Tissue Factor (TF) is the initiator of blood coagulation but also functions as a signal transduction receptor. TF expression in breast cancer is associated with higher tumor grade, metastasis and... Show moreTissue Factor (TF) is the initiator of blood coagulation but also functions as a signal transduction receptor. TF expression in breast cancer is associated with higher tumor grade, metastasis and poor survival. The role of TF signaling on the early phases of metastasis has never been addressed. Here, we show an association between TF expression and metastasis as well as cancer stemness in 574 breast cancer patients. In preclinical models, blockade of TF signaling inhibited metastasis tenfold independent of primary tumor growth. TF blockade caused a reduction in epithelial-to-mesenchymal-transition, cancer stemness and expression of the pro-metastatic markers Slug and SOX9 in several breast cancer cell lines and in ex vivo cultured tumor cells. Mechanistically, TF forms a complex with beta 1-integrin leading to inactivation of beta 1-integrin. Inhibition of TF signaling induces a shift in TF-binding from alpha 3 beta 1-integrin to alpha 6 beta 4 and dictates FAK recruitment, leading to reduced epithelial-to-mesenchymal-transition and tumor cell differentiation. In conclusion, TF signaling inhibition leads to reduced pro-metastatic transcriptional programs, and a subsequent integrin beta 1 and beta 4-dependent reduction in metastasic dissemination. Show less
PURPOSE For postmenopausal patients with breast cancer, previous subgroup analyses have shown a modest benefit from adjuvant bisphosphonate treatment. However, the efficacy of oral nitrogen... Show morePURPOSE For postmenopausal patients with breast cancer, previous subgroup analyses have shown a modest benefit from adjuvant bisphosphonate treatment. However, the efficacy of oral nitrogen-containing bisphosphonates such as ibandronate is unclear in this setting. TEAM-IIB investigates adjuvant ibandronate in postmenopausal women with estrogen receptor-positive (ER+) breast cancer. METHODS TEAM-IIB is a randomized, open-label, multicenter phase III study. Postmenopausal women with stage I-III ER+ breast cancer and an indication for adjuvant endocrine therapy (ET) were randomly assigned 1:1 to 5 years of ET with or without oral ibandronate 50 mg once daily for 3 years. Major ineligibility criteria were bilateral breast cancer, active gastroesophageal problems, and health conditions that might interfere with study treatment. Primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population. RESULTS Between February 1, 2007, and May 27, 2014, 1,116 patients were enrolled, 565 to ET with ibandronate (ibandronate arm) and 551 to ET alone (control arm). Median follow-up was 8.5 years. DFS was not significantly different between the ibandronate and control arms (HR, 0.97; 95% CI, 0.76 to 1.24; log-rank P = .811). Three years after random assignment, DFS was 94% in the ibandronate arm and 91% in the control arm. Five years after random assignment, this was 89% and 86%, respectively. In the ibandronate arm, 97/565 (17%) of patients stopped ibandronate early because of adverse events. Significantly more patients experienced GI issues, mainly dyspepsia, in the ibandronate arm than in the control arm (89 [16%] and 54 [10%], respectively; P < .003). Eleven patients in the ibandronate arm developed osteonecrosis of the jaw. CONCLUSION In postmenopausal women with ER+ breast cancer, adjuvant ibandronate 50 mg once daily does not improve DFS and should not be recommended as part of standard treatment regimens. Show less
PURPOSEFor postmenopausal patients with breast cancer, previous subgroup analyses have shown a modest benefit from adjuvant bisphosphonate treatment. However, the efficacy of oral nitrogen... Show morePURPOSEFor postmenopausal patients with breast cancer, previous subgroup analyses have shown a modest benefit from adjuvant bisphosphonate treatment. However, the efficacy of oral nitrogen-containing bisphosphonates such as ibandronate is unclear in this setting. TEAM-IIB investigates adjuvant ibandronate in postmenopausal women with estrogen receptor–positive (ER+) breast cancer.METHODSTEAM-IIB is a randomized, open-label, multicenter phase III study. Postmenopausal women with stage I-III ER+ breast cancer and an indication for adjuvant endocrine therapy (ET) were randomly assigned 1:1 to 5 years of ET with or without oral ibandronate 50 mg once daily for 3 years. Major ineligibility criteria were bilateral breast cancer, active gastroesophageal problems, and health conditions that might interfere with study treatment. Primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population.RESULTSBetween February 1, 2007, and May 27, 2014, 1,116 patients were enrolled, 565 to ET with ibandronate (ibandronate arm) and 551 to ET alone (control arm). Median follow-up was 8.5 years. DFS was not significantly different between the ibandronate and control arms (HR, 0.97; 95% CI, 0.76 to 1.24; log-rank P = .811). Three years after random assignment, DFS was 94% in the ibandronate arm and 91% in the control arm. Five years after random assignment, this was 89% and 86%, respectively. In the ibandronate arm, 97/565 (17%) of patients stopped ibandronate early because of adverse events. Significantly more patients experienced GI issues, mainly dyspepsia, in the ibandronate arm than in the control arm (89 [16%] and 54 [10%], respectively; P < .003). Eleven patients in the ibandronate arm developed osteonecrosis of the jaw.CONCLUSIONIn postmenopausal women with ER+ breast cancer, adjuvant ibandronate 50 mg once daily does not improve DFS and should not be recommended as part of standard treatment regimens. Show less
Introduction: Nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) is increasingly used for both breast cancer (TNSM) and risk reduction (RRNSM). The aim of the study is to... Show moreIntroduction: Nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) is increasingly used for both breast cancer (TNSM) and risk reduction (RRNSM). The aim of the study is to report the results of the INSPIRE registry assessing health-related quality of life (HRQoL) comparing baseline and 1-year follow-up, regarding surgical indications and chemotherapy (CT) received. Methods: INSPIRE is a prospective database including women undergoing NSM and IBR from 18 countries. HRQoL was measured using EORTC QLQC30 and QLQ-BR23 before surgery and after 1 year. Results: A total of 677 women were included, of whom 537 (79.3%) underwent TNSM and 140 (21.6%) RRNSM: in total, 806 NSM (556 TNSM and 250 RRNSM). Nipple involvement was present in 7.73% of TNSM and incidental carcinoma in 1.2% of the RRNSM group. Out of the overall 537 patients with systemic treatment, 177 (32.96%) received neoadjuvant chemotherapy (NCT) and 118 (21.92%) adjuvant chemotherapy (CT). A total of 227 patients (28.16%) developed at least one complication postoperatively, 164 (29.5%) in the TNSM group and 63 (25.2%) in the RRNSM group. The TNSM group improved in global health status and emotional functioning after 1 year. No differences were found when comparing HRQoL at 1 year between patients who received NCT and those who received adjuvant CT. The RRNSM group showed improvement in HRQoL, with better emotional functioning and fatigue after 1 year. Conclusions: This registry reports HRQoL findings after NSM. The impact of CT on worse HRQoL is independent from its timing. Patients with RRNSM showed an improved HRQoL at 1-year follow-up. Discussion of HRQoL outcomes with patients will facilitate the informed decision-making when considering NSM. Show less
Purpose: Individualized selection of patients with early-stage hormone receptor-positive (HR+) breast cancer for extended endocrine therapy (EET) is required to balance modest gains in outcome with... Show morePurpose: Individualized selection of patients with early-stage hormone receptor-positive (HR+) breast cancer for extended endocrine therapy (EET) is required to balance modest gains in outcome with toxicities of prolonged use. This study examined the Breast Cancer Index [BCI; HOXB13/IL17BR ratio (H/I)] as a predictive biomarker of EET benefit in patients from the Investigation on the Duration of Extended Adjuvant Letrozole trial.Experimental Design: BCI was tested in primary tumor specimens from 908 patients randomized to receive 2.5 versus 5 years of extended letrozole. The primary endpoint was recurrence-free interval. Cox models and likelihood ratios tested the interaction between HET and BCI (H/I).Results: BCI (H/I)-high significantly predicted benefit from extended letrozole in the overall cohort [HR 0.42; 95% confidence interval (CI), 0.21-0.84; P = 0.011] and any aromatase inhibitor subset [HR 0.34; 95% CI, 0.16-0.73; P - 0.004), whereas BCI (H/I)-low patients did not derive significant benefit (HR 0.95; 95% CI, 0.58-1.56; P - 0.84 and HR 0.90; 95% CI, 053-1.55; P - 0.71, respectively) treatment to hiomarker interaction was significant (P = 0.045, P = 0.025, respectively). BCI identified approximately 50% of patients with clinically high-risk disease that did not benefit, and with clinically low-risk disease that derived significant benefit, from an additional 2.5 years of EEL.Conclusions: BCI (H/I) predicted preferential benefit from 5 versus 2.5 years of EET and identified patients with improved outcomes from completing 10 years of adjuvant endocrine therapy. Findings expand the clinical utility of BCI (H/I) to a broader range of patients and beyond prognostic risk factors as a predictive endocrine response biomarker for early-stage HR+ breast cancer. Show less
Purpose: Individualized selection of patients with early stage hormone receptor positive (HR+) breast cancer for extended endocrine therapy (EET) are required to balance modest gains in outcome... Show morePurpose: Individualized selection of patients with early stage hormone receptor positive (HR+) breast cancer for extended endocrine therapy (EET) are required to balance modest gains in outcome with toxicities of prolonged use. This study examined the Breast Cancer Index (BCI) [HOXB13/IL17BR ratio (H/I)] as a predictive biomarker of EET benefit in patients from the Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) trial.Experimental design: BCI was tested in primary tumor specimens from 908 patients randomized to receive 2.5 vs 5 years of extended letrozole. The primary endpoint was recurrence-free interval (RFI). Cox models and likelihood ratios tested the interaction between EET and BCI (H/I).Results: BCI (H/I)-High significantly predicted benefit from extended letrozole in the Overall cohort (HR 0.42, 95% CI 0.21-0.84; P=0.011) and Any AI subset (HR 0.34, 0.16-0.73; P=0.004), whereas BCI (H/I)-Low patients did not derive significant benefit (HR 0.95, 0.58-1.56; P=0.84, HR 0.90, 0.53-1.55; P=0.71, respectively); treatment to biomarker interaction was significant (P=0.045, P=0.025, respectively). BCI identified ~50% of patients with clinically high-risk disease that did not benefit, and with clinically low-risk disease that derived significant benefit, from an additional 2.5 years of EET.Conclusions: BCI (H/I) predicted preferential benefit from 5 vs 2.5 years of EET and identified patients with improved outcomes from completing 10 years of adjuvant endocrine therapy. Findings expand the clinical utility of BCI (H/I) to a broader range of patients and beyond prognostic risk factors as a predictive endocrine response biomarker for early stage HR+ breast cancer. Show less
PURPOSEMost distant recurrences (DRs) in women with hormone receptor–positive breast cancer occur after 5 years from diagnosis. The Clinical Treatment Score post-5 years (CTS5) estimates DRs after... Show morePURPOSEMost distant recurrences (DRs) in women with hormone receptor–positive breast cancer occur after 5 years from diagnosis. The Clinical Treatment Score post-5 years (CTS5) estimates DRs after 5 years of adjuvant endocrine therapy (AET). The aim of this study was to externally validate the CTS5 as a prognostic/predictive tool.METHODSThe CTS5 categorizes patients who have been disease free for 5 years into low, intermediate, and high risk and calculates an absolute risk for developing DRs between 5 and 10 years. Discrimination and calibration were assessed using data from the TEAM and IDEAL trials. The predictive value of the CTS5 was tested with data from the IDEAL trial.RESULTSA total of 5,895 patients from the TEAM trial and 1,591 patients from the IDEAL trial were included. When assessing the CTS5 discrimination, significantly more DRs were found at 10 years after diagnosis in the CTS5 high- and intermediate-risk groups than in the low-risk group (hazard ratio, 5.7 [95% CI, 3.6 to 8.8] and 2.8 [95% CI, 1.7 to 4.4], respectively). In low- and intermediate-risk patients, the CTS5-predicted DR rates were higher, although not statistically significantly so, than observed rates. However, in high-risk patients, the CTS5-predicted DR rates were significantly higher than observed rates (29% v 19%, respectively; P < .001). The CTS5 was not predictive for extended AET duration.CONCLUSIONThe CTS5 score as applied to patients treated in the TEAM and IDEAL cohorts discriminates between risk categories but overestimates the risk of late DRs in high-risk patients. Therefore, the numerical risk assessment from the CTS5 calculator in its current form should be interpreted with caution when used in daily clinical practice, particularly in high-risk patients. Show less
PurposeIn breast cancer, hormone receptor (HR) status is generally a qualitative measure; positive or negative. Quantitatively measured oestrogen and progesterone receptors (ER and PR) are... Show morePurposeIn breast cancer, hormone receptor (HR) status is generally a qualitative measure; positive or negative. Quantitatively measured oestrogen and progesterone receptors (ER and PR) are frequently proposed prognostic and predictive markers, some guidelines even provide different treatment options for patients with strong versus weak expression.AimTo evaluate quantitative HR load assessed by immunohistochemistry as a prognostic and predictive measure in stage 1-3 breast cancer.MethodsWe reviewed all the available literature on quantitatively measured HRs using immunohistochemistry.ResultsAll included studies (n=19) comprised a cohort of 30,754 patients. Only 2 out of 17 studies found a clear correlation between higher quantitative ER and better disease outcome. Only one trial examined quantitative ER both as prognostic and predictive marker and found no association between ER% and survival. Ten studies examined quantitative PR load, only two of those found a significant correlation between higher PR load and better disease outcome. Two trials examined quantitative PR both as prognostic and predictive marker, neither found any association between PR% and disease outcome.ConclusionsThere is no clear evidence for using quantitatively assessed ER and PR as prognostic nor predictive marker in patients with stage 1-3 breast cancer. We recommend only using a qualitative HR status in future guidelines and treatment considerations. Show less
PURPOSE:In breast cancer, hormone receptor (HR) status is generally a qualitative measure; positive or negative. Quantitatively measured oestrogen and progesterone receptors (ER and PR) are... Show morePURPOSE:In breast cancer, hormone receptor (HR) status is generally a qualitative measure; positive or negative. Quantitatively measured oestrogen and progesterone receptors (ER and PR) are frequently proposed prognostic and predictive markers, some guidelines even provide different treatment options for patients with strong versus weak expression.AIM:To evaluate quantitative HR load assessed by immunohistochemistry as a prognostic and predictive measure in stage 1-3 breast cancer.METHODS:We reviewed all the available literature on quantitatively measured HRs using immunohistochemistry.RESULTS:All included studies (n = 19) comprised a cohort of 30,754 patients. Only 2 out of 17 studies found a clear correlation between higher quantitative ER and better disease outcome. Only one trial examined quantitative ER both as prognostic and predictive marker and found no association between ER% and survival. Ten studies examined quantitative PR load, only two of those found a significant correlation between higher PR load and better disease outcome. Two trials examined quantitative PR both as prognostic and predictive marker, neither found any association between PR% and disease outcome.CONCLUSIONS:There is no clear evidence for using quantitatively assessed ER and PR as prognostic nor predictive marker in patients with stage 1-3 breast cancer. We recommend only using a qualitative HR status in future guidelines and treatment considerations. Show less
Evrard, S.; Velde, C. van de; Noordhoek, I.; Caballero, C.; Ceelen, W.; Polom, K.; ... ; European Soc Surgical Oncology 2019
As part of its mission to promote the best surgical care for cancer patients, the European Society of Surgical Oncology (ESSO) has been developing multiple programmes for clinical research along... Show moreAs part of its mission to promote the best surgical care for cancer patients, the European Society of Surgical Oncology (ESSO) has been developing multiple programmes for clinical research along with its educational portfolio. This position paper describes the different research activities of the Society over the past decade and an action plan for the upcoming five years to lead innovative and high quality surgical oncology research. ESSO proposes to consider pragmatic research methodologies as a complement to randomised clinical trials (RCT), advocates for increased funding and operational support in conducting research and aims to enable young surgeons to be active in research and establish partnerships for translational research activities. Show less
Noordhoek, I.; Bastiaannet, E.; Velde, C.J.H. van de 2018
