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The risk of developing gastric cancer is increased in patients treated with radiotherapy for Hodgkin lymphoma (HL) or testicular cancer (TC). This study aims to assess if gastric adenocarcinoma after treatment for HL/TC (t-GC) is molecularly different from gastric adenocarcinoma in the general population. Molecular subtyping of 90 t-GCs resulted in 3% EBV, 8% MSI, 36% sCIN and 53% sGS. 3/6 of MSI t-GCs had MLH1 promoter methylation and 2/6 were explained by double somatic mutations in MMR genes. T-GCs were more frequently sGS than p-GCs (53% vs. 38%, p = 0.04). T-GC was more frequently sGS in HL/TC patients diagnosed before 1990, than after 1990 (63% vs. 38%, p = 0.03). T-GCs located in the antrum, an area that receives high irradiation doses, were more frequently sGS (61% vs. 28% in p-GCs, p = 0.02). Our results demonstrate that t-GCs are more frequently of the sGS subtype than p-GCs. An association of t-GC of the sGS subtype with prior anticancer treatment is suggested by the high frequency in HL/TC patients who were treated before 1990, a time period in which HL/TC treatments were more extensive.

Hodgkin lymphoma (HL) survivors are at increased risk of developing second primary esophageal squamous cell cancer (ESCC). We aimed to gain insight in the driving events of ESCC in HL survivors (hESCC) by using RNA sequencing and NanoString profiling. Objectives were to investigate differences in RNA signaling between hESCC and sporadic ESCC (sESCC), and to look for early malignant changes in non-neoplastic esophageal tissue of HL survivors (hNN-tissue). We analyzed material of 26 hESCC cases, identified via the Dutch pathology registry (PALGA) and 17 sESCC cases from one academic institute and RNA sequencing data of 44 sESCC cases from TCGA. Gene expression profiles for the NanoString panel PanCancer IO 360 were obtained from 16/26 hESCC and four hNN-tissue, while non-neoplastic squamous tissue of four sporadic cases (sNN-tissue) served as reference profile. Hierarchical clustering, differential expression and pathway analyses were performed. Overall, the molecular profiles of hESCC and sESCC were similar. There was increased immune, HMGB1 and ILK signaling compared to sNN-tissue. The profiles of hNN-tissue were distinct from sNN-tissue, indicating early field effects in the esophagus of HL survivors. The BRCA1 pathway was upregulated in hESCC tissue, compared to hNN tissue. Analysis of expression profiles reveals overlap between hESCC and sESCC, and differences between hESCC and its surrounding hNN-tissue. Further research is required to validate our results and to investigate whether the changes observed in hNN-tissue are already detectable before development of hESCC. In the future, our findings could be used to improve hESCC patient management.

ObjectiveHodgkin's lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the development of therapy-related CRC (t-CRC) by evaluating histopathological and molecular characteristics.Design54 t-CRCs diagnosed in a Hodgkin's lymphoma survivor cohort were analysed for mismatch repair (MMR) proteins by immunohistochemistry, microsatellite instability (MSI) and KRAS/BRAF mutations. MSI t-CRCs were evaluated for promoter methylation and mutations in MMR genes. Pathogenicity of MMR gene mutations was evaluated by in silico predictions and functional analyses. Frequencies were compared with a general population cohort of CRC (n=1111).ResultsKRAS and BRAF mutations were present in 41% and 15% t-CRCs, respectively. Compared with CRCs in the general population, t-CRCs had a higher MSI frequency (24% vs 11%, p=0.003) and more frequent loss of MSH2/MSH6 staining (13% vs 1%, p<0.001). Loss of MLH1/PMS2 staining and MLH1 promoter methylation were equally common in t-CRCs and the general population. In MSI CRCs without MLH1 promoter methylation, double somatic MMR gene mutations (or loss of heterozygosity as second hit) were detected in 7/10 (70%) t-CRCs and 8/36 (22%) CRCs in the general population (p=0.008). These MMR gene mutations in t-CRCs were classified as pathogenic. MSI t-CRC cases could not be ascribed to Lynch syndrome.ConclusionsWe have demonstrated a higher frequency of MSI among t-CRCs, which results from somatic MMR gene mutations. This suggests a novel association of somatic MMR gene mutations with prior anticancer treatment.

Background Pathological complete remission (pCR) of estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer is rarely achieved after neoadjuvant chemotherapy (NAC). In addition, the prognostic value of pCR for this breast cancer subtype is limited. We explored whether response evaluation by magnetic resonance imaging (MRI) is associated with recurrence-free survival after NAC in ER-positive/HER2-negative breast cancer. Methods MRI examinations were performed in 272 women with ER-positive/HER2-negative breast cancer before, during and after NAC. MRI interpretation included lesion morphology at baseline, changes in morphology and size, and contrast uptake kinetics. These MRI features, clinical characteristics and final pathology were correlated with recurrence-free survival. Results The median follow up time was 41 months. There were 35 women with events, including 19 breast-cancer-related deaths. On multivariable analysis, age younger than 50 years (hazard ratio (HR) = 2.55, 95 % confidence interval (CI) 1.3, 5.02, p  = 0.007), radiological complete response after NAC (HR = 14.11, CI 1.81, 1818; p  = 0.006) and smaller diameters of washout/plateau enhancement at MRI after NAC (HR = 1.02, CI 1.00, 1.04, p  = 0.036) were independently associated with best recurrence-free survival. Pathological response was not significant; HR = 2.12, CI 0.86, 4.64, p  = 0.096. Conclusions MRI after NAC in ER-positive/HER2-negative tumors may be predictive of recurrence-free survival. A radiological complete response at MRI after NAC is associated with an excellent prognosis.

Background Response-guided neoadjuvant chemotherapy (RG-NACT) with magnetic resonance imaging (MRI) is effective in treating oestrogen receptor positive/human epidermal growth factor receptor-2 negative (ER-positive/HER2-negative) breast cancer. We estimated the expected cost-effectiveness and resources required for its implementation compared to conventional-NACT. Methods A Markov model compared costs, quality-adjusted-life-years (QALYs) and costs/QALY of RG-NACT vs. conventional-NACT, from a hospital perspective over a 5-year time horizon. Health services required for and health outcomes of implementation were estimated via resource modelling analysis, considering a current (4 %) and a full (100 %) implementation scenario. Results RG-NACT was expected to be more effective and less costly than conventional NACT in both implementation scenarios, with 94 % (current) and 95 % (full) certainty, at a willingness to pay threshold of €20.000/QALY. Fully implementing RG-NACT in the Dutch target population of 6306 patients requires additional 5335 MRI examinations and an (absolute) increase in the number of MRI technologists, by 3.6 fte (full-time equivalent), and of breast radiologists, by 0.4 fte. On the other hand, it prevents 9 additional relapses, 143 cancer deaths, 23 congestive heart failure events and 2 myelodysplastic syndrome/acute myeloid leukaemia events. Conclusion Considering cost-effectiveness, RG-NACT is expected to dominate conventional-NACT. While personnel capacity is likely to be sufficient for a full implementation scenario, MRI utilization needs to be intensified.

Background Second primary malignancies are a major cause of excess morbidity and mortality in cancer survivors. Hodgkin lymphoma survivors who were treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine have an increased risk to develop colorectal cancer. Colonoscopy surveillance plays an important role in colorectal cancer prevention by removal of the precursor lesions (adenomas) and early detection of cancer, resulting in improved survival rates. Therefore, Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine could benefit from colonoscopy, or other surveillance modalities, which are expected to reduce colorectal cancer incidence and mortality. Current knowledge on clinicopathological and molecular characteristics of therapy-related colorectal cancer is limited. The pathogenesis of such colorectal cancers might be different from the pathogenesis in the general population and therefore these patients might require a different clinical approach. We designed a study with the primary aim to assess the diagnostic yield of a first surveillance colonoscopy among Hodgkin lymphoma survivors at increased risk of colorectal cancer and to compare these results with different screening modalities in the general population. Secondary aims include assessment of the test characteristics of stool tests and evaluation of burden, acceptance and satisfaction of CRC surveillance through two questionnaires. Methods/Design This prospective multicenter cohort study will include Hodgkin lymphoma survivors who survived ≥8 years after treatment with infradiaphragmatic radiotherapy and/or procarbazine (planned inclusion of 259 participants). Study procedures will consist of a surveillance colonoscopy with removal of precursor lesions (adenomas) and 6–8 normal colonic tissue biopsies, a fecal immunochemical test and a stool DNA test. All neoplastic lesions encountered will be classified using relevant histomorphological, immunohistochemical and molecular analyses in order to obtain more insight into colorectal carcinogenesis in Hodgkin lymphoma survivors. The Miscan-model will be used for cost-effectiveness analyses. Discussion Evaluation of the diagnostic performance, patient acceptance and burden of colorectal cancer surveillance is necessary for future implementation of an individualized colorectal cancer surveillance program for Hodgkin lymphoma survivors. In addition, more insight into treatment-induced colorectal carcinogenesis will provide the first step towards prevention and personalized treatment. This information may be extrapolated to other groups of cancer survivors. Trial registration Registered at the Dutch Trial Registry (NTR): NTR4961 .

Background Hodgkin lymphoma (HL) survivors have an increased risk of gastrointestinal (GI) cancer. This study aims to evaluate whether survival of patients who survived HL and developed GI cancer differs from survival of first primary GI cancer patients. Methods Overall and cause‐specific survival of GI cancer patients in a HL survivor cohort (GI‐HL, N = 104, including esophageal, gastric, small intestinal, and colorectal cancer) was compared with survival of a first primary GI cancer patient cohort (GI‐1, N = 1025, generated by case matching based on tumor site, gender, age, and year of diagnosis). Cox proportional hazards regression was used for survival analyses. Multivariable analyses were adjusted for GI cancer stage, grade of differentiation, surgery, radiotherapy, and chemotherapy. Results GI‐HL cancers were diagnosed at a median age of 54 years (interquartile range 45‐60). No differences in tumor stage or frequency of surgery were found. GI‐HL patients less often received radiotherapy (8% vs 23% in GI‐1 patients, P < 0.001) and chemotherapy (28% vs 41%, P = 0.01) for their GI tumor. Compared with GI‐1 patients, overall and disease‐specific survival of GI‐HL patients was worse (univariable hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.03‐1.65, P = 0.03; and HR 1.29, 95% CI 1.00‐1.67, P = 0.049, respectively; multivariable HR 1.33, 95% CI 1.05‐1.68, P = 0.02; and HR 1.33, 95% CI 1.03‐1.72, P = 0.03, respectively). Conclusions Long‐term overall and disease‐specific survival of GI cancer in HL survivors is worse compared with first primary GI cancer patients. Differences in tumor stage, grade of differentiation, or treatment could not explain this worse survival. Hodgkin lymphoma (HL) survivors have an increased risk of gastrointestinal (GI) cancer. This study evaluated whether survival of a cohort of 104 patients who survived HL and developed GI cancer differs from survival of a large population‐based cohort of first primary GI cancer patients. Long‐term overall and disease‐specific survival of GI cancer in HL survivors is worse compared with first primary GI cancer patients and this could not be explained by differences in tumor stage, grade of differentiation, or treatment.

IntroductionThe risk of developing gastric cancer is increased in patients treated with radiotherapy for Hodgkin lymphoma (HL) or testicular cancer (TC). This study aims to assess if gastric adenocarcinoma after treatment for HL/TC (t-GC) is molecularly different from gastric adenocarcinoma in the general population.MethodsPatients were diagnosed with t-GC ≥5 years after treatment for HL/TC. Four molecular subtypes were identified using immunohistochemical and molecular analyses: Epstein-Barr virus (EBV), mismatch repair (MMR) deficiency or microsatellite instability (MSI), aberrant p53 staining as surrogate for chromosomal instability (sCIN), and a surrogate for genomic stability (sGS) without these aberrations. Results were compared with gastric cancer in the general population (p-GC) described in literature.ResultsMolecular subtyping of 90 t-GCs resulted in 3% EBV, 8% MSI, 36% sCIN and 53% sGS. 3/6 of MSI t-GCs had MLH1 promoter methylation and 2/6 were explained by double somatic mutations in MMR genes. T-GCs were more frequently sGS than p-GCs (53% vs. 38%, p = 0.04). T-GC was more frequently sGS in HL/TC patients diagnosed before 1990, than after 1990 (63% vs. 38%, p = 0.03). T-GCs located in the antrum, an area that receives high irradiation doses, were more frequently sGS (61% vs. 28% in p-GCs, p = 0.02).ConclusionOur results demonstrate that t-GCs are more frequently of the sGS subtype than p-GCs. An association of t-GC of the sGS subtype with prior anticancer treatment is suggested by the high frequency in HL/TC patients who were treated before 1990, a time period in which HL/TC treatments were more extensive.

Background In a large number of patients with multiple gastrointestinal adenomatous polyps, no causal germline mutation can be found. Non-genetic factors may contribute to the development of adenomatous polyps in these unexplained polyposis patients. In the development of gastrointestinal cancer, prior exposure to abdominal radiotherapy has been identified as such a factor, as it increases the gastrointestinal cancer risk in cancer survivors. A relationship of radiotherapy with intestinal polyposis, however, has not yet been described. Despite the increased cancer risk, these cancer survivors do not receive gastrointestinal screening recommendations. This case series describes three patients with adenomatous polyposis after abdominal radiotherapy. Case presentation Patient 1 was diagnosed with testicular cancer at the age of 31 and was treated with hemicastration, radiotherapy and chemotherapy. Thirty-nine years later, he was diagnosed with more than 30 colonic adenomas. Additionally, gastroduodenoscopy revealed a well-differentiated adenocarcinoma in the antrum of the stomach. Patient 2 was diagnosed with a nephroblastoma at the age of 10, which was resected and treated with radiotherapy and chemotherapy. At age 36, a rectal adenocarcinoma was diagnosed and treated by radiotherapy and a total mesorectal excision. During 11 years of surveillance endoscopies, 21 colonic adenomas and three duodenal adenomas were detected. Patient 3 was diagnosed with Hodgkin lymphoma at the age of 20 and treated with radiotherapy, followed by chemotherapy for a recurrence 3 years later. At age 62, a subtotal colectomy was performed because of colonic polyposis: 36 adenomas were detected. During screening gastro-duodenoscopy, three duodenal adenomas were detected. In all three patients, germline analysis did not reveal a mutation in the APC and MYH genes . The gastric and rectal cancer were both microsatellite stable. Conclusion This report describes three patients with adenomatous polyposis, of which two developed a gastrointestinal cancer. The polyposis was not explained by a germline mutation in APC or MYH and all patients received abdominal radiotherapy. Although an etiologic role has not been established, an association between radiotherapy and intestinal adenomatous polyposis and the subsequent development of cancer seems very likely in our patients.

Background: Hodgkin lymphoma (HL) survivors have an increased colorectal cancer (CRC) risk. Diagnostic accuracy of quantitative fecal immunochemical testing (FIT, OC Sensor) and/or a multi-target stool DNA test (mt-sDNA, Cologuard®) for advanced neoplasia (AN) was evaluated. Methods: 101 HL survivors underwent a surveillance colonoscopy and were asked to perform two stool tests (FIT and mt-sDNA). Advanced adenoma (AA), advanced serrated lesion (ASL), and AN (AA, ASL, CRC) were evaluated. Sensitivity, specificity, and area under the curve (AUC) for AN were calculated for different FIT cut-offs and mt-sDNA with colonoscopy as reference. Results: FIT and mt-sDNA were analyzed in 73 (72%) and 82 (81%) participants, respectively. AN was detected in 19 (26%) and 22 (27%), respectively. AN sensitivities for FIT cut-off of 10 ug Hb/g feces (FIT10) and mt-sDNA were 37% (95% confidence interval (CI): 16–62) and 68% (95% CI: 45–86), with corresponding specificities of 91% (95% CI: 80–97) and 70% (95% CI: 57–86), respectively. AUC for FIT was 0.68 (95% CI: 0.54–0.82) and for mt-sDNA 0.76 (95% CI: 0.63–0.89). Conclusions: In HL survivors, mt-sDNA showed highest sensitivity but with relatively low specificity for AN. Cost-effectiveness analyses is necessary to determine the optimal surveillance strategy.