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Background: This phase Ib study was performed to determine the safety of combination capecitabine with alpleisib (phosphatidylinositol 3-kinase catalytic subunit p110α blockade) and determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination regimen in patients with advanced solid tumors refractory to standard therapy. The synergistic anti-tumor activity and pharmacokinetics (PK) were investigated. Methods: Dose escalation phases were conducted in patients with advanced solid cancers who were refractory to standard therapy regardless of PIK3CA mutation. Patients were administered orally once daily alpelisib (200mg and 300mg) and twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) every 3 weeks. Standard "3 + 3" dose escalation was used to define the MTD. The effect of alpelisib on the PK of capecitabine was assessed. Results: Patients with 6 colorectal cancer (three PIK3CA mutation) and 6 breast cancer (all PIK3CA mutation) were enrolled. The first three patients in dose level 0 (alpelisib 200mg daily, capecitabine 1,000 mg/m2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 1 (alpelisib increased to 300 mg daily, capecitabine 1,000mg twice daily), one of six patients had DLT (grade (Gr) 3 hyperglycemia). When dose level 2 (alpelisib 300mg daily, capecitabine 1,250 mg/m2 twice daily) was expanded to 3 patients, no patients had DLTs. The combination of alpelisib 300mg daily and capecitabine 1,250 mg/m2 twice daily was declared as the MTD/RP2D in patients with advanced solid tumors. The most common AEs were Gr 1-3 hyperglycemia (75.0%). Frequent all-grade, treatment-related AEs included Gr 2-3 nausea (75.0%), Gr 1-2 diarrhea (50.0%), Gr 1-2 hand-foot syndrome (41.7%), Gr 1-2 anorexia (41.7%), Gr 2 mucositis (33.3%). Antitumor activity was observed in patients with PIK3CA mutant breast cancer (3 partial response and 3 stable disease of total 6 patients). Alpelisib exposure (Cmax and AUC0-12) was unaffected by concomitant capecitabine. There were no clinically relevant drug-drug interactions observed between alpelisib and capecitabine. Conclusions: The combination of alpelisib and capecitabine is generally tolerated, without pharmacokinetic interactions, and shows antitumor activity in patients with PIK3CA mutant advanced cancers.
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Spartalizumab (PDR001) is a humanized IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We conducted a single-arm, phase 2 trial to investigate the efficacy and safety of spartalizumab in patients with refractory esophageal squamous cell carcinoma (ESCC). Patients with histologically confirmed ESCC who experienced disease progression after platinum-based chemotherapy received 300 mg of intravenous spartalizumab every three weeks until disease progression or occurrence of unacceptable toxicity. The primary endpoint was centrally assessed objective response according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were closely monitored throughout the study. From March 2020 through April 2021, 44 patients with ESCC were enrolled. Of the 44 patients, the objective response rate was 20.5% (95% confidence interval: 8.5-32.4). With a median follow-up of 10.9 months, median progression-free survival and overall survival were 3.2 months and 11.2 months, respectively. In addition, the median duration of response was 24.7 months. The most common grade 3 or 4 adverse event was grade 3 dysphagia (eight [18%] patients). Biomarker analyses explored programmed cell death ligand 1 and CD20 as potential predictive markers for PD-1 blockade. Spartalizumab showed promising activity with a manageable safety profile, indicating its potential as a new treatment option for patients with refractory ESCC. Trial registration: The trial was registered at ClinicalTrials.gov under the identifier NCT03785496.
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Anticorpos Monoclonais Humanizados , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Recidiva Local de Neoplasia , Humanos , Masculino , Feminino , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Pessoa de Meia-Idade , Idoso , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidade , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Adulto , Intervalo Livre de Progressão , Idoso de 80 Anos ou mais , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
Purpose: Varlitinib is a pan-human epidermal growth (HER) inhibitor targeting epidermal growth factor receptor (EGFR), HER2, and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC). Materials and Methods: Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (IHC) (≥1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity. Results: RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median PFS and overall survival (OS) were 3.3 months and 7.9 months, respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), AST/ALT elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D. Conclusion: A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.
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BACKGROUND: Microsatellite instability (MSI) and tumor mutational burden (TMB) are predictive biomarkers for pan-cancer immunotherapy. The interrelationship between MSI-high (MSI-H) and TMB-high (TMB-H) in human cancers and their predictive value for immunotherapy in lung cancer remain unclear. METHODS: We analyzed somatic mutation data from the Genomics Evidence Neoplasia Information Exchange (n = 46,320) to determine the relationship between MSI-H and TMB-H in human cancers using adjusted multivariate regression models. Patient survival was examined using the Cox proportional hazards model. The association between MSI and genetic mutations was assessed. RESULTS: Patients (31-89%) with MSI-H had TMB-low phenotypes across 22 cancer types. Colorectal and stomach cancers showed the strongest association between TMB and MSI. TMB-H patients with lung cancer who received immunotherapy exhibited significantly higher overall survival [HR, 0.61; 95% confidence interval (CI), 0.44-0.86] and progression-free survival (HR, 0.65; 95% CI, 0.47-0.91) compared to the TMB-low group; no significant benefit was observed in the MSI-H group. Patients with TMB and MSI phenotypes showed further improvement in overall survival and PFS. We identified several mutated genes associated with MSI-H phenotypes, including known mismatch repair genes and novel mutated genes, such as ARID1A and ARID1B. CONCLUSIONS: Our results demonstrate that TMB-H and/or a combination of MSI-H can serve as biomarkers for immunotherapies in lung cancer. IMPACT: These findings suggest that distinct or combined biomarkers should be considered for immunotherapy in human cancers because notable discrepancies exist between MSI-H and TMB-H across different cancer types.
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Biomarcadores Tumorais , Instabilidade de Microssatélites , Mutação , Humanos , Feminino , Masculino , Biomarcadores Tumorais/genética , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/terapia , Genômica/métodos , Pessoa de Meia-Idade , IdosoRESUMO
BACKGROUND/AIM: This study investigated the treatment patterns and prognosis of patients with metastatic or unresectable colorectal cancer (mCRC) treated with chemotherapy with targeting agents. PATIENTS AND METHODS: This longitudinal multicenter study included 963 patients with mCRC who were treated in Korea between 2016 and 2020. Treatment patterns and efficacy were compared according to the mutation status and clinical factors. RESULTS: As first-line therapy, most of the patients (83.5%) received FOLFOX plus bevacizumab (35.4%), followed by FOLFIRI plus bevacizumab (18.8%), FOLFIRI plus cetuximab (17.0%), and FOLFOX plus cetuximab (12.3%). Bevacizumab was the most frequent agent (78.8%) combined with chemotherapy in RAS-mutated CRC, while cetuximab (57.2%) in RAS wild-type CRC. Cetuximab was frequently combined with a doublet regimen in patients with left-sided CRC than in those with right-sided CRC (34.4% vs. 16%). As second-line therapy, most patients (63.4%) also received doublet regimens with bevacizumab, and FOLFIRI plus aflibercept was administered in 15.1%. The objective response rate with FOLFIRI plus cetuximab was significantly higher in patients with left-sided CRC than in those with right-sided CRC (59.2% vs. 30.8%, p=0.008) and marginally higher in patients with RAS wild-type CRC than in those with RAS-mutated CRC (55.6% vs. 0.0%, p=0.092). Progression-free survival (PFS) with FOLFOX plus bevacizumab was significantly shorter than that with FOLFIRI plus bevacizumab (p=0.030) in RAS-mutated CRC, whereas there were no significant differences between regimens in RAS wild-type CRC. CONCLUSION: In patients with unresectable metastatic colorectal cancer, doublet chemotherapy with targeting agents is the most common therapy and efficacy depends on the mutation status as well as clinical factors.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Cetuximab , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Prognóstico , Neoplasias Retais/tratamento farmacológicoRESUMO
PURPOSE: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents. METHODS: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284). RESULTS: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response. CONCLUSIONS: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.
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Adenocarcinoma , DNA Tumoral Circulante , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Receptor ErbB-2/genética , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: In this randomized phase II study, we evaluated the efficacy and safety of sorafenib in combination with capecitabine and cisplatin (XP) as first-line chemotherapy in advanced gastric cancer. PATIENTS AND METHODS: Patients with metastatic gastric or gastroesophageal junction adenocarcinoma were randomized (1:1) to receive either sorafenib plus XP (S + XP) or XP alone. In cases of disease progression in the XP arm, crossover to sorafenib alone was allowed. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), response rates, safety profiles, and biomarkers, and the response rates and PFS with secondline sorafenib alone after progression in the XP arm. RESULTS: Between Jan 2011 and Feb 2013, a total of 195 patients were accrued (97 in the S + XP arm and 98 in the XP alone arm). The overall response rate was 54% with S + XP, and 52% with XP alone (p = 0.83). With a median follow-up of 12.6 months (range, 0.1-29.2), the median PFS assessed by independent review was 5.6 months in the S + XP arm and 5.3 months in the XP arm (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.67-1.27, p = 0.61). Overall survival was not different between the two arms (median 11.7 vs. 10.8 months; HR 0.93, 95% CI 0.65-1.31, p = 0.66). Frequencies of grade 3/4 toxicities were similar between the S + XP and XP alone arms, except for neutropenia (21% vs. 37%), anorexia (0% vs. 5%), and hand-foot skin reaction (7% vs. 1%). Among 51 patients who crossed over to sorafenib alone after disease progression in the XP arm, there was no objective response and their median PFS was 1.3 months (95% CI, 1.2-1.7). CONCLUSION: The addition of sorafenib to XP chemotherapy was safe but not more effective than XP alone for first-line treatment of metastatic gastric cancer.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Capecitabina/efeitos adversos , Cisplatino/efeitos adversos , Sorafenibe/uso terapêutico , Progressão da Doença , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: BRCA1 and BRCA2 are among the most important genes involved in DNA repair via homologous recombination (HR). Germline BRCA1/2 (gBRCA1/2)-related cancers have specific characteristics and treatment options but conducting gBRCA1/2 testing and interpreting the genetic imprint are sometimes complicated. Here, we describe the concordance of gBRCA1/2 derived from a panel of clinical tumor tissues using next-generation sequencing (NGS) and genetic aspects of tumors harboring gBRCA1/2 pathogenic variants. MATERIALS AND METHODS: Targeted sequencing was performed using available tumor tissue from patients who underwent gBRCA1/2 testing. Comparative genomic analysis was performed according to gBRCA1/2 pathogenicity. RESULTS: A total of 321 patients who underwent gBRCA1/2 testing were screened, and 26 patients with gBRCA1/2 pathogenic (gBRCA1/2p) variants, eight patients with gBRCA1/2 variants of uncertain significance (VUS; gBRCA1/2v), and 43 patients with gBRCA1/2 wild-type (gBRCA1/2w) were included in analysis. Mutations in TP53 (49.4%) and PIK3CA (23.4%) were frequently detected in all samples. The number of single-nucleotide variants (SNVs) per tumor tissue was higher in the gBRCA1/2w group than that in the gBRCA1/2p group (14.81 vs. 18.86, p=0.278). Tumor mutation burden (TMB) was significantly higher in the gBRCA1/2w group than in the gBRCA1/2p group (10.21 vs. 13.47, p=0.017). Except for BRCA1/2, other HR-related genes were frequently mutated in patients with gBRCA1/2w. CONCLUSION: We demonstrated high sensitivity of gBRCA1/2 in tumors analyzed by NGS using a panel of tumor tissues. TMB value and aberration of non-BRCA1/2 HR-related genes differed significantly according to gBRCA1/2 pathogenicity in patients with breast cancer.
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Neoplasias da Mama , Neoplasias Ovarianas , Feminino , Humanos , Biomarcadores Tumorais/genética , Proteína BRCA1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Genes BRCA2 , Genômica , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Neoplasias Ovarianas/genéticaRESUMO
BACKGROUND: Although various coronavirus disease 2019 (COVID-19) vaccines have been delivered to the public worldwide, data on cancer populations are limited. Vaccine hesitancy related to safety concerns is observed among cancer patients. We report the perception of COVID-19 vaccines and their safety profile after vaccination among cancer patients. MATERIALS AND METHODS: Between April and November 2021, a multicenter survey was conducted on 318 patients treated in any hemato-oncology outpatient clinic among three hospitals under the Korea University Medical Center. The medical records of the patients were reviewed to obtain detailed clinical and hematological toxicity data. RESULTS: A perception survey was conducted among 293 patients. Among them, 53.9% were concerned about developing vaccine-related adverse events (VRAEs) and 23.5%, about negative effects on cancer treatment. During the study period, 255 and 186 patients participated in a safety survey after the first and second doses, respectively. After the first dose, 62% of patients reported VRAEs (2.4%, grade 3), whereas 48.9% reported VRAEs (2.7%, grade 3) after the second dose. For both doses, injection-site pain and sore arm pain were the most common VRAEs, followed by myalgia, fatigue, and headache. No grade 4/5 VRAEs were observed, and there were no differences in complete blood count after vaccination. Multivariate analysis revealed female sex, active cancer treatment, and mRNA vaccines as independent risk factors for VRAE development in cancer patients. CONCLUSION: Despite high levels of concern, COVID-19 vaccines were well tolerated by cancer patients, with a safety profile consistent with that of the general population.
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Vacinas contra COVID-19 , COVID-19 , Neoplasias , Feminino , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Neoplasias/terapia , Dor , Percepção , Vacinação/efeitos adversosRESUMO
This study aimed to identify novel biomarkers for metastatic colorectal cancer progression using exosomal RNA expression profiling. The exosomal RNA expression profiles of 54 patients with mCRC were investigated. Exosomal RNA profiling was performed at the time of relapse immediately before metastasectomy and cancer recurrence or progression after metastasectomy. The up- and down-regulated RNA expression profiles were screened and analyzed using H-cluster, principle component analysis and gene ontology. The tissue expression profile of the liver metastases was compared with the GSE 41258 set using GSEA tools. We identified two distinctive biological process gene sets (IFNA and PCDB families) related to metastatic progression. The interferon-α response gene set was enriched, especially when the tumor volume was ≥1 cm3. CXCL10, CXCL11 and SAMD 9 mRNA were highly expressed in the plasma exosome samples of patients with mCRC to the liver. Furthermore, high expression of CXCL10 but not CXCL11 or SAMD9 was associated with a poor prognosis and shorter progression-free survival. Conclusions: Cancer-derived exosomal CXCL10 may be a novel biomarker for liver metastasis of mCRC and a potential target for the prevention and treatment of mCRC with liver metastasis.
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PURPOSE: First-line choice of therapy is critical as it affects treatment decisions in later lines in patients with metastatic colorectal cancer (mCRC). We assessed changes in renal function for 1 year among patients diagnosed with mCRC who received first-line chemotherapy. We aimed to analyze the prognostic factors and effect of each chemotherapy regimen on the renal function of the patients. METHODS: We retrospectively investigated patients with mCRC who were treated with a standard triplet regimen (FOLFOX/FOLFIRI with bevacizumab/cetuximab) in the first-line setting at Korea University Anam Hospital from 2015 to 2020. We checked renal function at 3-month intervals for 12 months. We calculated changes in eGFR (â³eGFR, estimated glomerular filtration rate) and compared them with clinical factors such as age, sex, chronic disease, body mass index (BMI), disease status, baseline proteinuria, and first-line chemotherapy regimen. RESULTS: Among 472 patients with mCRC, the median eGFR at baseline was 90.9 mL/min/1.73 m2; it was significantly lower (80.1 mL/min/1.73 m2, p < 0.001) at 12 months after chemotherapy initiation. Particularly, the eGFR of patients treated with FOLFIRI + bevacizumab was 74.9 mL/min/1.73 m2. The 1-year incidence rate of acute kidney injury (AKI) was 9.1%, with the lowest occurrence in patients receiving FOLFOX/cetuximab (2.1%) and the highest in those receiving FOLFIRI + bevacizumab (19.2%). Renal dysfunction was more frequent with FOLFIRI + bevacizumab as compared to the other regimens. Additionally, old age, low BMI, and proteinuria at baseline were also associated with a decreased eGFR. CONCLUSIONS: These findings can serve as important factors when selecting the first-line chemotherapy regimen for patients with mCRC.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Camptotecina/efeitos adversos , Cetuximab/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Fluoruracila/efeitos adversos , Humanos , Rim/patologia , Rim/fisiologia , Leucovorina/efeitos adversos , Prognóstico , Proteinúria/induzido quimicamente , Proteinúria/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Estudos RetrospectivosRESUMO
PURPOSE: The combination of oxaliplatin and fluoropyrimidine for 6 months is one of the standard options for adjuvant therapy for high-risk stage II and III colorectal cancers (CRCs). The optimal duration of oxaliplatin to diminish neurotoxicity without compromising efficacy needs to be clarified. PATIENTS AND METHODS: This open-label, randomized, phase III, noninferiority trial randomly assigned patients with high-risk stage II and III CRC to 3 and 6 months of oxaliplatin with 6 months of fluoropyrimidine groups (3- and 6-month arms, respectively). The primary end point was disease-free survival (DFS), and the noninferiority margin was a hazard ratio (HR) of 1.25. RESULTS: In total, 1,788 patients were randomly assigned to the 6-month (n = 895) and 3-month (n = 893) arms, and 83.6% in the 6-month arm and 85.7% in the 3-month arm completed the treatment. The neuropathy rates with any grade were higher in the 6-month arm than in the 3-month arm (69.5% v 58.3%; P < .0001). The 3-year DFS rates were 83.7% and 84.7% in the 6-month and 3-month arms, respectively, with an HR of 0.953 (95% CI, 0.769 to 1.180; test for noninferiority, P = .0065) within the noninferiority margin. Among patients with stage III CRC treated by capecitabine plus oxaliplatin, the 3-year DFS of the 3-month arm was noninferior as compared with that of the 6-month arm with an HR of 0.713 (95% CI, 0.530 to 0.959; P = .0009). However, among patients with high-risk stage II and stage III CRC treated by infusional fluorouracil, leucovorin, and oxaliplatin, the noninferiority of the 3-month arm compared with the 6-month arm was not proven. CONCLUSION: This study suggests that adding 3 months of oxaliplatin to 6 months of capecitabine could be considered an alternative adjuvant treatment for stage III CRC (ClinicalTrials.gov identifier: NCT01092481).
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Neoplasias do Colo , Compostos Organoplatínicos , Oxaliplatina , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/uso terapêuticoRESUMO
Circulating cell-free DNA (cfDNA) can be used to characterize tumor genomes through next-generation sequencing (NGS)-based approaches. We aim to identify novel genetic alterations associated with drug resistance in lung cancer and colorectal cancer patients who were treated with EGFR-targeted therapy and cytotoxic chemotherapy through whole exome sequencing (WES) of cfDNA. A cohort of 18 lung cancer patients was treated with EGFR TKI or cytotoxic chemotherapy, and a cohort of 37 colorectal cancer patients was treated with EGFR monoclonal antibody or cytotoxic chemotherapy alone. Serum samples were drawn before and after development of drug resistance, and the genetic mutational profile was analyzed with WES data. For 110 paired cfDNA and matched germline DNA WES samples, mean coverage of 138x (range, 52-208.4x) and 47x (range, 30.5-125.1x) was achieved, respectively. After excluding synonymous variants, mutants identified in more than two patients at the time of acquired resistance were selected. Seven genes in lung cancer and 16 genes in colorectal cancer were found, namely, APC, TP53, KRAS, SMAD4, and EGFR. In addition, the GPR155 I357S mutation in lung cancer and ADAMTS20 S1597P and TTN R7415H mutations in colorectal cancer were frequently detected at the time of acquired resistance, indicating that these mutations have an important function in acquired resistance to chemotherapy. Our data suggest that novel genetic variants associated with drug resistance can be identified using cfDNA WES. Further validation is necessary, but these candidate genes are promising therapeutic targets for overcoming drug resistance in lung cancer and colorectal cancer.
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PURPOSE: Perioperative blood transfusion in early stage cancer patients had a negative effect on the prognosis of patients, but the prognostic impact of transfusion in advanced cancer patients remains unclear. To minimize and guide rational transfusion, an institutional patient blood management (PBM) program was launched, and we evaluated the new program that has changed the practice and impacted on the prognosis of advanced cancer patients. METHODS: We investigated the medical records of colorectal cancer patients who received chemotherapy from 2015 to 2020. The amount and frequency of transfusion, iron replacement and laboratory findings, and overall survival were compared before and after implementation of PBM. RESULTS: The rate of transfusion in colorectal cancer patients was significantly decreased from 23.5/100 person-quarter in 2015 to 1.2/100 person-quarter in 2020, but iron supplementation therapy was frequently used, and the proportion of patients who received transfusion under hemoglobin 7 g/dL significantly increased from 15.9% in 2015 to 55.3% in 2020. Multivariate analysis revealed that transfusion was a significant risk factor affecting the overall survival of patients (HR 2.70, 95% CI: 1.93-3.78, p<0.001). Kaplan-Meier analysis revealed that overall survival was significantly longer in non-transfused patients than in transfused patients (11.0 versus 22.4 months; HR 0.69, 95% CI: 0.56-0.86, p<0.001). CONCLUSIONS: This study shows that minimized transfusion through an institutional PBM can positively affect the prognosis of patients who are receiving chemotherapy for advanced colorectal cancer.
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Transfusão de Sangue , Neoplasias Colorretais , Neoplasias Colorretais/tratamento farmacológico , Humanos , Ferro , Estimativa de Kaplan-Meier , Prognóstico , Estudos RetrospectivosRESUMO
The fundamental principle of precision oncology is centralized on the identification of therapeutically exploitable targets that provides individual patients with cancer an opportunity to make informed decisions on a personalized level. To facilitate and adopt such concepts within clinical practice, we have initiated a nationwide, multi-institutional precision oncology screening program to examine and enroll patients into the most appropriate clinical trial based on their tumor's unique molecular properties. To determine the prevalence of essential major driver mutations and to explore their dynamic associations at both molecular and pathway levels, we present a comprehensive overview on the genomic properties of East Asian patients with cancer. We further delineate the extent of genomic diversity as well as clinical actionability in patients from Western and Eastern cultures at the pan-cancer and single-tumor entity levels. To support fellow oncology communities in future investigations involving large-scale analysis, all data have been made accessible to the public (https://kmportal.or.kr). SIGNIFICANCE: We present a comprehensive overview of molecular properties of East Asian pan-cancer patients and demonstrate significant diversity in terms of genomic characteristics as well as clinical utility compared with patients with European ancestry. The results of this study will lay the groundwork for designing personalized treatments in the clinical setting. See related commentary by Moyers and Subbiah, p. 886. This article is highlighted in the In This Issue feature, p. 873.
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Neoplasias , Genômica , Humanos , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisão , Estudos Prospectivos , República da CoreiaRESUMO
PURPOSE: K-MASTER project is a Korean national precision medicine platform that screened actionable mutations by analyzing next-generation sequencing (NGS) of solid tumor patients. We compared gene analyses between NGS panel from the K-MASTER project and orthogonal methods. MATERIALS AND METHODS: Colorectal, breast, non-small cell lung, and gastric cancer patients were included. We compared NGS results from K-MASTER projects with those of non-NGS orthogonal methods (KRAS, NRAS, and BRAF mutations in colorectal cancer [CRC]; epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK] fusion, and reactive oxygen species 1 [ROS1] fusion in non-small cell lung cancer [NSCLC], and Erb-B2 receptor tyrosine kinase 2 (ERBB2) positivity in breast and gastric cancers). RESULTS: In the CRC cohort (n=225), the sensitivity and specificity of NGS were 87.4% and 79.3% (KRAS); 88.9% and 98.9% (NRAS); and 77.8% and 100.0% (BRAF), respectively. In the NSCLC cohort (n=109), the sensitivity and specificity of NGS for EGFR were 86.2% and 97.5%, respectively. The concordance rate for ALK fusion was 100%, but ROS1 fusion was positive in only one of three cases that were positive in orthogonal tests. In the breast cancer cohort (n=260), ERBB2 amplification was detected in 45 by NGS. Compared with orthogonal methods that integrated immunohistochemistry and in situ hybridization, sensitivity and specificity were 53.7% and 99.4%, respectively. In the gastric cancer cohort (n=64), ERBB2 amplification was detected in six by NGS. Compared with orthogonal methods, sensitivity and specificity were 62.5% and 98.2%, respectively. CONCLUSION: The results of the K-MASTER NGS panel and orthogonal methods showed a different degree of agreement for each genetic alteration, but generally showed a high agreement rate.
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Sequenciamento de Nucleotídeos em Larga Escala/métodos , Medicina de Precisão/normas , Reparo Gênico Alvo-Dirigido/normas , Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , República da Coreia , Sensibilidade e Especificidade , Carcinoma de Pequenas Células do Pulmão/genética , Neoplasias Gástricas/genéticaRESUMO
Recently, several panels using two representative targeting methods have been developed but they do not reflect racial specificity, especially for Asians. We have developed and analytically validated the Korean Pan-cancer Companion Diagnostic (CDX) Panel to apply targeted anticancer drugs to Korean patients based on the molecular characteristics of tumors using tumor samples without matched patient normal samples. The panel included 31 genes with reported single nucleotide variants, 9 genes with reported copy number variations, and 15 genes with predictive responses to targeted drugs under clinical testing, enabling the panel to be analyzed for the targets of 30 targeted anticancer drugs. It is cost-effective and optimized for cancer type-specific therapy in Korean cancer patients across solid cancer types while minimizing the limitations of existing approaches. In addition, the optimized filtering protocol for somatic variants from tumor-only samples enables researchers to use this panel without matched normal samples. To verify the panel, 241 frozen tumor tissues and 71 formalin-fixed paraffin-embedded (FFPE) samples from several institutes were registered. This gene screening method is expected to reduce test turnaround time and cost, making it a balanced approach to investigate solid cancer-related gene regions.
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BACKGROUND & AIMS: The application of circulating tumor DNA (ctDNA) has been studied for predicting recurrent disease after surgery and treatment response during systemic treatment. Metastasectomy can be curative for well-selected patients with metastatic colorectal cancer (mCRC). This prospective study investigated the ctDNA level before and after metastasectomy in patients with mCRC to explore its potential as a predictive biomarker. METHODS: We collected data on 98 metastasectomies for mCRC performed from March 2017 to February 2020. Somatic mutations in the primary and metastatic tumors were identified and tumor-informed ctDNAs were selected by ultra-deep targeted sequencing. Plasma samples were mandatorily collected before and 3-4 weeks after metastasectomy and serially, if patients agreed. RESULTS: Data on 67 of 98 metastasectomies (58 patients) meeting the criteria were collected. ctDNA was detected in 9 (29%) of 31 cases treated with upfront metastasectomy and in 7 (19.4%) of 36 cases treated with metastasectomy after upfront chemotherapy. The detection rate of ctDNA was higher in liver metastasis (p = 0.0045) and tumors measuring ≥1 cm (p = 0.0183). ctDNA was less likely to be detected if the response to chemotherapy was good. After metastasectomy, ctDNA was found in 4 (6%) cases with rapid progressive disease. CONCLUSION: The biological factors affecting the ctDNA shedding from the tumor should be considered when applying ctDNA assays in a clinical setting. After metastasectomy for oligometastatic lesions in good responders of chemotherapy, most ctDNA was cleared or existed below the detection level. To assist clinical decision making after metastasectomy for mCRC using ctDNA, further studies for improving specific outcomes are needed.
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Cigarette smoke (CS) affects the expression of microRNAs (miRNAs), which are important regulators of gene expression by inducing DNA methylation. However, the effects of smoking on miRNA expression have not been fully elucidated in smoking-related lung carcinogenesis. Therefore, in this study, to investigate the change of miRNA expression pattern and to identify tumor suppressor miRNAs by smoking in lung carcinogenesis, we used lung carcinogenesis model cell lines that, derived from a murine xenograft model with human bronchial epithelial cells (BEAS-2B), exposed CS or not. The microarray analysis revealed that miR-584-5p expression was downregulated with cancer progression in lung carcinogenesis model cell lines. We confirmed by pyrosequencing that the methylation level of the miR-584-5p promoter increased with cancer progression. In vitro and in vivo experiments showed that miR-584-5p suppressed migration and invasion in non-small cell lung cancer (NSCLC) cells by targeting YKT6. Furthermore, we showed that high level of YKT6 was associated with a poor survival rate in NSCLC patients with a history of smoking. These results suggest that miR-584-5p acts as a tumor suppressor and is a potential molecular biomarker for smoking-related NSCLC.
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PURPOSE: Next-generation sequencing (NGS) can facilitate precision medicine approaches in metastatic colorectal cancer (mCRC) patients. We investigated the molecular profiling of Korean mCRC patients under the K-MASTER project which was initiated in June 2017 as a nationwide precision medicine oncology clinical trial platform which used NGS assay to screen actionable mutations. MATERIALS AND METHODS: As of 22 January 2020, total of 994 mCRC patients were registered in K-MASTER project. Targeted sequencing was performed using three platforms which were composed of the K-MASTER cancer panel v1.1 and the SNUH FIRST Cancer Panel v3.01. If tumor tissue was not available, cell-free DNA was extracted and the targeted sequencing was performed by Axen Cancer Panel as a liquid biopsy. RESULTS: In 994 mCRC patients, we found 1,564 clinically meaningful pathogenic variants which mutated in 71 genes. Anti-EGFR therapy candidates were 467 patients (47.0%) and BRAF V600E mutation (n=47, 4.7%), deficient mismatch repair/microsatellite instability-high (n=15, 1.5%), HER2 amplifications (n=10, 1.0%) could be incorporated with recently approved drugs. The patients with high tumor mutation burden (n=101, 12.7%) and DNA damaging response and repair defect pathway alteration (n=42, 4.2%) could be enrolled clinical trials with immune checkpoint inhibitors. There were more colorectal cancer molecular alterations such as PIK3CA, KRAS G12C, atypical BRAF, and HER2 mutations and even rarer but actionable genes that approved or ongoing clinical trials in other solid tumors. CONCLUSION: K-MASTER project provides an intriguing background to investigate new clinical trials with biomarkers and give therapeutic opportunity for mCRC patients.