Summary Background Cancer of unknown primary ranks in the top ten cancer presentations and has an extremely poor prognosis. Identification of the primary tumour and development of a tailored ...site-specific therapy could improve the survival of these patients. We examined the feasability of using DNA methylation profiles to determine the occult original cancer in cases of cancer of unknown primary. Methods We established a classifier of cancer type based on the microarray DNA methylation signatures (EPICUP) in a training set of 2790 tumour samples of known origin representing 38 tumour types and including 85 metastases. To validate the classifier, we used an independent set of 7691 known tumour samples from the same tumour types that included 534 metastases. We applied the developed diagnostic test to predict the tumour type of 216 well-characterised cases of cancer of unknown primary. We validated the accuracy of the predictions from the EPICUP assay using autopsy examination, follow-up for subsequent clinical detection of the primary sites months after the initial presentation, light microscopy, and comprehensive immunohistochemistry profiling. Findings The tumour type classifier based on the DNA methylation profiles showed a 99·6% specificity (95% CI 99·5–99·7), 97·7% sensitivity (96·1–99·2), 88·6% positive predictive value (85·8–91·3), and 99·9% negative predictive value (99·9–100·0) in the validation set of 7691 tumours. DNA methylation profiling predicted a primary cancer of origin in 188 (87%) of 216 patients with cancer with unknown primary. Patients with EPICUP diagnoses who received a tumour type-specific therapy showed improved overall survival compared with that in patients who received empiric therapy (hazard ratio HR 3·24, p=0·0051 95% CI 1·42–7·38; log-rank p=0·0029). Interpretation We show that the development of a DNA methylation based assay can significantly improve diagnoses of cancer of unknown primary and guide more precise therapies associated with better outcomes. Epigenetic profiling could be a useful approach to unmask the original primary tumour site of cancer of unknown primary cases and a step towards the improvement of the clinical management of these patients. Funding European Research Council (ERC), Cellex Foundation, the Institute of Health Carlos III (ISCIII), Cancer Australia, Victorian Cancer Agency, Samuel Waxman Cancer Research Foundation, the Health and Science Departments of the Generalitat de Catalunya, and Ferrer.
Abstract The prognostic value of human epidermal growth factor receptor 2 (HER2) in gastric cancer is controversial. Consensus guidelines have standardized the testing of HER2 status in gastric ...cancer. Overexpression of this receptor occurs in approximately 20% of gastric and gastro-esophageal junction adenocarcinomas, predominantly those of the intestinal type. Recently, trastuzumab has emerged as the first targeted drug to improve overall survival when combined with chemotherapy in advanced HER2-positive gastric cancer. Primary and secondary resistance to trastuzumab has become a major problem and new strategies to overcome this resistance are needed. A high percentage of advanced HER2-positive gastric cancer patients who progress on trastuzumab therapy are candidates for second-line therapy. New families of targeted drugs, including tyrosine kinase inhibitors (TKIs) such as lapatinib and PF-00299804, mammalian target of rapamycin (mTOR) pathway inhibitors such as everolimus, heat-shock protein 90 (HSP90) inhibitors such as AUY922, HER dimerization inhibitors such as pertuzumab, and antibody-chemotherapy conjugates such as trastuzumab-emtansine (T-DM1), could offer alternative second-line treatments when trastuzumab-based first-line therapy fails.
Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies, with few treatment options. NAPOLI 3 aimed to compare the efficacy and safety of NALIRIFOX versus nab-paclitaxel and ...gemcitabine as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC).
NAPOLI 3 was a randomised, open-label, phase 3 study conducted at 187 community and academic sites in 18 countries worldwide across Europe, North America, South America, Asia, and Australia. Patients with mPDAC and Eastern Cooperative Oncology Group performance status score 0 or 1 were randomly assigned (1:1) to receive NALIRIFOX (liposomal irinotecan 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2, administered sequentially as a continuous intravenous infusion over 46 h) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2, administered intravenously, on days 1, 8, and 15 of a 28-day cycle. Balanced block randomisation was stratified by geographical region, performance status, and liver metastases, managed through an interactive web response system. The primary endpoint was overall survival in the intention-to-treat population, evaluated when at least 543 events were observed across the two treatment groups. Safety was evaluated in all patients who received at least one dose of study treatment. This completed trial is registered with ClinicalTrials.gov, NCT04083235.
Between Feb 19, 2020 and Aug 17, 2021, 770 patients were randomly assigned (NALIRIFOX, 383; nab-paclitaxel–gemcitabine, 387; median follow-up 16·1 months IQR 13·4–19·1). Median overall survival was 11·1 months (95% CI 10·0–12·1) with NALIRIFOX versus 9·2 months (8·3–10·6) with nab-paclitaxel–gemcitabine (hazard ratio 0·83; 95% CI 0·70–0·99; p=0·036). Grade 3 or higher treatment-emergent adverse events occurred in 322 (87%) of 370 patients receiving NALIRIFOX and 326 (86%) of 379 patients receiving nab-paclitaxel–gemcitabine; treatment-related deaths occurred in six (2%) patients in the NALIRIFOX group and eight (2%) patients in the nab-paclitaxel–gemcitabine group.
Our findings support use of the NALIRIFOX regimen as a possible reference regimen for first-line treatment of mPDAC.
Ipsen.
For the plain language summary see Supplementary Materials section.
HER2 is overexpressed or amplified in a subset of biliary tract cancer. Zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, exhibited tolerability and preliminary anti-tumour ...activity in HER2-expressing or HER2 (also known as ERBB2)-amplified treatment-refractory biliary tract cancer.
HERIZON-BTC-01 is a global, multicentre, single-arm, phase 2b trial of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer with disease progression on previous gemcitabine-based therapy, recruited at 32 clinical trial sites in nine countries in North America, South America, Asia, and Europe. Eligible patients were aged 18 years or older with HER2-amplified biliary tract cancer confirmed by in-situ hybridisation per central testing, at least one measurable target lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were assigned into cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab 20 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review. Anti-tumour activity and safety were assessed in all participants who received any dose of zanidatamab. This trial is registered with ClinicalTrials.gov, NCT04466891, is ongoing, and is closed to recruitment.
Between Sept 15, 2020, and March 16, 2022, 87 patients were enrolled in HERIZON-BTC-01: 80 in cohort 1 (45 56% were female and 35 44% were male; 52 65% were Asian; median age was 64 years IQR 58–70) and seven in cohort 2 (five 71% were male and two 29% were female; five 71% were Asian; median age was 62 years IQR 58–77). At the time of the data cutoff (Oct 10, 2022), 18 (21%) patients (17 in cohort 1 and one in cohort 2) were continuing to receive zanidatamab; 69 (79%) discontinued treatment (radiographic progression in 64 74% patients). The median duration of follow-up was 12·4 months (IQR 9·4–17·2). Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41·3% 95% CI 30·4–52·8). 16 (18%) patients had grade 3 treatment-related adverse events; the most common were diarrhoea (four 5% patients) and decreased ejection fraction (three 3% patients). There were no grade 4 treatment-related adverse events and no treatment-related deaths.
Zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer. These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer.
Zymeworks, Jazz, and BeiGene.
Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal ...adenocarcinoma
. Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial
(programmed death ligand-1 (PD-L1) combined positive score ≥5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries
. Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively
. Treatment combining 1 mg kg
nivolumab with 3 mg kg
ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer
. Here we report both long-term follow-up results comparing nivolumab plus chemotherapy versus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive score ≥5 (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score ≥ 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma.
Patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) have poor prognosis. For these patients, treatment options are limited after first-line systemic therapy.
In this ...open-label phase III clinical study, patients with advanced or metastatic ESCC, whose tumor progressed after first-line systemic treatment, were randomly assigned (1:1) to receive intravenous tislelizumab, an anti-programmed cell death protein 1 antibody, 200 mg every 3 weeks or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). The primary end point was overall survival (OS) in all patients. The key secondary end point was OS in patients with programmed death-ligand 1 tumor area positivity (TAP) score ≥ 10%.
In total, 512 patients across 11 countries/regions were randomly assigned. At final analysis, conducted after 410 death events occurred, OS was significantly longer with tislelizumab versus chemotherapy in all patients (median, 8.6
6.3 months; hazard ratio HR, 0.70 95% CI, 0.57 to 0.85; one-sided
= .0001), and in patients with TAP ≥ 10% (median, 10.3 months
6.8 months; HR, 0.54 95% CI, 0.36 to 0.79; one-sided
= .0006). Survival benefit was consistently observed across all predefined subgroups, including those defined by baseline TAP score, region, and race. Treatment with tislelizumab was associated with higher objective response rate (20.3%
9.8%) and a more durable antitumor response (median, 7.1 months
4.0 months) versus chemotherapy in all patients. Fewer patients experienced ≥ grade 3 treatment-related adverse events (18.8%
55.8%) with tislelizumab versus chemotherapy.
Tislelizumab significantly improved OS compared with chemotherapy as second-line therapy in patients with advanced or metastatic ESCC, with a tolerable safety profile. Patients with programmed death-ligand 1 TAP ≥ 10% also demonstrated statistically significant survival benefit with tislelizumab versus chemotherapy.
Background
HER2‐positive gastric cancer (GC) affects 7%–34% of patients with GC. Trastuzumab‐based first‐line treatment has become the standard of care for HER2‐positive advanced gastric cancer ...(AGC). However, there are no clinically validated biomarkers for resistance to HER2‐targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2‐positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2‐positive AGC treated with trastuzumab.
Patients and Methods
Forty‐two HER2‐positive GC samples from patients treated with trastuzumab‐based first‐line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed.
Results
Concurrent genetic alterations were detected in 97.1% of HER2‐positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression‐free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab‐based chemotherapy in terms of OS and PFS.
Conclusion
Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2‐positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab.
Implications for Practice
This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2‐positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression‐free survival in AGC treated with trastuzumab‐based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2‐positive AGC.
摘要
背景。HER2阳性胃癌(GC)占所有胃癌的7%‐34% 。基于曲妥珠单抗的一线疗法已经成为HER2阳性晚期胃癌 (AGC)的标准治疗方法。然而,关于HER2靶向治疗耐药性,尚无经过临床验证的生物标志物。上调PI3K信号通路和酪氨酸激酶受体(TKR)改变已经被视为乳腺癌耐药性的分子机制。我们的研究旨在揭示HER2阳性AGC的分子特征,探索PI3K/Akt/mTOR信号通路激活和TKR基因拷贝数(GCN)增加作为预测性生物标志物在曲妥珠单抗经治HER2阳性AGC患者中的作用。
患者和方法。从接受基于曲妥珠单抗一线化疗方案治疗的患者中选取42份HER2阳性胃癌样本。DNA样本测序。实施PTEN和MET免疫组化。
结果。在97.1%的HER2阳性AGC样本中检测出并发的基因改变。我们在52.4%的患者中发现PI3K/Akt/mTOR信号通路激活,在38.1%的患者中发现TKR GCN增加。TKR GCN增加与总生存期(OS)或无进展生存期(PFS)无关。多变量Cox模型显示,PI3K/Akt/mTOR激活对基于曲妥珠单抗化疗的有效性(在OS和PFS方面)产生不利影响。
结论。我们的结果首次提供了HER2阳性AGC并发基因改变的详细分子谱。PI3K信号通路激活可作为此类患者人群预后不良的预测性标志物。此外,此类亚组人群中其它TKR基因拷贝数的增加也可能影响曲妥珠单抗治疗的生存益处。
实践意义:本文首次报告了HER2阳性晚期胃癌(AGC)患者基因改变的详细分子谱。PI3K/Akt/mTOR信号通路激活看起来对接受基于曲妥珠单抗化疗方案治疗的AGC患者的总生存期和无进展生存期产生了不同的不利作用。不同靶向药物的联合应用可能是改善HER2阳性AGC预后的成功治疗策略。
This article describes genomic profiling of patients with HER2‐positive advanced gastric cancer who were treated with first‐line trastuzumab‐based chemotherapy, focusing on whether PI3K/Akt/mTOR pathway status could be relevant in selecting suitable patients for targeted therapies.
Exosomes are endocytic-extracellular vesicles with a diameter around 100 nm that play an essential role on the communication between cells. In fact, they have been proposed as candidates for the ...diagnosis and the monitoring of different pathologies (such as Parkinson, Alzheimer, diabetes, cardiac damage, infection diseases or cancer). In this study, magnetic nanoparticles (Fe.sub.3O.sub.4NPs) were successfully functionalized with an exosome-binding antibody (anti-CD9) to mediate the magnetic capture in a microdevice. This was carried out under flow in a 1.6 mm (outer diameter) microchannel whose wall was in contact with a set of NdFeB permanent magnets, giving a high magnetic field across the channel diameter that allowed exosome separation with a high yield. To show the usefulness of the method, the direct capture of exosomes from whole blood of patients with pancreatic cancer (PC) was performed, as a proof of concept. The captured exosomes were then subjected to analysis of CA19-9, a protein often used to monitor PC patients. Here, we describe a new microfluidic device and the procedure for the isolation of exosomes from whole blood, without any need of previous isolation steps, thereby facilitating translation to the clinic. The results show that, for the cases analyzed, the evaluation of CA19-9 in exosomes was highly sensitive, compared to serum samples.
Previous studies have highlighted the importance of an appropriate human epidermal growth factor receptor 2 (HER2) evaluation for the proper identification of patients eligible for treatment with ...anti-HER2 targeted therapies. Today, the relationship remains unclear between the level of HER2 amplification and the outcome of HER2-positive gastric cancer treated with first-line chemotherapy with trastuzumab. The aim of this study was to determine whether the level of HER2 gene amplification determined by the HER2/CEP17 ratio and HER2 gene copy number could significantly predict some benefit in overall survival and response to therapy in advanced gastric cancer treated with trastuzumab-based chemotherapy.
Ninety patients with metastatic gastric cancer treated with first-line trastuzumab-based chemotherapy were studied. The optimal cutoff values for HER2/CEP17 ratio and HER2 gene copy number (GCN) for discriminating positive results in terms of response and prolonged survival were determined using receiver operating characteristic curves analyses.
In this study, a median HER2/CEP17 ratio of 6.11 (95% CI, 2.27 to 21.90) and a median HER2 gene copy number of 11.90 (95% CI, 3.30 to 43.80) were found. A mean HER2/CEP17 ratio of 4.7 was identified as the optimal cutoff value discriminating sensitive and refractory patients (P = .005). Similarly, the optimal cutoff for predicting survival longer than 12 months was 4.45 (P = .005), and for survival longer than 16 months was 5.15 (P = .004). For HER2 GCN, the optimal cutoff values were 9.4, 10.0, and 9.5, respectively (P = .02).
The level of HER2 gene amplification significantly predicts sensitivity to therapy and overall survival in advanced gastric cancer treated with trastuzumab-based chemotherapy.
Desmoid-Type Fibromatosis: Who, When, and How to Treat Martínez Trufero, Javier; Pajares Bernad, Isabel; Torres Ramón, Irene ...
Current treatment options in oncology,
05/2017, Letnik:
18, Številka:
5
Journal Article
Recenzirano
Opinion statement
Desmoid-type fibromatosis is a sarcoma subtype that gathers some singular characteristics, making it a difficult challenge to face in clinical practice. Despite its excellent ...survival prognosis, these tumors may be unpredictable, ranging from an asymptomatic indolent course to persistent, local, and extended recurrences that significantly impair quality of life. Although surgery was initially considered the first elective treatment, collected published data during the past few years are now pointing to the “wait and see” approach as a reasonable initial strategy because many patients can live a long life with the disease without having symptoms. When symptoms appear or there is a risk of functional impairment, a wide spectrum of therapies (local and systemic) can be useful in improving symptoms and controlling the disease. Because of the low incidence of desmoid-type fibromatosis, there is scarce scientific evidence supporting any specific treatment. Nonetheless, if volumetric responses are needed, chemotherapy may be a reasonable early option. However, if long-term control of disease is desirable, hormonal therapy, NSAIDs, and TKIs are the likely treatments of choice. Recent new findings in the biologic development of these tumors, such as the role of Wnt/β-catenin dependent pathway, have shown that the prognostic information provided by specific
CTNNB1
gene mutations and other genetic profiles can lead to better methods of selecting patients as candidates for other approaches. Based on recent research, the Notch pathway inhibition in DF is one of the most promising potential targets to explore. As an orphan disease, it is mandatory that as many patients as possible be included in clinical trials.
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