Prevalence of KRAS amplification in patients with metastatic cancer: Real-world next-generation sequencing analysis.

BACKGROUND: The Kirsten rat sarcoma virus (KRAS) is a prominent proto-oncogene. Several treatments for KRAS mutations have been developed. However, KRAS amplification, a KRAS alteration, is poorly understood, and there is currently no appropriate treatment other than conventional chemotherapy. This study aimed to elucidate the role of KRAS amplification in different types of cancers. METHODS: From October 2019 to June 2023, we performed next-generation sequencing using Trusight Oncology 500 on 3895 patients with 37 different cancer types at the Samsung Medical Center. We analyzed the distribution of KRAS amplification according to cancer type and its correlation with tumor mutation burden (TMB). Concomitant KRAS mutations were also identified. RESULTS: Of the total 3895 patients, 99 (2.5 %) had KRAS amplification. The highest frequency of KRAS amplification was detected in 2 % (27/1350) of patients with colorectal cancer, followed by 3.48 % (32/920) of patients with gastric cancer and 3.88 % (9/232) patients with of pancreatic cancer. MSI-High was not detected in patients with KRAS amplification. There was no correlation between KRAS copy number variation and TMB status. Among patients with KRAS amplification, 27.3 % (27/99) had a concomitant KRAS mutation. More than 50 % of patients had G12D or G12V mutations. In gastric cancer, patients with both KRAS amplification and mutation were extremely rare at 3.1 % (1/32); however, in colorectal cancer, more than half of the patients had KRAS amplification and mutation (51.9 %, 14/27). KRAS amplification and mutations are associated with mutations in tumor suppressor genes TP53, BRCA2, ARID1B, and PTCH1. CONCLUSIONS: Of the 3895 patients with metastatic solid tumors, 99 (2.5 %) had KRAS amplification, and next-generation sequencing analysis provided a deeper understanding of KRAS amplification.

Erdafitinib in Asian patients with advanced solid tumors: an open-label, single-arm, phase IIa trial.

BACKGROUND: FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer. METHODS: Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics. RESULTS: Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%). CONCLUSIONS: Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.

Clinical outcomes of neoadjuvant chemoradiotherapy followed by total mesorectal excision in locally advanced rectal cancer with mesorectal fascia involvement.

PURPOSE: For the treatment of locally advanced rectal cancer (LARC), research on primary lesions with mesorectal fascia (MRF) involvement is lacking. This study analyzed the clinical outcomes and efficacy of dose-escalated neoadjuvant concurrent chemoradiotherapy (NCRT) to patients with LARC involving MRF. MATERIALS AND METHODS: We retrospectively reviewed 301 patients who were diagnosed with LARC involving MRF and underwent NCRT followed by total mesorectal excision (TME). Patients who received radiotherapy (RT) doses of ≤50.4 Gy were defined as the non-boost group, while ≥54.0 Gy as the boost group. Pathological tumor response and survival outcomes, including intrapelvic recurrence-free survival (IPRFS), distant metastases-free survival (DMFS) and overall survival (OS), were analyzed. RESULTS: A total of 269 patients (89.4%) achieved a negative pathological circumferential resection margin and 104 (34.6%) had good pathological tumor regression grades. With a median follow-up of 32.4 months, IPRFS, DMFS, and OS rates at 5-years were 88.6%, 78.0%, and 91.2%, respectively. In the subgroup analysis by RT dose, the boost group included more advanced clinical stages of patients. For the non-boost group and boost group, 5-year IPRFS rates were 90.3% and 87.0% (p = 0.242), 5-year DMFS rates were 82.0% and 71.3% (p = 0.105), and 5-year OS rates were 93.0% and 80.6% (p = 0.439), respectively. Treatment related toxicity was comparable between the two groups (p = 0.211). CONCLUSION: Although this retrospective study failed to confirm the efficacy of dose-escalated NCRT, favorable IPRFS and pathological complete response was achieved with NCRT followed by TME. Further studies combining patient customized RT dose with systemic therapies are needed.

Bintrafusp alfa and chemotherapy as first-line treatment in biliary tract cancer: A randomized phase 2/3 trial.

BACKGROUND AND AIMS: We compared the safety and efficacy of bintrafusp alfa (BA) in combination with gemcitabine+cisplatin (GemCis), to those of GemCis alone, in patients with biliary tract cancer. APPROACH AND RESULTS: This randomized, double-blind, placebo-controlled, adaptive design phase 2/3 trial (NCT04066491) included adults who are treatment-naive with locally advanced/metastatic biliary tract cancer. Patients (N = 297) were randomized to receive an IV infusion of BA (2400 mg once/3 wk) plus GemCis (gemcitabine 1000 mg/m 2 +cisplatin 25 mg/m 2 on days 1 and 8/3 wk; 8 cycles) (BA group, n = 148) or placebo+GemCis (placebo group, n = 149). The primary end point was overall survival (OS). For adaptation analysis (phase 2-phase 3; data cutoff: May 20, 2021), efficacy was assessed in the first 150 patients who were antibiotic-naive when 80 progression-free survival events had occurred and ≥ 19 weeks of follow-up had been completed (BA, n = 73; placebo, n = 77). Median OS (95% CI) for the BA (11.5 mo [9.3-not estimable]) and placebo (11.5 mo [10.0-not estimable]) groups was comparable (hazard ration 1.23 [95% CI 0.66-2.28]; p = 0.7394); OS data maturity was 27.2% (41 events/151 patients). The most common grade ≥3 treatment-related adverse event was anemia (BA, 26.0%; placebo, 22.8%). Bleeding adverse events were reported more frequently in the BA group (28.8%) versus the placebo group (7.4%). Deaths within 60 days of the first dose were reported in 7.5% and 1.3% of patients in the BA and placebo groups, respectively. CONCLUSIONS: BA+GemCis did not provide a clinically meaningful benefit compared with GemCis alone as first-line treatment for biliary tract cancer, and the study was discontinued early (terminated: August 20, 2021).

Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]). INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. FUNDING: AstraZeneca.

Trastuzumab deruxtecan in patients with solid tumours harbouring specific activating HER2 mutations (DESTINY-PanTumor01): an international, phase 2 study.

BACKGROUND: Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations. METHODS: In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting. FINDINGS: Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis. INTERPRETATION: Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting. FUNDING: AstraZeneca and Daiichi Sankyo.

Characteristics and biomarkers associated with mortality in COVID-19 patients presenting to the emergency department.

This study aimed to investigate the diverse clinical manifestations and simple early biomarkers predicting mortality of COVID-19 patients admitted to the emergency department (ED). A total of 710 patients with COVID-19 were enrolled from 6,896 patients presenting to the ED between January 2022 and March 2022. During the study period, a total of 478 patients tested positive for COVID-19, among whom 222 (46.4%) presented with extrapulmonary manifestations of COVID-19; 49 (10.3%) patients displayed gastrointestinal manifestations, followed by neurological (n = 41; 8.6%) and cardiac manifestations (n = 31; 6.5%). In total, 54 (11.3%) patients died. A Cox proportional hazards model revealed that old age, acute kidney injury at presentation, increased total leukocyte counts, low platelet counts, decreased albumin levels, and increased LDH levels were the independent predictors of mortality. The albumin levels exhibited the highest area under the curve in receiver operating characteristic analysis, with a value of 0.860 (95% confidence interval, 0.796-0.875). The study showed the diverse clinical presentations and simple-to-measure prognostic markers in COVID-19 patients presenting to the ED. Serum albumin levels can serve as a novel and simple early biomarker to identify COVID-19 patients at high risk of death.

Impact and optimal timing of local therapy addition in borderline resectable or locally advanced pancreatic cancer after FOLFIRINOX chemotherapy.

Background: To evaluate the efficacy and optimal timing of local treatment in patients with borderline resectable (BR) or locally advanced pancreatic cancer (LAPC) treated with upfront FOLFIRINOX. Method: Between 2015 and 2020, 258 patients with pancreatic ductal adenocarcinoma (PDAC) were analysed. Treatment outcomes were compared between systemic treatment group (ST) and multimodality treatment groups (MT) using Kaplan-Meier curves and log-rank test. The MT were stratified as follows: FOLFIRINOX + radiation therapy (RT) (MT1), FOLFIRINOX + surgical resection (MT2), and FOLFIRINOX + RT + surgical resection (MT3). Results: With median follow-up period of 18 months, the 2-year overall survival (OS) for the ST was 22.0%, and it was significantly worse than MT (MT1, 46.3%; MT2, 65.7% and MT3; 90.2%; P < .001). The 2-year locoregional progression free survival (LRPFS) and overall PFS in ST were 10.7% and 7.0%, which were also significantly lower than those of MT (2-year LRPFS: MT1, 31.8%; MT2, 45.3%; MT3, 81.0%; 2-year overall PFS: MT1, 23.3%; MT2, 35.0%; MT3, 66.3%; P < .001). In time-varying multivariate Cox proportional hazard model, local treatment contributed to better treatment outcomes, with adjusted hazard ratios of 0.568 (95% confidence interval [CI], 0.398-0.811), 0.490 (95% CI, 0.331-0.726), and 0.656 (95% CI, 0.458-0.940) for OS, LRPFS, and overall PFS, respectively. The time window of 11-17 months after FOLFIRINOX appeared to demonstrate the maximal efficacy of local treatments in OS. Conclusions: Adding local treatment in BR/LAPC patients treated with upfront FOLFIRINOX seemed to contribute in improved treatment outcomes, and it showed maximal efficacy in OS when applied 11-17 months after the initiation of FOLFIRINOX. We suggest that administration of sufficient period of upfront FOLFIRINOX may intensify the efficacy of local treatments, and well controlled prospective trials are expected.

Prevalence of RAF1 Aberrations in Metastatic Cancer Patients: Real-World Data.

PURPOSE: Therapeutic targeting of RAF1 is a promising cancer treatment, but the relationship between clinical features and RAF1 aberrations in terms of the MAPK signaling pathway is poorly understood in various solid tumors. METHODS: Between October 2019 and June 2023 at Samsung Medical Center, 3895 patients with metastatic solid cancers underwent next-generation sequencing (NGS) using TruSight Oncology 500 (TSO500) assays as routine clinical practice. We surveyed the incidence of RAF1 aberrations including mutations (single-nucleotide variants [SNVs]), amplifications (copy number variation), and fusions. RESULTS: Among the 3895 metastatic cancer patients, 77 (2.0%) exhibited RAF1 aberrations. Of these 77 patients, 44 (1.1%) had RAF1 mutations (SNV), 25 (0.6%) had RAF1 amplifications, and 10 (0.3%) had RAF1 fusions. Among the 10 patients with RAF1 fusions, concurrent RAF1 amplifications and RAF1 mutations were detected in one patient each. The most common tumor types were bladder cancer (11.5%), followed by ampulla of Vater (AoV) cancer (5.3%), melanoma (3.0%), gallbladder (GB) cancer (2.6%), and gastric (2.3%) cancer. Microsatellite instability high (MSI-H) tumors were observed in five of 76 patients (6.6%) with RAF1 aberrations, while MSI-H tumors were found in only 2.1% of patients with wild-type RAF1 cancers (p < 0.0001). CONCLUSION: We demonstrated that approximately 2.0% of patients with metastatic solid cancers have RAF1 aberrations according to NGS of tumor specimens.

Patient-derived exosomes facilitate therapeutic targeting of oncogenic MET in advanced gastric cancer.

Gastric cancer (GC) with peritoneal metastases and malignant ascites continues to have poor prognosis. Exosomes mediate intercellular communication during cancer progression and promote therapeutic resistance. Here, we report the significance of exosomes derived from malignant ascites (EXOAscites) in cancer progression and use modified exosomes as resources for cancer therapy. EXOAscites from patients with GC stimulated invasiveness and angiogenesis in an ex vivo three-dimensional autologous tumor spheroid microfluidic system. EXOAscites concentration increased invasiveness, and blockade of their secretion suppressed tumor progression. In MET-amplified GC, EXOAscites contain abundant MET; their selective delivery to tumor cells enhanced angiogenesis and invasiveness. Exosomal MET depletion substantially reduced invasiveness; an additive therapeutic effect was induced when combined with MET and/or VEGFR2 inhibition in a patient-derived MET-amplified GC model. Allogeneic MET-harboring exosome delivery induced invasion and angiogenesis in a MET non-amplified GC model. MET-amplified patient tissues showed higher exosome concentration than their adjacent normal tissues. Manipulating exosome content and production may be a promising complementary strategy against GC.

Smoking Cessation and Pancreatic Cancer Risk in Individuals With Prediabetes and Diabetes: A Nationwide Cohort Study.

BACKGROUND: Individuals with diabetes and prediabetes are at increased risk of pancreatic cancer. However, little is known about the effects of smoking or smoking cessation on pancreatic cancer risk in individuals with diabetes and prediabetes. We investigated the association between smoking status (particularly smoking cessation) and pancreatic cancer risk according to glycemic status. PATIENTS AND METHODS: This nationwide cohort study included 9,520,629 adults without cancer who underwent the Korean National Health Screening in 2009 and were followed until 2018. Hazard ratios and 95% confidence intervals for pancreatic cancer were estimated after adjusting for potential confounders. RESULTS: During the 78.4 million person-years of follow-up, 15,245 patients were newly diagnosed with pancreatic cancer. Among individuals with diabetes and prediabetes, current smoking synergistically increased pancreatic cancer risk (all P<.01). However, quitters with diabetes and prediabetes had a pancreatic cancer risk comparable to that of never-smokers (all P>.05). For pancreatic cancer in current smokers, quitters, and never-smokers, respectively, the hazard ratios were 1.48 (95% CI, 1.40-1.58), 1.11 (95% CI, 1.03-1.19), and 1.00 (reference) among individuals with normoglycemia; 1.83 (95% CI, 1.70-1.97), 1.28 (95% CI, 1.18-1.39), and 1.20 (95% CI, 1.14-1.26) among individuals with prediabetes; and 2.72 (95% CI, 2.52-2.94), 1.78 (95% CI, 1.63-1.95), and 1.63 (95% CI, 1.54-1.72) among individuals with diabetes. There were no differences in risk between quitters with a <20 pack-year smoking history and never-smokers in all glycemic status groups. CONCLUSIONS: Pancreatic cancer risk synergistically increased in current smokers with diabetes and prediabetes. However, smoking cessation reduced the synergistically increased risk of pancreatic cancer to the level of never-smokers, especially when smoking history was <20 pack-years. More individualized and intensive cancer prevention education should be underscored for individuals at an increased risk of pancreatic cancer beyond the one-size-fits-all approach.

Pemetrexed and Erlotinib as a Salvage Treatment in Patients With Metastatic Biliary Tract Cancer Who Failed Gemcitabine-containing Chemotherapy: A Phase II Single-arm Prospective Study.

BACKGROUND/AIM: No standard treatment is currently recommended for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin. We aimed to evaluate the efficacy and safety of a pemetrexed and erlotinib combination in patients with BTC previously treated with gemcitabine. PATIENTS AND METHODS: This phase II, open-label, single-arm study enrolled patients with BTC who had previously failed gemcitabine-based first-line chemotherapy. Patients were treated with pemetrexed as a 500 mg/m2 intravenous infusion on day 1 for three weeks and erlotinib 100 mg daily until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR). RESULTS: The study enrolled 20 patients with BTC, including 12 (60%) with intrahepatic cholangiocarcinoma (IHCC), 3 (15%) with extrahepatic cholangiocarcinoma (EHCC), and 5 (25%) with gallbladder cancer (GBC). The ORR was 5%, and the disease control rate (DCR) was 55%. As of the cutoff point of March 31, 2023, the median progression-free survival (PFS) was 2.3 months [95% confidence interval (CI)=0.00-4.74] and the median overall survival (OS) was 5.6 months (95%CI=2.28-8.87). Patients with EHCC showed longer PFS and OS compared to patients with IHCC or GBC, but the differences were not significant. A baseline CEA greater than the upper normal limit was the only significant prognostic factor for a worse OS rate. The only treatment-related adverse event (TRAE) with severity grade ≥3 was anemia (5%). CONCLUSION: Salvage chemotherapy with pemetrexed plus erlotinib was well-tolerated and showed marginal clinical activity in BTC patients after failure to gemcitabine-based chemotherapy.

Clinical Implication of HER2 Aberration in Patients With Metastatic Cancer Using Next-Generation Sequencing: A Pan-Tumor Analysis.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) protein expression or gene amplification is a significant predictive biomarker for identifying patients with cancer, who may benefit from HER2-targeted therapy. The aim of this study was to survey the proportion of patients who had HER2 aberration and to investigate the correlation between HER2 amplification and HER2 overexpression in immunohistochemistry (IHC) as a real-world data. METHODS: We surveyed the incidence of HER2 aberration including mutation (single-nucleotide variant [SNV]), amplification (copy-number variation), and fusion by next-generation sequencing (NGS) in 2,119 patients with cancer from Samsung Medical Center in South Korea. RESULTS: Of 2,119 patients with cancer, 189 patients (8.9%) had HER2 aberration in their tumor specimen. Of 189 patients, 113 (5.3%) patients had HER2 amplification, 82 (3.9%) patients had HER2 mutations, and 11 (0.5%) patients had HER2 fusion. Of note, 10 patients (0.5%) had concurrent HER2 amplification and HER2 fusion. In addition, we identified that HER2 protein overexpression was strongly related to HER2 amplification by NGS. Of 74 patients with HER2 amplification only by NGS test, 64 patients (86.5%) had HER2 overexpression by IHC. Of 10 patients with concurrent HER2 amplification and fusion, 80% patients were HER2 overexpression. Among 51 patients with only HER2 mutation (SNV), 9 patients (17.6%) were HER2 (+). Interestingly, almost all patients with colorectal cancer (11 of 12) with HER2 amplification had very strong HER2 overexpression (3+) in their tumor specimen. CONCLUSION: In conclusion, we showed that when patients with metastatic cancer receive NGS test, approximately 8.9% have HER2 aberrations in their tumor specimen. Most patients have HER2 amplification, and a small percentage of patients have HER2 fusion. A great majority of patients with HER2 amplification and/or HER2 fusion had HER2 (+) tumor by IHC.

The efficacy of immune checkpoint inhibitors in biliary tract cancer with KRAS mutation.

Background: With a 15% incidence, KRAS is one of the most common mutations in biliary tract cancer (BTC) and is a poor prognostic factor. Immune checkpoint inhibitors (ICIs) as salvage therapy have modest activity in BTC. Objectives: There are limited data on the efficacy of ICIs according to KRAS mutation in BTC. We evaluated the efficacy of ICIs in BTC patients with or without KRAS mutations. Design: Retrospective observational study. Methods: We conducted molecular profiling in BTC patients who received ICIs as salvage therapy. The expression of programmed death ligand 1 (PD-L1) on tumor cells was assessed using immunohistochemistry. The TruSightTM Oncology 500 assay from Illumina was used as a cancer panel. We analyzed overall survival (OS) and progression-free survival (PFS) of ICI in BTC patients according to KRAS mutation and PD-L1 expression. Results: A total of 62 patients were included in this analysis. The median age was 68.0 years; 47 patients (75.8%) received pembrolizumab and 15 (24.2%) received nivolumab as salvage therapy. All patients received gemcitabine plus cisplatin as the frontline therapy, and 53.2% received fluoropyrimidine plus oxaliplatin (FOLFOX) before ICI. The median number of lines of prior chemotherapy was 2.5. The KRAS mutation was found in 13 patients (19.1%), and 28 patients (45.2%) showed 1% or more of tumor cells out of visible tumor cells positive for PD-L1. There was no statistical correlation between KRAS mutation and PD-L1 expression. The median OS and PFS with ICI were 5.6 [interquartile range (IQR): 3.3-8.0] and 3.8 (IQR: 3.0-4.5) months, respectively. There were no statistically significant differences in PFS with ICIs according to KRAS mutation (mutant type versus wild type) and PD-L1 expression (positive versus negative). In subgroup analysis, patients with both KRAS mutation and PD-L1 positivity had longer PFS compared with patients with KRAS mutation and PD-L1 negativity (10.1 versus 2.6 months, p = 0.047). This finding was not shown in patients with wild-type KRAS. Conclusion: Our analysis suggested that PD-L1 expression might be a useful biomarker for ICIs in BTC patients with KRAS mutation but not in those with wild-type KRAS.

Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. METHODS: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. FINDINGS: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7-30·4). Median overall survival was 12·7 months (95% CI 11·5-13·6) in the pembrolizumab group versus 10·9 months (9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. INTERPRETATION: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Increased Risk of Young-Onset Digestive Tract Cancers Among Young Adults Age 20-39 Years With Nonalcoholic Fatty Liver Disease: A Nationwide Cohort Study.

PURPOSE: Although the incidence of young-onset digestive tract cancers is increasing worldwide, their risk factors remain largely unknown. We investigated the association between nonalcoholic fatty liver disease (NAFLD) and young-onset digestive tract cancers. PATIENTS AND METHODS: This nationwide cohort study included 5,265,590 individuals age 20-39 years who underwent national health screening under the Korean National Health Insurance Service between 2009 and 2012. The fatty liver index was used as a diagnostic biomarker for NAFLD. The participants were followed up until December 2018 to determine the incidence of young-onset digestive tract cancers (ie, esophageal, stomach, colorectal, liver, pancreatic, biliary tract, and gallbladder). Multivariable Cox proportional hazards models were conducted to estimate the risk after adjusting for potential confounders. RESULTS: During the 38.8 million person-years of follow-up, 14,565 patients were newly diagnosed with young-onset digestive tract cancers. The cumulative incidence probability of each cancer type was consistently higher in individuals with NAFLD than in those without NAFLD (all log-rank P < .05). NAFLD was associated with an increased risk of overall digestive tract (adjusted hazard ratio [aHR], 1.16; 95% CI, 1.10 to 1.22), stomach (aHR, 1.14; 95% CI, 1.06 to 1.24), colorectal (aHR, 1.14; 95% CI, 1.06 to 1.22), liver (aHR, 1.13; 95% CI, 1.12 to 1.52), pancreatic (aHR, 1.23; 95% CI, 1.09 to 1.40), biliary tract (aHR, 1.29; 95% CI, 1.00 to 1.66), and gallbladder (aHR, 1.53; 95% CI, 1.01 to 2.31) cancer. These associations remained significant regardless of age, sex, smoking status, alcohol consumption, and obesity status (all P < .05; P for interaction >.05). The aHR for esophageal cancer was 1.67 (95% CI, 0.92 to 3.03). CONCLUSION: NAFLD may be an independent, modifiable risk factor for young-onset digestive tract cancers. Our findings suggest a crucial opportunity to reduce premature morbidity and mortality associated with young-onset digestive tract cancers in the next generation.

Combination treatment of T1-44, a PRMT5 inhibitor with Vactosertib, an inhibitor of TGF-ß signaling, inhibits invasion and prolongs survival in a mouse model of pancreatic tumors.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal type of cancer and the third leading cause of cancer death with the lowest 5-year survival rate. Heterogeneity, difficulty in diagnosis, and rapid metastatic progression are the causes of high mortality in pancreatic cancer. Recent studies have shown that Protein arginine methyltransferase 5 (PRMT5) is overexpressed in pancreatic cancers, and these patients have a worse prognosis. Recently, PRMT5 as an anti-cancer target has gained considerable interest. In this study, we investigated whether inhibition of PRMT5 activity was synergistic with blockade of TGF-ß1 signaling, which plays an important role in the construction of the desmoplastic matrix in pancreatic cancer and induces therapeutic vulnerability. Compared with T1-44, a selective inhibitor of PRMT5 activity, the combination of T1-44 with the TGF-ß1 signaling inhibitor Vactosertib significantly reduced tumor size and surrounding tissue invasion and significantly improved long-term survival. RNA sequencing analysis of mouse tumors revealed that the combination of T1-44 and Vactosertib significantly altered the expression of genes involved in cancer progression, such as cell migration, extracellular matrix, and apoptotic processes. In particular, the expression of Btg2, known as a tumor suppressor factor in various cancers, was markedly induced by combination treatment. Ectopic overexpression of Btg2 inhibited the EMT response, blocking cell migration, and promoted cancer cell death. These data demonstrate that the combination therapy of T1-44 with Vactosertib is synergistic for pancreatic cancer, suggesting that this novel combination therapy has value in the treatment strategy of patients with pancreatic cancer.

Comprehensive immunoprofile analysis of prognostic markers in pancreaticobiliary tract cancers.

Pancreaticobiliary tract cancer has a poor prognosis with unmet needs in a new target treatment. Some studies have reported that an enhancement of T-cell immunity is associated with a good prognosis. The aim of this study is to investigate the immunoprofile as a prognostic marker of pancreaticobiliary tract cancers. Unresectable pancreatic ductal adenocarcinoma (PDAC, n = 80) and biliary tract cancer (BTC, n = 74) diagnosed between January 2012 and December 2018 in Samsung Medical Center were analyzed. Expression levels of CD8, FOXP3, PD-1, PD-L1, and CXCL13 in PDAC and BTC tissue samples were examined with immunohistochemical staining, which was evaluated with various clinical factors. In PDAC, higher degree of PD-L1 expression was significantly associated with shorter overall survival (OS) (p = 0.0095). On the other hand, higher infiltrations of PD-1+ immune cells (p = 0.0002) and CD8+ T cells (p = 0.0067) were associated with longer OS. In BTC, higher FOXP3+ (p = 0.0343) and CD8+ (p = 0.0028) cell infiltrations were associated with better survival. Low infiltration of CD8+ (p = 0.0148), FOXP3+ (p = 0.0208), PD-1+ (p = 0.0318) cells in PDAC, and FOXP3+ cells (p = 0.005) in BTC were considerably related to metastasis. In a combined evaluation of clinical factors and immunoprofiles, univariate analysis revealed that operation after chemotherapy (p < 0.0001), mass size (p = 0.0004), metastasis (p = 0.006), PD-L1 (p < 0.0001), PD-1 (p = 0.003) and CD8 (p = 0.0063) was significantly associated with OS in PDAC, and CD8 (p = 0.007) was statistically related to OS in BTC. In multivariate analysis, prognostic factors were operation after chemotherapy (p = 0.021) in PDAC and CD8 (p = 0.037) in BTC. Therefore, immunoprofile analysis of cells expressing CD8, FOXP3, PD-1, and PD-L1 might have prognostic values in patients with pancreaticobiliary tract cancers.

A Phase II Study of Preoperative Chemoradiotherapy with Capecitabine Plus Simvastatin in Patients with Locally Advanced Rectal Cancer.

PURPOSE: The purpose of this phase II trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, to preoperative chemoradiotherapy (CRT) with capecitabine confers a clinical benefit to patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Patients with LARC (defined by clinical stage T3/4 and/or lymph node positivity) received preoperative radiation (45-50.4 Gy in 25-28 daily fractions) with concomitant capecitabine (825 mg/m2 twice per day) and simvastatin (80 mg, daily). Curative surgery was planned 4-8 weeks after completion of the CRT regimen. The primary endpoint was pathologic complete response (pCR). The secondary endpoints included sphincter-sparing surgery, R0 resection, disease-free survival, overall survival, the pattern of failure, and toxicity. RESULTS: Between October 2014 and July 2017, 61 patients were enrolled; 53 patients completed CRT regimen and underwent total mesorectal excision. The pCR rate was 18.9% (n=10) by per-protocol analysis. Sphincter-sparing surgery was performed in 51 patients (96.2%). R0 resection was achieved in 51 patients (96.2%). One patient experienced grade 3 liver enzyme elevation. No patient experienced additional toxicity caused by simvastatin. CONCLUSION: The combination of 80 mg simvastatin with CRT and capecitabine did not improve pCR in patients with LARC, although it did not increase toxicity.