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INTRODUCTION: Prophylactic total gastrectomy (PTG) can eliminate gastric cancer risk and is recommended in carriers of a germline CDH1 pathogenic variant. PTG has established risks and potential life-long morbidity. Decision-making regarding PTG is complex and not well-understood. METHODS: Individuals with germline CDH1 pathogenic or likely pathogenic variants who underwent surveillance endoscopy and recommended for PTG were evaluated. Factors associated with decision to pursue PTG (PTGpos) or not (PTGneg) were queried. A decision-regret survey was administered to patients who elected PTG. RESULTS: Decision-making was assessed in 120 patients. PTGpos patients (63%, 76/120) were younger than PTGneg (median 45 vs 58 years) and more often had a strong family history of gastric cancer (80.3% vs 34.1%). PTGpos patients reported decision-making based on family history more often and decided soon after diagnosis (8 vs 27 months) compared with PTGneg. Negative endoscopic surveillance results were more common among PTGneg patients. Age >60 years, male sex and longer time to decision were associated with deferring PTG. Strong family history, a family member who died of gastric cancer and carcinoma on endoscopic biopsies were associated with decision to pursue PTG. In the PTGpos group, 30 patients (43%) reported regret which was associated with occurrence of a postoperative complication and no carcinoma detected on final pathology. CONCLUSION: The decision to undergo PTG is influenced by family cancer history and surveillance endoscopy results. Regret is associated with surgical complications and pathological absence of cancer. Individual cancer-risk assessment is necessary to improve pre-operative counselling and inform the decision-making process. TRIAL REGISTRATION NUMBER: NCT03030404.
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Neoplasias Gástricas , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/patología , Predisposición Genética a la Enfermedad , Gastrectomía/métodos , Mutación de Línea Germinal , Emociones , Cadherinas/genética , Antígenos CDRESUMEN
Importance: Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants. Objective: To describe gastric and breast cancer risk estimates for individuals with CDH1 variants. Design, Setting, and Participants: Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022. Main Outcomes and Measures: Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years. Results: A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%). Conclusions and Relevance: Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.
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BACKGROUND: Loss of function variants in CDH1 are the most frequent cause of hereditary diffuse gastric cancer. Endoscopy is regarded as insufficient for early detection due to the infiltrative phenotype of diffuse-type cancers. Microscopic foci of invasive signet ring cells are pathognomonic of CDH1 and precede development of diffuse gastric cancer. We aimed to assess the safety and effectiveness of endoscopy for cancer interception in individuals with germline CDH1 variants, particularly in those who declined prophylactic total gastrectomy. METHODS: In this prospective cohort study, we included asymptomatic patients aged 2 years or older with pathogenic or likely pathogenic germline CDH1 variants who underwent endoscopic screening and surveillance at the National Institutes of Health (Bethesda, MD, USA) as part of a natural history study of hereditary gastric cancers (NCT03030404). Endoscopy was done with non-targeted biopsies and one or more targeted biopsy and assessment of focal lesions. Endoscopy findings, pathological data, personal and family cancer history, and demographics were recorded. Procedural morbidity, gastric cancer detection by endoscopy and gastrectomy, and cancer-specific events were assessed. Screening was defined as the initial endoscopy and all subsequent endoscopies were considered surveillance; follow-up endoscopy was at 6 to 12 months. The primary aim was to determine effectiveness of endoscopic surveillance for detection of gastric signet ring cell carcinoma. FINDINGS: Between Jan 25, 2017, and Dec 12, 2021, 270 patients (median age 46·6 years [IQR 36·5-59·8], 173 [64%] female participants, 97 [36%] male participants; 250 [93%] were non-Hispanic White, eight [3%] were multiracial, four [2%] were non-Hispanic Black, three [1%] were Hispanic, two [1%] were Asian, and one [<1%] was American Indian or Alaskan Native) with germline CDH1 variants were screened, in whom 467 endoscopies were done as of data cutoff (April 30, 2022). 213 (79%) of 270 patients had a family history of gastric cancer, and 176 (65%) reported a family history of breast cancer. Median follow-up was 31·1 months (IQR 17·1-42·1). 38 803 total gastric biopsy samples were obtained, of which 1163 (3%) were positive for invasive signet ring cell carcinoma. Signet ring cell carcinoma was detected in 76 (63%) of 120 patients who had two or more surveillance endoscopies, of whom 74 had occult cancer detected; the remaining two individuals developed focal ulcerations each corresponding to pT3N0 stage carcinoma. 98 (36%) of 270 patients proceeded to prophylactic total gastrectomy. Among patients who had a prophylactic total gastrectomy after an endoscopy with biopsy samples negative for cancer (42 [43%] of 98), multifocal stage IA gastric carcinoma was detected in 39 (93%). Two (1%) participants died during follow-up, one due to metastatic lobular breast cancer and the other due to underlying cerebrovascular disease, and no participants were diagnosed with advanced stage (III or IV) cancer during follow-up. INTERPRETATION: In our cohort, endoscopic cancer surveillance was an acceptable alternative to surgery in individuals with CDH1 variants who declined total gastrectomy. The low rate of incident tumours (>T1a) suggests that surveillance might be a rational alternative to surgery in individuals with CDH1 variants. FUNDING: Intramural Research Program, National Institutes of Health.
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Adenocarcinoma , Carcinoma de Células en Anillo de Sello , Neoplasias Gástricas , Masculino , Humanos , Femenino , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/genética , Estudios Prospectivos , Gastrectomía/efectos adversos , Adenocarcinoma/cirugía , Carcinoma de Células en Anillo de Sello/diagnóstico , Carcinoma de Células en Anillo de Sello/epidemiología , Carcinoma de Células en Anillo de Sello/genética , Mutación de Línea Germinal , Predisposición Genética a la EnfermedadRESUMEN
INTRODUCTION: There are no approved locoregional therapies for peritoneal carcinomatosis from gastric adenocarcinoma (GA). Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) represents a potential treatment for advanced GA with isolated peritoneal metastasis. PATIENTS AND METHODS: Two separate single-institution phase II, single-arm studies evaluating CRS-HIPEC using cisplatin with mitomycin C (NIH: NCT03092518, MDACC: NCT02891447) in patients with GA and confirmed peritoneal metastasis were analyzed. The primary endpoint of each trial was overall survival (OS). Clinical, pathologic, and treatment variables were analyzed for association with outcomes. RESULTS: Over 4 years, 41 patients with peritoneal carcinomatosis from GA underwent CRS-HIPEC. All patients had synchronous peritoneal metastasis and received systemic chemotherapy as front-line therapy. A total of 23 patients also received laparoscopic HIPEC prior to open CRS-HIPEC. The majority (63%, n = 26) were male, and median PCI score at CRS-HIPEC was 2. Median OS was 24.9 months from diagnosis and 14.4 months from CRS-HIPEC. Three-year OS was 25% from diagnosis and 22% from CRS-HIPEC. Median RFS was 7.4 months. The rate of 30-day Clavien-Dindo grade ≥ 3 complications was 32%; specifically, the rate of anastomotic leak was 22%. Multivariable analysis identified the number of pathologically positive lymph nodes as an independent predictor of postoperative OS. CONCLUSIONS: In patients with gastric adenocarcinoma and isolated peritoneal metastasis treated with CRS-HIPEC, 3-year OS was 22% from CRS-HIPEC, and complications were common. The number of pathologic lymph node metastases was inversely correlated with overall survival. Further investigation of CRS-HIPEC for GA should include patient selection based on response to systemic chemotherapy or incorporate novel intraperitoneal treatment strategies.
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Adenocarcinoma , Carcinoma , Hipertermia Inducida , Intervención Coronaria Percutánea , Neoplasias Peritoneales , Neoplasias Gástricas , Humanos , Masculino , Femenino , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Peritoneales/secundario , Procedimientos Quirúrgicos de Citorreducción , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hipertermia Inducida/efectos adversos , Carcinoma/patología , Adenocarcinoma/patología , Neoplasias Gástricas/patología , Tasa de Supervivencia , Estudios RetrospectivosRESUMEN
BACKGROUND: Staging laparoscopy (SL) with peritoneal lavage is usually performed on a separate day from the planned resection and is recommended in patients with gastric adenocarcinoma as it can identify radiographically occult metastases and malignant cytology, thus altering prognosis and treatment. SL can be done on the same day as planned resection (SLSR) or with delayed resection (SLDR). The purpose of this study was to determine utilization of SL and factors associated with SLSR and SLDR, among patients diagnosed with gastric adenocarcinoma. METHODS: SEER-Medicare linked data were used to identify patients diagnosed with gastric adenocarcinoma from 2004 through 2013. SL were defined as a laparoscopy that occurred up to 3 months postdiagnosis. Multivariate logistic regression was used to identify factors associated with the utilization of SLSR and SLDR. RESULTS: Of the 5610 patients with gastric adenocarcinoma who underwent a surgical procedure, 733 (13%) had a SL. Utilization of SL increased annually from 6.4% to 22.2% (p < 0.01). Receipt of SL was associated with patient demographics, tumor location, and treatment at a National Cancer Institute (NCI) Designated Cancer Center (CC). Of the 733 patients who underwent SL, 475 (65%) received further surgical procedures; 367 (77%) underwent SLSR, while 108 patients (23%) underwent SLDR. Compared with SLSR, SLDR was more common among patients who were younger, treated at an NCI-Designated CC and had proximal tumors. CONCLUSIONS: SL for optimal preoperative staging remains underutilized in the management of gastric adenocarcinoma. Expanded use of laparoscopy as a distinct procedure could minimize unnecessary interventions.
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Adenocarcinoma/diagnóstico , Gastrectomía/métodos , Laparoscopía/estadística & datos numéricos , Lavado Peritoneal/estadística & datos numéricos , Neoplasias Peritoneales/diagnóstico , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/patología , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Anciano , Anciano de 80 o más Años , Citodiagnóstico , Femenino , Humanos , Laparoscopía/métodos , Masculino , Medicare , Análisis Multivariante , Estadificación de Neoplasias/métodos , Lavado Peritoneal/métodos , Neoplasias Peritoneales/patología , Programa de VERF , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Estados UnidosRESUMEN
BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC), with most clinical data stemming from single-institution series. The variability in the literature lends support for analysis using a large national dataset. In doing so, we sought to (1) define the characteristics and outcomes of patients with FLC; (2) determine factors associated with survival in patients undergoing resection; and (3) compare the overall survival (OS) of patients with FLC with a matched group of patients with HCC. METHODS: The National Cancer Database was queried for patients with FLC, and their clinicopathologic features were recorded. Univariate and multivariate analyses were performed to delineate factors associated with survival. RESULTS: Between 2004 and 2015, 496 patients were diagnosed with FLC, 229 of whom underwent a curative resection. The median OS for patients with FLC undergoing curative resection was 78.5 months. Factors associated with abbreviated OS in this surgical cohort include multiple tumors [hazard ratio (HR) 3.15, p = 0.025], positive regional lymph nodes (HR 2.83, p = 0.023), and elevated serum α-fetoprotein (AFP; HR 2.81, p = 0.034). When the OS of patients with FLC was compared with a matched group of patients with HCC, no difference was detected (p = 0.748); however, patients with FLC and elevated AFP had abbreviated OS compared with patients with HCC and elevated AFP (43 vs. 82 months, p ≤ 0.001). CONCLUSIONS: Elevations in serum AFP occur more frequently than previously documented for patients with FLC and are associated with abbreviated OS. AFP levels may help guide the decision for operative intervention in patients with FLC.
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Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/mortalidad , Hepatectomía/mortalidad , alfa-Fetoproteínas/análisis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
PURPOSE: Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome. METHODS: Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing. RESULTS: One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months. CONCLUSION: RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Calidad de Vida , Gastrectomía/efectos adversos , Pruebas Genéticas , Adenocarcinoma/cirugía , Cadherinas/genética , Mutación de Línea Germinal , Predisposición Genética a la EnfermedadRESUMEN
More than 90% of individuals with germline pathogenic CDH1 variants will harbor occult, microscopic foci of signet ring cell carcinomas capable of progressing to advanced diffuse-type gastric cancer. Here, we present a protocol for high viability suspension of signet ring cells from human gastric tissue. We describe the steps for gastric mucosa isolation and tissue dissociation. We then detail procedures for embedding cells into HistoGel for immunohistochemistry staining and additional applications such as flow cytometry and single-cell sequencing.
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Carcinoma de Células en Anillo de Sello , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Carcinoma de Células en Anillo de Sello/patología , Mutación de Línea Germinal , Mucosa Gástrica/patología , Predisposición Genética a la EnfermedadRESUMEN
Background and Aims: Germline CDH1 variants resulting in E-cadherin loss of function result in an increased risk of diffuse type gastric cancer and lobular type breast cancer. However, the risk of developing other epithelial neoplasms, specifically colorectal cancer, is unknown. Methods: Patients enrolled in a prospective natural history study of hereditary gastric cancer who underwent at least one colonoscopy were evaluated. Results: Out of 300 patients with CDH1 pathogenic or likely pathogenic variants, 85 underwent colonoscopy. More than half of patients (56%, 48/85) had at least one colorectal polyp. Most of those patients (83%, 40/48) had at least one precancerous polyp (adenoma or sessile serrated lesion). More than half (56%) of patients younger than age 45 had a colorectal polyp. Of those with polyps, the most frequent CDH1 variant type was canonical splice site (27%, 13/48) followed by nonsense (21%, 10/48). There was no association between CDH1 variant type and increased likelihood of colorectal polyps. Conclusions: In summary, a majority of CDH1 variant carriers who underwent colonoscopy had colorectal polyps detected, and most subjects were less than 45 years old. This study of colorectal cancer risk based on the prevalence of colorectal polyps in the CDH1 population requires further investigation to appropriately counsel patients on colorectal cancer screening. Clinical trial registry website: https://clinicaltrials.gov/. Clinical trial number: NCT03030404.
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INTRODUCTION: Patients with germline variants in CDH1 who undergo prophylactic total gastrectomy (TG) are at risk of altered nutrient and drug absorption due to modified gastrointestinal anatomy. Bone mineral density loss and micronutrient deficiencies have not been described previously in this patient population. METHODS: In this study we included 94 patients with germline CDH1 variants who underwent prophylactic TG between October 2017 and February 2022. We examined pre- and post-gastrectomy bone mineral density (BMD); serum biomarkers including calcium, phosphorus, alkaline phosphatase, and 25 (OH)-vitamin D; and postoperative adherence to calcium and multivitamin supplementation. RESULTS: Almost all patients (92/94, 98%) lost a substantial amount of weight post-TG, with an average weight loss of 26.5% at 12 months post-surgery. Serum biomarkers of mineral metabolism, namely calcium and phosphorus, did not change significantly after TG. However, average BMD was decreased in all patients at 12 months post-TG. Nonadherence to calcium supplementation was associated with a decrease in BMD. Nonadherence to multivitamin supplementation was associated with greater percent BMD loss in the femoral neck and total hip. CONCLUSIONS: Appropriate micronutrient supplementation and nutritional counseling pre- and postoperatively in patients undergoing prophylactic TG are important to mitigate the long-term effects of gastrectomy on bone health.
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Densidad Ósea , Calcio , Humanos , Calcio/farmacología , Vitaminas/farmacología , Vitamina D , Calcio de la Dieta , Biomarcadores , Cuello Femoral , Suplementos Dietéticos , Gastrectomía/efectos adversos , Fósforo , Antígenos CD , CadherinasRESUMEN
Women with germline pathogenic variants in CDH1, which encodes E-cadherin protein, are at increased lifetime risk of invasive lobular carcinoma (ILC). The associated tumor characteristics of hereditary lobular breast carcinoma (HLBC) in this high-risk population are not well-known. A single-center prospective cohort study was conducted to determine the imaging and pathologic features of HLBC compared to population-based ILC using Surveillance, Epidemiology, and End Results (SEER) data. One hundred fifty-eight women with CDH1 variants were evaluated, of whom 48 (30%) also had an ILC diagnosis. The median age at CDH1 diagnosis was 45 years [interquartile range, IQR 34-57 years] whereas the median age at diagnosis of CDH1 with concomitant ILC (HLBC) was 53 [IQR 45-62] years. Among women with HLBC, 83% (40/48) were identified with CDH1 mutation after diagnosis of ILC. Among 76 women (48%, 76/158) undergoing surveillance for ILC with breast magnetic resonance imaging (MRI), 29% (22/76) had an abnormal MRI result with available biopsy data for comparison. MRI detected ILC in 7 out of 8 biopsy-confirmed cases, corresponding with high sensitivity (88%), specificity (75%), and negative predictive value (98%); however, false-positive and false-discovery rates were elevated also (25% and 68%, respectively). HLBC was most frequently diagnosed at age 40-49 years (44%, 21/48), significantly younger than the common age of diagnosis of ILC in SEER general population data (most frequent age range 60-69 years, 28%; p < 0.001). HLBC tumors were smaller than SEER-documented ILC tumors (median 1.40 vs. 2.00 cm; p = 0.002) and had a higher incidence of background lobular carcinoma in situ (88% vs. 1%; p < 0.001) as well as progesterone receptor positivity (95% vs. 81%, p = 0.032). These findings suggest that HLBC is often detected via conventional screening methods as an early-stage hormone receptor-positive tumor, thus the clinical benefit of intensive screening with MRI may be limited to a subset of women with germline CDH1 variants.
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Stage IA gastric adenocarcinoma, characterized by foci of intramucosal signet ring cells (SRC), is found in nearly all asymptomatic patients with germline pathogenic CDH1 variants and hereditary diffuse gastric cancer syndrome (HDGC). The molecular steps involved in initiating malignant transformation and promoting SRC dormancy in HDGC are unknown. Here, whole-exome bulk RNA sequencing (RNA-seq) of SRCs and adjacent non-SRC epithelium (NEP) was performed on laser-capture microdissected (LCM) regions of interest found in risk-reducing total gastrectomy specimens from patients with HDGC (Clinicaltrials.gov ID: NCT03030404). In total, 20 patients (6 male, 14 female) with confirmed HDGC were identified. Analysis of differentially expressed genes (DEG) demonstrated upregulation of certain individual EMT and proliferation genes. However, no oncogenic pathways were found to be upregulated in SRCs. Rather, SRC regions had significant enrichment in pathways involved in T-cell signaling. CIBERSORTx predicted significant increases in the presence of regulatory T cells (Treg) specific to SRC regions. IHC confirmed an increase in FOXP3+ cells in SRC foci, as well as elevations in CD4+ T cells and HLA-DR staining. In summary, the tumor immune microenvironment is microscopically inseparable from stage IA gastric SRCs using a granular isolation technique. An elevation in CD4+ T cells within SRC regions correlates with clinically observed SRC dormancy, while Treg upregulation represents a potential immune escape mechanism. IMPLICATIONS: Characterization of the tumor-immune microenvironment in HDGC underscores the potential for the immune system to shape the transcriptional profile of the earliest tumors, which suggests immune-directed therapy as a potential cancer interception strategy in diffuse-type gastric cancer.
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Adenocarcinoma , Carcinoma de Células en Anillo de Sello , Neoplasias Gástricas , Humanos , Masculino , Femenino , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Predisposición Genética a la Enfermedad , Gastrectomía , Mutación de Línea Germinal , Carcinogénesis/genética , Carcinoma de Células en Anillo de Sello/genética , Carcinoma de Células en Anillo de Sello/patología , Carcinoma de Células en Anillo de Sello/cirugía , Cadherinas/genética , Microambiente Tumoral , Antígenos CDRESUMEN
Inactivating germline variants in the CDH1 tumor suppressor gene cause the hereditary diffuse gastric cancer syndrome. Total gastrectomy is recommended for prevention, although it is associated with adverse outcomes and chronic health risks. Gastric cancer surveillance is an alternative to surgery; however, upper gastrointestinal endoscopy is limited by poor sensitivity. Cancer surveillance requires accurate detection of early carcinoma and patient-specific disease penetrance estimates. Current clinical care should incorporate up-to-date information on variable disease penetrance, which does not seem to correlate with CDH1 genotype. Affected patients and families warrant a balanced presentation of options for cancer surveillance and prophylaxis.
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Adenocarcinoma , Neoplasias Gástricas , Endoscopía del Sistema Digestivo , Gastrectomía , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirugíaRESUMEN
Pathogenic and likely pathogenic (P/LP) germline variants in the tumor suppressor gene CDH1 (E-cadherin) result in increased lifetime risk of diffuse-type gastric cancer and lobular breast cancer. CDH1 variants are also associated with hereditary cleft lip and palate (CLP), the mechanism of which is not well understood. We sought to determine the prevalence of CLP in families who carry P/LP CDH1 variants. Patients with P/LP CDH1 variants who were enrolled in a prospective clinical trial were reviewed (NCT03030404). The cohort included 299 individuals from 153 families that had 80 unique P/LP variants in CDH1. The rate of CLP was 19% (29/153) in families reporting CLP in at least one family member, and 2.7% (8/299) among individuals with confirmed germline CDH1 P/LP variants. There were 22 unique variants in CDH1 among the 29 families that reported CLP, or a CLP rate of 27.5% per variant (22/80). 10 of the variants were not previously reported to be associated with CLP. We observed that 24% (7/29) of CLP-associated gene variants involved large-scale (≥1 exon) deletions. Among families with CLP, 69% (20/29) had a member diagnosed with gastric cancer, and 79% (23/29) had a member with breast cancer, which were similar to rates observed in non-CLP families (p >0.3 for both). Our analysis suggests that the prevalence of CLP in families with germline CDH1 P/LP variants was high in this large cohort, and there was no genotype-phenotype pattern. Genetic testing for CDH1 variants should be considered in families with CLP and history of either diffuse-type gastric or lobular breast cancer.
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Importance: Hereditary cancer risk is informed by the presence of a germline gene variant more so than by family history of cancer. Objective: To assess gastric cancer risk among patients who received a diagnosis of hereditary lobular breast cancer (HLBC) owing to a germline loss-of-function variant in CDH1 by establishing prevalence of signet ring cell carcinomas among asymptomatic patients. Design, Setting, and Participants: A prospective cohort study of patients with germline CDH1 pathogenic or likely pathogenic (P/LP) variants at a quaternary medical center were enrolled between October 2017 and January 2021. Data analysis was performed in May 2021. Analyses for associations were performed for these 3 patient groups: (1) family history of breast cancer and no gastric cancer in the HLBC group; (2) family history of gastric cancer and no breast cancer in the hereditary diffuse gastric cancer (HDGC) group; and (3) family history of both breast and gastric cancers in the mixed group. Categorical variables were compared using the Pearson χ2 test. Main Outcomes and Measures: The primary end point of this study was the prevalence of occult signet ring cell carcinoma of the stomach in patients with HLBC. Personal and family medical history, genotype, and pathologic data from risk-reducing total gastrectomy and surveillance endoscopy were examined. Results: A total of 283 patients with CDH1 P/LP variants (199 [70.3%] were female, and 259 [91.5%] were White; median age, 48 years [range, 18-81 years]) were enrolled in a prospective study of HDGC. The cohort consisted of 151 families. Patients were categorized according to family history of breast and/or gastric cancer: HLBC 15.5% [44 of 283 patients]), HDGC (16.2% [46 of 283 patients]), and mixed (68.2% [193 of 283 patients]). The HLBC group included 31 distinct families with 19 CDH1 variants; 10 of those variants were also present in the HDGC and mixed groups (52.6% [10 of 19 variants]). Nearly all of the patients with HLBC (93.8% [15 of 16 variants]) who elected for risk-reducing total gastrectomy owing to their underlying CDH1 P/LP variant harbored occult signet ring cell gastric adenocarcinoma on final pathology (median age, 50 years [range, 21-67 years]). The prevalence of occult gastric cancer among asymptomatic patients in the HDGC group was similar (94.7% [18 of 19 of variants]; P = .98). Conclusions and Relevance: Carriers of CDH1 P/LP variants with no family history of gastric cancer exhibited high rates of occult signet ring cell gastric cancer. Germline CDH1 P/LP variants appear to have a highly penetrant gastric phenotype irrespective of family history. These data may prove useful for counseling families with CDH1 variants presumed to have HLBC.
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Antígenos CD/genética , Neoplasias de la Mama/genética , Cadherinas/genética , Carcinoma Lobular/genética , Carcinoma de Células en Anillo de Sello/genética , Neoplasias Gástricas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Consejo , Femenino , Mutación de Línea Germinal , Humanos , Mutación con Pérdida de Función , Persona de Mediana Edad , Estudios Prospectivos , Medición de RiesgoRESUMEN
Importance: Inherited variants in the tumor suppressor gene CDH1 are associated with an increased risk of gastric and breast cancers. This review aims to address the most current topics in management of the hereditary diffuse gastric cancer syndrome attributed to CDH1. Observations: Consensus management guidelines have broadened genetic testing criteria for CDH1. Prophylactic total gastrectomy is recommended for any pathogenic or likely pathogenic CDH1 variant carrier starting at the age of 20 years. Annual surveillance endoscopy is recommended to those who defer prophylactic total gastrectomy. Women with a CDH1 variant should initiate magnetic resonance imaging breast surveillance starting at age 30 years. Further research is needed to understand the pathogenesis of early-stage gastric cancers (T1a), which are pathognomonic of hereditary diffuse gastric cancer syndrome, that lead to advanced gastric cancer to develop both treatment and prevention strategies for this patient population. Conclusions and Relevance: The heritable CDH1 gene mutation is of importance to today's surgeons because it is associated with a substantial increased risk of developing both gastric and breast cancers. Management of this cancer syndrome currently uses prophylactic surgery and enhanced cancer surveillance strategies.
Asunto(s)
Antígenos CD/genética , Cadherinas/genética , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Gástricas/genética , Predisposición Genética a la Enfermedad , Humanos , Síndromes Neoplásicos Hereditarios/cirugía , Neoplasias Gástricas/cirugíaRESUMEN
BACKGROUND: Hereditary diffuse gastric cancer syndrome, attributed to inactivating germline CDH1 variants, is associated with an elevated lifetime risk of gastric cancer. We sought to evaluate cancer detection using probe-based confocal laser endomicroscopy (pCLE) during endoscopic surveillance. METHODS: A prospective, single-institution study was conducted in asymptomatic adults with pathogenic or likely pathogenic (P/LP) CDH1 variants. Subjects received endoscopic gastric surveillance using pCLE in conjunction with the Cambridge method (CM). Abnormalities visualized by pCLE were biopsied, followed by non-targeted mucosal biopsies according to the CM. Primary endpoint was to determine pCLE sensitivity for detection of occult SRC carcinoma compared to CM. RESULTS: Thirty-six patients with P/LP CDH1 variants underwent endoscopy using pCLE and CM. Majority were female (75%) with median age 47 years. Targeted biopsies of focal abnormalities on WLE were negative for carcinoma. Overall, 19.4% (7/36) patients had SRC detected on ≥1 biopsy. Non-targeted CM biopsies revealed SRC in 11.1% (4/36), whereas pCLE revealed SRC in 16.7% (6/36). Fifteen patients underwent total gastrectomy; all 15 explants contained occult carcinoma. In those 15 patients, the false-negative SRC detection rates for pCLE and CM were 67% and 87%, respectively. CONCLUSIONS: Confocal endomicroscopy alone has low sensitivity for occult cancer detection in CDH1 variant carriers, although it appeared no worse than the current recommended method and required fewer biopsies per patient. A more reliable endoscopic surveillance is needed as a viable alternative to surgery in this high-risk population (ClinicalTrials.gov, Number: NCT03648879).
RESUMEN
Operable gastrointestinal cancers continue to pose significant challenges. Radical resections are rarely curative, and chemotherapy is able to reduce tumor recurrence for only a small percentage of patients. Despite the obvious advantages of extirpation of the identifiable tumor(s), the inflammatory milieu that accompanies surgery and the obligate time off cytotoxic agents allows for activation of remote quiescent disseminated tumor cells, leading to metastatic recurrence. We are conducting a study to determine the safety and efficacy of immediate peri-operative MVT-5873, a cytotoxic monoclonal antibody targeting carbohydrate antigen 19-9 (CA 19-9), in patients undergoing resections pancreatic cancer, cholangiocarcinoma or metastatic colorectal cancer to the liver. Eligible patients will receive a single dose of MVT-5873 three days before resection and four post-operative infusions, before beginning standard adjuvant regimens. MVT-5873 is a human IgG1 antibody isolated from a patient following immunization with a sLea-KLH vaccine. MVT-5873 demonstrated cell surface binding in sLea positive human tumor lines and has been shown to be potent in complement-dependent cytotoxicity assays and antibody-dependent cell mediated cytotoxicity assays. In patients with metastatic CA 19-9 producing pancreatic adenocarcinoma, MVT-5873 treatment has been shown to decrease serum CA 19-9 levels and prevent tumor progression. The use of perioperative MVT-5873 has the potential to reduce recurrence rates and prolong survival after resection. This trial may open the door for investigation of additional and/or synergistic agents in the immediate peri-operative period and usher in a new paradigm in the management of surgically treated cancers. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03801915?term=MVT&rank=3.