients. Additonal analysis to determine the optimal biomarker for ICI response in TN-ILC is needed. Results of our study need to be validated in larger studies with survival correlation. Citation Format: Pooja Advani, Sachin Deshmukh, Sharon Wu, Jacob Andring, Joanne Xiu, Jose Leone, Priya Jayachandran, Stephanie Graff, Mathew Oberley, George Sledge, Asher Chanan-Khan. Comprehensive molecular and immune profiling of triple negative invasive lobular 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 7037.

Abstract Multiple myeloma (MM) therapeutics have evolved tremendously in recent years, with significant improvement in patient outcomes. As newer treatment options are developed, stem cell transplant (SCT) remains an important modality that provides excellent disease control and delays the progression of disease. Over the years, SCT use has increased overall in the U.S., but two distinct gaps remain, including suboptimal use overall, and racial-ethnic disparities. We evaluated the National Cancer Database (NCDB) to study what sociodemographic factors might play a role within a given racial-ethnic group leading to disparate SCT utilization, such that targeted approaches can be developed to optimize SCT use for all. In nearly 112,000 cases belonging to mutually exclusive categories of non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), Hispanics, non-Hispanic Asians (NHA), and others, we found certain factors including age, comorbidity index, payor type, facility type (academic vs. community) and facility volume to be uniformly associated with SCT use for all the racial-ethnic groups, while gender was not significant for any of the groups. There were several other factors which had a differential impact on SCT utilization among the various race-ethnicity groups studied, including year of diagnosis (significant for NHW, NHB and Hispanics), income level (significant for NHW and Hispanics), literacy level (significant for NHW and NHB), and geographic location of the treatment facility (significant for NHW and NHA). The suboptimal SCT utilization overall in the U.S., suggests that there may be room for improvement for all, even including the majority NHW, while we continue to work on factors that lead to disparities for the traditionally underserved populations. This study helps identify sociodemographic factors that may play a role specifically in each group and paves the way to devise targeted solutions such that resource utilization and impact can be maximized.

SummaryThis phase II study evaluated time‐limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenström macroglobulinaemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow‐up time of 25.7 months, the median progression‐free survival (PFS) was 22.9 months. While the primary end‐point was not met (CR rate at any time) and 28.5% discontinued treatment due to toxicity, ibrutinib plus ixazomib led to a clinically meaningful ORR and PFS. Combined Bruton's tyrosine kinase (BTK) and proteasome inhibition merits further evaluation in WM.