Annals of Oncology最新文献

{"title":"FOxTROT: is anti-EGFR a good dancing partner?","authors":"C. Montagut , V. Martelli , J. Vidal","doi":"10.1016/j.annonc.2025.02.001","DOIUrl":"10.1016/j.annonc.2025.02.001","url":null,"abstract":"","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"36 5","pages":"Pages 475-477"},"PeriodicalIF":56.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381584","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":"Genomic landscape of clinically acquired resistance alterations in patients treated with KRAS^G12C inhibitors.","authors":"J M Riedl, F Fece de la Cruz, J J Lin, C Parseghian, J E Kim, H Matsubara, H Barnes, B Caughey, B L Norden, A A Morales-Giron, E W Kushner, S Ehnstrom, H Nakamura, P S Patel, H Ellis, L Pappas, A Vakaris, J F Gainor, S Kopetz, S J Klempner, A R Parikh, A N Hata, R S Heist, R B Corcoran","doi":"10.1016/j.annonc.2025.01.020","DOIUrl":"10.1016/j.annonc.2025.01.020","url":null,"abstract":"<p><strong>Background: </strong>Mutant-selective inhibitors of KRAS^G12C (KRAS^G12Ci) have demonstrated efficacy in KRAS^G12C cancers. However, resistance invariably develops, resulting in short-lived responses. We aimed to define the genomic landscape of acquired resistance to KRAS^G12Ci and to elucidate whether novel classes of KRAS inhibitors can overcome these resistance mechanisms.</p><p><strong>Methods: </strong>To assess clinical frequencies of acquired resistance alterations, we evaluated genomic sequencing data from postprogression cell-free DNA samples in patients treated with KRAS^G12Ci at two United States cancer centers, alongside data from six previously published studies. Cell viability assays using engineered cell models were employed to functionally validate candidate resistance drivers and to evaluate novel classes of KRAS inhibitors.</p><p><strong>Results: </strong>A total of 143 patients were analyzed. Most patients had non-small-cell lung cancer (NSCLC, n = 68) or colorectal cancer (CRC, n = 58) and were treated with single-agent KRAS^G12Ci (n = 109) or combined with anti-EGFR antibodies (n = 30). RAS/MAPK alterations emerged in 46% of patients (n = 66), with 39% developing one or more new KRAS alterations (n = 56) and 23% (n = 33) showing multiple concurrent alterations. The genomic landscape of acquired alterations included KRAS-activating mutations (25% of patients), KRAS amplifications (22%), RAF/MAPK mutations/fusions (21%), KRAS switch-II pocket mutations (14%), and NRAS/HRAS mutations (8%). Notably, the proportion of patients with one or more acquired RAS/MAPK alteration was significantly higher in CRC compared with NSCLC (69% versus 26%, P < 0.001). Functional studies confirmed most alterations as resistance drivers. Sotorasib, adagrasib, and divarasib demonstrated distinct activity against KRAS switch-II pocket mutations, yet all were responsive to the RAS(ON) G12C-selective tri-complex inhibitor RM-018. The KRAS-selective inhibitor Pan KRAS-IN-1 effectively targeted KRAS-activating mutations, and the RAS(ON) multiselective tri-complex inhibitor RMC-7797 demonstrated high potency across all RAS alterations.</p><p><strong>Conclusions: </strong>Acquired RAS/MAPK alterations are recurrent drivers of resistance to KRAS^G12Ci detected in CRC and, less frequently, in NSCLC. Preclinical data suggest that novel (K)RAS inhibitors may overcome many of these resistance alterations.</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":56.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363589","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":"Whole genome sequencing-powered ctDNA sequencing for breast cancer detection.","authors":"I Garcia-Murillas, C W Abbott, R J Cutts, S M Boyle, J Pugh, K C Keough, B Li, R M Pyke, F C P Navarro, R O Chen, K Dunne, C Bunce, S R D Johnston, A Ring, S Russell, A Evans, A Skene, I E Smith, N C Turner","doi":"10.1016/j.annonc.2025.01.021","DOIUrl":"10.1016/j.annonc.2025.01.021","url":null,"abstract":"<p><strong>Background: </strong>Circulating tumour DNA (ctDNA)-based detection of molecular residual disease (MRD) presents a strategy to identify patients at high risk of relapse. In this article, we profile early breast cancer patients with an ultrasensitive, whole genome sequencing (WGS)-based, tumour-informed ctDNA platform.</p><p><strong>Materials and methods: </strong>We analysed 617 plasma samples (median 8, range 2-14) from 78 patients (23 triple-negative breast cancer, 35 human epidermal growth factor receptor 2-positive, 18 hormone receptor-positive, and 2 unknown). Samples were collected at diagnosis before therapy, cycle 2 of neoadjuvant chemotherapy, post-surgery after neoad'juvant therapy if administered, every 3 months during the first year, and every 6 months thereafter. Plasma DNA was analysed using the NeXT Personal MRD platform, a tumour-informed WGS approach to produce personalized ctDNA sequencing panels tracking a median of 1451 variants per patient. MRD detection was correlated with clinical outcomes.</p><p><strong>Results: </strong>ctDNA was detected at levels ranging from 2.19 parts per million (PPM) to 204 900 PPM (median 405 PPM), with 39% of all ctDNA detections in the ultra-low range <100 PPM. Of patients with samples at diagnosis, 98% (49/50) had ctDNA detected before treatment. At a median follow-up of 76 months (range 5-118 months), detection of ctDNA was associated with high risk of future relapse (P < 0.0001; log-rank test) and shortened overall survival (P < 0.0001) with a median lead time from ctDNA detection to clinical relapse of 15 months (range 0.9-61.5 months). MRD was identified in 100% (11/11) of patients who relapsed, with a median level of ctDNA at first MRD detection of 13.1 PPM. No ctDNA-undetected patients relapsed throughout follow-up (64/64). Comparison with exome-powered MRD detection assays showed improved sensitivity and lead time.</p><p><strong>Conclusions: </strong>A whole genome-powered MRD assay detected breast cancer relapse with a long lead time over clinical relapse, and was strongly associated with relapse-free survival. Rates of ctDNA detection at diagnosis were higher than those reported with exome-based tumour-informed assays.</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":56.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363608","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":"TNBC-DX genomic test in early-stage triple-negative breast cancer treated with neoadjuvant taxane-based therapy☆","authors":"M. Martín ,&nbsp;S.R. Stecklein ,&nbsp;O. Gluz ,&nbsp;G. Villacampa ,&nbsp;M. Monte-Millán ,&nbsp;U. Nitz ,&nbsp;S. Cobo ,&nbsp;M. Christgen ,&nbsp;F. Brasó-Maristany ,&nbsp;E.L. Álvarez ,&nbsp;I. Echavarría ,&nbsp;B. Conte ,&nbsp;S. Kuemmel ,&nbsp;C. Bueno-Muiño ,&nbsp;Y. Jerez ,&nbsp;R. Kates ,&nbsp;M. Cebollero ,&nbsp;C. Kolberg-Liedtke ,&nbsp;O. Bueno ,&nbsp;J.Á. García-Saenz ,&nbsp;N. Harbeck","doi":"10.1016/j.annonc.2024.10.012","DOIUrl":"10.1016/j.annonc.2024.10.012","url":null,"abstract":"<div><h3>Background</h3><div>Identification of biomarkers to optimize treatment strategies for early-stage triple-negative breast cancer (TNBC) is crucial. This study presents the development and validation of TNBC-DX, a novel test aimed at predicting both short- and long-term outcomes in early-stage TNBC. The objective of this study was to evaluate the association between TNBC-DX and efficacy outcomes [pathologic complete response (pCR), distant disease-free survival (DDFS) or event-free survival (EFS), and overall survival (OS)] in the validation cohorts.</div></div><div><h3>Methods</h3><div>Information from 1259 patients with early-stage TNBC (SCAN-B, CALGB-40603, and BrighTNess) was used to establish the TNBC-DX scores. Independent validation of TNBC-DX was carried out in three studies: (i) WSG-ADAPT-TN; (ii) MMJ-CAR-2014-01; and (iii) NeoPACT, including 527 patients with stage I-III TNBC undergoing neoadjuvant chemotherapy. In WSG-ADAPT-TN, patients were randomized to receive nab-paclitaxel plus gemcitabine or carboplatin. In MMJ-CAR-2014-01, patients received carboplatin plus docetaxel. In NeoPACT, patients received carboplatin plus docetaxel and pembrolizumab.</div></div><div><h3>Results</h3><div>TNBC-DX test was created incorporating the 10-gene Core Immune Gene module, the 4-gene tumor cell proliferation signature, tumor size, and nodal staging. In the two independent validation cohorts without pembrolizumab, the TNBC-DX pCR score was significantly associated with pCR after adjustment for clinicopathological variables and treatment regimen [odds ratio per 10-unit increment 1.34, 95% confidence interval (CI) 1.20-1.52, <em>P</em> &lt; 0.001]. pCR rates for the TNBC-DX pCR-high, pCR-medium, and pCR-low categories were 56.3%, 53.6%, and 22.5% respectively (odds ratio for pCR-high versus pCR-low 3.48, 95% CI 1.72-7.15, <em>P</em> &lt; 0.001). In addition, the TNBC-DX risk score was significantly associated with DDFS [hazard ratio (HR) high-risk versus low-risk 0.24, 95% CI 0.15-0.41, <em>P</em> &lt; 0.001] and OS (HR 0.19, 95% CI 0.11-0.35, <em>P</em> &lt; 0.001). In the validation cohort with pembrolizumab, the TNBC-DX scores were significantly associated with pCR, EFS, and OS.</div></div><div><h3>Conclusions</h3><div>TNBC-DX predicts pCR to neoadjuvant taxane–carboplatin in stage I-III TNBC and helps to forecast the patient’s long-term survival in the absence of neoadjuvant anthracycline–cyclophosphamide, and independent of pembrolizumab use.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"36 2","pages":"Pages 158-171"},"PeriodicalIF":56.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogens and breast cancer","authors":"J. Kim ,&nbsp;P.N. Munster","doi":"10.1016/j.annonc.2024.10.824","DOIUrl":"10.1016/j.annonc.2024.10.824","url":null,"abstract":"<div><div>Estrogens have been associated with an increase in breast cancer risk. Yet emerging clinical and experimental evidence points to progestogens [endogenous progesterone or synthetic progesterone (progestin)] as the primary hormonal driver underlying seemingly estrogen-associated breast cancer risk. Estrogens may contribute to breast cancer risk indirectly by induction of the progesterone receptor and thus amplifying progesterone signaling. Large studies of hormonal contraceptives suggest that the small increase in breast cancer risk from hormonal contraceptives is mainly attributable to progestins, not estrogens. Estrogen-plus-progestin hormone replacement therapy (HRT) has consistently shown an increase in breast cancer risk among postmenopausal women, whereas estrogen-alone HRT has little impact on breast cancer risk in naturally or surgically menopausal women. In particular, the long-term follow-up of the Women’s Health Initiative (WHI) randomized trials suggests a benefit of estrogen alone. Recent data further indicate that endogenously elevated estrogen during assisted reproductive technology (ART) exhibits little adverse effect on or potentially a reduction in breast cancer risk and recurrence. Also, accumulating evidence suggests that inhibition of progesterone signaling is a critical mechanism underlying the risk-reducing and therapeutic effects of antiestrogens. Estrogen HRT has shown an array of proven benefits, including ameliorating menopausal symptoms and improving bone health. Collective evidence thus suggests that estrogen HRT is likely to offer health benefits to perimenopausal or postmenopausal women, including breast cancer survivors, as well as young <em>BRCA</em><em>1/2</em> carriers with prophylactic oophorectomy for ovarian cancer prevention.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"36 2","pages":"Pages 134-148"},"PeriodicalIF":56.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adjuvant immunotherapy in patients with resected gastric and oesophagogastric junction cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1): European Organisation of Research and Treatment of Cancer (EORTC) 1707 VESTIGE study","authors":"F. Lordick ,&nbsp;M.E. Mauer ,&nbsp;G. Stocker ,&nbsp;C.A. Cella ,&nbsp;I. Ben-Aharon ,&nbsp;G. Piessen ,&nbsp;L. Wyrwicz ,&nbsp;G. Al-Haidari ,&nbsp;T. Fleitas-Kanonnikoff ,&nbsp;V. Boige ,&nbsp;R. Lordick Obermannová ,&nbsp;U.M. Martens ,&nbsp;C. Gomez-Martin ,&nbsp;P. Thuss-Patience ,&nbsp;V. Arrazubi ,&nbsp;A. Avallone ,&nbsp;K.K. Shiu ,&nbsp;P. Artru ,&nbsp;B. Brenner ,&nbsp;C. Buges Sanchez ,&nbsp;E. Smyth","doi":"10.1016/j.annonc.2024.10.829","DOIUrl":"10.1016/j.annonc.2024.10.829","url":null,"abstract":"<div><h3>Background</h3><div>Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection.</div></div><div><h3>Patients and methods</h3><div>VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.</div></div><div><h3>Results</h3><div>The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided <em>P</em> = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations.</div></div><div><h3>Conclusion</h3><div>Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"36 2","pages":"Pages 197-207"},"PeriodicalIF":56.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The immunotherapy challenge in locally advanced gastroesophageal cancer: VESTIGE trial’s insights and future pathways","authors":"I. Nakayama ,&nbsp;Y. Nakamura ,&nbsp;K. Shitara","doi":"10.1016/j.annonc.2024.11.004","DOIUrl":"10.1016/j.annonc.2024.11.004","url":null,"abstract":"","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"36 2","pages":"Pages 130-133"},"PeriodicalIF":56.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765598","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":"Expanding the role of CDK4/6 inhibitors in early breast cancer: insights from the NATALEE trial","authors":"Marcela Carausu ,&nbsp;Patrick Neven ,&nbsp;Michail Ignatiadis","doi":"10.1016/j.annonc.2025.01.004","DOIUrl":"10.1016/j.annonc.2025.01.004","url":null,"abstract":"","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"36 2","pages":"Pages 127-129"},"PeriodicalIF":56.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063205","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":"Authors’ reply to the Letters to the Editor discussing main outcomes of the PRODIGE 23 study","authors":"T. Conroy ,&nbsp;S. Gourgou ,&nbsp;C. Borg","doi":"10.1016/j.annonc.2024.10.007","DOIUrl":"10.1016/j.annonc.2024.10.007","url":null,"abstract":"","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"36 2","pages":"Pages 216-218"},"PeriodicalIF":56.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456506","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":"Chi-square and P-values versus machine learning feature selection","authors":"Y. Takefuji","doi":"10.1016/j.annonc.2024.10.013","DOIUrl":"10.1016/j.annonc.2024.10.013","url":null,"abstract":"","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"36 2","pages":"Pages 227-228"},"PeriodicalIF":56.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456507","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}