Michael Golatta

The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study

IntroductionWhile it has been reported that the risk of contralateral breast cancer in patients from BRCA1 or BRCA2 positive families is elevated, little is known about contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations.MethodsA retrospective, multicenter cohort study was performed from 1996 to 2011 and comprised 6,235 women with unilateral breast cancer from 6,230 high risk families that had tested positive for BRCA1 (n = 1,154) or BRCA2 (n = 575) mutations or tested negative (n = 4,501). Cumulative contralateral breast cancer risks were calculated using the Kaplan-Meier product-limit method and were compared between groups using the log-rank test. Cox regression analysis was applied to assess the impact of the age at first breast cancer and the familial history stratified by mutation status.ResultsThe cumulative risk of contralateral breast cancer 25 years after first breast cancer was 44.1% (95%CI, 37.6% to 50.6%) for patients from BRCA1 positive families, 33.5% (95%CI, 22.4% to 44.7%) for patients from BRCA2 positive families and 17.2% (95%CI, 14.5% to 19.9%) for patients from families that tested negative for BRCA1/2 mutations. Younger age at first breast cancer was associated with a higher risk of contralateral breast cancer. For women who had their first breast cancer before the age of 40 years, the cumulative risk of contralateral breast cancer after 25 years was 55.1% for BRCA1, 38.4% for BRCA2, and 28.4% for patients from BRCA1/2 negative families. If the first breast cancer was diagnosed at the age of 50 or later, 25-year cumulative risks were 21.6% for BRCA1, 15.5% for BRCA2, and 12.9% for BRCA1/2 negative families.ConclusionsContralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations is similar to the risk in patients with sporadic breast cancer. Thus, the mutation status should guide decision making for contralateral mastectomy.

Plasma microRNA panel for minimally invasive detection of breast cancer.

Over the last few years, circulating microRNAs (miRNAs) have emerged as promising novel and minimally invasive markers for various diseases, including cancer. We already showed that certain miRNAs are deregulated in the plasma of breast cancer patients when compared to healthy women. Herein we have further explored their potential to serve as breast cancer early detection markers in blood plasma. Circulating miR-127-3p, miR-376a and miR-652, selected as candidates from a miRNA array-based screening, were found to be associated with breast cancer for the first time (n = 417). Further we validated our previously reported circulating miRNAs (miR-148b, miR-376c, miR-409-3p and miR-801) in an independent cohort (n = 210) as elevated in the plasma of breast cancer patients compared to healthy women. We described, for the first time in breast cancer, an over-representation of deregulated miRNAs (miR-127-3p, miR-376a, miR-376c and miR-409-3p) originating from the chromosome 14q32 region. The inclusion of patients with benign breast tumors enabled the observation that miR-148b, miR-652 and miR-801 levels are even elevated in the plasma of women with benign tumors when compared to healthy controls. Furthermore, an analysis of samples stratified by cancer stage demonstrated that miR-127-3p, miR-148b, miR-409-3p, miR-652 and miR-801 can detect also stage I or stage II breast cancer thus making them attractive candidates for early detection. Finally, ROC curve analysis showed that a panel of these seven circulating miRNAs has substantial diagnostic potential with an AUC of 0.81 for the detection of benign and malignant breast tumors, which further increased to 0.86 in younger women (up to 50 years of age).

Evaluation of Virtual Touch Tissue Imaging Quantification, a New Shear Wave Velocity Imaging Method, for Breast Lesion Assessment by Ultrasound

Objectives. To evaluate virtual touch tissue imaging quantification (VTIQ) as a new elastography method concerning its intra- and interexaminer reliability and its ability to differentiate benign from malignant breast lesions in comparison to and in combination with ultrasound (US) B-mode breast imaging reporting and data system (BI-RADS) assessment. Materials and Methods. US and VTIQ were performed by two examiners in 103 women with 104 lesions. Intra- and interexaminer reliability of VTIQ was assessed. The area under the receiver operating curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of BIRADS, VTIQ, and combined data were compared. Results. Fifty-four of 104 lesions were malignant. Intraexaminer reliability was consistent, and interexaminer agreement showed a strong positive correlation (r = 0.93). The mean VTIQ values in malignant lesions were significantly higher than those in benign (7.73 m/s ± 1.02 versus 4.46 m/s ± 1.87; P < 0.0001). The combination of US-BIRADS with the optimal cut-off for clinical decision making of 5.18 m/s yielded a sensitivity of 98%, specificity of 82%, PPV of 86%, and NPV of 98%. The combination of BIRADS and VTIQ led to improved test validity. Conclusion. VTIQ is highly reliable and reproducible. There is a significant difference regarding the mean maximum velocity of benign and malignant lesions. Adding VTIQ to BIRADS assessment improves the specificity.

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.

Normal breast tissue stiffness measured by a new ultrasound technique: virtual touch tissue imaging quantification (VTIQ).

OBJECTIVE To evaluate normal breast tissue stiffness with virtual touch tissue imaging quantification (VTIQ) using prospectively collected data. MATERIALS AND METHODS B-mode ultrasound and VTIQ were performed in 132 breasts in 97 women. Mean values of VTIQ for parenchyma and fatty tissue were compared between those measured in healthy breasts and in the surrounding of histologically proven benign and malignant breast lesions. Moreover we reviewed VTIQ values according to breast density measured by the American College of Radiology (ACR) categories. In addition we analyzed re-test reliability of VTIQ. RESULTS In 132 breasts the mean VTIQ values in parenchyma were significantly higher than in fatty tissue (3.23 m/s ± 0.74 versus 2.5 m/s ± 0.61; p<0.0001). In healthy breasts as well as in the surrounding of a benign or malignant lesions the VTIQ values of parenchyma were similar (p=0.12). In fatty tissue, small differences between mean VTIQ values of 2.25 m/s ± 0.51, 2.52 m/s ± 0.48 and 2.65 m/s ± 0.71 (p=0.01) in the respective groups were observed. The comparison of mean VTIQ values of parenchyma and fatty tissue in more and less dense breasts (ACR 1+2 versus ACR 3+4 breasts) also yielded no statistically significant difference. The re-test reliability of VTIQ assessed with three independent measurements was moderate (interclass-correlation of 0.52 (p<0.0001)). CONCLUSION VTIQ is a reliable method for measuring the stiffness of breast tissue. We propose standard values for healthy parenchyma and fatty tissues independent of the surrounding tissue or the ACR category.

Outcome analysis of patients with primary breast cancer initially treated at a certified academic breast unit.

INTRODUCTION Evaluation of oncological outcome and prognostic factors of patients with primary breast cancer treated at a certified academic breast unit. PATIENTS AND METHODS We prospectively collected data of 3338 patients, diagnosed with primary breast cancer between 01.01.2003 and 31.12.2010 and treated at the Breast Unit Heidelberg, Germany, in order to analyze outcome in clinical practice. We evaluated local control rate (LCR), disease-free survival (DFS), distant disease-free survival (DDFS), observed overall survival (OS) and age-adjusted relative overall survival (ROS). In addition, the impact of known prognostic factors on these outcome variables was examined in univariate and multivariate analyses. RESULTS Of all patients, 368 (11.0%) had carcinoma in situ (CIS) and 197 (5.9%) had bilateral cancers. For the 2970 patients with invasive cancer, of which 49 patients (1.7%) had metastastic disease at time of diagnosis, DFS, LCR, DDFS, OS and ROS at 5 years were 79.8%, 84.7%, 81.2%, 86.3%, and 89.8%, respectively. In multivariate analysis age, pT category, nodal status, hormone receptor status and grading were identified as independent prognostic factors for OS. CONCLUSION Compared with recent population-based reports from Germany, more favourable patient characteristics and nominally higher survival was found among this large cohort of patients with primary breast cancer treated at a single certified breast unit.

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.

Change of aesthetic and functional outcome over time and their relationship to quality of life after breast conserving therapy.

PURPOSE We analyzed changes in aesthetic and functional outcome over time after breast conserving therapy. Our special interest resides in the question of whether these aspects gain or loose their influence on quality of life (QoL) with temporal progress. PATIENTS AND METHODS This prospective single centre cohort study included 138 patients, treated with breast conserving surgery and consecutive radiotherapy. Patients completed two questionnaires one week and one year after surgery: the BCTOS (Breast Cancer Treatment Outcome Scale) to measure Functional, Aesthetic, and Breast Sensitivity Status and the EORTC (European Organisation for Research and Treatment of Cancer) C30-BR23 to assess QoL. We applied correlation and multiple regression analysis as statistical methods. RESULTS Aesthetic and Functional Status did not change significantly over one year, whereas Breast Sensitivity Status and several QoL subscales showed significant improvement (p < 0.0001). Correlations between BCTOS scales and EORTC subscales remain similar over time. Functional and Aesthetic Status kept a strong impact on global health (Spearmans Rho = -0.28 to -0.45 depending on time of assessment). Increasing age and poorer Functional Status shortly after surgery are predictors of a decline in global health over one year (p < 0.001). CONCLUSION Functional and aesthetic outcome after breast conserving surgery maintain their impact on QoL over a one year follow-up period and are valuable predictors of QoL.

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.

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.