Pub Date : 2026-03-11Epub Date: 2026-01-31DOI: 10.1016/j.ejca.2026.116262
Ingrid A. Franken , Steven L.C. Ketelaars , Carmen Rubio-Alarcón , Pien Delis-van Diemen , Tessa O.M. Spaapen , Floor Heilijgers , Marcos da Silva Guimaraes , Sietske C.M.W. van Nassau , Suzanna J. Schraa , Wilma E. Mesker , Wendy W.J. de Leng , Onno Kranenburg , Gerrit A. Meijer , Miriam Koopman , Mark Sausen , Geraldine R. Vink , Sanne Abeln , Remond J.A. Fijneman , Jeanine M.L. Roodhart , on behalf of the PLCRC-MEDOCC group
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.
{"title":"Cancer-associated fibroblast signature and SMAD4 mutation in resistance to adjuvant chemotherapy in stage III colon cancer patients","authors":"Ingrid A. Franken , Steven L.C. Ketelaars , Carmen Rubio-Alarcón , Pien Delis-van Diemen , Tessa O.M. Spaapen , Floor Heilijgers , Marcos da Silva Guimaraes , Sietske C.M.W. van Nassau , Suzanna J. Schraa , Wilma E. Mesker , Wendy W.J. de Leng , Onno Kranenburg , Gerrit A. Meijer , Miriam Koopman , Mark Sausen , Geraldine R. Vink , Sanne Abeln , Remond J.A. Fijneman , Jeanine M.L. Roodhart , on behalf of the PLCRC-MEDOCC group","doi":"10.1016/j.ejca.2026.116262","DOIUrl":"10.1016/j.ejca.2026.116262","url":null,"abstract":"<div><h3>Introduction</h3><div>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.</div></div><div><h3>Materials and Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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).</div></div><div><h3>Discussion</h3><div>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.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"236 ","pages":"Article 116262"},"PeriodicalIF":7.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11Epub Date: 2026-02-03DOI: 10.1016/j.ejca.2026.116255
Deblina Ghosh , Aslamuzzaman Kazi , Hitesh Kumar Kantilal Vasiyani , Vignesh Vudatha , Nicolas Lecomte , Christine Iacobuzio-Donahue , Jose Trevino , Said M. Sebti
Introduction
The KRAS G12D inhibitor MRTX1133 represents a major advance in targeting oncogenic KRAS, but adaptive resistance driven by ERK reactivation, dependent on wild-type (WT) RAS membrane localization, limits its efficacy.
Results
Here, we identify a rational strategy to overcome this resistance mechanism using FGTI-2734, a dual farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT-1) inhibitor that disrupts WT RAS membrane localization. FGTI-2734 blocks MRTX1133-induced ERK feedback reactivation and synergizes with MRTX1133 to inhibit proliferation and induce apoptosis in KRAS G12D pancreatic cancer cell lines. Across organoids derived from 12 patients with KRAS G12D pancreatic cancer, including those with primary and metastatic tumors with diverse genetic alterations (KRAS, TP53, CDKN2A, SMAD4, RTKs, PI3K/AKT, JAK/STAT, DNA repair/cell cycle, and chromatin modifiers), the MRTX1133/FGTI-2734 combination produced robust synergy regardless of tumor stage, treatment status, or MRTX1133 resistance. In vivo, FGTI-2734 enhanced MRTX1133 anti-tumor activity, driving significant tumor regression in orthotopic patient-derived xenografts from a KRAS G12D pancreatic cancer patient who relapsed after radiation and chemotherapy, as well as KRAS G12D human pancreatic tumor cell xenografts. Notably, treatment of mice with FGTI-2734 inhibited MRTX1133-induced ERK reactivation in KRAS G12D pancreatic cancer xenografts.
Conclusion
These findings establish a combination strategy that overcomes a significant mechanism of resistance to MRTX1133 and offer a potential treatment option for pancreatic cancers, including those refractory to current therapies.
{"title":"FGTI-2734 prevents ERK-mediated resistance and enhances MRTX1133 efficacy in KRAS G12D pancreatic cancer","authors":"Deblina Ghosh , Aslamuzzaman Kazi , Hitesh Kumar Kantilal Vasiyani , Vignesh Vudatha , Nicolas Lecomte , Christine Iacobuzio-Donahue , Jose Trevino , Said M. Sebti","doi":"10.1016/j.ejca.2026.116255","DOIUrl":"10.1016/j.ejca.2026.116255","url":null,"abstract":"<div><h3>Introduction</h3><div>The <em>KRAS G12D</em> inhibitor MRTX1133 represents a major advance in targeting oncogenic <em>KRAS</em>, but adaptive resistance driven by ERK reactivation, dependent on wild-type (WT) RAS membrane localization, limits its efficacy.</div></div><div><h3>Results</h3><div>Here, we identify a rational strategy to overcome this resistance mechanism using FGTI-2734, a dual farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT-1) inhibitor that disrupts WT RAS membrane localization. FGTI-2734 blocks MRTX1133-induced ERK feedback reactivation and synergizes with MRTX1133 to inhibit proliferation and induce apoptosis in <em>KRAS G12D</em> pancreatic cancer cell lines. Across organoids derived from 12 patients with <em>KRAS G12D</em> pancreatic cancer, including those with primary and metastatic tumors with diverse genetic alterations (<em>KRAS, TP53, CDKN2A, SMAD4, RTKs, PI3K/AKT, JAK/STAT</em>, DNA repair/cell cycle, and chromatin modifiers), the MRTX1133/FGTI-2734 combination produced robust synergy regardless of tumor stage, treatment status, or MRTX1133 resistance. <em>In vivo</em>, FGTI-2734 enhanced MRTX1133 anti-tumor activity, driving significant tumor regression in orthotopic patient-derived xenografts from a <em>KRAS G12D</em> pancreatic cancer patient who relapsed after radiation and chemotherapy, as well as <em>KRAS G12D</em> human pancreatic tumor cell xenografts. Notably, treatment of mice with FGTI-2734 inhibited MRTX1133-induced ERK reactivation in <em>KRAS G12D</em> pancreatic cancer xenografts.</div></div><div><h3>Conclusion</h3><div>These findings establish a combination strategy that overcomes a significant mechanism of resistance to MRTX1133 and offer a potential treatment option for pancreatic cancers, including those refractory to current therapies.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"236 ","pages":"Article 116255"},"PeriodicalIF":7.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146775908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11Epub Date: 2026-01-23DOI: 10.1016/j.ejca.2026.116252
Jorge Hernando , Carlos Lopez , Alejandro Garcia-Alvarez , Santiago Aguín Losada , Olga Martínez-Sáez , Carlos Gonzalez-Perez , Ricardo López-Almaraz , Raúl Sánchez Morillas , Joseba Rebollo Liceaga , Laura Ferreira Freire , Miriam Pavon-Mengual , María Ruiz Vico , Miriam López-Gómez , Idoia Morilla , Delvys Rodríguez-Abreu , Jaume Capdevila
Background
Larotrectinib is a first-in-class, selective tropomyosin receptor kinase (TRK) inhibitor with proven activity across solid tumors. This study aimed to describe larotrectinib's effectiveness in patients with solid tumors in Spain.
Methods
SPAINTRK (NCT06837090) was a retrospective study including adult and pediatric patients with solid neoplasms treated with larotrectinib through compassionate use, between European Medicines Agency (EMA) approval and commercialization in Spain. TRK fusions were determined as part of standard care using next-generation sequencing (NGS), fluorescence in situ hybridization, or immunohistochemistry plus a confirmatory molecular test. The primary endpoint was duration of response (DoR). No formal sample size was calculated.
Results
From February to June 2025, 20 patients aged ten months to 81 years were included. Eight solid tumor types with TRK fusions were included involving NTRK1 gene in 8 patients (40 %), NTRK2 in 5 (25 %), and NTRK3 in 7 (35 %). NGS was used in 65 %. Median DoR was 24.5 months (95 % CI: 11.1- not reached) and objective response rate was 60 % (95 % CI: 36.1–80.9). At one year, 75 % of responses (9 out of 12) were ongoing, and 12 patients (60 %) remained progression-free. At data cutoff (median follow-up of 24.4 months (95 % CI: 13.2–35)), 41.7 % of the patients with a response were disease-free and/or remained on treatment. Treatment-related neutropenia and transaminitis were reported in 15 % of patients each.
Conclusions
Larotrectinib evoked broad and durable antitumor activity in a plethora of solid tumors with NTRK fusions. Safety profile was consistent with that of clinical trials, even after long-term administration. While NGS use is increasing, broader access is needed.
{"title":"Larotrectinib in patients with tropomyosin receptor kinase fusion solid tumors in Spain (SPAINTRK)","authors":"Jorge Hernando , Carlos Lopez , Alejandro Garcia-Alvarez , Santiago Aguín Losada , Olga Martínez-Sáez , Carlos Gonzalez-Perez , Ricardo López-Almaraz , Raúl Sánchez Morillas , Joseba Rebollo Liceaga , Laura Ferreira Freire , Miriam Pavon-Mengual , María Ruiz Vico , Miriam López-Gómez , Idoia Morilla , Delvys Rodríguez-Abreu , Jaume Capdevila","doi":"10.1016/j.ejca.2026.116252","DOIUrl":"10.1016/j.ejca.2026.116252","url":null,"abstract":"<div><h3>Background</h3><div>Larotrectinib is a first-in-class, selective tropomyosin receptor kinase (TRK) inhibitor with proven activity across solid tumors. This study aimed to describe larotrectinib's effectiveness in patients with solid tumors in Spain.</div></div><div><h3>Methods</h3><div>SPAINTRK (NCT06837090) was a retrospective study including adult and pediatric patients with solid neoplasms treated with larotrectinib through compassionate use, between European Medicines Agency (EMA) approval and commercialization in Spain. TRK fusions were determined as part of standard care using next-generation sequencing (NGS), fluorescence in situ hybridization, or immunohistochemistry plus a confirmatory molecular test. The primary endpoint was duration of response (DoR). No formal sample size was calculated.</div></div><div><h3>Results</h3><div>From February to June 2025, 20 patients aged ten months to 81 years were included. Eight solid tumor types with TRK fusions were included involving <em>NTRK1</em> gene in 8 patients (40 %), <em>NTRK2</em> in 5 (25 %), and <em>NTRK3</em> in 7 (35 %). NGS was used in 65 %. Median DoR was 24.5 months (95 % CI: 11.1- not reached) and objective response rate was 60 % (95 % CI: 36.1–80.9). At one year, 75 % of responses (9 out of 12) were ongoing, and 12 patients (60 %) remained progression-free. At data cutoff (median follow-up of 24.4 months (95 % CI: 13.2–35)), 41.7 % of the patients with a response were disease-free and/or remained on treatment. Treatment-related neutropenia and transaminitis were reported in 15 % of patients each.</div></div><div><h3>Conclusions</h3><div>Larotrectinib evoked broad and durable antitumor activity in a plethora of solid tumors with <em>NTRK</em> fusions. Safety profile was consistent with that of clinical trials, even after long-term administration. While NGS use is increasing, broader access is needed.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"236 ","pages":"Article 116252"},"PeriodicalIF":7.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11Epub Date: 2026-01-29DOI: 10.1016/j.ejca.2026.116263
Merlijn U.J.E. Graus , Aniek E. van Diepen , Thijmen Broekman , Casper W.F. van Eijck , Jeanin E. van Hooft , Marjolein Y.V. Homs , Miriam L. Wumkes , Johanna W. Wilmink , Ignace H.J.T. de Hingh , Liselot B.J. Valkenburg-van Iersel , Lydia G.M. van der Geest , Judith de Vos-Geelen , on behalf of the Dutch Pancreatic Cancer Group (DPCG)
Aim
The study aims to identify prognostic pre-treatment characteristics in patients with metastatic pancreatic adenocarcinoma (mPAC) initiating systemic therapy stratified for short- and long-term survival, to support personalised treatment and improve palliative care outcomes.
Methods
This retrospective nationwide study included patients diagnosed with synchronous mPAC and registered in the Netherlands Cancer Registry, 2015–2022, who received palliative systemic therapy. Patient, tumour and treatment characteristics were compared between short-term survivors (STS) (survival <90 days since diagnosis) and long-term survivors (LTS) (survival >365 days since diagnosis). A multivariate analysis was conducted to assess the independent prognostic value of various characteristics on short- and long-term survival outcomes.
Results
Among 2862 patients with mPAC, 18 % were LTS and 30 % STS. LTS showed better pre-treatment performance status, fewer cardiovascular comorbidities, smaller tumours, lower CA19–9 levels, and more frequently normal albumin and LDH levels. Lung-only metastases occurred more frequently in LTS, while multiple sites predominated in STS. LTS were more often treated with FOLFIRINOX (82 % vs. 61 %). Multivariable analysis showed that older age, poor performance, cardiovascular disease, hypalbuminaemia, elevated LDH and bilirubin levels were prognostic factors indicating worse survival, while diabetes, lower CA19–9 levels, and lung-only metastases favoured longer survival.
Conclusion
Patient- and tumour-specific characteristics strongly influence survival in mPAC patients receiving systemic therapy. These findings can support a more detailed risk stratification at diagnosis to optimise treatment selection, avoid both over- and undertreatment, and align care with individual patient expectations and values for more personalised treatment strategies.
{"title":"Comparing short- and long-term survivors in metastatic pancreatic cancer: Insights into patient and disease profiles impacting systemic therapy outcomes","authors":"Merlijn U.J.E. Graus , Aniek E. van Diepen , Thijmen Broekman , Casper W.F. van Eijck , Jeanin E. van Hooft , Marjolein Y.V. Homs , Miriam L. Wumkes , Johanna W. Wilmink , Ignace H.J.T. de Hingh , Liselot B.J. Valkenburg-van Iersel , Lydia G.M. van der Geest , Judith de Vos-Geelen , on behalf of the Dutch Pancreatic Cancer Group (DPCG)","doi":"10.1016/j.ejca.2026.116263","DOIUrl":"10.1016/j.ejca.2026.116263","url":null,"abstract":"<div><h3>Aim</h3><div>The study aims to identify prognostic pre-treatment characteristics in patients with metastatic pancreatic adenocarcinoma (mPAC) initiating systemic therapy stratified for short- and long-term survival, to support personalised treatment and improve palliative care outcomes.</div></div><div><h3>Methods</h3><div>This retrospective nationwide study included patients diagnosed with synchronous mPAC and registered in the Netherlands Cancer Registry, 2015–2022, who received palliative systemic therapy. Patient, tumour and treatment characteristics were compared between short-term survivors (STS) (survival <90 days since diagnosis) and long-term survivors (LTS) (survival >365 days since diagnosis). A multivariate analysis was conducted to assess the independent prognostic value of various characteristics on short- and long-term survival outcomes.</div></div><div><h3>Results</h3><div>Among 2862 patients with mPAC, 18 % were LTS and 30 % STS. LTS showed better pre-treatment performance status, fewer cardiovascular comorbidities, smaller tumours, lower CA19–9 levels, and more frequently normal albumin and LDH levels. Lung-only metastases occurred more frequently in LTS, while multiple sites predominated in STS. LTS were more often treated with FOLFIRINOX (82 % vs. 61 %). Multivariable analysis showed that older age, poor performance, cardiovascular disease, hypalbuminaemia, elevated LDH and bilirubin levels were prognostic factors indicating worse survival, while diabetes, lower CA19–9 levels, and lung-only metastases favoured longer survival.</div></div><div><h3>Conclusion</h3><div>Patient- and tumour-specific characteristics strongly influence survival in mPAC patients receiving systemic therapy. These findings can support a more detailed risk stratification at diagnosis to optimise treatment selection, avoid both over- and undertreatment, and align care with individual patient expectations and values for more personalised treatment strategies.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"236 ","pages":"Article 116263"},"PeriodicalIF":7.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11Epub Date: 2026-01-30DOI: 10.1016/j.ejca.2026.116267
Bhumesh Tyagi, Leelabati Toppo, Aishwarya Biradar
{"title":"Letter Re: Surgical stage in the era of molecular profiling of endometrial cancer","authors":"Bhumesh Tyagi, Leelabati Toppo, Aishwarya Biradar","doi":"10.1016/j.ejca.2026.116267","DOIUrl":"10.1016/j.ejca.2026.116267","url":null,"abstract":"","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"236 ","pages":"Article 116267"},"PeriodicalIF":7.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11Epub Date: 2026-01-30DOI: 10.1016/j.ejca.2026.116264
Michael Ong , Hiroyoshi Suzuki , Matthew Smith , Bertrand Tombal , Maha Hussain , Fred Saad , Karim Fizazi , Frank Verholen , Ha Pham , Shankar Srinivasan , Aly-Khan A. Lalani
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.
{"title":"Use of concomitant G-CSF in maintaining efficacious dose and safe delivery of docetaxel in combination with darolutamide in ARASENS: A phase III study","authors":"Michael Ong , Hiroyoshi Suzuki , Matthew Smith , Bertrand Tombal , Maha Hussain , Fred Saad , Karim Fizazi , Frank Verholen , Ha Pham , Shankar Srinivasan , Aly-Khan A. Lalani","doi":"10.1016/j.ejca.2026.116264","DOIUrl":"10.1016/j.ejca.2026.116264","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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 %).</div></div><div><h3>Results</h3><div>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 %).</div></div><div><h3>Conclusion</h3><div>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.</div></div><div><h3>Prior presentation</h3><div>Previously presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, San Francisco, CA.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"236 ","pages":"Article 116264"},"PeriodicalIF":7.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Overcoming anti-PD-L1 resistance with anti-PD1 therapy: A case report and putative rationale","authors":"Karim AMRANE , Coline LE MEUR, Christos CHOUAID, Christophe MASSARD, Aurélien MARABELLE","doi":"10.1016/j.ejca.2026.116257","DOIUrl":"10.1016/j.ejca.2026.116257","url":null,"abstract":"","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"236 ","pages":"Article 116257"},"PeriodicalIF":7.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146124221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11Epub Date: 2026-01-29DOI: 10.1016/j.ejca.2026.116260
Umberto Leone Roberti Maggiore , Francesco Fanfani , Ilaria Capasso , Emanuele Perrone , Giuseppe Parisi , Gian Franco Zannoni , Francesca Falcone , Alessandra Di Giovanni , Mario Malzoni , Anna Myriam Perrone , Francesco Mezzapesa , Pierandrea De Iaco , Simone Garzon , Pier Carlo Zorzato , Stefano Uccella , Maria Grazia Centurioni , Fabio Barra , Simone Ferrero , Dorella Franchi , Tommaso Bianchi , Francesco Raspagliesi
Background
Uterine smooth muscle tumors of uncertain malignant potential (STUMP) are rare neoplasms with unpredictable clinical behavior. Optimal management, particularly in reproductive-aged women, remains controversial, with limited data comparing the safety of fertility-sparing versus hysterectomy.
Methods
This multicentre retrospective cohort study included women aged 18–85 with histologically confirmed STUMP treated at 17 Italian gynecologic oncology centers from 2010 to 2023. Patients underwent either fertility-sparing surgery (myomectomy or hysteroscopic resection) or definitive surgery (hysterectomy ± salpingo-oophorectomy). Kaplan–Meier and Cox models were used to compare recurrence-free survival (RFS) and overall survival (OS).
Results
Median (range) follow-up was 51 (1−291) months. Among 401 women, 106 (26.4 %) received fertility-sparing treatment (mean [± SD] age: 35.3 ± 6.8 years) and 295 (73.6 %) underwent definitive surgery (mean [± SD] age: 47.7 ± 9.2). At total follow-up, recurrence occurred in 12.5 % of patients, predominantly within the pelvis. Median RFS was longer after definitive surgery than after fertility-sparing procedures (50.0 vs 42.5 months; HR 2.39 [95 % CI 1.36–4.19]), although this difference disappeared when benign (leiomyoma) recurrences were excluded (HR 1.74 [95 % CI 0.90–3.34]). At last available follow-up, 97.5 % of patients were alive, with no significant OS difference between treatment groups (HR 0.22 [95 % CI 0.27–1.79]). Outcomes were comparable across menopausal status and concurrent adnexal removal.
Conclusion
Definitive surgery reduces recurrence risk, but long-term survival is similarly excellent after fertility-sparing surgery in appropriately selected women with STUMP. Conservative management represents a reasonable option for patients desiring fertility, provided they receive counseling regarding recurrence risk, diagnostic uncertainty, and the need for long-term surveillance.
背景：子宫平滑肌肿瘤是一种临床表现难以预测的罕见肿瘤。最佳处理，特别是育龄妇女，仍然存在争议，比较保留生育能力与子宫切除术的安全性的数据有限。方法：这项多中心回顾性队列研究纳入了2010年至2023年在意大利17家妇科肿瘤中心接受组织学证实的树桩治疗的18-85岁女性。患者接受保留生育能力的手术（子宫肌瘤切除术或宫腔镜切除）或最终手术（子宫切除术±输卵管卵巢切除术）。Kaplan-Meier和Cox模型用于比较无复发生存期（RFS）和总生存期（OS）。结果：中位（范围）随访时间为51（1-291）个月。在401名女性中，106名（26.4 %）接受了保留生育能力的治疗（平均[±SD]年龄：35.3 ± 6.8岁），295名（73.6 %）接受了最终手术（平均[±SD]年龄：47.7 ± 9.2）。在总随访中，复发发生率为12. %，主要发生在骨盆内。最终手术后的中位RFS比保留生育能力手术后的中位RFS更长（50.0个月vs 42.5个月；HR 2.39[95 % CI 1.36-4.19]），尽管排除良性（平滑肌瘤）复发后这种差异消失（HR 1.74[95 % CI 0.90-3.34]）。在最后一次随访中，97.5 %的患者存活，治疗组间OS无显著差异（HR 0.22[95 % CI 0.27-1.79]）。绝经状态和同时切除附件的结果具有可比性。结论：最终手术降低了复发风险，但在适当选择的残肢残肢患者中，保留生育能力的手术后的长期生存率同样很好。对于希望生育的患者，保守治疗是一个合理的选择，前提是他们接受关于复发风险、诊断不确定性和需要长期监测的咨询。
{"title":"Fertility-sparing vs hysterectomy for uterine STUMP: A pragmatic clinical study","authors":"Umberto Leone Roberti Maggiore , Francesco Fanfani , Ilaria Capasso , Emanuele Perrone , Giuseppe Parisi , Gian Franco Zannoni , Francesca Falcone , Alessandra Di Giovanni , Mario Malzoni , Anna Myriam Perrone , Francesco Mezzapesa , Pierandrea De Iaco , Simone Garzon , Pier Carlo Zorzato , Stefano Uccella , Maria Grazia Centurioni , Fabio Barra , Simone Ferrero , Dorella Franchi , Tommaso Bianchi , Francesco Raspagliesi","doi":"10.1016/j.ejca.2026.116260","DOIUrl":"10.1016/j.ejca.2026.116260","url":null,"abstract":"<div><h3>Background</h3><div>Uterine smooth muscle tumors of uncertain malignant potential (STUMP) are rare neoplasms with unpredictable clinical behavior. Optimal management, particularly in reproductive-aged women, remains controversial, with limited data comparing the safety of fertility-sparing versus hysterectomy.</div></div><div><h3>Methods</h3><div>This multicentre retrospective cohort study included women aged 18–85 with histologically confirmed STUMP treated at 17 Italian gynecologic oncology centers from 2010 to 2023. Patients underwent either fertility-sparing surgery (myomectomy or hysteroscopic resection) or definitive surgery (hysterectomy ± salpingo-oophorectomy). Kaplan–Meier and Cox models were used to compare recurrence-free survival (RFS) and overall survival (OS).</div></div><div><h3>Results</h3><div>Median (range) follow-up was 51 (1−291) months. Among 401 women, 106 (26.4 %) received fertility-sparing treatment (mean [± SD] age: 35.3 ± 6.8 years) and 295 (73.6 %) underwent definitive surgery (mean [± SD] age: 47.7 ± 9.2). At total follow-up, recurrence occurred in 12.5 % of patients, predominantly within the pelvis. Median RFS was longer after definitive surgery than after fertility-sparing procedures (50.0 vs 42.5 months; HR 2.39 [95 % CI 1.36–4.19]), although this difference disappeared when benign (leiomyoma) recurrences were excluded (HR 1.74 [95 % CI 0.90–3.34]). At last available follow-up, 97.5 % of patients were alive, with no significant OS difference between treatment groups (HR 0.22 [95 % CI 0.27–1.79]). Outcomes were comparable across menopausal status and concurrent adnexal removal.</div></div><div><h3>Conclusion</h3><div>Definitive surgery reduces recurrence risk, but long-term survival is similarly excellent after fertility-sparing surgery in appropriately selected women with STUMP. Conservative management represents a reasonable option for patients desiring fertility, provided they receive counseling regarding recurrence risk, diagnostic uncertainty, and the need for long-term surveillance.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"236 ","pages":"Article 116260"},"PeriodicalIF":7.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146124209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11Epub Date: 2026-01-29DOI: 10.1016/j.ejca.2026.116254
Sveva Castelli , Franziska Schulze , Theresa M. Thole-Kliesch , Kathy Astrahantseff , Giuseppe Barone , Maja Beck-Popovic , Pablo Berlanga , Selim Corbacioglu , Matthias Fischer , Marion Gambart , Sally L. George , Louis Chesler , Juliet C. Gray , Barbara Hero , Annette Künkele , Tim Flaadt , Peter Lang , Holger N. Lode , Jan J. Molenaar , Gudrun Schleiermacher , Angelika Eggert
More than 50 % of patients with high-risk neuroblastoma (HRNB) will relapse despite intensive multimodal therapy. Most relapses occur within 2 years of diagnosis. Overall survival at relapse is 20 % at 4 years, but long-term survival can be achieved in a patient subset. A biopsy at relapse with in-depth molecular characterization should now become accepted as standard of care to confirm active neuroblastoma and identify potential targets for biomarker-based targeted therapy or immunotherapy. No clear consensus currently exists about optimal therapy because the field lacks umbrella trials covering all phases of relapse treatment (re-induction, consolidation, maintenance) in a homogenous strategy. Recruitment into clinical trials (e.g. BEACON2) should be prioritized. Current evidence supports starting re-induction therapy with a camptothecin-based chemotherapy regimen combined with monoclonal antibody therapy targeting GD2 or VEGF (or ALK inhibitors if ALK-aberrant) as the first choice. The RIST regimen is a promising first choice for MYCN-amplified disease. After an objective response to re-induction therapy, GD2-directed immunotherapy or cellular therapies harnessing the immune system (haploidentical stem cell transplantation, CAR T cells) are of high interest as a consolidation strategy. Long-term maintenance therapy must be feasible as outpatient treatment, have a low toxicity profile and be well-tolerable to suit patients with relapsed HRNB. For optimal care, new options must be tested as maintenance therapy in randomized trials. The most promising salvage options for patients responding insufficiently to treatment are the chemotherapy combinations, topotecan/vincristine/doxorubicin (TVD), topotecan/cyclophosphamide/etoposide (TCE), ifosfamide/carboplatin/etoposide (ICE) or topotecan/cyclophosphamide (TopoCy), or [131I]-mIBG therapy. Early-phase clinical trials are also a possible option in this setting.
{"title":"Current treatment strategies for first relapse of high-risk neuroblastoma","authors":"Sveva Castelli , Franziska Schulze , Theresa M. Thole-Kliesch , Kathy Astrahantseff , Giuseppe Barone , Maja Beck-Popovic , Pablo Berlanga , Selim Corbacioglu , Matthias Fischer , Marion Gambart , Sally L. George , Louis Chesler , Juliet C. Gray , Barbara Hero , Annette Künkele , Tim Flaadt , Peter Lang , Holger N. Lode , Jan J. Molenaar , Gudrun Schleiermacher , Angelika Eggert","doi":"10.1016/j.ejca.2026.116254","DOIUrl":"10.1016/j.ejca.2026.116254","url":null,"abstract":"<div><div>More than 50 % of patients with high-risk neuroblastoma (HRNB) will relapse despite intensive multimodal therapy. Most relapses occur within 2 years of diagnosis. Overall survival at relapse is 20 % at 4 years, but long-term survival can be achieved in a patient subset. A biopsy at relapse with in-depth molecular characterization should now become accepted as standard of care to confirm active neuroblastoma and identify potential targets for biomarker-based targeted therapy or immunotherapy. No clear consensus currently exists about optimal therapy because the field lacks umbrella trials covering all phases of relapse treatment (re-induction, consolidation, maintenance) in a homogenous strategy. Recruitment into clinical trials (e.g. BEACON2) should be prioritized. Current evidence supports starting re-induction therapy with a camptothecin-based chemotherapy regimen combined with monoclonal antibody therapy targeting GD2 or VEGF (or ALK inhibitors if <em>ALK</em>-aberrant) as the first choice. The RIST regimen is a promising first choice for <em>MYCN</em>-amplified disease. After an objective response to re-induction therapy, GD2-directed immunotherapy or cellular therapies harnessing the immune system (haploidentical stem cell transplantation, CAR T cells) are of high interest as a consolidation strategy. Long-term maintenance therapy must be feasible as outpatient treatment, have a low toxicity profile and be well-tolerable to suit patients with relapsed HRNB. For optimal care, new options must be tested as maintenance therapy in randomized trials. The most promising salvage options for patients responding insufficiently to treatment are the chemotherapy combinations, topotecan/vincristine/doxorubicin (TVD), topotecan/cyclophosphamide/etoposide (TCE), ifosfamide/carboplatin/etoposide (ICE) or topotecan/cyclophosphamide (TopoCy), or [<sup>131</sup>I]-mIBG therapy. Early-phase clinical trials are also a possible option in this setting.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"236 ","pages":"Article 116254"},"PeriodicalIF":7.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146124187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11Epub Date: 2026-01-30DOI: 10.1016/j.ejca.2026.116265
Friederike C. Althoff , Horst-Dieter Hummel , Konrad Kokowski , Corinna Elender , Christian Grah , Stefan Zacharias , Annette Fleitz , Martina Jänicke , Annika Groth , Paula Ludwig , Arnd Nusch , Marcel Reiser , Henning Pelz , Jörg Wiegand , Frank Griesinger , Michael Thomas , Wilfried E.E. Eberhardt , Martin Sebastian , for the CRISP Registry Group
Background
Molecular testing in NSCLC is essential for treatment selection, yet routine implementation remains inconsistent across institutions. Clinical evidence suggests that variability in testing may not be explained by patient or tumor characteristics but might be driven by institutional factors, potentially leading to adverse outcomes. We examined the extent to which variability in AGA testing is attributable to the treating institution.
Methods
We analyzed 6437 adults with stage IIIB/C or IV NSCLC enrolled in the prospective German real-world registry CRISP (2016–2022). Logistic mixed-effects models with AGA testing as the primary outcome were used to determine institutional variability across 171 institutions. Models included patient, tumor, and treatment-related fixed effects with institutions as random effects. Intraclass correlations (ICC) quantified institutional variability unexplained by other covariates. Institution type was tested in secondary analysis, and overall survival in exploratory analysis.
Findings
AGA testing was performed in 77.9 % of patients (n = 5016). Predicted probabilities for testing use ranged from 30.5 % to 93.2 % across institutions. Institutions significantly influenced testing use (p < 0.001), accounting for 21.4 % of the total variance. Variability significantly differed by institution type and was more pronounced in subgroups, e.g., squamous histology (ICC 29.5 %) and KRAS testing (ICC 34.4 %). Absence of AGA testing was independently associated with inferior survival (HRadj 1.11, 95 % CI 1.01–1.23, p = 0.029).
Interpretation
Substantial institutional variability exists in AGA testing for NSCLC, which was unexplained by patient or tumor characteristics. This objective evaluation of institution-based variability in testing may emphasize the importance of practice patterns on patient care and may therefore provide an avenue for change.
{"title":"Institutional variability in testing for actionable genetic alterations in patients with stage IIIB/C or IV non-small cell lung cancer: A real-world study from the German prospective, observational, multicenter CRISP registry (AIO-TRK-0315)","authors":"Friederike C. Althoff , Horst-Dieter Hummel , Konrad Kokowski , Corinna Elender , Christian Grah , Stefan Zacharias , Annette Fleitz , Martina Jänicke , Annika Groth , Paula Ludwig , Arnd Nusch , Marcel Reiser , Henning Pelz , Jörg Wiegand , Frank Griesinger , Michael Thomas , Wilfried E.E. Eberhardt , Martin Sebastian , for the CRISP Registry Group","doi":"10.1016/j.ejca.2026.116265","DOIUrl":"10.1016/j.ejca.2026.116265","url":null,"abstract":"<div><h3>Background</h3><div>Molecular testing in NSCLC is essential for treatment selection, yet routine implementation remains inconsistent across institutions. Clinical evidence suggests that variability in testing may not be explained by patient or tumor characteristics but might be driven by institutional factors, potentially leading to adverse outcomes. We examined the extent to which variability in AGA testing is attributable to the treating institution.</div></div><div><h3>Methods</h3><div>We analyzed 6437 adults with stage IIIB/C or IV NSCLC enrolled in the prospective German real-world registry CRISP (2016–2022). Logistic mixed-effects models with AGA testing as the primary outcome were used to determine institutional variability across 171 institutions. Models included patient, tumor, and treatment-related fixed effects with institutions as random effects. Intraclass correlations (ICC) quantified institutional variability unexplained by other covariates. Institution type was tested in secondary analysis, and overall survival in exploratory analysis.</div></div><div><h3>Findings</h3><div>AGA testing was performed in 77.9 % of patients (n = 5016). Predicted probabilities for testing use ranged from 30.5 % to 93.2 % across institutions. Institutions significantly influenced testing use (p < 0.001), accounting for 21.4 % of the total variance. Variability significantly differed by institution type and was more pronounced in subgroups, e.g., squamous histology (ICC 29.5 %) and KRAS testing (ICC 34.4 %). Absence of AGA testing was independently associated with inferior survival (HRadj 1.11, 95 % CI 1.01–1.23, p = 0.029).</div></div><div><h3>Interpretation</h3><div>Substantial institutional variability exists in AGA testing for NSCLC, which was unexplained by patient or tumor characteristics. This objective evaluation of institution-based variability in testing may emphasize the importance of practice patterns on patient care and may therefore provide an avenue for change.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"236 ","pages":"Article 116265"},"PeriodicalIF":7.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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