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Colorectal carcinoma (CRC) exhibits metastatic organotropism, primarily targeting liver, lung, and rarely the brain. Here, we study chromosomal imbalances (CIs) in cohorts of primary CRCs and metastases. Brain metastases show the highest burden of CIs, including aneuploidies and focal CIs, with enrichment of +12p encoding KRAS . Compared to liver and lung metastases, brain metastases present with increased co-occurrence of KRAS mutation and amplification. CRCs with concurrent KRAS mutation and amplification display significant metabolic reprogramming with upregulation of glycolysis, alongside upregulation of cell cycle pathways, including copy number gains of MDM2 and CDK4 . Evolutionary modeling suggests early acquisition of many organotropic CIs enriched in both liver and brain metastases, while brain-enriched CIs preferentially emerge later. Collectively, this study supports a model where cytogenetic events in CRCs favor site-specific metastatic colonization. These site-enriched CI patterns may serve as biomarkers for metastatic potential in precision oncology. The molecular basis of the preferential metastasis to specific organs in colorectal cancer (CRC) remains to be explored. Here, the authors identify the cytogenetic events that favor metastatic colonization at specific sites by studying cohorts of primary CRCs and metastases.

Neoadjuvant chemotherapy for unresectable colorectal liver metastases can downsize tumours for curative resection. We assessed the effectiveness of cetuximab combined with chemotherapy in this setting. Between Dec 2, 2004, and March 27, 2008, 114 patients were enrolled from 17 centres in Germany and Austria; three patients receiving FOLFOX6 alone were excluded from the analysis. Patients with non-resectable liver metastases (technically non-resectable or ≥5 metastases) were randomly assigned to receive cetuximab with either FOLFOX6 (oxaliplatin, fluorouracil, and folinic acid; group A) or FOLFIRI (irinotecan, fluorouracil, and folinic acid; group B). Randomisation was not blinded, and was stratified by technical resectability and number of metastases, use of PET staging, and EGFR expression status. They were assessed for response every 8 weeks by CT or MRI. A local multidisciplinary team reassessed resectability after 16 weeks, and then every 2 months up to 2 years. Patients with resectable disease were offered liver surgery within 4–6 weeks of the last treatment cycle. The primary endpoint was tumour response assessed by Response Evaluation Criteria In Solid Tumours (RECIST), analysed by modified intention to treat. A retrospective, blinded surgical review of patients with radiological images at both baseline and during treatment was done to assess objectively any changes in resectability. The study is registered with ClinicalTrials.gov, number NCT00153998. 56 patients were randomly assigned to group A and 55 to group B. One patient in each group were excluded from the analysis of the primary endpoint because they discontinued treatment before first full dose, one patient in group B was excluded because of early pulmonary embolism. A confirmed partial or complete response was noted in 36 (68%) of 53 patients in group A, and 30 (57%) of 53 patients in group B (difference 11%, 95% CI −8 to 30; odds ratio [OR] 1·62, 0·74–3·59; p=0·23). The most frequent grade 3 and 4 toxicities were skin toxicity (15 of 54 patients in group A, and 22 of 55 patients in group B), and neutropenia (13 of 54 patients in group A and 12 of 55 patients in group B). R0 resection was done in 20 (38%) of 53 patients in group A and 16 (30%) of 53 of patients in group B. In a retrospective analysis of response by KRAS status, a partial or complete response was noted in 47 (70%) of 67 patients with KRAS wild-type tumours versus 11 (41%) of 27 patients with KRAS-mutated tumours (OR 3·42, 1·35–8·66; p=0·0080). According to the retrospective review, resectability rates increased from 32% (22 of 68 patients) at baseline to 60% (41 of 68) after chemotherapy (p<0·0001). Chemotherapy with cetuximab yields high response rates compared with historical controls, and leads to significantly increased resectability. Merck-Serono, Sanofi-Aventis, and Pfizer.

This randomized trial compared preoperative with postoperative chemoradiotherapy for locally advanced rectal cancer. Overall survival was similar in the two groups, but patients assigned to preoperative chemoradiotherapy had lower rates of local recurrence and fewer long-term toxic effects than patients in the postoperative group. In this trial of nearly 800 patients, those assigned to preoperative chemoradiotherapy had lower rates of local recurrence and fewer toxic effects. Adjuvant radiotherapy with or without chemotherapy has been used widely to improve outcomes in patients with rectal cancer. For locally advanced disease, postoperative chemoradiotherapy significantly improves both local control and overall survival as compared with surgery alone or surgery plus irradiation. 1 , 2 This information prompted a National Institutes of Health consensus conference, convened in 1990, to recommend postoperative adjuvant chemoradiotherapy as standard treatment for patients with rectal cancer classified as tumor–node–metastasis (TNM) stage II (i.e., a tumor penetrating the rectal wall, without regional lymph-node involvement) or stage III (i.e., any tumor with regional lymph-node involvement). 3 Several randomized studies have found . . .

Background Abrogation of growth factor-dependent signaling represents an effective therapeutic strategy for patients with colorectal cancer (CRC). Here we evaluated the effectiveness of targeting the epidermal growth factor (EGF) receptors HER-2 and HER-3 in the three cell lines LS513, LS1034 and SW837. Methods Treatment with HER-2-specific antibodies trastuzumab and pertuzumab resulted in a mild reduction of cellular viability. In contrast, the antibody-drug conjugate T-DM1 mediated a strong and dose-dependent decrease of viability and Akt phosphorylation. Results The most striking effects were observed with the dual tyrosine kinase inhibitor lapatinib, and the Pan-ErbB inhibitor afatinib. Selectively, the effect of EGF receptor inhibition was augmented by a combination with 5-fluorouracil and oxaliplatin. Finally, high expression of HER-3 was detected in 121 of 172 locally advanced rectal cancers (70.3%). In conclusion, inhibition of EGF receptors effectively blocks downstream signaling and significantly impairs viability of CRC cells. However, the effectiveness of receptor inhibition highly depends on the inhibitors’ mode of action, as targeting HER-2 alone is not sufficient. Conclusion Since HER-2 and HER-3 are expressed in a relevant number of patients, targeting both receptors may represent a promising therapeutic strategy for CRC.

Background The question whether lymphocyte radiosensitivity is representative of patients’ response to radiotherapy (RT) remains unsolved. We analyzed lymphocyte cytogenetic damage in patients who were homogeneously treated with preoperative radiochemotherapy (RCT) for rectal cancer within clinical trials. We tested for interindividual variation and consistent radiosensitivity after in-vivo and in-vitro irradiation, analyzed the effect of patients’ and RCT characteristics on cytogenetic damage, and tested for correlations with patients’ outcome in terms of tumor response, survival and treatment-related toxicity. Methods The cytokinesis-block micronucleus cytome (CBMNcyt) assay was performed on the peripheral blood lymphocytes (PBLCs) of 134 patients obtained before, during, at the end of RCT, and during the 2-year follow-up. A subset of PBLCs obtained before RCT was irradiated in-vitro with 3 Gy. RCT included 50.4 Gy of pelvic RT with 5-fluorouracil (5-FU) alone ( n  = 78) or 5-FU plus oxaliplatin ( n  = 56). The analyzed variables included patients’ age, gender, RT characteristics (planning target volume size [PTV size], RT technique), and chemotherapy characteristics (5-FU plasma levels, addition of oxaliplatin). Outcome was analyzed as tumor regression, patient survival, and acute and late toxicity. Results Cytogenetic damage increased significantly with the radiation dose and varied substantially between individuals. Women were more sensitive than men; no significant age-dependent differences were observed. There was a significant correlation between the cytogenetic damage after in-vitro irradiation and in-vivo RCT. We found a significant effect of the PTV size on the yields of cytogenetic damage after RCT, while the RT technique had no effect. Neither the addition of oxaliplatin nor the 5-FU levels influenced cytogenetic damage. We found no correlation between patient outcome and the cytogenetic damage. Conclusions We found consistent cytogenetic damage in lymphocytes after in-vivo RCT and in-vitro irradiation. Gender was confirmed as a well-known, and the PTV size was identified as a less well-known influencing variable on lymphocyte cytogenetic damage after partial-body irradiation. A consistent level of cytogenetic damage after in-vivo and in-vitro irradiation may indicate the importance of genetic factors for individual radiosensitivity. However, we found no evidence that in-vivo or in-vitro irradiation-induced cytogenetic damage is an adequate biomarker for the response to RCT in rectal cancer patients.

Formalin fixed and paraffin-embedded human tissue resected during cancer surgery is indispensable for diagnostic and therapeutic purposes and represents a vast and largely unexploited resource for research. Optical microscopy of such specimen is curtailed by the diffraction-limited resolution of conventional optical microscopy. To overcome this limitation, we used STED super-resolution microscopy enabling optical resolution well below the diffraction barrier. We visualized nanoscale protein distributions in sections of well-annotated paraffin-embedded human rectal cancer tissue stored in a clinical repository. Using antisera against several mitochondrial proteins, STED microscopy revealed distinct sub-mitochondrial protein distributions, suggesting a high level of structural preservation. Analysis of human tissues stored for up to 17 years demonstrated that these samples were still amenable for super-resolution microscopy. STED microscopy of sections of HER2 positive rectal adenocarcinoma revealed details in the surface and intracellular HER2 distribution that were blurred in the corresponding conventional images, demonstrating the potential of super-resolution microscopy to explore the thus far largely untapped nanoscale regime in tissues stored in biorepositories.

Background Response to preoperative radiochemotherapy (RCT) in patients with locally advanced rectal cancer is very heterogeneous. Pathologic complete response (pCR) is accompanied by a favorable outcome. However, most patients show incomplete response. The aim of this investigation was to find indications for risk stratification in the group of intermediate responders to RCT. Methods From a prospective database of 496 patients with rectal adenocarcinoma, 107 patients with stage II/III cancers and intermediate response to preoperative 5-FU based RCT (ypT2/3 and TRG 2/3), treated within the German Rectal Cancer Trials were studied. Surgical treatment comprised curative (R0) total mesorectal excision (TME) in all cases. In 95 patients available for statistical analyses, residual transmural infiltration of the mesorectal compartment, nodal involvement and histolologic tumor grading were investigated for their prognostic impact on disease-free (DFS) and overall survival (OS). Results Residual tumor transgression into the mesorectal compartment (ypT3) did not influence DFS and OS rates (p = 0.619, p = 0.602, respectively). Nodal involvement after preoperative RCT (ypN1/2) turned out to be a valid prognostic factor with decreased DFS and OS (p = 0.0463, p = 0.0236, respectively). Persistent tumor infiltration of the mesorectum (ypT3) and histologic tumor grading of residual tumor cell clusters were strongly correlated with lymph node metastases after neoadjuvant treatment (p < 0.001). Conclusions Advanced transmural tumor invasion after RCT does not affect prognosis when curative (R0) resection is achievable. Residual nodal status is the most important predictor of individual outcome in intermediate responders to preoperative RCT. Furthermore, ypT stage and tumor grading turn out to be additional auxiliary factors. Future clinical trials for risk-adapted adjuvant therapy should be based on a synopsis of clinicopathologic parameters.

Preoperative MRI of the breasts has been proven to be the most sensitive imaging modality in the detection of multifocal or multicentric tumor manifestations as well as simultaneous contralateral breast cancer. The aim of the presented retrospective study was to evaluate the benefit of preoperative MRI for patients with breast cancer. Preoperative MRI performed in 121 patients (group A) were compared to 225 patients without preoperative MRI (group B). Patients of group A underwent contrast-enhanced MR imaging of the breast using a 2D FLASH sequence technique (TR/TE/FA 336 ms/5 ms/90 degrees; 32 slices of 4-mm thickness, time of acquisition 1:27 min, contrast agent dosage 0.1 mmol Gd-DTPA/kg bw). All patients had histologically verified breast cancer and follow-up for more than 20 months (mean time group A: 40.3 months, group B: 41 months). Both groups received the same types of systemic treatment after breast conserving surgery. The in-breast tumor recurrence rate in group A was 1/86 (1.2%) compared to 9/133 (6.8%) in group B. Contralateral carcinoma were detected within follow-up in 2/121 (1.7%) in group A vs. 9/225 (4%) in group B. All results were statistically significant (P<0.001). Based on these results, preoperative MRI of the breasts is recommended in patients with histopathologically verified breast cancer for local staging.

Liver metastasis development in breast cancer patients is common and confers a poor prognosis. So far, the prognostic significance of surgical resection and clinical relevance of biomarker analysis in metastatic tissue have barely been investigated. We previously demonstrated an impact of WNT signaling in breast cancer brain metastasis. This study aimed to investigate the value of established prognostic markers and WNT signaling components in liver metastases. Overall N = 34 breast cancer liver metastases (with matched primaries in 19/34 cases) were included in this retrospective study. Primaries and metastatic samples were analyzed for their expression of the estrogen (ER) and progesterone receptor, HER-2, Ki67, and various WNT signaling-components by immunohistochemistry. Furthermore, β-catenin-dependent and -independent WNT scores were generated and analyzed for their prognostic value. Additionally, the influence of the alternative WNT receptor ROR on signaling and invasiveness was analyzed in vitro. ER positivity (HR 0.09, 95 % CI 0.01–0.56) and high Ki67 (HR 3.68, 95 % CI 1.12–12.06) in the primaries had prognostic impact. However, only Ki67 remained prognostic in the metastatic tissue (HR 2.46, 95 % CI 1.11–5.44). Additionally, the β-catenin-independent WNT score correlated with reduced overall survival only in the metastasized situation (HR 2.19, 95 % CI 1.02–4.69, p  = 0.0391). This is in line with the in vitro results of the alternative WNT receptors ROR1 and ROR2, which foster invasion. In breast cancer, the value of prognostic markers established in primary tumors cannot directly be translated to metastases. Our results revealed β-catenin-independent WNT signaling to be associated with poor prognosis in patients with breast cancer liver metastasis.

We tested whether adjuvant radioimmunotherapy (RAIT) given after R0 resection of liver metastases (LM) of colorectal cancer is safe and can improve survival. Resection of LM from colorectal cancer is the standard of care in this setting, yet two thirds will eventually relapse, and adjuvant systemic chemotherapy has failed to improve survival. Twenty-three patients who underwent R0 resection for LM of colorectal cancer received a dose of 40 to 60 mCi/m(2) (131)I-labetuzumab, a humanized monoclonal antibody against carcinoembryonic antigen. Safety (n = 23), disease-free survival, and overall survival (n = 19) were analyzed, and efficacy was then compared retrospectively with a similar contemporaneous group of control patients (n = 19) treated at the same institution during the same time period but without RAIT. At a median follow-up of 91 months (95% confidence interval [CI], 68.0 months to infinity), the median overall survival for RAIT patients was 58.0 months (95% CI, 55.0 months to infinity), versus 31.0 months (95% CI, 26.0 months to infinity) at a 51-month median follow-up for the controls (P = .032). The median disease-free survival for RAIT patients was 18.0 months (95% CI, 11.0-31.0 months), versus 12.0 months (95% CI, 6.5-27.0 months) for the controls (P = .565). Corresponding survival rates (Kaplan-Meier analyses) were estimated to be 94.7% at 1 year, 78.9% at 2 years, 68.4% at 3 years, and 42.1% at 5 years with RAIT and 94.7%, 68.4%, 36.8%, and 15.8%, respectively, for the controls. RAIT was beneficial independently of bilobar involvement, size and number of LM, or resection margins. Transient myelosuppression was the principal adverse effect. This first evidence of a promising survival advantage of adjuvant RAIT after long-term follow-up of colorectal cancer patients given salvage resection of LM warrants confirmation in a prospective randomized trial.