Annette Lebeau

Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer

Using an Affymetrix 10K SNP array to screen for gene copy number changes in breast cancer, we detected a single-gene amplification of the ESR1 gene, which encodes estrogen receptor alpha, at 6q25. A subsequent tissue microarray analysis of more than 2,000 clinical breast cancer samples showed ESR1 amplification in 20.6% of breast cancers. Ninety-nine percent of tumors with ESR1 amplification showed estrogen receptor protein overexpression, compared with 66.6% cancers without ESR1 amplification (P < 0.0001). In 175 women who had received adjuvant tamoxifen monotherapy, survival was significantly longer for women with cancer with ESR1 amplification than for women with estrogen receptor–expressing cancers without ESR1 amplification (P = 0.023). Notably, we also found ESR1 amplification in benign and precancerous breast diseases, suggesting that ESR1 amplification may be a common mechanism in proliferative breast disease and a very early genetic alteration in a large subset of breast cancers.

Monitoring Primary Systemic Therapy of Large and Locally Advanced Breast Cancer by Using Sequential Positron Emission Tomography Imaging With [18F]Fluorodeoxyglucose

PURPOSEnTo evaluate positron emission tomography (PET) using [(18)F]fluorodeoxyglucose (FDG) for prediction of histopathologic response early during primary systemic therapy of large or locally advanced breast cancer.nnnPATIENTS AND METHODSnIn a prospective multicenter trial, 272 FDG-PET scans were performed in 104 patients at baseline (n = 104) and after the first (n = 87) and second cycle (n = 81) of chemotherapy. The level and relative changes in standardized uptake value (SUV) of FDG uptake were assessed regarding their ability to predict histopathologic response. All patients underwent surgery after chemotherapy, and histopathologic response defined as minimal residual disease or gross residual disease served as the reference standard.nnnRESULTSnSeventeen (16%) of 104 patients were histopathologic responders and 87 were (84%) nonresponders. All patients for whom baseline SUV was less than 3.0 (n = 24) did not achieve a histopathologic response. SUV decreased by 51% +/- 18% after the first cycle of chemotherapy in histopathologic responders (n = 15), compared with 37% +/- 21% in nonresponders (n = 54; P = .01). A threshold of 45% decrease in SUV correctly identified 11 of 15 responders, and histopathologic nonresponders were identified with a negative predictive value of 90%. Similar results were found after the second cycle when using a threshold of 55% relative decrease in SUV.nnnCONCLUSIONnFDG-PET allows for prediction of treatment response by the level of FDG uptake in terms of SUV at baseline and after each cycle of chemotherapy. Moreover, relative changes in SUV after the first and second cycle are a strong predictor of response. Thus, FDG-PET may be helpful for individual treatment stratification in breast cancer patients.

Interdisciplinary consensus on the uses and technique of MR-guided vacuum-assisted breast biopsy (VAB): Results of a European consensus meeting

PURPOSEnQuality assurance of MR-guided vacuum-assisted breast biopsy (VAB).nnnMETHODnA consensus was achieved based on the existing literature and experience of an interdisciplinary group comprising European specialists in breast imaging and VAB.nnnRESULTSnFull imaging work-up must be completed according to existing standards before an indication for MR-guided VAB is established. The procedure should be reserved for lesions demonstrable by MRI alone. Acquisition of >24 cores (11-Gauge) should be routinely attempted, with the intention of sufficiently removing small lesions for accurate diagnosis. Following biopsy the patient should be re-imaged to demonstrate the biopsy site and its proximity to the lesion and hence the likely accuracy of the sampling. All patients should be discussed in a regular interdisciplinary conference and a documented consensus reached regarding patient management. Regular audit and review of all MR-guided VAB results and subsequent follow-up are recommended.nnnCONCLUSIONnThis consensus includes protocols for the indication, performance parameters, interdisciplinary interpretation therapeutic recommendation, documentation and follow-up of MR-guided VAB. It does not replace official recommendations for percutaneous biopsy.

Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 2008

ZusammenfassungDie aktualisierte Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 2008 vermittelt den wissenschaftlichen Kenntnisstand in evidenz- und konsensbasierter Form und ist unter Beteiligung der Deutschen Gesellschaft für Chirurgie e.V, der Deutschen Gesellschaft der Plastischen, Rekonstruktiven und Ästhetischen Chirurgen e.V. und 29 weiterer Fachgesellschaften, Berufsverbänden und nichtärztlichen Organisationen erstellt. Ziel der Stufe-3-Leitlinie ist es, Ärzte sowie gesunde und betroffene Frauen durch evidenzbasierte und formal konsentierte Empfehlungen bei anstehenden medizinischen Entscheidungen im Rahmen der Diagnosekette zur Früherkennung von Brustkrebs zu unterstützen. Die Leitlinie umfasst neben den Empfehlungen zur Diagnosekette die Beschreibung zur Ausgestaltung der Qualitätssicherung von Struktur-, Prozess- und Ergebnisqualität (Outcomes) sowie deren Evaluation durch einen Qualitätsindikatorensatz.Die aktualisierte Stufe-3-Leitlinie 2008 löst die 2003 erstellte Leitlinie ab.Die Leitlinienempfehlungen werden dargestellt. Die Details sind der Publikation in Geburtsh Frauenh 2008; 68: 251–26 zu entnehmen. Die Langfassung der Leitlinie ist als Buch im W. Zuckschwerdt Verlag GmbH/München erschienen und ist, wie der Methodenreport und der Evidenzreport auch, über die Internetseite www.awmf-leitlinien.de (Reg.: Nr. 077/001) frei zugänglich.AbstractThe updated 2008 German Guideline for Early Detection of Breast Cancer provides evidence-based and consensus-based recommendations of the knowledge gained by the German Society for Surgery and the German Society of Plastic, Aesthetic, and Reconstructive Surgeons together with 29 professional societies, associations, and nonmedical organizations. The guideline is meant to assist physicians, healthy women, and patients in medical decisions with recommendations regarding the diagnostic chain in early detection of breast cancer. In addition to these recommendations, the guideline also includes descriptions of quality assurance for resources, procedures, outcomes, and evaluation using a set of quality indicators. It updates the previous version from 2003. The guideline’s recommendations are presented. They are described in detail in the full publication (in German) Geburtsh Frauenh 2008; 68:251–261. The long version of the Guideline, methods report, and evidence report are available on the internet at www.awmf-leitlinien.de (reg. no. 077/001) with free access.The updated 2008 German Guideline for Early Detection of Breast Cancer provides evidence-based and consensus-based recommendations of the knowledge gained by the German Society for Surgery and the German Society of Plastic, Aesthetic, and Reconstructive Surgeons together with 29 professional societies, associations, and nonmedical organizations. The guideline is meant to assist physicians, healthy women, and patients in medical decisions with recommendations regarding the diagnostic chain in early detection of breast cancer. In addition to these recommendations, the guideline also includes descriptions of quality assurance for resources, procedures, outcomes, and evaluation using a set of quality indicators. It updates the previous version from 2003. The guidelines recommendations are presented. They are described in detail in the full publication (in German) Geburtsh Frauenh 2008; 68:251-261. The long version of the Guideline, methods report, and evidence report are available on the internet at www.awmf-leitlinien.de (reg. no. 077/001) with free access.

Gene amplification in ductal carcinoma in situ of the breast

Multiple different biologically and clinically relevant genes are often amplified in invasive breast cancer, including HER2, ESR1, CCND1, and MYC. So far, little is known about their role in tumor progression. To investigate their significance for tumor invasion, we compared pure ductal carcinoma in situ (DCIS) and DCIS associated with invasive cancer with regard to the amplification of these genes. Fluorescence in situ hybridization (FISH) was performed on a tissue microarray containing samples from 130 pure DCIS and 159 DCIS associated with invasive breast cancer. Of the latter patients, we analyzed the intraductal and invasive components separately. In addition, lymph node metastases of 23 patients with invasive carcinoma were included. Amplification rates of pure DCIS and DCIS associated with invasive cancer did not differ significantly (pure DCIS vs. DCIS associated with invasive cancer: HER2 22.7 vs. 24.2%, ESR1 19.0 vs. 24.1%, CCND1 10.0 vs. 14.8%, MYC 11.8 vs. 6.5%; Pxa0>xa00.05). Furthermore, we observed a high concordance of the amplification status for all genes if in situ and invasive carcinoma of individual patients were compared. This applied also to the corresponding lymph node metastases. Our results indicate no significant differences between the gene amplification status of DCIS and invasive breast cancer concerning HER2, ESR1, CCND1, and MYC. Therefore, our data suggest an early role of all analyzed gene amplifications in breast cancer development but not in the initiation of invasive tumor growth.

Assessment of residual tumour by FDG-PET: Conventional imaging and clinical examination following primary chemotherapy of large and locally advanced breast cancer

Background:The aim of this was to evaluate FDG-PET (2-(fluorine-18)-fluoro-2-deoxy-D-glucose positron emission tomography) for assessment of residual tumour after primary chemotherapy of large and locally advanced breast cancer in comparison with conventional imaging modalities.Methods:In a prospective multicentre trial, 99 patients underwent one or more breast imaging modalities before surgery in addition to clinical examination, namely, FDG-PET (n=89), mammography (n=47), ultrasound (n=46), and magnetic resonance imaging (MRI) (n=46). The presence of residual tumour by conventional imaging, dichotomised as positive or negative, and the level of FDG uptake (standardised uptake values, SUV) were compared with histopathology, which served as the reference standard. Patients with no residual tumour or only small microscopic foci of residual tumour were classified as having minimal residual disease and those with extensive microscopic and macroscopic residual tumour tissue were classified as having gross residual disease.Results:By applying a threshold SUV of 2.0, the sensitivity of FDG-PET for residual tumour was 32.9% (specificity, 87.5%) and increased to 57.5% (specificity, 62.5%) at a threshold SUV of 1.5. Conventional imaging modalities were more sensitive in identifying residual tumour, but had a low corresponding specificity; sensitivity and specificity were as follows: MRI 97.6 and 40.0%, mammography 92.5 and 57.1%, ultrasound 92.0 and 37.5%, respectively. Breast MRI provided the highest accuracy (91.3%), whereas FDG-PET had the lowest accuracy (42.7%).Conclusions:FDG-PET does not provide an accurate assessment of residual tumour after primary chemotherapy of breast cancer. Magnetic resonance imaging offers the highest sensitivity, but all imaging modalities have distinct limitations in the assessment of residual tumour tissue when compared with histopathology.

Rare oncogenic mutations of predictive markers for targeted therapy in triple-negative breast cancer

Women with triple-negative breast cancer (TNBC) do not benefit from endocrine therapy or trastuzumab. Chemotherapy is the only systemic therapy currently available. To reduce the elevated risk of disease progression in these patients, better treatment options are needed, which are less toxic and more targeted to this patient population. We performed a comprehensive analysis of potential targetable genetic aberrations affecting the receptor tyrosine kinase/RAS/MAPK pathway, which are observed at higher frequencies in adenocarcinomas of other organs. Sixty-five individual TNBCs were studied by sequence analysis for HER2 (exon 18–23), EGFR (exon 18–21), KRAS (exon 2), and BRAF (exon 15) mutations. In addition, a tissue microarray was constructed to screen for EGFR gene copy gain and EML4-ALK fusion by FISH. Triple-negative status was confirmed by immunohistochemistry and FISH on tissue microarray sections. EGFR and CK5/6 immunohistochemical analyses were performed for identification of the basal-like phenotype. In addition, mutation analysis of TP53 (exon 5–8) was included. Sequence analysis revealed HER2 gene mutation in only one patient (heterozygous missense mutation in exon 19: p.L755S). No mutations were found in EGFR, KRAS, and BRAF. High polysomy of EGFR was detected in 5 of the 62 informative cases by FISH. True EGFR gene amplification accompanied by strong membranous EGFR protein expression was observed in only one case. No rearrangement of the ALK gene was detected. Basal-like phenotype was identified in 38 of the 65 TNBCs (58.5xa0%). TP53 gene mutation was found in 36/63 (57.1xa0%) tumors. We conclude that targetable genetic aberrations in the receptor tyrosine kinase/RAS/MAPK pathway occur rarely in TNBC.

2008 update of the guideline: early detection of breast cancer in Germany

IntroductionThe goal of the 2008 updated guideline: early detection of breast cancer in Germany is to support physicians as well as healthy and affected women in the decision-making process involved in the diagnostic chain for the early detection of breast cancer by providing them with evidence- and consensus-based recommendations. The updated guideline replaces the guideline issued in 2003.Materials and methodsThe guideline forms the basis for developing an effective and efficient national early breast cancer detection program that meets the standards set by the Council of Europe and WHO for cancer control programs. The guideline presents the current, evidence- and consensus-based state of scientific knowledge in a multidisciplinary approach for the entire diagnostic chain, consisting of history taking and risk consultation, information on health behavior, clinical breast examination, diagnostic imaging, image-guided percutaneous tissue-acquisition techniques, open surgical excisional biopsy and pathomorphological tissue evaluation. The guideline recommends a set of quality indicators to assure resource availability, performance quality and outcomes enhancing total quality management for early breast cancer diagnosis.Conclusion Currently, early detection of breast cancer offers the most promising possibility to optimize the diagnosis and treatment of breast cancer and, as a result, reduce breast cancer mortality and improve health related quality of life in women.

Oestrogen receptor gene (ESR1) amplification is frequent in endometrial carcinoma and its precursor lesions.

Oestrogen receptor alpha (ER) plays a critical, diverse and not fully understood role in endometrial carcinoma. Most endometrial carcinomas express ER and some of these tumours respond favourably to anti‐oestrogen therapy. On the other hand, tamoxifen therapy constitutes a major risk factor for endometrial carcinoma development. Amplification of the ESR1 gene encoding ER was recently shown to constitute a mechanism for ER over‐expression in breast carcinoma. This study was designed to determine the potential role of ESR1 amplifications in endometrial carcinoma. Tissue microarrays of 368 endometrial carcinomas and large sections of 43 cases of endometrial hyperplasia were analysed for ESR1 gene amplification and ER protein expression by means of fluorescence in situ hybridization (FISH) and immunohistochemistry. FISH revealed ESR1 amplification in 40/176 (23%) cancers, 6/19 (32%) atypical complex hyperplasias, 3/10 (30%) complex hyperplasias without atypia and 2/14 (14%) simple hyperplasias without atypia. Strong ER protein expression was significantly linked to ESR1 amplification in endometrial carcinoma (p = 0.0036). These data indicate that ESR1 amplification might be one mechanism for ER over‐expression in endometrial carcinoma, and suggest an early role for ESR1 amplification in the development of a significant fraction of endometrial carcinoma. Given the predictive role of ESR1 amplification for tamoxifen response in breast carcinoma, it will be interesting to investigate the response of ESR1‐amplified endometrial cancers to anti‐oestrogenic drugs. Copyright

Prognostic relevance of AIB1 (NCoA3) amplification and overexpression in breast cancer

AIB1 (amplified in breast cancer 1) is an estrogen receptorα (ERα) co-activator, known to be amplified and overexpressed in a fraction of breast cancers. It has been linked to prognosis and tamoxifen resistance. However, results have been ambiguous. The different functions of AIB1 in ERα-positive and -negative disease are poorly understood. Therefore, we analyzed the clinical significance of AIB1 in breast cancer with respect to ERα-status and characterized the subgroups. 2,197 breast carcinomas sampled on a pre-existing tissue microarray (TMA) were analyzed for AIB1 expression and amplification by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Results: AIB1 expression was detected in 60xa0% of the tumors. It was associated with tumor size (pxa0=xa00.003), high histological grade (pxa0<xa00.0001), poor disease-specific, and overall survival (pxa0=xa00.0018 and pxa0=xa00.003). There was a strong inverse relationship between AIB1 and ERα expression (pxa0<xa00.0001). AIB1 overexpression was associated with increased Ki67 labeling index (pxa0<xa00.0001), even if analyzed for different ER expression levels. AIB1 amplification was found in 11xa0% of the carcinomas. It was associated with high histological grade (pxa0=xa00.0012), lymph node involvement (pxa0=xa00.0163), and poor disease-specific survival (pxa0=xa00.0032) but not with overall survival (pxa0=xa00.1672) or ER status (pxa0=xa00.4456). If ER-positive tumors were stratified according to their AIB1 amplification status, there was a significant worse disease-specific survival in cases showing AIB1 amplification (pxa0=xa00.0017). AIB1 expression is associated with unfavorable prognosis and tumor phenotype. It seems to unfold its oncogenic potential at least in part independent from its role as an ERα co-activator. AIB1 has an impact on cell cycle regulation in ERα-positive as well as ERα-negative tumors. Furthermore, AIB1 amplification characterizes a subgroup of ERα-positive breast cancer with worse outcome. Therefore, AIB1 might be helpful to identify those ERα-positive breast cancers patients who are candidates for adjuvant chemotherapy.