Although reduced mortality associated with moderate-to-vigorous physical activity has been reported among cancer survivors, the benefits of a concentrated physical activity pattern remain unclear. This prospective cohort study included 6075 cancer survivors from the UK Biobank accelerometry dataset: 2390 (39.3%) were inactive (<150 minutes/week), 1295 (21.3%) were active concentrated (≥150 minutes/week and achieved ≥50% total moderate-to-vigorous physical activity within 1-2 days), and 2390 (39.3%) were active regular (≥150 minutes/week but other than concentrated). After a median follow-up of 8 years (interquartile range [IQR] = 7.5 to 8.5 years), 634 deaths occurred. Active concentrated and regular patterns were associated with similar reduced all-cause mortality (hazard ratio [HR] = 0.72, 95% CI = 0.60 to 0.86; HR = 0.71, 95% CI = 0.56 to 0.89) and noncancer mortality (HR = 0.66, 95% CI = 0.47 to 0.92; HR = 0.56, 95% CI = 0.35 to 0.89). These findings highlight the concentrated physical activity pattern as a lifestyle intervention for cancer survivors.

e13020 Background: The optimal sequencing strategy for antibody-drug conjugates (ADCs) following progression on prior ADC therapy in advanced breast cancer remains uncertain. However, most pivotal trials excluded patients previously exposed to another ADC, leaving real-world evidence as the primary source to inform sequencing strategies, particularly across different HER2 expression levels. Methods: This single-center retrospective study included 82 patients with advanced breast cancer who received at least two different anti-HER2 ADCs sequentially between January 2019 and December 2023. Patients were stratified by HER2 status (HER2-positive, n = 51; HER2-low, n = 31). The second ADC (ADC2) treatments included trastuzumab deruxtecan (T-DXd, n = 43), trastuzumab emtansine (T-DM1, n = 9), disitamab vedotin (RC48, n = 26), and other agents including sacituzumab govitecan (n = 4). The primary endpoint was progression-free survival (PFS), analyzed as PFS on the first ADC (PFS1), PFS on the second ADC (PFS2), and total PFS from the initiation of the first ADC. Results: In the overall cohort, the median total PFS was 15.12 months for patients receiving T-DXd as ADC2, compared with 11.11 months for T-DM1 (P = 0.697) and 11.01 months for RC48 (P = 0.887), although these differences were not statistically significant. Analysis of sequential patterns revealed that the T-DM1 → T-DXd sequence (T-D pattern) was associated with the longest median total PFS (24.07 months). In the HER2-positive subgroup, T-DXd as ADC2 resulted in a median PFS2 of 15.98 months. Conversely, patients with HER2-low disease derived limited benefit from sequential ADC therapy, with a median PFS2 of 3–4 months and an objective response rate (ORR2) below 10%. Conclusions: In real-world clinical practice, sequential ADC therapy demonstrated clinically meaningful activity, particularly in HER2-positive advanced breast cancer. The T-DM1 → T-DXd sequence appears to be a promising approach. However, efficacy is significantly limited in the heavily pretreated HER2-low population, underscoring a "diminishing returns" phenomenon and the need for novel therapeutic strategies and a deeper understanding of cross-resistance mechanisms.

Neoadjuvant immunotherapy in combination with chemotherapy has been approved for resectable lung squamous cell carcinoma (LUSC) patients. However, the dynamic protein changes in the local tumor microenvironment (TME) associated with treatment remains unclear. We sought to spatially profile the treatment-related protein landscape changes in LUSC. A total of 11 LUSC patients who received 2 to 4 cycles of neoadjuvant PD-1 inhibitors in combination with chemotherapy (nab-paclitaxel and carboplatin) were recruited. Formalin-fixed paraffin-embedded (FFPE) pre-treatment lung biopsy and paired post-operative surgery samples were collected. To investigate the immune landscape change related to neoadjuvant immunotherapy, we utilized the GeoMx Digital Spatial Profiler (DSP) to spatially profile the expression of >570 proteins in tumor- (pan-CK+), immune- (CD45+), and cancer-associated fibroblast (CAF, a-SMA+) regions in pre- and post-treatment specimens. Differential expression analyses, and GSEA were performed. We found that active YAP1, BAX, and IRF3 in the tumor region, and CD11a, CXCR3, and CD34 in the immune region were upregulated after treatment, while Syndecan-1, Tuberin, and PAK1 in the immune region and MEK1, CD3G, and VEGFD in the CAF region were downregulated after treatment (all FDR < 0.05). GSEA highlighted that the neoadjuvant immunochemotherapy downregulated differentiation, HIF1, Insulin, and mTOR pathway (NES: -1.70, -1.76, -1.77, and -1.64, respectively) in immune and CAF regions (all adjusted P < 0.05). Findings suggested that neoadjuvant immunochemotherapy may improve oxygenation via the HIF1 pathway, induce metabolic stress and nutrient depletion via the mTOR and insulin pathways, promote dedifferentiation or epithelial-to-mesenchymal transition, as well as reduce immune evasion by modifying the tumor microenvironment. This study provides clues and preliminary evidence to further understand the treatment mechanism of neoadjuvant immunochemotherapy for LUSC. In this spatial biology study, we found dynamic changes in proteins between pre- and post-neoadjuvant immunochemotherapy among LUSC patients. The dynamic changes revealed some potential impacts of NAT on LUSC, including improving oxygenation, reducing mTOR and insulin activity, and mitigating immune evasion. Understanding these mechanisms can guide the development of combination therapies to improve patient outcome. Zheshen Han, Haoting Shi, Xue Wang, Yufei Wang, Ruixin Pan, Chao Hu, Qing Qu, Rong Cai. Dynamic change in immune landscape among NSCLC patients who received neo-adjuvant PD-1 treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 749.

AIMS:Cancer patients face a higher risk of adverse effects from coronavirus disease 2019 (COVID-19) compared to the general population. However, the safety of restarting antitumor therapy following COVID-19 recovery remains unclear. METHODS:In this prospective, multicenter study conducted between January 1 and 30 March 2023, 419 eligible cancer patients who had recovered from COVID-19 were screened across four medical centers. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) during the first cycle of antitumor therapy resumed within 3 months after COVID-19 recovery. Changes in clinical laboratory parameters were assessed as secondary endpoints. RESULTS:A total of 270 eligible participants were included in this study. The common grade 3 or worse TEAEs were fatigue (3.3%), anemia (1.1%), leukopenia (0.7%), and elevated alanine transaminase (0.3%). No severe cardiac toxicity and significant abnormalities on the chest computed tomography (CT) were observed. D-dimer and cardiac troponin I (cTNI) were significantly increased after treatment (p < 0.05). Increased inflammatory cytokines of peripheral blood could be observed after administration of oxaliplatin and trastuzumab. CONCLUSIONS:Restarting systemic antitumor therapy in solid tumor patients after COVID-19 recovery is generally safe. Systemic inflammatory and coagulation function of patients should be monitored during treatment.

Cyclin-dependent kinases 4/6 (CDK4/6) inhibitor is a standard-of-care for hormone receptor-positive/human epidermal growth factor receptor 2 negative metastases breast cancer (HR+/HER2- mBC), while substantial proportion of patients suffer from intrinsic resistance (IR), and the mechanism at the spatial level remains unclear. A total of 10 eligible HR+/HER2- mBC patients (age: median age 63, range 40-67 years) with liver metastases who underwent liver biopsies and received CDK4/6 inhibitor were included. The majority (N = 7, 70%) were of first-line treatment at metastatic disease settings and in combination with fulvestrant (N = 9, 90%). After a median follow-up of 22.2 months, four patients were determined as IR, with a median PFS of 4.2 months. We collected formalin-fixed paraffin-embedded samples from these patients and spatially profiled the expression of more than 570 proteins across tumor (panCK+), immune (CD45+), and cancer-associated fibroblast region (CAF, α-SMA+) regions, respectively using the GeoMx Digital Spatial Profiler (DSP) platform. The differentially expressed proteins (DEPs) were identified and GSEA analyses were performed. Elevated expression of MHC I proteins (HLA B7 and HLA E), extracellular matrix (ECM)-associated protein (FAK, Fibronectin, and Periostin), antioxidant-associated proteins (NQO1 and G6PD), and mucin-related proteins (Muc5AC and Muc1) were observed in tumor regions (all FDR < 0.05) among IR patients. Similarly, HLA B7, Fibronectin, MucAC5 and NQO1 were found to be overexpressed in CAF region. The proteins associated with the target of CDK4/6 inhibitor were down-regulated among IR patients [NF-kB p105, CK8 (phosphor S431), and Cyclin D1], suggesting that the IR could be partially explained by loss-of- drug-target. Meanwhile, downregulation of Caveolin-1 and CD63 were identified in CAF regions, while downregulation of HLA-DR and MHC II proteins were observed in immune regions. GSEA results showed that MHC I antigen presentation pathway was significantly upregulated in CAF regions (NES 1.87, FDR 0.016), while TGF-beta pathway and autophagy pathway were significantly downregulated in CAF regions (NES -1.77 [FDR 0.016] and -1.84 [FDR 0.040], respectively). These findings suggested that IR might be driven by the immune escape associated with CAFs. Our results showed that Bcl-2 expression in tumor region has the highest value in predicting IR (AUROC 0.989). Leveraging high-plex spatial proteomics data from HR+/HER2- mBC patients, the IR of CDK4/6 inhibitor might be associated with loss-of-target in tumor cells, immune escape driven by CAFs, and alterations in the ECM. Haoting Shi, Zheshen Han, Xue Wang, Yufei Wang, Chao Hu, Ruixin Pan, Xiaosong Chen, Qing Qu, Rong Cai, Kunwei Shen. Profiling the immune landscape of CDK4/6 inhibitor intrinsic resistance among metastatic HR+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 778.

PDF file - 132K, LCN2 does not affect PTEN activity.

PDF file - 131K, LCN2 does not affect ERK and NF-kB pathways.

PDF file - 344K, Endogenous HIC1 knockdown promotes cell migration and invasion in MCF-10A cells.

PDF file - 141K, HIC1 and LCN2 do not affect epithelial-mesenchymal transition (EMT).

PDF file - 116K, Correlation between expression of HIC1 and clinical pathological features in tissue microarrays.

PDF file - 570K, LCN2 promotes lung metastasis in balb/c nude mice.

PDF file - 77K, LCN2 does not affect MMP9 expression.

PDF file - 623K, Effects of restoring HIC1 expression in MDA-468 cells.

PDF file - 118K, Serum levels of LCN2 in breast cancer patients.

PDF file - 142K, The AKT signaling pathway is partly inactivated after NGALR knockdown.

p53 is mutated in half of cancer cases. However, no p53-targeting drugs have been approved. Here, we reposition decitabine for triple-negative breast cancer (TNBC), a subtype with frequent p53 mutations and extremely poor prognosis. In a retrospective study on tissue microarrays with 132 TNBC cases, DNMT1 overexpression was associated with p53 mutations ( P = 0.037) and poor overall survival (OS) ( P = 0.010). In a prospective DEciTabinE and Carboplatin in TNBC (DETECT) trial (NCT03295552), decitabine with carboplatin produced an objective response rate (ORR) of 42% in 12 patients with stage IV TNBC. Among the 9 trialed patients with available TP53 sequencing results, the 6 patients with p53 mutations had higher ORR (3/6 vs. 0/3) and better OS (16.0 vs. 4.0 months) than the patients with wild-type p53. In a mechanistic study, isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53. In the DETECT trial, decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line (upregulation by 16-fold) and the most responsive patient with TNBC. Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

Purpose: To identify a predictive biomarker of immune checkpoint inhibitor (ICI) therapies for renal cell carcinoma (RCC). Methods: Survival analysis of mutations in a panel of 468 cancer-related genes in a cohort of 151 RCC patients who underwent the ICI treatment using Cox regression model univariate or multivariate analysis in publicly available datasets. Results: We found that VHL mutations were the only promising independent predictor for overall survival (OS) (HR=0.44, 95% CI=0.25-0.77 and P=0.004). More specifically, compared with 26 months of survival in the wildtype patients, metastatic RCC patients carrying truncated VHL mutations had a significantly longer survival time of nearly 70 months (HR=0.45, 95% CI=0.25-0.82 and P=0.008) in the presence of the ICI therapy. This survival benefit was also observed in another cohort of 35 patients with clear cell RCC from Dana-Farber Cancer Institute (DFCI): compared with 29 months in the wildtype patients, patients with VHL truncated mutations also had a longer median OS of 33 months (HR=0.59, 95% CI=0.24-1.44 and P=0.243). These observed survival benefits were independent of VHL expression and tumor infiltration immune cells in The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA KIRC). Conclusion: VHL mutational inactivation may have an effect on the RCC response to ICI therapy, likely by the upregulation of PD-L1 via attenuating degradation of HIF-1α. To our knowledge, this is the first report of VHL mutations as an independent predictive biomarker for the ICI therapy in RCC, which, once validated by larger clinical trials, may help improve clinical decision-making in individualized treatment of RCC patients.

Background: Human epidermal growth factor receptor 2 (HER2 )-positive breast cancer tends to metastasize and is associated with poor prognosis. Anti-HER2 treatment combined with chemotherapy or endocrine therapy is often used for HER2-positive metastatic breast cancer (MBC). For later lines of therapy in HER2-positive MBC, there is no standard treatment. We investigated the efficacy of pyrotinib, a new irreversible tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor, HER2 , and HER4 , in lapatinib-resistant HER2-positive MBC patients. Methods: This is a retrospective observational study including lapatinib-resistant HER2-positive MBC patients who received pyrotinib-based treatment. We used the Kaplan-Meier method for the survival analyses. Results: A total of 31 patients were included. Concurrent treatments included cytotoxic chemotherapy (29 patients, 93.6%), endocrine therapy (1 patient, 3.2%), and another targeted therapy (1 patient, 3.2%). The objective response rate (ORR) was 25.8% and the median progression-free survival in the study population was 4.5 months (95% CI: 3.1-5.9 months). The treatment-related adverse events (AEs) included diarrhea, neutropenia, vomiting, fatigue, and thrombocytopenia. Dose reduction to 320 mg was conducted in 19.4% of all cases due to severe AEs. Conclusions: Pyrotinib-based treatment was effective and generally well tolerated in lapatinib-resistant HER2-positive MBC for later line treatment.

前段时间热播的电视剧《小欢喜》里,“最好的妈妈”刘静被检查出了乳腺癌,却选择向家人隐瞒,不想让丈夫和孩子担心,这一情节让不少观众流下了眼泪.乳腺癌是世界范围内威胁女性健康的“头号杀手”,由于生活节奏加快、饮食习惯改变、精神压力增加等因素影响,过去20年我国乳腺癌的发病率呈不断上升趋势,城市尤为显著.

Background: Interleukin-6 (IL-6) is commonly highly secreted in the breast cancer (BrCA) microenvironment and implicated in disease development. In this study, we aimed to determine the role of the IL-6/pSTAT3/HIC1 axis in the breast cancer microenvironment, including in cancer-associated fibroblasts (CAFs) and breast cancer cells. Methods: Stromal fibroblasts from the breast cancer tissue were isolated, and the supernatants of the fibroblasts were analyzed. Recombinant human IL-6 (rhIL-6) was applied to simulate the effect of CAF-derived IL-6 to study the mechanism of HIC1 (tumor suppressor hypermethylated in cancer 1) downregulation. IL-6 was knocked down in the high IL-6-expressing BrCA cell line MDA-MB-231, which enabled the investigation of the IL-6/pSTAT3/HIC1 axis in the autocrine pathway. Results: Increased IL-6 was found in the supernatant of isolated CAFs, which suppressed HIC1 expression in cancer cells and promoted BrCA cell proliferation. After stimulating the BrCA cell line SK-BR-3 (where IL-6R is highly expressed) with rhIL-6, signal transducers and activators of transcription 3 (STAT3) was found to be phosphorylated and HIC1 decreased, and a STAT3 inhibitor completely rescued HIC1 expression. Moreover, HIC1 was restored upon knocking down IL-6 expression in MDA-MB-231 cells, accompanied by a decrease in STAT3 activity. Conclusions: These findings indicate that IL-6 downregulates the tumor suppressor HIC1 and promotes BrCA development in the tumor microenvironment through paracrine or autocrine signaling.