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Background: BRCA1 is a key protein in cell network, involved in DNA repair pathways and cell cycle. Recently, the ENIGMA consortium has reported a high number of alternative splicing (AS) events at this locus in blood-derived samples. However, BRCA1 splicing pattern in breast tissue samples is unknown. Here, we provide an accurate description of BRCA1 splicing events distribution in breast tissue samples., Methods: BRCA1 splicing events were scanned in 70 breast tumor samples, 4 breast samples from healthy individuals and in 72 blood-derived samples by capillary electrophoresis (capillary EP). Molecular subtype was identified in all tumor samples. Splicing events were considered predominant if their relative expression level was at least the 10% of the full-length reference signal., Results: 54 BRCA1 AS events were identified, 27 of them were annotated as predominant in at least one sample. Δ5q, Δ13, Δ9, Δ5 and ▼1aA were significantly more frequently annotated as predominant in breast tumor samples than in blood-derived samples. Predominant splicing events were, on average, more frequent in tumor samples than in normal breast tissue samples (P = 0.010). Similarly, likely inactivating splicing events (PTC-NMDs, Non-Coding, Δ5 and Δ18) were more frequently annotated as predominant in tumor than in normal breast samples (P = 0.020), whereas there were no significant differences for other splicing events (No-Fs) frequency distribution between tumor and normal breast samples (P = 0.689)., Conclusions: Our results complement recent findings by the ENIGMA consortium, demonstrating that BRCA1 AS, despite its tremendous complexity, is similar in breast and blood samples, with no evidences for tissue specific AS events. Further on, we conclude that somatic inactivation of BRCA1 through spliciogenic mutations is, at best, a rare mechanism in breast carcinogenesis, albeit our data detects an excess of likely inactivating AS events in breast tumor samples.

Background: The need for axillary lymph node dissection (ALND) in breast cancer patients with sentinel lymph node (SLN) micrometastases remains controversial. The aims of the study were to evaluate the locoregional failure and outcome of breast cancer patients with sentinel node micrometastases who did not undergo completion ALND., Methods: Between November 2000 and December 2006, SLN biopsy was successfully performed in 1178 patients with invasive breast carcinoma. Only patients with macrometastasis (>2 mm) underwent ALND, while patients with negative SLN or micrometastases did not undergo further treatment of the axilla, by either surgery or radiotherapy. Regarding adjuvant therapy decision, patients with SLN-micrometastases (pN1(mi)) were considered as node-positive patients., Results: Of 1,178 patients, 59 (5%) had micrometastases. Of those with micrometastases, 14 (24%) underwent ALND because the intraoperative study of the SLN yielded a positive result. With a median follow-up of 60 (range, 8-94) months, none of the patients with SLN micrometastases in whom ALND was omitted developed an axillary recurrence, while one patient in whom ALND was performed developed infraclavicular lymph node recurrence. One patient, who declined postoperative breast irradiation, developed breast recurrence and distant metastasis., Conclusions: Breast cancer patients with SLN micrometastases in whom ALND was omitted had a very low locoregional failure rate. This study supports the theory that ALND might be avoided in these patients, providing that adjuvant systemic treatment equal to treatment provided to treat node-positive disease is administered. However, longer follow-up and results of additional prospective studies are needed.

Aim: To study the predictive role of HER-2 and Topoisomerase IIalpha (TOP2A) in response to primary doxorubicin., Methods: Two hundred and thirty-two patients with operable breast cancer were treated with doxorubicin prior to surgery. ER, PgR, grade, Ki-67 and HER-2 status were prospectively assessed. HER-2 overexpression was evaluated with immunohistochemistry; positive cases were then studied for gene copy number of HER-2, TOP2A and chromosome 17 centromere by chromogenic in situ hybridisation. Clinical response was assessed by mammography. Pathological response was evaluated as the percentage of tumour replaced by changes due to chemotherapy., Results: HER-2 amplification was associated with clinical response (p=0.04). ER and PgR negativity, high Ki-67 and HER-2 amplification significantly correlated to pathological response (p<0.05). Tumours with coamplification of HER-2 and TOP2A showed a higher percentage of pathological changes (p=0.6). However, in the multivariate analysis for complete pathological response, ER negativity and high Ki-67 index were the only parameters that maintained statistical significance., Conclusion: HER2 and Topoisomerase IIalpha amplification failed to show an association with pathological response to doxorubicin, whereas ER negativity and a high proliferation rate were predictive of complete pathological response to this regime.

Objective: To evaluate the influence of tumour quadrant localization on the sentinel node (SN) detection and the visualisation of internal mammary chain (IM) drainage by radioisotopic techniques. 316 patients with breast cancer were studied. Mean age 57 years (range 29-88). All patients received 37-74 MBq of 99mTc-albumin nanocolloid in 2 ml by peritumoral injection. The breast cancer was located in the upper outer quadrant in 189 patients, in the upper inner in 57, in the lower outer in 57, in the lower inner in 55 and in the subareolar area in 18 patients. At two hours p.i., anterior and lateral chest lymphographies were obtained. The SN location was marked on the patient skin with permanent ink. SN was identified intraoperatively by the gamma probe. Histopatological analysis included imprints, delayed hematoxilin-eosin, inmunohistochemistry CAM 19-2 and PCR., Results: The scintigraphy and surgical detection was in the upper outer quadrant of 90 % and 93 % respectively; in the lower outer quadrant of 91 % and 95 %, in the upper inner quadrant of 93 % and 95 %, in the lower inner quadrant 87 % and 95 % and in the subareolar area in 94 % and 83 %. The IM chain drainage was of 6 % in the UO, in the LO of 5 %, in the UI of 12 %, in the LI of 20 % and none in subareolar., Conclusions: Our data suggest that sentinel node location (quadrant) is not a influential factor in the scintigraphy and surgical detection. Tumours localised in internal quadrant show a higher rate of IM chain drainage.

Objective: To obtain correct location of non-palpable breast lesions, with high suspicion of malignancy and detection of SN by radiosotopic techniques., Material and Methods: Thirty-one patients whose ages ranged from 35 to 79 years, with non-palpable breast lesions detected by mammography and/or ultrasonography were studied. All the patients were diagnosed of breast cancer and treated with primary chemotherapy. All the patients underwent total axillary dissection. At 24 hours of the intervention, all patients received one dose of 37 MBq (1 mCi) of 99mTc labeled macroaggregated albumin (MAA) in the center of the lesion by ultrasonographic guide. Scintigraphic images were performed in anterior and lateral projections (in prone decubitus with hanging breast) to verify the correct location of the radiopharmaceutical. After, a study of the SN was performed by subdermal administration of an 18 MBq (0.5 mCi) dose of 99mTc labeled nanocolloid. The SN site was labeled on the skin with indelible ink. The intrasurgical site of the breast lesion and SN was performed using a gamma detector probe. Correct placement of the intralesional radiopharmaceutical, existence of disease free borders and histological study of SN were performed by the pathologist in the surgical act. The differed pathology study was performed with hematoxilin-eosin and immunohistochemistry., Result: In 29 of the 31 lesion sites, there was good placement of the radiotracer (93.5 %). There was 1 case of contamination of the needle pathway and another that did not coincide with the lesion, due to poor placement. Location of the SN was 96 % in the axilla and 4 % in axilla and internal mammary chain. The SN was located in surgery in 28/31 patients (90 %)., Conclusion: Simultaneous radioguided location of the hidden breast lesions and sentinel node is a simple method, which is well tolerated by the patients and can be done in a single operation act.

Background: Primary chemotherapy (PC) is becoming an accepted practice to treat large tumors to avoid mastectomies and as a surrogate of outcome., Methods: A series of 305 patients with tumors >3 cm with T2-3N0-1M0 classification were treated with a multimodal approach that consisted of 3 courses of primary cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) followed by appropriate local treatment and 3 more courses of CMF or 4 courses of doxorubicin. Response was assessed by mammography., Results: The overall response rate was 48% (a 3% pathologic complete response rate). Conservative surgery was achieved in 79.64% of the patients with a low rate of local disease recurrences (5%). Toxicity was minimal. With a median follow-up of 104 months, the 8-year disease-free survival (DFS) rate was 57.63% and the 8-year overall survival (OS) was 67.65%. The DFS and OS rates for patients with a clinical response were significantly longer, i.e., 70% (P=0.0048) and 90% (P=0.0042), respectively., Conclusions: PC with CMF was feasible. A high rate of breast-conservative surgery was achieved. The current results stressed the value of PC to increase conservative surgery and as a predictor of outcome., (Copyright (c) 2005 American Cancer Society.)

Objective: The objective of this study is to analyze the influence of tumor size and age of the patient in the detection of the SN in breast neoplasms., Material and Methods: A total of 190 patients affected of breast cancer with a mean age of 57 years (range from 28 to 87 years) were studied. According to age, the following were distinguished: under 40 years, 23 patients; between 40 and 60 years, 102 patients and over 60 years, 65 patients. The lesions were classified based on size (in mm) into: less than 10 in 27 patients, between 10 and 20 in 61 patients, between 20 and 30 in 64 patients, and greater than 30 in 38 patients. In all the cases, a scintigraphy was performed at 2 hr. post-injection of 3 mCi of 99mTc-nanocoloide, in the peritumoral area. After lymphoscintigraphy detection of the SN, cutaneous labeling was performed and it was detected surgically by a gamma detector probe. A complete lymphadenectomy was performed in all the patients. The histopathology was performed with hematoxylin-eosin and immunohistochemistry techniques and the state of the SN was compared with the remaining lymph nodes of the lymphadenectomy., Results: The SN was located in 169 of the 190 cases (89%). In 164 cases, it was found in the axilla. The greatest percentage of those not detected was observed in tumors over 30 mm (32%) and patients older than 60 years (30%). No false negative were observed in tumors under 10 mm or in patients under 40 years, but the false negative rate increased with the patient's age and the tumor size., Conclusions: The patient's age and tumor size seem to influence SN detection rates. The FN rates seem to be superior in patients over 60 years. Patients under 40 years with tumors less than 10 mm are those who benefit most from this technique.

The aim of this study was to demonstrate that radionuclide sentinel node detection can be applied to patients with non-palpable breast cancer. One hundred and ten consecutive women with unilateral breast cancer were studied. Group 1 was made up of 80 patients with palpable breast cancer (mean age, 58 years) and group 2 of 30 patients with non-palpable breast cancer detected mammographically (mean age, 55 years). Tc-nanocolloid (111 MBq) was injected peritumorally in palpable tumours, and in the tumour area (ultrasound guided) in non-palpable tumours. At 2 h post-injection, anterior and lateral scintigrams were obtained from patients in the supine position. The location of the sentinel node was marked on the patient's skin. Patients with non-palpable tumours were moved to the surgery room 3 h later, and those with palpable tumours 24 h later. The histopathological study included three haematoxylineosin sections and immunochemistry. All patients underwent axillary lymphadenectomy. The sentinel node was detected in 67 cases (84%) in group 1 and in 28 cases (93%) in group 2. In four patients (5%) in group 1 and two patients (7%) in group 2, no axillary sentinel node was detected in the surgical bed, although it had been seen in scintigraphy. In nine patients (11%) in group 1, neither scintigraphic nor surgical detection was successful. Skip metastasis was seen in six cases (10%) of palpable tumours and in one case (4%) of non-palpable tumours. It can be concluded that non-palpable breast tumours cannot be considered an exclusion criterion for sentinel node localization and biopsy. Ultrasonography-guided injection, followed by scintigraphic and surgical detection of the sentinel node, may help in the management of patients with non-palpable breast tumours.

The pathologic changes associated to response to primary chemotherapy in a series of 303 operable breast cancers are evaluated and correlated to patients' follow-up (interval free of disease and survival). In our series, the incidence of microscopic changes related to chemotherapy is 43.9%. Tumor replacement by loose fibrosis is the most common pathologic event. In most cases, the intensity of fibrotic change is proportional to the degree of clinical-mammographic reduction of the tumor mass. However, some discrepancies exist in the sense of absence of microscopic changes in cases of well-documented mammographic reduction as well as in cases without clinical reduction but with large areas of chemotherapy-related fibrosis. The presence of pathologic response is significantly associated with better survival rate.

The aim of this study was to analyse the accuracy of scintigraphic and gamma probe sentinel node (SN) localization in breast cancer patients who have been submitted to neoadjuvant chemotherapy (NC). Seventy-six patients with single breast cancer were included in the study, and were classified into two groups. Group 1 consisted of 40 women who had received NC, and Group 2 consisted of 36 women who did not receive NC. All patients received 111 MBq (3 mCi) of 99Tcm-nanocolloid in 3 ml, by peritumoural injection. Anterior and lateral thoracic scans were obtained 2 h post-injection. The following day (18-24 h post-injection) the patients underwent surgery and sentinel nodes were localized by using a gamma probe. Complete axillary lymph node dissection was performed in all patients. Histological analysis included haematoxylin-eosin in all cases and immunohistochemistry in 10 cases. In Group 1, SNs were localized in 36/40 patients, histological analysis was performed in 34 and there were four false negatives (22%). In Group 2, SNs were localized in 32/36 patients, histological analysis was performed in 29 and there were two false negatives (9%). Predictive negative values were 78% and 90% in Groups 1 and 2, respectively. In summary, sentinel node localization in breast cancer patients submitted to previous neoadjuvant chemotherapy is less accurate than in patients who do not receive this therapy. The procedure is not sufficiently accurate to localize the sentinel node, thus it cannot be recommended in these patients.

The aim of this preliminary work is to show the results of the radioisotopic localization of the sentinel node in breast cancer and the surgical resection using a gamma probe. We studied 10 patients with breast cancer without primary chemotherapy and 3 patients with primary chemotherapy before surgery. A lymphoscintigraphy was made after injection of 111 MBq of Tc99m-nanocolloid in a volume of 3 ml. The scans were performed after 30 minutes, 2 hours, 4 hours and 24 hours after injection. We detected the node and then a skin mark was made. The next day, surgical resection of this node was performed, guided by a gamma probe. We detected all sentinel nodes but one: 12 sentinel nodes and 7 second echelon nodes. The mean time for a surgical detection was about 16 minutes. In our experience this technique allows an accurate localization of the sentinel node in patients with breast cancer. We are able to localize the node in the surgical room guided with gamma probe. The peroperatory evaluation by anatomopathological techniques shown the status of this node. All this, does not delay the surgical time.

The presence of the tumor in women with breast cancer provokes a profile of biochemical change characterized by hypoglycemia, hyperuremia and high levels of free fatty acids and ketone bodies in plasma. The total circulating levels of amino acids and lactate are slightly higher in patients with breast cancer. Moreover, alterations in the circulating levels of free and total fatty acids are associated with enhanced levels of total free fatty acids and significantly lower levels of esterified arachidonic acid. This profile may indicate a state of moderate catabolic activation in breast cancer patients and may also be associated with a slight mobilization of proteins and fatty acids by some of the peripheral tissues in order to cover the needs of the host and the tumor. However, the alteration in the distribution of different fatty acids (saturated, mono-unsaturated and poly-unsaturated) and the different behaviour of the free and esterified fractions may be the result of a greater release of only specific fatty acids by tumor or other host tissues, rather than a higher release of the whole spectrum of free fatty acids. Thus, it is proposed that some of the alterations may be directly related to localized tumor activity.