ABSTRACT
Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole-transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin-18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD-L1). Concurrently, WTS was employed as part of the analyses in MONSTAR-SCREEN-2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD-L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC-positive patients treated with anti-HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression-free survival (ERBB2-high vs. -low: median 9.0 vs. 5.6 months, log-rank p = 0.046). IHC-based molecular profiling revealed significantly high expression of CLDN18 in RTK-negative patients, with 78.4% positive for either CLDN18 or PD-L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC-negative but WTS-positive status may benefit from specific biomarker-targeted therapies.
Subject(s)
Biomarkers, Tumor , Esophageal Neoplasms , Esophagogastric Junction , Immunohistochemistry , Receptor, ErbB-2 , Stomach Neoplasms , Humans , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Stomach Neoplasms/metabolism , Male , Female , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Esophageal Neoplasms/mortality , Esophageal Neoplasms/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Middle Aged , Aged , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Esophagogastric Junction/pathology , Esophagogastric Junction/metabolism , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Claudins/genetics , Claudins/metabolism , Adult , Aged, 80 and over , Transcriptome , Gene Expression Profiling/methodsABSTRACT
BACKGROUND: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard treatment for locally advanced rectal cancer (LARC). We reported the short-term outcomes of the VOLTAGE trial that investigated the safety and efficacy of preoperative CRT followed by nivolumab and surgery. Here, we present the 3-year outcomes of this trial. METHODS: Thirty-nine patients with microsatellite stable (MSS) LARC and five patients with microsatellite instability-high (MSI-H) LARC underwent CRT (50.4 Gy) followed by five doses of nivolumab (240 mg) and surgery. The 3-year relapse-free survival (RFS), overall survival (OS), and associations with biomarkers were evaluated. RESULTS: The 3-year RFS rates in patients with MSS and MSI-H were 79.5% and 100%, respectively, and the 3-year OS rates were 97.4% and 100%, respectively. Of the MSS patients, those with pre-CRT PD-L1 positivity, pre-CRT high CD8 + T cell/effector regulatory T cell (eTreg) ratio, pre-CRT high expression of Ki-67, CTLA-4, and PD-1 had a trend toward better 3-year RFS than those without. CONCLUSIONS: Three-year outcomes of patients with MSI-H were better than those of patients with MSS. PD-L1 positivity, elevated CD8/eTreg ratio, and high expression of Ki-67, CTLA-4, and PD-1 could be positive predictors of prognosis in patients with MSS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02948348.
Subject(s)
Chemoradiotherapy , Microsatellite Instability , Nivolumab , Rectal Neoplasms , Adult , Aged , Female , Humans , Male , Middle Aged , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/administration & dosage , B7-H1 Antigen/genetics , Chemoradiotherapy/methods , CTLA-4 Antigen , Nivolumab/administration & dosage , Nivolumab/therapeutic use , Rectal Neoplasms/therapy , Rectal Neoplasms/genetics , Rectal Neoplasms/pathology , Rectal Neoplasms/mortality , Treatment OutcomeABSTRACT
BACKGROUND: Although nivolumab has a high efficacy, reliable biomarkers are needed to predict the efficacy. We evaluated the nivolumab efficacy according to the TP53 mutation in advanced gastric cancer patients enrolled in the GI-SCREEN project. METHODS: Sequence data of tumour specimens and clinicopathological information of 913 patients with advanced gastric cancer who were enrolled between April 2015 and March 2017 were obtained from the GI-SCREEN database. The follow-up information of 266 patients treated with nivolumab was also provided. RESULTS: Among 266 patients treated with nivolumab, the objective response rate (ORR) of TP53 wild type (wt) patients (24.6%) was higher than that of TP53 mutant patients (14.8%). Among TP53 mutant patients, the ORR of the frameshift type tended to be higher than the transition and transversion type (23.1%, 13.6%, and 13.0%, respectively). The median progression-free survival (PFS) was statistically longer in TP53 wt patients than in mutant patients (3.3 vs 2.1 months, HR 1.4, 95% CI 1.1-1.9). Among TP53 mutant patients, PFS was statistically longer in the frameshift type than in the transversion type. CONCLUSION: Nivolumab showed better efficacy in TP53 wt patients than in mutant patients. Among TP53 mutant patients, the frameshift type may have efficacy from nivolumab treatment.
Subject(s)
Antineoplastic Agents, Immunological , Stomach Neoplasms , Humans , Nivolumab/therapeutic use , Genes, p53 , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Antineoplastic Agents, Immunological/therapeutic use , Treatment Outcome , Mutation , Tumor Suppressor Protein p53/geneticsABSTRACT
BACKGROUND: Trifluridine/tipiracil plus VEGF inhibition with ramucirumab (RAM) for advanced gastric cancer (AGC) demonstrated clinical activity with an acceptable toxicity profile in previous phase II trial. However, little is known about its efficacy and safety in clinical practice in comparison with trifluridine/tipiracil monotherapy. METHODS: We retrospectively investigated efficacy and safety of trifluridine/tipiracil plus RAM and trifluridine/tipiracil monotherapy as third or later line treatment for AGC patients. RESULTS: Forty-one patients receiving trifluridine/tipiracil plus RAM and 60 patients receiving trifluridine/tipiracil monotherapy were analyzed. The objective response rate (ORR) and the disease control rate (DCR) were 13.5% and 64.9% in the trifluridine/tipiracil plus RAM group, and 3.8% and 42.3% in the trifluridine/tipiracil monotherapy group, respectively (ORR; P = 0.122, DCR; P = 0.052). The median progression-free survival (PFS) and the median overall survival (OS) were 3.0 months and 7.2 months in the trifluridine/tipiracil plus RAM group, and 1.8 months and 3.8 months in the trifluridine/tipiracil monotherapy group, respectively (HR for PFS = 0.66; P = 0.059, HR for OS = 0.50; P = 0.007). Multivariate analysis showed significantly longer PFS (HR = 0.52; P = 0.011) and OS (HR = 0.51; P = 0.031) in the trifluridine/tipiracil plus RAM group compared to the trifluridine/tipiracil monotherapy group. No unexpected adverse events were observed in both groups. CONCLUSIONS: Trifluridine/tipiracil plus RAM might show favorable anti-tumor activity with an acceptable toxicity profile in comparison with trifluridine/tipiracil monotherapy, suggesting one treatment option for AGC patients in salvage line. The combination needs further evaluation in ongoing randomized trials.
Subject(s)
Colorectal Neoplasms , Stomach Neoplasms , Humans , Uracil/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Trifluridine/adverse effects , Retrospective Studies , Drug Combinations , Antineoplastic Combined Chemotherapy Protocols/adverse effects , RamucirumabABSTRACT
BACKGROUND: Although definitive chemoradiotherapy (CRT) is the standard therapy for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC), poor survival has been reported. Although the complete response (CR) rate is strongly correlated with good prognosis, the predictive factors for CR have not been elucidated. METHODS: This registry study aimed to identify predictors of CR to definitive CRT in patients with unresectable locally advanced ESCC. "Unresectable" was defined as the primary lesion invading unresectable adjacent structures such as the aorta, vertebral body, and trachea (T4b), or the regional and/or supraclavicular lymph nodes invading unresectable adjacent structures (LNT4b). RESULTS: Overall, 175 patients who started definitive CRT between January 2013 and March 2020 were included. The confirmed CR (cCR) rate was 24% (42/175). The 2-year progression-free survival (PFS) and overall survival (OS) rates of cCR cases vs. non-cCR cases were 59% vs. 2% (log-rank p < 0.001) and 90% vs. 31% (log-rank p < 0.001), with a median follow-up period of 18.5 and 40.5 months, respectively. Multivariate analysis of clinicopathological factors revealed that tumor length ≥ 6 cm [odds ratio (OR) 0.446; 95% CI 0.220-0.905; p = 0.025] was a predictor of cCR. CONCLUSIONS: Favorable PFS and OS rates were observed in patients with cCR. Tumor length was a predictive factor for cCR.
Subject(s)
Carcinoma, Squamous Cell , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Esophageal Squamous Cell Carcinoma/therapy , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/radiotherapy , Carcinoma, Squamous Cell/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , ChemoradiotherapyABSTRACT
According to the current international guidelines, high-risk patients diagnosed with pathological T1 (pT1) colorectal cancer (CRC) who underwent complete local resection but may have risk of developing lymph node metastasis (LNM) are recommended additional intestinal resection with lymph node dissection. However, around 90% of the patients without LNM are exposed to the risk of being overtreated due to the insufficient pathological criteria for risk stratification of LNM. Circulating tumor DNA (ctDNA) is a noninvasive biomarker for molecular residual disease and relapse detection after treatments including surgical and endoscopic resection of solid tumors. The CIRCULATE-Japan project includes a large-scale patient-screening registry of the GALAXY study to track ctDNA status of patients with stage II to IV or recurrent CRC that can be completely resected. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective study, within the GALAXY study for patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk stratification criteria for LNM. The aim of this study is to explore the ability of predicting LNM using ctDNA analysis compared with the standard pathological criteria. The ctDNA assay will build new evidence to establish a noninvasive personalized diagnosis in patients, which will facilitate tailored/optimal treatment strategies for CRC patients.
Subject(s)
Circulating Tumor DNA , Colorectal Neoplasms , Circulating Tumor DNA/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/surgery , Humans , Liquid Biopsy , Lymph Node Excision , Lymph Nodes/pathology , Lymphatic Metastasis/pathology , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prospective Studies , Retrospective Studies , Risk FactorsABSTRACT
Radiotherapy (RT) combined with immune checkpoint inhibitors has recently produced outstanding results and is expected to be adaptable for various cancers. However, the precise molecular mechanism by which immune reactions are induced by fractionated RT is still controversial. We aimed to investigate the mechanism of the immune response regarding multifractionated, long-term radiation, which is most often combined with immunotherapy. Two human esophageal cancer cell lines, KYSE-450 and OE-21, were irradiated by fractionated irradiation (FIR) daily at a dose of 3 Gy in 5 d/wk for 2 weeks. Western blot analysis and RNA sequencing identified type I interferon (IFN) and the stimulator of IFN genes (STING) pathway as candidates that regulate immune response by FIR. We inhibited STING, IFNAR1, STAT1, and IFN regulatory factor 1 (IRF1) and investigated the effects on the immune response in cancer cells and the invasion of surrounding immune cells. We herein revealed type I IFN-dependent immune reactions and the positive feedback of STING, IRF1, and phosphorylated STAT1 induced by FIR. Knocking out STING, IFNAR1, STAT1, and IRF1 resulted in a poorer immunological response than that in WT cells. The STING-KO KYSE-450 cell line showed significantly less invasion of PBMCs than the WT cell line under FIR. In the analysis of STING-KO cells and migrated PBMCs, we confirmed the occurrence of STING-dependent immune activation under FIR. In conclusion, we identified that the STING-IFNAR1-STAT1-IRF1 axis regulates immune reactions in cancer cells triggered by FIR and that the STING pathway also contributes to immune cell invasion of cancer cells.
Subject(s)
Esophageal Neoplasms , Immunity , Interferon Regulatory Factor-1 , STAT1 Transcription Factor , Cell Line/radiation effects , Esophageal Neoplasms/genetics , Humans , Immunity/radiation effects , Interferon Regulatory Factor-1/genetics , Interferon Regulatory Factor-1/metabolism , Interferon Regulatory Factor-1/radiation effects , Interferon Type I , Membrane Proteins/genetics , Membrane Proteins/metabolism , Membrane Proteins/radiation effects , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , Receptor, Interferon alpha-beta/radiation effects , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , STAT1 Transcription Factor/radiation effectsABSTRACT
BACKGROUND: In older adults, skeletal muscle mass is an important factor for health and prognosis. The loss of SMM during neoadjuvant therapy affects the prognosis of patients with locally advanced esophageal cancer. However, information is limited regarding this possibility in older patients. This study aimed to establish the prognostic impact of SMM loss during neoadjuvant chemotherapy on older patients with locally advanced esophageal cancer. METHODS: This was a single-center retrospective cohort study. Patients age 65 years or older had undergone R0 curative esophagectomy after NAC. The skeletal muscle mass index before and after NAC was calculated from computed tomography images. The percentage change in the SMI during NAC (SMI%) was calculated from the SMI before and after NAC. RESULTS: The study analyzed 150 patients with a mean age of 71.1 ± 3.7 years. The mean value of the SMI was 42.7 ± 7.2 cm2/m2 before NAC, and the SMI% was - 6.4% ± 5.9%. The cutoff of SMI% for overall survival was defined by the log-rank test as - 12%. The Cox proportional hazard model showed that major loss of the SMI (≥ 12%) significantly influenced OS (hazard ratio, 2.490; 95% confidence interval, 1.121-5.529; p = 0.025) independently of age, sex, pathologic T and N factors, or treatment regimen. CONCLUSIONS: Major SMI loss has an impact on OS after R0 curative esophagectomy for older patients with locally advanced esophageal cancer.
Subject(s)
Esophageal Neoplasms , Sarcopenia , Humans , Aged , Neoadjuvant Therapy/methods , Prognosis , Retrospective Studies , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/surgery , Esophageal Neoplasms/pathology , Muscle, Skeletal/pathology , Sarcopenia/chemically induced , Sarcopenia/pathologyABSTRACT
BACKGROUND AND AIMS: Lymph node recurrence (LNR) after endoscopic resection (ER) in patients with esophageal squamous cell carcinoma (ESCC) pathologically invading the muscularis mucosae (pMM) without lymphovascular invasion (LVI) has been reported as non-negligible in the ER guidelines for esophageal cancer by the Japan Gastroenterological Endoscopy Society. However, these data were not regarded as high-level evidence because several retrospective case series were tabulated without sufficient long-term follow-up. Hence, this guideline stated that the administration of additional treatment after ER could not be determined for this population. This study aimed to clarify the long-term clinical outcomes after ER of pMM ESCC without LVI. METHODS: Between January 2009 and November 2017, we enrolled followed patients who underwent ER and were diagnosed with pMM ESCC without LVI with no additional treatments. We retrospectively investigated the cumulative recurrence rate and recurrence-free, overall, and disease-specific survival at 5 years after ER. RESULTS: Eighty-seven patients were enrolled. During the median follow-up period of 64 months (range, 12-117), 3 patients developed lymph node and/or distant recurrence, and 2 of these cases occurred more than 3 years after ER; all 3 patients died of the primary disease. The 5-year cumulative recurrence rate was 4.3%, and the 5-year recurrence-free, disease-specific, and overall survival rates were 88.8%, 98.2%, and 91.7%, respectively. CONCLUSIONS: The long-term outcome for patients with pMM ESCC without LVI was favorable after ER; however, this population had a risk of recurrence directly leading to death. Long-term follow-up is necessary, with attention to the timing of recurrence.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Endoscopy , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/surgery , Humans , Mucous Membrane/pathology , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/pathology , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Although several randomized trials (RCTs) showed survival benefits of immune checkpoint inhibitor (ICI) plus first-line chemotherapy for advanced gastric or gastroesophageal cancer (AGC), these trials could enroll patients who fulfilled the strict eligibility criteria or waited for certain screening period for central assessment of PD-L1 status. METHODS: We retrospectively compared characteristics and clinical outcomes of the patients with AGC who received first-line chemotherapy in control arm of RCTs with ICIs (control group) or clinical practice (practice group) at our institution from February 2016 to April 2019. RESULTS: The control group had a better baseline Eastern Cooperative Oncology Group performance status (PS0, 81.2% vs. 51.4%, p < 0.001) and a longer interval from first visit to first-line chemotherapy initiation (19 days vs. 9 days, p < 0.001) than the practice group. Median overall survival (OS) was 20.3 months in control group and 15.7 months in practice group, with a trend of longer OS in control group than that in practice group (hazard ratio, 0.71; p = 0.062). More patients in control group were treated with subsequent chemotherapy including ICIs. CONCLUSION: Patients with AGC in RCTs of ICIs had a better PS or a higher chance to receive subsequent chemotherapy, resulting in a better prognosis than those treated in clinical practice. This information should be considered when interpreting RCT results and applying new treatments into clinical practice.
Subject(s)
Lung Neoplasms , Stomach Neoplasms , Humans , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Prognosis , Proportional Hazards Models , Randomized Controlled Trials as Topic , Stomach Neoplasms/drug therapyABSTRACT
BACKGROUND: Recently, the JCOG0502 has shown a comparable efficacy of chemoradiotherapy and esophagectomy in patients with clinical T1N0M0 esophageal squamous cell carcinoma. However, few studies have compared the clinical outcomes of these treatments in esophageal squamous cell carcinoma patients (including elderly patients) based on real-world data. METHODS: This retrospective study determined real-world outcomes in patients who underwent chemoradiotherapy or esophagectomy, including those with clinical T1N0M0 esophageal squamous cell carcinoma, between 2009 and 2017 at the National Cancer Center Hospital East. RESULTS: Among a total of 156 patients, 120 and 36 patients underwent esophagectomy and chemoradiotherapy, respectively; 138, 12 and 6 patients had Eastern Cooperative Oncology Group performance status 0, 1, and 2, respectively; and 33 and 123 patients had clinical tumor depth MM-SM1 and SM2-SM3, respectively. In a median follow-up of 72 months, 5-year progression-free survival and overall survival were respectively 77.0% and 81.5% in the esophagectomy group and 74.4% and 82.6% in the chemoradiotherapy group (P = 0.48 and, P = 0.89). Moreover, no treatment-related death was detected in both groups. In elderly patients (75 years or older), 5-year progression-free survival and overall survival were not significantly different between esophagectomy and chemoradiotherapy groups (5-year progression-free survival: 72.3% vs. 81.8%, P = 0.38; 5-year overall survival: 76.9% vs. 81.8%, P = 0.59). CONCLUSIONS: This real-world study confirms the results of a previous clinical trial, and the present findings support chemoradiotherapy as one of the standard treatment options in patients of all ages with clinical T1N0M0 esophageal squamous cell carcinoma.
Subject(s)
Carcinoma, Squamous Cell , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Aged , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/surgery , Chemoradiotherapy/methods , Combined Modality Therapy , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/surgery , Esophageal Squamous Cell Carcinoma/drug therapy , Esophageal Squamous Cell Carcinoma/surgery , Esophagectomy/methods , Humans , Retrospective Studies , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: In Japan, standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC) includes preoperative chemotherapy with fluorouracil plus cisplatin followed by esophagectomy. However, its efficacy is unclear in patients with recurrent disease with < 6 months of chemotherapy-free interval (CFI) after preoperative chemotherapy followed by esophagectomy and in those with ≥ 6 months of CFI and poor pathological response to prior preoperative chemotherapy. METHOD: We retrospectively evaluated the efficacy of fluorouracil plus platinum in patients with recurrent ESCC who received preoperative chemotherapy followed by curative esophagectomy. RESULTS: Among 105 patients with recurrent ESCC after preoperative chemotherapy followed by esophagectomy, a total of 55 patients received fluorouracil plus platinum for recurrent disease. Patients with a CFI < 6 months (n = 20) had significantly shorter overall survival (OS) (median, 7.1 vs 14.5 months, P = 0.008) compared with those with a CFI ≥ 6 months (n = 35). Multivariate analysis showed that OS was worse in patients with a CFI < 6 months or a tumor regression grade (TRG) ≤ 1a. Furthermore, in patients with a CFI ≥ 6 months, TRG ≤ 1a was associated with significantly shorter OS (11.1 months vs. not reached, P = 0.001). CONCLUSION: Fluorouracil plus platinum was ineffective for recurrent ESCC in patients with a CFI < 6 months and in those with a CFI ≥ 6 months and a TRG ≤ 1a. Alternate regimens including nivolumab or pembrolizumab might be considered for the treatment for recurrence in these patients.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cisplatin/therapeutic use , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Esophageal Neoplasms/surgery , Esophageal Squamous Cell Carcinoma/drug therapy , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/surgery , Esophagectomy , Fluorouracil/therapeutic use , Humans , Neoplasm Recurrence, Local/pathology , Platinum/therapeutic use , Retrospective StudiesABSTRACT
BACKGROUND: Endoscopic resection (ER) is performed for early esophageal squamous cell carcinoma (ESCC) cases. Additional esophagectomy or chemoradiotherapy is recommended for non-curative resection (NCR) even with pathologically negative vertical margins (pVM0); however, their clinical outcomes remain unknown. We examined the long-term clinical outcomes of NCR for ESCCs according to additional treatments. METHODS: We retrospectively analyzed the data of patients who underwent ER for cT1N0M0 ESCC between 2009 and 2017 judged to have NCR, which defined when pathologically diagnosed as invading the submucosa (SM) or muscularis mucosae (MM) involving lymphovascular invasion (LVI), pVM0, and endoscopically judged as negative horizontal margin. Additional esophagectomy (involving three-field lymphadenectomy), chemoradiotherapy [mainly cisplatin and 5-fluorouracil with concurrent radiotherapy (41.4 Gy)], or observation was undertaken. Thereafter, computed tomography was performed every 6-12 months. The cumulative recurrence (CRR) and recurrence-free survival (RFS) rates were evaluated. RESULTS: Eighty-nine patients were included. Among them, 14 had pathologically diagnosed pMM with LVI; 9 and 6, and 32 and 28 patients had pSM1 and pSM2 without and with LVI. Twenty-one patients underwent observation, whereas 18 and 50 underwent esophagectomy and chemoradiotherapy. During the 60.6-month median follow-up period, nine patients had recurrence; among them, six patients had occurrence at > 4 years after ER. The 5-year CRR/RFS rates were 35.7%/48.1%, 13.4%/80.4%, and 0.0%/98.0% in the observation, esophagectomy, and chemoradiotherapy groups, respectively (observation vs. chemoradiotherapy; P < 0.001). CONCLUSIONS: Additional treatments showed better long-term outcomes than observation for patients with NCR. As recurrence may occur at > 4 years after ER, careful long-term follow-up examinations are needed.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Esophageal Neoplasms/surgery , Esophageal Squamous Cell Carcinoma/surgery , Humans , Mucous Membrane/pathology , Retrospective Studies , Treatment OutcomeABSTRACT
Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively conducted large-scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in the GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for ctDNA-negative and -positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA-guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.
Subject(s)
Circulating Tumor DNA/blood , Colorectal Neoplasms/blood , Neoplasm Recurrence, Local/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Capecitabine/administration & dosage , Chemotherapy, Adjuvant , Colonic Neoplasms/blood , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Colonic Neoplasms/therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Double-Blind Method , Humans , Japan , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Oxaliplatin/administration & dosage , Prospective Studies , Pyrrolidines/administration & dosage , Thymine/administration & dosage , Trifluridine/administration & dosageABSTRACT
BACKGROUND: KRAS is one of the most frequently mutated oncogenes in colorectal cancer (CRC). Recently, a novel therapy targeting KRAS G12C mutation has demonstrated promising activities for corresponding advanced solid tumors, including metastatic CRC (mCRC). However, the prognostic impact of the KRAS G12C mutation remains unclear in patients with mCRC. MATERIALS AND METHODS: We retrospectively reviewed medical records of patients with mCRC who received first-line chemotherapy between January 2005 and December 2017 at four large oncology facilities in Japan. Survival outcomes were compared between patients with KRAS G12C and those with non-G12C mutations. RESULTS: Among 2,457 patients with mCRC, 1,632 met selection criteria, and of these, 696 had KRAS exon 2 mutations, including 45 with KRAS G12C mutation tumors. Patient characteristics were not significantly different between the KRAS G12C and non-G12C groups. At a median follow-up of 64.8 months, patients with the KRAS G12C mutation showed significantly shorter first-line progression-free survival (PFS; median, 9.4 vs. 10.8 months; p = .015) and overall survival (OS; median, 21.1 vs. 27.3 months; p = .015) than those with non-G12C mutations. Multivariate analysis also showed that KRAS G12C mutation was significantly associated with shorter PFS (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.04-1.96, p = .030) and OS (HR, 1.42; 95% CI, 1.01-2.00; p = .044). CONCLUSION: We demonstrate that, compared with non-G12C mutations, KRAS G12C mutation is significantly correlated with shorter first-line PFS and OS. These findings indicate the relevance of a stratified treatment targeting KRAS G12C mutation in mCRC. IMPLICATIONS FOR PRACTICE: Among patients with KRAS exon 2 mutated metastatic colorectal cancer (mCRC), median progression-free survival (PFS) and overall survival (OS) were 9.4 and 21.1 months, respectively, for G12C mutation and 10.8 and 27.3 months, respectively, for patients with non-G12C mutations, indicating significantly shorter PFS (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.08-2.01; p = .015) and OS (HR, 1.50; 95% CI, 1.08-2.08; p = .015) in patients with G12C mutation than in those with non-G12C mutations. Furthermore, multivariate analysis showed that KRAS G12C mutation was independently associated with shorter first-line PFS and OS. Thus, these findings underscore the relevance of a stratified treatment targeting KRAS G12C mutation in mCRC.
Subject(s)
Colorectal Neoplasms , Proto-Oncogene Proteins p21(ras) , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Humans , Mutation , Prognosis , Proto-Oncogene Proteins p21(ras)/genetics , Retrospective StudiesABSTRACT
Background FOLFOXIRI plus bevacizumab is the first-line treatment for metastatic colorectal cancer (mCRC) but demonstrates high neutropenia incidence among Asian patients. Hence, we conducted the randomized phase II QUATTRO-II study (ClinicalTrials.gov identifier: NCT04097444; Japan Registry of Clinical Trials identifier: jRTCs041190072) to evaluate the safety and efficacy of capecitabine, oxaliplatin, and irinotecan (CAPOXIRI) combination plus bevacizumab versus FOLFOXIRI plus bevacizumab, expecting a lower incidence of neutropenia without compromising the efficacy. Methods We investigated the recommended doses (RD) of oxaliplatin and irinotecan as a safety lead-in portion of Step 1 before initiating the randomized portion as Step 2. Four dose levels of CAPOXIRI (fixed dose of capecitabine, 1600 mg/m2; escalated/de-escalated doses of oxaliplatin and irinotecan) plus bevacizumab (7.5 mg/kg) were investigated in a 3 + 3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results In Step 1, we included nine patients (three and six in levels 0 and + 1, respectively). Level 0 (irinotecan, 200 mg/m2; oxaliplatin, 100 mg/m2) did not demonstrate DLTs. In level + 1 (irinotecan, 200 mg/m2; oxaliplatin, 130 mg/m2), although one patient experienced grade 4 febrile neutropenia, no further safety concerns were observed. As a preliminary efficacy result, the objective response rate in all nine patients was 89 % (100 and 83 % in levels 0 and + 1, respectively). Conclusions The RD of CAPOXIRI plus bevacizumab was 200, 130, and 1600 mg/m2 for irinotecan, oxaliplatin, and capecitabine, respectively, and 7.5 mg/kg for bevacizumab. The randomized portion is still ongoing.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/therapeutic use , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Capecitabine/therapeutic use , Colorectal Neoplasms/pathology , Dose-Response Relationship, Drug , Female , Fluorouracil/therapeutic use , Humans , Irinotecan/therapeutic use , Leucovorin/therapeutic use , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Metastasis , Organoplatinum Compounds/therapeutic use , Oxaliplatin/therapeutic useABSTRACT
BACKGROUND: Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge. METHODS: This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360). DISCUSSION: Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative. TRIAL REGISTRATION: The REMARRY study: UMIN, UMIN000036424 . Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096 . Registered date: October 1, 2019.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Biomarkers, Tumor/blood , Colorectal Neoplasms/drug therapy , Irinotecan/administration & dosage , Panitumumab/administration & dosage , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/genetics , Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , Clinical Trials, Phase II as Topic , Colorectal Neoplasms/blood , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , Humans , Irinotecan/adverse effects , Japan , Liquid Biopsy , Male , Middle Aged , Multicenter Studies as Topic , Observational Studies as Topic , Panitumumab/adverse effects , Prospective Studies , Treatment Outcome , ras Proteins/blood , ras Proteins/geneticsABSTRACT
Circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) assays have advantages over classic tissue-based analyses because of their low invasiveness and availability of repeated sampling. Because of the low incidence of target gene alterations such as HER2 or BRAF V600E in gastrointestinal cancers, very large screening platforms are needed to develop genome-based clinical trials. For those reasons, ctDNA-based screening studies are being actively conducted; among them are the GOZILA (Guardant Originates in Zipangu Liquid biopsy Arrival) study in Japan and the COLOMATE (COlorectal Cancer Liquid BiOpsy Screening Protocol for Molecularly Assigned ThErapy) study in the United States. Although only patients with metastatic colorectal cancer (mCRC) who had previously received standard chemotherapies are eligible for the COLOMATE study, patients with various types of solid tumors at any line of treatment are eligible for GOZILA. This broad coverage of the eligible population allows a target of 5000 patients. By contrast, effective screening of selected candidate patients for companion trials using rapid turnaround time by ctDNA-based NGS assay is the key for COLOMATE. The companion trials of targeted therapies in mCRC are similar between GOZILA and COLOMATE. Both studies have identified patients eligible for studies by examining ERBB2 (HER2), BRAF V600E, BRAF non-V600E, and FGFR alterations, as well as MET amplification and rechallenge with anti-EGFR antibodies. The existence of various companion trials for common alterations that can be potential therapy targets on the 2 platforms can lead to future international collaboration.
Subject(s)
Circulating Tumor DNA/genetics , Gastrointestinal Neoplasms/genetics , Genes, Neoplasm/genetics , High-Throughput Nucleotide Sequencing/methods , Biomarkers, Tumor , Clinical Trials as Topic , Colorectal Neoplasms/genetics , High-Throughput Nucleotide Sequencing/standards , Humans , Research DesignABSTRACT
BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX) has shown non-inferiority to paclitaxel (PTX) as second-line therapy for advanced gastric cancer (AGC) with fewer infusion-related reactions. The efficacy and safety of nab-PTX plus ramucirumab (RAM) was reported in a phase II trial; however, there is no randomized trial comparing this regimen with PTX plus RAM in patients with AGC. This retrospective study aimed to investigate the efficacy and safety of nab-PTX plus RAM versus PTX plus RAM in patients with AGC. METHODS: This study included patients with AGC who received nab-PTX plus RAM from September 2017 to January 2019 or PTX plus RAM from June 2015 to August 2017 as second-line chemotherapy in our hospital. RESULTS: A total of 113 and 138 patients who received nab-PTX plus RAM and PTX plus RAM, respectively, were analyzed. Median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI]: 3.4-4.3) in the nab-PTX plus RAM group and 3.9 months (95% CI: 3.1-4.7) in the PTX plus RAM group (hazard ratio [HR]: 1.08; 95% CI: 0.83-1.40; P = 0.573). Median overall survival (OS) was 10.9 months (95% CI: 9.3-12.7) in the nab-PTX plus RAM group and 10.3 months (95% CI: 8.5-12.0) in the PTX plus RAM group (hazard ratio: 0.82; 95% CI: 0.61-1.10; P = 0.188). In patients with moderate/massive ascites, favorable outcomes for progression-free survival were observed in the nab-PTX plus RAM group compared with the PTX plus RAM group. Although anemia and fatigue (any grade) were more frequent in the nab-PTX plus RAM group, discontinuation of study treatment was not increased in the nab-PTX plus RAM group. There was no occurrence of hypersensitivity reaction in the nab-PTX plus RAM group, while two patients (1.4%) experienced grade 3 hypersensitivity reactions in the PTX plus RAM group. CONCLUSIONS: The combination of nab-PTX plus RAM showed a similar efficacy and safety profile to PTX plus RAM as second-line treatment for patients with AGC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Delivery Systems , Nanoparticles/administration & dosage , Stomach Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Albumin-Bound Paclitaxel/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Female , Follow-Up Studies , Humans , Male , Middle Aged , Nanoparticles/chemistry , Paclitaxel/administration & dosage , Prognosis , Retrospective Studies , Stomach Neoplasms/pathology , Survival Rate , RamucirumabABSTRACT
BACKGROUND: The standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy (CRT) using 5-FU plus cisplatin. However, complete response (CR) rates are low at 11-25%, resulting in 9-10 months of median overall survival (OS). An improved therapeutic efficacy by combining immunotherapy with radiation has been reported in patients with locally advanced non-small cell lung cancer. The results using ESCC cell lines suggest sequential treatment with anti-PD-L1 agents soon after completion of CRT is the most effective combination. METHODS: TENERGY trial is a multicenter, phase II, proof-of-concept study to assess the efficacy and safety of atezolizumab following definitive CRT in patients with locally advanced ESCC. The main inclusion criteria are unresectable locally advanced ESCC without distant metastasis, completion of 60 Gy of radiation plus two concomitant cycles of chemotherapy (cisplatin 70 mg/m2 on day 1 and 5-FU 700 mg/m2 on days 1-4, every 28 days), and adequate organ function. Within 6 weeks after CRT, participants will start taking 1200 mg of atezolizumab every three weeks and continue until 12 months or disease progression. The primary endpoint is the confirmed CR rate by the investigator's assessment. Secondary endpoints include overall response rate, progression-free survival (PFS), OS, adverse events, and confirmed CR rate by central assessment. We will enroll 50 patients (40 with primary locally advanced ESCC and 10 with postoperative locoregionally recurrent ESCC). We will obtain biopsies from the primary site and will collect blood at 3 time points (before CRT, after CRT, and four weeks after the start of atezolizumab) for an exploratory biomarker study. We will analyze the phenotype of immune-competent cells, neoantigens, tumor mutational burden, PD-L1 status, and Human Leukocyte Antigen haplotyping. DISCUSSION: The synergistic efficacies of the sequential combination of CRT and atezolizumab should improve the CR rate, resulting in survival improvement for patients with unresectable locally advanced ESCC. Because CRT is a standard treatment option for patients with early stage to locally advanced ESCC, the sequential combination of CRT and atezolizumab has the potential to change the standard ESCC treatments. TRIAL REGISTRATION: UMIN000034373, 10/04/2018 and EPOC1802.