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.

Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

Phase I/Ib study of crenolanib with ramucirumab and paclitaxel as second-line therapy for advanced esophagogastric adenocarcinoma.

PURPOSE: Paclitaxel plus ramucirumab is a standard second-line regimen for patients with advanced gastric adenocarcinoma, but clinical benefit remains modest. One potential resistance mechanism to VEGFR2 inhibition is activation of the PDGF/PDGFR pathway, which can be blocked by the selective inhibitor crenolanib. Therefore, we performed a phase I/Ib study of crenolanib in combination with paclitaxel/ramucirumab. METHODS: Patients with metastatic esophagogastric adenocarcinoma refractory to first-line therapy received escalating doses of crenolanib [60 mg twice daily (BID) to 100 mg three times daily (TID)] in combination with paclitaxel 80 mg/m2 intravenously on days 1, 8 and 15 and ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary objective was to determine the maximally tolerated dose (MTD) of crenolanib. Additional patients were enrolled in the dose expansion cohort to assess 6-month progression-free survival (PFS) at the MTD. RESULTS: We enrolled 19 patients in the dose escalation phase and 8 patients in the dose expansion phase at the MTD of crenolanib 100 mg BID. Common grade 3/4 treatment-emergent adverse events included leukopenia (19%), anemia (11%) and neutropenia (11%). In the 14 patients treated at the MTD, 6-month PFS was 43% [95% confidence interval (CI) 23-78%] and the objective response rate (ORR) was 42% (95% CI 15-72%). The trial was terminated early due to withdrawal of crenolanib by the sponsor. CONCLUSIONS: The addition of crenolanib to paclitaxel/ramucirumab is safe and well-tolerated at a dose level up to 100 mg BID. CLINICAL TRIAL REGISTRATION: NCT03193918. June 19, 2017.

Prevalence of Germline Alterations on Targeted Tumor-Normal Sequencing of Esophagogastric Cancer.

Importance: Among patients with esophagogastric cancers, only individuals who present with known features of heritable cancer syndromes are referred for genetic testing. Broader testing might identify additional patients with germline alterations. Objectives: To examine the prevalence of likely pathogenic or pathogenic (LP/P) germline alterations among patients with esophagogastric cancer and to assess associations between germline variant prevalence and demographic and clinicopathologic features. Design, Setting, and Participants: This cross-sectional study was performed at a tertiary referral cancer center from January 1, 2014, to December 31, 2019, in 515 patients with esophagogastric cancer who consented to tumor and blood sequencing. Main Outcomes and Measures: Presence or absence of LP/P variants in up to 88 genes associated with cancer predisposition syndromes as identified by targeted sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets). Results: Among 515 patients (median age, 59 years; range, 18-87 years; 368 [71.5%] male; 398 [77.3%] White), 243 (47.2%) had gastric cancer, 111 (21.6%) had gastroesophageal junction (GEJ) cancer, and 161 (31.3%) had esophageal cancer. A total of 48 patients with gastric cancer (19.8%), 16 (14.4%) with GEJ cancer, and 17 (10.6%) with esophageal cancer had LP/P germline variants. The number of LP/P variants in high- and moderate-penetrance genes was significantly higher in patients with gastric cancer (29 [11.9%]; 95% CI, 8.1%-16.7%) vs patients with esophageal cancer (8 [5.0%]; 95% CI, 2.2%-9.6%; P = .03), and the difference was greater for high-penetrance germline alterations in patients with gastric cancer (25 [10.3%]; 95% CI, 6.8%-14.8%) vs in patients with esophageal cancer (3 [1.9%]; 95% CI, 0.38%-5.3%; P = .001). The most frequent high- and moderate-penetrance LP/P alterations were in BRCA1/2 (14 [2.7%]), ATM (11 [2.1%]), CDH1 (6 [1.2%]), and MSH2 (4 [0.8%]). Those with early-onset disease (≤50 years of age at diagnosis) were more likely to harbor an LP/P germline variant (29 [21.0%]; 95% CI, 14.5%-28.8%) vs those with late-onset disease (patients >50 years of age at diagnosis) (52 [13.8%]; 95% CI, 10.5%-17.7%; P = .046). ATM LP/P variants occurred in 6 patients (4.3%; 95% CI, 1.6%-9.1%) with early-onset esophagogastric cancer vs 5 (1.3%; 95% CI, 0.4%-3.1%; P = .08) of those with late-onset esophagogastric cancer. Conclusions and Relevance: These results suggest that pathogenic germline variants are enriched in gastric and early-onset esophagogastric cancer and that germline testing should be considered in these populations. The role of ATM alterations in esophagogastric cancer risk warrants further investigation.

First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial.

BACKGROUND: Addition of trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer. We assessed the safety and activity of pembrolizumab in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric (gastric, oesophageal, or gastroesophageal junction) cancer. METHODS: This study was an investigator-initiated, open-label, non-randomised, single-arm, single centre, phase 2 trial in patients aged 18 years or older with HER2-positive metastatic oesophagogastric cancer. Eligible patients had measurable or evaluable non-measurable disease, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and left ventricular ejection fraction of at least 53%. Patients were eligible to receive an initial induction cycle of 200 mg flat dose of intravenous pembrolizumab and 8 mg/kg loading dose of intravenous trastuzumab. For subsequent cycles, patients received 130 mg/m2 of intravenous oxaliplatin or 80 mg/m2 of cisplatin on day 1, 850 mg/m2 of oral capecitabine twice a day for 2 weeks followed by 1 week off (or intravenous 5-fluorouracil, 800 mg/m2 per day on days 1-5), and a 200 mg flat dose of intravenous pembrolizumab, and 6 mg/kg of trastuzumab, administered on day 1 of each 3-week cycle. The primary endpoint was 6-month progression-free survival, defined as the proportion of patients alive and free of progression at 6 months, assessed in patients who received at least one dose of trastuzumab and pembrolizumab. The regimen would be considered worthy of further investigation if 26 or more of 37 patients were progression-free at 6 months. This trial is registered with ClinicalTrials.gov, NCT02954536, and is ongoing, but closed to enrolment. FINDINGS: Between Nov 11, 2016, and Jan 23, 2019, 37 patients were enrolled. At the time of data cutoff on Aug 6, 2019, median follow-up among survivors was 13·0 months (IQR 11·7-23·5). The primary endpoint was achieved; 26 (70%; 95% CI 54-83) of 37 patients were progression-free at 6 months. The most common treatment-related adverse event of any grade was neuropathy, which was reported in 36 (97%) of 37 patients. The most common grade 3 or 4 adverse events were lymphocytopenia (seven [19%] patients with grade 3 and two [5%] with grade 4), grade 3 decreased electrolytes (six [16%] patients), and grade 3 anaemia (four [11%] patients). Serious adverse events occurred in two patients patients (both grade 3 nephritis leading to treatment discontinuation). Four patients discontinued pembrolizumab because of immune-related adverse events. There were no treatment-related deaths. INTERPRETATION: Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive metastatic oesophagogastric cancer. A randomised phase 3 clinical trial assessing the efficacy and safety of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric cancer is underway. FUNDING: Merck & Co.

Efficacy of Combined VEGFR1-3, PDGFα/ß, and FGFR1-3 Blockade Using Nintedanib for Esophagogastric Cancer.

PURPOSE: VEGFR2-directed therapy is commonly used to treat metastatic esophagogastric cancer, but disease progresses in most patients within months. Therapeutic resistance is likely mediated in part by co-occurring amplifications of the genes for multiple oncogenic receptor tyrosine kinases (RTK). We therefore tested the efficacy of combined inhibition of VEGFR1-3, PDGFα/ß, and FGFR1-3 using nintedanib. PATIENTS AND METHODS: Patients with metastatic esophagogastric adenocarcinoma and disease progression on first-line chemotherapy were treated with nintedanib 200 mg twice daily. The primary endpoint was progression-free survival (PFS) at 6 months; secondary endpoints included tumor response and safety. Tumor biopsies were profiled by targeted capture next-generation sequencing (NGS) to identify molecular predictors of drug response. RESULTS: The study achieved its primary endpoint; 6 of 32 patients (19%) were progression-free at 6 months. With a median follow-up of 14.5 months among survivors, median overall survival (OS) was 14.2 months [95% confidence interval (CI), 10.8 months-NR]. Nintedanib was well tolerated; grade ≥ 3 toxicities were uncommon and included grade 3 hypertension (15%) and liver enzyme elevation (4%). FGFR2 alterations were identified in 18% of patients but were not predictive of clinical outcome on nintedanib therapy. Alterations in cell-cycle pathway genes were associated with worse median PFS (1.61 months for patients with cell-cycle pathway alterations vs. 2.66 months for patients without, P = 0.019). CONCLUSIONS: Nintedanib treatment resulted in modest disease stabilization in patients with metastatic esophagogastric cancer. Alterations in cell-cycle pathway genes and increased global copy-number alteration (CNA) burden warrant further study as prognostic or predictive biomarkers.

Issues in the management of esophageal cancer and geriatric patients.

Esophageal cancer is a disease occurring in older adults and given the aging population, the incidence of cancer in the elderly will continue to rise. However, older patients are less likely to receive treatment for their cancers based on age alone. There are limited data and guidelines for how to manage the older patient population but elderly patients can derive benefit from treatment. This review will describe issues specific to older patients with esophageal cancer with a focus on the utilization of geriatric assessment (GA) tools and how to apply geriatric principles to this cancer patients.

Issues in the Management of Esophagogastric Cancer in Geriatric Patients.

Esophagogastric cancers predominantly affect older adults; however, older patients are less likely to be recommended for both curative and palliative treatment. Older patients have unique challenges that need to be addressed during their oncologic care. Tools such as complete geriatric assessments may help to better identify fit older adults and stratify patients for aggressive treatment strategies. This review evaluates the current knowledge and the remaining challenges in optimally managing elderly patients with esophagogastric cancers.

Use of positron emission tomography scan response to guide treatment change for locally advanced gastric cancer: the Memorial Sloan Kettering Cancer Center experience.

BACKGROUND: Early metabolic response on 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) during neoadjuvant chemotherapy is PET non-responders have poor outcomes whether continuing chemotherapy or proceeding directly to surgery. Use of PET may identify early treatment failure, sparing patients from inactive therapy and allowing for crossover to alternative therapies. We examined the effectiveness of PET directed switching to salvage chemotherapy in the PET non-responders. METHODS: Patients with locally advanced resectable FDG-avid gastric or gastroesophageal junction (GEJ) adenocarcinoma received bevacizumab 15 mg/kg, epirubicin 50 mg/m(2), cisplatin 60 mg/m(2) day 1, and capecitabine 625 mg/m(2) bid (ECX) every 21 days. PET scan was obtained at baseline and after cycle 1. PET responders, (i.e., ≥35% reduction in FDG uptake at the primary tumor) continued ECX + bev. Non-responders switched to docetaxel 30 mg/m(2), irinotecan 50 mg/mg(2) day 1 and 8 plus bevacizumab every 21 days for 2 cycles. Patients then underwent surgery. The primary objective was to improve the 2-year disease free survival (DFS) from 30% (historical control) to 53% in the non-responders. RESULTS: Twenty evaluable patients enrolled before the study closed for poor accrual. Eleven were PET responders and the 9 non-responders switched to the salvage regimen. With a median follow-up of 38.2 months, the 2-year DFS was 55% [95% confidence interval (CI), 30-85%] in responders compared with 56% in the non-responder group (95% CI, 20-80%, P=0.93). CONCLUSIONS: The results suggest that changing chemotherapy regimens in PET non-responding patients may improve outcomes. Results from this pilot trial are hypothesis generating and suggest that PET directed neoadjuvant therapy merits evaluation in a larger trial.

Designing exercise clinical trials for older adults with cancer: Recommendations from 2015 Cancer and Aging Research Group NCI U13 Meeting.

Cancer and its treatment can lead to a myriad of adverse events and negatively impact quality of life of older cancer patients and survivors. Unmet physical activity needs vary across the cancer continuum and remain an important yet understudied area of research in this population. Exercise interventions have been shown to be effective in treating both the physical and psychological declines associated with cancer and its treatment, with a potential to improve cancer-related outcomes. Despite the current evidence, exercise is clearly underutilized due to several barriers and knowledge gaps in existing trials that include appropriate population identification, design, and outcome measures selection. The benefits of regular exercise in both the primary and secondary prevention of chronic conditions are well established in the non-cancer population. In older cancer patients and survivors, further research is needed before exercise gains widespread acceptance. The Cancer and Aging Research Group convened experts in exercise, aging and cancer to evaluate current scientific evidence and knowledge gaps in geriatric exercise oncology. This report summarizes these findings and provides future research directions.

Gaps in nutritional research among older adults with cancer.

Nutritional issues among older adults with cancer are an understudied area of research despite significant prognostic implications for treatment side effects, cancer-specific mortality, and overall survival. In May of 2015, the National Cancer Institute and the National Institute on Aging co-sponsored a conference focused on future directions in geriatric oncology research. Nutritional research among older adults with cancer was highlighted as a major area of concern as most nutritional cancer research has been conducted among younger adults, with limited evidence to guide the care of nutritional issues among older adults with cancer. Cancer diagnoses among older adults are increasing, and the care of the older adult with cancer is complicated due to multimorbidity, heterogeneous functional status, polypharmacy, deficits in cognitive and mental health, and several other non-cancer factors. Due to this complexity, nutritional needs are dynamic, multifaceted, and dependent on the clinical scenario. This manuscript outlines the proceedings of this conference including knowledge gaps and recommendations for future nutritional research among older adults with cancer. Three common clinical scenarios encountered by oncologists include (1) weight loss during anti-cancer therapy, (2) malnutrition during advanced disease, and (3) obesity during survivorship. In this manuscript, we provide a brief overview of relevant cancer literature within these three areas, knowledge gaps that exist, and recommendations for future research.

HER2 directed therapy for gastric/esophageal cancers.

OPINION STATEMENT: The majority of patients with esophagogastric cancer present with advanced disease, which is incurable. Systemic chemotherapy can lead to a decrease in cancer-related symptoms and prolongs survival. However, even with treatment, the prognosis remains poor; most patients with advanced disease have a median overall survival less than one year. Molecularly targeted therapies, such as those targeting human epidermal growth factor receptor 2 (HER2), are anticipated to improve the current status of systemic treatment beyond conventional cytotoxic therapy. Trastuzumab in combination with chemotherapy in patients is the first molecular agent in metastatic HER2 positive gastric and gastroesophageal adenocarcinomas to result in improvements in response rates, time to progression and survival. Trastuzumab is now being investigated in the neoadjuvant and adjuvant setting. Unfortunately, as with breast cancer, many esophagogastric patients will develop resistance to trastuzumab. Several promising therapies are currently under investigation as monotherapy and in combination with chemotherapy in the first and second line setting.

Management of localized esophageal cancer in the older patient.

Most patients with gastroesophageal cancers are older than 65 years of age. The management of older patients poses challenges because they have multiple comorbidities and physiological changes associated with aging. Furthermore, data are limited on tolerance of cancer therapy and the use of combined-modality treatments in this patient population to guide their treatment. In this article, we focus on the management of older patients with localized esophageal cancer, highlighting the role of comprehensive geriatric assessment to identify and better tailor treatment approaches in this patient population. We review the literature and discuss the role of surgical resection and potential complications specific to an older patient. We review the rationale of combined-modality treatment and the potential benefits of a chemoradiotherapy-based approach in this patient population.

CA125 level association with chemotherapy toxicity and functional status in older women with ovarian cancer.

OBJECTIVE: Older women with ovarian cancer have increased cancer-related mortality and chemotherapy toxicity. CA125 is a sensitive biomarker for tumor burden. The study evaluates the association between CA125, geriatric assessment (GA), and treatment toxicity. METHODS: This is a secondary subset analysis of patients 65 years or older with ovarian cancer accrued to a multicenter prospective study that developed a predictive toxicity score for older adults with cancer. Clinical and geriatric covariates included sociodemographics, GA (comorbidity, social support, functional, nutritional, psychological, cognitive status), treatment, and laboratory studies. Using bivariate analyses, we determined the association of abnormal CA125 (≥35 U/mL) with baseline GA, grades 3 to 5 toxicity (Common Terminology Criteria for Adverse Events version 3), dose adjustments, and hospitalization. Logistic regression analysis was used to check for potential confounder for association between CA125 and chemotherapy toxicity. RESULTS: Fifty-one (10%) of 500 patients accrued to the primary study had a diagnosis of ovarian (92%), peritoneal (4%), or fallopian tube (4%) cancer. Median age was 72 years (range, 65-86 years). Forty-six patients (90%) had stage III-IV disease. Twenty-three patients (45%) received first-line chemotherapy, and 34 (67%) received platinum-doublet therapy. Thirty-six (71%) had an abnormal CA125. Grades 3 to 5 toxicity occurred in 19 patients (37%). Abnormal CA125 was associated with assistance with instrumental activities of daily living (P < 0.05), lower performance status (P = 0.05), grades 3 to 5 toxicity (P = 0.03), nonheme toxicity (P = 0.04), and dose reductions (P = 0.01). No association between CA125 level and total toxicity score was observed. CONCLUSIONS: Among older women with ovarian cancer, abnormal CA125 was associated with poor pretreatment functional status and an increased probability of chemotherapy toxicity and dose reduction.

The use of mole-mapping diagrams to increase skin self-examination accuracy.

BACKGROUND: Monthly skin self-examination (SSE) is associated with reduced incidence of advanced melanoma, but SSE is prone to error in detecting early changes of melanoma. OBJECTIVE: We sought to improve SSE accuracy by requiring participants to complete a mole-mapping diagram. METHODS: After completing a baseline survey, participants received SSE instruction, had their backs digitally photographed, and half were randomized to complete a mole-mapping diagram. Some photographs were altered by adding an image of a 5-mm pigmented lesion. At follow-up, participants were asked to identify any changes introduced to their photographs. RESULTS: A total of 88 participants completed the study. In all, 33% (n = 15) of the control group (no diagram) and 52% (n = 22) of the intervention group (mole-mapping diagram) (P = .06) gave accurate assessments. Analysis of only altered images indicated that the intervention group gave more accurate assessments (60% vs 33%, P = .01). LIMITATIONS: This study was limited by sample size, only addressed lesions on the back, and did not involve actual melanomas in study participants. CONCLUSIONS: Mole-mapping diagrams may improve SSE accuracy, and may be useful as a simple, cost-effective intervention in reducing melanoma mortality.