Regine Wolters

Survival of patients with bilateral versus unilateral breast cancer and impact of guideline adherent adjuvant treatment: a multi-centre cohort study of 5292 patients.

UNLABELLED This retrospective multi-centre study is focussed on recurrence free and overall survival of bilateral breast cancer (BBC) versus unilateral breast cancer (UBC). The impact of BBC on survival is stratified to guideline adherence, according to the German national S3-guideline. Another aim of the study is to identify the influence of various guideline violations in adjuvant treatment on survival of BBC patients. 229 (4.3%) patients had BBC and 5063 (95.7%) had UBC. There is a significant association between BBC/UBC and recurrence free (RFS: p < 0.001) and overall survival (OAS: p = 0.003). Only 15.7% of patients with BBC are treated 100% guideline adherent (index- + contralateral tumour). 31.0% (30.5%) were guideline adherent with respect to the index (contralateral) tumour. The outcome decreases significantly with the number of guideline violations. There was no significant difference in RFS and OAS between BBC and UBC after adjusting for tumour size, nodal status, grading and if guideline adherent treatment was applied. CONCLUSION 1. Patients with BBC have primarily a worse prognosis in terms of RFS and OAS than patients with primarily UBC. 2. There is a strong association between guideline adherence and RFS/OAS of patients with BBC or UBC. The outcome decreases with the number of guideline violations. 3. If guideline adherent treatment was applied (for both tumours in case of BBC) there was no significant difference in RFS and OAS between BBC and UBC after adjusting for tumour size, nodal status, grading.

Does Guideline-Adherent Therapy Improve the Outcome for Early-Onset Breast Cancer Patients?

Background and Objective: Guidelines for the treatment of early-onset breast cancer have been proposed in several countries, but to date, their impact on outcomes is unverified. The objective of this study was to evaluate the association between guideline-adherent versus nonadherent treatment and recurrence-free survival (RFS) and overall survival (OAS) in early-onset breast cancer patients. Methods: A total of 1,778 patients were included in the study, of whom 111 were 35 years or younger and 1,667 were between 36 and 55 years. RFS and OAS were compared between the two groups, with respect to multiple parameters. All survival data were adjusted for tumor characteristics and analyzed with respect to guideline adherence according to the German Step 3 guidelines. Results: Statistically significant differences between the two groups (<35 years, 36–55 years) were observed with regard to breast surgery (p = 0.002) and hormone therapy (p = 0.006). Both groups were treated identically in terms of guideline adherence concerning axillary dissection (p = 0.9), radiation therapy (p = 0.7) and chemotherapy (p = 0.556). Young breast cancer patients whose treatment adhered to guideline recommendations had increased RFS and OAS [RFS: p = 0.030, hazard ratio (HR) 2.95, 95% confidence interval (CI) 1.11–7.83; OAS: p ≤ 0.001, HR 2.92, 95% CI 2.01–4.23]. Conclusion: Guideline-adherent treatment for early-onset breast cancer patients significantly improves OAS and RFS and should therefore be demanded for all patients.

A comparison of international breast cancer guidelines – Do the national guidelines differ in treatment recommendations?

AIM OF THE STUDY Clinical practice guidelines (CPG) are an appropriate method to optimise routine clinical care. Numerous CPGs for the diagnosis and treatment of breast cancer have been developed by national health institutions or medical societies. While a comparison of methodological criteria has been undertaken before, it is unknown whether these CPGs differ in their actual treatment recommendations. METHODS We included national breast cancer CPGs from the USA, Canada, Australia, the UK, and Germany that satisfy internationally recognised methodological criteria and are in widespread use in daily clinical care. Treatment recommendations for adjuvant invasive breast cancer including surgery, radiation, endocrine therapy, chemotherapy and anti-HER2-therapy were compared. RESULTS Recommendations for endocrine therapy show discordances regarding optimal usage of ovarian function suppression for premenopausal patients and aromatase inhibitors for postmenopausal patients. However, most other treatment recommendations exhibit a large degree of congruency. This reflects the fact that they rest on the same evidence base, and that many national guidelines are adopted from other guidelines so that well accepted guidelines are cited within other guidelines. CONCLUDING STATEMENT Considering that the development of guidelines is a very expensive and resource-intensive task the question arises whether the development of national guidelines in numerous countries is worth the effort since the recommendations differ only marginally.

Impact of Guideline Conformity on Breast Cancer Therapy: Results of a 13-Year Retrospective Cohort Study

Background: To date, few studies have investigated whether the implementation of national breast cancer guidelines fulfills the goal to optimize the national standard of care. Therefore, we aimed to evaluate retrospectively the guideline-related 13-year data on breast cancer patients treated at our institution. Patients and Methods: In a retrospective cohort study, the records of a total of 2,231 patients with primary breast cancer treated during the period of 1992–2005 at the Department of Obstetrics and Gynecology, University of Ulm, Germany, were analyzed. Based on the German national Step 3 (S3) guideline, a model was created to classify groups according to therapy ‘conforming’ and ‘non-conforming’ to guideline recommendations. Results: In 2005, 70.2% of all patients included received both surgical and systemic adjuvant therapies conforming to the guideline. Guideline-conforming treatment was accompanied with significant advantages in terms of recurrence-free survival (RFS) and overall survival (OAS) rates. Conclusions: It has to be demanded that breast cancer patients are treated in con-formity with the S3 guidelines. The reasons for a treatment not conforming to the guidelines should be analyzed for the detection of barrier factors, in order to optimize adherence to the guidelines and therefore to prolong RFS and OAS.

The impact of adjuvant radiotherapy on the survival of primary breast cancer patients: a retrospective multicenter cohort study of 8935 subjects

BACKGROUND Radiotherapy (RT) is proven to be an important backbone for adjuvant therapy in randomized, controlled trials, but it is unclear if these effects are provable in a daily routine cohort of breast cancer patients. This study sought to answer the following questions in a daily routine cohort of breast cancer patients: 1. Does guideline-adherent RT improve primary breast cancer patient survival? 2. Is breast-conserving surgery (BCS) followed by RT equal to a mastectomy (MA) with regard to outcome parameters? 3. Does adjuvant RT compensate for an incomplete tumor resection (R1)? PATIENTS AND METHODS In this retrospective, multicenter cohort study, we investigated data from 8935 primary breast cancer patients recruited from 17 participating certified breast cancer centers in Germany between 1992 and 2008. Guideline adherence based on internationally validated guidelines. RESULTS The patients who received guideline-adherent RT for primary breast cancer were associated with significantly improved survival parameters [recurrence-free survival (RFS): P < 0.001; overall survival (OS): P < 0.001] compared with patients who did not receive guideline-adherent adjuvant RT. Furthermore, the results demonstrated that there were no significant differences in RFS and OS between BCS followed by RT and MA [RFS: P = 0.293; OS: P = 0.104]. Adjuvant RT did not improve the outcome of patients receiving nonguideline-adherent incomplete tumor resection via BCS (R1); these patients showed a significantly impaired RFS [P < 0.001] and OS [P < 0.001] compared with patients who underwent guideline-adherent complete tumor resection via BCS (R0). In addition, non-guideline-adherent RT after MA (overtherapy) did not significantly influence survival [RFS: P = 0.838; OS: P = 0.613]. CONCLUSION Our study confirms the importance of guideline-adherent adjuvant RT. It shows highly significant associations between RFS or OS and guideline adherent RT. Nevertheless, inadequate (R1-) surgical resection in a daily routine cohort of patients increases the risk of local recurrence and appears not to be compensated by the following RT.BACKGROUND Radiotherapy (RT) is proven to be an important backbone for adjuvant therapy in randomized, controlled trials, but it is unclear if these effects are provable in a daily routine cohort of breast cancer patients. This study sought to answer the following questions in a daily routine cohort of breast cancer patients: 1. Does guideline-adherent RT improve primary breast cancer patient survival? 2. Is breast-conserving surgery (BCS) followed by RT equal to a mastectomy (MA) with regard to outcome parameters? 3. Does adjuvant RT compensate for an incomplete tumor resection (R1)? PATIENTS AND METHODS In this retrospective, multicenter cohort study, we investigated data from 8935 primary breast cancer patients recruited from 17 participating certified breast cancer centers in Germany between 1992 and 2008. Guideline adherence based on internationally validated guidelines. RESULTS The patients who received guideline-adherent RT for primary breast cancer were associated with significantly improved survival parameters [recurrence-free survival (RFS): P < 0.001; overall survival (OS): P < 0.001] compared with patients who did not receive guideline-adherent adjuvant RT. Furthermore, the results demonstrated that there were no significant differences in RFS and OS between BCS followed by RT and MA [RFS: P = 0.293; OS: P = 0.104]. Adjuvant RT did not improve the outcome of patients receiving nonguideline-adherent incomplete tumor resection via BCS (R1); these patients showed a significantly impaired RFS [P < 0.001] and OS [P < 0.001] compared with patients who underwent guideline-adherent complete tumor resection via BCS (R0). In addition, non-guideline-adherent RT after MA (overtherapy) did not significantly influence survival [RFS: P = 0.838; OS: P = 0.613]. CONCLUSION Our study confirms the importance of guideline-adherent adjuvant RT. It shows highly significant associations between RFS or OS and guideline adherent RT. Nevertheless, inadequate (R1-) surgical resection in a daily routine cohort of patients increases the risk of local recurrence and appears not to be compensated by the following RT.

An internally and externally validated prognostic score for metastatic breast cancer: analysis of 2269 patients

BACKGROUND The prognosis of metastatic breast cancer (MBC) is extremely heterogeneous. Although patients with MBC will uniformly die to their disease, survival may range from a few months to several years. This underscores the importance of defining prognostic factors to develop risk-adopted treatment strategies. Our aim has been to use simple measures to judge a patients prognosis when metastatic disease is diagnosed. PATIENTS AND METHODS We retrospectively analyzed 2269 patients from four clinical cancer registries. The prognostic score was calculated from the regression coefficients found in the Cox regression analysis. Based on the score, patients were classified into high-, intermediate-, and low-risk groups. Bootstrapping and time-dependent receiver operating characteristic curves were used for internal validation. Two independent datasets were used for external validation. RESULTS Metastatic-free interval, localization of metastases, and hormone receptor status were identified as significant prognostic factors in the multivariate analysis. The three prognostic groups showed highly significant differences regarding overall survival from the time of metastasis [intermediate compared with low risk: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.36-2.27, P < 0.001; high compared with low risk: HR 3.54, 95% CI 2.81-4.45, P < 0.001). The median overall survival in these three groups were 61, 38, and 22 months, respectively. The external validation showed congruent results. CONCLUSIONS We developed a prognostic score, based on routine parameters easily accessible in daily clinical care. Although major progress has been made, the optimal therapeutic management of the individual patient is still unknown. Besides elaborative molecular classification of tumors, simple clinical measures such as our model may be helpful to further individualize optimal breast cancer care.BACKGROUND The prognosis of metastatic breast cancer (MBC) is extremely heterogeneous. Although patients with MBC will uniformly die to their disease, survival may range from a few months to several years. This underscores the importance of defining prognostic factors to develop risk-adopted treatment strategies. Our aim has been to use simple measures to judge a patients prognosis when metastatic disease is diagnosed. PATIENTS AND METHODS We retrospectively analyzed 2269 patients from four clinical cancer registries. The prognostic score was calculated from the regression coefficients found in the Cox regression analysis. Based on the score, patients were classified into high-, intermediate-, and low-risk groups. Bootstrapping and time-dependent receiver operating characteristic curves were used for internal validation. Two independent datasets were used for external validation. RESULTS Metastatic-free interval, localization of metastases, and hormone receptor status were identified as significant prognostic factors in the multivariate analysis. The three prognostic groups showed highly significant differences regarding overall survival from the time of metastasis [intermediate compared with low risk: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.36-2.27, P < 0.001; high compared with low risk: HR 3.54, 95% CI 2.81-4.45, P < 0.001). The median overall survival in these three groups were 61, 38, and 22 months, respectively. The external validation showed congruent results. CONCLUSIONS We developed a prognostic score, based on routine parameters easily accessible in daily clinical care. Although major progress has been made, the optimal therapeutic management of the individual patient is still unknown. Besides elaborative molecular classification of tumors, simple clinical measures such as our model may be helpful to further individualize optimal breast cancer care.

Clinical Criteria Replenish High-Sensitive Troponin and Inflammatory Markers in the Stratification of Patients with Suspected Acute Coronary Syndrome

Objectives In patients with suspected acute coronary syndrome (ACS), rapid triage is essential. The aim of this study was to establish a tool for risk prediction of 30-day cardiac events (CE) on admission. 30-day cardiac events (CE) were defined as early coronary revascularization, subsequent myocardial infarction, or cardiovascular death within 30 days. Methods and Results This single-centre, prospective cohort study included 377 consecutive patients presenting to the emergency department with suspected ACS and for whom troponin T measurements were requested on clinical grounds. Fifteen biomarkers were analyzed in the admission sample, and clinical parameters were assessed by the TIMI risk score for unstable angina/Non-ST myocardial infarction and the GRACE risk score. Sixty-nine (18%) patients presented with and 308 (82%) without ST-elevations, respectively. Coronary angiography was performed in 165 (44%) patients with subsequent percutaneous coronary intervention – accounting for the majority of CE – in 123 (33%) patients, respectively. Eleven out of 15 biomarkers were elevated in patients with CE compared to those without. High-sensitive troponin T (hs-cTnT) was the best univariate biomarker to predict CE in Non-ST-elevation patients (AUC 0.80), but did not yield incremental information above clinical TIMI risk score (AUC 0.80 vs 0.82, p = 0.69). Equivalence testing of AUCs of risk models and non-inferiority testing demonstrated that the clinical TIMI risk score alone was non-inferior to its combination with hs-cTnT in predicting CE. Conclusions In patients presenting without ST-elevations, identification of those prone to CE is best based on clinical assessment based on TIMI risk score criteria and hs-cTnT.

Abstract P5-14-03: The impact of adjuvant radiotherapy on survival in primary breast caner: What is the role of guideline adherence in radiotherapy – A retrospective multi-center cohort study of 8935

Introduction: Breast cancer remains the most common malignancy in women in industrialized countries. Over the last decades improved adjuvant therapy strategies were the key for a favorable prognosis in patients. Among these, radiotherapy is one of the important backbones in adjuvant therapy strategies. This study tries to answer the following questions: 1. Does guideline adherent radiotherapy improve survival in primary breast cancer patients? 2. Is breast conserving surgery followed by RT equal to mastectomy in outcome parameters? 3. Is there a difference in survival between patients receiving BCT followed by RT with non guideline conform incomplete tumor resection (R1)? Does adjuvant RT compensate incomplete resection of the tumor? Material and Methods: In this German retrospective multi-center cohort study called BRENDA (breast cancer care under evidence based guidelines) we investigate data of 8.935 primary breast cancer patients recruited from 17 participating breast cancer centers in Germany (all certified breast cancer centers by the German Cancer Society). Guideline adherence is established in all adjuvant treatment modalities based on internationally validated guidelines. Results: Patients who received guideline adherent RT in primary breast cancer were associated with significantly improved survival parameters [RFS: p Discussion: Guideline adherent adjuvant RT is associated with an improvement of survival parameters in primary breast cancer. Patients undergoing guideline conform BCT (R0) followed by RT present an equal outcome as patients undergoing mastectomy. However adjuvant RT can not compensate an inadequate tumor resection via BCT and RT overtherapy after mastectomy does not improve survival parameters. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-03.

There Is a Significant Association between 100% Treatment Adherence and Higher Recurrence-Free and Overall Survival in Early-Onset Patients with Breast Cancer – Conclusions from an Empty Subset of Patients Do Not Change This Statement

tic modalities (surgical therapy, radiotherapy, endocrine therapy) were determined on this basis of the recommendations and statements as shown in table 3 of our original study [1] . In the model, a patient was treated with (100%) guideline-adherent therapies if the study evaluation did not show any deviation from the recommendations in any of the items (A–D). Patients were excluded from this study if they could not be evaluated for guideline adherence in at least 1 of the 4 therapeutic options for any reason. The St. Gallen covenants and risk classifications were used for defining whether the individual therapeutic options applied in the dataset could be ranked as cytostatic therapies adherent or non-adherent to guideline recommendations. Non-adherent therapies were additionally divided into overand undertreatments. The number of guideline violations can be greater than the number of therapeutic modalities because for every modality several options were checked separately. Guidelines are designed to assist the clinician in making appropriate decisions about patient care, but they do not address the levels of adherence of various pharmacological therapies. Therefore, this aspect was excluded from this study. We take the opportunity to clear up some questions and criticisms by Hoffmann and Andersohn [in this issue, pp. 301–302] concerning our paper [1] . The authors suppose implausible results on the basis of possible ‘immortal time bias’ and ‘healthy adherer bias’. Furthermore, they criticize a non-transparent representation of the ‘operationalization of guideline adherence’. We thank Hoffmann and Andersohn for these remarks, which allow us in the following to give our view on the various criticisms.

Guideline Compliant Irradiation Following Breast Conserving Surgery or Mastectomy Improves Recurrence Free Survival.

Purpose: Two pivotal studies by Veronesi and Fisher have established the concept of breast conserving surgery for small breast cancers stage T1 or with size less than 4 cm respectively. The aim of this retrospective study was to validate the current practice of BCS in an unselected cohort of patients within the network of 16 regional breast cancer centres in germany and to quantify the detrimental effect of guideline non-compliant locoregional therapy on recurrence free survival.Methods: 4507 patients who received primary therapy between 1992 and 2005 were recorded. Data on surgery, axillary dissection and postoperative irradiation were used to categorize patients according to adherence to guidelines. The effect of guideline compliant locoregional therapy on recurrence free survival was calculated.Results: Out of 3579 patients (79.4%) who were treated by BCS 3036 (84.8%) received postoperative irradiation as mandated by the guideline. A total of 928 (20.6%) patients underwent mastectomy, out of these a fraction of 344 patients received postoperative irradiation as required by the guideline. No significant difference in recurrence free survival was found between patients who underwent BCS plus postoperative irradiation and those patients who underwent mastectomy (T1: HR=1.08 (95%-CI: 0.70-1.67), p=0.281; T2: HR=1.21 (95%-CI: 0.61 - 2.39), p=0.577). Guideline compliant locoregional therapy resulted in a significant improvement in RFS as shown for patients receiving guideline compliant BCS plus irradiation or guideline compliant mastectomy without irradiation versus patients with any type of non-compliant locoregional therapy (HR=3.53, 95%-CI: 2.97-4.18, p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4106.