UZ Leuven

The requirements of a specialist Breast Unit. Perry N, Wilson A, Ellis I, Blichert-Toft M, Rosselli del Turco M, Garas I, Greco M, Julien JP, Christiaens R, van de Velde C, Holland R, Elston C, Pentek Z, Cataliotti L. Eur J Cancer 2000;36:2288-2293. A real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) to detect breast carcinoma cells in peripheral blood. Aerts J, Wynendaele W, Paridaens R, Christiaens MR, Van den Bogaert W, Van Oosterom AT, Vandekerckhove F. Ann Oncol 2001;12(1):39-46. 56 Abstract: BACKGROUND: The detection of occult carcinoma cells in patients with breast cancer has been shown to predict disease recurrence and metastasis. MATERIALS AND METHODS: To improve on molecular detection of breast carcinoma cells in blood, we have developed a sensitive and quantitative assay using real-time quantitative RT-PCR identifying transcripts of the cytokeratin-19 (CK19) gene. RESULTS: This real-time quantitative RT-PCR is sensitive, accurate and has a high reproducibility within a wide dynamic range, which permits simultaneous quantitative analysis of samples with varying input concentrations.
Furthermore, the procedure offers several technical advantages over classic quantitative PCR methods (competitive RT-PCR, Northern blotting) such as decreased likelihood of contamination due to absence of post-PCR manipulations, high sample throughput because of absence of post-PCR processing time (no agarose gel electrophoresis). In this pilot
study, we detected significantly elevated CK19 transcript levels in < 10% of the volunteers, in +/- 30% of stage I-IIIa patients preoperatively and in > 70% of the and stage IV breast cancer patients. CONCLUSIONS: Analyses using this real time quantitative RT-PCR for CK19 mRNA may prove to have clinical implications in the assessment of circulating tumour cells in peripheral blood, micrometastases in bone marrow or lymph nodes in breast cancer patients. Application of this technique in a clinical population may improve diagnosis and monitoring of metastatic breast cancer and its validation is currently ongoing.

Detection of micrometastatic disease and monitoring of perioperative tumor cell dissemination in primary operable breast cancer patients using realtime quantitative revers transcription-PCR. Ismail MS, Wynendaele W, Aerts JLE, Paridaens R, Gaafar R, Shakankiry N, Khaled HM, Christiaens MR, Wildiers H, Omar S, Vandekerckhove P, Van Oosterom AT. Clin Cancer Res 2004;10:196-201.Abstract: Purpose: We previously found a statistically significant number of cytokeratin 19 (CK19)+ cells in peripheral blood (PB) of stage IV breast cancer (BC) patients compared with those of healthy volunteers, using a quantitative real-time reverse transcription-PCR. We aimed to apply the technique on bone marrow (BM) of primary operable BC patients. Preand postoperative PB samples of these patients were further analyzed to investigate possible shedding of CK19+ cells during the operation. Experimental Design: In 54 primary operable BC patients, we analyzed 50 BM samples taken preoperatively and 297 PB samples. PB samples were collected before surgery; immediately after surgery; on the first, second, and fifth day postoperatively; and one month  postoperatively. Results : In BM of controls and BC patients, we detected a median of 28 and 568 CK19+ cells/5 x 106 leukocytes, respectively (P < 0.001). In preoperative blood (B-1) samples, we measured a median of 109 CK19+ cells. Using the upper limit of 95% confidenceinterval of controls as cutoff, 74% and 52% of BM and (B-1), respectively were considered CK19+. There was no significant correlation between CK19+ cells in BM and (B-1) and classical prognostic factors. We found no significant difference between blood samples at different time points with respect to the average CK19+ cells. Conclusions: In primary BC patients, we detected high numbers of CK19+ cells in BM and PB (B-1) samples compared with controls. However, no significant correlation between the presence of CK19+ cells in BM and PB and classical prognostic factors was found. We detected no statistically significant influence of surgical manipulation on CK19+ cells.

Implications of the sentinel lymph node procedure for local and systemic adjuvant treatment. Smeets A, Christiaens MR. Curr Opin Oncol 2005;17(6):539-544. Abstract: PURPOSE OF REVIEW: The objective of the sentinel lymph node procedure in breast cancer is to perform an accurate axillary staging and provide good local control, while sparing the patients the morbidity of an axillary lymph node dissection.  Since its routine clinical use, questions were raised concerning the implications for local and systemic adjuvant treatment. This review provides an update of the recent literature. RECENT FINDINGS: As a result of a more detailed histopathologic work-up of the sentinel  ymph node, higher rates of lymph node metastases are detected. This leads to an upstaging of a subset of node-negative patients and an increase in the overall percentage of node-positive patients. However, the clinical implications of micrometastases and isolated  umor cells remain unclear. Furthermore, sentinel lymph nodes may be found in the internal mammary lymph node chain but the treatment of these nodes is subject of debate. SUMMARY: Current guidelines recommend axillary lymph node dissection in patients with a positive sentinel node. The surgical removal of the internal mammary lymph node is only indicated in the context of a clinical trial. Radiation therapy of the axilla is an acceptable  alternative for patients who refuse an axillary lymph node dissection (clinical trial). The value of radiotherapy to the internal mammary lymph node has never been established. Systemic treatment decisions in patients with a macrometastasis or micrometastasis in the sentinel lymph node follow the guidelines of node-positive patients, whereas in patients with isolated tumor cells only, guidelines for node-negative patients are followed. The  results of ongoing clinical trials will be important for the development of further guidelines.

Association between tumour characteristics and HER-2/neu by immunohostochemistry in 1362 women with primary operable breast cancer. Huang HJ, Neven P, Drijkoningen M, Paridaens R, Wildiers H, Van Limbergen Eric,  Berteloot P, Amant F, Vergote I, Christiaens MR. J Clin Pathol 2005;58:611–616. Abstract: Aims: To investigate the association between tumour characteristics and HER-2/neu by immunohistochemistry in primary operable breast cancer. Methods: The association between HER-2/neu and other clinicopathological factors was evaluated in 1362 consecutive patients with primary breast cancer treated between 2000 and July 2003 in one centre. Microscopic tumour size, tumour grade, lymph node status, patient’s age, oestrogen receptor (ER), progesterone receptor (PR), and joint ER/PR status were evaluated, using the 2 test for univariate analysis and logistic regression for multivariate analysis. The hormone receptors and HER-2/neu were studied immunohistochemically. Using the HER-2/neu DAKO scoring system, scores of 0, 1+, or 2+ were defined as negative and 3+ as positive. Data for DAKO scores 2+/3+ versus 0/1+ are also presented. Results : Hormone receptor negative  breast cancers were more often HER-2/neu positive than hormone receptor positive cancers, both for ER (28.7% v 6.8%) and PR (19.9% v 5.9%). In multivariate analysis, both ER, PR, and tumour grade were independently associated with HER-2/neu. In ER+ tumours, HER- 2/neu overexpression was significantly lower in PR+ than in PR– cases (11.5% v 5.4%). HER-2/neu overexpression (2.7%) was lowest in the large subgroup of ER+PR+ tumours with low tumour grade (grade 1–2), comprising 46.1% of all patients. Conclusions: ER, PR, and tumour grade are independent predictors for HER-2/neu overexpression in women with primary operable breast cancer. ER and PR are negatively associated with HER-2/neu, whereas tumour grade is positively associated with HER-2/neu. In women with ER+ tumours, PR status also affects the likelihood of HER-2/neu expression.

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