The influence of obesity on survival in early, high-risk breast cancer: results from the randomized SUCCESS A trial

Introduction: Obese breast cancer patients have worse prognosis than normal weight patients, but the level at which obesity is prognostically unfavorable is unclear. Methods: This retrospective analysis was performed using data from the SUCCESS A trial, in which 3754 patients with high-risk early breast cancer were randomized to anthracycline- and taxane-based chemotherapy with or without gemcitabine. Patients were classified as underweight/normal weight (body mass index (BMI) < 25.0), overweight (BMI 25.0–29.9), slightly obese (BMI 30.0–34.9), moderately obese (BMI 35.0–39.9) and severely obese (BMI ≥ 40.0), and the effect of BMI on disease-free survival (DFS) and overall survival (OS) was evaluated (median follow-up 65 months). In addition, subgroup analyses were conducted to assess the effect of BMI in luminal A-like, luminal B-like, HER2 (human epidermal growth factor 2)-positive and triple-negative tumors. Results: Multivariate analyses revealed an independent prognostic effect of BMI on DFS (p = 0.001) and OS (p = 0.005). Compared with underweight/normal weight patients, severely obese patients had worse DFS (hazard ratio (HR) 2.70, 95 % confidence interval (CI) 1.71–4.28, p < 0.001) and OS (HR 2.79, 95 % CI 1.63–4.77, p < 0.001), while moderately obese, slightly obese and overweight patients did not differ from underweight/normal weight patients with regard to DFS or OS. Subgroup analyses showed a similar significant effect of BMI on DFS and OS in patients with triple-negative breast cancer (TNBC), but not in patients with other tumor subtypes. Conclusions: Severe obesity (BMI ≥ 40) significantly worsens prognosis in early breast cancer patients, particularly for triple-negative tumors. Trial registration: Clinicaltrials.gov NCT02181101. Registered September 200

Adhäsions- und Nidationsprophylaxe nach i.p.-Implantation von SCOV3.ip-Zellen in SCID-Mäuse mittels Icodextrin, Hyaluronsäure und physiologischer NaCl-Lösung im Vergleich

The problem of postsurgical adhesion formation is still in focus of scientific investigations. Although no clinical standard has been established for the prevention or therapy till today, there are promising attempts to solve the problem. Currently, the most promising approach can be seen in the application of physical adhesive barriers. These solutions allow a separation between the injured peritoneal surfaces and neighbouring structures during the postoperative healing phase. Nevertheless, their clinical application is still limited to the prevention of adhesion formation. It is known from literature that the pathology of postoperative adhesion formation shows parallels to the formation of peritoneal metastases and tumour implantation. Therefore, it becomes obvious that the formation of peritoneal carcinosis as a result of ovarian carcinoma due to peritoneal adhesion of tumour cells is possible. The aim of the present animal study was to evaluate the efficacy of the three barrier products icodextrin (Adept®), hyaluronic acid (Hyalobarrier®-Gel) and physiologic saline on adhesion formation as well as on tumour recurrence after surgery of ovarian carcinoma. Forty SCID-mice (NOD.CB17-Prkdcscid/J) were enclosed into the study and randomly assigned to four experimental groups of ten animals each: group 1: Icodextrin (Adept®), group 2: hyaluronic acid (Hyalobarrier®-Gel), group 3: physiologic saline, group 4: control group (no treatment). Peritoneal trauma was induced by standardized peritoneal lesion of the right abdominal wall. Ovarian carcinoma cell line SCOV3.ip was injected intraabdominally in all animals to induce specific tumour load. Afterwards the animals were treated by intraabdominal injection of the barrier products. After 21 postoperative days all animals were relaparotomized for analyses. Adhesion formation and tumour growth were measured using well established scores. Moreover, the tumour weight was gaged and tumour samples were taken for histological studies. All test substances (icodextrin, hyaluronic acid and physiologic saline) reduced postoperative adhesion formation and tumour growth. In the control group adhesion formation and tumour load were significantly increased compared to all other experimental groups. In mice treated with hyaluronic acid adhesion formation was significantly reduced compared to the other groups. Focusing on the parameter tumour growth, hyaluronic acid showed the best results again, but no statistic differences could be found between icodextrin, hyaluronic acid and saline. Histologic evaluation of the tumour tissue samples showed positive results of peritoneal carcinosis in all cases. With the limitation of an animal study, the results allow to suppose that the liquid compounds icodextrin, hyaluronic acid and physiologic saline may be beneficial adjuvants for prevention of postoperative adhesion formation and tumour recurrence. Further studies will have to focus on the evaluation of other barrier methods as well as on the realisation of in vivo studies with patients

Adhäsions- und Nidationsprophylaxe nach i.p.-Implantation von SCOV3.ip-Zellen in SCID-Mäuse mittels Icodextrin, Hyaluronsäure und physiologischer NaCl-Lösung im Vergleich

The problem of postsurgical adhesion formation is still in focus of scientific investigations. Although no clinical standard has been established for the prevention or therapy till today, there are promising attempts to solve the problem. Currently, the most promising approach can be seen in the application of physical adhesive barriers. These solutions allow a separation between the injured peritoneal surfaces and neighbouring structures during the postoperative healing phase. Nevertheless, their clinical application is still limited to the prevention of adhesion formation. It is known from literature that the pathology of postoperative adhesion formation shows parallels to the formation of peritoneal metastases and tumour implantation. Therefore, it becomes obvious that the formation of peritoneal carcinosis as a result of ovarian carcinoma due to peritoneal adhesion of tumour cells is possible. The aim of the present animal study was to evaluate the efficacy of the three barrier products icodextrin (Adept®), hyaluronic acid (Hyalobarrier®-Gel) and physiologic saline on adhesion formation as well as on tumour recurrence after surgery of ovarian carcinoma. Forty SCID-mice (NOD.CB17-Prkdcscid/J) were enclosed into the study and randomly assigned to four experimental groups of ten animals each: group 1: Icodextrin (Adept®), group 2: hyaluronic acid (Hyalobarrier®-Gel), group 3: physiologic saline, group 4: control group (no treatment). Peritoneal trauma was induced by standardized peritoneal lesion of the right abdominal wall. Ovarian carcinoma cell line SCOV3.ip was injected intraabdominally in all animals to induce specific tumour load. Afterwards the animals were treated by intraabdominal injection of the barrier products. After 21 postoperative days all animals were relaparotomized for analyses. Adhesion formation and tumour growth were measured using well established scores. Moreover, the tumour weight was gaged and tumour samples were taken for histological studies. All test substances (icodextrin, hyaluronic acid and physiologic saline) reduced postoperative adhesion formation and tumour growth. In the control group adhesion formation and tumour load were significantly increased compared to all other experimental groups. In mice treated with hyaluronic acid adhesion formation was significantly reduced compared to the other groups. Focusing on the parameter tumour growth, hyaluronic acid showed the best results again, but no statistic differences could be found between icodextrin, hyaluronic acid and saline. Histologic evaluation of the tumour tissue samples showed positive results of peritoneal carcinosis in all cases. With the limitation of an animal study, the results allow to suppose that the liquid compounds icodextrin, hyaluronic acid and physiologic saline may be beneficial adjuvants for prevention of postoperative adhesion formation and tumour recurrence. Further studies will have to focus on the evaluation of other barrier methods as well as on the realisation of in vivo studies with patients

Nectin‐2 in ovarian cancer: how is it expressed and what might be its functional role?

Nectin‐2 is an adhesion molecule that has been reported to play a role in tumor growth, metastasis and tumor angiogenesis. Herein, we investigated Nectin‐2 in ovarian cancer patients and in cell culture. Tumor as well as peritoneal biopsies of 60 ovarian cancer patients and 22 controls were dual stained for Nectin‐2 and CD31 using immunohistochemistry. Gene expression of Nectin‐2 was quantified by real‐time PCR and differences analyzed in relation to various tumor characteristics. In the serum of patients, vascular endothelial growth factor (VEGF) was quantified by ELISA. Effect of VEGF on Nectin‐2 expression as well as permeability was investigated in HUVEC. In tumor biopsies, Nectin‐2 protein was mainly localized in tumor cells, whereas in peritoneal biopsies, clear colocalization was found in the vasculature. T3 patients had a significantly higher percentage of positive lymph nodes and this correlated with survival. Nectin‐2 was significantly upregulated in tumor biopsies in patients with lymph node metastasis and with residual tumor >1 cm after surgery. Nectin‐2 expression was significantly suppressed in the peritoneal endothelium of patients associated with significantly increased VEGF serum levels. In cell culture, VEGF stimulation led to a significant downregulation of Nectin‐2 which was reversed by VEGF‐inhibition. In addition, Nectin‐2 knockdown in endothelial cells was associated with significantly increased endothelial permeability. Nectin‐2 expression in ovarian cancer may support tumor cell adhesion, leading to growth and lymph node metastasis. In addition, VEGF‐induced Nectin‐2 suppression in peritoneal endothelium may support an increase in vascular permeability leading to ascites production

Does VEGF facilitate local tumor growth and spread into the abdominal cavity by suppressing endothelial cell adhesion, thus increasing vascular peritoneal permeability followed by ascites production in ovarian cancer?

Background: Ovarian cancer is mostly associated with pathologically regulated permeability of peritoneal vessels, leading to ascites. Here, we investigated the molecular regulation of endothelial permeability by the vascular endothelial growth factor (VEGF) and both tight and adherens junction proteins (VE-cadherin and claudin 5) with regards to the tumor biology of different ovarian cancer types. Methods: Serum and ascites samples before and after surgery, as well as peritoneal biopsies of 68 ovarian cancer patients and 20 healthy controls were collected. In serum and ascites VEGF protein was measured by ELISA. In peritoneal biopsies co-localization of VE-cadherin and claudin 5 was investigated using immunohistochemical dual staining. In addition, the gene expression of VE-cadherin and claudin 5 was quantified by Real-time PCR. Differences in VEGF levels, VE-cadherin and claudin 5 gene expression were analyzed in relation to various tumor characteristics (tumor stage, grading, histological subtypes, resection status after surgery) and then compared to controls. Furthermore, human primary ovarian cancer cells were co-cultured with human umbilical vein endothelial cells (HUVEC) and changes in VE-cadherin and claudin 5 were investigated after VEGF inhibition. Results: VEGF was significantly increased in tumor patients in comparison to controls and accumulates in ascites. The highest VEGF levels were found in patients diagnosed with advanced tumor stages, with tumors of poor differentiation, or in the group of solid / cystic-solid tumors. Patients with residual tumor after operation showed significantly higher levels of VEGF both before and after surgery as compared to tumor-free resected patients. Results of an immunohistochemical double-staining experiment indicated co-localization of VE-cadherin and claudin 5 in the peritoneal vasculature. Compared to controls, expression of VE-cadherin and claudin 5 was significantly suppressed in peritoneal vessels of tumor patients, but there were no significant differences regarding VE-cadherin and claudin 5 expression in relation to different tumor characteristics. A significant positive correlation was found between VE-cadherin and claudin 5 expression. VEGF inhibition in vitro was associated with significant increase in VE-cadherin and claudin 5. Conclusions: Our results indicate that increased peritoneal permeability in ovarian cancer is due to down-regulation of adhesion proteins via tumor derived VEGF. Advanced ovarian cancer with aggressive tumor biology may be associated with early dysregulation of vascular permeability leading to ascites. These patients may benefit from therapeutic VEGF inhibition

Cardiac late effects after modern 3D-conformal radiotherapy in breast cancer patients: a retrospective cohort study in Germany (ESCaRa)

Purpose!#!Radiotherapy (RT) was identified as a risk factor for long-term cardiac effects in breast cancer patients treated until the 1990s. However, modern techniques reduce radiation exposure of the heart, but some exposure remains unavoidable. In a retrospective cohort study, we investigated cardiac mortality and morbidity of breast cancer survivors treated with recent RT in Germany.!##!Methods!#!A total of 11,982 breast cancer patients treated between 1998 and 2008 were included. A mortality follow-up was conducted until 06/2018. In order to assess cardiac morbidity occurring after breast cancer treatment, a questionnaire was sent out in 2014 and 2019. The effect of breast cancer laterality on cardiac mortality and morbidity was investigated as a proxy for radiation exposure. We used Cox Proportional Hazards regression analysis, taking potential confounders into account.!##!Results!#!After a median follow-up time of 11.1 years, there was no significant association of tumor laterality with cardiac mortality in irradiated patients (hazard ratio (HR) for left-sided versus right-sided tumor 1.09; 95% confidence interval (CI) 0.85-1.41). Furthermore, tumor laterality was not identified as a significant risk factor for cardiac morbidity (HR = 1.05; 95%CI 0.88-1.25).!##!Conclusions!#!Even though RT for left-sided breast cancer on average incurs higher radiation dose to the heart than RT for right-sided tumors, we found no evidence that laterality is a strong risk factor for cardiac disease after contemporary RT. However, larger sample sizes, longer follow-up, detailed information on individual risk factors and heart dose are needed to assess clinically manifest late effects of current cancer therapy

BRENDA-Score, a hghly significant, internally and externally validated prognostic marker for metastatic recurrence: analysis of 10,449 primary breast cancer patients

Background Current research in breast cancer focuses on individualization of local and systemic therapies with adequate escalation or de-escalation strategies. As a result, about two-thirds of breast cancer patients can be cured, but up to one-third eventually develop metastatic disease, which is considered incurable with currently available treatment options. This underscores the importance to develop a metastatic recurrence score to escalate or de-escalate treatment strategies. Patients and methods Data from 10,499 patients were available from 17 clinical cancer registries (BRENDA-project. In total, 8566 were used to develop the BRENDA-Index. This index was calculated from the regression coefficients of a Cox regression model for metastasis-free survival (MFS). Based on this index, patients were categorized into very high, high, intermediate, low, and very low risk groups forming the BRENDA-Score. Bootstrapping was used for internal validation and an independent dataset of 1883 patients for external validation. The predictive accuracy was checked by Harrell's c-index. In addition, the BRENDA-Score was analyzed as a marker for overall survival (OS) and compared to the Nottingham prognostic score (NPS). Results: Intrinsic subtypes, tumour size, grading, and nodal status were identified as statistically significant prognostic factors in the multivariate analysis. The five prognostic groups of the BRENDA-Score showed highly significant (p < 0.001) differences regarding MFS:low risk: hazard ratio (HR) = 2.4, 95%CI (1.7–3.3); intermediate risk: HR = 5.0, 95%CI.(3.6–6.9); high risk: HR = 10.3, 95%CI (7.4–14.3) and very high risk: HR = 18.1, 95%CI (13.2–24.9). The external validation showed congruent results. A multivariate Cox regression model for OS with BRENDA-Score and NPS as covariates showed that of these two scores only the BRENDA-Score is significant (BRENDA-Score p < 0.001; NPS p = 0.447). Therefore, the BRENDA-Score is also a good prognostic marker for OS. Conclusion: The BRENDA-Score is an internally and externally validated robust predictive tool for metastatic recurrence in breast cancer patients. It is based on routine parameters easily accessible in daily clinical care. In addition, the BRENDA-Score is a good prognostic marker for overall survival. Highlights: The BRENDA-Score is a highly significant predictive tool for metastatic recurrence of breast cancer patients. The BRENDA-Score is stable for at least the first five years after primary diagnosis, i.e., the sensitivities and specificities of this predicting system is rather similar to the NPI with AUCs between 0.76 and 0.81 the BRENDA-Score is a good prognostic marker for overall survival