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Breast cancers in gene mutation carriers may escape mammographic detection because of rapid growth and tumor expansion. Therefore, they may mimic benign lesions on the mammogram. Twenty-nine BRCA 1/2 mutation carriers under surveillance developed 31 breast cancers between 1994 and 2001 at a mean age of 44.2 years. Controls were 63 women with 67 breast cancers in the same period at a mean age of 53.8 years, also under surveillance because of a life time risk of at least 15%. In 26% of the carriers vs. 48% of the controls, mammography was the method that first suspected a malignancy. Seven radiologists performed a retrospective review of the original mammograms to establish technical assessment, with special attention for circumscribed lesions and estimated probability of malignancy. In the mutation carriers seven (23%) circumscribed non-calcified mammographic masses were found and three in the controls (4.5%) P=0.01. These masses were proven to be malignant. In both groups around 70% of these fast-growing circumscribed lesions were detected by the patients. The masses were situated in breasts with a good interpretable breast pattern. BRCA 1/2 mutation carriers had a significantly higher percentage of circumscribed non-calcified mammographic masses that proved to be malignant. These mammographic lesions in women at high risk should be described as at least Birads 0 and worked-up with ultrasound and needle biopsy.

196 Background: An important benefit of neoadjuvant chemotherapy (NAC) is the increase in breast-conserving surgery. At present the response of axillary lymph node metastases to chemotherapy cannot be accurately assessed. Therefore axilla-conserving therapy is not yet a benefit. We aimed to assess a new surgical method to evaluate the axillary response: the MARI procedure, which stands for Marking of the Axillary lymph node with Radioactive Iodine seeds. Methods: Prior to NAC, proven tumor-positive axillary lymph nodes were marked with a Iodine-125 seed. After NAC, the marked lymph node was selectively removed with the use of a gamma-detection probe. A complementary axillary lymph node dissection was performed to assess whether pathological response in the marked node was indicative for the pathological response in the additional lymph nodes. Results: Tumor-positive axillary lymph nodes were successfully marked with Iodine-125 seeds in 68 patients. The marked lymph node (MARI-node) was surgically detected and selectively removed after NAC in all patients. The pathological response to chemotherapy in the MARI-node was indicative for the overall response in the additionally removed lymph nodes. In 47 patients the MARI-node contained residual disease (n=45 macrometastasis, n= 2 ITC). Thirty-five of them had macro- or micro metastases in the complementary axillary lymph node dissection specimen. In 21 patients the MARI-node was tumor negative. In 2 patients a macro metastasis was found in the additionally removed nodes, in 2 patients ITC were found and in the remaining 17 patients no residual tumor was found in the additionaly removed lymphnodes. (false negative rate of the MARI procedure: 9.5%). Conclusions: This study shows that marking and selectively removing metastatic lymph nodes after NAC is feasible. The tumor-response in the marked lymph node may be used to tailor further axillary treatment, and herewith enabling axilla-conserving surgery after neoadjuvant chemotherapy.

Accurate tumor excision is crucial in the locoregional treatment of cancer, and for this purpose, surgeons often rely on guide wires or radioactive markers for guidance toward the lesion. Further improvement may be obtained by adding optical guidance to currently used methods, in the form of intra-operative fluorescence imaging. To achieve such a multimodal approach, we have generated markers that can be used in a pre-, intra-, and post-operative setting, based on a cocktail of a dual-emissive inorganic dye, lipids, and pertechnetate. Phantom experiments demonstrate that these seeds can be placed accurately around a surrogate tumor using ultrasound. Three-dimensional bracketing provides delineation of the entire lesion. Combined with the multimodal nature, this provides the opportunity to predetermine the resection margins by validating the placement accuracy using multiple imaging modalities (namely, x ray, MRI, SPECT/CT, and ultrasound). The dual-emissive fluorescent properties of the dye provide the unique opportunity to intra-operatively estimate the depth of the seed in the tissue via multispectral imaging: emission green λmax=520 nm≤5 mm penetration versus emission red λmax=660 nm≤12 mm penetration. By using particles with different colors, the original geographic orientation of the excised tissue can be determined.

2531 Background: Preoperative chemotherapy is increasingly employed to treat primary breast cancer, allowing an ‘in vivo chemosensitivity test’. Markers which predict a pathological complete response are urgently needed to refine this strategy. This study was conducted to evaluate the use of gene expression profiling to predict response to neoadjuvant anthracycline- or taxane-based chemotherapy. Methods: Patients with operable or locally advanced HER2-negative breast cancer received preoperative chemotherapy: either dose- dense doxorubicin and cyclophosphamide (ddAC) or capecitabine and docetaxel (CD). Core needle biopsies were taken before treatment and gene expression profiling was performed using 35k oligo microarrays. Results: Gene expression profiles were obtained from pretreatment biopsies of 63 tumors. 27% of the patients achieved a (near) pathologic complete remission (pCR), 40% of the patients had a partial remission and 33% of the patients did not respond to chemotherapy. Based on the gene expression profiles, tumors were assigned to the previously identified “molecular subtypes” luminal, basal-like or ERBB2-like (Sorlie et al., PNAS 98: 10869, 2001). 13 out of 25 patients with a basal-like tumor (52%) achieved a complete remission, whereas for the luminal tumors a pCR was only obtained in 2 out of 29 patients. Using four published gene expression classifiers of response to chemotherapy, a reasonable separation between responders and non-responders could be observed for two of these. We also performed exploratory supervised classification analyses on our dataset to identify a novel classifier. This resulted in a classifier for response to therapy irrespective of the chemotherapy regimen used and a second classifier specifically associated with response to ddAC chemotherapy. We will perform validation of these classifiers in samples from patients that are currently being enrolled in the study. Conclusions: Basal-like tumors have a better response to neoadjuvant chemotherapy as compared to other tumor types. The identification of robust gene expression signatures for better response prediction may require larger patient groups and should probably be established separately for each of the molecular subtypes of breast cancer. No significant financial relationships to disclose.

10507 Background: About 20% of ductal carcinoma in situ (DCIS) lesions diagnosed by stereotactic core needle biopsy (SCNB) are shown to be invasive on postoperative pathology examination. Sentinel lymph node biopsy (SLNB) is an accurate method of evaluating axillary lymph nodes in patients with invasive breast cancer. The aim of this study was to review our experience with lymphatic mapping in patients with a SCNB diagnosis of pure DCIS, to evaluate the DCIS underestimation rate and consequently the risk of lymph node metastases. Methods: Files from 160 patients diagnosed with pure DCIS by SCNB between July 1999 and March 2005 were retrieved from our database. Patients with DCIS were selected for SLNB if there was concern for presence of an invasive component on the basis of size, palpability or imaging. Results: The median age of the study group was 55 years (range 29–85 years) and median DCIS size on mammography was 25 mm (range 4–96 mm). Thirty-six (23%) out of the 160 women underwent a SLNB. Macrometastases in the sentinel node were detected in seven (19%) patients and one (3%) patient was found to have a micrometastasis. Twenty (56%) of these 36 patients had invasive lesions on final pathology. Of the 124 women who did not receive SLNB, 29 (24%) turned out to have invasive lesions on postoperative evaluation. In total, 49/160 (31%) patients with pure DCIS diagnosed by SCNB had invasive breast cancer (range pT1mic-pT2) on final pathology. Finally, 88 patients underwent lymphatic staging by SLNB, basal node sampling or complete axillary lymph node dissection. Nodal involvement was present in 14 (16%) out of these 88 patients with initially diagnosed DCIS: 36% in patients with invasive breast cancer and 2% with pure DCIS on final pathology. Conclusion: Postoperative pathology examination of the specimen demonstrates DCIS underestimation in nearly one third of SCNB diagnosed DCIS patients. SLNB is of benefit for these patients as in 19% of the patients who undergo a SLNB macrometastatic disease in the sentinel node can be found. No significant financial relationships to disclose.

20005 Background: Neoadjuvant chemotherapy is increasingly employed in operable breast cancer. Our initial studies on a cDNA array platform failed to identify gene expression patterns predicting response to neoadjuvant chemotherapy in breast cancer patients (J Clin Oncol 23:3331, 2005). Now we included more patients and used oligo microarrays. Methods: Patients with operable or locally advanced breast cancer were included in a randomized phase II study or received neoadjuvant chemotherapy off protocol. All except 7 patients began chemotherapy with 3 courses of dose-dense adriamycin and cyclophosphamide (ddAC) and response was evaluated by MRI. Patients with a response and a HER2-positive tumor were then randomized between either 3 additional courses of ddAC or six weekly courses of carboplatin, paclitaxel and trastuzumab (CPT). Patients without response were switched to CPT. Patients with HER2-negative tumors were randomized between 3 courses of either ddAC or capecitabine and docetaxel (CD). After evaluation, patients without response were switched to the alternative treatment arm. From all patients 14G core needle biopsies were taken before treatment and total RNA was isolated. Amplified mRNA was labeled and hybridized to 35k human oligo microarrays from our microarray facility. Results: So far, 77 patients have been included into the study. From 48 of these, good quality RNA from tissue with >50% tumor cells was isolated. 43 patients had received ddAC as initial chemotherapy; 32 of these had not been switched to another regimen. In a training set containing 11 pathological complete remissions (pCR) and 9 non-responders (NR) we could separate these groups by using 20 genes in a supervised classification and a 9-step cross validation. These results could be validated in an independent set of 11 samples (6 pCR, 5 NR). From 10 out of 11 samples, response status could be predicted correctly, independent from the treatment regimen. Although ER-positive tumors have a lower pCR rate than ER-negative ones, the steroid hormone receptors were not present in the classifier. Conclusions: We conclude that it should be possible to identify a reliable gene expression profile associated with response to adriamycin based neoadjuvant chemotherapy in breast cancer. No significant financial relationships to disclose.

502 Introduction: It is currently not possible to predict sensitivity of locally advanced breast cancer (LABC) to specific drugs. This study was designed to identify gene expression patterns in LAB...