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e12562 Background: Previous research has suggested that breast cancer (BC) diagnosed during pregnancy or the postpartum period exhibits more aggressive clinical features, possibly due to pregnancy-related hormonal changes, immune modulation, and alterations in the mammary microenvironment compared to nulligravid or women many years out from pregnancy. Emerging data have demonstrated potential worse outcomes for patients (pts) diagnosed in post-partum. This study evaluated the influence of timing of diagnosis in relation to pregnancy history and recency of childbirth on long-term outcomes in a modern cohort of young pts with early-stage BC. Methods: Pts with stage I–III BC age < 40y in the prospective Young Women’s Breast Cancer Study (YWBCS) were categorized at diagnosis as Nulligravid (no prior pregnancy), Nulliparous (prior pregnancy without live birth), Currently Pregnant, or Parous (subdivided by time since last childbirth: within 5 years [≤ 5y PP], and 5–10 years postpartum [5–10y PP]). Baseline characteristics and outcomes were compared across BC subtypes (estrogen receptor+/HER2- [ER+/HER2-], HER2+, and triple-negative BC [TNBC]). Prognostic analyses for distant recurrence-free survival (DRFS) used Cox models. Results: 859 pts were included, 257 (30%) nulligravid, 50 (6%) nulliparous, 37 (4%) pregnant, and 515 (60%) parous (348 [68%] were ≤5y PP, and 167 [32%] were 5–10y PP). Median follow-up was 133 (6–209) months. Median age at diagnosis was lower in nulligravid pts (33 vs. 35–38 years); T1 tumors were most common in pts >5y PP (62%), and N0 status was highest in nulligravid pts (64%) (all p < 0.0001). Pregnant pts had higher rates of TNBC (27%), and T3 tumors (14%), N1 status, N1 (41%), and Grade 3 (81%) tumors compared to other groups (all p < 0.0001). Overall, only tumor size (T2-T4 vs T1, HR 2.03; 95% CI 1.37–3.03) and nodal status (N1 vs N0, HR 2.22; 1.48–3.34; N2/3 vs N0, HR 3.23; 1.96-5.33) were independently associated with worse DRFS; pregnancy history was not: nulligravid + nulliparous pts had no significant differences in DRFS compared to Pregnant (HR 1.46; 0.75–2.86), Parous <5y PP (HR 0.86; 0.58–1.26), and Parous 5–10y PP (HR 0.89; 0.54–1.48). Subgroup analyses by BC subtype (Table) and sensitivity analyses (excluding currently pregnant pts or separating nulligravid and nulliparous pts) demonstrated no significant associations between pregnancy history and DRFS. Conclusions: In this cohort study of very young patients with early breast cancer with contemporary treatment including management of breast cancer during pregnancy, pregnancy history and recency of pregnancy were not independent predictors of long-term disease outcomes. DRFS results by subgroup. Pregnancy Group N (%) HR (95% CI) ER+/HER2- Nulligravid + Nulliparous 173 (38.1) Ref Pregnant 16 (3.5) 0.93 (0.32–2.70) Parous ≤5y PP 177 (39.0) 0.77 (0.45–1.29) Parous 5–10y PP 88 (19.4) 0.78 (0.39–1.53) HER2+ Nulligravid + Nulliparous 77 (30.8) Ref Pregnant 11 (4.4) 3.27 (0.80–13.38) Parous ≤5y PP 113 (45.2) 1.50 (0.60–3.75) Parous 5–10y PP 49 (19.6) 1.45 (0.45–4.66) TNBC Nulligravid + Nulliparous 56 (36.8) Ref Pregnant 10 (6.6) 1.92 (0.61–6.09) Parous ≤5y PP 57 (37.5) 0.68 (0.28–1.63) Parous 5–10y PP 29 (19.1) 1.16 (0.43–3.14)

ABSTRACT Patients undergoing transcatheter aortic valve implantation (TAVI) often require long‐term oral anticoagulation (OAC), but it is unclear whether to continue or interrupt OAC during the procedure. This meta‐analysis compares clinical outcomes of continuing versus interrupting OAC during TAVI. PubMed, Embase, and Cochrane Central databases were searched from inception to September 2024 for studies comparing continuation versus interruption of OAC in patients undergoing TAVI with an indication for OAC, including vitamin K antagonists and direct oral anticoagulants. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a random‐effects model. Sensitivity analysis was performed using the Hartung‐Knapp‐Sidik‐Jonkman method. Three studies were included, one randomized controlled trial and two cohort studies, with 2773 patients, of whom 1314 (47.4%) continued OAC during TAVI. At a 30‐day follow‐up after TAVI, there were no significant differences between groups in all‐cause mortality (RR 0.74; 95% CI 0.45–1.20; p = 0.22), any bleeding (RR 1.08; 95% CI 0.81–1.43; p = 0.60), and major bleeding (RR 0.90; 95% CI 0.67–1.21; p = 0.48). However, the continued OAC group was associated with a lower stroke rate (RR 0.65; 95% CI 0.42–1.01; p = 0.053), also attested after a sensitivity analysis (RR 0.65; 95% CI 0.47–0.90; p < 0.03). In patients with an indication for OAC undergoing TAVI, uninterrupted anticoagulation is associated with similar thrombotic and hemorrhagic outcomes compared to interrupted OAC. Stroke risk was lower in the continued OAC group, with a significant reduction, as demonstrated in sensitivity analysis.

ABSTRACT Lung cancer is the leading cause of cancer-related deaths worldwide and, despite treatment advances, immune suppression remains an obstacle to effective therapy. Effector CD4 + T cells (CD4 + Teffs) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Tregs), which accumulate in lung tumors and perform suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Here, we identify the extracellular ATP receptor P2RX7 as a key regulator of Treg function in lung tumors. Using a murine lung cancer model induced by Lewis lung carcinoma cells, we demonstrate that P2RX7 enhances the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell-specific P2RX7-KO mice, reduced Treg infiltration was accompanied by increased CD4 + Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibit reduced tumor growth, confirming a cell-intrinsic role of P2RX7 in Tregs. Suppression assays revealed that tumor-infiltrating WT Tregs have greater suppressive activity compared to P2RX7-KO Tregs, which failed to inhibit type 1 and Tfh-like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that WT Tregs express higher levels of the immunosuppressive surface molecule CTLA-4 when compared to P2RX7-KO Tregs. In summary, we show that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer, and targeting of P2RX7 may constitute a novel strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.

Abstract The Phase 2 IMPRIME 1 study evaluated the combination of the pathogen-associated molecular pattern (PAMP) Imprime with the immune checkpoint inhibitor (ICI) pembrolizumab as second or later line of treatment (2 L+) for patients with metastatic triple-negative breast cancer (mTNBC). Eligible patients with mTNBC received weekly Imprime (4 mg/kg) intravenously in combination with pembrolizumab (200 mg every 3 weeks). Primary endpoints were overall response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression free survival (PFS), and overall survival (OS). Exploratory endpoints included correlations between immune cell activation markers in tumor tissues and blood and response to therapy. Of the 42 evaluable patients, six had a response (one complete, five partial), with an ORR of 14.3% by RECIST v1.1. Median PFS was 2.7 months, median OS was 16.4 months, and DCR was 54.8%, with responders achieving a median DoR of 15.2 months. Therapy was generally well tolerated and resulted in an increase of immune activation markers, with higher levels of activation in peripheral blood associated with response and improved survival. The combination of Imprime and pembrolizumab was safe and demonstrated immune activation in tumor tissues and peripheral blood in patients with TNBC. Improved response rates were observed compared to historical studies of ICI monotherapy in similar patient populations. Study number (ClinicalTrials.gov trial registration): NCT02981303.

Abstract Durable T cell immunity against cancer depends on the continual replenishment of effector CD8+ T cells. Thymic output has been correlated with favorable prognosis in cancer patients across a range of ages, suggesting that the thymus is an important source for replenishing T cells capable of controlling cancer progression. However, the effector potential of thymic mature CD8+ T cells and their regulation have not been clearly defined. In this study, we identified the ability of thymic single positive CD8+ T cells to gain effector potential after thymic selection, but they are subject to the regulation of PD-1. We found a previously undisclosed role of PD-1 in limiting both the cytotoxic and exhaustion potential of thymic and peripheral CD8+ T cells. Our results show that although PD-1 inhibition facilitates the expansion of effector CD8+ T cells, effector CD8+ cells gradually lose their antitumor activity within tumor tissues due to advanced exhaustion in the absence of PD-1. Thus, although the preset effector potential in thymic mature CD8+ T cells allows them to rapidly respond to malignant cells in the periphery, PD-1, as a checkpoint, is embedded in the thymic mature CD8+ T cells after positive selection to balance their effector function from exaggeration and exhaustion. Therefore, we propose that a strategy capable of upholding the cytotoxic capacity and avoiding exhaustion of CD8+ T cells during the early stages of PD-1 inhibition therapy is needed to achieve durable antitumor immunity.

Multiple myeloma (MM) is an incurable plasma cell (PC) malignancy. Despite therapeutic advances that have vastly improved survival, all patients are expected to relapse. Current standard of care includes autologous stem cell transplant (ASCT) with high-dose melphalan (HDM) administered as a conditioning agent. Cytotoxic chemotherapies such as melphalan have been shown to drive therapy-induced senescence (TIS) in several tissues. We hypothesize that HDM activates TIS pathways in surviving MM cells and that this may correlate with patient outcomes post-ASCT. We developed an in vitro HDM model using 5TGM1 mouse MM cells treated with vehicle (Veh) or HDM (10µM, IC90) for 6h, followed by co-culture with primary mouse bone marrow stromal cells. Image analysis was performed to quantify proliferation by cumulative population doublings (CPDs) over 10 days, after which 5TGM1 cells were evaluated for cell size, telomere-associated DNA damage foci (TAFs), sensitivity to senolysis, and senescence gene expression (scRNA-seq and RT-qPCR). The effect of HDM on CPDs and cell size was also evaluated in human MM cell lines RPMI-8226 and H929. scRNA-seq was used to analyze CD138+ PCs from MM patients at various timepoints post-ASCT. Longitudinal MM patient iliac crest biopsies (diagnosis, post-ASCT; N=20) were stained for CD138+ PCs; PC burden was quantified by AI-assisted histology. Lastly, we established an in vivo model of induction therapy (bortezomib) followed by HDM/SCT in Vk*MYC mouse MM engrafted C57BL/6 mice. Tumor burden was tracked by serum protein electrophoresis for M-spike using submandibular bleeds. Bone marrow was then flushed from long bones and analyzed by flow cytometry and immunofluorescence. HDM-5TGM1 showed decreased CPDs (HDM 0.32±0.31, Veh 6.72±0.69, p&lt;0.0001, N=3), increased size (median pixel size: HDM 413.2±99.98, Veh 207±8.88, p&lt;0.05, N=3), and increased TAF+ cells (Percent TAF+ cells: HDM 34.77%±10.74%, Veh 11.41%±1.58%, p&lt;0.05, N=3) consistent with known TIS features. Preliminary assessment (N=1) of human MM cell lines showed similar growth arrest (RPMI-8226 CPDs: HDM 0.058±0.101, Veh 4.185±0.358; H929 CPDs: HDM 0±0, Veh 4.61±0.243) and size increase (RPMI-8226 mean pixel size: HDM 804.1±6.048, Veh 526.9±2.115; H929 mean pixel size: HDM 371.2±26.95, Veh 130.3±41.43), suggesting a translatable mechanism. HDM-5TGM1 cells were more sensitive to senolysis by dasatinib+quercetin (viability: HDM 54.9%±0.09%, Veh 76.0%±0.05%, N=2). scRNA-seq analysis showed that HDM-5TGM1 were enriched for gene sets related to senescence pathways, including the published set SenMayo (FDR&lt;0.25). HDM-5TGM1 cells also exhibited myeloid gene expression consistent with previous publications on MM dormancy. RT-qPCR confirmed significant increases in HDM-5TGM1 (p&lt;0.001, N=3) in senescence markers (Cdkn1a, Cdkn1c, Glb1), senescent cell anti-apoptosis pathway genes (SCAPs, Bcl2l1), senescence associated secretory phenotype (SASP) genes (Ccl5, Icam1, Mmp13), and myeloid markers (Axl, Fcer1g, Mpeg1). scRNA-seq of patient CD138+ PCs confirmed a myeloid-like cluster that gained prominence in relapsed patients with resistant disease. CD138+ PCs were detected in patient bone biopsies post-ASCT. Interestingly, patients who relapsed (≤3 years, N=9) had a greater percent reduction in PC burden from diagnosis to post-ASCT when compared to patients that did not relapse (N=11) in that time (p=0.02). Further, CD138+ PC burden post-ASCT positively correlated with time in remission in relapsed patients (R=0.697, p=0.03). Bortezomib reduced serum M-spike in Vk*MYC-engrafted mice (p=0.0003); M-spike was further reduced by HDM/SCT compared to Veh-treated mice (p=0.0007). Flow cytometry confirmed a decrease in Vk*MYC cells after HDM/SCT (p=0.0043), and the percentage of Vk*MYC cells with greater size and complexity was increased compared to Veh-treated mice (p=0.0043), consistent with our in vitro data. Vk*MYC cells from HDM-treated mice also trended for more TAF+ cells (&gt;3 TAFs) compared to Veh-treated mice (p=0.0714). Our findings suggest that HDM can induce a TIS and myeloid signature in surviving MM cells. Greater MM burden post-ASCT appears to be associated with longer durable response, again suggesting that these cells may be in growth arrest consistent with TIS. Finally, senolytics may be a novel approach to eliminate surviving MM cells and prevent relapse.

IMPORTANCEYoung adults aged 18 to 39 years represent the minority of breast cancer diagnoses but are particularly vulnerable to financial hardship. Factors contributing to sustained financial hardship are unknown.OBJECTIVESTo identify financial hardship patterns over time and characterize factors associated with discrete trajectories; it was hypothesized that treatment-related arm morbidity, a key source of expense, would be associated with long-term financial difficulty.DESIGN, SETTING, AND PARTICIPANTSThis cohort study included US young adults aged 40 years or younger treated between 2006 and 2016. Eligible patients were treated for stage 0 to stage III breast cancer at institutions participating in the Young Women’s Breast Cancer Study, which included a specialized cancer institute and 12 other academic and community hospitals. Patients who responded at baseline and returned a 1-year survey were included in analysis. Data were analyzed in March 2024.MAIN OUTCOMES AND MEASURESTrajectory modeling classified patterns of financial difficulty from baseline through 10 years postdiagnosis using the Cancer Rehabilitation Evaluation System (CARES) scale. Multinomial regression examined characteristics, including treatment-related arm morbidity, associated with each trajectory.RESULTSA total 1008 patients were included (median [IQR] age at diagnosis, 36 [33-39] years; 60 Asian [6.0%], 35 Black [3.5%], 47 Hispanic [4.7%], 884 White [87.7%]); 840 patients were college graduates (83.3%), 764 were partnered at baseline (75.8%), 649 were nulliparous (64.4%), and 908 were without comorbidities at enrollment (90.1%). Patients’ tumors were primarily stage I-II (778 [77.2%]), estrogen receptor/progesterone receptor–positive (754 [74.8%]), and ERBB2-negative (formerly HER2) (686 [68.1%]). Patients were more frequently treated with mastectomy than breast conservation (771 [76.5%] vs 297 [29.5%]; P &amp;lt; .001). A majority of patients received radiation therapy (627 [62.2%]), chemotherapy (760 [75.4%]), and endocrine therapy (610 [60.6%]). A total of 727 patients (72.1%) reported arm symptoms within 2 years of surgery. Three distinct trajectories of experiences with finances emerged: 551 patients (54.7%) had low financial difficulty (trajectory 1), 293 (29.1%) had mild difficulty that improved (trajectory 2), and 164 (16.3%) had moderate to severe difficulty peaking several years after diagnosis before improving (trajectory 3). Hispanic ethnicity (OR, 3.71; 95% CI, 1.47-9.36), unemployment at baseline and 1 year (OR, 2.66; 95% CI, 1.63-4.33), and arm symptoms (OR, 1.77; 95% CI, 1.06-2.96) were associated with increased odds of experiencing trajectory 3. Having a college degree (OR, 0.20; 95% CI, 0.12-0.34) or being partnered (OR, 0.24; 95% CI, 0.15-0.38) were associated with increased odds of experiencing trajectory 1.CONCLUSIONIn this cohort study of young adults with breast cancer, we identified a subset of patients who experienced a high degree of financial difficulty persisting into early survivorship. Targeted interventions to mitigate financial toxicity—modifiable factors that include support for the employability or return to work support for those experiencing arm symptoms after treatment—are needed.

363 Background: The incidence of BC in young adults is increasing; given their extended survivorship, characterizing healthcare utilization and adherence to surveillance guidelines can inform unmet health needs and gaps in care. Methods: The multi-center Young Women’s BC Cohort Study enrolled 1302 women ≤40 yrs with newly diagnosed (dx) BC from 2006-2016. Participants completed surveys every 6 mos for 3 yrs post-dx, then annually. The current analysis includes patients with Stage 0-III BC without recurrence who completed the 7-yr survey assessing survivorship care, including types of providers visited, BC surveillance, and other health maintenance practices. Multivariate logistic regression evaluated factors (clinical, demographics, concern about recurrence) associated with 1) full transition to a primary care provider (PCP) for follow-up; adherence to 2) mammography (among women who had a unilateral mastectomy or lumpectomy) and 3) bone density scans (among current hormonal therapy [HT] users), per ASCO/ACS guidelines. Results: Of 660 women with Stage 0-III BC, median age at dx was 37 (range: 17-40); 89% identified as White, 5%, Asian, 3%, Black, 3% as other/multiracial, and 4%, Hispanic. Most had received chemotherapy (75%) and radiation (61%) and 35% reported current HT; 12% had a BRCA1/2 mutation. For cancer-related follow-up, 57% reported seeing an oncology provider only, 12%, PCP only, and 29% saw a PCP + oncology provider. Among women with remaining breast(s) (n=348), 90% reported a mammogram in the last year. Adherence to other health maintenance practices varied: 68% reported having had a flu shot, 76% a pap test/pelvic exam, and 56% cholesterol screening within the last 2 yrs. Among current HT users (n=210), 46% reported a bone density scan within the last 2 yrs. In multivariate analyses assessing the odds of seeing a PCP only (vs. oncology + PCP), having stage 0 vs I disease (OR 2.74 95% CI 1.01-6.80) was associated with higher odds while any HT use (OR .31 95% CI .16-.58) and concern about recurrence (OR .23 95% CI .12-.47) were associated with lower odds. The table includes factors significantly associated with non-adherence to mammography and bone density scans. Conclusions: At 7-years post-dx, most young survivors participating in a cohort study receive cancer follow-up care from an oncology provider and have not fully transitioned their care to a PCP. Adherence to recommendations related to bone health among HT users was suboptimal. Additional research to identify barriers/facilitators to receipt of guideline-concordant follow-up care at the patient, provider, and systems levels may inform strategies to optimize survivorship in young BC survivors. Multivariable analysis: factors associated with non-adherence. MammogramOR 95% CI Bone density scanOR 95% CI Her2+ .38, .15 -.98 NS BRCA1/2 + 8.36, 1.38-50.47 .17, .05 -.62 Chemotherapy NS .22, .06 -.78 Unilateral mastectomy vs lumpectomy 6.64, 2.69-16.34 NS