Joerg Heil

Circulating miRNAs as Surrogate Markers for Circulating Tumor Cells and Prognostic Markers in Metastatic Breast Cancer

Purpose: The use of circulating tumor cells (CTC) as a prognostic marker in metastatic breast cancer (MBC) has been well established. However, their efficacy and accuracy are still under scrutiny mainly because of methods of their enrichment and identification. We hypothesized that circulating miRNAs can predict the CTC status of patients with MBC, and tested for the same. Furthermore, we aimed at establishing a panel of circulating miRNAs capable of differentiating MBC cases from healthy controls. Experimental Design: Circulating miRNAs from plasma of CTC-positive and CTC-negative patients with MBC, and healthy controls, were profiled by TaqMan Human MicroRNA arrays. Candidates from the initial screen were validated in an extended cohort of 269 individuals (61 CTC-positive, 72 CTC-negative, 60 CTC-low MBC cases, and 76 controls). Results: CTC-positive had significantly higher levels of miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-375, and miR-801 than CTC-negative MBC and controls (P < 0.00001), whereas miR-768-3p was present in lower amounts in MBC cases (P < 0.05). miR-200b was singled out as the best marker for distinguishing CTC-positive from CTC-negative patients (AUC 0.88). We identified combinations of miRNAs for differentiating MBC cases from controls (AUC 0.95 for CTC-positive; AUC 0.78 for CTC-negative). Combinations of miRNAs and miR-200b alone were found to be promising prognostic marker for progression-free and overall survival. Conclusion: This is the first study to document the capacity of circulating miRNAs to indicate CTC status and their potential as prognostic markers in patients with MBC. Clin Cancer Res; 18(21); 5972–82. ©2012 AACR.

Mastectomy trends for early-stage breast cancer: A report from the EUSOMA multi-institutional European database

INTRODUCTION Recent single-institution reports have shown increased mastectomy rates during the last decade. Further studies aiming to determine if these reports could be reflecting a national trend in the United States of America (US) have shown conflicting results. We report these trends from a multi-institutional European database. PATIENTS AND METHODS Our source of data was the eusomaDB, a central data warehouse of prospectively collected information of the European Society of Breast Cancer Specialists (EUSOMA). We identified patients with newly diagnosed unilateral early-stage breast cancer (stages 0, I or II) to examine rates and trends in surgical treatment. RESULTS A total of 15,369 early-stage breast cancer cases underwent surgery in 13 Breast Units from 2003 to 2010. Breast conservation was successful in 11,263 cases (73.3%). Adjusted trend by year showed a statistically significant decrease in mastectomy rates from 2005 to 2010 (p = 0.003) with a progressive reduction of 4.24% per year. A multivariate model showed a statistically significant association of the following factors with mastectomy: age < 40 or ≥ 70 years, pTis, pT1mi, positive axillary nodes, lobular histology, tumour grade II and III, negative progesterone receptors and multiple lesions. CONCLUSION Our study demonstrates that a high proportion of patients with newly diagnosed unilateral early-stage breast cancer from the eusomaDB underwent breast-conserving surgery. It also shows a significant trend of decreasing mastectomy rates from 2005 to 2010. Moreover, our study suggests mastectomy rates in the population from the eusomaDB are lower than those reported in the US.

Recommendations for the aesthetic evaluation of breast cancer conservative treatment

During the Turning Subjective Into Objective seminar held in Lisbon in May 2011, experts in the topic gathered to discuss the unsolved problems of aesthetic evaluation of breast-conserving treatment (BCT). The purpose of this study is to review the main methodological issues related to the aesthetic evaluation of BCT, to discuss currently used methods of evaluation and the lack of a gold standard, and to write a set of recommendations that can be used as guidance for the aesthetic evaluation of BCT.

Interobserver reliability of automated breast volume scanner (ABVS) interpretation and agreement of ABVS findings with hand held breast ultrasound (HHUS), mammography and pathology results

OBJECTIVES Handheld breast ultrasound (HHUS) lacks standardization and reproducibility. The automated breast volume scanner (ABVS) could overcome this limitation. To analyze the interobserver reliability of ABVS and the agreement with HHUS, mammography and pathology is the aim of this study. METHODS All 42 study participants (=84 breasts) received an ABVS examination in addition to the conventional breast diagnostic work-up. 25 breasts (30%) showed at least one lesion. The scans were interpreted by six breast diagnostic specialists blinded to results of breast imaging and medical history. 32 lesions received histological work-up: 20 cancers were detected. We used kappa statistics to interpret agreement between examiners and diagnostic instruments. RESULTS On the basis of the Breast Imaging Reporting and Data System (BI-RADS) classification of the 84 breasts an agreement (defined as ≥4 of 6 examiners) was achieved in 63 cases (75%) (mk=0.35) and even improved when dichotomizing the interpretation in benign (BI-RADS 1, 2) and suspicious (BI-RADS 4, 5) to 98% (mk=0.52). Agreement of ABVS examination to HHUS, mammography and pathology was fair to substantial depending on the specific analysis. CONCLUSIONS The development of an ABVS seems to be a promising diagnostic method with a good interobserver reliability, as well as a comparable good test criteria as HHUS.

Aesthetic and functional results after breast conserving surgery as correlates of quality of life measured by a German version of the Breast Cancer Treatment Outcome Scale (BCTOS).

This prospective cohort study was carried out to develop a German version of the Breast Cancer Treatment Outcome Scale (BCTOS) and to examine the relations of aesthetic and functional outcome after breast conserving surgery with quality of life (QoL). The study included 189 patients with one-sided, early stage breast cancer. A factor analysis indicated three internally consistent scales of the German BCTOS: Aesthetic Status, Functional Status and Breast Sensitivity Status. QoL was measured by the EORTC Quality of Life Questionnaire C30-BR23 (EORTC). All BCTOS scales were correlated with scales of the EORTC. Correlation magnitudes ranged from 0.24 to 0.67 (p < 0.001). A multiple regression analyses confirmed these results. The analysis of relevant covariates demonstrated that younger patients revealed poorer status on all BCTOS scales. Aesthetic and functional outcome seems to be closely related to quality of Life. The German BCTOS demonstrated to be a useful instrument.

Simultaneous integrated boost for adjuvant treatment of breast cancer- intensity modulated vs. conventional radiotherapy: The IMRT-MC2 trial

BackgroundRadiation therapy is an essential modality in the treatment of breast cancer. Addition of radiotherapy to surgery has significantly increased local control and survival rates of the disease. However, radiotherapy is also associated with side effects, such as tissue fibrosis or enhanced vascular morbidity. Modern radiotherapy strategies, such as intensity modulated radiotherapy (IMRT), can shorten the overall treatment time by integration of the additional tumor bed boost significantly. To what extent this might be possible without impairing treatment outcome and cosmetic results remains to be clarified.Methods/DesignThe IMRT-MC2 study is a prospective, two armed, multicenter, randomized phase-III-trial comparing intensity modulated radiotherapy with integrated boost to conventional radiotherapy with consecutive boost in patients with breast cancer after breast conserving surgery. 502 patients will be recruited and randomized into two arms: patients in arm A will receive IMRT in 28 fractions delivering 50.4 Gy to the breast and 64.4 Gy to the tumor bed by integrated boost, while patients in arm B will receive conventional radiotherapy of the breast in 28 fractions to a dose of 50.4 Gy and consecutive boost in 8 fractions to a total dose of 66.4 Gy.DiscussionPrimary objectives of the study are the evaluation of the cosmetic results 6 weeks and 2 years post treatment and the 2- and 5-year local recurrence rates for the two different radiotherapy strategies. Secondary objectives are long term overall survival, disease free survival and quality of life.Trial RegistrationClinicalTrials.gov Protocol ID: NCT01322854.

Objective assessment of aesthetic outcome after breast conserving therapy: subjective third party panel rating and objective BCCT.core software evaluation.

We analysed intra- and inter-rater agreement of subjective third party assessment and agreement with a semi-automated objective software evaluation tool (BCCT.core). We presented standardized photographs of 50 patients, taken shortly and one year after surgery to a panel of five breast surgeons, six breast nurses, seven members of a breast cancer support group, five medical and seven non-medical students. In two turns they rated aesthetic outcome on a four point scale. Moreover the same photographs were evaluated by the BCCT.core software. Intra-rater agreement in the panel members was moderate to substantial (k = 0.4-0.5; wk = 0.6-0.7; according to different subgroups and times of assessment). In contrast inter-rater agreement was only slight to fair (mk = 0.1-0.3). Agreement between the panel participants and the software was fair (wk = 0.24-0.45). Subjective third party assessment only fairly agree with objective BCCT.core evaluation just as third party participants do not agree well among each other.

Pooled analysis of the prognostic relevance of progesterone receptor status in five German cohort studies

The progesterone receptor (PR) has been increasingly well described as an important mediator of the pathogenesis and progression of breast cancer. The aim of this study was to assess the role of PR status as a prognostic factor in addition to other well-established prognostic factors. Data from five independent German breast cancer centers were pooled. A total of 7,965 breast cancer patients were included for whom information about their PR status was known, as well as other patient and tumor characteristics commonly used as prognostic factors. Cox proportional hazards models were built to compare the predictive value of PR status in addition to age at diagnosis, tumor size, nodal status, grading, and estrogen receptor (ER) status. PR status significantly increased the accuracy of prognostic predictions with regard to overall survival, distant disease-free survival, and local recurrence-free survival. There were differences with regard to its prognostic value relative to subgroups such as nodal status, ER status, and grading. The prognostic value of PR status was greatest in patients with a positive nodal status, negative ER status, and low grading. The PR-status adds prognostic value in addition to ER status and should not be omitted from clinical routine testing. The significantly greater prognostic value in node-positive and high-grade tumors suggests a greater role in the progression of advanced and aggressive tumors.

The effect of EUSOMA certification on quality of breast cancer care

AIM OF THE STUDY The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast units to establish minimum standards and ensure specialist multidisciplinary care. In the present study we assess the impact of EUSOMA certification for all breast units for which sufficient information was available before and after certification. MATERIALS AND METHODS For 22 EUSOMA certified breast units data of 30,444 patients could be extracted from the EUSOMA database on the evolution of QIs before and after certification. RESULTS On the average of all units, the minimum standard of care was achieved for 12/13 QIs before and after EUSOMA certification (not met for DCIS receiving just one operation). There was a significant improvement of 5 QIs after certification. The proportion of patients with invasive cancer undergoing an axillary clearance containing >9 lymph nodes (91.5% vs 89.4%, p 0.003) and patients with invasive cancer having just 1 operation (83.1% vs 80.4%, p < 0.001) dropped, but remained above the minimum standard. The targeted standard of breast care was reached for the same 4/13 QIs before and after EUSOMA certification. CONCLUSION Although the absolute effect of EUSOMA certification was modest it further increases standards of care and should be regarded as part of a process aiming for excellence. Dedicated units already provide a high level of care before certification, but continuous monitoring and audit remains of paramount importance as complete adherence to guidelines is difficult to achieve.

Efficacy and toxicity profile of pegylated liposomal doxorubicin (Caelyx) in patients with advanced breast cancer.

Many patients with metastatic breast cancer (MBC) have been treated previously with taxanes and/or anthracyclines, which renders reinduction of anthracyclines in the palliative setting impossible because of the high cardiotoxicity of these drugs. Pegylated liposomal doxorubicin represents a means of reinducing anthracyclines without increasing cardiotoxicity. The aim of this retrospective study was to evaluate the efficacy and toxicity of Caelyx in patients with MBC. Patients with histologically confirmed MBC were eligible for this retrospective study if they had received palliative chemotherapy with pegylated liposomal doxorubicin between 1 January 2002 and 31 December 2006 at the Department for Gynecology and Obstetrics at the University of Heidelberg (Germany). The main endpoints were time to progression, overall survival, and safety of the treatment with pegylated liposomal doxorubicin. In all, 141 patients were included in this retrospective trial. The median age of the patients was 54 years (range 24–84 years). Of the patients, 43% had received five to six previous chemotherapy regimens before pegylated liposomal doxorubicin was recommended. In 33% of patients, more than three organs were involved. The most commonly involved organs were bones, liver, and lungs; 37 patients had received three or at least six cycles of Caelyx. During the treatment with pegylated liposomal doxorubicin, left ventricular ejection function was not reduced by more than 15%. The major effects (grade 4) were hematological toxicity (anemia, leukopenia, and thrombocytopenia), hand–foot syndrome, and stomatitis. In nine patients, the dose was reduced and in three patients chemotherapy with Caelyx was stopped owing to hematological toxicity. In 20 patients, the dose was reduced and in nine patients chemotherapy was stopped owing to nonhematological toxicity. The median time to disease progression was 6.5 months; the overall median survival was 13 months after the first course of pegylated liposomal doxorubicin was initiated. This retrospective study confirmed the efficacy and good tolerability of pegylated liposomal doxorubicin in patients with MBC who had been treated previously with anthracycline. A dosage of 40 mg/m2 body surface every 4 weeks is equally effective with less toxicity.