M. Rudas

The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients.

Background:ER+/HER2− breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy.Methods:A total of 1702 postmenopausal ER+/HER2− breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan–Meier method and Cox regression analysis were used in an early (0–5 years) and late time interval (>5 years post diagnosis).Results:EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up.Conclusion:The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer

Background In early estrogen receptor (ER)-positive/HER2-negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria. The combined molecular/clinical EndoPredict test (EPclin) has been validated to accurately assess prognosis in this population. In this study, the clinical relevance of EPclin in relation to well-established clinical guidelines is assessed. Patients and methods We assigned risk groups to 1702 ER-positive/HER2-negative postmenopausal women from two large phase III trials treated only with endocrine therapy. Prognosis was assigned according to National Comprehensive Cancer Center Network-, German S3-, St Gallen guidelines and the EPclin. Prognostic groups were compared using the Kaplan–Meier survival analysis. Results After 10 years, absolute risk reductions (ARR) between the high- and low-risk groups ranged from 6.9% to 11.2% if assigned according to guidelines. It was at 18.7% for EPclin. EPclin reassigned 58%–61% of women classified as high-/intermediate-risk (according to clinical guidelines) to low risk. Women reclassified to low risk showed a 5% rate of distant metastasis at 10 years. Conclusion The EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors.

A combined high temporal and high spatial resolution 3 Tesla MR imaging protocol for the assessment of breast lesions: initial results.

Purpose:To develop a 3.0 Tesla breast imaging protocol that combines high temporal and spatial resolution three-dimensional MR sequences for quantitative time course and morphologic analysis of breast lesions. Materials and Methods:Thirty-four patients were included in the study (age range, 31–82; mean age, 54.3). The study protocol was approved by the Institutional Review Board and written informed consent was obtained from all patients. The magnetic resonance imaging protocol included: a coronal T1-weighted volume-interpolated-breathhold-examination sequence, focused on high temporal resolution for optimal assessment of the contrast-enhancement behavior of lesions (SI 1.7 mm isotropic; TA 3.45 minutes for 17 measurements); a coronal T1-weighted turbo fast-low-angle-shot-three-dimensional sequence, with water-excitation and fat suppression, focused on high spatial resolution for morphologic analysis (SI 1 mm isotropic; TA 2 minutes); and a repeated coronal volume-interpolated-breathhold-examination sequence for detection of washout. Lesion size and morphology were assessed. Region-of-interests for suspicious areas were manually drawn and evaluated for contrast-enhancement behavior by plotting intensity courses against time. Sensitivity and specificity with a 95% confidence interval and the negative predictive value and positive predictive value were calculated. Diagnostic accuracy was assessed. The histopathological diagnoses were used as a standard of reference. Results:Fifty-five lesions were detected in 34 patients. All malignant breast lesions were identified correctly. There were 5 false-positive lesions. The sensitivity of contrast-enhanced magnetic resonance imaging of the breast at 3 T was 100%, with a 95% confidence interval (CI) of 90.6% to 100%. The specificity was 72.2%, with a 95% CI of 49.1% to 87.5%. The positive predictive value was 0.88 and the negative predictive value was 1. Diagnostic accuracy was 91% with a 95% CI of 80.4% to 96.1%. Conclusion:Our prospective study demonstrates that the presented 3 Tesla MR imaging protocol, comprising both high temporal and high spatial resolution, enables accurate detection and assessment of breast lesions.

p53 protein expression, cell proliferation and steroid hormone receptors in ductal and lobular in situ carcinomas of the breast

p53 and c-erbB-2 expression, and their correlation with cell proliferation and steroid hormone receptors, were investigated in 121 carcinomas, 23 lobular in situ carcinomas (LCIS), 74 intraductal carcinomas (DCIS) and 24 minimal invasive carcinomas. DCIS were classified according to the EORTC classification. All markers were measured immunohistochemically on paraffin sections. None of the LCIS, 9 DCIS and 9 minimal invasive cancers showed nuclear positivity for p53. A strong association between histological type and p53 expression was found. Proliferation rates correlated with p53 expression. c-erbB-2 positivity was found in 1 LCIS, 27 DCIS and 12 minimal invasive cancers. There was a significant correlation between p53 expression and c-erbB-2. Both parameters were associated with high proliferation rate and negativity for steroid hormone receptor status. Nuclear pleomorphism could become a comparable prognostic marker in DCIS as it is for infiltrating carcinomas.

CXCR4 is Expressed in Ductal Carcinoma in situ of the Breast and in Atypical Ductal Hyperplasia

Recent evidence attributed important influence of chemokines and their receptors on motility, homing, and proliferation of cancer cells at specific metastatic sites. Here we report that the CXCL12 (SDF-1α) chemokine receptor CXCR4 is expressed in human ductal carcinoma in situ (DCIS) as well as in atypical ductal hyperplasia. CXCR4 was expressed in pure DCIS and DCIS with concurrent invasive disease. In 66% of the samples, atypical ductal hyperplasia was present, and >92% exhibited positive CXCR4-staining. Expression of CXCR4 at this very early step of tumor development indicates a role of this receptor in providing a selective advantage to such cells on their way to metastasizing carcinomas. These results strengthen the ideas to target chemokine networks involved in tumor progression and metastatis as a therapeutic approach in malignant disease or as a chemoprevention strategy, blocking the transition from premalignancy to malignancy.

It is possible to omit postoperative irradiation in a highly selected group of elderly breast cancer patients

The purpose of this study was the evaluation of the necessity of routinely applied postoperative radiotherapy in a highly selected patient-group after breast conserving surgery. Between 1983 and May 1994, 356 women over 60 years of age with Stage I or II breast cancer were treated by quadrantectomy and axillary dissection followed by either adjuvant irradiation or no radiotherapy. We have analysed our data retrospectively to investigate whether irradiation has any benefit in elderly patients with respect to locoregional recurrence rates. After a median follow-up of 60 months the multivariate model revealed lymph node status (p=0.002) as highly significant with regard to local recurrence free survival. We were not able to identify a positive effect of adjuvant irradiation in patients with negative lymph nodes and positive receptor status: both patient groups with or without irradiation had similar locoregional recurrence rates of 3%. In a subgroup of patients who were lymph node negative, receptor positive, and received adjuvant tamoxifen therapy, the local recurrence rates were as low as 2% in both groups. Concerning these results it may be possible to avoid the morbidity and potential psychological side effects of radiotherapy in breast cancer patients over 60 years of age treated by breast conserving surgery (T1, N0, positive hormone receptor, adjuvant tamoxifen) without increasing risk of locoregional recurrence. These data have to be confirmed in a prospectively randomized fashion.

Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases

Background:Trastuzumab-based therapy after diagnosis of brain metastases (BM) may improve survival due to prolonged systemic disease control. We investigated whether lapatinib may yield additional survival benefit.Methods:Eighty patients with BM from HER2-positive breast cancer were identified. Karnofsky Performance Score (KPS) of at least 70 was required. We included a control group of 37 patients treated before 2003, when continuation of trastuzumab after diagnosis of BM was not yet recommended. Remainders received either trastuzumab or lapatinib and trastuzumab (either concomitantly or sequentially) with or without chemotherapy.Results:Median overall survival (OS) in patients receiving trastuzumab after diagnosis of BM was 13 months; corresponding numbers were 9 months in patients treated with chemotherapy, and 3 months with radiotherapy alone. Median OS was not reached in the lapatinib group. Addition of lapatinib prolonged OS over trastuzumab alone (P=0.002). After correction for potential confounders, lapatinib therapy remained an independent positive predictor for survival (HR 0.279; P=0.012).Interpretation:This retrospective single-centre study suggests that the introduction of lapatinib improved survival in patients with BM from HER2-positive breast cancer. Patients with KPS ⩾70 may benefit when treated with lapatinib in addition to trastuzumab after completion of local therapy.

Thymidine labeling index and Ki-67 growth fraction in breast cancer: Comparison and correlation with prognosis

SummaryIn situ determination of proliferative activity was performed on 184 consecutive primary invasive breast cancers. Methods used were monoclonal antibody Ki-67 in immunohistochemistry and thymidine labeling index. Tumor proliferation correlated between both methods (p = 0.0001). For thymidine labeling index and Ki-67, respectively, significant correlations existed with histologic tumour grade and steroid hormone receptors (Tumor grade: TLIp = 0.0001; Ki-67 p = 0.0001. ER-ICA: TLI = 0.0001; Ki-67 p = 0.014. PgR-ICA: TLIp = 0.0001; Ki-67 p = 0.0008).For thymidine labeling index a significant correlation was demonstrated for overall survival (p = 0.001) and recurrence free survival (p = 0.01). No statistical significance was observed for clinical outcome and Ki-67 (overall survival p = 0.18; recurrence free survival p = 0.1). None of the factors, TLI or Ki-67, was an independent prognostic factor as demonstrated by multivariate analysis.

Brain metastases free survival differs between breast cancer subtypes

Background:Brain metastases (BM) are frequently diagnosed in patients with HER-2-positive metastatic breast cancer; in addition, an increasing incidence was reported for triple-negative tumours. We aimed to compare brain metastases free survival (BMFS) of breast cancer subtypes in patients treated between 1996 until 2010.Methods:Brain metastases free survival was measured as the interval from diagnosis of extracranial breast cancer metastases until diagnosis of BM. HER-2 status was analysed by immunohistochemistry and reanalysed by fluorescent in situ hybridisation if a score of 2+ was gained. Oestrogen-receptor (ER) and progesterone-receptor (PgR) status was analysed by immunohistochemistry. Brain metastases free survival curves were estimated with the Kaplan–Meier method and compared with the log-rank test.Results:Data of 213 patients (46 luminal/124 HER-2/43 triple-negative subtype) with BM from breast cancer were available for the analysis. Brain metastases free survival differed significantly between breast cancer subtypes. Median BMFS in triple-negative tumours was 14 months (95% CI: 11.34–16.66) compared with 18 months (95% CI: 14.46–21.54) in HER-2-positive tumours (P=0.001) and 34 months (95% CI: 23.71–44.29) in luminal tumours (P=0.001), respectively. In HER-2-positive patients, co-positivity for ER and HER-2 prolonged BMFS (26 vs 15 m; P=0.033); in luminal tumours, co-expression of ER and PgR was not significantly associated with BMFS. Brain metastases free survival in patients with lung metastases was significantly shorter (17 vs 21 months; P=0.014).Conclusion:Brain metastases free survival in triple-negative breast cancer, as well as in HER-2-positive/ER-negative, is significantly shorter compared with HER-2/ER co-positive or luminal tumours, mirroring the aggressiveness of these breast cancer subtypes.

Tumour-associated macrophages in breast cancer and their prognostic correlations

Abstract Breast cancer is known as a macrophage (Mps) infiltrated type of tumour. The biological and prognostic significance of this phenomenon is not clear. The intensity of intratumoural Mps infiltration as well as its correlation with reliable prognostic parameters has been studied. The extent of Mps infiltration was evaluated by immunohistochemistry in paraffin-embedded sections from formalin-fixed samples of 34 node-negative and 86 node-positive primary breast cancers using KP-1 (CD-68) DAKO monoclonal antibody (MoAB) and polyclonal antibody to lysozyme. Intensive Mps infiltration was closely associated with absence of regional metastases: 16 (47%) node-negative and only 5 (5.8%) node-positive tumours were infiltrated intensively (more than 500 KP-1+ cells in 40 high-power fields). However, when stratified into subgroups, intensity of Mps infiltration was strongly associated with prognostic parameters, which are traditionally considered to be the signs of bad prognosis (high tumour grade, oestrogen receptor (ER) negative, progesterone receptor (PgR) negative and high mitotic rate).