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Despite advances in treatment and response assessment in locally advanced rectal cancer (LARC), it is unclear which patients should undergo nonoperative management (NOM). We performed a single-center, retrospective study to evaluate post-total neoadjuvant therapy (TNT) circulating tumor DNA (ctDNA) in predicting treatment response. We found that post-TNT ctDNA had a sensitivity of 23% and specificity of 100% for predicting residual disease upon resection, with a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 47%. For predicting poor tumor regression on MRI, ctDNA had a sensitivity of 16% and specificity of 96%, with a PPV of 75% and NPV of 60%. A commercially available ctDNA assay was insufficient to predict residual disease after TNT and should not be used alone to select patients for NOM in LARC.
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DNA Tumoral Circulante , Neoplasias Retais , Humanos , Terapia Neoadjuvante , DNA Tumoral Circulante/genética , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/genética , Neoplasias Retais/terapia , Estudos Retrospectivos , QuimiorradioterapiaRESUMO
Treatment of locally advanced rectal cancer with multimodal treatment courses can result in significant morbidity. Nonoperative management is feasible for patients with clinical complete response to neoadjuvant therapies. Several recent reports have evaluated the use of immunotherapy with checkpoint inhibition for patients with mismatch repair-deficient rectal and colon cancers, with striking results.
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Neoplasias do Colo , Neoplasias Retais , Humanos , Inibidores de Checkpoint Imunológico , Terapia Neoadjuvante/métodos , Reto , Neoplasias Retais/tratamento farmacológicoRESUMO
Previous short-hairpin RNA knockdown studies have established that depletion of human uracil DNA glycosylase (hUNG) sensitizes some cell lines to 5-fluorodeoxyuridine (FdU). Here, we selectively inhibit the catalytic activity of hUNG by lentiviral transduction of uracil DNA glycosylase inhibitor protein into a large panel of cancer cell lines under control of a doxycycline-inducible promoter. This induced inhibition strategy better assesses the therapeutic potential of small-molecule targeting of hUNG. In total, 6 of 11 colorectal lines showed 6- to 70-fold increases in FdU potency upon hUNG inhibition ("responsive"). This hUNG-dependent response was not observed with fluorouracil (FU), indicating that FU does not operate through the same DNA repair mechanism as FdU in vitro. Potency of the thymidylate synthase inhibitor raltitrexed (RTX), which elevates deoxyuridine triphosphate levels, was only incrementally enhanced upon hUNG inhibition (<40%), suggesting that responsiveness is associated with incorporation and persistence of FdU in DNA rather than deoxyuridine. The importance of FU/A and FU/G lesions in the toxicity of FdU is supported by the observation that dT supplementation completely rescued the toxic effects of U/A lesions resulting from RTX, but dT only increased the IC50 for FdU, which forms both FU/A and FU/G mismatches. Contrary to previous reports, cellular responsiveness to hUNG inhibition did not correlate with p53 status or thymine DNA glycosylase expression. A model is suggested in which the persistence of FU/A and FU/G base pairs in the absence of hUNG activity elicits an apoptotic DNA damage response in both responsive and nonresponsive colorectal lines. SIGNIFICANCE STATEMENT: The pyrimidine base 5-fluorouracil is a mainstay chemotherapeutic for treatment of advanced colorectal cancer. Here, this study shows that its deoxynucleoside form, 5-fluorodeoxyuridine (FdU), operates by a distinct DNA incorporation mechanism that is strongly potentiated by inhibition of the DNA repair enzyme human uracil DNA glycosylase. The hUNG-dependent mechanism was present in over 50% of colorectal cell lines tested, suggesting that a significant fraction of human cancers may be sensitized to FdU in the presence of a small-molecule hUNG inhibitor.
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Antineoplásicos/farmacologia , Neoplasias Colorretais/patologia , Floxuridina/farmacologia , Fluoruracila/farmacologia , Quinazolinas/farmacologia , Tiofenos/farmacologia , Uracila-DNA Glicosidase/antagonistas & inibidores , Linhagem Celular Tumoral , Dano ao DNA , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Uracila-DNA Glicosidase/metabolismoRESUMO
Pancreatic ductal adenocarcinoma is the seventh leading cause of cancer death worldwide with an estimated 432â242 deaths occurring in 2018. This estimate, in conjunction with the findings that pancreatic ductal adenocarcinoma incidence is rising and that pancreatic ductal adenocarcinoma has the highest case-fatality rate of any solid tumour, highlights the urgency for designing novel therapeutic strategies to combat this deadly disease. Through the efforts of the global research community, our knowledge of the factors that lead to the development of pancreatic ductal adenocarcinoma, its progression, and the interplay between tumour cells and their surrounding microenvironment have improved substantially. Although these scientific advances have not yet translated into targeted or immunotherapy strategies that are effective for most patients with pancreatic ductal adenocarcinoma, important incremental progress has been made particularly for the treatment of specific molecular subgroups of tumours. Although PD-1 inhibitors for mismatch-repair-deficient tumours and NTRK inhibitors for tumours containing NTRK gene fusions are the most recent targeted agents approved by the US Food and Drug Administration, olaparib for germline BRCA-mutated pancreatic ductal adenocarcinoma is expected to be approved soon in the maintenance setting. These recent advances show the accelerated pace at which pancreatic ductal adenocarcinoma drugs are achieving successful clinical outcomes. Here we review the current understanding of the pathophysiology of pancreatic ductal adenocarcinoma, recent advances in the understanding of the stromal microenvironment, current standard-of-care treatment, and novel therapeutic targets and strategies that hold promise for improving patient outcomes. We predict that there will be major breakthroughs in the treatment of pancreatic ductal adenocarcinoma in the next 5-10 years. These breakthroughs will result from the increased understanding of the treatment barriers imposed by the tumour-associated stroma, and from the development of novel approaches to re-engineer the tumour microenvironment in favour of effective anticancer responses.
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Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desenvolvimento de Medicamentos/tendências , Descoberta de Drogas/tendências , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Difusão de Inovações , Previsões , Humanos , Terapia de Alvo Molecular/tendências , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , Microambiente TumoralRESUMO
BACKGROUND/PURPOSE: TrkA overexpression occurs in over 20% of breast cancers, including triple-negative breast cancers (TNBC), and has recently been recognized as a potential driver of carcinogenesis. Recent clinical trials of pan-Trk inhibitors have demonstrated targeted activity against tumors harboring NTRK fusions, a relatively rare alteration across human cancers. Despite this success, current clinical trials have not investigated TrkA overexpression as an additional therapeutic target for pan-Trk inhibitors. Here, we evaluate the cancerous phenotypes of TrkA overexpression relative to NTRK1 fusions in human cells and assess response to pharmacologic Trk inhibition. EXPERIMENTAL DESIGN/METHODS: To evaluate the clinical utility of TrkA overexpression, a panel of TrkA overexpressing cells were developed via stable transfection of an NTRK1 vector into the non-tumorigenic breast cell lines, MCF10A and hTERT-IMEC. A panel of positive controls was generated via stable transfection with a CD74-NTRK1 fusion vector into MCF10A cells. Cells were assessed via various in vitro and in vivo analyses to determine the transformative potential and targetability of TrkA overexpression. RESULTS: TrkA overexpressing cells demonstrated transformative phenotypes similar to Trk fusions, indicating increased oncogenic potential. TrkA overexpressing cells demonstrated growth factor-independent proliferation, increased PI3Kinase and MAPKinase pathway activation, anchorage-independent growth, and increased migratory capacity. These phenotypes were abrogated by the addition of the pan-Trk inhibitor, larotrectinib. In vivo analysis demonstrated increased tumorgenicity and metastatic potential of TrkA overexpressing breast cancer cells. CONCLUSIONS: Herein, we demonstrate TrkA overexpressing cells show increased tumorgenicity and are sensitive to pan-Trk inhibitors. These data suggest that TrkA overexpression may be an additional target for pan-Trk inhibitors and provide a targeted therapy for breast cancer patients.
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Biomarcadores Tumorais , Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Expressão Gênica , Oncogenes , Receptor trkA/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de SinaisRESUMO
PURPOSE: Estrogen receptor-alpha (ER) is a therapeutic target of ER-positive (ER+) breast cancers. Although ER signaling is complex, many mediators of this pathway have been identified. Specifically, phosphorylation of ER at serine 118 affects responses to estrogen and therapeutic ligands and has been correlated with clinical outcomes in ER+ breast cancer patients. We hypothesized that a newly described germline variant (S118P) at this residue would drive cellular changes consistent with breast cancer development and/or hormone resistance. METHODS: Isogenic human breast epithelial cell line models harboring ER S118P were developed via genome editing and characterized to determine the functional effects of this variant. We also examined the frequency of ER S118P in a case-control study (N = 536) of women with and without breast cancer with a familial risk. RESULTS: In heterozygous knock-in models, the S118P variant demonstrated no significant change in proliferation, migration, MAP Kinase pathway signaling, or response to the endocrine therapies tamoxifen and fulvestrant. Further, there was no difference in the prevalence of S118P between women with and without cancer relative to population registry databases. CONCLUSIONS: This study suggests that the ER S118P variant does not affect risk for breast cancer or hormone therapy resistance. Germline screening and modification of treatments for patients harboring this variant are likely not warranted.
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Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Receptor alfa de Estrogênio/genética , Mutação em Linhagem Germinativa , Adulto , Idoso , Neoplasias da Mama/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Receptor alfa de Estrogênio/metabolismo , Feminino , Fulvestranto/uso terapêutico , Variação Genética , Humanos , Incidência , Células MCF-7 , Pessoa de Meia-Idade , Fosforilação , Análise de Sobrevida , Tamoxifeno/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: Prostate adenocarcinoma represents a leading cause of cancer-related mortality. Increased emphasis on understanding the molecular basis of prostate cancer has identified a substantial burden of homologous recombination (HR) pathway mutations, which are enriched in castrate-resistant disease. This discovery has yielded novel therapeutic opportunities. Areas covered: We will discuss the treatment of castrate-resistant prostate cancer (CRPC), with a focus on the use of poly (ADP-ribose) polymerase (PARP) inhibitors in this space. Evidence for use in HR-deficient patients will be outlined with discussion of the mechanism of action for this drug class, pathways of resistance, and approaches for expanding PARP inhibitor use to non-HR-deficient prostate cancer subgroups. Expert opinion: PARP inhibition represents an exciting tool for management of HR-inactivated CRPC. With rapid adoption of next-generation sequencing technologies and other molecular techniques, the number of patients in this category is likely to increase. Ongoing and future investigations will be critical for improved understanding of the promise and appropriate treatment sequencing of PARP inhibition and optimal options for HR-proficient and -deficient prostate cancer populations. Questions remain about the clinical significance of monoallelic vs. biallelic HR mutations, the relevance of germline vs. somatic-only mutations, and the importance of mutations in non-canonical HR genes.
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Antineoplásicos/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Mutação em Linhagem Germinativa , Recombinação Homóloga , Humanos , Masculino , Mutação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
BACKGROUND: Advanced glycation end products (AGEs) and their receptors are regarded as central to the development of diabetic complications, but associations with diabetes and cardiometabolic outcomes in previous studies are mixed. METHODS: Using ELISA assays, we measured N(6)-carboxymethyllysine (AGE-CML), soluble receptor for AGEs (sRAGE), and endogenous secreted receptor for AGEs (esRAGE) in 1874 participants from the Atherosclerosis Risk in Communities study. We conducted a cross-sectional analysis to evaluate associations of these biomarkers with demographics, diabetes, hyperglycemia, cardiometabolic measures, and genetic variants in the gene encoding RAGE, AGER (advanced glycosylation end-product specific receptor). RESULTS: After adjustment for demographics and body mass index (BMI), there were no significant differences in AGE-CML, sRAGE, or esRAGE by diabetes or hemoglobin A1c. Black race and AGER genetic variants were strongly associated with lower sRAGE and esRAGE even after adjustment [percent difference (95% CI) in black vs whites in sRAGE: -29.17 (-34.86 to -23.48), esRAGE: -26.97 (-33.11 to -20.84); with rs2070600 in sRAGE: -30.13 (-40.98 to -19.29), and esRAGE: -30.32 (-42.42 to -18.21); with rs2071288 in sRAGE: -20.03 (-34.87 to -5.18), and esRAGE: -37.70 (-55.75 to -19.65)]. Estimated glomerular filtration rate and albuminuria significantly correlated with sRAGE and esRAGE. BMI and C-reactive protein significantly negatively correlated with AGE-CML, sRAGE, and esRAGE. AGE-CML was modestly correlated with fructosamine and glycated albumin. CONCLUSIONS: AGE-CML, sRAGE, and esRAGE were more related to genetic, kidney, and inflammatory measures than to diabetes in this community-based population. Our results suggest that, when measured by ELISA, these biomarkers lack specificity and are of limited value in evaluating the role of these compounds in diabetes.
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Biomarcadores/sangue , Doenças das Artérias Carótidas/sangue , Diabetes Mellitus/sangue , Receptor para Produtos Finais de Glicação Avançada/sangue , Índice de Massa Corporal , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Variação Genética , Humanos , Receptor para Produtos Finais de Glicação Avançada/genética , Fatores de RiscoRESUMO
BACKGROUND: Molecular-based diagnostics have great utility for cancer detection. We have used droplet digital PCR (ddPCR) as a platform for identifying mutations in circulating plasma tumor DNA (ptDNA). We present the unexpected finding of a spurious mutant allele fraction that was discovered to be artifactual because of the presence of a single-nucleotide polymorphism (SNP) in a patient sample. DESIGN AND METHODS: Probe and primer combinations for the K700 and V701 loci of the SF3B1 spliceosome gene were designed for ddPCR to identify the percentage of mutant and wild-type alleles. Clinical samples from patients with cancer with known SF3B1 mutations were collected and tested to evaluate the assays' ability to detect SF3B1 mutations in ptDNA. RESULTS: Patient samples showed SF3B1 K700E mutations within the ptDNA of 4 patients with acute leukemia and 3 with myelodysplastic syndrome who were known to harbor this mutation. A blood sample from a patient with lung cancer with a known SF3B1 V701F mutation was also analyzed and this mutation was successfully identified in ptDNA. However, 1 of the patients with a K700E mutation was found to have a mutational burden of 98%. After careful analysis of this locus by Sanger sequencing and ddPCR, this patient was found to have an SNP (R702R), which prevented binding of the ddPCR wild-type probe to its cognate allele. CONCLUSIONS: These results further support that ddPCR-based assays may be valuable companion diagnostics for the identification and monitoring of patients with cancer, but the results also emphasize the need to identify SNPs at loci that are being analyzed.
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Alelos , DNA de Neoplasias/genética , Fosfoproteínas/genética , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Processamento de RNA/genética , DNA de Neoplasias/sangue , Reações Falso-Positivas , Humanos , MutaçãoRESUMO
INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a dismal five-year survival rate of less than 10%. Neutrophils are key components of the innate immune system, playing a pivotal role in the PDAC immune microenvironment. AREAS COVERED: This review provides a comprehensive survey of the pivotal involvement of neutrophils in the tumorigenesis and progression of PDAC. Furthermore, it synthesizes preclinical and clinical explorations aimed at targeting neutrophils within the milieu of PDAC, subsequently proposing a conceptual framework to propel further inquiry focused on enhancing the therapeutic efficacy of PDAC through neutrophil-targeted strategies. PubMed and Web of Science databases were utilized for researching neutrophils in pancreatic cancer publications prior to 2024. EXPERT OPINION: Neutrophils play roles in promoting tumor growth and metastasis in PDAC and are associated with poor prognosis. However, the heterogeneity and plasticity of neutrophils and their complex relationships with other immune cells and extracellular matrix also provide new insights for immunotherapy targeting neutrophils to achieve a better prognosis for PDAC.
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Carcinoma Ductal Pancreático , Imunoterapia , Neutrófilos , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Neutrófilos/imunologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/imunologia , Animais , Imunoterapia/métodos , Imunidade Inata , PrognósticoRESUMO
Background: Total neoadjuvant therapy (TNT) is an accepted approach for the management of locally advanced rectal cancer (LARC) and is associated with a decreased risk of development of metastatic disease compared to standard neoadjuvant therapy. However, questions remain regarding surgical outcomes and local control in patients who proceed to surgery, particularly when radiation is given first in the neoadjuvant sequence. We report on our institution's experience with patients who underwent short-course radiation therapy, consolidation chemotherapy, and surgery. Methods: We retrospectively reviewed surgical specimen outcomes, postoperative complications, and local/pelvic control in a large cohort of patients with LARC who underwent neoadjuvant therapy incorporating upfront short-course radiation therapy followed by consolidation chemotherapy. Results: In our cohort of 83 patients who proceeded to surgery, a complete/near-complete mesorectal specimen was achieved in 90 % of patients. This outcome was not associated with the time interval from completion of radiation to surgery. Postoperative complications were acceptably low. Local control at two years was 93.4 % for all patients- 97.6 % for those with low-risk disease and 90.4 % for high-risk disease. Conclusion: Upfront short-course radiation therapy and consolidation chemotherapy is an effective treatment course. Extended interval from completion of short-course radiation therapy did not impact surgical specimen quality.
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Introduction: The highest incidence of colorectal cancer (CRC) is in patients diagnosed at 80 years or older highlighting a need for understanding the clinical and molecular features of these tumors. Methods. In this retrospective cohort study, 544 CRCs underwent next generation sequencing and mismatch repair (MMR) evaluation. Molecular and clinical features were compared between 251 patients with traditional-onset CRC (50-69 years at diagnosis) and 60 with late-onset CRC (>80 years at diagnosis). Results: Late-onset CRC showed a significantly higher rate of right-sided tumors (82% vs 35%), MMR deficiency (35% vs. 8%) and BRAF p.V600E mutations (35% vs. 8%) and a significantly lower rate of stage IV disease (15% vs 28%) and APC mutations (52% vs. 78%). Association of these features with advanced age was supported by stratifying patients into 6 age groups (<40, 40-49, 50-59, 60-69, 70-79 and >80 years). However, the age-related rise in MMR deficient (dMMR) CRC was only seen in the female patients with an incidence of 48% (vs. 10% in the male patient) in the >80y group. In addition, BRAF p.V600E was significantly enriched in MMR deficient CRC of advanced age (67% in late-onset CRC). Categorizing CRC by mutational profiling, late-onset CRC revealed a significantly higher rate of dMMR/BRAF + APC - (18% vs. 2.0%), dMMR/BRAF - APC - (8.3% vs. 1.2%) and MMR proficient (pMMR)/BRAF + APC - (12% vs. 4.0%) as compared to traditional-onset CRC. Discussion: In summary, there was a higher rate of dMMR and BRAF p.V600E in late-onset CRC, independently or in combination. The higher incidence of dMMR in late-onset CRC in females is most likely predominantly driven by BRAF p.V600E induced hypermethylation. Prospective studies with treatment plans designed specifically for these older patients are warranted to improve their outcomes.
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Colorectal cancer is the third most common cancer diagnosis in the world, and the second most common cause of cancer-related deaths. Despite significant progress in management strategies for colorectal cancer over the last several decades, metastatic disease remains difficult to treat and is often considered incurable. However, for patients with colorectal liver metastases (CRLM), surgical resection offers the best opportunity for survival, can be curative, and remains the gold standard. Unfortunately, surgical treatment options are underutilized. Misperceptions regarding resectable and unresectable CRLM likely play a role in this. The assessment of factors that impact resectability status like medical fitness, technical considerations, and disease biology can be difficult, necessitating careful multidisciplinary input and discussion. The identification of ideal operative time windows that align with the multimodal management of these patients can also be perplexing. For all patients with CRLM it may therefore be advantageous to obtain surgical evaluation at the time of discovering liver metastases to mitigate these challenges and minimize the risk of undertreatment. In this review we summarize current surgical management strategies for CRLM and discuss factors to be considered when determining resectability.
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The treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) is frequently characterized by significant toxicity and rapid development of resistance to current approved therapies. More reliable biomarkers of response are needed to guide clinical decision making. We evaluated cell-free DNA (cfDNA) using a tumor-agnostic platform and traditional biomarkers (CEA and CA19-9) levels in 12 patients treated at Johns Hopkins University on NCT02324543 "Study of Gemcitabine/Nab-Paclitaxel/Xeloda (GAX) in Combination With Cisplatin and Irinotecan in Subjects With Metastatic Pancreatic Cancer." The pretreatment values, levels after 2 months of treatment, and change in biomarker levels with treatment were compared with clinical outcomes to determine their predictive value. The variant allele frequency (VAF) of KRAS and TP53 mutations in cfDNA after 2 months of treatment was predictive of progression-free survival (PFS) and overall survival (OS). In particular, patients with a lower-than-average KRAS VAF after 2 months of treatment had a substantially longer PFS than patients with higher posttreatment KRAS VAF (20.96 vs. 4.39 months). Changes in CEA and CA19-9 after 2 months of treatment were also good predictors of PFS. Comparison via concordance index demonstrated KRAS or TP53 VAF after 2 months of treatment to be better predictors of PFS and OS than CA19-9 or CEA. This pilot study requires validation but suggests cfDNA measurement is a useful adjunct to traditional protein biomarkers and imaging evaluation and could distinguish between patients who are likely to achieve prolonged responses versus those that will have early progression and may benefit from a change in treatment approach. Significance: We report on the association of cfDNA with response durability for patients undergoing treatment with a novel metronomic chemotherapy regimen (gemcitabine, nab-paclitaxel, capecitabine, cisplatin, irinotecan; GAX-CI) for metastatic PDAC. This investigation offers encouraging evidence that cfDNA may prove to be a valuable diagnostic tool to guide clinical management.
Assuntos
Carcinoma Ductal Pancreático , Ácidos Nucleicos Livres , Neoplasias Pancreáticas , Humanos , Irinotecano/uso terapêutico , Cisplatino/uso terapêutico , Desoxicitidina/uso terapêutico , Ácidos Nucleicos Livres/genética , Antígeno CA-19-9/uso terapêutico , Projetos Piloto , Proteínas Proto-Oncogênicas p21(ras)/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Capecitabina , Neoplasias PancreáticasRESUMO
Solid organ transplants are associated with a modestly increased risk of colorectal cancers (CRC). However, the molecular profile of these cancers has not been described. We hypothesized that transplant-related immunosuppression may promote development of more immunogenic tumors as suggested by a high tumor mutation burden or mismatch repair deficiency. We performed an electronic medical record search for patients seen in the Johns Hopkins University Health System (JHHS) between 2017 and 2022 who developed CRC following solid organ transplantation. A comparator cohort of patients treated for CRC at JHHS with molecular profiling data was also identified. In this case, 29 patients were identified that developed post-transplant CRC (renal transplant, n = 18; liver transplant, n = 8; kidney-liver transplantation, n = 3). Compared to the JHHS general population CRC cohort, patients who developed post-transplant CRC had a higher rate of mismatch repair deficiency (41% versus 12%, p-value = 0.0038), and elevated tumor mutation burden (median of 22 mut/Mb versus 3.5 mut/Mb, p-value = 0.033) (range 3.52-53.65). Post-transplant tumors were enriched for PIK3CA mutations (43% versus 24%, p-value = 0.042). Post-Transplant CRCs are associated with clinical and molecular features of immune sensitivity, supporting a potential role for impaired immune surveillance in shaping the landscape of CRCs. These results may help inform the management of patients with post-transplant CRC.
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Neoplasias Colorretais , Transplante de Fígado , Síndromes Neoplásicas Hereditárias , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Síndromes Neoplásicas Hereditárias/genética , Classe I de Fosfatidilinositol 3-Quinases/genéticaRESUMO
PURPOSE: The purpose of his study was to report on a cohort of patients managed with nonoperative management (NOM) with a watch-and-wait strategy after achieving complete response (CR) to sequential short-course radiation therapy (SCRT) and consolidation chemotherapy. METHODS: This was a retrospective study of patients treated SCRT and chemotherapy who achieved a CR and were managed with NOM. Bowel function was assessed with European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30, EORTC Quality of Life Questionnaire-Colorectal Cancer 29, and the low anterior resection syndrome (LARS) questionnaires. Endpoints included overall survival (OS), freedom from local failure (FFLF), freedom from distant metastasis, and disease-free survival (DFS). RESULTS: Twenty-six patients met inclusion criteria. Seven (26.9%) patients developed local failure at a median of 6.8 months following CR, of which 5 were successfully salvaged. Median FFLF was not reached, with 6-month, 1-, and 2-year FFLF rates of 100.0%, 82.3%, and 71.3%. Median OS was not reached, with 6-month, 1-, and 2-year OS rates of 100%. Median DFS was not reached, with 6-month, 1-, and 2-year DFS rates of 100%, 95.0%, and 89.4%. Questionnaire response rate was 83.3%. Median LARS score was 27. Major, minor, and no LARS occurred in 3 (20%), 6 (40%), and 6 (40%) patients, respectively. There were no differences in questionnaire scores between patients who had the majority of their anal sphincter complex irradiated and those who did not. CONCLUSION: NOM with a watch-and-wait strategy is safe and feasible in patients with locally advanced rectal cancer who achieve CR after sequential SCRT and chemotherapy, with evidence for good anorectal function.
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Neoplasias Retais , Humanos , Terapia Neoadjuvante , Complicações Pós-Operatórias , Qualidade de Vida , Neoplasias Retais/patologia , Estudos Retrospectivos , SíndromeAssuntos
DNA Tumoral Circulante , Neoplasias Colorretais , Células Neoplásicas Circulantes , Humanos , DNA Tumoral Circulante/genética , Recidiva Local de Neoplasia , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Neoplasias Colorretais/patologia , Células Neoplásicas Circulantes/patologia , Doença Crônica , Biomarcadores Tumorais/genéticaRESUMO
Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers.
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Reprogramação Celular , Mutação , Proteínas de Neoplasias/metabolismo , Neoplasias , Fosfoproteínas , Proteoma/metabolismo , Fatores de Processamento de RNA , Serina , Transcriptoma , Animais , Linhagem Celular Tumoral , Metabolismo Energético/genética , Glicina , Humanos , Camundongos , Proteínas de Neoplasias/genética , Neoplasias/dietoterapia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fosfoglicerato Desidrogenase/genética , Fosfoglicerato Desidrogenase/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteoma/genética , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Genomic testing is often limited by the exhaustible nature of human tissue and blood samples. Here we describe biotinylated amplicon sequencing (BAmSeq), a method that allows for the creation of PCR amplicon based next-generation sequencing (NGS) libraries while retaining the original source DNA. DESIGN AND METHODS: Biotinylated primers for different loci were designed to create NGS libraries using human genomic DNA from cell lines, plasma, and formalin-fixed paraffin embedded (FFPE) tissues using the BAmSeq protocol. DNA from the original template used for each BAmSeq library was recovered after separation with streptavidin magnetic beads. The recovered DNA was then used for end-point, quantitative and droplet digital PCR (ddPCR) as well as NGS using a cancer gene panel. RESULTS: Recovered DNA was analyzed and compared to the original DNA after one or two rounds of BAmSeq. Recovered DNA revealed comparable genomic distributions and mutational allelic frequencies when compared to original source DNA. Sufficient quantities of recovered DNA after BAmSeq were obtained, allowing for additional downstream applications. CONCLUSIONS: We demonstrate that BAmSeq allows original DNA template to be recovered with comparable quality and quantity to the source DNA. This recovered DNA is suitable for many downstream applications and may prevent sample exhaustion, especially when DNA quantity or source material is limiting.
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PURPOSE: Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice. METHODS: A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration-approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing. RESULTS: One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off-label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months (95% CI, 2.9 months to not reached), and the progression-free survival probability at 6 months was 43%(95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports. CONCLUSION: The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy.