Microsatellite instability: A 2024 update.

Deficient mismatch repair (dMMR) results in microsatellite instability (MSI), a pronounced mutator phenotype. High-frequency MSI (MSI-H)/dMMR is gaining increasing interest as a biomarker for advanced cancer patients to determine their eligibility for immune checkpoint inhibitors (ICIs). Various methods based on next-generation sequencing (NGS) have been developed to assess the MSI status. Comprehensive genomic profiling (CGP) testing can precisely ascertain the MSI status as well as genomic alterations in a single NGS test. The MSI status can be also ascertained through the liquid biopsy-based CGP assays. MSI-H has thus been identified in various classes of tumors, resulting in a greater adoption of immunotherapy, which is hypothesized to be effective against malignancies that possess a substantial number of mutations and/or neoantigens. NGS-based studies have also characterized MSI-driven carcinogenesis, including significant rates of fusion kinases in colorectal cancers (CRCs) with MSI-H that are targets for therapeutic kinase inhibitors, particularly in MLH1-methylated CRCs with wild-type KRAS/BRAF. NTRK fusion is linked to the colorectal serrated neoplasia pathway. Recent advances in investigations of MSI-H malignancies have resulted in the development of novel diagnostic or therapeutic techniques, such as a synthetic lethal therapy that targets the Werner gene. DNA sensing in cancer cells is required for antitumor immunity induced by dMMR, opening up novel avenues and biomarkers for immunotherapy. Therefore, clinical relevance exists for analyses of MSI and MSI-H-associated genomic alterations in malignancy. In this article, we provide an update on MSI-driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies.

The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions.

Neuregulin 1 (NRG1) fusions are oncogenic drivers that have been detected in non-small-cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. NRG1 fusions are rare, occurring in less than 1% of solid tumors. Patients with NRG1 fusion positive (NRG1+) cancer have limited therapeutic options. Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a 'Dock & Block®' mechanism of action. Here, we describe the rationale and design of the phase II component of the eNRGy trial, part of the overall, open-label phase I/II, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC or other solid tumors.

eNRGy: a clinical trial of zenocutuzumab for cancer caused by NRG1 gene fusionsNRG1 gene fusions are rare mutations that cause cancer cells to grow. These fusions are found in many different types of cancer. Tumors with NRG1 gene fusions do not respond well to standard treatment options. Zenocutuzumab, or Zeno, is a treatment that is being tested to see if it can stop cancer that is growing because of NRG1 gene fusions. Here, we describe the reasoning for and design of an ongoing clinical trial (eNRGy) designed to study the efficacy (how well it works) and safety of Zeno in patients with cancer that has NRG1 gene fusions. The eNRGy trial is recruiting patients with cancer that has NRG1 gene fusions, including non-small-cell lung cancer, pancreatic cancer and others. Patients who join this trial will receive Zeno once every 2 weeks until their cancer grows. The main goal (primary end point) of this trial is to determine the percentage of patients whose tumors decrease in size by 30% or more. The eNRGy trial is currently enrolling patients. For more information, refer to ClinicalTrials.gov (Identifier: NCT02912949), visit https://nrg1.com/, or call 1-833-NRG-1234.

Current status of the cost burden of first-line systemic treatment for patients with advanced hepatocellular carcinoma in Japan, 2021-22.

BACKGROUND: Although recent advances in systemic therapies for hepatocellular carcinoma (HCC) have led to prolonged patient survival, the high costs of the drugs place a heavy burden on both patients and society. The objectives of this study were to examine the treatment regimens used as first-line systemic treatment for patients with advanced HCC in Japan and to estimate the treatment costs per regimen. METHODS: For this study, we aggregated the data of patients who had received first-line systemic treatment for advanced HCC between July 2021 and June 2022. The treatment cost per month of each regimen was estimated based on standard usage, assuming an average weight of 60 kg for male patients. The data were categorized by the treatment regimen, and the treatments were categorized based on the cost into very high-cost (≥1 000 000 Japanese yen [JPY]/month), high-cost (≥500 000 JPY/month) and other (<500 000 JPY/month) treatments. RESULTS: Of the total of 552 patients from 24 institutions whose data were analyzed in this study, 439 (79.5%) received atezolizumab plus bevacizumab, 98 (17.8%) received lenvatinib and 15 (2.7%) received sorafenib as the first-line treatment. The treatment cost per month for each of the above regimens was as follows: atezolizumab plus bevacizumab, 1 176 284 JPY; lenvatinib, 362 295 JPY and sorafenib, 571 644 JPY. In total, 82.2% of patients received high-cost regimens, and the majority of these patients received a very high-cost regimen of atezolizumab plus bevacizumab. CONCLUSIONS: Advances in systemic therapies for HCC have led to prolonged patient survival. However, the treatment costs are also increasing, imposing a burden on both the patients and society.

Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer.

BACKGROUND: Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC. METHODS: This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment. RESULTS: In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively). CONCLUSION: The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.

Comprehensive review of undifferentiated carcinoma of the pancreas: from epidemiology to treatment.

Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer displaying no definitive direction of differentiation. UC has been reported as a highly aggressive malignant neoplasm, with a median overall survival of <1 year, except for several surgical series. On the other hand, UC tissue sometimes contains non-neoplastic osteoclast-like giant cells (OGCs), and such cases have been reported to have relatively longer survival. Thus, the World Health Organization (WHO) classification histologically distinguishes UC with OGCs (UCOGCs) from UC, and UCs were subclassified into three subtypes: anaplastic UC, sarcomatoid UC and carcinosarcoma. However, still less is known about UC due to its rarity, and such situations lead to further difficulties in treatment for UC. To date, only surgical resection can offer curative treatment for patients with UC, and no clear evidence for chemotherapy exists for them. However, a retrospective cohort study and case reports showed that relatively promising results paclitaxel-containing regimens for treatment of patients with unresectable UC. Furthermore, high programmed cell death protein 1 expression has been reported in sarcomatoid UCs and UCOGCs, and promising responses to anti-programmed death-ligand 1 therapy have been described in case reports of UCOGCs. Recent advances in chemotherapeutic agents and molecular technologies are opening up the possibilities for expanded treatments.

Comparing the Efficacy and Safety of Gemcitabine plus Nab-Paclitaxel versus Gemcitabine Alone in Older Adults with Unresectable Pancreatic Cancer.

BACKGROUND: Gemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC. PATIENTS AND METHODS: In this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses. RESULTS: GnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant. CONCLUSION: GnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.

Efficacy of chemotherapy for patients with metastatic or recurrent pancreatic adenosquamous carcinoma: A multicenter retrospective analysis.

BACKGROUND/OBJECTIVES: Pancreatic adenosquamous carcinoma (PASC) is a rare variant of pancreatic ductal adenocarcinoma (PDAC). The usual treatment for metastatic or recurrent PASC is systemic chemotherapy in accordance with the PDAC treatment strategy. This study aimed to investigate the efficacy of chemotherapy, especially the benefit of recent combination therapies, in patients with metastatic or recurrent PASC. METHODS: We conducted a multicenter retrospective analysis of 116 patients with metastatic or recurrent PASC treated with first-line chemotherapy between April 2001 and December 2017 at 24 Japanese institutions. RESULTS: Combination chemotherapies included gemcitabine + nab-paclitaxel (GnP, n = 28), fluorouracil/leucovorin + irinotecan + oxaliplatin (FFX, n = 10), gemcitabine + S-1 (GS, n = 10), and others (n = 9). Monotherapies included gemcitabine (n = 51) and S-1 (n = 8). The median overall survival (OS) was 6.5, 7.3, and 4.3 months for the whole cohort, the combination therapy group, and the monotherapy group, respectively. Multivariate analysis indicated that combination therapy showed a better trend in OS than monotherapy (hazard ratio = 0.68; 95% confidence interval, 0.38-1.20). GnP or FFX were selected in 58.7% of patients after FFX was approved in Japan, and revealed a median OS, median progression-free survival, and objective response rate of 7.3 months, 2.8 months, and 26.9% in GnP and 7.2 months, 2.3 months, and 20.0% in FFX respectively. CONCLUSIONS: This study suggests that combination therapy may be more effective than monotherapy. GnP and FFX showed similar and clinically meaningful efficacy for patients with metastatic or recurrent PASC.

Impact of Body Weight Loss on Survival in Patients with Advanced Gastric Cancer Receiving Second-Line Treatment.

Limited information is available regarding the impact of body weight loss (BWL) in patients with advanced gastric cancer (AGC) who receive second-line chemotherapy. We retrospectively reviewed data for consecutive AGC patients who received second-line treatment with taxane-based chemotherapy at our institution between January 2014 and September 2018. We calculated variables, including percent BWL per month during chemotherapy (%BWL/m), and analyzed the correlations between BWL and other clinicopathological parameters with survival. Forty-four AGC patients were registered (median age, 67.5 years; females, n = 16 [36.3%]; severe ascites, n = 12 [27.3%]). The median overall survival was significantly shorter among patients with a %BWL/m of 1% or more, compared with patients with less weight loss (6.3 mo, vs. 12.3 mo, P = 0.038). The %BWL/m (≥1% vs. <1%) was significantly correlated with survival in a univariate analysis (HR = 2.11, P = 0.04), and the survival period was shorter for patients with severe ascites (HR = 1.92; 95% CI, 0.90-3.90) and if their %BWL/m was 1% or more (HR = 2.01; 95% CI, 0.98-4.10) in a multivariate analysis. In conclusion, BWL during second-line chemotherapy was associated with a poor prognosis among patients with AGC.

The potential application of PD-1 blockade therapy for early-stage biliary tract cancer.

Biliary tract cancer (BTC) is an aggressive cancer with a poor prognosis partially due to the limited success in developing novel therapies, including molecularly targeted therapies and immunotherapies. Programmed cell death-1 (PD-1) blockade therapy is less effective against BTCs, necessitating further studies to understand the detailed immunological status of the tumor microenvironment (TME) in BTC. Here, we examined the immunological status of the TME in 37 BTCs with early- to late-stage disease, especially focusing on PD-1+CD8+ T cells. PD-1+CD8+ T cells, which are reportedly associated with the clinical response to PD-1 blockade therapy, were frequently observed in early-stage BTC and decreased with disease progression. Imaging mass cytometry for representative PD-1+CD8+TIL-high and -low patients demonstrated that tumor-infiltrating PD-1+CD8+ T cells were localized adjacent to tumor cells, whereas PD-1-CD8+ T cells were detected mainly in the stroma of the TME. In a mouse model, PD-1 expression by tumor-infiltrating CD8+ T cells was higher in smaller tumors and decreased with tumor growth. Consequently, large tumors became resistant to PD-1 blockade, while small tumors containing higher numbers of PD-1+CD8+ T cells were sensitive. We propose the important role of tumor-infiltrating PD-1+CD8+ T cells in anti-tumor immunity and the potential application of PD-1 blockade therapy for early-stage BTC.

Risk stratification and prognostic factors in patients with unresectable undifferentiated carcinoma of the pancreas.

BACKGROUND: Undifferentiated carcinoma (UC) of the pancreas has been considered a highly aggressive malignancy. However, only a few studies have systematically described the clinical course of UC patients. The aim of this study was to clarify the prognosis and construct a prognostic model for patients with unresectable UC. METHODS: This study was conducted at 17 institutions in Japan, and a total of 55 patients were analyzed. RESULTS: The median overall survival (OS) of patients with unresectable UC was 3.95 months. In the multivariate Cox proportional hazards (CPH) model, age ≥65 years, Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, and C-reactive protein (CRP) >10 mg/L were independent prognostic factors for OS (age ≥65 years: hazard ratio [HR], 2.732; 95% confidence interval [CI], 1.353-5.515; ECOG PS ≥ 2: HR, 7.866; 95% CI, 1.981-31.241; CRP >10 mg/L: HR, 1.956; 95% CI, 1.013-3.775). Based on the ß coefficients from the CPH model, the prognostic scores were defined as follows: age ≥65 years (3 points), ECOG PS ≥ 2 (6 points), and CRP >10 ml/L (2 points). The final prognostic model was the sum of the points. The derived prognostic model stratified patients into high-risk (score ≥4) and low-risk (score 0-3) groups, with significant differences in OS (1.45 vs. 8.19 months, respectively; p < 0.001). CONCLUSIONS: The prognostic model stratified patients into high-risk and low-risk groups. These findings suggest that this model can serve as a tool for patient information and decision-making with regard to the therapeutic strategy for UC.

Clinical outcomes of chemotherapy in patients with undifferentiated carcinoma of the pancreas: a retrospective multicenter cohort study.

BACKGROUND: Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer. Although UC has been considered a highly aggressive malignancy, no clinical studies have addressed the efficacy of chemotherapy for unresectable UC. Therefore, we conducted multicenter retrospective study to investigate the efficacy of chemotherapy in patients with UC of the pancreas. METHODS: This multicenter retrospective cohort study was conducted at 17 institutions in Japan between January 2007 and December 2017. A total of 50 patients treated with chemotherapy were analyzed. RESULTS: The median overall survival (OS) in UC patients treated with chemotherapy was 4.08 months. The details of first-line chemotherapy were as follows: gemcitabine (n = 24), S-1 (n = 12), gemcitabine plus nab-paclitaxel (n = 6), and other treatment (n = 8). The median progression-free survival (PFS) was 1.61 months in the gemcitabine group, 2.96 months in the S-1 group, and 4.60 months in the gemcitabine plus nab-paclitaxel group. Gemcitabine plus nab-paclitaxel significantly improved PFS compared with gemcitabine (p = 0.014). The objective response rate (ORR) was 4.2% in the gemcitabine group, 0.0% in the S-1 group, and 33.3% in the gemcitabine plus nab-paclitaxel group. Gemcitabine plus nab-paclitaxel also showed a significantly higher ORR compared with both gemcitabine and S-1 (gemcitabine plus nab-paclitaxel vs. gemcitabine: p = 0.033; gemcitabine plus nab-paclitaxel vs. S-1: p = 0.034). A paclitaxel-containing first-line regimen significantly improved OS compared with a non-paclitaxel-containing regimen (6.94 months vs. 3.75 months, respectively; p = 0.041). After adjustment, use of a paclitaxel-containing regimen in any line was still an independent predictor of OS (hazard ratio for OS, 0.221; 95% confidence interval, 0.076-0.647; p = 0.006) in multiple imputation by chained equation. CONCLUSIONS: The results of the present study indicate that a paclitaxel-containing regimen would offer relatively longer survival, and it is considered a reasonable option for treating patients with unresectable UC.

Alternate Endpoints for Phase II Trials in Advanced Neuroendocrine Tumors.

BACKGROUND: In phase II trials for neuroendocrine tumors (NETs), the objective response rate (ORR) is traditionally used as a primary endpoint. However, the validity of the ORR as a primary endpoint has never been systematically examined. Therefore, a literature-based analysis of phase II trials for NETs was performed to identify valid alternative endpoints for predicting median progression-free survival (PFS) in clinical trials for NETs. MATERIALS AND METHODS: Phase II trials of medical treatment for advanced NETs were identified based on a systematic search using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. RESULTS: A total of 22 trials were identified, and 1,310 patients and 27 treatment arms were included in the analysis. There was no significant relationship between the ORR and median PFS (r = .374; 95% confidence interval [CI], -0.051 to 0.800; p = .085). Conversely, 12-month PFS rates showed very strong correlations with median PFS (r = .929; 95% CI, 0.831-1.027; p < .001). CONCLUSION: The results of the present analysis indicate that the ORR is not significantly correlated with median PFS and suggest that 12-month PFS rates are good alternate endpoints for screening phase II trials for NETs. IMPLICATIONS FOR PRACTICE: Phase II trials are screening trials that seek to identify agents with sufficient activity to continue development. Thus, earlier endpoints are preferable, and the objective response rate (ORR) has been traditionally used as a surrogate endpoint in phase II trials for neuroendocrine tumors (NETs). However, the present study showed that the ORR was not significantly correlated with median progression-free survival (PFS). On the other hand, the 12-month PFS rate showed very strong correlation with median PFS and is considered a good alternate endpoint for screening phase II trials for NETs.

Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (Edition 1.0).

In Japan, the social (medical) health-care system is on the way to being developed to advance personalized medicine through the implementation of cancer genomic medicine, known as "cancer clinical sequencing," which uses a next-generation sequencer. However, no Japanese guidance for cancer genomic testing exists. Gene panel testing can be carried out to help determine patient treatment, confirm diagnosis, and evaluate prognostic predictions of patients with mainly solid cancers for whom no standard treatment is available. This guidance describes how to utilize gene panel testing according to the type of cancer: childhood cancer, rare cancer, carcinoma of unknown primary, and other cancers. The level of evidence classification for unified use in Japan is also detailed. This guidance establishes the basic principles of the quality control of specimens, requirements of medical institutions, informed consent, handling of data during the postanalysis stage, and treatment options based on the evidence level. In Japan, gene panel testing for cancer treatment and diagnosis is recommended to comply with this guidance. This is a collaborative work of the Japanese Society of Medical Oncology, Japan Society of Clinical Oncology, and the Japanese Cancer Association.

Clinical characteristics of Japanese patients with epithelioid hemangioendothelioma: a multicenter retrospective study.

BACKGROUND: Epithelioid hemangioendothelioma is an exceedingly rare sarcoma often occurring as an indolent angiocentric vascular tumor at various anatomic sites. Few reports have evaluated large case series of epithelioid hemangioendothelioma. METHODS: We conducted a retrospective analysis of the clinical data of 42 consecutive patients with epithelioid hemangioendothelioma who were pathologically diagnosed between 1990 and 2014 at 13 Japanese tertiary hospitals. We analyzed their clinical characteristics, tumor features and prognostic factors. RESULTS: The study included 22 men and 20 women, with a median age of 54 (range, 18-78) years. Pain was the most common symptom, occurring in 15 (68%) of the 22 symptomatic patients. The median maximum tumor diameter was 4.0 (range, 1.0-12.8) cm. The most commonly involved organs were the liver (81%), lungs (57%), and bones (12%). The overall survival rates were 79.5% at 1 year and 72.0% at 5 years. Substantially better survival was observed in asymptomatic patients than in symptomatic patients (P = 0.03), and better survival was also ovserved in patients with Ki-67 index ≤10% than in those with Ki-67 index > 10% (P = 0.04). By multivariate analysis, tumor size > 3.0 cm was associated with decreased survival (P = 0.049, hazard ratio 13.33). CONCLUSIONS: This study showed the clinical characteristics of Japanese patients with epithelioid hemangioendothelioma. Tumor size > 3.0 cm is an independent indicator of a poor prognosis in epithelioid hemangioendothelioma. The presence of symptoms at the time of diagnosis and high Ki-67 index implied poor survival.

Screening rate for hepatitis B virus infection in patients undergoing chemotherapy in Japan.

BACKGROUND: The aim of this study was to investigate the screening rate for hepatitis B virus (HBV) infection, which is recommended by some guidelines for the prevention of HBV reactivation, in patients undergoing chemotherapy for malignancy in Japan. METHODS: The study subjects were 3302 patients who had received first-line chemotherapy for malignancy from Apr 2008 through Mar 2013 utilizing the Claims Database of the Japan Medical Data Center. The proportion of patients who had been tested for HBsAg (P-HBsAg) and the proportion of HBsAg-negative patients who had undergone tests for anti-HBc and anti-HBs (P-HBc/HBsAb) before chemotherapy were investigated. RESULTS: P-HBsAg and P-HBc/HBsAb in all 3302 patients were 66.3 and 19.9 %, respectively. P-HBsAg in patients with solid tumors and those with hematological malignancies were 66.1 and 67.5 % (p = 0.61), respectively, and P-HBc/HBsAb were 12.3 and 75.8 % (p < 0.0001), respectively. P-HBsAg in patients from cancer centers and non-cancer centers were 66.9 and 65.5 % (p = 0.43), respectively, and P-HBc/HBsAb were 25.1 and 12.4 % (p < 0.0001), respectively. P-HBsAg in patients encountered before and after the announcement of the Japanese guideline were 51.3 and 67.1 % (p < 0.001), respectively, and P-HBc/HBsAb were 7.9 and 20.4 % (p = 0.01), respectively. CONCLUSIONS: The screening rate for HBV among cancer patients scheduled for chemotherapy remains unsatisfactory, especially in patients with solid tumors and those from non-cancer centers. Although the figures are improving after the announcement of the Japanese guideline, intensive measures to improve awareness about HBV reactivation during/after chemotherapy are needed.

The Molecular Landscape of Gastric Cancers for Novel Targeted Therapies from Real-World Genomic Profiling.

BACKGROUND: Panel-based comprehensive genomic profiling is used in clinical practice worldwide; however, large real-world datasets of patients with advanced gastric cancer are not well known. OBJECTIVE: We investigated what differences exist in clinically relevant alterations for molecularly defined or age-stratified subgroups. METHODS: This was a collaborative biomarker study of a real-world dataset from comprehensive genomic profiling testing (Foundation Medicine, Inc.). Hybrid capture was carried out on at least 324 cancer-related genes and select introns from 31 genes frequently rearranged in cancer. Overall, 4634 patients were available for analyses and were stratified by age (≥ 40/< 40 years), microsatellite instability status, tumor mutational burden status (high 10 ≥ /low < 10 Muts/Mb), Epstein-Barr virus status, and select gene alterations. We analyzed the frequency of alterations with a chi-square test with Yate's correction. RESULTS: Genes with frequent alterations included TP53 (60.1%), ARID1A (19.6%), CDKN2A (18.2%), KRAS (16.6%), and CDH1 (15.8%). Differences in comprehensive genomic profiling were observed according to molecularly defined or age-stratified subgroups. Druggable genomic alterations were detected in 31.4% of patients; ATM (4.4%), BRAF V600E (0.4%), BRCA1 (1.5%), BRCA2 (2.9%), ERBB2 amplification (9.2%), IDH1 (0.2%), KRAS G12C (0.7%), microsatellite instability-high (4.8%), NTRK1/2/3 fusion (0.13%), PIK3CA mutation (11.4%), and tumor mutational burden-high (9.4%). CDH1 alterations and MET amplification were significantly more frequent in patients aged < 40 years (27.7 and 6.2%) than in those aged ≥ 40 years (14.7 and 4.0%). CONCLUSIONS: Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer.

Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer.

BACKGROUND: CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC). MATERIAL AND METHODS: Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37-high and CDC37-low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37-high (top quartile, N = 5055) and CDC37-low (bottom quartile, N = 5055) CRCs. RESULTS: In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11-0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28-0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature. CONCLUSIONS: CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways.

Clinical utility of geriatric assessment tools in older patients with gastrointestinal cancer.

Background: Geriatric 8 (G8) and instrumental activities of daily living (IADL) are recommended to predict overall survival (OS) or risk of serious adverse events (SAEs) in older cancer patients. However, the clinical utility is relatively unknown in older patients suffering malnutrition with gastrointestinal (GI) cancer, including gastric cancer (GC) and pancreatic cancer (PC). Materials and methods: We retrospectively included patients aged ≥65 years with GC, PC, and colorectal cancer (CRC) who received a G8 questionnaire at first visit from April 2018 to March 2020. The associations between G8/IADL and safety or OS were assessed in patients with advanced/unresectable tumors. Results: Of 207 patients (median age: 75 years), the median G8 score was 10.5 and normal G8 score rate was 6.8%. Both the median G8 score and normal G8 (>14) score rate numerically increased in the order of GC < PC < CRC. There was no clear association between the G8 standard cutoff value of 14 and SAEs or OS. However, OS was significantly longer in patients with G8 >11 than in those with G8 ≤11 (19.3 vs. 10.5 months, p = 0.0017). Furthermore, OS was significantly better in patients with normal IADL than in those with abnormal IADL (17.6 vs. 11.4 months, p = 0.049). Conclusion: The G8 cutoff value of 14 would not be clinically useful in patients with GI cancer for predicting OS or SAEs; however, the cutoff value of 11 and IADL may be useful to predict OS for older patients with GI cancers including GC and PC.

Identification of an optimal mutant allele frequency to detect activating KRAS, NRAS, and BRAF mutations in a commercial cell-free DNA next-generation sequencing assay in colorectal and pancreatic adenocarcinomas.

Background: Evaluation for activating mutations in KRAS, NRAS, and BRAF in colorectal cancer (CRC) and in KRAS in pancreatic ductal adenocarcinoma (PDAC) is essential for clinical care. Plasma cell-free DNA (cfDNA) next-generation sequencing (NGS) allows convenient assessment of a tumor's molecular profile, however low tumor DNA shedding limits sensitivity. We investigated mutant allele frequency (MAF) of other oncogenic dominant genes to identify a threshold for accurate detection of KRAS, NRAS, and BRAF (RAS/RAF) mutations in cfDNA. Methods: Molecular and clinical data were obtained from the Duke Molecular Registry of Tumors and the SCRUM-Japan GOZILA study. Patients with CRC or PDAC and a KRAS, NRAS, or BRAF activating single nucleotide variant (SNV) present on tissue NGS and with available cfDNA assays were included. Recursive partitioning and Wilcoxon-rank statistics methods identified potential cut-points for discriminative MAF values. Results: One hundred and thirty-five CRC and 30 PDAC cases with 198 total cfDNA assays met criteria. Greatest non-RAS/RAF dominant gene MAF of 0.34% provided maximum discrimination for predicting RAS/RAF SNV detection. Sensitivity for RAS/RAF SNVs increased with dominant gene MAF, with MAF ≥1% predicting sensitivity >98%, MAF between 0.34 and 1% predicting sensitivity of 84.0%, and MAF £0.34% predicting sensitivity of 50%. For 43 cfDNA assays that did not detect RAS/RAF SNVs, 18 assays detected 34 other oncogenic variants, of which 80.6% were not also detected on tissue. Conclusions: Non-RAS/RAF dominant oncogenic mutation MAF ≥1% on cfDNA NGS predicts high sensitivity to detect RAS/RAF oncogenic SNVs in CRC and PDAC. MAF £0.34% indicates an assay may not reliably detect RAS/RAF SNVs, despite detection on tissue testing. Most variants from assays that did not detect RAS/RAF had MAF <1% and were not detected on tissue, suggesting potential confounding. These data suggest a practical approach to determining cfDNA assay adequacy, with implications for guiding clinical decisions in CRC and PDAC.

Nivolumab for treating patients with occupational cholangiocarcinoma.

Tanaka et al. previously reported a case in which nivolumab for recurrent occupational cholangiocarcinoma resulted in complete response persisting for 26 months after discontinuation. Afterward, in that clinical trial, nivolumab was administered to two patients for recurrence. Both patients achieved complete response, suggesting that nivolumab is effective for occupational cholangiocarcinoma.