Gabriel Zanón

c-erbB-2 oncoprotein, CEA, and CA 15.3 in patients with breast cancer: prognostic value.

The diagnostic value of a new tumor marker, c-erbB-2, was studied in the sera of 50 healthy subjects, 58 patients with benign breast diseases, and 413 patients with breast cancer (186 locoregional, 185 with advanced disease, and 42 with no evidence of disease). Using 15 U/ml as the cut-off, no healthy subjects or patients with benign diseases and only 2.4% of no evidence of disease patients had elevated serum levels. Abnormal c-erbB-2 levels were found in 29% (101/370) of the patients with breast carcinoma (locoregional 9%, metastases 45.4%). CEA (cut-off 5 U/ml) and CA 15.3 (cut-off 35 U/ml) sensitivity was 18% and 16% in patients with locoregional disease and 61% and 70% in those patients with advanced disease, respectively. A trend toward higher serum levels of all three tumor markers in patients with nodal involvement or greater tumor size was found, but was statistically significant only with CEA (p < 0.01). By contrast, c-erbB-2 was related to steroid receptors, in both locoregional and metastatic tumors. When the prognostic value of these markers was evaluated, patients with abnormally high presurgical CEA and c-erbB-2 had a worse prognosis than those patients with normal values, in both node-negative (p < 0.05 and p < 0.001, respectively) and node-positive patients (p < 0.556 and p < 0.001, respectively). By contrast, no relationship was found between CA 15.3 values and prognosis. Multivariate analysis showed that CEA and c-erbB-2 were also prognostic factors. The correlation between serum and tissue levels of c-erbB-2 was studied in the tumors of 161 patients. Significantly higher c-erbB-2 serum levels were found in patients with overexpression in tissue by immunohistochemistry, in both locoregional and advanced disease (p=0.0001). Serum concentrations in patients with advanced disease were related to the site of recurrence, with significantly higher values in patients with metastases (mainly in those with liver metastases) than in those with locoregional recurrence. In summary, c-erbB-2 serum levels seem to be a useful tumor marker in the prognosis of patients with breast cancer. Using all three tumor markers, sensitivity was 35% in patients with locoregional breast cancer and 88% in patients with recurrence.

Use of serial carcinoembryonic antigen and CA 15.3 assays in detecting relapses in breast cancer patients

SummaryTo evaluate the utility of CEA and CA 15.3 for early diagnosis of recurrence, serial serum determinations of both antigens were performed in 1023 patients (follow-up: 1–10 years, mean 6.2 years) with primary breast cancer (CA 15.3 in 533 cases) and no evidence of residual disease (NED) after radical treatment (radical mastectomy or simple mastectomy and radiotherapy). 246 patients developed metastases during follow-up.Results: CEA and CA 15.3 were elevated (> 10 ng/ml or > 60 U/ml, respectively) prior to diagnosis in 40% (98/246) and 41% (37/91) of the patients with recurrence, with a lead time of 4.9 ± 2.2 and 4.2 ± 2.3 months, respectively. When patients with locoregional recurrences were excluded, sensitivity improved to 46% (CEA) and 54% (CA 15.3), and to 64% with both tumor markers (CEA and/or CA 15.3). Higher levels of both CEA and CA 15.3 at diagnosis of recurrence, higher sensitivity in early diagnosis of relapse, and a higher lead time were found in ER+ (CEA) or PgR+ patients (CA 15.3) than in those that were negative for these receptors in the primary tumor (p < 0.001). Specificity of the tumor markers was 99% for both CEA (777 NED patients) and for CA 15.3 (444 NED patients), respectively. In conclusion, CEA and CA 15.3 are useful tools for early diagnosis of metastases, mainly in those patients with ER+ or PR+ tumors.

Clinical relevance of sentinel lymph nodes in the internal mammary chain in breast cancer patients

PurposeDespite the widespread use of sentinel lymph node (SLN) biopsy in breast cancer patients, some controversy exists about the correct management of extra-axillary nodes, especially those located in the internal mammary chain. The aim of this study was to evaluate the incidence of SLNs in this region, calculate the lymphoscintigraphic and surgical detection rates and evaluate the clinical impact on staging and therapeutic decisions.MethodsThe study involved 383 consecutive women diagnosed with early breast cancer with T1 or T2 tumours. Eight patients had a bilateral tumour, which brought the total to 391 lesions. Lymphoscintigraphy was performed on the day before surgery by injection of 99mTc-labelled nanocolloid. The injection site was subdermal (68 patients), peritumoural (107 patients) or intratumoural (216 patients). During surgery a gamma probe was used to guide the surgeon and the SLNs were removed. SLNs were analysed by a conventional pathological study and processed for H&E examination and immunohistochemistry.ResultsLymphoscintigraphy detected at least one SLN in 369 out of the 391 procedures (94.4%). SLNs were found in the axillary chain in 367 cases and in the internal mammary chain in 55. In two of these 55 cases (3.6%), the SLN was the only one detected. There was no drainage to the internal mammary chain in any case of subdermal injection but such drainage was found in 15.9% of cases with peritumoural injection and 17.6% of those with intratumoural injection. Compared with tumours located in the outer quadrants, a higher percentage of tumours located in the inner quadrants showed drainage to the internal mammary chain (p<0.001). A total of 42 SLNs in the internal mammary chain could be removed in 32 patients without appreciable morbidity. In 20 cases both axillary and internal mammary SLNs were negative, in four both were positive, and in five axillary SLNs were positive and internal mammary SLNs were negative. More interestingly, in the remaining patient with both axillary and internal mammary SLNs, the axillary SLN was negative while malignant cells were found in the internal mammary region. In the evaluation of the clinical impact of internal mammary SLN biopsy, we found that staging was modified from pN1a to pN1c in four patients and, more importantly, from pN0 to pN0(i+) in one patient. The change in stage led to a modification of the postoperative treatment plan with respect to radiotherapy and systemic therapy.ConclusionEvaluation of the SLNs in the internal mammary chain provides more accurate staging of breast cancer patients. If internal mammary sampling is not performed, patients can be understaged. This technique can offer a better indication of those patients who will benefit from selective treatment options like radiotherapy to this region or systemic therapy.

Added Value of Intraoperative Real-Time Imaging in Searches for Difficult-to-Locate Sentinel Nodes

Localization of sentinel lymph nodes can be challenging if they are in difficult anatomic locations or near high radiotracer activity. The purpose of this study was to assess the value of intraoperative real-time imaging using a portable γ-camera in conjunction with a conventional γ-counting probe when it is difficult to localize the sentinel node. Methods: After 99mTc-nanocolloid injection, patients with various malignancies underwent presurgical lymphoscintigraphy followed by surgery (usually the next day). We evaluated 20 patients who required sentinel lymph node biopsy and in whom the location or other characteristics of the sentinel node would make intraoperative retrieval difficult. During surgery, the sentinel node was localized using a portable γ-camera together with a hand-held γ-probe. A 153Gd pointer or 125I seed was used to better depict the sentinel node location in real time. Results: Using only a conventional hand-held γ-probe, surgeons were able to definitively localize the sentinel node in 15 of 20 patients. Intraoperatively, the portable γ-camera showed uptake by the definite sentinel node in 19 of 20 patients and helped to precisely localize the node with the hand-held γ-probe in 4 patients. In 1 of these patients, the sentinel node was metastatic. Conclusion: The combination of a standard hand-held γ-probe and real-time imaging provided by a portable γ-camera offers a high intraoperative detection rate in patients with difficult sentinel node localization as assessed by presurgical lymphoscintigraphy.

Exeresis and Brachytherapy as Salvage Treatment for Local Recurrence After Conservative Treatment for Breast Cancer: Results of a Ten-Year Pilot Study

PURPOSE To analyze the long-term results of a pilot study assessing excision and brachytherapy as salvage treatment for local recurrence after conservative treatment of breast cancer. METHODS AND MATERIALS Between December 1990 and March 2001, 36 patients with breast-only recurrence less than 3 cm in diameter after conservative treatment for Stage I or II breast carcinoma were treated with local excision followed by high-dose rate brachytherapy implants (30 Gy in 12 fractions over a period of 5 days). No patient was lost to follow-up. Special attention was paid to local, regional, or distant recurrences; survival; cosmesis; and early and late side effects. RESULTS All patients completed treatment. During follow-up (range, 1-13 years), 8 patients presented metastases (2 regional and 6 distant) as their first site of failure, 1 had a differed local recurrence, and 1 died of the disease. Actuarial results at 10 years were as follows: local control, 89.4%; disease-free survival, 64.4%; and survival, 96.7%. Cosmetic results were satisfactory in 90.4%. No patient had Grade 3 or 4 early or late complications. Of the 11 patients followed up for at least 10 years, all but 1 still had their breast in place at the 10-year stage. CONCLUSIONS High-dose rate brachytherapy is a safe, effective treatment for small-size, low-risk local recurrence after local excision in conservatively treated patients. The dose of 30 Gy of high-dose rate brachytherapy (12 fractions over a period of 5 days twice daily) was well tolerated. The excellent results support the use of breast preservation as salvage treatment in selected patients with local recurrence after conservative treatment for breast cancer.

Prospective Evaluation of Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 15.3 (CA 15.3) in Patients with Primary Locoregional Breast Cancer

BACKGROUND The utility of carcinoembryonic antigen (CEA) and carbohydrate antigen 15.3 (CA 15.3) as prognostic factors in primary breast cancer is unclear. METHODS We prospectively studied CEA and CA 15.3 in the sera of 2062 patients with untreated primary breast cancer diagnosed between 1984 and 2008. RESULTS Increased CEA (>5 microg/L) and CA 15.3 (>30 kU/L) concentrations were found in 12.7% and 19.6% of the patients, respectively, and 1 or both tumor markers were increased in 28% (570 of 2062). Increases in each tumor marker correlated with larger tumor sizes and nodal involvement. Tumor size, estrogen receptor (ER), and CEA were independent prognostic factors by multivariate analysis in the total group [disease free survival (DFS) and overall survival (OS)] as well as in node-positive (NP) and node-negative (NN) patients. Nodal involvement and histological grade were independent prognostic factors in the total group as well as in NP patients. By contrast, adjuvant treatment and CA 15.3 were independent prognostic factors only in NN patients (DFS and OS). All patients with CEA >7.5 microg/L had recurrence during follow-up. Use of both tumor markers allowed discrimination of the groups of risk in T1 NN patients: 56.3% of recurrences were seen when 1 or both tumor markers were increased, whereas only 9.4% of recurrences were seen in T1 NN patients without increases of either marker. CONCLUSIONS CEA and CA 15.3 are useful prognostic factors in NP and NN breast cancer patients. CEA >7.5 microg/L is associated with a high probability of subclinical metastases.

A practical approach to intraoperative evaluation of sentinel lymph node biopsy in breast carcinoma and review of the current methods

BackgroundSentinel lymph node (SLN) biopsy is increasingly becoming an alternative method for assessing axillary status in breast carcinoma patients. Intraoperative SLN evaluation can potentially select patients for immediate axillary clearance and spare most of them a second surgical procedure. Nevertheless, no standard protocol for intraoperative SLN evaluation has been developed. The aims of this study were to establish the reliability of SLN intraoperative evaluation in breast carcinoma staging, to review the published methods currently used, and to propose a standard protocol.MethodsOne hundred fifty-two SLNs were collected from 86 patients. Lymphoscintigraphy, blue dye, and gamma camera intraoperative controls were used for localization. Each SLN was sliced 2 mm thick and was intraoperatively evaluated by using the combination of frozen section and imprint cytology. The final examination included standard hematoxylin and eosin staining, and, in case of persistent negativity, further sectioning, including hematoxylin and eosin combined with immunohistochemistry (CAM5.2 cytokeratin), was performed.ResultsThe combination of frozen section and imprint cytology for intraoperative SLN evaluation yielded an intraoperative sensitivity of 78% and a specificity of 100%. All macrometastases (>2 mm) were detected during surgery, as were 2 micrometastases. Final examination detected seven more micrometastases, six of which consisted of isolated tumor cells.ConclusionsWe propose a fast, cost-effective, and accurate procedure for SLN evaluation that is useful for making intraoperative decisions, feasible for most institutions, and reliable because of its high sensitivity (100% for macrometastases) and specificity.

Predicting Non-Sentinel Lymph Node Status in Breast Cancer Patients with Sentinel Lymph Node Involvement: Evaluation of Two Scoring Systems

Abstract:  The aim of this study was to validate a nomogram and a scoring system to predict non‐sentinel lymph node status in breast cancer patients with sentinel lymph node (SLN) involvement. A total of 516 breast cancer patients underwent sentinel lymph node biopsy at our institution from January 2001 to August 2006. A prospective database was used to identify breast cancer patients with a positive SLN biopsy examination who underwent a completion axillary lymph node dissection. A total of 114 patients were identified. The Memorial Sloan‐Kettering Cancer Center (MSKCC) nomogram and an axilla scoring system from Paris (Hôpital Tenon) were used to predict the probability of having non‐SLN involvement. One hundred fourteen patients were included in the study. The areas under the receiver operating characteristics (ROC) curves were 0.671 (95% CI: 0.552–0.790) for the MSKCC nomogram and 0.703 (95% CI: 0.596–0.811) for the Tenon score. The univariate analysis shows that size of SLN metastases, the number of positive and negative SLN and the proportion of positive SLN were statistically significant. On multivariate logistic regression analysis, the size of SLN metastases and the proportion of positive SLN were statistically significant. The two scoring systems are similar according to their area under ROC curves, but should be improved to be valid and determinant to the general population. Meanwhile, the use of scoring systems could be applied in an individual manner in some patients.

Partial Breast Brachytherapy after Lumpectomy as Salvage Treatment of Local Recurrences after Conservative Treatment of Breast Cancer: Eighteen-year Results of a Non-randomized Comparison with Mastectomy

Purpose/Objective(s): To report the long term results obtained in a prospective group of patients (pts) treated for local recurrence after conservative treatment of breast cancer treated by a second conservative surgery or by total mastectomy. Materials/Methods: Between 12/1990 and 10/2004, 85 patients with <3cm, low-risk local recurrence after conservative treatment for breast cancer were offered total mastectomy. 48 of them refused it and were treated by a second lumpectomy followed by HDR brachytherapy implant to the tumor bed plus a 3 cm margin. 30 Gy in 12 fractions in 5 days were given. Patients treated by mastectomy had no further radiotherapy treatment. Postmenopausal patients with negative receptors had no systemic treatment. The rest of the patients had chemo or hormonal treatment. No patient was lost for follow-up. Results: All patients completed treatment. During the 17-year, 1-year minimum follow-up, in the 2nd conservative group there were 8 pts who had regional (2 pts) or distant metastases (6 pts) as their first site of failure. 3 of them experienced a differed local recurrence and 1 died from the disease. In the total mastectomy group, there were 2 local recurrences, 1 regional recurrence and 5 distant metastases as first site of failure. One patient died from the disease. Actuarial results at 17-year for 2nd conservative and total mastectomy were respectively: local control 84.2% 71.7%; disease free survival 65.4%-63.8%; and survival 90.7% and 88.2%. Cosmetic results were satisfactory in 89.4 % treated conservatively. No patient experienced arm edema or grade 3-4 early or late complications. Between the 14 pts that were followed-up for at least 10-years, 13 of them were with their breast still in place. Conclusions: Second conservative treatment by HDR brachytherapy was a safe and effective method of treatment for small-size, lowrisk, local recurrence after local excision in conservatively treated patients. Partial breast irradiation with wide margins probed to be enough treatment, without significant side-effects in previously intesively irradiated patients. Lumpectomy and partial breast brachytherapy can be conidered the treatment of choice in selected patients with low-risk recurrent breast tumors.