Clinical and molecular characteristics of early-onset vs average-onset esophagogastric cancer.

BACKGROUND: The rate of esophagogastric cancer is rising among individuals under 50 years of age. It remains unknown whether early-onset esophagogastric cancer represents a unique entity. This study investigated the clinical and molecular characteristics of early-onset and average-onset esophagogastric cancer . METHODS: We reviewed the Memorial Sloan Kettering Cancer Center gastric, esophageal, and gastroesophageal junction cancer database. Associations between baseline characteristics and tumor and germline molecular alterations were compared between those with early-onset and average-onset esophagogastric cancer using Fisher exact tests and the Benjamini-Hochberg method for multiple-hypothesis correction. RESULTS: We included 1123 patients with early-onset esophagogastric cancer (n = 219; median age = 43 years [range = 18-49 years]) and average-onset esophagogastric cancer (n = 904; median age = 67 years [range = 50-94 years]) treated between 2005 and 2018. The early-onset group had more women (39% vs 28%, P = .002). Patients with early-onset esophagogastric cancer were more likely to have a gastric primary site (64% vs 44%, P < .0001). The signet ring cell and/or diffuse type was 3 times more common in the early-onset esophagogastric cancer group (31% vs 9%, P < .0001). Early-onsite tumors were more frequently genomically stable (31% vs 18%, P = .0002) and unlikely to be microsatellite instability high (2% vs 7%, P = .003). After restricting to adenocarcinoma and signet ring cell and/or diffuse type carcinomas, we observed no difference in stage (P = .40) or overall survival from stage IV diagnosis (median = 22.7 vs 22.1 months, P = .78). CONCLUSIONS: Our study supported a preponderance of gastric primary disease sites, signet ring histology, and genomically stable molecular subtypes in early-onset esophagogastric cancer. Our findings highlight the need for further research to define the underlying pathogenesis and strategies for early detection and prevention.

First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial.

BACKGROUND: The addition of nivolumab to chemotherapy improves survival in patients with advanced oesophagogastric (oesophageal, gastric, or gastro-oesophageal junction) adenocarcinoma; however, outcomes remain poor. We assessed the safety and activity of regorafenib in combination with nivolumab and chemotherapy in the first-line treatment of advanced oesophagogastric adenocarcinoma. METHODS: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with previously untreated, HER2-negative, metastatic oesophagogastric adenocarcinoma was done at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients had measurable disease or non-measurable disease that was evaluable (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received FOLFOX chemotherapy (fluorouracil [400 mg/m2 bolus followed by 2400 mg/m2 over 48 h], leucovorin [400 mg/m2], and oxaliplatin [85 mg/m2]) and nivolumab (240 mg) intravenously on days 1 and 15, and oral regorafenib (80 mg) on days 1-21 of a 28-day cycle. Treatment was continued until disease progression (defined by RECIST version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival in the per-protocol population (ie, all participants who received a dose of all study treatments). The regimen would be considered worthy of further investigation if at least 24 of 35 patients were progression free at 6 months. Safety was assessed in all participants who received at least one dose of any study treatment. This trial is registered with ClinicalTrials.gov, NCT04757363, and is now complete. FINDINGS: Between Feb 11, 2021, and May 4, 2022, 39 patients were enrolled, received at least one dose of study drug, and were included in safety analyses. 35 patients were evaluable for 6-month progression-free survival. Median age was 57 years (IQR 52-66), nine (26%) patients were women, 26 (74%) were men, 28 (80%) were White, and seven (20%) were Asian. At data cutoff (March 3, 2023), median follow-up was 18·1 months (IQR 12·7-20·4). The primary endpoint was reached, with 25 (71%; 95% CI 54-85) of 35 patients progression free at 6 months. Nine (26%) of 35 patients had disease progression and one (3%) patient died; the death was unrelated to treatment. The most common adverse event of any grade was fatigue (36 [92%] of 39). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (six [15%]), dry skin, pruritus, or rash (five [13%]), and anaemia (four [10%]). Serious treatment-related adverse events occurred in ten (26%) patients, which were acute kidney injury (three [8%]), hepatotoxicity (two [5%]), sepsis (two [5%]), dry skin, pruritus, or rash (one [3%]), nausea (one [3%]), and gastric perforation (one [3%]). There were no treatment-related deaths. INTERPRETATION: Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic oesophagogastric cancer. A randomised, phase 3 clinical trial is planned. FUNDING: Bristol Myers Squibb, Bayer and National Institutes of Health/National Cancer Institute.

Current treatment and recent progress in gastric cancer.

Gastric cancer is not a top-10 malignancy in the United States but represents one of the most common causes of cancer death worldwide. Biological differences between tumors from Eastern and Western countries add to the complexity of identifying standard-of-care therapy based on international trials. Systemic chemotherapy, radiotherapy, surgery, immunotherapy, and targeted therapy all have proven efficacy in gastric adenocarcinoma; therefore, multidisciplinary treatment is paramount to treatment selection. Triplet chemotherapy for resectable gastric cancer is now accepted and could represent a plateau of standard cytotoxic chemotherapy for localized disease. Classification of gastric cancer based on molecular subtypes is providing an opportunity for personalized therapy. Biomarkers, in particular microsatellite instability (MSI), programmed cell death ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutation burden, and Epstein-Barr virus, are increasingly driving systemic therapy approaches and allowing for the identification of populations most likely to benefit from immunotherapy and targeted therapy. Significant research opportunities remain for the less differentiated histologic subtypes of gastric adenocarcinoma and those without markers of immunotherapy activity.

Clinical Assessment of 5-Fluorouracil/Leucovorin, Nab-Paclitaxel, and Irinotecan (FOLFIRABRAX) in Untreated Patients with Gastrointestinal Cancer Using UGT1A1 Genotype-Guided Dosing.

PURPOSE: 5-Fluorouracil (5-FU)/leucovorin, irinotecan, and nab-paclitaxel are all active agents in gastrointestinal cancers; the combination, FOLFIRABRAX, has not been previously evaluated. UDP Glucuronosyltransferase 1A1 (UGT1A1) clears SN-38, the active metabolite of irinotecan. UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with UGT1A1 genotype-guided dosing of irinotecan. PATIENTS AND METHODS: Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. UGT1A1 *1/*1, *1/*28, and *28/*28 patients received initial irinotecan doses of 180, 135, and 90 mg/m2, respectively. 5-FU 2,400 mg/m2 over 46 hours, leucovorin 400 mg/m2, and nab-paclitaxel 125 mg/m2 were administered. Doses were deemed tolerable if the dose-limiting toxicity (DLT) rate during cycle 1 was ≤35% in each genotype group. DLTs were monitored using a sequential procedure. RESULTS: Fifty patients enrolled, 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5 of 23 (22%) *1/*1 patients, 1 of 19 (5%) *1/*28 patients, and 0 of 7 *28/*28 patients. DLTs were all grade 3: diarrhea (3 patients), nausea (2 patients), and febrile neutropenia (1 patient). The overall response rate was 31%. Response rates in pancreatic, gastroesophageal, and biliary tract cancers were 34%, 50%, and 11%, respectively. Eighteen patients (36%) received therapy for at least 24 weeks. CONCLUSIONS: FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Too few *28/*28 patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.

Circulating Tumor DNA Sequencing Analysis of Gastroesophageal Adenocarcinoma.

PURPOSE: Gastroesophageal adenocarcinoma (GEA) has a poor prognosis and few therapeutic options. Utilizing a 73-gene plasma-based next-generation sequencing (NGS) cell-free circulating tumor DNA (ctDNA-NGS) test, we sought to evaluate the role of ctDNA-NGS in guiding clinical decision-making in GEA. EXPERIMENTAL DESIGN: We evaluated a large cohort (n = 2,140 tests; 1,630 patients) of ctDNA-NGS results (including 369 clinically annotated patients). Patients were assessed for genomic alteration (GA) distribution and correlation with clinicopathologic characteristics and outcomes. RESULTS: Treatment history, tumor site, and disease burden dictated tumor-DNA shedding and consequent ctDNA-NGS maximum somatic variant allele frequency. Patients with locally advanced disease having detectable ctDNA postoperatively experienced inferior median disease-free survival (P = 0.03). The genomic landscape was similar but not identical to tissue-NGS, reflecting temporospatial molecular heterogeneity, with some targetable GAs identified at higher frequency via ctDNA-NGS compared with previous primary tumor-NGS cohorts. Patients with known microsatellite instability-high (MSI-High) tumors were robustly detected with ctDNA-NGS. Predictive biomarker assessment was optimized by incorporating tissue-NGS and ctDNA-NGS assessment in a complementary manner. HER2 inhibition demonstrated a profound survival benefit in HER2-amplified patients by ctDNA-NGS and/or tissue-NGS (median overall survival, 26.3 vs. 7.4 months; P = 0.002), as did EGFR inhibition in EGFR-amplified patients (median overall survival, 21.1 vs. 14.4 months; P = 0.01). CONCLUSIONS: ctDNA-NGS characterized GEA molecular heterogeneity and rendered important prognostic and predictive information, complementary to tissue-NGS.See related commentary by Frankell and Smyth, p. 6893.

A UGT1A1 genotype-guided dosing study of modified FOLFIRINOX in previously untreated patients with advanced gastrointestinal malignancies.

BACKGROUND: FOLFIRINOX (5-fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) is an effective but toxic therapy for pancreatic cancer. UGT1A1 (UDP glucuronosyltransferase 1A1) eliminates the active metabolite of irinotecan. Polymorphisms reduce UGT1A1 activity, leading to toxicity. The primary objective was to determine the dose-limiting toxicity (DLT) rate in cycle 1 of modified FOLFIRINOX (mFOLFIRINOX) using genotype-guided dosing of irinotecan for the most common UGT1A1 genotypes (*1/*1, *1/*28) in advanced gastrointestinal malignancies, with expansion in pancreatic and biliary tract cancers. METHOD: 5-FU (2400 mg/m2 over 46 hours), leucovorin (400 mg/m2 ), oxaliplatin (85 mg/m2 ), and irinotecan were given every 14 days. Irinotecan doses of 180, 135, and 90 mg/m2 were administered for UGT1A1 genotypes *1/*1, *1/*28, and *28/*28, respectively. Prophylactic pegfilgrastim was omitted in cycle 1 for cohort 1 (tolerability by genotype), but was given in cohort 2 (tolerability by tumor type). Doses were tolerable if the upper limit of a 2-sided 80% confidence interval for DLT rate was ≤33%. RESULTS: In cohort 1, DLTs (most commonly febrile neutropenia, fatigue, diarrhea) occurred in 2/15 (13%), 3/16 (19%), and 4/10 (40%) patients with *1/*1, *1/*28, and *28/*28 genotypes, respectively. In cohort 2, 6/19 (32%) pancreatic and 4/19 (21%) biliary tract cancer patients experienced DLTs (most commonly fatigue, diarrhea, nausea/vomiting). In cohort 2, upper confidence limits of DLT rates exceeded 33%. Response rates were 38% in pancreatic and 21% in biliary tract cancers. CONCLUSION: On the basis of our prespecified criteria, tolerability of UGT1A1 genotype-guided mFOLFIRINOX was not established in pancreatic and biliary tract cancers. However, this regimen was effective.

Pembrolizumab for treatment of advanced gastric and gastroesophageal junction adenocarcinoma.

Pembrolizumab is a monoclonal antibody directed against PD-1 that is US FDA approved for treatment of advanced PD-L1 positive gastric and gastroesophageal junction adenocarcinoma in patients who have progressed on at least two prior lines of chemotherapy. This article summarizes the clinical evidence regarding safety, tolerability and efficacy of pembrolizumab in this setting. In addition, this article describes the investigational use of pembrolizumab as first- and second-line therapy and in combination with other treatments. Finally, this review compares other checkpoint inhibitors to pembrolizumab for the treatment of this disease, and explores predictive biomarkers of response to PD-1 blockade.

Effects of epidermal growth factor receptor inhibitor-induced dermatologic toxicities on quality of life.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors frequently result in dermatologic toxicities, including rash, xerosis, pruritus, and paronychia. Although the frequency and severity of these events have been described, their effect on health-related quality of life (QoL) remains poorly understood. By using a dermatology-specific questionnaire, the authors examined the effect of these toxicities on QoL. METHODS: Patients completed the Skindex-16, a questionnaire that measures the effects on 3 domains of QoL: symptoms, emotions, and functioning. The severity of dermatologic toxicities was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (NCI-CTCAE). Correlations of dermatology QoL scores with NCI-CTCAE grade, skin phototype (SPT), sex, age, type of EGFR inhibitor, and cancer type were investigated. RESULTS: Concordant with greater severity of rash grade, there was an increase in median scores for symptoms (P=.0006), emotions (P<.0001), function (P=.001), and overall score (P<.0001). There was an inverse correlation between age and emotions (r=-0.26; P=.03) and overall score (r=-0.25; P=.04). There was a significant difference between patients aged50 years with regard to symptoms (P=.02), emotions (P=.03), functioning (P=.04), and overall score (P=.02). There were no significant differences between QoL and SPT, sex, treatment type, or cancer type (P>.05). CONCLUSIONS: Toxicities, including rash, xerosis, paronychia, and pruritus, adversely affected QoL, and rash was associated with a QoL greater decrease. Younger patients reported lower overall QoL than older patients who had the same toxicities. The current results support using the NCI-CTCAE as a correlative tool for measuring the effects of rash on dermatology-specific QoL.

Sarcoidosis mimicking a venous ulcer: a case report.

Sarcoidosis--a chronic, multisystem disease of unknown etiology characterized by noncaseating granulomas--may cause ulcerative lesions, particularly in African American women. A case of ulcerative sarcoidosis mimicking a venous ulcer is presented. The patient is a 44-year-old African American hypertensive, obese woman with a nonhealing medially based lower leg ulcer of 3 years' duration clinically consistent with a venous ulcer. The ulcer did not heal with compression therapy and pentoxifylline. Subsequent biopsies showed granulomatous inflammation consistent with sarcoidosis. When intralesional triamcinolone was added to compression therapy, the ulcer resolved after 3 months. Given its propensity toward formation on the lower extremities and ulcerative and atrophic appearance, ulcerative sarcoidosis should be considered in the differential diagnosis of a venous ulcer refractory to standard therapy, especially in African American women.

Comparison of electrodesiccation and potassium-titanyl-phosphate laser for treatment of dermatosis papulosa nigra.

BACKGROUND: There is a lack of randomized split-face studies investigating treatments for dermatosis papulosa nigra (DPN) in dark skin. OBJECTIVE: To compare the efficacy, safety, and tolerability of potassium-titanyl-phosphate (KTP) laser with efficacy, safety, and tolerability of electrodesiccation in the treatment of DPN in subjects with Fitzpatrick skin phototypes IV to VI. METHODS: Fourteen subjects with Fitzpatrick skin phototypes IV to VI were randomized to receive two KTP laser treatments 4 weeks apart to half of the face. The contralateral half received two electrodesiccation treatments 4 weeks apart. Response was evaluated by photography reviewed by blinded dermatologists at 4 weeks after the second treatment. A treatment quality questionnaire about side effects and cosmetic outcome was also administered. RESULTS: Difference in improvement of DPN between the KTP side and the electrodesiccation side per each rater (p=.99, p=.54) and per raters combined (p=.50) did not reach statistical significance. There was no treatment difference for subjective effectiveness (p=.06) or subjective confidence improvement (p=.99), although there was a significant treatment difference for subjective discomfort (p=.002) in favor of KTP. Both treatments were well tolerated without significant adverse effects. CONCLUSIONS: Although treatment of DPN with KTP laser and electrodesiccation are comparable in efficacy, KTP laser is preferable for patient comfort.

Effectiveness, safety, and effect on quality of life of topical salicylic acid peels for treatment of postinflammatory hyperpigmentation in dark skin.

BACKGROUND: There are no randomized split-face model studies investigating treatments for postinflammatory hyperpigmentation (PIH) in dark skin. OBJECTIVE: To assess the efficacy, safety, and effect on quality of life of salicylic acid peels for PIH in dark skin. METHODS: Ten subjects with Fitzpatrick skin phototypes IV to VI were randomized to receive two 20% salicylic acid peels followed by three 30% salicylic acid peels to half of the face. The contralateral half remained untreated. Response was evaluated by photography reviewed by three blinded dermatologists. The Visual Analog Scale, Dermatology Life Quality Index (DLQI), and treatment quality questionnaire were administered. RESULTS: Improvement of PIH on the treatment side according to each rater (p=.81, p=.81, p=.42) and according to the raters combined (p=.11) approached but did not reach statistical significance. Subjects' Visual Analog Scale scores indicated significantly greater improvement of PIH on the treatment side than in the control (p=.004). Quality of life measured according to the DLQI improved after treatment but not statistically significantly so (p=.13). Treatment had no significant adverse effects. CONCLUSIONS: Salicylic acid peels are safe in this population. Although patients rated them as clinically effective, blinded raters found a brief series of peels to have less efficacy. Measured quality of life improved nominally.