Browse Articles

Evaluation of circulating tumor DNA (ctDNA) burden, detected mutations, and clinical outcomes in metastatic colorectal cancer (mCRC) using real-world data (RWD).

3659 Background: ctDNA is a promising prognostic biomarker in colorectal cancer; however, there is limited RWD on its prognostic value in mCRC. We leveraged RWD to assess pre-treatment (Tx) ctDNA burden and gene mutations, and evaluated the association between ctDNA burden and clinical outcomes in patients (pts) with mCRC. Methods: Pts with mCRC identified in the GuardantINFORM database who underwent Guardant 360 comprehensive genomic profiling between June 1, 2014 to June 30, 2023 were included. First metastatic diagnosis date was used as the index date. ctDNA burden (% max variant allele fraction ctDNA levels) was categorized as below limit of detection (no ctDNA), ≤ median value (low ctDNA), and > median value (high ctDNA). ctDNA burden and gene mutations/alterations detected prior to 1L systemic therapy were summarized. Associations with OS, time to next Tx (TTNT), and time to Tx discontinuation (TTD) were assessed using Cox proportional hazards models for the overall cohort and by microsatellite instability (MSI) status, stratified by 1L and 2L Tx. Results: There were 3273 pts with mCRC included (non-MSI-high [H], n = 2750; MSI-H, n = 100; missing, n = 423). Mean ctDNA burden was 19.9% overall, 20.7% in non-MSI-H, and 14.6% in MSI-H cohorts. Top 3 gene mutations were TP53 (65.8% and 67.2%), APC (59.7% and 60.7%), and KRAS (40.6% and 41.2%) in the overall and non-MSI-H cohorts; and, ARIDIA (71.0%), TP53 (67.0%), and APC (65.0%) in the MSI-H cohort. Top 3 specific variants were EGFR AMP (23.7% and 25.3%), KRAS G12D (11.3% and 11.4%), and KRAS G12V (8.2% and 8.5%) in the overall and non-MSI-H cohorts; and BRAF V600E (39.0%), ARIDIA D1850fs (22.0%), and PIK3CA H1047R (21.0%) in the MSI-H cohort. In the overall cohort, high ctDNA compared to low ctDNA was statistically significantly associated with shorter OS (HR [95% CI]: 1L, 1.63 [1.43-1.87]; 2L, 1.42 [1.19-1.70]) and TTNT (1L, 1.43 [1.27-1.60]; 2L, 1.39 [1.19-1.63]) after adjusting for confounders. Conversely, no ctDNA compared to low ctDNA was statistically significantly associated with longer OS (0.70 [0.53-0.91]) and TTNT (0.75 [0.58-0.97]) in the 1L setting after adjusting for confounders; these associations were also observed when stratified by MSI status. ctDNA burden was not statistically significantly associated with TTD in 1L regardless of MSI status. In 2L, high ctDNA was associated with shorter TTD compared to low ctDNA overall (1.19 [1.05-1.34]), with similar findings in the non-MSI-H cohort. Conclusions: High ctDNA burden prior to 1L and 2L therapy was associated with shorter OS and TTNT, suggesting a higher disease burden or more aggressive disease. The absence of detectable ctDNA was associated with improved survival and may identify pts with better prognosis or slower-growing tumors. These findings provide growing evidence for ctDNA as a potential prognostic biomarker in mCRC.

Acute respiratory distress syndrome and non-metastatic solid tumor: A propensity score–matched analysis of the National Inpatient Sample database.

e14044 Background: Acute Respiratory Distress Syndrome (ARDS) remains a major cause of morbidity and mortality in hospitalized adults. Patients with non-metastatic solid tumors (NMST) may be at increased risk for adverse outcomes due to cancer-related inflammation and treatment-associated toxicities. Limited national-level data exist evaluating the impact of NMST on ARDS outcomes. This study assesses the association between NMST and inpatient outcomes among adults hospitalized with ARDS. Methods: The National Inpatient Sample (2017–2021) was analyzed to identify adults ≥18 years with ARDS using ICD-10 codes. Patients with missing data were excluded. Primary outcomes included inpatient mortality, length of stay (LOS), sepsis, and the need for endotracheal intubation or vasopressor support. Propensity score matching (PSM) was performed (1:1) to balance covariates between NMST and non-NMST groups. Matching variables included diabetes, COPD, coronary artery disease, hypertension, dyslipidemia, liver disease, obesity, obstructive sleep apnea, and pulmonary hypertension. Post-matching comparisons were conducted using univariate and multivariate regression models. Results: A total of 84,790 ARDS hospitalizations were identified, of which 2,617 involved NMST. The mean age was 60.3 ± 15.6 years, and 57.6% were male. After 1:1 PSM, 2,617 NMST patients were matched to 2,617 non-NMST patients, achieving standardized differences <0.10 across covariates. Compared with matched controls, NMST patients had higher rates of mortality (61.44% vs. 48.42%), sepsis (68.48% vs. 62.23%), and vasopressor use (17.88% vs. 16.11%). Rates of acute kidney injury (59.08% vs. 58.91%), endotracheal intubation (43.33% vs. 43.91%), and LOS (~18 days) were similar between groups. In adjusted analyses, NMST was significantly associated with increased mortality (OR 1.25; 95% CI 1.12–1.39; p<0.01) and sepsis (OR 1.27; 95% CI 1.13–1.43; p<0.01). Conclusions: NMST is independently associated with higher mortality and sepsis among adults hospitalized with ARDS. These findings highlight the need for early recognition and tailored management strategies for ARDS in patients with underlying NMST. Further research is warranted to define optimal approaches for this high-risk population.

Metastatic male breast cancer: What do we know about treatment efficacy and survival? a multicenter retrospective study.

e13100 Background: Male breast cancer is a rare malignancy, representing less than 1% of all breast cancer cases worldwide. While treatment outcomes in breast cancer have improved substantially, male patients remain underrepresented in prospective trials, resulting in limited high-quality evidence to guide clinical decision-making. In routine practice, men are often diagnosed at an early stage and respond well to standard therapies. In the metastatic setting, however, the disease behaves as a chronic condition requiring long-term systemic treatment. Methods: A retrospective multicenter study across eight Polish cancer centers included 244 men diagnosed with breast cancer between 2010 and 2025. Clinical data on patient characteristics, tumor features, treatment modalities, and survival outcome were analyzed. Survival outcomes analyses were performed using Kaplan-Meier method and median overall survival (OS), progression-free survival (PFS) and survival rates were reported. Results: In the palliative cohort (79 patients), luminal breast cancer represented the largest biological subgroup (46%), followed by HER2-positive disease (28%). HER2-low tumors were particularly rare, occurring in 22 patients (28%), a rate lower than typically reported in unselected breast cancer populations. By contrast, triple-negative disease was extremely rare (n = 1). Median progression-free survival (PFS) was 16.5 months in the first-line setting and 12.6 months in the second line. Despite the predominance of hormone receptor–positive disease, CDK4/6 inhibitors were administered to only five patients. In first-line therapy, median PFS reached 20 months for luminal tumors and 16.5 months for HER2-positive disease. Bone, lung, and liver were the predominant sites of metastatic disease. Overall survival in the palliative cohort remained relatively prolonged, with a median OS of 47.5 months and a 5-year OS rate of 42.2%. Conclusions: Despite substantial progress in breast cancer treatment overall, the management of male breast cancer remains a significant clinical challenge. The current evidence base is still limited. Larger, well-designed studies are therefore required to better characterize this rare disease and to develop more effective, evidence-based therapeutic strategies for male patients.

Efficacy and safety of FOLFIRINOX versus gemcitabine-based regimens in locally advanced pancreatic carcinoma: A systematic review and meta-analysis.

e16391 Background: Locally advanced pancreatic cancer (LAPC) is often unresectable due to vascular involvement, and systemic therapy is the treatment backbone with the goal of improving survival and, in selected patients, enabling resection. FOLFIRINOX is commonly used in fit patients, but its comparative benefit over gemcitabine-based regimens in LAPC remains uncertain. We conducted a systematic review and meta-analysis to compare efficacy and safety of these approaches in LAPC. Methods: We searched PubMed, Embase, Scopus, CENTRAL, and ClinicalTrials.gov for randomized controlled trials and comparative cohort studies in adults with LAPC evaluating FOLFIRINOX versus gemcitabine-based regimens (including nab-paclitaxel). Random-effects meta-analysis pooled hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS), and risk ratios (RR) for response, progression, resection, and grade ≥3 hematologic toxicity. Subgroup analyses were performed by comparator regimen. Results: Six comparative studies (n = 1,766) were included. Overall survival (OS) favored FOLFIRINOX but did not reach statistical significance (HR 0.81; 95% CI 0.66–1.01; p = 0.06; I² = 45). Progression free survival (PFS) showed no significant difference (HR 1.11; 95% CI 0.79–1.54; p = 0.55; I² = 60%). There were no significant differences in objective response (RR 1.07; 95% CI 0.79–1.47; p = 0.65; I² = 38%), disease control (RR 1.13; 95% CI 0.99–1.30; p = 0.08; I² = 0%), progressive disease (RR 0.82; 95%CI 0.43–1.56; p = 0.54; I² = 55%), or resection rate (RR 1.03; 95% CI 0.57–1.86; p = 0.91; I² = 0%). Grade ≥3 neutropenia was higher with FOLFIRINOX (RR 2.21; 95% CI 1.21–4.04; p = 0.01; I² = 49%), as was febrile neutropenia (RR 4.26; 95% CI 1.78–10.17; p = 0.001; I² = 0%) with consistent findings in subgroup analyses. Conclusions: In LAPC, FOLFIRINOX showed borderline, non-significant improvement in overall survival and no improvement in progression-free survival. Response, disease control, progression, and resection outcomes were similar between regimens. FOLFIRINOX increased the risk of grade ≥3 neutropenia and febrile neutropenia. Treatment selection should be individualized based on patient fitness and toxicity risk, and perspective comparative studies are needed.

Neoadjuvant ivonescimab (AK112, a PD-1/VEGF bispecific antibody) combined with nab-paclitaxel and cisplatin (AP) for resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC): An exploratory phase II study.

6014 Background: Previously, neoadjuvant PD-1 plus AP followed by surgery and radiotherapy showed promising disease control and laryngeal preservation in resectable LA-HNSCC. Ivonescimab, a PD-1/VEGF bispecific antibody, potentially exerts synergistic anti-tumor activity by normalizing tumor vasculature and enhancing immune infiltration. This study evaluates the efficacy and safety of neoadjuvant Ivonescimab plus AP in resectable LA-HNSCC. Methods: This single-center phase II trial enrolled patients (18-70 yrs) with resectable stage III-IVa LA-HNSCC (oral cavity, oropharynx, hypopharynx, or larynx). Neoadjuvant therapy: 3 cycles of Ivonescimab (20mg/kg Q3W) plus AP, followed by surgery. Postoperative treatment included radiotherapy ± chemotherapy and maintenance Ivonescimab (10mg/kg Q3W) for 14 cycles. Primary endpoints: pCR and 2-year EFS. MRD and PD-L1 CPS were also investigated. Results: By November 2025, 36 patients were enrolled (median age 58; 75% Stage IV). Primary tumor sites were hypopharynx (50.0%), larynx (25.0%) and oral cavity (19.4%). Radiological assessment performed prior to Cycle 3 demonstrated an exceptional objective response rate (ORR) of 100% among 34 evaluable patients. Notably, a remarkably deep radiological response was achieved, with a complete response (CR) rate of 50.0% (17/34) and a partial response (PR) rate of 50.0% (17/34). Deep tumor shrinkage was observed in all cases. 30 patients underwent surgery with a 100% R0 resection rate. The overall pCR rate was 50.0% (15/30). Specifically, pCR was achieved in 70.0% (21/30) of primary lesions and 64.3% (18/28) of lymph nodes. While robust pathological responses were observed in the hypopharynx (64.3%), tongue (57.1%), and oropharynx (50.0%), the pCR rate in the larynx was markedly lower at 12.5%. Crucially, the profound tumor downsizing induced by Ivonescimab enabled volume-reduced resections, achieving 100% successful laryngeal and pharyngeal preservation while maintaining negative margins. High PD-L1 predicted efficacy; median CPS was 30.0 in pCR vs. 10.0 in non-pCR (p=0.18). Notably, 100% of pts with CPS > 30 achieved pCR. Pre-op MRD specificity for pathological conversion was 91.7% (sensitivity 37.5%). Safety: The most common Grade≥3 AEs were pharyngeal fistula (surgical-related) and transient transaminase elevation. Most drug-related AEs were manageable and consistent with the known profiles of PD-1 and VEGF inhibitors. Conclusions: Neoadjuvant Ivonescimab plus chemotherapy demonstrated unprecedented radiological response depth and pathological remission rates in LA-HNSCC. This novel PD-1/VEGF-based dual blockade may redefine neoadjuvant standards for head and neck cancer. High CPS and MRD negativity are robust predictors of deep pathological response. Clinical trial information: NCT06537011 .

Phase I study of LB1410, a bivalent TIM-3/PD-1 bispecific antibody, in patients with advanced solid tumors.

2639 Background: LB1410 is a recombinant humanized anti-PD-1/TIM-3 bispecific antibody (BsAb) developed by L&L Bio Co., Ltd, Shanghai, China for patients (pts) resistant/refractory (R/R) to anti-PD-(L)1 therapies. Pre-clinical studies revealed superior T cell and DC activity and in vivo antitumor efficacy compared to the combined use of TIM-3 and PD-1 monoclonal antibodies. This ongoing open-label phase I trial evaluates LB1410 monotherapy in pts with advanced solid tumors. Methods: Eligible pts were ≥18 yrs old with ECOG PS 0-1. Dose ranged from 0.001 to 20 mg/kg IV Q2W or 2000 mg/kg IV Q3W in an accelerated titration or a traditional 3+3 design. The RPIID of 20 mg/kg was used for efficacy expansion in pts with advanced clear cell renal cell carcinoma (ccRCC), cervical cancer (CC) and hepatocellular carcinoma (HCC). The primary objective was safety, including dose-limiting toxicities (DLTs); secondary objectives included efficacy, pharmacokinetics (PK) and immunogenicity. Results: As of Jan 4, 2026, 94 pts were enrolled: median age 59 yrs (31-73 yrs); 64.9% male; 84.0% ECOG PS 1. Tumor types included NSCLC (26.6%), CRC (21.3%, all non-MSI-H), CC (14.9%), ccRCC (11.7%), HCC (9.6%) and others (16.0%). 77 pts (81.9%) had received ≥ 2 prior lines of therapy. 98.6% non-CRC pts (73/74) were R/R to anti-PD-(L)1 therapies. 72 pts (76.6%) experienced TRAEs. The most common TRAEs (≥ 10%) included anemia (25.5%), proteinuria (11.7%), elevated ALT (11.7%), elevated AST (11.7%) and elevated lactate dehydrogenase (10.6%). Only 10 pts (10.6%) experienced Grade 3-4 TRAEs, most frequently hypertension (4.3%) and hypokalemia (2.1%). Only 1 hypertension and 1 elevated GGT in 1 pt were Grade 4. Serious TRAEs occurred in 3 pts (3.2%). No DLTs were observed. Among pts with available on-treatment scans, the overall ORR per RECIST 1.1 was 7.1% (6/85) with 5 confirmed PRs and 1 confirmed CR; the DCR was 48.2% (41/85). Notably, among CC pts previously treated with anti-PD-(L)1 therapies, there were 4 confirmed PRs and 1 confirmed CR: ORR 38.5% (5/13); DCR 69.2% (9/13); mPFS 7.5 months. 5 pts with CR/PR/SD remained on treatment (max. 16 treatment cycles; max. follow-up 14.4 months). The CR patient had received 5 prior lines of therapy, including PD-1/CTLA-4 BsAb. In anti-PD-1-resistant ccRCC, LB1410 monotherapy had an ORR of 11.1% (1/9) and a DCR of 77.8% (7/9). Conclusions: LB1410 showed an excellent safety profile and promising antitumor efficacy in pts with immune-oncology (IO)-R/R CC. Further studies of LB1410 as monotherapy and in combination with lenvatinib in pts with IO-R/R CC are ongoing. Clinical trial information: NCT05357651 .

Factors associated with clinical presentation and survival in early-onset triple-negative breast cancer: A real-world analysis.

e12751 Background: Early-onset triple-negative breast cancer (TNBC) is typically viewed as biologically aggressive, yet the factors underlying younger age at diagnosis and survival in these patients remain understudied. Using national real-world data, we examined clinical and sociodemographic factors associated with early-onset and overall survival (OS) among patients with TNBC. Methods: Using the National Cancer Database, we identified women younger than 40 with stage I–IV TNBC diagnosed from 2010–2019. Multivariable logistic regression evaluated factors associated with early-onset diagnosis (ages 18–40) compared to a “later-onset” reference group (ages 40–49). Multivariable Cox regression evaluated factors associated with three-year OS. Analyses adjusted for stage, diagnosis year, race/ethnicity, insurance, comorbidity index, and zip-code income quartile. Propensity-score matching (PSM) by these covariates was used to compare OS between age groups. Results: Among the final cohort with complete data for covariates, 16,529 patients were classified as early-onset. In the multivariable logistic regression, higher stage at diagnosis was strongly associated with early-onset compared with stage I (stage II: adjusted odds ratio [aOR] 1.38, 95% CI 1.31–1.46; stage III: aOR 1.50, 95% CI 1.40–1.60; stage IV: aOR 1.20, 95% CI 1.07–1.34; all p < 0.001). Compared to non-Hispanic White, Hispanic ethnicity (aOR 1.40, 95% CI 1.29–1.51, p < 0.001) and Asian American/Pacific Islander (AAPI) race (aOR 1.22, 95% CI 1.09–1.38, p < 0.001) were associated with increased odds of early-onset diagnosis, whereas non-Hispanic Black (NHB) race was associated with lower odds (aOR 0.85, 95% CI 0.80–0.90, p < 0.001). In the multivariable Cox regression, among patients with early-onset TNBC, higher stage was the strongest predictor of three-year mortality (stage IV vs stage I: adjusted hazard ratio [aHR] 30.09, 95% CI 27.64–32.75, p < 0.001). Diagnosis in 2015–2019 (versus 2010–2014: aHR 0.81, 95% CI 0.77–0.85, p < 0.001), Hispanic ethnicity (aHR 0.70, 95% CI 0.65–0.76, p < 0.001), and AAPI race (aHR 0.74, 95% CI 0.65–0.85, p < 0.001) were associated with better OS. NHB race (aHR 1.09, 95% CI 1.04–1.15, p = 0.001), uninsured status (aHR 1.56, 95% CI 1.39–1.75, p < 0.001), higher comorbidity index (≥2 vs 0: aHR 1.69, 95% CI 1.42–2.02, p < 0.001), and lower zip-code income quartile were associated with worse OS. After PSM, compared with ages 40–49, three-year mortality hazard was modestly higher for ages 30–39 (aHR 1.10, 95% CI 1.03–1.16, p = 0.003) but borderline significant for ages 20–29 (aHR 1.14, 95% CI 0.99–1.33, p = 0.08). Conclusions: Clinical and sociodemographic factors varied in their association with early-onset TNBC and OS. These findings suggest that many disparities persist in this subset of patients, and survival differences identified in our analysis may warrant further investigation.

A logic-gated chimeric antigen receptor T-cell (CAR T) therapy with an armored, membrane-tethered IL-12 booster in patients with advanced solid tumors with HLA-A*02 loss of heterozygosity (LOH): EVEREST-2, a phase 1/2 study.

TPS2673 Background: The main challenge for developing CAR T therapies for solid tumors is the lack of targets that distinguish tumor from normal cells, resulting in on-target, off-tumor toxicity. Tmod logic-gated CAR T therapy addresses this challenge by incorporating 2 CARs on the same T cell: an activator targeting a marker on both tumor and normal cells, and a blocker targeting HLA-A*02 that inhibits CAR T activity against normal cells while allowing activation against tumor cells (with HLA-A*02 LOH), improving tumor selectivity and decreasing toxicity. Early safety results from 3 ongoing phase 1/2 clinical trials of logic-gated, Tmod CAR T therapy (EVEREST-1, EVEREST-2, and DENALI-1) have demonstrated manageable safety and tolerability in patients with advanced solid tumors (Grierson et al, SITC , 2024; Ward et al, SITC 2025; Specht et al, SABCS , 2025). Early efficacy results include the first ever reported complete response in a patient with non-small cell lung cancer following treatment with a CAR T-cell therapy (A2B694). A2B543 is an autologous Tmod CAR T therapy that contains the same Tmod construct as A2B694 with an added membrane-tethered IL-12 (memIL12) booster. Specifically, A2B543 is comprised of autologous Tmod cells transduced with 2 lentiviral vectors: one expressing both the HLA-A*02-targeted blocker and the mesothelin-targeted CAR activator; and a second expressing the memIL12 booster. Interleukin 12 (IL-12) is a potent, pro-inflammatory cytokine that plays a crucial role in inducing antitumor immune responses; however, systemic IL-12 can be prohibitively toxic (Jia et al, Front Immunol , 2022). In A2B543, expression of the memIL12 cassette is under the control of an NFAT promoter and is induced during antigen engagement or T cell activation. This inducible memIL12 is designed to reduce the toxicity associated with systemic IL-12 while enhancing the long-term potency and persistence of Tmod (Zhang et al, J Immunother Cancer , 2025). Methods: EVEREST-2 (NCT06051695) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B543 in adults with recurrent/metastatic mesothelin-expressing cancers with tumor-associated HLA-A*02 LOH, including mesothelioma, colorectal, non-small cell lung, pancreatic, or ovarian cancer. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH via next-generation sequencing and cryopreserves leukapheresis product. Upon progression, A2B543 is manufactured and then administered after lymphodepletion. The phase 1 primary objective is to evaluate the safety and tolerability of A2B543 and identify a recommended phase 2 dose (RP2D). The phase 2 primary objective is to assess overall response rate. Clinical trial information: NCT06051695 .

Association of social isolation with overall survival in cancer patients.

12011 Background: Social isolation has been associated with increased all-cause mortality, particularly in cardiovascular and mental health conditions. Prior studies show that larger social networks, greater perceived social support, and marital status are associated with improved survival. However, the impact of social isolation on cancer patients remains incompletely characterized. This study examines the association between social isolation and overall survival (OS) in a large cancer cohort. Methods: 47,562 adult cancer patients treated at British Columbia Cancer between April 1, 2011, and December 31, 2016, who completed the Psychosocial Screen for Cancer (PSSCAN-Revised) questionnaire at their initial visit were included. Patients with prior malignancies were excluded. OS was estimated using Kaplan-Meier methods and compared using log-rank tests. Multivariable Cox proportional hazards regression was used to identify independent associations with OS. Results: The mean age was 64.5 years (SD 13.9). 55.2% were female. At their initial visit, 67% had non-metastatic disease, 17% had metastatic disease, and metastatic status was unknown in 16%. Social isolation was prevalent: 24.7% lived alone, 14.1% had lost a partner, 11.6% lacked assistance with instrumental activities of daily living (IADLs), 4.7% lacked regular social contact, 6.9% lacked emotional support, and 29.3% had at least one domain of social isolation. Median OS was shorter across all five domains of social isolation: patients living alone (37 vs 58 months), those who lost a partner (34 vs 56 months), those without regular social contact (32 vs 52 months), those without IADL support (49 vs 53 months), and those lacking emotional support (45 vs 53 months; all p<0.05). Anxiety (36.8%) and depression (25.6%) were also associated with worse survival (p<0.001). In multivariable Cox regression, independent predictors of increased mortality included metastatic disease (HR 4.41), depression (HR 1.44), anxiety (HR 1.29), lack of regular social contact (HR 1.26), male sex (HR 1.22), living alone (HR 1.18), and older age at presentation (HR 1.04 per year; all p<0.001). Conclusions: Multiple domains of social isolation were independently associated with shorter OS in cancer patients. These findings highlight social isolation as a clinically relevant prognostic factor and support the incorporation of psychosocial risk assessments into oncology care to inform risk stratification and supportive interventions.

Fast-TRACKing precision oncology for rare cancers: A national decentralized trial offering comprehensive genomic profiling and a molecular tumor board.

3147 Background: The TargetCancer Foundation TCF-001 TRACK study (Target RAre Cancer Knowledge, NCT04504604) initiated on Oct 01, 2020, is a fully remote, advocacy-driven decentralized precision trial seeking to evaluate the clinical impact of utilizing comprehensive genomic profiling (CGP) reviewed by a molecular tumor board (MTB) for patients (pts) with rare cancers. Methods: Pts were remotely enrolled/consented. Blood samples were collected via mobile phlebotomy and tested with FoundationOne Liquid CDx; tissue biopsies (TBx) were tested using FoundationOne CDx ± laboratory developed (LD) FoundationOne RNA or LD FoundationOne Heme. Liquid biopsy testing (LBx) included algorithmic predictions for clonal hematopoiesis (CH). MTB reviewed results and provided recommendations. Results: As of Oct 01, 2025, 230 pts from 46 US states were enrolled with evaluable results; 76% (175/230) had TBx and LBx, 22% LBx, and 2% TBx biopsies. MTB review was completed for 226 pts. Median age was 57 years (interquartile range [IQR]: 47,66); > 60 tumor types were represented: cholangiocarcinoma (35%), gastrointestinal (19%), soft tissue-related sarcomas (17%), brain (14%), and others (15%). First on-study TBx CGP (n=173) showed microsatellite instability high in 2%, homologous repair deficiency-signature in 2%, and median tumor mutational burden (TMB) of 1.3 mut/Mb (IQR: 0.8,3.6; 5 pts ≥ 10 mut/Mb). In LBx (n=57), ctDNA tumor fraction (TF) was ≥1% in 28% of pts; median blood TMB was 1.3 (IQR: 0,2.5; 1 pt ≥ 10 mut/Mb). Overall, 95% (219/230) of tumors had >1 pathogenic alteration; TBx CGP detected alterations in 96% (172/179), most frequently TP53 (35%), CDKN2A (29%), CDKN2B (21%), KRAS (19%), MTAP (17%), and TERT (14%). LBx CGP detected alterations in 85% (192/225), with tumor-derived (TD) variants in KRAS (11%), IDH1 (7%), and CDKN2A (6%). TP53 (31%) included both TD and CH variants, while DNM3TA (30%), ATM (10%), TET2 (10%), and CHEK2 (8%) were mostly CH. In brain tumors, 52 variants from 28 pts with LBx identified 45 CH, 4 germline, and 3 TD. Across all tumor types, 9% (20/230) had biomarkers for FDA-approved tissue-agnostic therapies. This includes ERBB2 amplification (2% overall), which is often correlated with HER2 immunohistochemistry positivity. LBx sensitivity for DNA tissue-detected clonal SVs and rearrangements was 85% (95% CI: 0.74,0.92) when ctDNA TF≥1%; 24% (95% CI: 0.19,0.29) when <1%. Pathogenic fusions detected by RNA sequencing were not detected by DNA in 33% of cases (9/27). Conclusions: CGP identified pathogenic alterations in nearly all rare cancer patients, with tissue-agnostic biomarkers in 9%. RNA sequencing adds diagnostic yield. CH in liquid biopsies underscores need for expert MTB interpretation. TRACK, a first-of-its-kind national decentralized trial, provides a scalable framework for equitable precision oncology access. Clinical trial information: NCT04504604 .

Sleep disorders in cancer survivors: A cross-sectional study from Morocco.

e24133 Background: Sleep disturbances are among the most frequent and burdensome symptoms in patients with cancer and often persist into survivorship. The National Cancer Institute (NCI) defines a cancer survivor as any individual from the moment of diagnosis throughout the remainder of life, regardless of treatment status or time elapsed. Although the 5-year survival mark is commonly used as a symbolic threshold for long-term survival, many survivors continue to experience persistent physical and psychological sequelae that impair sleep. This study aimed to assess the prevalence and characteristics of sleep disorders among cancer survivors in a tertiary Moroccan oncology setting. Methods: We conducted a cross-sectional descriptive and analytical study over a 5-year period at Hassan II University Hospital, Fez, Morocco. Ethical approval and written informed consent were obtained. A subset of 63 cancer survivors was analyzed from a larger cohort of 323 oncology patients. Sleep disturbances were assessed using validated questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and Epworth Sleepiness Scale. Results: The cohort had a mean age of 53.7 years (range 16–90), with 58.8% males. The most frequent cancers were colorectal (24.5%), prostate (24.1%), and gastric (22.6%). Most patients had metastatic disease (73.4%), and 63.2% were receiving chemotherapy. Sleep disturbances were highly prevalent: poor sleep quality (PSQI ≥5) in 96.0%, clinical insomnia (ISI >7) in 95.6%, and daytime sleepiness in 95.7%. Mean sleep duration was 4.79 hours, with a sleep latency of 1.7 hours. Sleep disorders were significantly associated with metastatic stage (p=0.013) and gastric cancer (p=0.046). Lifestyle factors showed no significant association. Only 11.5% of patients received hypnotic treatment. Conclusions: Sleep disturbances are extremely common among cancer survivors, particularly those with metastatic disease or receiving systemic therapy, and significantly impair quality of life. Disease- and treatment-related factors appear to outweigh lifestyle contributors. The marked gap between prevalence and management highlights the need for systematic screening and integration of evidence-based interventions, such as cognitive behavioral therapy for insomnia, into routine oncology care.

Racial representation in clinical trials supporting NCCN breast cancer guidelines: A retrospective analysis.

1651 Background: Racial disparities in breast cancer are well established, with Black women having disproportionately higher mortality rates. The NCCN guidelines are valuable in the management of breast cancer, highlighting the importance of evaluating racial representation and its trends over time within the studies cited in these guidelines. Methods: We conducted a retrospective analysis of 735 references cited in NCCN Breast Cancer Guidelines Version 4.2025. All clinical trials were included, while reviews, case reports, and non-clinical references were excluded. The primary outcome of interest was the reporting of racial demographics within each reference. Fisher’s exact test was used to assess statistically significant differences in racial representation across time periods. Results: Of 735 references screened, 384 met the inclusion criteria, and 89 (23%) reported racial demographics. Studies reported a total of 87.9% White, 4.5% Black, 4.1% Asian, 0.5% Hispanic, 0.1% American Indian/Alaska Native, 0.0% Native Hawaiian/Pacific Islander, and 0.1% reporting more than one race. Time block 5 had significantly more reported races than blocks 2, 3, and 4 (p-value < 0.05). A statistically significant decrease in percentage reported as White was seen when comparing time blocks 1 to 5 (p = 0.0495), 2 to 5 (p = 0.0336), and 2 to 6 (p = 0.028). Changes in representation among other racial groups were primarily driven by Black and Asian groups, with Asians comprising the largest proportion in time blocks 4 (6.1%) and 6 (17.9%), while the Black race was the largest group in all other time blocks. All other racial groups remained consistently low across time blocks. Conclusions: Only 23% of references reported racial data. While the proportion of the White race decreased over time and an increased representation of other racial groups was observed, the overall reporting of these groups remained low across all time periods. This emphasizes the need for standardized reporting of race in clinical trials to ensure that NCCN guidelines accurately reflect the diversity of patients in breast cancer care. Race demographics from clinical trials cited in the NCCN breast cancer guidelines. Time block Time Bracket Percentage of White Percentage of Non-White Percentage of Black Percentage of Asian Percentage of Hispanic Percentage of AI/AN Percentage of NI/PI Percentage of More than one race 1 1980-1999 95.6% 1.6% 2.8% 0.0% 0.0% 0.0% 0.0% 0.0% 2 2000-2004 92.4% 1.4% 4.6% 0.1% 1.3% 0.0% 0.0% 0.2% 3 2005-2009 86.9% 5.4% 5.2% 1.6% 0.9% 0.0% 0.0% 0.0% 4 2010-2014 88.7% 1.8% 2.8% 6.1% 0.1% 0.0% 0.0% 0.5% 5 2015-2019 87.1% 1.8% 5.7% 4.7% 0.3% 0.3% 0.1% 0.1% 6 2020-2025 78.3% 0.2% 3.1% 17.9% 0.3% 0.1% 0.0% 0.1% Total 87.9% 2.7% 4.5% 4.1% 0.5% 0.1% 0.0% 0.1% AI/AN = American Indian/Alaska Native; NH/PI = Native Hawaiian/Pacific Islander.

A phase III multicenter randomized non-inferiority trial comparing selective versus modified neck dissection in node-positive oral squamous cell carcinoma (SND vs MND).

TPS6133 Background: Neck dissection is a critical component in the management of oral squamous cell carcinoma (OSCC) with nodal involvement. While modified neck dissection (MND) is widely practised in node-positive disease, selective neck dissection (SND) may offer comparable oncologic outcomes with reduced morbidity. Retrospective studies and meta-analyses suggest similar survival and regional control with SND in selected patients; however, high-quality prospective randomized evidence is lacking. This trial aims to evaluate whether SND is non-inferior to MND in terms of disease-free survival in treatment-naïve, node-positive OSCC patients. Methods: This is a prospective, multicenter, randomized, non-inferiority controlled trial enrolling patients aged 18–70 years with clinically and radiologically confirmed node-positive OSCC (T1–T4, N+), ECOG performance status 0–1, and adequate organ function. Eligible participants are randomized 1:1 to undergo primary tumor resection with either selective neck dissection (Arm A) or modified neck dissection (Arm B). Adjuvant radiotherapy or chemoradiotherapy is administered according to adverse pathological features, including extracapsular extension and positive margins. Randomization is stratified by participating centres. The planned accrual period is 3 years, followed by 2 years of follow-up. The study is conducted at four tertiary cancer centres in India. The primary endpoint is disease-free survival. Secondary endpoints include overall survival, regional recurrence rate, treatment-related morbidity, and quality of life assessed using EORTC QLQ-C30 and QLQ-H&N35 questionnaires. Statistical Considerations: Assuming a 24-month DFS of 85% in the MND arm and a non-inferiority margin of 10%, a total of 432 patients (216 per arm) provides 80% power with a one-sided alpha of 0.05. Non-inferiority will be concluded if the upper bound of the 90% confidence interval for the hazard ratio is less than 1.5. Survival analyses will be performed using Kaplan–Meier methods and Cox proportional hazards models. The study has received institutional ethics approvals at participating centres and is registered with the Clinical Trials Registry of India. Patient recruitment is ongoing. This trial will provide prospective evidence regarding the oncologic equivalence of selective and modified neck dissection in node-positive OSCC and may help define a less morbid standard surgical approach. This trial will provide prospective evidence regarding the oncologic equivalence of selective and modified neck dissection in node-positive OSCC and may help define a less morbid standard surgical approach. Clinical trial information: CTRI/2024/11/076784.

A clinically applicable toolkit for cervical gastric-type adenocarcinoma: Diagnostic model, predictive survival nomograms, and risk stratification.

e17509 Background: Cervical gastric-type adenocarcinoma (GAS), an aggressive non-HPV-associated malignancy, is often misdiagnosed and correlated with unsatisfactory treatment efficacy and poor prognosis. The lack of diagnostic and prognostic tools poses challenges to clinical management. We aimed to develop a comprehensive toolkit for accurate preoperative diagnosis, individualized prediction of recurrence and survival as well as postoperative risk stratification for GAS patients. Methods: In this retrospective, multicenter study, 160 GAS and 194 non-GAS patients from four tertiary centers in Shanghai, China were included. Clinicopathological data, including symptoms, HPV status, imaging findings, tumor markers, postoperative pathological features, adjuvant treatment and survival outcomes, were collected. A multivariate logistic regression model was developed for preoperative diagnosis of GAS. Prognostic nomograms for recurrence-free survival (RFS) and overall survival (OS) were established using least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox analysis. Besides, recursive partitioning analysis (RPA) was applied for simplified risk stratification for RFS of GAS. Model performance was evaluated using area under the curve (AUC) and concordance index (C-index). Results: The preoperative diagnostic model, incorporating symptoms, HPV status, imaging features, and CA199 levels, achieved an AUC of 0.93 in the training cohort and 0.84 in the validation cohort. Prognostic nomograms for RFS and OS were developed manifesting robust predictive accuracy, with 2-year, 5-year C-indexes ranging from 0.829 to 0.844 in the training set and 0.624 to 0.728 upon external validation. Notably, the RFS model incorporated ovarian involvement, maximum tumor diameter, vaginal involvement, positive vaginal resection margin, parametrial metastasis, and pelvic lymph node metastasis, whereas the OS model included ovarian involvement, positive vaginal resection margin, parametrial metastasis, and pelvic lymph node metastasis. Moreover, the RPA-based risk stratification model classified GAS patients into three distinct groups based on parametrial involvement and pelvic lymph node metastasis, with significant differences in 5-year RFS (Low-risk: 78.86%, 95% CI: 64.84%-95.90%; Intermediate-risk: 38.90%, 95% CI: 21.30%-71.00%; High-risk: 24.79%, 95% CI: 13.79%-44.57%; p<0.001), potentially guiding adjuvant therapeutic strategies. Conclusions: This study presents a clinically applicable toolkit for GAS, comprising an accurate diagnostic model for preoperative identification, survival nomograms for individualized prognosis prediction, and a simplified risk stratification system for postoperative risk assessment, offering a novel framework to optimize the clinical management of GAS.

Trends in mortality and disparities in small intestine neoplasms among U.S. adults aged 65 years and older: A retrospective analysis of 25 years.

e15684 Background: Small intestine neoplasms are relatively rare malignancies but contribute to a growing cancer-related mortality burden in the United States, with notable variation across demographic and geographic populations. This study aimed to evaluate temporal trends in age-adjusted mortality rates in adults over 65 years of age due to small intestine neoplasms from 1999 to 2023 and to assess disparities by sex, race/ethnicity, urbanization, geographic region, state, and place of death. Methods: Mortality data was obtained from the Centers for Disease Control and Prevention (CDC) mortality data base. International Classification of Disease (ICD-10) code C17 was used to obtain data. Adults aged ≥65 years were included in this study. Joinpoint regression was used to calculate and (Average Annual Percent Change) values for the entire study period. A p value < 0.05 was considered statistically significant. Results: Between 1999 and 2023, small intestine neoplasms led to 27,203 deaths, with the most deaths being recorded at the decedent's home (44.31%). The AAMR rose from 2.35 in 1999 to 3.17 in 2023 with an associated AAPC of 1.2899 (95% CI: 0.91 to 1.66; p < 0.000001). In 1999, men had an AAMR of 3.08, almost twice as high as women, who had an AAMR of 1.85. These differences became less pronounced over time, and in 2023 men had an AAMR of 3.94 (AAPC: 1.11; 95% CI: 0.60 to 1.62; p = 0.000019), while women had an AAMR of 2.55 (AAPC: 1.22; 95% CI: 0.62 to 1.83; p = 0.000056). Urban areas experienced slightly higher AAMR increases (AAPC: 1.0869*, 95% CI: 0.58 to 1.59 p = 0.00002) than rural areas (AAPC: 0.9411*, 95% CI: 0.32 to 1.56 p = 0.0045). AAMR in urban areas increased from 2.35 in 1999 to 2.93 in 2020, while in rural areas, it increased from 2.27 to 2.68. Non-Hispanic Black individuals experienced the highest AAMR in 2023 at 4.23 (AAPC: 1.6041; 95% CI: 0.96 to 2.24; p = 0.000026), followed by Non-Hispanic White individuals who had an AAMR of 3.11 in 2023 (AAPC: 1.2429; 95% CI: 0.84 to 1.64; p = < 0.000001) and Hispanic or Latino individuals with an AAMR of 2.4 in 2023 (AAPC = 1.2885; 95% CI: -0.50 to 3.11; p = 0.159467) respectively. States with the highest AAMRs included South Dakota (3.49), Iowa (3.47) and Washington (3.31); states with the lowest AAMRs included Wyoming (1.82), Arizona (1.78) and New Mexico (1.74). Geographically, the Midwest had the highest AAMR in 2023 (3.5), followed by the West (3.12), the South (3.1) and the Northeast (2.83). The decedent's home recorded the highest number of deaths (44.31%). Conclusions: Small intestine neoplasm-related mortality has increased significantly from 1999 to 2023, with a disproportionate burden in men, residents of metropolitan areas and Blacks Individuals. Targeted interventions like risk-group-focused prevention, age appropriate care and early screening can help reduce morbidity and mortality and improve clinical outcomes.

JSKN016, a first-in-class anti-TROP2/HER3 bispecific antibody-drug conjugate (ADC), in patients (pts) with HER2-negative locally advanced or metastatic breast cancer: Results from a phase I study.

1123 Background: TROP2 and HER3 are frequently overexpressed in most of solid tumors. JSKN016 is a first-in-class bispecific ADC targeting TROP2/HER3, site specifically conjugated to topoisomerase I inhibitor via a cleavable linker (DAR4). Glycan conjugation provides high stability and minimizes off-target toxicity. Methods: JSKN016-101 (NCT06592417) is a first-in-human, dose-escalation and expansion study in China, enrolling patients with advanced solid tumors to receive JSKN016 monotherapy. This analysis focused on the HER2-negative BC cohort. Results: As of December 22, 2025, JSKN016 was escalated to 8 mg/kg IV Q3W without reaching the maximum tolerated dose. A total of 82 HER2- BC pts were enrolled: 50 TNBC and 32 HR+/HER2- BC, treated at 4 mg/kg (n=14), 6 mg/kg (recommended phase II dose [RP2D]; n=65), and 8 mg/kg (n=3). Overall, 98.8% (81/82) had stage IV disease including 13.4% (11/82) with brain metastases. Median age was 50 (TNBC) and 52y (HR+/HER2- BC); ECOG PS 1 was reported in 78.7% and 76.7%, respectively. All TNBC pts had prior taxane-based chemotherapy, 28.0% had received ≥3 prior systemic regimens. All HR+/HER2- BC pts had progressed after ≥1 endocrine therapy with CDK4/6 inhibition and ≥1 chemotherapy. Among 47 efficacy-evaluable TNBC pts, objective response rate (ORR) was 61.7% (by INV and IRC). At RP2D (n=31), ORR was 64.5% (INV) and 61.3% (IRC), with disease control rates (DCR) of 83.9% and 90.3%. The median PFS was 7.9 months (95%CI: 5.5, NE) by IRC and 7.6 months (95%CI: 4.1, NE) by INV. Among 30 efficacy-evaluable HR+/HER2- BC pts, ORR was 50.0% (INV) and 53.3% (IRC); at RP2D (n=29), ORR was 51.7% (INV) and 55.2% (IRC), with DCR of both 100%. The median PFS was 11.1 months (8.3, NE) by IRC and was not yet mature by INV. With a median follow-up of 8 months, grade 3 or above TRAEs occurred in 25.6% (21/82) pts, with no G4 or 5 events reported. The most common G3 TRAEs were neutrophil count decreased (6.1%), amylase increased (4.9%), white blood cell count decreased (4.9%), stomatitis (3.7%), asthenia (2.4%), lymphopenia (2.4%). The incidence of TRAEs was 9.8%. Only one TRAE (G3 conjunctivitis) led to treatment discontinuation. No interstitial lung disease (ILD) was reported. Conclusions: JSKN016 demonstrated robust antitumor activity with good safety profile in pts with HER2-negative BC. The results support further development of JSKN016 as monotherapy or in combination. Clinical trial information: NCT06592417 . Efficacy of JSKN016 in HER2-BC at 6 mg/kg Q3W. TNBC (N=31) HR+/HER2- BC (N=29) Assessed by INV IRC INV IRC uORR, % (95% CI) 64.5 (45.4, 80.8) 61.3 (42.2, 78.2) 51.7 (32.5, 70.6) 55.2 (35.7, 73.6) DCR, % (95% CI) 83.9 (66.3, 94.5) 90.3 (74.2, 98.0) 100 (88.1, 100) 100 (88.1, 100) mPFS, mos (95% CI) 7.6 (4.1, NE) 7.9 (5.5, NE) NR 11.1 (8.3, NE) 6-months PFS rate, % 57.7 (38.5, 72.9) 68.4 (47.9, 82.2) 74.0 (53.0, 86.7) 84.5 (63.8, 93.9)

AI-assisted systematic review and pooled analysis of anthracycline- versus taxane-based chemotherapy in advanced or metastatic angiosarcoma.

11522 Background: Comparative evidence for first-line anthracycline- (Ant) vs taxane-based (Tax) chemotherapy in advanced angiosarcoma (AS) is limited by small, heterogeneous retrospective studies. We performed an AI-assisted systematic review and pooled analysis to overcome fragmented reporting and evaluate efficacy and safety across clinically relevant subgroups, including cutaneous and radiation-induced AS (RIAS). Methods: A PubMed search (2000–2025) identified 11 eligible studies, 6 providing quantitative class-specific outcomes. An AI-assisted workflow (GPT-5) harmonized heterogeneous datasets, resolved denominator inconsistencies, and enabled supervised reconstruction of missing subgroup numerators. Endpoints included objective response rate (ORR), disease control rate (DCR), survival outcomes, and toxicity. ORR and DCR were compared using two-proportion z-tests. PFS, OS, and safety outcomes were summarized descriptively based on reported medians, due to incomplete and heterogeneous reporting that precluded pooling. Results: Among 426 evaluable patients (Ant n = 245; Tax n = 181), Tax demonstrated higher pooled ORR (44.8% vs 29.0%, p = 0.001) and DCR (63.7% vs 52.6%, p = 0.018). Benefits were marked in cutaneous AS (ORR 50.8% vs 31.5%, p = 0.017) and RIAS (41.8% vs 30.2%, p = 0.036), while non-cutaneous AS showed comparable ORR (25.3% vs 27.8%, p = 0.68). Reported median PFS (6.2 vs 5.0 months) and OS (14.3 vs 12.2 months) numerically favored Tax. Safety analysis, enabled by AI integration of fragmented datasets, showed that Tax was mainly associated with low-grade neuropathy and mild myelosuppression. Ant toxicity reporting was sparse but included fatal neutropenic events, indicating greater hematologic risk. Conclusions: Tax shows superior antitumor activity in cutaneous AS and RIAS with favorable tolerability. Anthracyclines remain an option for selected patients, although higher hematologic toxicity is expected. These findings, derived through AI-assisted reconstruction of incomplete datasets, highlight both the therapeutic relevance of Tax in AS and the potential of AI to enhance evidence synthesis in rare cancers.

Cs ₃ Bi ₂ Br ₉ Quantum Dots‐Driven Photogenerated Bromine Radical Relay Enables Efficient Cleavage of C <i> _α </i> /C <i> _β </i> ─O Bonds for Lignin Depolymerization

ABSTRACT With the remarkable activation efficiency, hydrogen atom transfer (HAT) strategy has emerged as a promising approach for promoting lignin depolymerization; yet, it faces substantial challenges in using stoichiometric HAT reagents or acidic/basic additives. Herein, a catalytic system comprising Cs 3 Bi 2 Br 9 quantum dots (CBB QDs) and catalytic amounts of bromine sources that achieves 99% conversion in depolymerizing α ‐O‐4 and β ‐O‐4 model compounds to benzaldehyde (∼87%) and phenol (∼92%) through a bromine radical (•Br) relay mechanism. Also, this system accomplishes the first effective photocatalytic depolymerization of an advanced ( α ‐O‐4)‐( β ‐O‐4) dilinkage model compound, helping to clarify the substantial reactivity discrepancies between monomeric models and native lignin. Catalytic reactions of birch lignin demonstrate cleavage of C α /C β ─O bonds with &gt; 99% selectivity, yielding high‐value aromatic aldehydes and phenolic products. Notably, this system overcomes the inherent cycling instability of QDs photocatalysts, maintaining 95% of the initial conversion after seven recycles. Mechanistic studies establish that the exceptional performance originates from the unique halogen exchange capability of CBB QDs, coupled with the optimal band alignment, which enables continuous •Br generation and sustains persistent HAT cycles.

Recent overviews on the moxifloxacin based novel delivery system for the treatment of bacterial keratitis

Capture of <i>B</i> 31‐Type MnSe _0.5 Te _0.5 Phase With Structure‐Borne Superconductivity Initiated by Pressure‐Induced Jahn–Teller Distortions

ABSTRACT Superconductivity in manganese‐based compounds is strongly dependent on their high‐pressure phases. Consequently, capturing high‐pressure superconducting phases, particularly those that cannot be crystallized in their bulk form at ambient condition yet retain superconductivity, is of significant interest. Here, we report the capture of a superconducting high‐pressure B 31‐type MnSe 0.5 Te 0.5 phase (space group Pnma ) at ambient pressure, achieved via chemical substitution‐induced irreversible phase transitions ( Fm m ⇀ P 6 3 / mmc ⇀ Pnma ) and reversible spin‐crossover under a hydrostatic compression‐decompression cycle up to ≈40 GPa. Upon decompression, the B 31 phase exhibits structure‐borne superconductivity that persists down to ≈4 GPa, with a maximum T c of ≈7.5 K at ≈8 GPa. DFT calculations reveal that the accumulated pressure‐induced charge transfer (ligand‐to‐Mn 2+ ) causes an abrupt Jahn–Teller distortion (JTD) in MnX 6 octahedra by lifting the t 2g orbital degeneracy in low‐spin Mn 2+ ( d 5 ). The JTD triggers Peierls‐like metallic Mn–Mn dimerization, facilitating electron‐pairing by driving local electron redistribution, thereby initiating superconductivity in the orthorhombic phase. These findings demonstrate an approach to retain a superconducting phase through chemical substitution‐induced irreversible phase transition under high‐pressure.