Cell division-dependent dissemination following E-cadherin loss underlies initiation of diffuse-type gastric cancer.

Loss of the cell-cell adhesion protein E-cadherin underlies the development of diffuse-type gastric cancer (DGC), which is characterized by the gradual accumulation of tumor cells originating from the gastric epithelium in the surrounding stroma. How E-cadherin deficiency drives DGC formation remains elusive. Therefore, we investigated the consequences of E-cadherin loss on gastric epithelial organization utilizing a human gastric organoid model and histological analyses of early-stage DGC lesions. E-cadherin depletion from gastric organoids recapitulates DGC initiation, with progressive loss of a single-layered architecture and detachment of individual cells. We found that E-cadherin deficiency in gastric epithelia does not lead to a general loss of epithelial cohesion but disrupts the spindle orientation machinery. This leads to a loss of planar cell division orientation and, consequently, daughter cells are positioned outside of the gastric epithelial layer. Although basally delaminated cells fail to detach and instead reintegrate into the epithelium, apically mispositioned daughter cells can trigger the gradual loss of the single-layered epithelial architecture. This impaired architecture hampers reintegration of mispositioned daughter cells and enables basally delaminated cells to disseminate into the surrounding matrix. Taken together, our findings describe how E-cadherin deficiency disrupts gastric epithelial architecture through displacement of dividing cells and provide new insights in the onset of DGC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Referral rate of patients with incidental gallbladder cancer and survival: outcomes of a multicentre retrospective study.

BACKGROUND: Treatment outcomes of incidental gallbladder cancer generally stem from tertiary referral centres, while many patients are initially diagnosed and managed in secondary care centres. Referral patterns of patients with incidental gallbladder cancer are poorly reported. This study aimed to evaluate incidental gallbladder cancer treatment in secondary centres, rates of referral to tertiary centres and its impact on survival. METHODS: Medical records of patients with incidental gallbladder cancer diagnosed between 2000 and 2019 in 27 Dutch secondary centres were retrospectively reviewed. Patient characteristics, surgical treatment, tumour characteristics, referral pattern and survival were assessed. Predictors for overall survival were determined using multivariable Cox regression. RESULTS: In total, 382 patients with incidental gallbladder cancer were included. Of 243 patients eligible for re-resection (pT1b-pT3, M0), 131 (53.9%) were referred to a tertiary centre. The reason not to refer, despite indication for re-resection, was not documented for 52 of 112 non-referred patients (46.4%). In total, 98 patients underwent additional surgery with curative intent (40.3%), 12 of these in the secondary centre. Median overall survival was 33 months (95% c.i. 24 to 42 months) in referred patients versus 17 months (95% c.i. 3 to 31 months) in the non-referred group (P = 0.019). Referral to a tertiary centre was independently associated with improved survival after correction for age, ASA classification, tumour stage and resection margin (HR 0.60, 95% c.i. 0.38 to 0.97; P = 0.037). CONCLUSION: Poor incidental gallbladder cancer referral rates were associated with worse survival. Age, performance status, resection margin or tumour stage should not preclude referral of a patient with incidental gallbladder cancer to a tertiary centre.

Biological background of colorectal polyps and carcinomas with heterotopic ossification: A national study and literature review.

The biological mechanisms and potential clinical impact of heterotopic ossification (HO) in colorectal neoplasms are not fully understood. This study investigates the clinicopathological characteristics of colorectal neoplasms associated with HO and examines the potential role of the bone morphogenetic protein (BMP) pathway in development of HO. An artificial intelligence (AI) based classification of colorectal cancers (CRC) exhibiting HO and their association with consensus molecular subtypes (CMS) is performed. The study included 77 cases via the Dutch nationwide Pathology databank. Immunohistochemistry for BMP2, SMAD4, and Osterix was performed. An AI algorithm assessed the tumour-stroma ratio to approximate the CMS. A literature search yielded 96 case reports, which were analysed and compared with our cases for clinicopathological parameters. HO was more frequently observed in our cohort in traditional serrated adenomas (25%), tubulovillous adenomas (25%) and juvenile polyps (25%), while in the literature it was most often seen in juvenile polyps (38.2%) and inflammatory polyps (29.4%). In both cohorts, carcinomas were mostly conventional (>60%) followed by mucinous and serrated adenocarcinomas. Higher expression of BMP2, SMAD4, and Osterix was observed in tumour and/or stromal cells directly surrounding bone, indicating activation of the BMP pathway. The tumour-stroma analysis appointed >50% of the cases to the mesenchymal subtype (CMS4) (59%). HO has a predilection for serrated and juvenile/inflammatory polyps, mucinous and serrated adenocarcinomas. BMP signalling is activated and seems to play a role in formation of HO in colorectal neoplasms. In line with TGFß/BMP pathway activation associated with CMS4 CRC, HO seems associated with CMS4.

The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2.

PURPOSE: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies. METHODS: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291). RESULTS: In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins. CONCLUSION: Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.

Lymph node regression after neoadjuvant chemoradiotherapy in rectal cancer.

AIMS: Lymph node metastases (LNM) are one of the most important prognostic indicators in solid tumours and a major component of cancer staging. Neoadjuvant therapy might influence nodal status by induction of regression. Our aim is to determine the prevalence and role of regression of LNM on outcomes in patients with rectal cancer. METHODS AND RESULTS: Four independent study populations of rectal cancer patients treated with similar regimens of chemoradiotherapy were pooled together to obtain a total cohort of 469 patients. Post-treatment nodal status (ypN) and signs of tumour regression (Reg) were incorporated to form three-tiered (ypN- Reg+, ypN- Reg- and ypN+) and four-tiered (ypN- Reg+, ypN- Reg-, ypN+ Reg+ and ypN+ Reg-) classifications. In our cohort, 31% of patients presented with ypN+ rectal cancer. As expected, we found significantly worse overall survival (OS) in ypN+ patients compared to ypN- patients (P = 0.002). The percentage of ypN- patients with lymph nodes with complete regression was 20% in our cohort. While node-negative patients with and without regression had similar OS (P = 0.09), disease-free survival (DFS) was significantly better in node-negative patients with regression (P = 0.009). CONCLUSIONS: Regression in lymph nodes is frequent, and node-negative patients with evidence of lymph node regression have better DFS compared to node-negative patients without such evidence.

Deficient mismatch repair screening of advanced adenomas in the population screening program for colorectal cancer is not effective.

AIM: Currently, screening of colorectal cancers (CRC) by assessing mismatch repair deficiency (dMMR) or microsatellite instability (MSI) is used to identify Lynch syndrome (LS) patients. Advanced adenomas are considered immediate precursor lesions of CRC. In this study we investigate the relevance of screening of advanced adenomas for LS in population screening. METHODS AND RESULTS: Advanced adenomas (n = 1572) were selected from the Dutch colorectal cancer population screening programme, based on one or more of the criteria: tubulovillous (n = 848, 54%) or villous adenoma (n = 118, 7.5%), diameter ≥ 1 cm (n = 1286, 82%) and/or high-grade dysplasia (n = 176, 11%). In 86 cases (5%), all three criteria were fulfilled at the same time. MMR-IHC and/or MSI analyses were performed on all cases. Only five advanced adenomas (0.3%) showed dMMR and MSI, including two cases with hypermethylation. In at least two patients a germline event was suspected based on allelic frequencies. No pathogenic explanation was found in the last case. CONCLUSION: Timely testing of precursor lesions would be preferable to detect new LS patients before CRC development. However, standard assessment of dMMR of advanced adenomas from the population screening is not effective.

The influence of Helicobacter pylori, proton pump inhibitor, and obesity on the gastric microbiome in relation to gastric cancer development.

Helicobacter pylori infection is still the main risk factor for the development of gastric cancer (GC). We explore the scientific evidence for the role of the gastric microbiome beyond Helicobacter pylori (H. pylori) in gastric carcinogenesis. The composition of the gastric microbiome in healthy individuals, in presence and absence of H. pylori infection, in proton pump inhibitor (PPI)-users, obese individuals, and GC patients was investigated. Possible mechanisms for microbial involvement, limitations of available research and options for future studies are provided. A common finding amongst studies was increased levels of Streptococcus, Prevotella, Neisseria, and Actinomyces in healthy individuals or those with H. pylori-negative gastritis. In PPI-users the risk for GC increases with the treatment duration, and the gastric microbiome shifts, with the most consistent increase in the genus Streptococcus. Similarly, in obese individuals, Streptococcus was the most abundant genus, with an increased risk for cardia GC. The genera Streptococcus, Lactobacillus and Prevotella were found to be more prominent in GC patients in multiple studies. Potential mechanisms of non-H. pylori microbiota contributing to GC are linked to lipopolysaccharide production, contribution to inflammatory pathways, and the formation of N-nitroso compounds and reactive oxygen species. In conclusion, the knowledge of the gastric microbiome in GC is mainly descriptive and based on sequencing of gastric mucosal samples. For a better mechanistic understanding of microbes in GC development, longitudinal cohorts including precancerous lesions, different regions in the stomach, and subtypes of GC, and gastric organoid models for diffuse and intestinal type GC should be employed.

Multimodal Therapy Versus Primary Surgery for Gastric and Gastroesophageal Junction Diffuse Type Carcinoma, with a Focus on Signet Ring Cell Carcinoma: A Nationwide Study.

BACKGROUND: Diffuse type adenocarcinoma and, more specifically, signet ring cell carcinoma (SRCC) of the stomach and gastroesophageal junction (GEJ) have a poor prognosis and the value of neoadjuvant chemo(radio)therapy (nCRT) is unclear. METHODS: All patients who underwent surgery for diffuse type gastric and GEJ carcinoma between 2004 and 2015 were retrospectively included from the Netherlands Cancer Registry. The primary outcome was overall survival after surgery. Kaplan-Meier curves were plotted. Furthermore, multivariable Poisson and Cox regressions were performed, correcting for confounders. To comply with the Cox regression proportional hazard assumption, gastric cancer survival was split into two groups, i.e. <90 days and >90 days, postoperatively by adding an interaction variable. RESULTS: Analyses included 2046 patients with diffuse type cancer: 1728 gastric cancers (50% SRCC) and 318 GEJ cancers (39% SRCC). In the gastric cancer group, 49% received neoadjuvant chemotherapy (nCT) and 51% received primary surgery (PS). All-cause mortality within 90 days postoperatively was lower after nCT (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.20-0.44; p < 0.001). Also after 90 days, mortality was lower in the nCT group (HR for the interaction variable 2.84, 95% CI 1.87-4.30, p < 0.001; total HR 0.29*2.84 = 0.84). In the GEJ group, 38% received nCT, 22% received nCRT, and 39% received PS. All-cause mortality was lower after nCT (HR 0.63, 95% CI 0.43-0.93; p = 0.020) compared with PS. The nCRT group was removed from the Cox regression analysis since the Kaplan-Meier curves of nCRT and PS intersected. The results for gastric and GEJ carcinomas were similar between the SRCC and non-SRCC subgroups. CONCLUSION: For gastric and GEJ diffuse type cancer, including SRCC, nCT was associated with increased survival.

Relevance of shrinkage versus fragmented response patterns in rectal cancer.

AIMS: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome. METHODS AND RESULTS: The study included a test (n = 197) and a validation cohort (n = 218) of post-CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three-step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II-IV, 78% versus 35%; P < 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19-3.50, P = 0.008) and disease-free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23-5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS. CONCLUSIONS: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response.

Clinicopathological and Molecular Insights into Gallbladder Cancer.

Although gallbladder cancer (GBC) is rare, it is one of the few cancers with a higher mortality rate than incidence, accounting for 1 [...].

Microsatellite instability in noncolorectal and nonendometrial malignancies in patients with Lynch syndrome.

BACKGROUND: Individuals with Lynch syndrome are at increased hereditary risk of colorectal and endometrial carcinomas with microsatellite instability (MSI-H) and mismatch repair-deficiency (dMMR), which make these tumors vulnerable to therapy with immune checkpoint inhibitors. Our aim is to assess how often other tumor types in these individuals share these characteristics. METHODS: We retrieved the full tumor history of a historical clinic-based cohort of 1745 individuals with Lynch syndrome and calculated the standardized incidence ratio for all tumor types. MSI status, somatic second hit alterations, and immunohistochemistry-based MMR status were analyzed in 236 noncolorectal and nonendometrial malignant tumors. RESULTS: In individuals with Lynch syndrome MSI-H/dMMR occurred both in Lynch-spectrum and in non-Lynch-spectrum malignancies (85% vs 37%, P < .01). MSI-H/dMMR malignancies were found in nearly all non-Lynch-spectrum tumor types. Almost all breast carcinomas had medullary features, and most of them were MSI-H/dMMR. Breast carcinoma with medullary features were shown to be associated with Lynch syndrome (standardized incidence ratio = 38.8, 95% confidence interval = 16.7 to 76.5). CONCLUSIONS: In individuals with Lynch syndrome, MSI-H/dMMR occurs in more than one-half of the malignancies other than colorectal and endometrial carcinomas, including tumor types without increased incidence. The Lynch-spectrum tumors should be expanded to breast carcinomas with medullary features. All malignancies in patients with Lynch syndrome, independent of subtype, should be tested for MSI-H/dMMR in case therapy with immune checkpoint inhibitors is considered. Moreover, Lynch syndrome should be considered an underlying cause of all MSI-H/dMMR malignancies other than colorectal and endometrial carcinomas.

The effectiveness of neoadjuvant chemoradiotherapy in oesophageal adenocarcinoma with presence of extracellular mucin, signet-ring cells, and/or poorly cohesive cells.

Oesophageal adenocarcinomas may show different histopathological patterns, including excessive acellular mucin pools, signet-ring cells (SRCs), and poorly cohesive cells (PCCs). These components have been suggested to correlate with poor outcomes after neoadjuvant chemoradiotherapy (nCRT), which might influence patient management. However, these factors have not been studied independently of each other with adjustment for tumour differentiation grade (i.e. the presence of well-formed glands), which is a possible confounder. We studied the pre- and post-treatment presence of extracellular mucin, SRCs, and/or PCCs in relation to pathological response and prognosis after nCRT in patients with oesophageal or oesophagogastric junction adenocarcinoma. A total of 325 patients were retrospectively identified from institutional databases of two university hospitals. All patients were scheduled for ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) nCRT and oesophagectomy between 2001 and 2019. Percentages of well-formed glands, extracellular mucin, SRCs, and PCCs were scored in pre-treatment biopsies and post-treatment resection specimens. The association between histopathological factors (≥1 and >10%) and tumour regression grade 3-4 (i.e. >10% residual tumour), overall survival, and disease-free survival (DFS) was evaluated, adjusted for tumour differentiation grade amongst other clinicopathological variables. In pre-treatment biopsies, ≥1% extracellular mucin was present in 66 of 325 patients (20%); ≥1% SRCs in 43 of 325 (13%), and ≥1% PCCs in 126 of 325 (39%). We show that pre-treatment histopathological factors were unrelated to tumour regression grade. Pre-treatment presence of >10% PCCs was associated with lower DFS (hazard ratio [HR] 1.73, 95% CI 1.19-2.53). Patients with post-treatment presence of ≥1% SRCs had higher risk of death (HR 1.81, 95% CI 1.10-2.99). In conclusion, pre-treatment presence of extracellular mucin, SRCs, and/or PCCs is unrelated to pathological response. The presence of these factors should not be an argument to refrain from CROSS. At least 10% PCCs pre-treatment and any SRCs post-treatment, irrespective of the tumour differentiation grade, seem indicative of inferior prognosis, but require further validation in larger cohorts.

Circulating tumor DNA detection after neoadjuvant treatment and surgery predicts recurrence in patients with early-stage and locally advanced rectal cancer.

INTRODUCTION: Patients with early-stage and locally advanced rectal cancer are often treated with neoadjuvant therapy followed by surgery or watch and wait. This study evaluated the role of circulating tumor DNA (ctDNA) to measure disease after neoadjuvant treatment and surgery to optimize treatment choices. MATERIALS AND METHODS: Patients with rectal cancer treated with both chemotherapy and radiotherapy were included and diagnostic biopsies were analyzed for tumor-specific mutations. Presence of ctDNA was measured in plasma by tracing the tumor-informed mutations using a next-generation sequencing panel. The association between ctDNA detection and clinicopathological characteristics and progression-free survival was measured. RESULTS: Before treatment ctDNA was detected in 69% (35/51) of patients. After neoadjuvant therapy ctDNA was detected in only 15% (5/34) of patients. In none of the patients with a complete clinical response who were selected for a watch and wait strategy (0/10) or patients with ypN0 disease (0/8) ctDNA was detected, whereas it was detected in 31% (5/16) of patients with ypN + disease. After surgery ctDNA was detected in 16% (3/19) of patients, of which all (3/3) developed recurrent disease compared to only 13% (2/16) in patients with undetected ctDNA after surgery. In an exploratory survival analysis, both ctDNA detection after neoadjuvant therapy and after surgery was associated with worse progression-free survival (p = 0.01 and p = 0.007, respectively, Cox-regression). CONCLUSION: These data show that in patients with early-stage and locally advanced rectal cancer tumor-informed ctDNA detection in plasma using ultradeep sequencing may have clinical value to complement response prediction after neoadjuvant therapy and surgery.

Clinical Validity of Tumor-Informed Circulating Tumor DNA Analysis in Patients Undergoing Surgery of Colorectal Metastases.

BACKGROUND: Accurate biomarkers to monitor tumor load and response in metastatic colorectal cancer patients undergoing surgery could optimize treatment regimens. OBJECTIVE: This study aimed to explore the clinical validity of tumor-informed quantification of circulating tumor DNA in blood using ultradeep sequencing. DESIGN: Resection specimens from 53 colorectal cancer patients were analyzed for tumor-specific mutations in 15 genes. These mutations were used to measure the presence of circulating tumor DNA in preoperatively collected plasma samples using hybrid capture-based sequencing. Additional postoperative measurements were performed 1 week after surgery in 16 patients. SETTINGS: The study was conducted at the Radboud University Medical Center. PATIENTS: A total of 53 colorectal cancer patients undergoing surgery of metastases were included. MAIN OUTCOME MEASURES: The detection of circulating tumor DNA. RESULTS: At least 1 tumor-specific mutation was detected in all tumor samples. In preoperative plasma samples, circulating tumor DNA was detected in 88% (37/42) of systemic treatment-naïve patients and in 55% (6/11) of patients who received preoperative chemotherapy. More specifically, circulating tumor DNA was detected in 0% (0/3) of cases with a subtotal or partial pathologic response and in 75% (6/8) of cases without a pathologic response in the resection specimen ( p = 0.06). In postoperative plasma samples, circulating tumor DNA was detected in 80% (4/5) of patients with an incomplete resection and in 0% (0/11) of those with a complete resection ( p = 0.003). LIMITATIONS: The study was limited by the heterogeneity of the cohort and the small number of postoperative plasma samples. CONCLUSIONS: These data indicate that tumor-informed circulating tumor DNA detection in the plasma of patients undergoing surgery for metastatic colorectal cancer is feasible and may have clinical value in response monitoring and predicting residual disease. Prospective studies are needed to establish the clinical utility of circulating tumor DNA analysis to guide treatment decisions in these patients. See Video Abstract at http://links.lww.com/DCR/B990 . VALIDEZ CLNICA DEL ANLISIS DE ADN DEL TUMOR CIRCULANTE INFORMADO POR EL TUMOR EN PACIENTES SOMETIDOS A CIRUGA DE METSTASIS COLORRECTALES: ANTECEDENTES:Los biomarcadores precisos para monitorear la carga tumoral y la respuesta en pacientes con cáncer colorrectal metastásico que se someten a cirugía podrían optimizar los regímenes de tratamiento.OBJETIVO:Este estudio explora la validez clínica de la cuantificación informada por el tumor del ADN tumoral circulante en sangre mediante secuenciación ultraprofunda.DISEÑO:Se analizaron muestras de resección de 53 pacientes con cáncer colorrectal en busca de mutaciones específicas del tumor en quince genes. Estas mutaciones se usaron para medir la presencia de ADN tumoral circulante en muestras de plasma recolectadas antes de la operación usando secuenciación basada en captura híbrida. Se realizaron mediciones postoperatorias adicionales una semana después de la cirugía en dieciséis pacientes.AJUSTES:El estudio se realizó en el centro médico de la universidad de Radboud.PACIENTES:Se incluyeron un total de 53 pacientes con cáncer colorrectal sometidos a cirugía de metástasis.PRINCIPALES MEDIDAS DE RESULTADO:La detección de ADN tumoral circulante.RESULTADOS:Se detectó al menos una mutación específica de tumor en todas las muestras de tumor. En muestras de plasma preoperatorias, se detectó ADN tumoral circulante en el 88% (37/42) de los pacientes sin tratamiento sistémico previo y en el 55% (6/11) de los pacientes que recibieron quimioterapia preoperatoria. Más concretamente, en el 0% (0/3) de los casos con respuesta patológica subtotal o parcial y en el 75% (6/8) de los casos sin respuesta patológica en la pieza de resección ( p = 0,06). En muestras de plasma postoperatorio se detectó ADN tumoral circulante en el 80% (4/5) de los pacientes con una resección incompleta y en el 0% (0/11) de los que tenían resección completa ( p = 0,003).LIMITACIONES:El estudio estuvo limitado por la heterogeneidad de la cohorte y el pequeño número de muestras de plasma postoperatorias.CONCLUSIONES:Estos datos indican que la detección de ADN tumoral circulante informado por el tumor en el plasma de pacientes sometidos a cirugía por cáncer colorrectal metastásico es factible y puede tener valor clínico en el control de la respuesta y la predicción de la enfermedad residual. Se necesitan estudios prospectivos para establecer la utilidad clínica del análisis de ADN tumoral circulante para guiar las decisiones de tratamiento en estos pacientes. Consulte Video Resumen en http://links.lww.com/DCR/B990 . (Traducción-Dr. Mauricio Santamaria ).

Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome.

BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. METHODS: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. RESULTS: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. CONCLUSIONS: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.

Comprehensive clinicopathological and genomic profiling of gallbladder cancer reveals actionable targets in half of patients.

Gallbladder cancer (GBC) is a rare, highly aggressive malignancy with a 5-year survival rate of 5-10% in advanced cases, highlighting the need for more effective therapies. The aim of this study was to identify potentially actionable therapeutic targets for GBC. Specimens and clinicopathological data of 642 GBC patients, diagnosed between 2000 and 2019 were collected using the Dutch Pathology Registry (PALGA) and the Netherlands Cancer Registry. All cases were histologically reviewed and a subset was subjected to a comprehensive next generation sequencing panel. We assessed mutations and gene amplifications in a panel of 54 actionable genes, tumor-mutational burden (TMB), and microsatellite instability (MSI). Additionally, the entire cohort was screened for HER2, PD-L1, pan-TRK, and p53 expression with immunohistochemistry. Histopathological subtypes comprised biliary-type adenocarcinoma (AC, 69.6%), intestinal-type AC (20.1%) and other subtypes (10.3%). The median total TMB was 5.5 mutations/Mb (range: 0-161.1) and 17.7% of evaluable cases had a TMB of >10 mutations/Mb. MSI was observed in two cases. Apart from mutations in TP53 (64%), tumors were molecularly highly heterogeneous. Half of the tumors (50%) carried at least one molecular alteration that is targetable in other tumor types, including alterations in CDKN2A (6.0% biallelically inactivated), ERBB2 (9.3%) and PIK3CA (10%). Immunohistochemistry results correlated well with NGS results for HER2 and p53: Pearson r = 0.82 and 0.83, respectively. As half of GBC patients carry at least one potentially actionable molecular alteration, molecular testing may open the way to explore targeted therapy options for GBC patients.

Circulating Tumor DNA-Based Disease Monitoring of Patients with Locally Advanced Esophageal Cancer.

Patients diagnosed with locally advanced esophageal cancer are often treated with neoadjuvant chemoradiotherapy followed by surgery. This study explored whether detection of circulating tumor DNA (ctDNA) in plasma can be used to predict residual disease during treatment. Diagnostic tissue biopsies from patients with esophageal cancer receiving neoadjuvant chemoradiotherapy and surgery were analyzed for tumor-specific mutations. These tumor-informed mutations were used to measure the presence of ctDNA in serially collected plasma samples using hybrid capture-based sequencing. Plasma samples were obtained before chemoradiotherapy, and prior to surgery. The association between ctDNA detection and progression-free and overall survival was measured. Before chemoradiotherapy, ctDNA was detected in 56% (44/78) of patients and detection was associated with tumor stage and volume (p = 0.05, Fisher exact and p = 0.02, Mann-Whitney, respectively). After chemoradiotherapy, ctDNA was detected in 10% (8/78) of patients. This preoperative detection of ctDNA was independently associated with recurrent disease (hazard ratio 2.8, 95% confidence interval 1.1-6.8, p = 0.03, multivariable Cox-regression) and worse overall survival (hazard ratio 2.9, 95% confidence interval 1.2-7.1, p = 0.02, multivariable Cox-regression).Ultradeep sequencing-based detection of ctDNA in preoperative plasma of patients with locally advanced esophageal cancer may help to assess which patients have a high risk of recurrence after neoadjuvant chemoradiotherapy and surgery.

Detection and Yield of Colorectal Cancer Surveillance in Adults with PTEN Hamartoma Tumour Syndrome.

Colorectal cancer surveillance (CCS) with colonoscopy every five years is advised for PTEN Hamartoma Tumour Syndrome (PHTS) patients aged ≥40 due to an increased colorectal cancer (CRC) risk. However, data to support CCS guidelines are scarce and available CRC risks are low (0-5% at age 50) and likely overestimated. We aimed to assess the detection and yield of CCS for PHTS patients without a CRC history. A retrospective cohort study including PHTS patients aged ≥40 with CCS at a PHTS expertise centre between 2011 and 2022. Adenomas with a ≥10 mm size, (tubulo)villous histology, or high-grade dysplasia were considered advanced. During 67 follow-up years, 37 patients (median age 47 years) underwent 61 colonoscopies. CCS yielded no CRCs. Adenomas were diagnosed in 13/37 (35%) patients during 23/100 colonoscopies (95% CI: 14-36), including one advanced adenoma. Baseline adenoma detection rates were similar to follow-up and higher in patients aged above 50 (50/100, 95% CI: 24-76) vs. age 50 or below (11/100, 95% CI: 3-30; p = 0.021). The low CRC and advanced adenoma yield allow for a more personalised surveillance program. Following our findings combined with literature on CRC risk and progression, we suggest starting CCS at age 40 with variable follow-up intervals between 1 and 10 years depending on previous colonoscopy findings.

Bite-on-bite biopsies for the detection of residual esophageal cancer after neoadjuvant chemoradiotherapy.

BACKGROUND: Active surveillance after neoadjuvant treatment is increasingly implemented. The success of this strategy relies on the accurate detection of residual cancer. This study aimed to assess the diagnostic value of a second (bite-on-bite) biopsy for the detection of residual esophageal cancer and to correlate outcomes to the distribution of residual cancer found in the resection specimen. METHODS: A multicenter prospective study of esophageal cancer patients undergoing active surveillance after neoadjuvant chemoradiotherapy was performed. At clinical response evaluations, an upper gastrointestinal (GI) endoscopy was performed with at least four bite-on-bite biopsies of the primary tumor site. First and second biopsies were analyzed separately. Patients with histopathological evidence of residual cancer were included in the primary analysis. Two pathologists blinded for biopsy outcome examined all resection specimens. RESULTS: Between October 2017 and July 2020, 626 upper GI endoscopies were performed in 367 patients. Of 138 patients with residual cancer, 112 patients (81 %) had at least one positive biopsy. In 14 patients (10 %) only the first biopsy was positive and in 25 patients (18 %) only the second biopsy (P = 0.11). Remarkably, the rates of patients with tumor-free mucosa and deeper located tumors were higher in patients detected by the first biopsy. The second biopsy increased the false-positive rate by 3 percentage points. No adverse events occurred. CONCLUSIONS: A second (bite-on-bite) biopsy improves the detection of residual esophageal cancer by almost 20 percentage points, at the expense of increasing the false-positive rate by 3 percentage points. The higher detection rate is explained by the higher number of biopsies obtained rather than by the penetration depth.