OBJECTIVE:This study aimed to assess the prognostic impact of celiac lymph node involvement in patients with advanced high-grade serous ovarian cancer. METHODS:We conducted a retrospective, single-center study including patients who underwent celiac lymph node resection during either upfront or interval complete cytoreductive surgery as frontline treatment for advanced high-grade serous ovarian cancer between January 2002 and December 2022. Patients were categorized into 2 groups based on celiac lymph node status. Univariable and multi-variable analyses were performed, and survival rates were estimated using the Kaplan-Meier method. RESULTS:Among 820 patients who underwent cytoreductive surgery for ovarian cancer during the study period, 65 (7.9%) had celiac lymph node resection and were included. Celiac lymph node metastases were identified in 42 (64.6%) cases. Celiac lymph node-positive patients had a higher tumor burden (p =.001), more frequent bowel involvement (p =.026), and higher rates of left hemicolectomy (17.1% vs 0.0%) and inguinal lymphadenectomy (16.7% vs 0.0%). Median overall survival was 30.9 months in the celiac lymph node-positive group and 50.6 months in the celiac lymph node-negative group (p =.270); median disease-free survival was 10.8 and 14.6 months (p =.082), respectively. In multi-variable analysis, celiac lymph node involvement was significantly associated with decreased disease-free survival (hazard ratio 2.87 [1.38 to 5.93], p =.005). CONCLUSIONS:Celiac lymph node involvement is associated with a higher tumor burden and significantly associated with a decrease in disease-free survival in cases of advanced high-grade serous ovarian cancer. These results highlight the need to identify celiac lymph node involvement for better risk stratification.

Abstract Background: We developed a composite Gene Expression Signature (cGES) comprising 22 protective (P) and 19 adverse (A) genes, agnostic of the tumor type, stratifying IO-treated pts in 3 risk groups: low (L-), intermediate (I-) and high-risk (H-) (abstract#6360 AACR2025). Herein, we validate its predictive value for progression free (PFS) and overall survival (OS) in a prospective cohort and uncover the single-cell and spatial determinants underlying clinical outcomes. Methods: (1) The cGES was computed in 170 pts with LA/M SCCHN from 2 trials (NCT03226756; NCT03412058). (2) Next, we built a scRNAseq SCCHN atlas (scAt) of 219,138 cells from 77 independant pts including 19 and 21 pts classified as H-risk and L-risk respectively, and studied the distribution and functional states of cell populations between the 2 groups of pts. Cell-type-specific enrichments of A & P genes werequantified and intercellular communication networks were inferred to identify ligand-receptor (L-R) interactions. (3) Deconvoluted Visium data from 12 of the 77 SCCHN including 3 H-risk and 3 L-risk pts were used to map the spatial organization of cGES and to localize specific L-R interactions. Results: (1) Multivariate analysis adjusted for ECOG, age, gender, and alcohol/tobacco use showed that I- and L-risk pts had significantly better outcomes. For PFS, hazard ratios were 0.64 (p=0.04) and 0.51 (p=0.005), and for OS 0.81 (p>0.05) and 0.54 (p=0.015), respectively. (2) Analysis of the scAt revealed that A genes from cGES were mainly expressed by epithelial and stromal cells. Conversely, P genes were mainly expressed by immune cells. H-risk tumors exhibited an altered communication landscape marked by strengthened epithelial junctions, developmental signaling, and universally increased EGFR L-R activity, whereas L-risk tumors showed an immune-enriched network dominated by extracellular remodeling, adaptive immune activation and immune cell recruitment. (3) Visium deconvolution identified 5 major cell-composition clusters (C), with epithelial-enriched C2 showing the highest A genes expression, while T cell-enriched C4/C5 displayed the strongest P genes expression. H-risk tumors exhibited prominent EGFR ligand expression, consistent with the results from the scAt data. In contrast, L-risk tumors displayed increased antigen-presentation, T-cell chemotaxis, and complement signaling. Conclusion: cGES reliably stratified prognosis and reflects tumor ecosystem biology. H-risk tumors were dominated by epithelial-driven, EGFR-centered signaling, whereas L-risk tumors showed coordinated inflammatory T-cell-oriented programs. These findings suggest cGES as a prognostic and mechanistic biomarker, and provides a rational for EGFR-IO combination strategies to improve outcomes in LA/M SCCHN. Citation Format: Mehdi Lamkhioued, Thimothee Casini, Elodie Girard, Karène Mahtouk, Sonia Canjura-Rodriguez, Valery Attignon, Bastien Cabarrou, Constance Lamy, Anne Schnitzler, Frederique Penault-Llorca, Caroline Even, Christophe Le Tourneau, Ellen Van Obberghen-Schilling, Nicolas Servant, Fayette Jerome, Nathalie Bendriss-Vermare, Ivan Bièche, Pierre Saintigny. Single cell and spatially resolved determinants of the clinical outcome of patients (pts) treated with locally advanced/metastatic head and neck squamous cell carcinoma (LA/M SCCHN) treated with immunotherapy (IO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1037.

Abstract Background: IO efficacy in LA/M HNSCC patients is limited. Identifying biomarkers of resistance and response is crucial to better stratify patients. We characterized the genomic and transcriptomic landscape of IO-naive HNSCC patients to identify specific genomic and transcriptomic signatures of response to IO. Methods: We analyzed baseline FFPE samples of 176 LA/M HNSCC patients treated with IO from CHECK’UP (NCT03412058) and TOPNIVO (NCT03226756) trials, for whom baseline RNAseq data were available. A penalized Cox model with Elastic Net procedure was used to identify gene signatures associated with PFS and OS. Using a resampling procedure, a bootstrap selection stability (BSS) index was computed for each gene and only those with a BSS > 30% were included in the final model to determine a score for both PFS and OS. In addition, 149 paired tumor and germline DNA were sequenced using whole exome. For biostatistics analysis using genomic alterations, only variants (SNVs, Indels, CNVs) in oncogenes, tumor suppressor genes with a variant allele frequency (VAF) of at least 10% and altered signaling pathways were considered. Results: The cohort (median age 62.5 yo) included a majority of oropharynx (39.8%) and oral cavity (29.8%) tumors, 77.8% males, 62.3% with alcohol and 81.7% with tobacco use history and 60.0% of them were metastatic. Objective response rate was 17.4%, median PFS and OS were 1.9 months (mo) (95%CI=[1.8-2.5]) and 8.1 mo (95%CI=[6.1-9.7]), respectively (median follow-up of 33.3 mo, 95%CI=[28.7-36.5]). The most frequent genomic alterations affected CCND1, CDKN2A, FAT1, TERT, TP53 genes and a gain of 3q26-q28. In univariable analyses, the presence of TERT or FAT1 alteration were significantly associated with worse PFS. After adjustment for clinical variable, the presence of FAT1 alteration and the upregulation of Hippo signalling pathway remained associated with worse PFS. The presence of TERT mutation was also associated with worse OS whereas the PI3K/AKT/mTOR pathway was associated with improved OS in univariable and multivariable analysis, respectively. Among the 500 most differentially expressed transcripts, 21- and 18-gene expression signatures were selected to assess their association with PFS and OS, respectively. C-Index was 0.72 and 0.71 (0.58 and 0.57 after internal bootstrap validation) for PFS and OS, respectively. Scores were dichotomized using time-dependent ROC Curve (Low vs High) and HR adjusted for clinical factors were 3.62 (95%CI = [2.42; 5.43]) and 3.86 (95%CI = [2.52; 5.91]; p<0.0001) for PFS and OS, respectively. Conclusions: We identified robust transcriptomic signatures and genomic alterations strongly associated with IO resistance, offering potential biomarkers for patient stratification. TERT or FAT1 alteration were associated with worse prognosis. Citation Format: Elodie Girard, Sonia Canjura-Rodriguez, Bastien Cabarrou, Constance Lamy, Anne Schnitzler, Frédérique Penault-Llorca, Emmanuel Bouilhol, Roger Sun, Eric Deutsch, François Legrand, Séverine Tabone-Eglinger, Valery Attignon, Caroline Even, Christophe Le Tourneau, Ellen Van Obberghen-Schilling, Marta Jimenez, Nicolas Servant, Thomas Filleron, Edith Borcoman, Pierre Saintigny, Ivan Bièche. Transcriptomic and genomic signatures associated with response or resistance to immunotherapy(IO) in locally advanced/metastatic (LA/M) head and neck squamous cell carcinoma (HNSCC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1034.

T-cell exhaustion is typically studied in the context of immune checkpoint blockade, where proliferation and reinvigoration of exhausted cells drives therapeutic responses. However, terminal exhaustion may also represent a marker of chronic tumor-specific activation, raising the possibility that exhausted T cells reflect ongoing endogenous tumor control. Here, we sought to evaluate T-cell exhaustion as a prognostic marker using high-grade serous ovarian cancer (HGSC), an immunotherapy-resistant malignancy, as a model. In a cohort of 80 patients with stage III/IV HGSC, we assessed T-cell infiltration and exhaustion according to homologous recombination (HR) deficiency status. While overall immune infiltration was comparable between HR-deficient and proficient tumors, terminally exhausted CD8 and conventional CD4 T cells were enriched in HR-deficient tumors, where their presence correlated with improved progression-free survival. These findings suggest that exhausted T cells may indicate protective immunity even outside the context of immunotherapy and underscore their prognostic relevance in solid tumors.

Abstract The contribution of neoantigen-specific T cells to PD-(L)1 efficacy has largely been inferred from tumor mutational burden. We functionally profiled circulating T cell responses against 7,038 predicted HLA-I–restricted and 21,453 HLA-II–restricted neopeptides in 27 patients with advanced non-small cell lung cancer treated with anti–PD-(L)1. CD4 responses were frequent and correlated with neoantigen availability but not clinical benefit. In contrast, the magnitude and breadth of neoantigen-specific CD8 T cell responses were associated with clinical benefit, progression-free and overall survival, independently of tumor mutational burden. Patients mounting coordinated CD4 and CD8 responses experienced improved progression-free survival. Tumors from CD8 responders displayed immune signatures indicative of both T cell priming and effector functions. Circulating neoantigen-specific CD8 T cells recognized endogenously processed antigens, trafficked to tumors, and selectively expanded under therapy while retaining CD28, CD226, and CXCR3 expression. These findings identify coordinated, functionally engaged neoantigen-specific T cell responses as central determinants of PD-(L)1 efficacy.

e13000 Background: The optimal management of oligometastatic breast cancer (OMBC) remains undefined. Given its biological heterogeneity, subgroup-specific analyses are warranted. Data focusing on triple-negative (TN) OMBC are lacking. We aimed to describe the clinical characteristics, initial metastatic patterns, treatments, outcomes, and pattern of progression of a consecutive de novo TN OMBC and oligorecurrent TN metastatic breast cancer (MBC) cohort. Methods: We retrospectively identified all consecutive patients treated for de novo or recurrent MBC between 2012 and 2020 at a single institution. Among them, TN OMBC was defined as breast cancer with 1–5 metastatic lesions without hormone receptor or HER2 expression. Metastatic presentation, treatments including standard systemic therapy (SOC) and local ablative treatment (LAT), and patterns of progression at first relapse were analyzed. Survival outcomes were analyzed using the Kaplan–Meier method, log-rank tests and Cox proportional hazards models. Results: TN OMBC accounted for 49 cases, corresponding to 2.5% (49/1,980) of all metastatic breast cancers. 33% were de novo, while the remainder were metachronous, occurring before (29.2%) or after 24 months (37.5%). A single organ was involved in 81.6% of patients, and 1–3 metastases were observed in 87.8%. Distant lymph nodes were the most frequent metastatic site (38%), exceeding lung, liver, brain, and bone involvement. Overall, 28.6% of patients received local ablative treatment (LAT), either alone or combined with systemic therapy. No patients received immunotherapy during the study period. With a median follow-up of 75.9 months (95%CI [54.4; 82.0]), median progression-free survival was 6.7 months (95%CI [4.8; 9.8]) and median overall survival was 23.1 months (95%CI [17.2; 29.5]). At 36 months, PFS was 10.4% (95% CI [3.8–20.9]) and OS was 31.8% (95% CI [19.3–45.0]). No prognostic factor was identified in univariable analyses including treatment, metastatic distribution, and metastatic chronology. After first-line treatment, 43 patients (87.7%) experienced disease progression. Local control was achieved in 47.9% of cases. Among patients with disease progression, 65.9% presented with oligoprogression. LAT targeting progressive lesions was administered in 23.3% of progressing patients. Conclusions: This study provides the first dedicated description of TN OMBC. TN OMBC is a rare clinical entity. The metastatic pattern showed a frequent involvement of distant lymph nodes. At three years, nearly one-third of patients are still alive. Following first-line systemic therapy, oligoprogression represented the predominant pattern of disease progression. Within the limitations of this retrospective study, these findings suggest that TN OMBC may represent a distinct clinical presentation compared with unselected TN metastatic breast cancer, and support further dedicated investigation.

Introduction Les carcinomes sarcomatoïdes (CS) représentent 0,4 % des cancers broncho-pulmonaires et peu de données sont disponibles sur l’efficacité des premières lignes de traitement en particulier des associations de la chimiothérapie avec l’immunothérapie. Cette étude évalue, à partir des données du programme épidémio-stratégie et médico-économique (ESME), l’efficacité des traitements systémiques dans les CS. Méthodes Il s’agit d’une étude rétrospective multicentrique portant sur les patients avec CS pris en charge entre 01/2015 et 07/2022, ayant bénéficié en première ligne d’un traitement systémique par chimiothérapie à base de platine seule (CT) ou par immunothérapie (ICI) associée ou non à la CT. Les données recueillies ont porté sur les caractéristiques sociodémographiques des patients, les caractéristiques des tumeurs notamment les stades, les sites métastatiques et l’expression de PD-L1 ainsi que le profil de biologie moléculaire de ces tumeurs (KRAS, MET, BRAF, EGFR, ALK et ROS 1). L’analyse de l’efficacité a été évaluée sur la survie sans progression (SSP) et la survie globale (SG). Des analyses uni- et multivariables sur la SSP et la SG ont été réalisées. Résultats Parmi les 42 219 patients de la base ESME ayant un CBNPC localement avancé ou métastatique à partir de 2015, 229 (0,54 %) avaient une histologie de CS. Parmi ces CS, 49/229 (21,4 %) n’ont pas reçu de 1re ligne, et 19/229 (8,3 %) n’ont pas reçu une première ligne d’intérêt. L’analyse a donc concerné 161 patients, 94/161 (58,4 %) traités par CT et 67 (41,6 %) par ICI±CT : âge médian 66 ans (min–max : 39–89), 70,2 % de sexe masculin, 86,2 % de fumeurs ou ex-fumeurs, 69,8 % avec un performance status (PS) à 0–1. La majorité des patients (83,9 %) était métastatique d’emblée et parmi eux 26,8 % avaient des métastases cérébrales dont 13,4 % étaient symptomatiques. Au total, 113/161 patients (70,2 %) ont une analyse biologique moléculaire dont 40 (35,4 %) avaient une anomalie oncogénique (KRAS, MET, BRAF, EGFR, ALK et ROS 1). Le niveau d’expression du PDL1 était≥50 %, compris entre 1 et 49 %, <1 % dans respectivement 68,6 %, 8,6 % 22,9 % des cas. Après un suivi médian de 66,6 (IC95 % : 53,4–73,7) mois pour le groupe CT et de 34,8 (IC95 % : 28,1–41,6) mois pour le groupe ICI±CT, les médianes de SSP étaient de 2,2 (IC95 %, 2,0–3,0) mois pour le groupe CT et de 4,6 (IC95 %, 2,1–8,2) mois pour le groupe ICI±CT ; les médianes de SG étaient respectivement de 6,8 (IC95 %, 4,3–10,0) et de 20,6 (IC95 %, 10,3–32,4) mois. En analyse multivarié, l’ajout de la chimiothérapie n’était pas statistiquement significatif aussi bien pour la SSP (p=0,365) que pour la SG (p=0,911). Conclusion L’immunothérapie semble avoir considérablement amélioré le pronostic de ces cancers exprimant pour la majorité fortement PD-L1.

OBJECTIVE:The aim of this study was to compare surgical complexity, post-operative complications, and survival outcomes between patients with minimal residual disease (completeness of cytoreduction (CC) score) CC-1 at the time of primary debulking surgery and those with complete cytoreduction (CC-0) at the time of interval debulking surgery. METHODS:A retrospective multicenter study was conducted of patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIIC-IV) who underwent cytoreductive surgery achieving either minimal or no residual disease between January 2008 and December 2015. Patients underwent either primary or interval debulking surgery after receiving ≥3 cycles of neoadjuvant chemotherapy. The sub-group of patients with primary debulking surgery/CC-1 was compared with those with interval debulking surgery/CC-0. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. RESULTS:A total of 549 patients were included, with upfront surgery performed in 175 patients (31.9%) and 374 patients (68.1%) undergoing interval debulking surgery. After primary debulking surgery, 157/175 (89.7%) had complete cytoreduction and 18/175 (10.3%) had minimal residual disease (primary debulking surgery/CC-1 group), while after interval debulking surgery, 324/374 (86.6%) had complete cytoreduction (interval debulking surgery/CC-0 group) and 50/374 (13.4%) had minimal residual disease. The rate of patients with peritoneal cancer index >10 was 14/17 (82.4%) for the primary debulking surgery/CC-1 group and 129/322 (40.1%) for the interval debulking surgery/CC-0 (p<0.001). The rate of patients with an Aletti score of ≥8 was 11/18 (61.1%) and 132/324 (40.7%), respectively (p=0.09) and the rate of major post-operative complications was 5/18 (27.8%) and 64/324 (19.8%), respectively (p=0.38). Overall median disease-free and overall survival were 19.4 months (95% CI 18.0 to 20.6) and 56.7 months (95%CI 50.2 to 65.8), respectively. Median disease-free survival for the primary debulking surgery/CC-1 group was 16.7 months (95% CI 13.6 to 20.0) versus 18.2 months (95% CI 16.4 to 20.0) for the interval debulking surgery/CC-0 group (p=0.56). Median overall survival for the primary debulking surgery/CC-1 group was 44.7 months (95% CI 34.3 to not reached) and 49.4 months (95% CI 46.2 to 57.3) for the interval debulking surgery/CC-0 group (p=0.97). CONCLUSIONS:Patients with primary debulking surgery with minimal residual disease and those with interval debulking surgery with no residual disease had similar survival outcomes. Interval surgery should be considered when achieving absence of residual disease is challenging at upfront surgery, given the lower tumor burden found during surgery.

Hypo-fractionated stereotactic radiotherapy (HFSRT) may enhance anti-PDL1 immunotherapy efficacy in recurrent glioblastoma by promoting immunogenic cell death. After establishing the safety of HFSRT combined with Durvalumab in a phase I trial, we present the results of the randomized phase II STERIMGLI trial (NCT02866747). Eligible patients with recurrent glioblastoma (WHO 2016 classification) and tumor volume ≤35 mm were randomized 1:2 to receive HFSRT alone (24 Gy in 3 fractions over 5 days, Arm A) or the same HFSRT plus Durvalumab 1500 mg on day 5, then every 4 weeks until progression or 12 months (Arm B). The primary endpoint was overall survival (OS) from randomization. With 100 patients and 77 events, the study had 85% power to detect an HR of 0.57 (one-sided, 10%-level test). Between February 2018 and April 2023, 102 patients (median age 61.5 years old, range [26-87]) were randomized (n=34 and 68 in Arm A and B). Baseline characteristics were balanced, except for more prior targeted therapy in Arm B (22.1% vs 2.9%) and more IDH-mutated in Arm A (15.6% vs 6.1%). Treatment was well tolerated, 12.4% of patients experienced grade 3 treatment-related adverse events (no grade 4 or 5). After a median follow-up of 34.1 months, 78 deaths were reported, median OS was 13.3 months in Arm A vs, 16.1 months in Arm B (Hazard Ratio (HR)=0.77, 80%CI = [0.56;1.06], one-sided p=0.146). In multivariate analysis, adjusted HR for prognostic factors was 0.41 (80%CI = [0.28;0.60]). Among patients with IDH-wildtype glioblastoma (WHO 2021), median OS was 10.9 vs, 16.1 months (HR=0.54, 80%CI=[0.39;0.76], one-sided p=0.010). The median intracranial progression-free interval assessed by investigators with RANO criteria was 2.3 vs, 3.5 months (HR=0.91, 80%CI=[0.68;1.23], one-sided p=0.349). Re-irradiation with HFSRT (24 Gy/3 fractions) combined with Durvalumab is safe and improves overall survival in patients with recurrent glioblastoma.

Immune checkpoint inhibitors improve the treatment of many solid tumors and have shown encouraging results in advanced squamous cell carcinoma (SCC), yet only a minority of patients respond to immune checkpoint inhibitor monotherapy. We conducted the PEVOsq trial, an open-label, nonrandomized, multicenter, basket phase 2 trial to evaluate the combination of pembrolizumab and vorinostat in recurrent/metastatic SCC of various origins. The primary endpoint was the objective response rate (ORR) in each tumor cohort during treatment as per the investigators’ assessment. Secondary endpoints included safety and antitumor activity evaluation in terms of centrally confirmed ORR, progression-free survival, overall survival and duration of response. In the efficacy population (n = 107), the ORR was met in cervical (39 NCT04357873 . Borcoman and colleagues present the efficacy and safety results of the phase 2 PEVOsq basket trial investigating the combination of pembrolizumab with the epidrug vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma.

Background Continuous therapy with covalent BTK inhibitors (BTKi) has become a cornerstone strategy for patients with chronic lymphocytic leukemia (CLL). However, unlimited administration of BTKi has raised concerns, including risk of clonal evolutionwith therapeutic resistance and accumulation of adverse events, which can be particularly detrimental in elderly or frail patients. We investigated an 18-month limited-duration therapy with the BTKi acalabrutinib (ACA) in frail patients with previously untreated CLL. Methods The STAIR study is a French investigator-sponsored (FILO) multicenter, randomized phase 2 trial evaluating the impact of ACA discontinuation on progression-free survival (PFS) in elderly and frail patients with untreated CLL (NCT04963946). Key inclusion criteria were : age >70 years, previously untreated CLL requiring treatment (iwCLL2018 criteria), CIRS score > 6 or impaired creatinine clearance (31-69 mL/min, Cockroft). Patients received continuous ACA at 100 mg BID for 18 months before being randomized (1:2) to the control arm A (continuing ACA) or the experimental arm B (discontinuing ACA), with stratification based on complex karyotype (> or = 3 abnormalities) and TP53 alterations. Patients in arm B who experienced CLL progression restarted ACA per protocol in case of relapse or progression with symptomatic disease (reviewed by an independent board). The primary endpoint was the PFS after randomization. The strategy was considered insufficiently promising if 1-year PFS rate was lower than 75% in the experimental arm. Results Among the 172 patients screened for eligibility between October 2021 and June 2023 across 29 centers in France, 160 were enrolled. One patient did not receive ACA and 38 (24%) discontinued ACA within the first 18 months and were not subsequently randomized. Reasons for discontinuation were toxicity (13 patients), disease progression as CLL (7 patients) or Richter transformation (2 patients), secondary primary malignancies (5 patients), deaths (4 patients) and patients' or physicians' decision (4 and 3, respectively). A total of 121 patients were randomized to continuing ACA (arm A, n=41) or discontinuing ACA (arm B, n=80). At randomization, median age was 77 years (range, 71-98), 57.9% were male, 57.9% had CIRS>6, and 79.3% had clearance <70mL/min. Regarding genetic features, 12.4% had TP53 mutations, 11.9% had del(17p) and 27% harbored complex karyotype. The majority of patients had unmutated IGHV (65.0%). At the date of data-cut off (June 1st, 2025), the median follow-up time from randomization was 14.2 months (95%CI, 11.3-16.7). In the control arm A (n=41), 7 patients experienced permanent ACA interruption, for toxicity in 6 cases. At data cut-off, rates of PFS and OS at 1 year after randomization were 96.3% (CI 76.5-99.5) and 100%, respectively. In the experimental arm B (n=80), 39 PFS events were observed, including 37 CLL progressions and 2 deaths. The rate of PFS at 1 year after randomization was 53.1% (CI 40.2-64.5) (one-sample logrank P>0.99). Among subgroups, patients with mutated IGHV had significantly higher 1-year PFS rate (90.4% (CI 65.9-97.6)) than those with unmutated IGHV (34.0% (CI 19.7-48.8)) (P<0.001). Of the patients who progressed after ACA discontinuation, 25 (67.6%) presented symptomatic disease requiring therapy per iwCLL2018 criteria. The rate of time-to-next-treatment at 1 year after randomization was 74.0% (CI 61.7-82.9). Twenty-four restarted ACA per protocol and 1 received venetoclax. Fourteen (77.8%) patients responded to ACA, 4 (22.2%) were stable and 7 were non evaluated at data cut-off. The rate of OS at 1 year after randomization was 96.8% (CI 87.9-99.2). In the overall population (n=160), the most common grade 3-4 treatment-emergent adverse event (AE) were haematologic : neutropenia (12%) and thrombocytopenia (3%). Atrial fibrillation (any grade) occured in 11 (6.9%) patients and grade 3-4 infections in 12 (7.5%). A total of 35 patients presented second primary malignancies including 23 non-melanoma skin cancers. After randomization, grade 3-4 AEs occured in 10 (24.4%) patients in arm A and 8 (13.8%) patients in arm B. Conclusion Limiting time of ACA therapy to 18 months results in a significant decreased rate of PFS at 1 year, particularly among patients with unmutated IGHV. Longer follow-up is warranted to investigate the further impact of ACA interruption on duration of response, AE burden and OS and to assess the response to ACA reinitiation.

The majority of early-onset colorectal cancers (EOCRCs) are not substantiated by germline variants in the main CRC predisposition genes (the “DIGE” panel). To identify potentially novel EOCRC-specific predisposition genes, we analyzed 585 cancer pathway genes in an EOCRC patient cohort (n = 87, diagnosis ≤ 40 years, DIGE-), and compared their variant spectrum to the GnomAD cancer-free database. We identified high-impact variants (HVs) in 15 genes significantly over-represented in EOCRC. Among the 32 unrelated patients with a CRC family history (i.e., with a potentially dominant transmission pattern), 9 presented HVs in ten genes, four of which had a DNA repair function. We subsequently sequenced these 15 genes in a cohort of 82 late-onset CRCs (diagnosis ≥ 50 years, DIGE-) and found variants in 11 of these genes to be specific to EOCRC. We then screened these 11 genes in our patient database (n = 6482), which only contained 2% of EOCRCs (DIGE-), and identified two other EOCRC cases diagnosed after our cohort constitution, with HVs in RECQL4 and NUTM1. Altogether, we found that 37.5% and 18.75% of patients carrying heterozygous NUTM1 and RECQL4 HVs, respectively, in our database were diagnosed with EOCRC. Our work has identified a pattern of germline variants not previously associated with EOCRC.

Early-onset colorectal cancer (EOCRC) incidence is increasing rapidly worldwide. However, the majority of EOCRCs are not substantiated by germline variants in the main colorectal cancer (CRC) predisposition genes (the DIGE panel). To investigate a potential genetic transmission of EOCRC (dominant, recessive and oligogenic hypotheses) and thus identify potentially novel EOCRC-specific predisposition genes, we conducted an analysis of 585 cancer pathway genes on an EOCRC patient cohort (n=87 patients diagnosed at less than or equal to 40 years of age, DIGE-) with or without a CRC family history. By comparing this germline variant spectrum to the GnomAD cancer-free database, we identified high impact variants (HVs) in 15 genes significantly over-represented in the EOCRC cohort. Among the 32 unrelated patients with a CRC family history (i.e. with a potentially dominant transmission pattern), nine presented HVs in ten of the genes tested, four of these genes had a DNA repair function. A potentially recessive transmission of EOCRC in patients without a CRC family history cannot be supported by our results nor can an oligogenic transmission. We subsequently sequenced these 15 genes in a cohort of 82 late-onset CRCs (cancer diagnosis greater than or equal to 50 years, DIGE-) and found variants in 11 of these genes to be specific to EOCRC. To evaluate whether variants in these 11 genes would allow to specifically detect EOCRC patients, we screened our patient database (n=6482), which only contained 2% of EOCRCs (DIGE-), and identified two other EOCRC cases diagnosed after the constitution of our cohort, with individual HVs in RECQL4 and NUTM1. Altogether, we showed that 37.5% and 18.75% of heterozygous NUTM1 and RECQL4 HVs of our database were diagnosed with EOCRC. Our work has identified a pattern of germline gene variants not previously associated with EOCRC. This paves the way to addressing the contribution of these variants to EOCRC risk and oncogenesis. ### Competing Interest Statement The authors have declared no competing interest.

BACKGROUND AND PURPOSE:The aim of the present prospective exploratory study was to investigate the long-term impact of treatment on brain structure integrity and memory functions in pediatric posterior fossa tumor (PFT) survivors using diffusion tensor imaging (DTI), to determine whether the latter could provide useful biomarkers of memory impairment. MATERIAL AND METHODS:Sixty participants were included in this study, divided into three groups: 22 irradiated PFT, 17 non-irradiated PFT, and 21 healthy controls. All underwent memory tests and multimodal MRI, including a DTI sequence. Mean diffusivity and fractional anisotropy values were extracted for bilateral brain structures involved in memory, in order to carry out between-group comparisons and calculate correlations with memory test scores and radiotherapy doses. Statistical tests were two-sided, and p values < 0.05 were considered statistically significant. RESULTS:DTI metrics were significantly higher for irradiated PFT survivors than in non-irradiated PFT survivors and controls (p < 0.05). Memory test scores were significantly lower for PFT survivors, particularly irradiated patients (p < 0.02), and were correlated with DTI metrics. (-0.27 < r < -0.62, p < 0.04). DTI metrics were correlated with either total or maximum dose for some structures. CONCLUSION:Preliminary results of this study point to microstructural damage in memory-related brain areas in PFT survivors, particularly in irradiated patients, and identify DTI metrics as potential biomarkers of memory deficit.

Background: The effects of postoperative pancreatic fistula on survival rates remain controversial. The aim of the present study was to evaluate the influence of postoperative pancreatic fistula on overall survival and recurrence-free survival after upfront pancreatoduodenectomy for pancreatic ductal adenocarcinoma. Methods: Patients operated on between January 2007 and December 2017 at seven tertiary pancreatic centres for pancreatic ductal adenocarcinoma were included in the study. Postoperative pancreatic fistula was defined using the 2016 International Study Group on Pancreatic Surgery grading system. The impact of postoperative pancreatic fistula on overall survival, recurrence-free survival (excluding 90-day postoperative deaths) and corresponding risk factors were investigated by univariable and multivariable analyses. Comparisons between groups were made using the chi-squared or Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. Odds ratios were estimated with their 95% confidence intervals. Survival rates were calculated using the Kaplan-Meier method with their 95% confidence intervals. Results: A total of 819 patients were included between 2007 and 2017. Postoperative pancreatic fistula occurred in 14.4% (n = 118) of patients; of those, 7.8% (n = 64) and 6.6% (n = 54) accounted for grade B and grade C postoperative pancreatic fistula respectively. The 5-year overall survival was 37.0% in the non-postoperative pancreatic fistula group and 45.3% in the postoperative pancreatic fistula cohort (P = 0.127). Grade C postoperative pancreatic fistula (excluding 90-day postoperative deaths) was not a prognostic factor for overall survival. The 5-year recurrence-free survival was 26.0% for patients without postoperative pancreatic fistula and 43.7% for patients with postoperative pancreatic fistula (P = 0.003). Eight independent prognostic factors for recurrence-free survival were identified: age over 70 years, diabetes, moderate or poor tumour differentiation, T3/T4 tumour stage, lymph node positive status, resection margins R1, vascular emboli and perineural invasion. Conclusion: This high-volume cohort showed that grade C postoperative pancreatic fistula, based on the 2016 International Study Group on Pancreatic Surgery grading system, does not impact overall or recurrence-free survival (excluding 90-day postoperative deaths).

BackgroundCurrent guidelines recommend that patients with HER2-low metastatic breast cancer (MBC) receive sequentially two antibody-drug conjugates (ADCs): Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd), despite a similar payload. However, the effectiveness of one after another is unknown.MethodsADC-Low is a multicentre, retrospective study evaluating the efficacy of SG and T-DXd, one after another, with or without intermediary lines of chemotherapy, in patients with HER2-low MBC.ResultsOne hundred and seventy-nine patients were included: the majority with HR-negative tumours received SG first (ADC1) (n = 100/108) while most with HR-positive tumours received T-DXd first (n = 56/71). Median progression-free survival 2 was short: 2.7 months (95% CI: 2.4-3.3) in the whole population, respectively, 3.1 (95% CI: 2.6-3.6) and 2.2 months (95% CI: 1.9-2.7) for patients receiving T-DXd or SG second (ADC2). Intermediary lines of chemotherapy between ADC1 and ADC2 had no impact. Primary resistance to ADC2 occurred in 54.4% of patients. Certain patients showed initial response to ADC2.ConclusionsClinical benefit of sequentially administered SG and T-DXd is limited for most patients. Nevertheless, a subset of patients might benefit-on the short term-from a second ADC. Additional studies are needed to identify patients who could benefit from two ADCs with similar payloads.