Pagani O, Niman SM, Ruggeri M
… +38 more, Peccatori FA, Azim HA, Colleoni M, Saura C, Shimizu C, Sætersdal AB, Kroep JR, Warner E, Amant F, Mailliez A, Moore HCF, Ruiz-Borrego M, Walshe JM, Borges VF, Gombos A, Kataoka A, Rousset-Jablonski C, Borstnar S, Takei J, Lee JE, Saunders C, Bjelic-Radisic V, Susnjar S, Cardoso F, Klar NJ, Ferreiro T, Ribi K, Ruddy KJ, Kammler R, El-Abed S, Viale G, Piccart M, Korde LA, Goldhirsch A, Gelber RD, Partridge AH, International Breast Cancer Study Group, POSITIVE Trial Consortium
BACKGROUND: In patients with hormone receptor-positive (HR+) early breast cancer (BC), the POSITIVE trial demonstrated that temporary interruption of adjuvant endocrine therapy (ET) for pregnancy is feasible and safe in...BACKGROUND: In patients with hormone receptor-positive (HR+) early breast cancer (BC), the POSITIVE trial demonstrated that temporary interruption of adjuvant endocrine therapy (ET) for pregnancy is feasible and safe in early follow-up (median 41 months). Here we report updated results from a pre-planned analysis with 2.5 years of additional follow-up. PATIENTS AND METHODS: POSITIVE, a single-arm prospective trial evaluating temporary interruption of adjuvant ET (after 18-30 months and for up to 2 years) to attempt pregnancy in young BC patients, enrolled 518 eligible women (<42 years of age, stage I-III BC, desiring pregnancy) from 12/2014 to 12/2019. Using the bootstrap-matching method, 5-year breast cancer-free interval (BCFI) and distant recurrence-free interval (DRFI) event rates are compared to those of SOFT/TEXT trials as external controls. RESULTS: At a median follow-up of 71 months in the POSITIVE cohort and 80 months in the SOFT/TEXT cohort, the 5-year cumulative incidence of BCFI events was 12.3% in POSITIVE and 13.2% in SOFT/TEXT (-0.9% difference, 95% CI -4.2% to 2.6%). The 5-year cumulative incidence of DRFI events was 6.2% and 8.3%, respectively, (-2.1% difference, 95% CI -4.5% to 0.4%). Among 497 women followed for non-disease outcomes, 377 (76%) had >1 documented pregnancy on trial, 343/497 (69%) had >1 live birth, with 440 offspring. In an unadjusted analysis comparing the 180 women (36%) who had pre-enrollment embryo/oocyte cryopreservation to those who did not, the 5-year cumulative incidence of BCFI events was 14.0% (95% CI: 9.6% to 20.2%) and 11.5% (95% CI: 8.4% to 15.7%), respectively. CONCLUSION: Longer-term follow-up of the POSITIVE trial demonstrates that temporary interruption of ET for pregnancy including use of fertility preservation does not increase risk of BC events. Continued follow-up is warranted given the known risk of late recurrence in this population.
Cantore T, Hoang DT, Pal LR
… +18 more, Stemmer A, Chang TG, Dhruba SR, Shulman E, Campagnolo E, Lee JS, Levy J, Yao K, Liao I, Stemmer SM, Sammut SJ, Lipkowitz S, Rajagopal PS, Filipits M, Caldas C, Yuan Y, Nair DNU, Ruppin DE
BACKGROUND: While expression-based signatures inform adjuvant therapy in breast cancer (BC), no approved molecular biomarkers exist for the neoadjuvant setting, where early response prediction could inform treatment deci...BACKGROUND: While expression-based signatures inform adjuvant therapy in breast cancer (BC), no approved molecular biomarkers exist for the neoadjuvant setting, where early response prediction could inform treatment decisions. This challenge is compounded by intratumoral heterogeneity, as multiple malignant subtypes may coexist within a tumor and influence therapy sensitivity. METHODS: We developed BRIDGE, a computational framework that deconvolves the pre-treatment bulk tumor transcriptome to estimate molecular subtype composition and predict pathological complete response (pCR) to neoadjuvant therapy. BRIDGE was trained on 10 transcriptomics datasets and tested on 24 independent ones spanning different sub-types. Six additional datasets with pre-treatment H&E slides and response data were analyzed to evaluate histology-based predictions. RESULTS: Analyzing measured transcriptomics, BRIDGE outperformed surrogate implementations of established commercial signatures (Oncotype DX, MammaPrint, ROR-S) in ER+/HER2- tumors, and exceeded other transcriptomic predictors in HER2+ and TNBC disease. In ER+/HER2- patients, it yields an ROC-AUC of 0.84 with a high Odds Ratio (OR = 8); in HER2+ disease, an AUC of 0.77 (OR = 8.3); and in TNBC, an AUC of 0.73 (OR = 3.1). We further developed BRIDGE-Slide, which applies BRIDGE to pre-treatment histopathology slides via deep learning-inferred transcriptomics. BRIDGE-Slide outperforms direct slide-to-response models, underscoring its potential as a first-of-its-kind, fast, low-cost biomarker. Exploratory leave-one-dataset-out analyses across datasets treated with alternative neoadjuvant regimens suggest generalizability to ICB-treated ER+/HER2- tumors, pending validation in larger cohorts. Finally, spatial transcriptomics shows that BRIDGE-derived subtype assignments form spatially cohesive regions aligned with canonical molecular features, reinforcing its biological interpretability. CONCLUSIONS: BRIDGE is a biologically grounded framework for neoadjuvant BC response prediction, validated on a rich set of different patients' cohorts. Its histopathology-based version opens the door for fast and low-cost prediction in the neoadjuvant setting, upon further prospective testing and validation.
The T cell antigen coupler (TAC) is a novel genetically engineered receptor that recruits the native T cell receptor upon recognition of an antigen. The downstream activation of TAC T cells has been effective against tum...The T cell antigen coupler (TAC) is a novel genetically engineered receptor that recruits the native T cell receptor upon recognition of an antigen. The downstream activation of TAC T cells has been effective against tumors in preclinical models and safer than chimeric antigen receptor T cells. Human epidermal growth factor receptor 2 (HER2) is a validated biomarker for cancer-targeted therapy, but cell therapy approaches have been met with unmanageable toxicity. We designed a phase 1 clinical trial of TAC01-HER2, an autologous T cell product that targets HER2, in patients with HER2-positive advanced solid tumors. The trial had a dose-escalation phase and a dose-expansion at the recommended phase 2 dose (RP2D). A total of 23 patients with HER2-positive solid tumors were enrolled in this study. The most common treatment-related adverse events were cytokine release syndrome (n=14, 60.9%), anemia (n=5, 21.7%), and increased alanine aminotransferase (n=5, 21.7%). The RP2D was 6-8 × 10 per kg. No treatment-related deaths or adverse events leading to study discontinuation were reported. Two of 9 patients with gastric and gastroesophageal junction (GEJ) cancers had partial responses, and the disease control rate (stable disease or partial response) was 61.1% in the 18 patients with evaluable assessments. The median progression-free survival was 2.6 months (range 0.8-12.4 months), and the overall survival rate at 6 months was 57.9% (95% CI, 36.3%-76.9%). Persistence of TAC T cells in peripheral blood was observed in all patients until at least day 29 after the first infusion. In summary, we demonstrated that treatment with TAC T cells was safe, feasible, and well-tolerated. TAC01-HER2 showed manageable toxicity and early efficacy for patients with HER2-positive gastric, GEJ or esophageal adenocarcinoma who have undergone extensive previous treatments. These results suggest that TAC may offer a promising approach to control T cell activity through cellular therapy.
BACKGROUND: BEGONIA (NCT03742102) is a phase Ib/II, Simon's 2-stage, open-label, platform study evaluating the safety and efficacy of durvalumab, an anti-programmed death ligand-1 (PD-L1) antibody, combined with novel th...BACKGROUND: BEGONIA (NCT03742102) is a phase Ib/II, Simon's 2-stage, open-label, platform study evaluating the safety and efficacy of durvalumab, an anti-programmed death ligand-1 (PD-L1) antibody, combined with novel therapies, as first-line treatment for patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC). Arms 7 and 8 of BEGONIA assessed the combination of datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, with durvalumab. PATIENTS AND METHODS: Arm 7 included patients regardless of tumor PD-L1 expression level. Arm 8 then enrolled patients with PD-L1-high tumors, as determined by local immunohistochemistry-based testing. In Arms 7 and 8, patients received Dato-DXd 6 mg/kg intravenously plus durvalumab 1120 mg intravenously every 3 weeks. Primary endpoints were safety and tolerability, and investigator-assessed confirmed objective response rate (cORR). Secondary endpoints included cORR (Part 1), duration of response (DoR), progression-free survival (PFS) per RECIST 1.1 and overall survival (OS). RESULTS: Overall, 62 and 33 patients had received Dato-DXd and durvalumab in Arms 7 and 8, respectively. At data cutoff (29 November 2024), median study follow-up was 35.0 and 10.7 months in Arms 7 and 8, respectively. In Arm 7, cORR was 79.0% [95% confidence interval (CI) 66.8-88.3], median DoR was 17.6 months (95% CI 10.5-27.3), median PFS was 14.0 months (11.0-21.1) and median OS was not reached. In Arm 8, cORR was 81.8% (95% CI 64.5-93.0). The median DoR and median PFS for Arm 8 were immature given the short median follow-up (8.3 months in censored patients). The safety profile of the combination was manageable, with no new safety signals versus prior studies. CONCLUSIONS: First-line Dato-DXd plus durvalumab demonstrated substantial and durable antitumor activity in locally advanced unresectable or metastatic TNBC, regardless of PD-L1 status.
BACKGROUND: Tebentafusp demonstrated an overall survival benefit compared with investigator's choice in a phase 3 trial in HLA-A∗02:01-positive adult patients with unresectable or metastatic uveal melanoma (mUM) and is n...BACKGROUND: Tebentafusp demonstrated an overall survival benefit compared with investigator's choice in a phase 3 trial in HLA-A∗02:01-positive adult patients with unresectable or metastatic uveal melanoma (mUM) and is now the first-line standard of care for this population. In this study, we report the final 5-year analysis of overall survival. PATIENTS AND METHODS: In this international, open-label, phase 3 trial, previously untreated HLA-A∗02:01-positive patients with mUM were randomized 2:1 to receive tebentafusp or investigator's choice of pembrolizumab, ipilimumab, or dacarbazine (control group), stratified by lactate dehydrogenase. The primary endpoint was overall survival; circulating tumor DNA (ctDNA) reduction was an exploratory endpoint. RESULTS: After a minimum of 5 years of follow-up, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (stratified hazard ratio 0.67, 95% confidence interval 0.54-0.85). Overall survival at 5 years was 16% versus 8%, respectively. Tebentafusp improved survival even in poor-prognosis groups, such as patients with baseline tumors ≥10 cm or those whose best RECISTv1.1 response was progressive disease, including cases where target tumor growth exceeded 20%. After adjusting for covariates, a post hoc analysis showed that patients who were treated with tebentafusp beyond radiographic progression had longer overall survival than those who discontinued treatment. In the tebentafusp group, longer overall survival was associated with undetectable ctDNA at baseline or ctDNA reductions ≥50% by week 9. Deep ctDNA reductions occurred regardless of baseline tumor burden or radiographic response. CONCLUSIONS: In the longest survival follow-up of a randomized trial in mUM, tebentafusp continues to provide long-term survival benefit in previously untreated HLA-A∗02:01-positive patients. GOV IDENTIFIER: NCT03070392.
Dugo M, Huang CS, Egle D
… +25 more, Bermejo B, Seitz RS, Nielsen TJ, Zamagni C, Thill M, Antón-Torres A, Russo S, Sevillano E, Ciruelos EM, Schweitzer BL, Galbardi B, Greil R, Semiglazov V, Colleoni M, Kelly CM, Del Mastro L, Mariani G, Viale G, Győrffy B, Ali HR, Pusztai L, Viale G, Callari M, Gianni L, Bianchini G
BACKGROUND: Triple-negative breast cancer (TNBC) is immunogenic, but only a subset of patients benefits from neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy. Predictive biomarkers to guide pati...BACKGROUND: Triple-negative breast cancer (TNBC) is immunogenic, but only a subset of patients benefits from neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy. Predictive biomarkers to guide patient selection and treatment adaptation are lacking. PATIENTS AND METHODS: In the randomized phase III NeoTRIPaPDL1 trial, 280 patients with high-risk TNBC received neoadjuvant carboplatin plus nab-paclitaxel (CT, n=142) or the same regimen with atezolizumab (CT/A, n=138). Tumor biopsies were collected at baseline and on the first day of the second cycle (D1C2). Longitudinal RNA sequencing was performed to evaluate hallmark, immune, and ferroptosis-related gene signatures. Associations with pathologic complete response (pCR) were assessed using univariable logistic regression and multivariable XGBoost models. RESULTS: At baseline, in the CT/A arm higher proliferation and lower stromal and metabolic programs were associated with increased pCR rate. Absence of tumor cells in early on-treatment biopsies strongly predicted surgical pCR in both treatment arms. Comparison of on-treatment with baseline samples revealed a reduced proliferation and increased immune and stromal signatures. These changes were more pronounced in tumors achieving pCR, particularly in patients receiving chemoimmunotherapy. Immune deconvolution analyses confirmed dynamic remodeling of the tumor microenvironment during treatment, with response-associated enrichment of immune cell populations and reduction of tumor epithelial fractions. While several metabolic signatures were associated with outcome at baseline, most lost predictive value on-treatment, where immune-related programs became the dominant correlates of response. Exploratory multivariable analyses suggested complementary contributions of on-treatment cytotoxic immune activity and iron metabolism in shaping response to chemoimmunotherapy. CONCLUSIONS: Longitudinal transcriptomic profiling revealed dynamic tumor and microenvironment remodeling during neoadjuvant therapy in TNBC. Baseline tumor-intrinsic features and early treatment-induced immune activation provide complementary information for predicting response to chemoimmunotherapy. Early tumor clearance in on-treatment biopsies represents a strong surrogate of pCR and supports investigation of response-adapted neoadjuvant strategies.
Ruan DY, Lin SY, Huang JJ
… +36 more, Li YH, Li N, Qu XJ, Du XB, Yin YM, Yuan ZY, Shi YX, Xu F, An X, Hong RX, Xia W, Xue C, Bi XW, Jiang KK, Zheng QF, Zhang YQ, Peng JJ, Liu ZY, Xiong HH, Suo AL, Lin RB, Zhang S, Tang SN, Yu Y, Li X, Wang X, Tian X, Lv P, Shen C, Lou LG, Wang L, Zhang ZP, Xu TJ, Chen TX, Wang SS, Xu RH
BACKGROUND: TQB2102 is a next-generation biparatopic antibody-drug conjugate targeting human epidermal growth factor receptor 2 (HER2) extracellular domain 2 (ECD2) and ECD4 epitopes that is conjugated to a topoisomerase...BACKGROUND: TQB2102 is a next-generation biparatopic antibody-drug conjugate targeting human epidermal growth factor receptor 2 (HER2) extracellular domain 2 (ECD2) and ECD4 epitopes that is conjugated to a topoisomerase I inhibitor via an enzyme-cleavable linker. This study evaluated the safety, efficacy, and pharmacokinetics of TQB2102 in patients with advanced solid tumors. PATIENTS AND METHODS: In this phase I, multicenter, first-in-human trial, patients with advanced solid tumors were recruited from 12 centers in China. Eligible patients received intravenous TQB2102 once every 3 weeks. This phase I trial included a dose-escalation phase (1.5, 3.0, 4.5, 6.0, 7.5, and 9.0 mg/kg) and a dose-expansion phase (6.0 and 7.5 mg/kg). The primary endpoints were to assess the safety and determine the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of TQB2102. RESULTS: Between 8 March 2023 and 1 February 2025, 195 patients were enrolled, mainly those having metastatic breast cancer (MBC, n = 80), colorectal cancer (CRC, n = 37), and gastric/gastroesophageal junction (G/GEJ) adenocarcinoma (n = 37). No DLTs occurred, and the MTD was not reached. The RP2D was selected as 6.0 mg/kg and 7.5 mg/kg every 3 weeks. The most common grade ≥3 treatment-related adverse events were decreased neutrophil count (23.2%), decreased white blood cell count (10.8%), anemia (8.8%), and decreased lymphocyte count (8.2%). Only one patient (0.5%) had drug-related interstitial lung disease. The objective response rate (ORR) was attained in patients with HER2-positive solid tumors, including MBC at 52.4%, CRC at 38.7%, and G/GEJ adenocarcinoma at 40.0%. Notably, patients with HER2-low MBC achieved an ORR of 47.2%. The ORRs were 70.0% and 50.0% in HER2-positive and HER2-low MBC patients with brain metastases. CONCLUSIONS: TQB2102 demonstrates a manageable safety profile and preliminary antitumor activity in advanced solid tumors. A phase III trial in patients with HER2-low MBC has been initiated.
Albiges L, Bourlon MT, Chacón M
… +22 more, Cutuli HJ, Chuken YAL, Zurawski B, Mota JM, Magri I, Burotto M, Luz M, de Menezes J, Ruiz EPY, Fu S, Richardet M, Valderrama BP, Maruzzo M, Bracarda S, Breckenridge M, Vezina HE, Rathod D, Yu Z, Zhao Y, Dixon M, Perumal D, George S
Garrigós L, Ruiz-Borrego M, Pérez-García JM
… +23 more, Guerrero-Zotano A, Cortés-Salgado A, Kuemmel S, Colleoni M, Reboredo-Rendo C, Bermejo B, Blancas I, Gavila J, Fabi A, Morales C, Stradella A, Carañana V, Martínez-de Dueñas E, Albacar C, Ballesteros-Cidras O, Martrat G, Iacobucci S, Boix O, Berenguer-Molins P, Alcalá-López D, Cortés J, Llombart-Cussac A, PHERGain-2 investigators
BACKGROUND: PHERGain-2 is a multicenter, single-arm, phase II study evaluating a pathologic complete response (pCR)-guided de-escalation strategy to omit chemotherapy in selected patients with HER2-positive early breast...BACKGROUND: PHERGain-2 is a multicenter, single-arm, phase II study evaluating a pathologic complete response (pCR)-guided de-escalation strategy to omit chemotherapy in selected patients with HER2-positive early breast cancer (EBC). PATIENTS AND METHODS: Eligible patients were adults, treatment-naive, centrally confirmed HER2-positive (immunohistochemistry 3+), node-negative EBC, with tumors 5-30 mm by magnetic resonance imaging. Patients received eight cycles of neoadjuvant trastuzumab-pertuzumab (HP) (600 mg H + 1200 mg P loading dose, followed by 600 mg H + 600 mg P maintenance dose) every 3 weeks. Patients with hormone receptor (HR)-positive tumors also received endocrine therapy. After surgery, patients received 10 cycles of adjuvant therapy guided by the pathological response: HP for patients with pCR (ypT0/is ypN0) (cohort A), trastuzumab emtansine (T-DM1; 3.6 mg/kg) for patients with residual invasive breast tumors and/or ypN0(i+/mol+), ypN1mi (cohort B), and optional chemotherapy followed by T-DM1 for patients with ypN1-3 (cohort C). Co-primary endpoints were 1-year health-related quality of life (HRQoL) decline (based on the European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire) and 3-year recurrence-free interval (based on the Standardized Definitions for Efficacy End Points). Key secondary endpoints included overall and HR-specific pCR rates and safety. RESULTS: From August 2021 to March 2024, 396 patients initiated neoadjuvant treatment, 391 (98.7%) underwent surgery. A total of 236 patients (59.6%) achieved pCR (cohort A). Among those with residual disease, 148 (37.8%) entered cohort B and 7 (1.8%) cohort C. One year after initiation of neoadjuvant treatment, ≥10% decline rate in global HRQoL was 42.8% [95% confidence interval (CI) 36.9% to 48.8%]; 37.3% (95% CI 30.1% to 44.9%) in patients with pCR and 51.9% (95% CI 41.9% to 61.7%) in those with residual disease. Treatment-related adverse events occurred in 86.6% of patients (5.6% grade ≥3). Serious adverse events occurred in 6.1% of patients. One death (0.3%) due to pneumonitis was attributed to T-DM1. CONCLUSIONS: PHERGain-2 shows meaningful HRQoL preservation, expected HP/T-DM1 toxicity, and an outstanding pCR rate comparable with standard chemotherapy plus HP regimens in this patient population.
Rao S, Samalin-Scalzi E, Evesque L
… +18 more, Ben Abdelghani M, Morano F, Roy A, Dahan L, Tamberi S, Dhadda AS, Zampino MG, Casanova N, Guimbaud R, Lievre A, Maurel J, Zhang P, Munteanu MC, Jones M, de la Fouchardiere C, Takashima A, Fakih M, Spano J
BACKGROUND: In the primary analysis of the POD1UM-303/InterAACT 2 trial, median progression-free survival (PFS) was significantly longer with retifanlimab plus carboplatin-paclitaxel than with placebo plus carboplatin-pa...BACKGROUND: In the primary analysis of the POD1UM-303/InterAACT 2 trial, median progression-free survival (PFS) was significantly longer with retifanlimab plus carboplatin-paclitaxel than with placebo plus carboplatin-paclitaxel in adult, systemic treatment-naïve patients with advanced/metastatic squamous cell carcinoma of the anal canal (SCAC). Here, the final overall survival (OS) data from PODIUM-303/InterAACT 2, along with subgroup and exploratory analyses, are presented. PATIENTS AND METHODS: POD1UM-303/InterAACT-2 was a phase 3, randomized, double-blind, controlled, multicenter trial with an optional crossover period undertaken in Europe, Australia, Japan, the UK, and the US. The primary endpoint was PFS, and OS was the key secondary endpoint. Other endpoints included response, safety, and exploratory subgroup analyses. RESULTS: A total of 308 patients were randomized (n = 154 for each of the retifanlimab + carboplatin-paclitaxel and placebo + carboplatin-paclitaxel groups), and 77 patients in the placebo plus carboplatin-paclitaxel group crossed over to receive retifanlimab monotherapy. When retifanlimab plus carboplatin-paclitaxel was compared with placebo plus carboplatin-paclitaxel in the updated efficacy analysis, there was a continued PFS benefit (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.47-0.81; nominal P = 0.0002) and a consistent and clinically meaningful improvement in OS (HR 0.75, 95% CI 0.55-1.01; P = 0.0305); median OS was 32.8 versus 22.2 months. Overall response rate was 56.5% versus 44.8%, and disease control rates were 87.7% versus 80.5%. The results of the crossover-adjusted analysis were consistent with the main analysis, and there was a consistent OS benefit in favor of retifanlimab plus carboplatin-paclitaxel in all subgroups analyzed. No new safety signals or trends were reported. CONCLUSION: This final analysis confirms the benefits of retifanlimab plus chemotherapy in SCAC. The results suggest that retifanlimab represents a new reference treatment and standard of care for patients with inoperable, locally recurrent or metastatic SCAC.
Mirallas O, Pretelli G, Balsa M
… +10 more, Jiménez-Labaig P, Hernando-Calvo A, Tan HN, Selvadurai P, Tallón de Lara P, Vieito M, Martin-Liberal J, Harrington KJ, Champiat S, Garralda E
BACKGROUND: Regulatory T cells (Tregs) form a distinct subset of CD4 T cells essential for maintaining immune balance and preventing autoimmunity by expressing CD25 and CTLA-4. Tregs, which are defined by the expression...BACKGROUND: Regulatory T cells (Tregs) form a distinct subset of CD4 T cells essential for maintaining immune balance and preventing autoimmunity by expressing CD25 and CTLA-4. Tregs, which are defined by the expression of the transcription factor FOXP3 in mice, restrain excessive immune activation through mechanisms such as IL-10 expression, TGF-β expression, metabolic regulation, acting as an IL-2 cytokine sink, and cell-to-cell interaction through co-inhibitory receptors. Although they are indispensable for immune tolerance, Tregs can be co-opted by tumors, where their suppressive activity promotes immune escape. High Treg infiltration within the tumor microenvironment has been linked to variable prognosis depending on the tumor type, highlighting Tregs' contradictory roles as both guardians of tolerance and enablers of tumor progression. DESIGN: In this review, we summarize Treg biology, Tregs' contribution to cancer immunity, and emerging therapeutic strategies designed to modulate or deplete Tregs. We conducted a targeted literature review using PubMed/MEDLINE, Web of Science, ClinicalTrials.gov, and ASCO/ESMO meeting libraries, complemented by manual reference screening. We also discuss the limitations of existing therapeutic approaches and outline future directions. RESULTS: Efforts to therapeutically modulate Tregs have focused on three main strategies: depletion (e.g., anti-CD25, anti-CCR4, or anti-CCR8 antibodies), functional blockade (e.g., targeting CTLA-4 or TIGIT), and disruption of metabolic pathways (e.g., adenosine or PI3K signaling) that support Tregs' biological functions. Although preclinical studies have shown that targeting Tregs have antitumor effects, clinical trials have demonstrated variable efficacy and toxic effects, reflecting the fine balance between immune activation and tolerance. Newer approaches aim to selectively impair intratumoral Tregs while preserving peripheral immune control, guided by T-cell subsets such as FOXP3HeliosCCR8 cells, which may help predict therapeutic response. CONCLUSION(S): A deeper understanding of Treg regulation is needed to unlock their therapeutic potential without compromising immune equilibrium.
Mavrikios A, Bortolot M, Le Péchoux C
… +21 more, Remon J, Botticella A, Aldea M, Brown PD, Rusthoven CG, Lavaud P, Frélaut M, Abdayem P, Lavigne D, Camps-Maléa A, Besse B, Planchard D, Barlesi F, Jacob J, Gougis P, Knafo S, Chargari C, Dhermain F, Deutsch E, Faivre-Finn C, Levy A
Brain metastases occur in nearly half of patients with lung cancer and significantly impair survival and quality of life. Historically, limited blood-brain barrier penetration and low intracranial efficacy of systemic th...Brain metastases occur in nearly half of patients with lung cancer and significantly impair survival and quality of life. Historically, limited blood-brain barrier penetration and low intracranial efficacy of systemic therapies restricted treatment options. However, advances in immune checkpoint inhibitors and next-generation central nervous system-penetrant targeted therapies have reshaped the therapeutic landscape, improving intracranial control and patient outcomes. In parallel, stereotactic radiotherapy has emerged as a precise and effective local treatment with a more favorable safety profile than whole-brain radiotherapy. The integration of systemic and local approaches, guided by personalized medicine, offers new opportunities to optimize central nervous system disease control. Nevertheless, these advances raise key challenges regarding treatment sequencing, patient selection, and risk-adapted strategies. This review summarizes the evolving management of lung cancer brain metastases and highlights future directions for clinical trial design, emphasizing the integration of clinical, biological, and radiological tools to guide individualized treatment strategies.
Wang Y, Drubay D, Jonas SF
… +65 more, Dixon-Douglas J, Acs B, Adams S, André F, Badve S, Bataillon G, Carter JM, Chia S, Cockenpot V, Colleoni MA, Criscitiello C, Curigliano G, Dackus GMHE, Demaria S, Denkert C, van Deurzen CHM, Dieci MV, Giardiello D, Goetz MP, Gray RJ, Hauptmann M, Ter Hoeve ND, Jóźwiak K, Koop EA, de Jong VMT, Joensuu H, Jules-Clément G, Kammler R, Kellokumpu-Lehtinen PL, Kim SB, Kok M, Lacroix-Triki M, Lambertini M, Lee HJ, Lemonnier J, Leon-Ferre RA, Leung S, Linderholm B, Loibl S, Martens JWM, Nielsen TO, Opdam M, Pharoah P, Penault-Llorca F, Piccart M, Pustzai L, Riaz N, Vincent-Salomon A, Sparano J, Shimoi T, Sotiriou C, Suman VJ, Timmermans AM, van Diest PJ, Voogd AC, Viale G, Wolff AC, Yazaki S, Yoshida M, Salgado R, Linn SC, Schmidt MK, Loi S, Michiels S, A report on behalf of the International Immuno-Oncology Biomarker Working Group
BACKGROUND: Stromal tumor-infiltrating lymphocytes (sTILs) are a strong prognostic marker in patients with triple-negative breast cancer (TNBC). We aimed to incorporate sTILs into the PREDICT model for women with early-s...BACKGROUND: Stromal tumor-infiltrating lymphocytes (sTILs) are a strong prognostic marker in patients with triple-negative breast cancer (TNBC). We aimed to incorporate sTILs into the PREDICT model for women with early-stage TNBC to guide chemotherapy decisions. PATIENTS AND METHODS: We included 3698 women with early-stage TNBC, diagnosed between 1979 and 2017, from two pooled cohorts with sTILs scored according to international guidelines to update PREDICT version 2.3. The updated model, PREDICT_sTILs, is a Cox regression model with sTILs and the PREDICT prognostic index as predictors and breast cancer-specific survival as the outcome. Internal-external validation was conducted using leave-one-region-out cross-validation, with calibration assessed by the observed-to-expected (O/E) ratio and discrimination by area under the curve (AUC). We compared the clinical values of PREDICT_sTILs and PREDICT through decision curve analysis, examining net true high-risk and low-risk classifications across risk thresholds of 10-year breast cancer mortality above 8%-15%. RESULTS: Among the 3698 patients, 1806 received chemotherapy while 1892 were chemotherapy-naïve. Chemotherapy-treated patients had a median age of 50 years, a tumor size of 25 mm, and one positive lymph node. The chemotherapy-naïve patients had a median age of 55 years, a tumor size of 20 mm, and 0 positive lymph nodes. Within 5 and 10 years, 741 and 860 deaths were attributed to breast cancer, respectively. PREDICT_sTILs showed strong internal-external validity, with comparable calibration and discrimination at both time points: pooled O/E ratios of 0.98 [95% confidence interval (CI) 0.69-1.41] at 5 years and 0.99 (95% CI 0.72-1.35) at 10 years, and AUCs of 0.74 (95% CI 0.72-0.77) and 0.74 (95% CI 0.70-0.78), respectively. Compared with PREDICT, PREDICT_sTILs identified 19-60 additional net true low-risk patients and 3-10 additional net true high-risk patients per 1000 chemotherapy-naïve patients at the risk thresholds of 8%-15% at 10 years. CONCLUSION: Adding sTILs to PREDICT improves its ability to inform chemotherapy decisions for early-stage patients with TNBC, especially in identifying low-risk individuals who may safely forgo chemotherapy.
Chen X, Qiu MY, Zhang JP
… +30 more, Xia YD, Cao K, Cao WW, Yao LS, Lambert L, Li SY, Liang YT, Lin H, Yu YF, Yao JW, Guo WC, Xu J, Zheng ZL, Mao Y, Chen ZW, Shi Y, Kovarnik T, Vocka M, Ye XH, Zhou J, Xie CM, Wang QF, Guo YM, Liang D, Ma ZL, Lai LS, Huang X, Jia YL, Zhang L, Liu ZY
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer deaths, with early screening vital to reduce mortality. While methods such as colonoscopy and computed tomography (CT) colonography are available, they fac...BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer deaths, with early screening vital to reduce mortality. While methods such as colonoscopy and computed tomography (CT) colonography are available, they face challenges such as bowel preparation, invasiveness, and low adherence. We aimed to develop COCA (COlorectal Cancer detection with AI), a novel, noninvasive, cost-effective, and scalable method for CRC screening using noncontrast CT scans. PATIENTS AND METHODS: This retrospective, multicenter, and international study included 1321 CRC patients and 1357 normal controls from two centers to develop COCA. We enhanced the CRC detection capabilities of COCA by employing a joint lesion segmentation and classification architecture, optimized with mixed-supervised learning. For validation, we gathered abdominal and pelvic CT data from four external centers and chest CT data from four centers. A reader study involving 10 radiologists with varying levels of experience evaluated diagnostic performance on noncontrast CT first without COCA assistance and then with it. Additionally, we evaluated both the initial and iteratively improved versions of COCA in two real-world, multi-scenario cohorts comprising 27 433 consecutive patients. RESULTS: In a multicenter and international validation involving 2053 patients across six centers, COCA demonstrated an area under the curve ranging from 0.967 to 0.996 for CRC detection. COCA improved CRC detection sensitivity by 20.4% and specificity by 5.4% compared with radiologists. In the first real-world multi-scenario validation with 9014 consecutive patients, COCA achieved a sensitivity of 88.2% and specificity of 99.5% for CRC detection. In the second external real-world validation involving 18 419 consecutive patients, COCA maintained a sensitivity of 86.6% and specificity of 99.8%, with a positive predictive value of 63.4%. CONCLUSIONS: COCA demonstrated robust performance across various clinical scenarios, including physical exams, emergency departments, outpatient, and inpatient settings, effectively preventing missed CRC diagnoses. These findings suggest that COCA could serve as a potential tool for large-scale opportunistic CRC screening.