Secondary Primary Cancer Risk After Radiation Therapy in Rectal Cancer: A Population-Based Cohort Study With Propensity Score Matching.

BACKGROUND: It remains unclear whether radiation therapy (RT) has an impact on the development of secondary primary cancer (SC) in rectal cancer (RC) patients, especially within the true pelvis. AIM: To examine the incidence of SC in a population-based cohort of RC after surgical treatment with or without radiation therapy (RT, NRT). PATIENTS AND METHODS: The epidemiological cohort consisting of 13,919 RC patients with primary M0 stage diagnosed between 1998 and 2019 was collected from cancer registry data of Upper Bavaria. Competing risk analyses were conducted regarding the development of SC on 11 687 first malignancies, stratified by RT/NRT. A propensity score (PS) was generated by logistic regression modeling of RT to repeat competing risk analyses on a PS-matched cohort. RESULTS: The median age (interquartile range) of the epidemiological cohort was 68.9 years (60.4-76.7). About 60.8%, were men, 38.7% had UICC III, 35.8% of tumors were localized lower than 8 cm, 41.3% underwent RT. Only 17.1% of patients older than 80 years at diagnosis received RT. In general, RT patients were 5 years younger than NRT patients (65.9 years [58.0-73.0] vs. 71.3 years [62.4-79.2], P < .0001). The 20-year cumulative incidence of SC was 16.5% in RT and 17.4% in NRT patients (P = .2298). Men with RT had a lower risk of prostate cancer (HR = 0.55, 95%CI [0.34-0.91], P = .0168). In the PS-matched cohort, RT patients had a significantly higher risk of bladder cancer during follow-up (10-year cumulative incidence of 1.1% vs. 0.6% in NRT). The direction of the RT effects in men and women and different tumor sites may cancel each other. CONCLUSION: A protective effect of RT in rectal cancer patients on developing prostate SC by half is reproduced. Further analyses studying the long-term SC risks of RT should essentially focus on stratification by sex, and focus on more recent data.

Expanding mammography screening for women aged 40-80 years: evidence from a modeling approach using real-world data.

If a mammography screening program (MS) is to be expanded, the benefit must be demonstrated for each additional age cohort. For the age interval between 40 and 80 years, the association between tumor-related and tumor-independent mortality of 21 2-year cohorts is modeled using up-to-date, valid data to determine MS outcome. Disease trajectories with and without biennial MS are extrapolated for each age cohort using the available data and knowledge on MS. The competing mortality is randomly generated for each age cohort with and without MS for a follow-up period of 20 years. Analyses of the modeled cohorts describe incremental change for each year, quantifying the changing benefits of MS. With increasing age, the proportion of tumor-independent mortality before and with metastatic disease increases and the benefit decreases. The simulations with 21 studies on the age interval 40-80 years provide four parameters to determine the benefits and costs of MS: The number of prevented deaths, required mammography screening exams (MSE) and their costs, life-years gained, and the required MSEs. If one additional MSE is offered for age groups 48/70 years, this will result in 311/320 prevented breast cancer (BC) deaths with 1742/1494 required MSEs or 8784/4168 life-years gained with 64/140 required MSEs. A rational cutoff cannot be quantified. The mortality effect of MS between 40 and 80 years is quantified in 21 steps using two metrics, number of MSEs per tumor-related mortality prevented and per life-year gained. This provides a decision support for stepwise expansions. Given this real-world evidence no rational age cutoffs for MS becomes evident. A society has to decide which MS costs, including side effects of MS for women who remain BC-free, it is willing and able to accept in order to reduce breast cancer mortality.

The other colon cancer: a population-based cohort study of appendix tumour trends and prognosis.

AIM: Appendiceal neoplasms are rare subtypes of colorectal tumours that mainly affect younger patients some 20 years earlier than other colon tumours. The aim of this study was to gain more insight into the histological subtypes of this rare disease and include cases previously excluded, such as mucinous neoplasia. METHOD: The cohort study included 1097 patients from the Munich Cancer Registry (MCR) diagnosed between 1998 and 2020. Joinpoint analysis was used to determine trend in incidence. Baseline demographic comparisons and survival analyses using competing risk and univariate/multivariate methods were conducted according to tumour histology: adenocarcinoma (ADENO), neuroendocrine neoplasia (NEN), mixed adeno-neuroendocrine carcinoma (MANEC), and low- (LAMN) and high-grade mucinous neoplasia (HAMN). RESULTS: Up to 2016 the number of cases increased significantly [annual per cent change (APC) = 6.86, p < 0.001] followed by a decline in the following years (APC = -14.82, p = 0.014; average APC = 2.5, p = 0.046). Comparison of all patients showed that NEN (48.4%) and mucinous neoplasms (11.6%) had a considerably better prognosis than ADENO (36.0%) and MANEC (3.0%, p < 0.0001). A multivariate analysis within the NEN and ADENO subgroups revealed that further histological classification was not prognostically relevant, while older age and regional tumour spread at diagnosis were associated with a poor prognosis. ADENO histology with high tumour grade and appendectomy only was also associated with poorer survival. CONCLUSION: Appendiceal neoplasms are histologically heterogeneous; however, this diversity becomes less relevant compared with the marked difference from cancers of the remaining colon. The previously observed increase in cases appears to be abating; fewer cases of appendicitis and/or appendectomies or changes in histopathological assessment may be behind this trend.

Breast cancer: emerging principles of metastasis, adjuvant and neoadjuvant treatment from cancer registry data.

PURPOSE: Growing primary breast cancers (PT) can initiate local recurrences (LR), regional lymph nodes (pLN) and distant metastases (MET). Components of these progressions are initiation, frequency, growth duration, and survival. These characteristics describe principles which proposed molecular concepts and hypotheses must align with. METHODS: In a population-based retrospective modeling approach using data from the Munich Cancer Registry key steps and factors associated with metastasis were identified and quantified. Analysis of 66.800 patient datasets over four time periods since 1978, reliable evidence is obtained even in small subgroups. Together with results of clinical trials on prevention and adjuvant treatment (AT) principles for the MET process and AT are derived. RESULTS: The median growth periods for PT/MET/LR/pLN comes to 12.5/8.8/5/3.5 years, respectively. Even if 30% of METs only appear after 10 years, a pre-diagnosis MET initiation principle not a delayed one should be true. The growth times of PTs and METs vary by a factor of 10 or more but their ratio is robust at about 1.4. Principles of AT are 50% PT eradication, the selective and partial eradication of bone and lung METs. This cannot be improved by extending the duration of the previously known ATs. CONCLUSION: A paradigm of ten principles for the MET process and ATs is derived from real world data and clinical trials indicates that there is no rationale for the long-term application of endocrine ATs, risk of PTs by hormone replacement therapies, or cascading initiation of METs. The principles show limits and opportunities for innovation also through alternative interpretations of well-known studies. The outlined MET process should be generalizable to all solid tumors.

The Role of Thoracic Surgery in Small Cell Lung Cancer - A Large Longitudinal Analysis (2002-2015) Based on Real-World Data.

BACKGROUND: Most SCLC patients are diagnosed with extensive disease (ED) and the prognosis in this cohort remains poor. However, some patients are diagnosed with limited (LD) or very limited (VLD, T1-2, N0-1, M0) disease and previous data suggest that surgical resection might improve outcomes in these patients. Most of the existing evidence comes from small case series. For this reason, we investigated clinical features and surgical outcomes in a large cohort of resected SCLC patients. PATIENTS AND METHODS: We used a large pseudomized dataset (n = 32432) provided by the Munich Cancer Registry to analyze all documented SCLC patients (n = 5043) between 2002 and 2015. We correlated patients' characteristics as well as surgery modalities with survival data and describe trends in the role of surgery in SCLC over the time. RESULTS: We analyzed 5043 SCLC patients. A total of 161 (3.2%) received either oncological (lobectomy, bilobectomy and pneumonectomy) or limited resection (segmentectomy and wedge resection). We found a significant trend suggesting that resections in SCLC patients become less common in all stages of disease, accompanied by an increased proportion of oncological resections. This suggests a more accurate preoperative staging. In VLD resection was significantly associated with longer survival compared to nonsurgical management (log-rank P = .013). Survival was better with oncological resection compared to atypical resection. Administration of adjuvant chemotherapy was associated with better outcome in all resected patients (P = .01). CONCLUSION: VLD SCLC patients benefit from oncological resection. We recommend invasive staging in these patients to ensure VLD. Furthermore, adjuvant chemotherapy should be offered to all resected patients.

Colonoscopy and polypectomy: beside age, size of polyps main factor for long-term risk of colorectal cancer in a screening population.

PURPOSE: Despite national and international guideline recommendations, few studies have been conducted to estimate the impact of colonoscopy screening on long-term colorectal cancer incidence. Aim of this study was to determine the long-term impact of a full colonoscopy with polypectomy on colorectal cancer incidence in a large screening population. METHODS: In this prospective observational cohort study, a total of 10,947 colonoscopy screening participants from within the scope of the Munich Cancer Registry were consecutively recruited from participating gastroenterology practices and their subsequent colorectal cancer incidence assessed. Predictive factors associated with colorectal cancer were also evaluated in univariate and multivariate analyses. RESULTS: After a median follow-up of 14.24 years (95% CI [14.21-14.25]), 93 colorectal cancer cases were observed. This is equivalent to a truncated age-standardized rate of 69.0 (95% CI [43.3-94.7]) for male and 43.4 (95% CI [29.4-57.5]) for female participants (≥ 50 years at colonoscopy). The ratio of this observed to the expected rate from cancer registry data showed a 67% decrease in colorectal cancer incidence in the male and 65% in the female participants (p < 0.0001). In multivariate analysis of screening patients, age at screening (p < 0.0001) was the main predictive factor for colorectal cancer. In the subgroup with positive polyp findings, age (p < 0.0001) and the polyp size (p = 0.0002) were associated with colorectal cancer. CONCLUSION: These results underline the significance of a full colonoscopy screening combined with polypectomy in reducing the total disease burden of colorectal cancer.

Patients with colorectal cancer and brain metastasis: The relevance of extracranial metastatic patterns predicting time intervals to first occurrence of intracranial metastasis and survival.

The aim of the study was to investigate the predictive impact of extracranial metastatic patterns on course of disease and survival in patients with colorectal cancer (CRC) and brain metastasis (BM). A total of 228 patients (134 male [59%], 94 female [41%]) with histologically proven CRC and BM were classified into different groups according to extracranial metastatic patterns. Time intervals to metastatic events and survival times from initial CRC diagnosis, extracranial and intracranial metastasis were analyzed. Extracranial organs mostly affected were liver (102 of 228 [44.7%]) and lung (96 of 228 [42.1%]). Liver and lung metastases were detected in 31 patients (13.6%). Calculated over the entire course of disease, patients with lung metastasis showed longer overall survival (OS) than patients with liver metastasis or patients without lung metastasis (43.9 vs 34.6 [P = .002] vs 35.0 months [P = .002]). From the date of initial CRC diagnosis, lung metastasis occurred later in CRC history than liver metastasis (24.3 vs 7.5 months). Once lung metastasis was diagnosed, BM occurred faster than in patients with liver metastasis (15.8 vs 26.0 months; Δ 10.2 months). Accordingly, OS from the diagnosis of liver metastasis was longer than from lung metastasis (27.1 vs 19.6 months [P = .08]). Once BM was present, patients with lung metastasis lived longer than patients with liver metastasis (3.8 vs 1.1 months [P = .028]). Shortest survival times in all survival categories analyzed revealed patients with concurrent liver and lung metastasis. Patients with CRC and BM form a heterogeneous cohort where extracranial metastasis to liver or lungs predicts survival.

Cancer Testis Antigens and Immunotherapy: Expression of PRAME Is Associated with Prognosis in Soft Tissue Sarcoma.

(1) Background: PRAME, NY-ESO-1, and SSX2 are cancer testis antigens (CTAs), which are expressed in testicular germ cells with re-expression in numerous cancer types. Their ability to elicit humoral and cellular immune responses have rendered them promising targets for cancer immunotherapy, but they have never been studied in a large and well-characterised cohort of soft tissue sarcomas (STS). (2) Methods: On a protein level, we examined PRAME, NY-ESO-1, and SSX2 expression in tumour tissues of 249 high-risk STS using immunohistochemistry. We correlated expression levels with clinicopathological parameters including tumour-infiltrating lymphocyte (TIL) counts, grading, and long-term survival. (3) Results: Expression of PRAME, NY-ESO-1, and SSX2 was observed in 25 (10%), 19 (8%), and 11 (4%) of 249 specimens with distinct patterns for histo-subtypes. Expression of PRAME was associated with shorter patient survival (p = 0.005) and higher grade (G2 vs. G3, p = 0.001), while NY-ESO-1 expression was correlated with more favourable survival (p = 0.037) and lower grade (G2 vs. G3, p = 0.029). Both PRAME and NY-ESO-1 expression were more frequent in STS with low TIL counts. In multivariate analysis, high PRAME and low SSX2 expression levels as well as metastatic disease and non-radical resections were independent predictors of shorter overall survival. (4) Conclusions: CTAs PRAME, NY-ESO-1, and SSX2 show distinct expression patterns in different STS subtypes. These results demonstrate their prognostic relevance and may guide future immunotherapeutic approaches in STS.

Distinct Expression Patterns of VEGFR 1-3 in Gastroenteropancreatic Neuroendocrine Neoplasms: Supporting Clinical Relevance, but not a Prognostic Factor.

INTRODUCTION: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are an increasing tumor entity. Since many patients are diagnosed at an advanced stage, treatment is still challenging and dependent on many tumor and patient specific factors. Therefore, the aim of the present study was to elucidate the expression rates and the prognostic value of vascular endothelial growth factor receptor (VEGFR) 1-3 in GEP-NENs. A potential association to immune checkpoint markers was further investigated. MATERIAL AND METHODS: The expression levels of VEGFR 1-3 were analyzed by immunohistochemistry and correlated with the expression of the checkpoint markers PD-1 and PD-L1. Furthermore, the tumor samples of 249 GEP-NEN patients were studied and correlated with overall survival rates and clinicopathological features. Kaplan-Meier analyses and the log rank test were used for survival analyses. Categorical variables were compared by the χ2 test. RESULTS: The most common primary tumor site was the small intestine (50.6%), followed by the pancreas (25.7%). VEGFR 1 was highly expressed in 59%, VEGFR 2 in 6.4%, and VEGFR 3 in 61.8% of the analyzed samples. The expression of VEGFR 1-3 was not significantly associated with survival rates. Pancreatic NENs had the highest expression of VEGFR 1 and 3 in 80% of the cases. VEGFR 1-3 positivity correlated with the expression levels of immune checkpoint markers. DISCUSSION: VEGFR 1-3 show a distinct expression pattern in different subgroups of neuroendocrine neoplasias indicating a conceivable target. Moreover, there was a substantial association between VEGFRs and immune checkpoint markers. Taken together, anti-VEGFR therapy represents a promising therapeutic approach in GEP-NEN patients and should be addressed in future studies.

Breast cancer: are long-term and intermittent endocrine therapies equally effective?

PURPOSE: In breast cancer (BC), the duration of endocrine adjuvant therapies (AT) has been extended continuously up to 10 years. We present an alternative explanation for the effect, which could enable shorter treatments. METHOD: The relevant literature on chemoprevention and (neo-)adjuvant therapy was reviewed. Data for initiation and growth of primary and contralateral BCs and their metastases (MET) were considered. Also, population-based data from the Munich Cancer Registry for MET-free survival, time trends of MET patterns, and survival achieved by improved ATs are used to estimate all events in the long-term follow-up. RESULTS: Extended ATs (EAT) that continue after 1, 2, or 5 years reduce mortality only slightly. The effect is delayed, occurring more than 5 years after extension. EATs does not affect the prognosis of 1stBCs, they preventively eradicate contralateral 2ndBCs and thus their future life-threatening METs. Because chemoprevention can eradicate BCs from the smallest clusters to almost detectable BCs, ATs can be temporarily suspended without imposing harm. Results equal to EATs can be achieved by short-term ATs of the 1stBC and by repeated neo-ATs targeted at the indefinitely developing 2ndBCs. Considering this potential in de-escalation, a 70-80% reduction of overtreatment seems possible. CONCLUSION: Knowledge of initiation and growth of tumors with known effects of neo-ATs suggest that intermittent endocrine ATs may achieve the same results as EATs but with improved quality of life and survival because of fewer side effects and better compliance. The challenge for developments of repeated ATs becomes: how short is short enough.

Prognosis of patients with chronic myeloid leukemia presenting in advanced phase is defined mainly by blast count, but also by age, chromosomal aberrations and hemoglobin.

Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known about the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% blasts, the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7-2.6]). Patients with 20-29% blasts had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2-4.0], P = .008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs non-high risk) with an HR of 3.01 (95%-CI: [1.81-5.00], P < .001). Regarding the contrasting definitions of blast crisis, our data clearly supported the 20% cut-off over the 30% cut-off in this cohort. Based on our results, we conclude that a one-phase rather than a two-phase categorization of de novo advanced phase CML patients is appropriate.

Immune checkpoint markers in gastroenteropancreatic neuroendocrine neoplasia.

Cancer immunotherapy has evolved major breakthroughs in the last years. The cell-surface receptor programmed death-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1), have been detected in various cancer types. However, the analysis on gastroenteropancreatic neoplasia (GEP-NENs) is limited. Therefore, the aim of this study was to characterize GEP-NENs with regard to PD-1/PD-L1 pathway and tumor-infiltrating lymphocytes (TILs). On protein level, we examined TILs, PD-1 and PD-L1 expression in tumor tissue of 244 GEP-NENs using immunohistochemistry. Expression levels were correlated with clinicopathological parameters including long-term survival in an observational study. In total, 244 patients could be included. Most of the patients had a NEN of the small intestine (52.5%) or the pancreas (29.5%). All tumors could be graded by their morphology and Ki67 index, with 57.8% G1, 34% G2 and 8.2% G3 tumors. High TILs (19.6%) and high PD-1 (16.1%) expression showed a significant correlation with shorter patient survival (P < 0.05) and with a higher grading. Furthermore, expression of PD-L1 (8.7%) showed a trend to shorter patient survival. High TILs and PD-1 expression are significantly associated with shorter patient survival and higher grading in GEP-NENs. PD-L1 expression showed a trend to shorter patient survival. Immunotherapy might be a promising therapeutic approach in GEP-NENs especially in tumors with high TILs.

Perioperative chemotherapy vs. neoadjuvant chemoradiation in gastroesophageal junction adenocarcinoma : A population-based evaluation of the Munich Cancer Registry.

BACKGROUND: To date, it remains unclear whether locally advanced adenocarcinoma of the gastroesophageal junction (AEG) should be treated with neoadjuvant chemoradiation (nCRT), analogous to esophageal cancer, or with perioperative chemotherapy (pCT), analogous to gastric cancer. The purpose of this study was to analyze the data of the Munich Cancer Registry (MCR) and to compare pCT and nCRT in AEG patients. PATIENTS AND METHODS: A total of 2,992 AEG patients, treated between 1998 and 2014, were included in the study. Baseline and tumor parameters as well as overall survival (OS) and tumor recurrence were compared between 56 patients undergoing nCRT and 64 patients undergoing pCT with UICC stage II/III cancer. In addition, uni- and multivariate analyses using Cox regression models were performed to evaluate the effect of tumor characteristics and treatment regimens on OS. RESULTS: In patients with UICC stage II/III AEG treated with either nCRT or pCT, no significant differences were seen for baseline and tumor characteristics. While there was a significantly higher cumulative incidence of locoregional treatment failure after pCT (32.8%; 95% CI: 18.0-48.4%) compared with nCRT (7.4%; 95% CI: 2.3-16.5%; p = 0.007), there was no significant difference for distant treatment failure (52.9%; 95% CI: 35.4-67.7% and 38.4%; 95% CI: 23.7-52.9%; p = 0.347). When analyzing the whole cohort, patients who received pCT were younger (58.3 years vs. 63.0 years; p = 0.016), had a higher chance of complete tumor resection (81% vs. 67%; p = 0.033), more resected lymph nodes (p = 0.036), and fewer lymph node metastases (p = 0.038) compared with patients who received nCRT. Nevertheless, there was still a strong trend toward a higher incidence of local treatment failure after pCT (25.8%; 95% CI: 14.7-38.3% vs. 12.6%; 95% CI: 5.5-22.8%; p = 0.053). Comparable to the results for patients with UICC stage II/III, no difference was seen for the incidence of distant treatment failure. When excluding patients with UICC stage IV cancer, no significant difference was found for OS. CONCLUSION: For UICC stage II/III carcinoma, nCRT was associated with an improved locoregional tumor control compared with pCT, while no further significant differences were seen between nCRT and pCT for UICC stage II/III AEG. Moreover, there was a strong trend toward improved locoregional tumor control after nCRT when analyzing all patients treated with nCRT or pCT, despite these patients having higher risk factors.

Use of Multicenter Data in a Large Cancer Registry for Evaluation of Outcome and Implementation of Novel Concepts.

Large clinical cancer registries (CCRs) in Germany shall be strengthened by the German Social Code Book V (SGB V) and implemented until the end of 2017. There are currently several large cancer registries that support clinical data for outcome analysis and knowledge acquisition. The various examples of the Munich Cancer Registry outlined in this paper present many-sided possibilities using and analyzing registry data. The main objective of population-based cancer registration within a defined area and the performance of outcomes research is to provide feedback regarding the results to the broad public, the reporting doctors, and the scientific community. These tasks determine principles of operation and data usage by CCRs. Each clinical department delivers its own findings and applied therapy. The compilation of these data in CCRs provides information on patient progress through the regional network of medical care and delivers meaningful information on the course of oncological diseases. Successful implementation of CCRs allows for presenting the statistical outcomes of health-care delivery, improving the quality of care within the region, accelerating the process of implementing innovative therapies, and generating new hypotheses as a stimulus for research activities.

Synchronous colorectal liver metastases: focus on the elderly : An Effectiveness Study from Routine Care.

PURPOSE: The goal of this study was to analyze the use and the effectiveness of both surgery and different chemotherapies in patients with synchronous colorectal liver metastases (CLMs) ≥70 years compared to younger patients. METHODS: Survival was analyzed in 456 patients (24.3% ≥70 years) treated for CLM in a single center using Kaplan-Meier estimation of overall survival (OS), calculation of relative survival as estimate for disease-specific survival, and a Cox regression model. RESULTS: Complete surgical resections were achieved more often in patients aged <70 years (39.2 vs. 28.1%, P = 0.056), and young patients more frequently received irinotecan or platin-based chemotherapies (70.3 vs. 41.6%, P < 0.001). Three-year OS and relative survival of patients ≥70 years were significantly lower compared to younger patients (OS 34.3 vs. 43.5%, P = 0.0114). In a Cox regression model, complete surgical removal of liver metastases was the most effective treatment (HR 0.313, P < 0.001) followed by chemotherapy (irinotecan/platin-based: HR 0.371, 5-FU only: HR 0.673, P < 0.001). Having >5 liver metastases, the presence of extrahepatic metastases, high grading, and a nodal positive primary but not age ≥70 years were associated with an increased risk of death. CONCLUSIONS: Our data support radical resection and highly effective chemotherapy in selected elderly patients with CLM.

Prognostic significance of BRAF and NRAS mutations in melanoma: a German study from routine care.

BACKGROUND: Hotspot mutations of the oncogenes BRAF and NRAS are the most common genetic alterations in cutaneous melanoma. Specific inhibitors of BRAF and MEK have shown significant survival benefits in large phase III trials. However, the prognostic significance of BRAF and NRAS mutations outside of clinical trials remains unclear. METHODS: The mutational status of BRAF (exon 15) and NRAS (exon 2 and 3) was determined in melanoma samples of 217 patients with pyrosequencing and Sanger sequencing. The genotypes were correlated with clinical outcomes and pathologic features of the primary tumors. Time to disease progression was calculated with the cumulative incidence function. Survival analyses were performed with Kaplan-Meier estimates and Cox proportional hazards regression analysis. Relative survival was calculated with the Ederer-II method. Treatment with BRAF and MEK inhibitors and immune checkpoint blockade (ICB) was allowed. RESULTS: Mutations in BRAF and NRAS were identified in 40.1 and 24.4% of cases, respectively. Concurrent mutations in both genes were detected in further 2.3%. The remaining 33.2% were wild type for the investigated exons (WT). BRAF mutations were significantly associated with younger age at first diagnosis (p < 0.001) and truncal localization of the culprit primary (p = 0.002). The nodular subtype was most common in the NRAS cohort. In addition, NRAS-mutant melanoma patients showed a higher frequency of nodal relapse (p = 0.013) and development of metastatic disease (p = 0.021). The time to loco-regional nodal relapse was shortest in NRAS-mutant melanoma (p = 0.002). Presence of NRAS mutation was an independent risk factor for disease progression in multivariate analysis (HR 2.01; 95% CI 1.02 - 3.98). BRAF-mutant melanoma patients showed a tendency for better overall and relative survival. Genotype was not a consistent risk factor in multivariate analysis. Instead, positive sentinel lymph node status (HR 2.65; 95% CI 1.15 - 6.10) and treatment with ICB in stage IV disease (HR 0.17; 95% CI 0.06-0.48) were significant multivariate risk factors. CONCLUSIONS: NRAS-mutant tumors tended to behave more aggressively particularly in early stages of the disease in this high-risk melanoma population. Treatment with immune checkpoint blockade improved survival in stage IV disease in a real-world setting.

Prognostic factors and treatment outcomes in 444 patients with mucosal melanoma.

BACKGROUND: Mucosal melanoma (MM) is a rare but diverse cancer entity. Prognostic factors are not well established for Caucasians with MM. PATIENTS AND METHODS: We analysed the disease course of 444 patients from 15 German skin cancer centres. Disease progression was determined with the cumulative incidence function. Survival times were estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariate Cox regression analysis. RESULTS: Common anatomic sites of primary tumours were head and neck (MMHN, 37.2%), female genital tract (MMFG, 30.4%) and anorectal region (MMAN, 21.8%). MMAN patients showed the highest vertical tumour thickness (p = 0.001), had a more advanced nodal status (p = 0.014) and a higher percentage of metastatic disease (p = 0.001) at diagnosis. Mutations of NRAS (13.8%), KIT (8.6%) and BRAF (6.4%) were evenly distributed across all tumour site groups. Local relapses were observed in 32.4% and most commonly occurred in the MMHN group (p = 0.016). Male gender (p = 0.047), advanced tumour stage (p = 0.001), nodal disease (p = 0.001) and incomplete resection status (p = 0.001) were independent risk factors for disease progression. Overall survival (OS) was highest in the MMFG group (p = 0.030) and in patients without ulceration (p = 0.004). Multivariate risk factors for OS were M stage at diagnosis (p = 0.002) and incomplete resection of the primary tumour (p = 0.001). CONCLUSION: In this large series of MM patients in a European population, anorectal MM was associated with the poorest prognosis.

Prognosis of mucinous and signet-ring cell colorectal cancer in a population-based cohort.

PURPOSE: Besides classical colorectal adenocarcinomas (AC), mucinous adenocarcinomas (MAC) and signet-ring cell carcinomas (SC) occur. Controversy remains regarding their prognostic role. Aim of this study was to define prognostic and histopathological specifications of mucinous and signet-ring cell colorectal cancer. METHODS: A total of 28,056 patients with AC, MAC, and SC between 1998 and 2012 in the catchment area of the Munich Cancer Registry were analyzed. Time to locoregional recurrence and distant recurrence was calculated by cumulative incidence. Survival was analyzed by the Kaplan-Meier method, calculation of relative survival, and Cox proportional hazards regression. RESULTS: AC occurred in 25,172 patients (90 %), MAC in 2724 (9.7 %), and SC in 160 (0.6 %). AC were less frequently localized in the proximal colon (34 %) compared to MAC (57 %, p < 0.001) and SC (76 %, p < 0.001). Both, MAC and SC had higher T, N, and M categories, lymphatic invasion, and worse grading (p < 0.001 for each). There were significant differences regarding the 10-year cumulative incidence of locoregional recurrence (p < 0.001), and distant recurrence (p < 0.001). For AC, the 5-year overall survival was 59 % (95 % confidence interval 58.0; 59.3), for MAC 52 % (50.2; 54.2), and for SC 40 % (32.1; 48.5; p < 0.001). However, MAC or SC did not remain independent prognostic factors for overall survival compared to AC upon multivariable analysis (p = 0.981). CONCLUSION: This large cohort reveals specific histopathological and recurrence patterns for patients with colorectal AC, MAC, and SC. MAC and SC are diagnosed at more advanced tumor stages and therefore entail reduced survival rates.