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Open accessJournal ArticleDOI: 10.6004/JNCCN.2021.0012

Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

02 Mar 2021-Journal of The National Comprehensive Cancer Network (Cold Spring Publishing LLC)-Vol. 19, Iss: 3, pp 329-359
Abstract: This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.

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Topics: Targeted therapy (52%)

127 results found

Open accessJournal ArticleDOI: 10.1016/J.CTRV.2021.102187
Abstract: Although urothelial carcinoma (UC) is considered a chemotherapy-sensitive tumor, progression-free survival and overall survival (OS) are typically short following standard first-line (1L) platinum-containing chemotherapy in patients with locally advanced or metastatic disease. Immune checkpoint inhibitors (ICIs) have antitumor activity in UC and favorable safety profiles compared with chemotherapy; however, trials of 1L ICI monotherapy or chemotherapy + ICI combinations have not yet shown improved OS vs chemotherapy alone. In addition to direct cytotoxicity, chemotherapy has potential immunogenic effects, providing a rationale for assessing ICIs as switch-maintenance therapy. In the JAVELIN Bladder 100 phase 3 trial, avelumab administered as 1L maintenance with best supportive care (BSC) significantly prolonged OS vs BSC alone in patients with locally advanced or metastatic UC that had not progressed with 1L platinum-containing chemotherapy (median OS, 21.4 vs 14.3 months; hazard ratio, 0.69 [95% CI, 0.56–0.86]; P = 0.001). Efficacy benefits were seen across various subgroups, including recipients of 1L cisplatin- or carboplatin-based chemotherapy, patients with PD-L1+ or PD-L1− tumors, and patients with diverse characteristics. Results from JAVELIN Bladder 100 led to the approval of avelumab as 1L maintenance therapy for patients with locally advanced or metastatic UC that has not progressed with platinum-containing chemotherapy. Avelumab 1L maintenance is also included as a standard of care in treatment guidelines for advanced UC with level 1 evidence. This review summarizes the data that supported these developments and discusses practical considerations for administering avelumab maintenance in clinical practice, including patient selection and treatment management.

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Topics: Maintenance therapy (59%), Bladder cancer (55%), Metastatic Urothelial Carcinoma (52%) ... read more

5 Citations

Journal ArticleDOI: 10.1038/S41585-021-00438-4
Abstract: The introduction of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy. SG-ARAs provide similar therapeutic benefit to abiraterone, a potent CYP17 inhibitor, and do not require the co-administration of prednisone. Despite considerable improvements in clinical outcomes in the settings of both castration sensitivity and castration resistance, the durability of clinical response to the SG-ARAs enzalutamide, apalutamide and darolutamide, similar to abiraterone, is limited by inevitable acquired resistance. Genomic aberrations that confer resistance to SG-ARAs or provide potential alternative treatment modalities have been identified in numerous studies, including alterations of the androgen receptor, DNA repair, cell cycle, PI3K-AKT-mTOR and Wnt-β-catenin pathways. To combat resistance, researchers have explored approaches to optimizing the utility of available treatments, as well as the use of alternative agents with a variety of targets, including AR-V7, AKT, EZH2 and HIF1α. Ongoing research to establish predictive biomarkers for the treatment of tumours with resistance to SG-ARAs led to the approval of the PARP inhibitors olaparib and rucaparib in pre-treated metastatic castration-resistant prostate cancer. The results of ongoing studies will help to shape precision medicine in prostate cancer and further optimize treatment paradigms to maximize clinical outcomes.

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Topics: Apalutamide (61%), Castration Resistance (60%), Enzalutamide (60%) ... read more

4 Citations

Open accessJournal ArticleDOI: 10.2217/FON-2021-0273
19 May 2021-Future Oncology
Abstract: Muscle-invasive bladder cancer (MIBC) is associated with high rates of recurrence and poor prognosis despite aggressive treatment. Neoadjuvant chemotherapy before radical cystectomy (RC) improves outcomes in cisplatin-eligible patients; however, the improvement in overall survival is modest. Standard of care for cisplatin-ineligible patients remains RC; more effective systemic therapies are needed. Recent Phase Ib/II studies suggest pembrolizumab monotherapy and combination therapy are effective neoadjuvant therapies for MIBC. The randomized Phase III KEYNOTE-866 and KEYNOTE-905/EV-303 studies are being conducted to evaluate efficacy and safety of perioperative pembrolizumab or placebo with chemotherapy in cisplatin-eligible patients with MIBC (KEYNOTE-866) and of pembrolizumab monotherapy versus pembrolizumab plus enfortumab vedotin versus RC plus pelvic lymph node dissection alone in cisplatin-ineligible patients with MIBC (KEYNOTE-905/EV-303). Clinical trial registration: NCT03924856 & NCT03924895 (

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Topics: Pembrolizumab (58%), Bladder cancer (52%)

4 Citations

Open accessJournal ArticleDOI: 10.1007/S40336-021-00426-Z
David Groheux1, Elif Hindié2Institutions (2)
Abstract: Precise staging is needed to plan optimal management in breast cancer. 18F-fluorodeoxyglucose positron emission tomography coupled with computed tomography (FDG-PET/CT) offers high sensitivity in detecting extra axillary lymph nodes and distant metastases. This review aims to clarify in which groups of patients staging with FDG-PET/CT would be beneficial and should be offered. We also discuss how tumor biology and breast cancer subtypes should be taken into account when interpreting FDG-PET/CT scans. We performed a comprehensive literature review and rigorous appraisal of research studies assessing indications for FDG-PET/CT in breast cancer. This assessment regarding breast cancer served as a basis for the recommendations set by a working group of the French Society of Nuclear Medicine, in collaboration with oncological societies, for developing good clinical practice recommendations on the use of FDG-PET/CT in oncology. FDG-PET/CT is useful for initial staging of breast cancer, independently of tumor phenotype (triple negative, luminal or HER2 +) and regardless of tumor grade. Considering histological subtype, FDG-PET/CT performs better for staging invasive ductal carcinoma, although it is also helpful for staging invasive lobular carcinomas. Based on the available data, FDG-PET/CT becomes useful for staging starting from clinical stage IIB. FDG-PET/CT is possibly useful in patients with clinical stage IIA (T1N1 or T2N0), but there is not enough strong data to recommend routine use in this subgroup. For clinical stage I (T1N0) patients, staging with FDG-PET/CT offers no added value. FDG-PET/CT is useful for staging patients with breast cancer, starting from clinical stage IIB.

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Topics: Breast cancer (60%), Axillary lymph nodes (55%), PET-CT (55%) ... read more

4 Citations

Journal ArticleDOI: 10.1007/S00428-021-03085-7
17 Mar 2021-Virchows Archiv
Abstract: Primary gastrointestinal neuroendocrine carcinoma (GI-NEC) cannot be distinguished morphologically from pulmonary neuroendocrine carcinoma (P-NEC). This can present a significant diagnostic challenge in cases where site of origin cannot be readily determined. To identify immunohistochemical (IHC) markers that can be used to reliably distinguish between GI-NECs and P-NECs, we constructed 3-mm tissue microarrays, one containing 13 GI-NECs and one containing 20 P-NECs. IHC was performed on both microarrays using 21 stains: AE1/AE3, CK7, CK20, synaptophysin, chromogranin, CD56, INSM1, SSTR2A, CDX2, SATB2, TTF1, Napsin A, PR, GATA3, PAX8, ISL1, beta-catenin, AFP, SMAD4, Rb, and p53. For GI-NEC, the most strongly expressed marker was synaptophysin (mean H-score 248), while AE1/AE3 was the most strongly expressed in P-NEC (mean H-score 230), which was stronger than in GI-NEC (p = 0.011). Other markers that were stronger overall in P-NEC than in GI-NEC included CK7 (p < 0.0001) and TTF1 (p < 0.0001). Markers that were stronger overall in GI-NEC than in P-NEC included SSTR2A (p = 0.0021), SATB2 (p = 0.018), CDX2 (p = 0.019), and beta-catenin (nuclear; p = 0.029). SMAD4, Rb, and p53 showed similar rates of abnormal protein expression. Based on these results, a stepwise algorithmic approach utilizing CK7, TTF1, beta-catenin, CDX2, and SSTR2A had a 91% overall accuracy in distinguishing these GI-NEC from P-NEC. This was tested on a second cohort of 10 metastatic GI-NEC and 10 metastatic P-NEC, with an accuracy in this cohort of 85% and an overall accuracy of 89% for the 53 cases tested. Our algorithm reasonably discriminates GI-NEC from P-NEC using currently available IHC stains.

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Topics: Synaptophysin (51%)

3 Citations


307 results found

Journal ArticleDOI: 10.1056/NEJMOA032691
Abstract: background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. methods Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. results The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progressionfree survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. conclusions The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.

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Topics: IFL Regimen (73%), Bevacizumab (56%), FOLFIRI (55%) ... read more

9,747 Citations

Open accessJournal ArticleDOI: 10.1056/NEJMOA1200690
Abstract: Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castrationresistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drugrelated adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; number, NCT00730639.)

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Topics: Cancer (61%), Pembrolizumab (58%), Lung cancer (57%) ... read more

9,399 Citations

Open accessJournal ArticleDOI: 10.1038/NATURE00766
Helen Davies1, Graham R. Bignell1, Charles Cox1, Philip J. Stephens1  +48 moreInstitutions (9)
27 Jun 2002-Nature
Abstract: Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.

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Topics: BRAF Gene Mutation (67%), Encorafenib (65%), c-Raf (63%) ... read more

9,162 Citations

Open accessJournal ArticleDOI: 10.1056/NEJMOA1500596
Dung T. Le, Jennifer N. Uram1, Hao Wang2, Bjarne Bartlett3  +33 moreInstitutions (6)
Abstract: BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. ResultsThe immune-related objective response rate and immune-related progression-free survival ...

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Topics: Pembrolizumab (55%), PMS2 (54%), Immune checkpoint (54%) ... read more

5,399 Citations

Journal ArticleDOI: 10.1056/NEJMOA033025
David Cunningham1, Yves Humblet2, Salvatore Siena, David Khayat3  +8 moreInstitutions (7)
Abstract: background The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan. methods We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. results The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combinationtherapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone. conclusions Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.

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Topics: Irinotecan (65%), FOLFIRI (63%), Cetuximab (62%) ... read more

4,484 Citations

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