European Journal of Cancer最新文献

Introduction: Stage III colon cancer (CC) is routinely treated with resection followed by adjuvant chemotherapy (ACT). However, 50 % of patients are cured by surgical intervention alone, whilst another 30 % experience disease recurrence despite ACT. This study aimed to identify biomarkers prognostic of recurrence and/or predictive of response to ACT.

Materials and methods: Prognostic value of clinicopathological features, transcriptional profiles and genomic mutations was examined for patients with microsatellite stable (MSS) and instable (MSI) CC receiving ACT, as well as in a sub-cohort of patients with minimal residual disease (MSS-MRD) detected by post-surgery circulating tumour DNA.

Results: In MSS patients (N = 199), recurrence was associated with pT4 and/or pN2 tumours (HR 3.5 [2.0-5.9], p < 0.001); CMS4 (HR 2.6 [1.2-5.4], p = 0.008); a high cancer-associated fibroblast (CAF) signature (HR 2.2 [1.4-3.6], p = 0.001); and SMAD4 mutations (HR 2.1 [1.1-4.2], p = 0.027). In the MSS-MRD sub-cohort (N = 23), lack of response to ACT was associated with a high CAF-signature (HR 5.3 [1.7-17], p = 0.002) and SMAD4 mutations (HR 3.4 [0.9-13], p = 0.060).

Discussion: A high CAF-signature and SMAD4 mutations have prognostic value for recurrence both in MSS CC and in MRD, indicating potential predictive value for response to ACT. This molecular profile provides leads to design novel therapies for patients resistant to standard ACT.

Purpose: Ovarian function suppression (OFS) combined with tamoxifen or aromatase inhibitor (AI) are standard treatment options for young women with hormone receptor-positive breast cancer. Suboptimal OFS may reduce the efficacy of the endocrine treatment (ET). This study evaluated factors associated with suboptimal OFS induced by gonadotropin-releasing hormone agonist (GnRHa).

Methods: PREFER (NCT02895165) and GIM 23-POSTER (NCT05730647) are multicentric Italian prospective, observational studies enrolling premenopausal women undergoing (neo)adjuvant chemotherapy and/or ET. The present analysis includes only patients enrolled at the coordinating center. Patients receiving ET with OFS were classified into suboptimal (estradiol >25.1 ng/L measured by chemiluminescent immunoassay or resumed menstruation) or adequate OFS.

Results: As of June 2024, 488 patients were enrolled (median follow-up: 44.4 months, IQR 20.6-84.0). Of 343 patients receiving adjuvant ET, 315 were in the adequately suppressed group and 28 in the suboptimal suppression group (of whom 55.9 % and 92.9 %, respectively, were receiving an AI). Clinical characteristics (age, BMI, baseline FSH, and estradiol levels) and previous chemotherapy (with or without concurrent GnRHa) showed no association with suboptimal OFS. Concurrent treatment with AI was the only factor significantly associated with suboptimal OFS (HR 12.83, 95 % CI 3.01-54.65; p = 0.001). The proportion of patients with suboptimal suppression was 5.1 % (95 % CI 3.2-8.2) in the first year of ET, rising to 10.5 % (95 % CI 7.1-15.4) within five years.

Conclusions: Approximately 10 % of premenopausal women receiving GnRHa as part of adjuvant ET did not achieve complete OFS. Use of AI was the only factor linked to suboptimal OFS.

Purpose: Perioperative chemotherapy with FLOT is a standard of care for patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. This trial evaluated the anti-PD-1 monoclonal antibody spartalizumab combined with FLOT as perioperative treatment for resectable patients.

Patients and methods: GASPAR is a multicenter, single-arm, Simon two-stage phase 2 trial. Patients with untreated localized gastric or GEJ adenocarcinoma considered resectable (≥ cT2 or cN+) received 4 pre- and post-operative cycles of FLOT and 2 pre- and post-operative cycles of spartalizumab. The main endpoint was the rate of pathological complete regression (pCR) according to the Becker criteria, requiring 67 patients (H0/H1 =10/23 %, α=5 %, β=20 %).

Results: Overall, 68 patients were included: men (78 %), median age 63 years [range 31-79], cT3 51 %, GEJ 60 %, cN+ 58 %. Treatment was started in 67 patients. Delayed FLOT administration for toxicity and dose reduction concerned 14 (21 %) and 28 (42 %) patients, respectively. Surgery was R0 in 62 (95 %) of the patients operated on. Among 64 patients assessable for efficacy, pCR was observed in 20 patients (31 %), and major pathological response in 12 patients (19 %), meaning a major response rate of 50 %. Five patients developed grade 3 immune-mediated adverse events. One death related to pneumocystis occurred. Severe post-surgery complications occurred in 15 patients (23 %). After a median follow-up of 30 months [range 4-42], OS and DFS at 2 years were 86 % [77.8-94.9] and 77.5 % [68.1-88.2], respectively.

Conclusions: Spartalizumab combined with FLOT shows high efficacy as perioperative treatment in patients with resectable gastric cancer, and an acceptable safety profile.

Trial registration: ClinicalTrials.gov Identifier: NCT04736485.

Background: We assessed the impact of granulocyte colony-stimulating factor (G-CSF) use and docetaxel relative dose intensity (RDI) on the safety profile of the ARASENS (NCT02799602) triplet regimen with darolutamide in patients with metastatic hormone-sensitive prostate cancer.

Methods: Patients were randomized to darolutamide 600 mg orally twice daily or placebo, with androgen deprivation therapy (ADT) and docetaxel. Baseline characteristics, G-CSF use, and safety were analyzed according to docetaxel RDI (≤85 % vs >85 %).

Results: Of 1273 patients with docetaxel RDI data (darolutamide n = 637; placebo n = 636), > 97 % received an efficacious dose of docetaxel (RDI >80 %). Patient demographics and baseline disease characteristics were generally similar between RDI subgroups; > 60 % of patients with RDI ≤ 85 % were from the Asia-Pacific region. Concomitant G-CSF, with/without docetaxel dose modification, was used in 42.4 % (darolutamide) and 44.6 % (placebo) of patients, mainly as secondary prophylaxis; 61.3 % (darolutamide) and 64.4 % (placebo) received both docetaxel dose modifications and G-CSF. Grade ≥ 3 treatment-emergent adverse events (TEAEs), grade ≥ 3 neutropenia, and grade ≥ 3 febrile neutropenia were higher with docetaxel RDI ≤ 85 %, but docetaxel discontinuation rates were similar between subgroups (RDI ≤85 %: darolutamide 7.2 %, placebo 10.8 %; RDI >85 %: darolutamide 8.1 %, placebo 10.5 %). TEAEs leading to docetaxel dose modification were more frequent with docetaxel RDI ≤ 85 % (darolutamide 92.8 %; placebo 97.3 %) versus RDI > 85 % (darolutamide 26.0 %; placebo 25.3 %).

Conclusion: Appropriate docetaxel dose modifications and early G-CSF use allowed almost all patients to receive an efficacious dose of docetaxel in combination with darolutamide and ADT and may prevent neutropenic complications in patients receiving docetaxel.

Prior presentation: Previously presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, San Francisco, CA.

Background: There is a great need for non-estrogenic treatment of vulvovaginal atrophy (VVA) symptoms affecting sexual function and quality of life. Women with breast cancer on anti-estrogenic therapy are particularly vulnerable and in need of help. The primary aim of this proof-of-concept trial was to evaluate the efficacy of vaginal tamoxifen in reducing the most troublesome VVA symptom.

Methods: In this randomized, double blind, placebo-controlled study, 115 postmenopausal women, with or without breast cancer, were randomized to 20 mg vaginal tamoxifen once weekly or placebo (1:1). Follow-up after one and three-months of treatment, included self-reported VVA symptoms on the Endocrine Symptom Subscale of FACT-B, and gynecologic exams for VVA score and measurement of vaginal pH and endometrial thickness.

Findings: After three months, 37 (68.6 %) of women on vaginal tamoxifen reported their most troublesome VVA symptom to be mild or not present at all, whereas corresponding number in the placebo group was 5 (9.1 %), p < 0.001. Expressed as odds, women on vaginal tamoxifen were more likely to report no or minor symptoms after three-months, OR 21.76 (95 % CI 7.36 - 64.3). The improvement in self-reported outcomes was accompanied by improvements in VVA scores and vaginal pH, p < 0.001.

Interpretation: This study has demonstrated that more than two-thirds of the women on vaginal tamoxifen improved in their most troublesome VVA symptom. This is likely due to a tamoxifen-induced estrogen agonistic effects in vagina in a low-estrogen environment. While findings are promising, further studies on improved vaginal administration and endometrial safety concerns are needed.