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The treatment of breast cancer is a sophisticated multi-specialty and multi-modality undertaking. In the ideal setting, breast cancer care conferences which involve the patient, the surgical pathologist, surgeons, oncologists, radiation oncologists, nursing, and social workers help to make a coordinated decision.


Axillary sentinel lymph node dissection  
Prophylactic mastectomy  
Chemotherapy and Chemoprophylaxis  
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National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000.

Eifel P, Axelson JA, Costa J, Crowley J, Curran WJ Jr, Deshler A, Fulton S, Hendricks CB, Kemeny M, Kornblith AB, Louis TA, Markman M, Mayer R, Roter D.

The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.

J Natl Cancer Inst 2001 Jul 4;93(13):979-89 Abstract quote

OBJECTIVE: Our goal was to provide health-care providers, patients, and the general public with an assessment of currently available data regarding the use of adjuvant therapy for breast cancer.

PARTICIPANTS: The participants included a non-Federal, non-advocate, 14-member panel representing the fields of oncology, radiology, surgery, pathology, statistics, public health, and health policy as well as patient representatives. In addition, 30 experts in medical oncology, radiation oncology, biostatistics, epidemiology, surgical oncology, and clinical trials presented data to the panel and to a conference audience of 1000.

EVIDENCE: The literature was searched with the use of MEDLINE(TM) for January 1995 through July 2000, and an extensive bibliography of 2230 references was provided to the panel. Experts prepared abstracts for their conference presentations with relevant citations from the literature. Evidence from randomized clinical trials and evidence from prospective studies were given precedence over clinical anecdotal experience.

Consensus Process: The panel, answering predefined questions, developed its conclusions based on the evidence presented in open forum and the scientific literature. The panel composed a draft statement, which was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. The draft statement was made available on the World Wide Web immediately after its release at the conference and was updated with the panel's final revisions. The statement is available at http://consensus.nih.gov.

CONCLUSIONS: The panel concludes that decisions regarding adjuvant hormonal therapy should be based on the presence of hormone receptor protein in tumor tissues. Adjuvant hormonal therapy should be offered only to women whose tumors express hormone receptor protein. Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status. The inclusion of anthracyclines in adjuvant chemotherapy regimens produces a small but statistically significant improvement in survival over non-anthracycline-containing regimens. Available data are currently inconclusive regarding the use of taxanes in adjuvant treatment of lymph node-positive breast cancer. The use of adjuvant dose-intensive chemotherapy regimens in high-risk breast cancer and of taxanes in lymph node-negative breast cancer should be restricted to randomized trials. Ongoing studies evaluating these treatment strategies should be supported to determine if such strategies have a role in adjuvant treatment. Studies to date have included few patients older than 70 years. There is a critical need for trials to evaluate the role of adjuvant chemotherapy in these women. There is evidence that women with a high risk of locoregional tumor recurrence after mastectomy benefit from postoperative radiotherapy. This high-risk group includes women with four or more positive lymph nodes or an advanced primary cancer. Currently, the role of postmastectomy radiotherapy for patients with one to three positive lymph nodes remains uncertain and should be tested in a randomized controlled trial. Individual patients differ in the importance they place on the risks and benefits of adjuvant treatments. Quality of life needs to be evaluated in selected randomized clinical trials to examine the impact of the major acute and long-term side effects of adjuvant treatments, particularly premature menopause, weight gain, mild memory loss, and fatigue. Methods to support shared decision-making between patients and their physicians have been successful in trials; they need to be tailored for diverse populations and should be tested for broader dissemination.

Intraoperative evaluation of lumpectomy margins by imprint cytology with histologic correlation: a community hospital experience.

Creager AJ, Shaw JA, Young PR, Geisinger KR.

Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.

Arch Pathol Lab Med 2002 Jul;126(7):846-8 Abstract quote

BACKGROUND: Several well-controlled studies have demonstrated significantly increased local recurrence rates in patients with low-stage breast carcinoma treated with breast conservation therapy in whom focally positive margins were not reexcised. Imprint cytology is a rapid technique for evaluating surgical margins intraoperatively, thus allowing reexcisions to be performed during the initial surgery. The large majority of studies on the use of intraoperative imprint cytologic examination of breast conservation therapy margins have been performed at university-based academic centers.

OBJECTIVE: To evaluate the utility of intraoperative imprint cytologic evaluation of breast conservation therapy margins in a community hospital setting.

METHODS: We retrospectively reviewed the intraoperative imprint cytology margins of 141 lumpectomy specimens that had been obtained from 137 patients between May 1997 and May 2001.

RESULTS: We evaluated 758 separate margins. On a patient basis, the sensitivity was 80%, the specificity was 85%, the positive predictive value was 40%, the negative predictive value was 97%, and the overall accuracy was 85%. There were no cytologically unsatisfactory margins.

CONCLUSION: Imprint cytology is an accurate, simple, rapid, and cost-effective method for determining the margin status of breast conservation therapy specimens intraoperatively in the community hospital setting. This method allows a survey of the entire surface area of the lumpectomy specimen, which is not practical using frozen section evaluation.

Occult axillary lymph node metastases in breast cancer do matter: results of 10-year survival analysis.

Cummings MC, Walsh MD, Hohn BG, Bennett IC, Wright RG, McGuckin MA.

Am J Surg Pathol 2002 Oct;26(10):1286-95 Abstract quote

Axillary lymph node status is one of the most powerful prognostic factors for patients with breast cancer and is often critical in stratifying patients into adjuvant treatment regimens.

In 203 apparently node-negative cases of breast cancer, a combination of immunohistochemical staining and step-sectioning identified occult metastases in 25% of cases. Ten-year follow-up information is available for these patients. Histologic features of the primary tumor and immunohistochemical staining for estrogen receptor, progesterone receptor, Her-2, and p53 were also evaluated. With multivariate analysis, both occult metastases and higher histologic grade of the primary tumor were independent predictors of disease-free survival. Histologic grade was the only significant independent predictor of overall survival. Estrogen receptor, progesterone receptor, Her-2, and p53 status did not predict the presence of metastases or survival when all tumor types were considered together.

Metastases >0.5 mm significantly predicted a poorer disease-free survival when invasive ductal carcinomas were considered alone. Histologic grade was significantly associated with disease-free survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients.

The presence of occult metastases approached significance for overall survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients.



This has emerged as a useful alternative to total axillary lymph node dissection

Injecting a vital blue dye solution alone or in combination with a technitium-labled sulfur colloid around the cancer site, the dye or radiolabel is followed to the first sentinel node of the axilla.

A frozen section is performed upon this lymph node and if cancer is found, a complete axillary dissection is performed

If no cancer is found, the lymph node is submitted for permanent sections and multiple step sections and cytokeratin stains are performed-if cancer is found on these permanent sections, a complete axillary dissection is performed

Sentinel node micrometastasis in breast carcinoma may not be an indication for complete axillary dissection.

Rutledge H, Davis J, Chiu R, Cibull M, Brill Y, McGrath P, Samayoa L.

[1] 1Department of Pathology, University of Kentucky, Lexington, KY, USA [2] 2Veterans Administration Medical Center, Lexington, KY, USA.
Mod Pathol. 2005 Jun;18(6):762-8. Abstract quote  

The decision whether to proceed with complete axillary node dissection based on sentinel node status is clear for patients with negative or macrometastatic disease. However, the course of action based on sentinel node micrometastasis remains controversial.

We reviewed 358 cases from 6/1999 to 7/2003. All sentinel nodes were evaluated at three levels by frozen section, touch preparation, and scrape preparation. Micrometastasis was defined as tumor deposits between 0.2 and 2 mm. Size, grade, and lymphvascular invasion of the primary tumor, as well as number, status, size of metastatic disease, and presence of extranodal capsular extension of sentinel and nonsentinel nodes were recorded.

Of the 358 cases, 89 had positive sentinel nodes, 29 of which represented micrometastases. Only one (3%) of the 29 cases contained a nonsentinel node with macrometastasis. In 60 of the 89 cases sentinel nodes contained macrometastases. Of these, 38 cases (63%) had metastatic tumor in nonsentinel nodes. Intraoperative consult was performed in 53 of the 89 cases with positive sentinel nodes. Only 1 of the 19 (5%) intraoperative consult cases with micrometastatic sentinel nodes had positive nonsentinel nodes, while 21 of 34 (62%) of macrometastatic sentinel nodes at intraoperative consult had tumor in nonsentinel nodes. No single variable studied discriminated between micro- vs macrometastatic disease. At intraoperative consult, macrometastatic disease was present in all three diagnostic preparations, while diagnostic material in micrometastatic sentinel nodes was usually present in only one modality.

This analysis suggests that the risk of finding tumor in nonsentinel nodes differs significantly between cases with micro (3%)- vs macro (63%)-metastatic disease in sentinel nodes. This holds true for cases assessed by intraoperative consult.

Considering the known morbidity of complete axillary dissection, assessments of risk vs benefit of undertaking this procedure should be performed on a case-by-case basis in patients with sentinel node micrometastases.
Frozen section diagnosis for axillary sentinel lymph nodes: the first six years.

Mitchell ML.

1Department of Pathology, Christiana Care Health Services, Newark, DE, USA.
Mod Pathol. 2005 Jan;18(1):58-61. Abstract quote

Intraoperative frozen section of axillary lymph nodes for the detection of metastatic breast cancer has been controversial because of the labor-intensive techniques necessary to obtain a highly sensitive test, and because of the uncertain significance of frequently detected submicrometastatic carcinoma.

In total, 874 consecutive axillary sentinel lymph node cases examined by intraoperative frozen section over a 6-year period were reviewed retrospectively. Frozen section had a sensitivity of 60% and was 100% specific, but when cases with submicrometastatic tumor cells were considered negative, the sensitivity rose to 83%.

Rare cases were called 'atypical' on frozen section; almost all of these cases were negative for carcinoma on permanent sections.
Benign Mechanical Transport of Breast Epithelial Cells to Sentinel Lymph Nodes.

Diaz NM, Cox CE, Ebert M, Clark JD, Vrcel V, Stowell N, Sharma A, Jakub JW, Cantor A, Centeno BA, Dupont E, Muro-Cacho C, Nicosia S.

From the Departments of *Interdisciplinary Oncology and daggerSurgery, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL.

Am J Surg Pathol. 2004 Dec;28(12):1641-1645. Abstract quote  

The evaluation of sentinel lymph nodes (SLNs) for the presence of malignant epithelial cells is essential to the staging of breast cancer patients. Recently, increased attention has focused on the possibility that epithelial cells may reach SLNs by benign mechanical means, rather than by metastasis.

The purpose of this study was to test the hypothesis that pre-SLN biopsy breast massage, which we currently use to facilitate the localization of SLNs, might represent a mode of benign mechanical transport.

We studied 56 patients with invasive and/or in situ ductal carcinoma and axillary SLNs with only epithelial cells and/or cell clusters (</=0.2 mm in diameter and not associated with features of established metastases) detected predominantly in subcapsular sinuses of SLNs on hematoxylin and eosin- and/or anti-cytokeratin-stained sections. No patient had an SLN involved by either micro- or macro-metastatic carcinoma. Epithelial cells and cell clusters, </=0.2 mm in size and without features of established metastases, occurred more frequently in the SLNs of patients who underwent pre-SLN biopsy breast massage (P < 0.001, chi test).

The latter finding supports the hypothesis that pre-SLN biopsy breast massage is a mode of benign mechanical transport of epithelial cells to SLNs.
RT-PCR for Mammaglobin Genes, MGB1 and MGB2, Identifies Breast Cancer Micrometastases in Sentinel Lymph Nodes

Rodney J. Ouellette, , MD, PhD, Dominique Richard, PhD, and Emmanuel Maïcas, MD, PhD
Am J Clin Pathol 2004;121:637-643 Abstract quote

In the present study, we examined the expression of the mammaglobin genes, MGB1 and MGB2, in the sentinel lymph nodes (SLNs) of patients with breast cancer and compared our results with the histologic status of the same SLNs. Compared with immunohistochemical staining for cytokeratin 8, which detected metastases in 17 of 42 patients, reverse transcription–polymerase chain reaction (RT-PCR) for MGB1 or MGB2 genes was positive in 22 patients. The concordance between the expression of any mammaglobin and histologic status was 79% (33/42), with a sensitivity of 88% and specificity of 72%.

The detection of patients with metastases was more sensitive when testing for both MGB1 and MGB2 (P < .0001) rather than MGB2 (P < .0005) or MGB1 (P < .05) alone.

The increased detection rate relative to histologic examination suggests that using RT-PCR for the mammaglobin genes might identify patients at higher risk compared with patients with negative RT-PCR results.

Histologic localization of sentinel lymph node metastases in breast cancer.

Diaz LK, Hunt K, Ames F, Meric F, Kuerer H, Babiera G, Ross M, Singletary E, Middleton LP, Symmans WF, Krishnamurthy S, Sahin A, Sneige N, Gilcrease MZ

Am J Surg Pathol 2003 Mar;27(3):385-9 Abstract quote

Data from a recent study support the hypothesis that axillary lymph node metastases frequently localize near the inflow junction of the afferent lymphatic vessel.

Our goal was to evaluate the microscopic location of axillary sentinel lymph node metastases in a prospective study of breast cancer patients. A total of 305 axillary sentinel lymph nodes from 213 breast cancer patients undergoing surgery at our institution were evaluated. Preoperative lymphoscintigraphy using technetium-labeled sulfur colloid and intraoperative isosulfan blue dye injection were used for identifying the sentinel lymph node. Intraoperatively, the surgeon placed a suture either at the point of entry of isosulfan blue dye or at the area with the highest radioactive counts, and this area was inked at the grossing bench before processing.

Metastases were identified in 55 of the 305 lymph nodes examined. Thirty-four nodes contained metastases in both the inked half and the opposite half. Metastatic tumor was identified in the inked half alone in 18 lymph nodes. Only three nodes contained metastatic tumor in the opposite half with no tumor in the inked half (p <0.001). Similar results were found when nodes tagged at the point of blue dye entry and nodes tagged at the area with the highest radioactive counts were analyzed separately.

Our findings suggest that metastatic tumor has a higher probability of being present in the region of the inflow junction of the afferent lymphatic vessel. This information may be useful in determining the optimal method for evaluating axillary sentinel lymph node specimens from breast cancer patients.

Recommendations for Sentinel Lymph Node Processing in Breast Cancer

M. A. Yared, M.D.; L. P. Middleton, M.D.; T. L. Smith, M.D.; H. W. Kim, M.S.; M. I. Ross, M.D.; K. K. Hunt, M.D.; A. A. Sahin, M.D.

From the Department of Pathology and Laboratory Medicine (M.A.Y.), University of Texas Health Science Center at Houston, and the Departments of Pathology (L.P.M., A.A.S.), Biostatistics (T.L.S., H.W.K.), and Surgical Oncology (M.I.R., K.K.H.), University of Texas, M.D. Anderson Cancer Center, Houston, Texas, U.S.A.


Am J Surg Pathol 2002;26:377-382 Abstract quote

The status of the sentinel lymph node (SLN) has been shown to accurately reflect the presence or absence of metastases in the axilla in patients with breast cancer.

This study was designed to determine the optimal protocol for SLN processing. A total of 173 SLNs from 96 breast cancer patients who had successful SLN localization and underwent completion axillary node dissection were identified. All SLNs were negative for metastases by initial routine histologic evaluation. The nodes were submitted in a total of 300 blocks.

Each block was serially sectioned to produce 10 levels. Pan-cytokeratin stain was performed on levels 3 and 8. All other levels were stained with hematoxylin and eosin. Metastases were identified in 22 SLNs from 19 patients by examining all 10 levels. The first two hematoxylin and eosin- or the first cytokeratin-stained levels were positive for metastases in 21 (95.5%) of the 22 positive SLNs. Two additional hematoxylin and eosin-stained and one cytokeratin-stained levels of each SLN correctly identified the status of the node in 94 (97.9%) of 96 patients.

Therefore, we recommend that after an initial hematoxylin and eosin-stained section, two additional hematoxylin and eosin-stained sections and one cytokeratin-stained section should be evaluated.


N Engl J Med 1998;339:941-946
Breast J 1998;4:67-74
JAMA 1996;276:1818-1822
Ann Surg 1998;227:645-653
Ann Surg 1995;222:394-401
Ann Surg 1994;220:391-401
Lancet 1997;349:1864-1867

Overall, at multicenters, technical success has ranged from 92-98% with at least one SLN identified in 98% of these cases
Positive predictive value of SLN in predicting final axillary status was 97%
Sensitivity 89%
Specificity 100%
False negative rate 11.4%
Predictive value of negative SLN was 96% (This rate can be reduced as surgeon gains experience)

SLN identified:
Outside axilla in 8%
Outside level I in 11%

Positive SLN's identified in:
Outside axilla in 3%

Evaluation of nonoccult metastases

Cancer 2000;88:1099-1107

Multicenter study
Lymph node status reclassified in 3.5% of cases (occult metastases by second review)
Review done by conventional H and E staining without IPOX stains

385 cases of invasive cancer
267 TN
14 FN (11.9%)
104 TP
PPV of 100%
NPV 95%

If SLN was positive, 13.4x more likely that a nonsentinel LN was positive than if the SLN was negative

Evaluation of occult metastases

Cancer 2000;88:1099-1107

214 cases with additional sections taken at 100 and 200 microns and CK stains performed

Occut metastases found in 10.3% (22/214)
12.3x more likely to find occult mets in SLN than in non SLN
15 cases were ductal CA
7 cases were lobular CA
All were </=1.0mm in greatest dimension
90%</=0.5 mm

Occult mets more likely to be found in tumors between 1-2 cm

Deeper sections and IHC cytokeratin stains identified occult mets in 18% (2/11) of the false negative SLN cases but also identified additional false negative cases
In 1.4% (3/214) mets were present in nonsentinel nodes while SLN were negative
Additional sections and IHC cytokeratin staining may reduce the false negative rate but will not entirely eliminate false negative cases

Evaluation of immunohistochemistry and multiple-level sectioning in sentinel lymph nodes from patients with breast cancer.

Pargaonkar AS, Beissner RS, Snyder S, Speights VO.

Department of Pathology, Scott & White Memorial Hospital and Clinic, Scott, Sherwood and Brindley Foundation, The Texas A&M University System Health Science Center, College of Medicine, Temple, Tex.


Arch Pathol Lab Med 2003 Jun;127(6):701-5 Abstract quote

Context.-Previous investigations on sentinel lymph node biopsies have demonstrated their importance in nodal staging of patients with breast cancer. However, sentinel node biopsy in breast cancer is currently a controversial procedure and continues to provoke debate.

Objectives.-We designed our study to determine the usefulness of a standard protocol for evaluating sentinel lymph node metastases and to assess the value of sentinel node biopsy as the only procedure in nodal staging in breast cancer patients.

Materials and Methods.-A retrospective analysis of 84 breast cancer patients with sentinel node biopsies, who also underwent axillary dissection, was conducted using a standard protocol (3 levels of immunohistochemical stains for keratin and 2 levels of hematoxylin-eosin (HE) stains on the first 3 negative lymph nodes).

Results.-Hematoxylin-eosin staining identified 20 patients (23.8%) with sentinel node metastases. The remaining 64 negative patients (76.1%) were tumor free on sentinel lymph nodes at level 1 HE. Additional immunohistochemical stains for keratin and HE stains on specimens from these 64 patients showed an additional 5 patients (7.8%) to be positive for lymph node micrometastases (<2 mm). The total percentage of cases with sentinel lymph node metastases detected by HE staining and immunohistochemistry was 29.7%. Of the remaining 59 cases that were negative on HE and immunohistochemistry, axillary dissection revealed 3 cases that had metastases in the axillary lymph nodes. The false-negative rate was 10.7%. The concordance rate between sentinel lymph nodes and axillary lymph nodes was 96.4%. The sensitivity was 89% and specificity was 100%.

Conclusion.-Immunohistochemistry and multiple-level sectioning increased detection of metastases by 7.8% in sentinel lymph nodes. Caution should be used in accepting sentinel node biopsy alone as the only procedure for staging due to a high false-negative rate (10.7%). A predictive value of 96.4% confirms that sentinel lymph node biopsy is most likely to contain metastatic carcinoma. Sentinel lymph node examination with the protocol we describe, combined with axillary dissection, increased the yield of metastatic disease by identifying 8 additional cases of nodal metastatic disease (an increase of 28%), as compared to standard axillary nodal dissection and single-section sentinel lymph node examination alone.

Identification and Evaluation of Axillary Sentinel Lymph Nodes in Patients With Breast Carcinoma Treated With Neoadjuvant Chemotherapy

Lisa F. Cohen, M.D.; Tara M. Breslin, M.D.; Henry M. Kuerer, M.D., Ph.D.; Merrick I. Ross, M.D.; Kelly K. Hunt, M.D.; Aysegul A. Sahin, M.D. Singeltary SE, ed.

From the Departments of Pathology (L.F.C., A.A.S.) and Surgical Oncology (T.M.B., H.M.K., K.K.H.), The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.

Am J Surg Pathol 2000;24:1266-1272 Abstract quote

Sentinel lymph node (SLN) biopsy has been shown to predict axillary metastases accurately in early stage breast cancer. Some patients with locally advanced breast cancer receive preoperative (neoadjuvant) chemotherapy, which may alter lymphatic drainage and lymph node structure.

In this study, we examined the feasibility and accuracy of SLN mapping in these patients and whether serial sectioning and keratin immunohistochemical (IHC) staining would improve the identification of metastases in lymph nodes with chemotherapy-induced changes.

Thirty-eight patients with stage II or III breast cancer treated with neoadjuvant chemotherapy were included. In all patients, SLN biopsy was attempted, and immediately afterward, axillary lymph node dissection was performed. If the result of the SLN biopsy was negative on initial hematoxylin and eosin-stained sections, all axillary nodes were examined with three additional hematoxylin and eosin sections and one keratin IHC stain. SLNs were identified in 31 (82%) of 38 patients. The SLN accurately predicted axillary status in 28 (90%) of 31 patients (three false negatives). On examination of the original hematoxylin and eosin-stained sections, 20 patients were found to have tumor-free SLNs. With the additional sections, 4 (20%) of these 20 patients were found to have occult lymph node metastases. These metastatic foci were seen on the hematoxylin and eosin staining and keratin IHC staining.

Our findings indicate that lymph node mapping in patients with breast cancer treated with neoadjuvant chemotherapy can identify the SLN, and SLN biopsy in this group accurately predicts axillary nodal status in most patients. Furthermore, serial sectioning and IHC staining aid in the identification of occult micrometastases in lymph nodes with chemotherapy-induced changes.

Cytokeratin Immunohistochemical Validation of the Sentinel Node Hypothesis in Patients With Breast Cancer

Karyn B. Stitzenberg, MD
Benjamin F. Calvo, MD
Mary V. Iacocca, MD
Brian H. Neelon, MS
Leah B. Sansbury
Lynn G. Dressler, MA
David W. Ollila, MD

Am J Clin Pathol 2002;117:729-737 Abstract quote

No standard method for handling and histopathologic examination of the sentinel node (SN) exists.

We hypothesized that a focused examination of all nodes with serial sectioning and cytokeratin immunohistochemical staining would confirm the SN as the node most likely to harbor metastasis. Intraoperative lymphatic mapping and sentinel lymphadenectomy using blue dye and 99mtechnetium-labeled sulfur colloid were performed. All nodes were stained with H&E. All tumor-free nodes underwent additional sectioning and staining with H&E and an immunohistochemical stain.

Routine H&E examination detected SN metastases in 27.6% of cases. Occult SN metastases were identified in 12.7% of cases. None of the 724 non-SNs examined contained occult metastases. The SN false-negative rate was zero. This study confirms histopathologically that the SN has biologic significance as the axillary node most likely to harbor metastatic tumor.

Standardization of the handling, sectioning, and staining of the SN is necessary as lymphatic mapping and sentinel lymphadenectomy become integrated into the care of patients with breast cancer.

Accuracy of sentinel lymph node biopsy for patients with T2 and T3 breast cancers.

Wong SL, Chao C, Edwards MJ, Tuttle TM, Noyes RD, Carlson DJ, Laidley AL, McGlothin TQ, Ley PB, Brown CM, Glaser RL, Pennington RE, Turk PS, Simpson D, McMasters KM.

Department of Surgery, University of Louisville, Kentucky, USA.

Am Surg 2001 Jun;67(6):522-6 Abstract quote

Although numerous studies have demonstrated that sentinel lymph node (SLN) biopsy can accurately determine the axillary nodal status for early breast cancer some studies have suggested that SLN biopsy may be less reliable for tumors >2 cm in size.

This analysis was performed to determine whether tumor size affects the accuracy of SLN biopsy. The University of Louisville Breast Cancer Sentinel Lymph Node Study is a prospective multi-institutional study involving 226 surgeons. The study was approved by the Institutional Review Board of each institution, and informed consent was obtained from all patients.

Patients with clinical stage T1-2 N0 breast cancer were eligible for the study. Some patients with T3 tumors were included because they were clinically staged as T2 but on final pathology were found to have tumors >5 cm. This analysis includes 2148 patients who were enrolled from August 1997 through October 2000. All patients underwent SLN biopsy using a combination of radioactive colloid and blue dye injection followed by completion Level I/II axillary dissection. Statistical comparison was performed by chi-square analysis.

The SLN identification rate, false negative rate, and overall accuracy of SLN biopsy were not significantly different among tumor stages T1, T2, and T3.

We conclude that SLN biopsy is no less accurate for T2-3 breast cancers compared with T1 tumors.

Sentinel lymph node biopsy for breast cancer: impact of the number of sentinel nodes removed on the false-negative rate.

Wong SL, Edwards MJ, Chao C, Tuttle TM, Noyes RD, Carlson DJ, Cerrito PB, McMasters KM.

Department of Surgery, University of Louisville, KY, USA.

J Am Coll Surg 2001 Jun;192(6):684-9; discussion 689-91 Abstract quote

BACKGROUND: Numerous studies have demonstrated that sentinel lymph node (SLN) biopsy can accurately determine axillary nodal status for breast cancer, but unacceptably high false negative rates have also been reported. Attention has been focused on factors associated with improved accuracy. We have previously shown that injection of blue dye in combination with radioactive colloid reduces the false negative rate compared with injection of blue dye alone. We hypothesized that this may be from the increased ability to identify multiple sentinel nodes. The purpose of this analysis was to determine whether removal of multiple SLNs results in a lower false negative rate.

STUDY DESIGN: The University of Louisville Breast Cancer Sentinel Lymph Node Study is a prospective multiinstitutional study. Patients with clinical stage T1-2, N0 breast cancer were eligible for enrollment. All patients underwent SLN biopsy using blue dye alone, radioactive colloid alone, or both agents in combination, followed by completion level I and II axillary dissection.

RESULTS: A total of 1,436 patients were enrolled in the study from August 1997 to February 2000. SLNs were identified in 1,287 patients (90%), with an overall false negative rate of 8.3%. A single SLN was removed in 537 patients. Multiple SLNs were removed in 750 patients. The false negative rates were 14.3% and 4.3% for patients with a single sentinel node versus multiple sentinel nodes removed, respectively (p = 0.0004, chi-square). Logistic regression analysis revealed that use of blue dye injection alone was the only factor independently associated with identification of a single SLN (p<0.0001), and patient age, tumor size, tumor location, surgeon's previous experience, and type of operation were not significant.

CONCLUSIONS: The ability to identify multiple sentinel nodes, when they exist, improves the diagnostic accuracy of SLN biopsy. Injection of radioactive colloid in combination with blue dye improves the ability to identify multiple sentinel nodes compared with the use of blue dye alone.

Comparison between periareolar and peritumoral injection of radiotracer for sentinel lymph node biopsy in patients with breast cancer.

Shimazu K, Tamaki Y, Taguchi T, Takamura Y, Noguchi S.

Department of Surgical Oncology, Osaka University Medical School, Osaka, Japan.

Surgery 2002 Mar;131(3):277-86 Abstract quote

BACKGROUND: The technique of sentinel lymph node (SLN) biopsy in patients with breast cancer varies among reports, and the optimal method remains to be established, particularly with regard to the site of radiotracer injection. The aim of this study was to compare periareolar and peritumoral injection of radiotracer in detecting SLN in patients with breast cancer.

METHODS: Patients with T1-2 breast cancer (n = 155) were enrolled in this study. In phase 1 (n = 62), SLN biopsy was performed by using peritumoral injection of blue dye alone followed by backup axillary lymph node dissection. In phase 2, SLN biopsy was performed by using peritumoral injection of blue dye and peritumoral (group A, n = 41) or periareolar (group B, n = 52) injection of technetium 99m tin colloid.

RESULTS: In phase 1, the detection rate of SLN was 81% and the false-negative rate was 5.6%, indicating our skill in SLN biopsy. In phase 2, the success rate of lymphoscintigraphy was significantly (P <.001) higher in group B (90%) than in group A (51%). The mean ex vivo radioactivity of SLN in group B (117 counts per second; range, 5 to 900) was also significantly (P <.05) higher than in group A (51 counts per second; range, 8 to 260). In addition, the detection rate of SLN was significantly (P <.05) higher in group B (100%) than in group A (90%).

CONCLUSIONS: Periareolar injection of radiotracer for SLN biopsy is superior to peritumoral injection because of its simplicity, achieving a high success rate in lymphoscintigraphy and SLN detection.

Histological detection of minimal metastatic involvement in axillary sentinel nodes: a rational basis for a sensitive methodology usable in daily practice.

Freneaux P, Nos C, Vincent-Salomon A, Genin P, Sigal-Zafrani B, Al Ghuzlan A, Birolini MJ, Clough K, Sastre-Garau X.

Departments of Pathology (PF, AV-S, PG, BS-Z, AAG, M-JB, XS-G) and Surgery (CN, KC), Institut Curie, Paris, France.

Mod Pathol 2002 Jun;15(6):641-6 Abstract quote

There is no consensus method for the histological analysis of axillary sentinel nodes (SN). This study aimed to (1) assess the rate of occult metastases in SN using large serial sectioning and immunohistochemistry (IHC), (2) evaluate whether occult metastases were predictive of metastases in the downstream axillary nodes, and (3) specify a methodology of analysis of SN that could be both sensitive and applicable in daily practice.

One hundred three patients with breast carcinoma underwent SN biopsy and then axillary dissection. SN free of tumor at standard examination of one section were sectioned at six levels (150-microm intervals) and immunostained for cytokeratin. The number and localization of labeled metastatic cells (occult metastases) were recorded. In 29 of the 103 patients (28%), SN were found to be metastatic after standard examination. The SN of the remaining 74 patients were further analyzed using IHC. Occult metastases were detected in 35 of these patients (47.3%), leading to an overall SN involvement rate of 62% (29+35/103). In 33 of these 35 cases, the plurality and the dispersion of the immunostained cells implied that the screening of only 3 of the 6 levels would have led to the detection of diagnostic positive events. Only one of the 35 patients (2.8%) with occult metastases showed metastatic lymph node in the downstream axilla.

In our series of axillary SN, the analysis of one standard histologic section and, when negative, of only three additional sections after IHC revealed >60% of metastasis or occult metastasis. Metastasis detected by standard analysis had a high predictive value of downstream node metastasis, whereas the predictive value of occult metastasis revealed by IHC was poor. The clinical significance of occult metastases in SN needs to be specified by long-term follow-up analysis.

Proceedings of the consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast April 19 to 22, 2001, Philadelphia, Pennsylvania.

Schwartz GF, Giuliano AE, Veronesi U.

Sponsored by the Breast Health Institute and the Fashion Group International, Philadelphia.

Hum Pathol 2002 Jun;33(6):579-89 Abstract quote

A consensus conference on the role of sentinel node biopsy in breast cancer was held in Philadelphia in April 2001. The participants included many highly respected American and European investigators in this area.

This report summarizes the deliberations of the group and promotes its current guidelines for the integration of this new technique into contemporary clinical practice.

Intraoperative analysis of sentinel lymph nodes by imprint cytology for cancer of the breast.

Shiver SA, Creager AJ, Geisinger K, Perrier ND, Shen P, Levine EA.

Department of Surgery, Surgical Oncology Service, Wake Forest University School of Medicine, Medical Center Blvd., 27157, Winston-Salem, NC, USA


Am J Surg 2002 Nov;184(5):424-7 Abstract quote

The utilization of lymphatic mapping techniques for breast carcinoma has made intraoperative evaluation of sentinel lymph nodes (SLN) attractive, because axillary lymph node dissection can be performed during the initial surgery if the SLN is positive. The optimal technique for rapid SLN assessment has not been determined. Both frozen sectioning and imprint cytology are used for rapid intraoperative SLN evaluation.

A retrospective review of the intraoperative imprint cytology results of 133 SLN mapping procedures from132 breast carcinoma patients was performed. SLN were evaluated intraoperatively by bisecting the lymph node and making imprints of each cut surface. Imprints were stained with hematoxylin and eosin (H&E) and Diff-Quik. Permanent sections were evaluated with up to four H&E stained levels and cytokeratin immunohistochemistry. Imprint cytology results were compared with final histologic results.

Sensitivity and specificity of imprint cytology were 56% and 100%, respectively, producing a 100% positive predictive value and 88% negative predictive value. Imprint cytology was significantly more sensitive for macrometastasis than micrometastasis 87% versus 22% (P = 0.00007). Of 13 total false negatives, 11 were found to be due to sampling error and 2 due to errors in intraoperative interpretation. Both intraoperative interpretation errors involved a diagnosis of lobular breast carcinoma.

The sensitivity and specificity of imprint cytology are similar to that of frozen section evaluation. Imprint cytology is therefore a viable alternative to frozen sectioning when intraoperative evaluation is required. If SLN micrometastasis is used to determine the need for further lymphadenectomy, more sensitive intraoperative methods will be needed to avoid a second operation.

Discontinuous or "skip" metastases in breast carcinoma. Analysis of 1228 axillary dissections.

Rosen PP, Lesser ML, Kinne DW, Beattie EJ.

Ann Surg 1983 Mar;197(3):276-83 Abstract quote

Patterns of axillary lymph node metastases were analyzed in 1228 recently performed modified, radical, and extended radical mastectomies. In these specimens the position or level of lymph nodes was designated intraoperatively by the surgeon.

No lymph node metastases were found in 720 (58) of the specimens while the remainder (508 or 41%) had at least one affected lymph node. The distribution of involvement by level showed progressive spread from level I to III as the number of positive lymph nodes increased. Discontinuous or "skip" metastases not following this pattern occurred in 1.6% of all cases and 3% of those with lymph node metastases (95% confidence interval, 1-5%). Half of those with "skip" metastases had tumor limited to level II. The presence of "skip" metastases was not related to the size, location in the breast, or histologic type of the primary tumor.

It is apparent that the potential risk from "skip" metastases is not great and that this should not be a major consideration in therapeutic decisions. The risk is likely to be negligible for women treated by axillary dissections that include level II.

Significance of isolated cytokeratin positive cells in sentinel lymph nodes

Cancer 1999;86:2668-73
Cancer 1999;86:2589-92.
Arch Pathol Lab Med 2000; 124:966-978

Prognostic factors in breast cancer. CAP Consensus statement 1999.

Although there is no consensus on the biological meening of these cells, there is a consensus (at least partial) from the CAP and UICC experts that these should not be reported as node positive (stage II or pN1a),but should be considered as pN0 (Stage I) therefore should not be treated as node positive

This is controversial and additional data needs to be evaluated


J Clin Pathol 1999; 52:922-924
Am J Clin Pathol 2000; 113:351-354.
J Clin Pathol 2000; 53 (October issue):733-741

Some of the "isolated tumor cells" are in deeper section associated with micrometastases, and some of the micrometastases on deeper sections become larger than 2 mm

Protocols vary by institution varying from a mean of 20-25 levels sampled to 45-50 levels

Such a detailed analysis may "upstage" the axilla in a number of cases

Cytokeratin immunostaining patterns of benign, reactive lymph nodes: applications for the evaluation of sentinel lymph node specimen.

Linden MD, Zarbo RJ.

Department of Pathology, Henry Ford Hospital, Detroit, Michigan 48202, USA.

Appl Immunohistochem Mol Morphol 2001 Dec;9(4):297-301 Abstract quote

The use and interpretation of cytokeratin (CK) immunostains of sentinel lymph node specimens for breast carcinoma remain controversial. Variable immunoreactivity with anti-CK antibodies and CK-positive interstitial reticulum cells may complicate interpretation.

The authors examined a series of reactive lymph nodes selected from patients without a history of malignancy. To demonstrate potential diagnostic pitfalls, three different CK antibody combinations were studied to characterize the immunostaining patterns. Formalin-fixed sections of lymph nodes were immunostained with a labeled streptavidin-biotin method using a DAKO autostainer. The anti-CK antibody preparations evaluated were AE1/AE3, CAM 5.2, and an in-house-prepared CK cocktail composed of 7 antibodies. The authors observed that up to 10% of cells in benign, reactive lymph nodes may be immunoreactive with anti-CK antibodies. AE1/AE3 stained 2 of 20 cases with rare immunoreactive reticulum cells, whereas CAM 5.2 and the CK cocktail immunostained cells in 85% of cases with reticulum cells in sinuses and the paracortex. Rare positive to 2+ cells were present in a similar distribution with these two antibodies.

Careful interpretation of CK immunostaining of sentinel lymph node biopsies is essential, as is awareness of the presence of CK-positive native reticulum cells, to avoid confusion with single cells of metastatic carcinoma.


Separate Cavity Margin Sampling at the Time of Initial Breast Lumpectomy Significantly Reduces the Need for Reexcisions.

Cao D, Lin C, Woo SH, Vang R, Tsangaris TN, Argani P.

From the Departments of *Pathology, daggerSurgery, and double daggerOncology, Johns Hopkins Hospital, Baltimore, MD.

Am J Surg Pathol. 2005 Dec;29(12):1625-1632. Abstract quote  

In breast conservation therapy, the margin status of the specimen predicts local recurrence and determines the need for reexcision. Many surgeons now take, at the time of lumpectomy, multiple separate "cavity margins" (CM) (the entire wall of the residual cavity) as final margins that supersede the oriented lumpectomy margins (LMs).

We studied the efficacy of this method in 126 patients (23 with ductal carcinoma in situ [DCIS] only and 103 with invasive carcinoma with or without DCIS) who had an oriented lumpectomy specimen and also had four to six additional CMs. The tumors were evaluated for the following: size, grade, LM status (distance of tumor from margin and, if involved, extent of involvement), vascular invasion, lymph node status, and presence or absence of extensive intraductal component. The additional CM specimens were evaluated for residual carcinoma (if any) and its distance from the inked true margins, and the results were correlated with the corresponding LMs.

Only approximately 50% of patients (52 of 103) with histologically positive LMs (defined as carcinoma within 2 mm of the inked surface) had residual carcinoma in their CMs. Additional CM sampling rendered the overall final margin status histologically negative in 61 of 103 (59%) cases with histologically positive LMs, therefore significantly reducing the need for reexcision.

Younger patient age, higher number of positive LMs, high tumor grade, and the presence of extensive intraductal component were predictive of residual carcinoma in CM specimens, whereas the distance of carcinoma from the inked surface and the extent of tumor involvement of histologically positive LMs were not. Because CM specimens taken from patients with histologically positive LMs usually lack tumor, we suspect that many positive LMs are likely false positives.

Possible factors accounting for false-positive LMs include seepage of ink into crevices of the specimen promoted by excessive inking, tumor friability promoting displacement of tumor into ink, manipulation of specimens for radiographs, and retraction artifact.
Factors Associated Witth Ipsilateral Breast Failure and Distant Metastases in Patients With Invasive Breast Carcinoma Treated With Breast-Conserving Therapy A Clinicopathologic Study of 607 Neoplasms From 583 Patients

Neal S. Goldstein, MD, Larry Kestin, MD, and Frank Vicini, MD
Am J Clin Pathol 2003;120:500-527 Abstract quote

All slides from 607 consecutive invasive breast carcinomas from 583 patients were reviewed. Margin distance, composite width of invasive carcinoma, and number of ducts with intraductal carcinoma within the one-half low-power field (LPF) adjacent to the final margin were recorded. Final margin groups were positive (carcinoma at margin), near ( £ ½ LPF of margin), and negative (>½ LPF). There were 39 ipsilateral breast failures (IBFs), and 63 patients (10.8%) developed distant metastases (DMs). Decreasing margin distance and increasing amounts of carcinoma near the margin were associated with IBF and DM.

The 5-tiered composite factor of margin distance and amount of carcinoma near margin (negative margins, near least amount, near intermediate amount, near greatest amount, and positive margins) resulted in 12-year IBF rates of 9%, 6%, 18%, 24%, and 30%, respectively ( P < .001). The composite factor, margin amount of carcinoma near margin, and invasive carcinoma/initial excision specimen dimension ratio were the most precise parameters assessing excision adequacy and, ultimately, IBF risk.

The amount of carcinoma near the margin and volume of excised parenchyma related directly to the amount of residual carcinoma in the adjacent breast parenchyma.




Prophylactic mastectomy: pathologic findings in high-risk patients.

Khurana KK, Loosmann A, Numann PJ, Khan SA.

Department of Pathology, State University of of New York, Syracuse 13210, USA.

Arch Pathol Lab Med 2000 Mar;124(3):378-81 Abstract quote

BACKGROUND: According to recently published data, prophylactic mastectomy (PM) appears to prevent about 90% of the expected malignant neoplasms in women with a family history of breast cancer.

OBJECTIVES: To identify the frequency of high-risk lesions in PM specimens and to determine occurrence of any new primary breast cancer following PM.

DESIGN: We performed a retrospective study of women undergoing unilateral or bilateral PM. Medical charts and pathologic findings of 35 patients who underwent bilateral mastectomies at University Hospital, Syracuse, NY, from 1989 to 1996 were reviewed. Patients with biopsy-proven bilateral breast cancer were excluded. Patients were divided into 3 groups: (A) positive family history and no known breast cancer (n = 9), (B) positive family history and contralateral neoplasia (n = 13), and (C) negative family history and contralateral neoplasia (n = 13). These findings were compared with those found in reduction mammoplasty specimens from 10 women at standard risk of breast cancer.

RESULTS: The mean age of the control group of women undergoing reduction mammoplasty was 38 years. The pathologic specimens demonstrated no significant pathologic findings in 9 and fibrocystic change in 1. In group A, the mean number of affected relatives was 3.1, and the mean age was 38 years. Two of these 9 women had atypical duct hyperplasia and 1 had atypical lobular hyperplasia in their breasts (ie, 33% with high-risk pathologic findings). Of the 13 group B women (mean age, 46.6 years; mean of 2.5 affected relatives and unilateral breast cancer), the contralateral PM specimen contained duct carcinoma in situ in one and invasive ductal cancer in a second (15% with occult malignant neoplasms). In 13 group C patients (mean age, 47.1 years), 3 (23.1%) of the contralateral PM specimens displayed atypical duct hyperplasia or atypical lobular hyperplasia. At a mean follow-up of 4.8 years, there have been no new breast malignant neoplasms in these 45 women.

CONCLUSIONS: The occurrence of unilateral cancer in patients with family history of breast cancer is associated with a 15.4% probability of simultaneous occult malignant neoplasms in the contralateral breast. Patients with a strong family history but no evidence of breast cancer have a substantially similar rate of proliferative disease in their PM specimens as those women who have unilateral cancer but no significant family history.



Accelerated treatment of breast cancer.

Vicini FA, Baglan KL, Kestin LL, Mitchell C, Chen PY, Frazier RC, Edmundson G, Goldstein NS, Benitez P, Huang RR, Martinez A.

Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI 48073, USA.

J Clin Oncol 2001 Apr 1;19(7):1993-2001 Abstract quote

PURPOSE: Radiation therapy (RT) restricted to the tumor bed, by means of an interstitial implant, and lasting 4 to 5 days after lumpectomy was prospectively evaluated in early-stage breast cancer patients treated with breast-conserving therapy (BCT). The goals of the study were to determine whether treatment time can be reduced and whether elective treatment of the entire breast is necessary.

MATERIALS AND METHODS: Between January 1993 and January 2000, 174 cases of early-stage breast cancer were managed with lumpectomy followed by RT restricted to the tumor bed using an interstitial implant. Each brachytherapy patient was matched with one external-beam RT (ERT) patient derived from a reference group of 1,388 patients treated with standard BCT. Patients were matched for age, tumor size, histology, margins of excision, absence of an extensive intraductal component, nodal status, estrogen receptor status, and tamoxifen use. Median follow-up for both the ERT and brachytherapy groups was 36 months.

RESULTS: No statistically significant differences were noted in the 5-year actuarial rates of ipsilateral breast treatment failure or locoregional failure between ERT and brachytherapy patients (1% v 0%, P =.31 and 2% v 1%, P =.63, respectively). In addition, there were no statistically significant differences noted in rates of distant metastasis (6% v 3%, P =.24), disease-free survival (87% v 91%, P =.55), overall survival (90% v 93%, P =.66), or cause-specific survival (97% v 99%, P =.28).

CONCLUSION: Accelerated treatment of breast cancer using an interstitial implant to deliver radiation to the tumor bed alone over 4 to 5 days seems to produce 5-year results equivalent to those achieved with conventional ERT. Extended follow-up will be required to determine the long-term efficacy of this treatment approach.

Ipsilateral supraclavicular lymph nodes metastases from breast cancer as only site of disseminated disease. Chemotherapy alone vs. induction chemotherapy to radical radiation therapy.

Pergolizzi S, Settineri N, Santacaterina A, Spadaro P, Maisano R, Caristi N, Adamo V, De Renzis C, Mesiti M, Cascinu S.

Institute of Radiological Science, Department of Radiation Oncology University of Messina, Italy.

Ann Oncol 2001 Aug;12(8):1091-5 Abstract quote

BACKGROUND: To define the role of radiotherapy (RT) in the treatment of ipsilateral supraclavicular lymph-nodes metastases (ISLM) from breast cancer as only site of disseminated disease, we started a prospective non-randomized clinical trial in 1989. Here we report the final results with a median follow-up of 8.75 years.

PATIENTS AND METHODS: Thirty-seven patients (pts), with ISLM from breast cancer, were consecutively enrolled into two arms. Arm A (18 pts): chemotherapy (CT) for six courses. Arm B (19 pts): CT for three courses followed by RT to the site of ISLM at 'radical' dose of 50-60 Gy.

RESULTS: In arm A, a median Time to Progression (TtP) of 7 months with a median Overall Survival (OS) of 28 months was recorded. In comparison, patients in arm B had a longer median TtP with 20 months as well as a better median OS with 41 months, respectively. An actuarial five-year disease-free survival of 5.5% was obtained in arm A vs. 21% in arm B. A statistically significant difference in TtP was demonstrated between the two groups (P = 0.01).

CONCLUSIONS: These data demonstrate that a better event-free survival could be achieved in patients with ISLM submitted to induction CT and radical irradiation. This also translated into a longer survival although this did not achieve statistical significance. We want to stress the importance of local control by RT since it does imply that not all of these patients have micrometastases at the time of relapse in the supraclavicular fossa.


Association of frequency and duration of aspirin use and hormone receptor status with breast cancer risk.

Terry MB, Gammon MD, Zhang FF, Tawfik H, Teitelbaum SL, Britton JA, Subbaramaiah K, Dannenberg AJ, Neugut AI.

Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
JAMA. 2004 May 26;291(20):2433-40. Abstract quote  

CONTEXT: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with a decrease in the risk of several cancers, including breast cancer. NSAIDs inhibit cyclooxygenase activity and thereby reduce prostaglandin synthesis; prostaglandins stimulate aromatase gene expression and thereby stimulate estrogen biosynthesis. Given the importance of estrogen in the pathogenesis of breast cancer, the ability of aspirin and other NSAIDs to protect against breast cancer could vary according to hormone receptor status.

OBJECTIVES: To determine the association between the frequency and duration of use of aspirin and other NSAIDs and breast cancer risk and to investigate whether any observed association is more pronounced for women with hormone receptor-positive breast cancers.

DESIGN, SETTING, AND PATIENTS: Population-based case-control study of women with breast cancer, including in-person interviews conducted on Long Island, NY, during 1996-1997 (1442 cases and 1420 controls).

MAIN OUTCOME MEASURE: Incident invasive and in situ breast cancer by aspirin and NSAID use and hormone receptor status.

RESULTS: Ever use of aspirin or other NSAIDs at least once per week for 6 months or longer was reported in 301 cases (20.9%) and 345 controls (24.3%) (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.66-0.97 for ever vs nonusers). The inverse association was most pronounced among frequent users (> or =7 tablets per week) (OR, 0.72; 95% CI, 0.58-0.90). The results for ibuprofen, which was used by fewer women on a regular basis, were generally weaker (OR, 0.78; 95% CI, 0.55-1.10 for <3 times per week vs OR, 0.92; 95% CI, 0.70-1.22 for > or =3 times per week). Use of acetaminophen, an analgesic that does not inhibit prostaglandin synthesis, was not associated with a reduction in the incidence of breast cancer. The reduction in risk with aspirin use was seen among those with hormone receptor-positive tumors (OR, 0.74; 95% CI, 0.60-0.93) but not for women with hormone receptor-negative tumors (OR, 0.97; 95% CI, 0.67-1.40).

CONCLUSION: These data add to the growing evidence that supports the regular use of aspirin and other NSAIDs (which may operate through inhibition of estrogen biosynthesis) as effective chemopreventive agents for breast cancer.

Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.

Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N.

National Surgical Adjuvant Breast and Bowel Project, Allegheny University of the Health Sciences, Pittsburgh, PA 15212-5234, USA.

J Natl Cancer Inst 1998 Sep 16;90(18):1371-88 Abstract quote

BACKGROUND: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992.

METHODS: Women (N=13388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35-59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n=6707) or 20 mg/day tamoxifen (n=6681) for 5 years. Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time.

RESULTS: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50-59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35-4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older.

CONCLUSIONS: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease.

HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15.

Paik S, Bryant J, Tan-Chiu E, Yothers G, Park C, Wickerham DL, Wolmark N.

Division of Pathology, National Surgical Adjuvant Breast and Bowel Project, Allegheny General Hospital, Pittsburgh, PA 15212-5234, USA.

J Natl Cancer Inst 2000 Dec 20;92(24):1991-8 Abstract quote

BACKGROUND: Recent retrospective analyses have suggested that breast cancer patients whose tumors overexpress HER2 derive preferential benefit from treatment with anthracyclines such as doxorubicin. This has led some clinicians to propose that HER2 should be used as a predictive marker in choosing between anthracycline-based regimens and combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). We evaluated this recommendation in a retrospective study of National Surgical Adjuvant Breast and Bowel Project Protocol B-15, in which patients received a combination of doxorubicin and cyclophosphamide (AC), CMF, or AC followed by CMF. We hypothesized that AC would be superior to CMF only in the HER2-positive patients.

METHODS: Immunohistochemical detection of HER2 was performed on tumor sections from 2034 of 2295 eligible patients. We used statistical analysis to evaluate the interaction between the efficacy of the assigned treatments and HER2 overexpression. All statistical tests were two-sided.

RESULTS: Tumor sections from 599 patients (29%) stained positive for HER2. AC was superior to CMF in HER2-positive patients only, although differences in outcomes did not reach statistical significance. In the HER2-positive cohort, relative risks of failure (i.e., after AC treatment as compared with CMF treatment) were 0.84 for disease-free survival (DFS) (95% confidence interval [CI] = 0.65--1.07; P =.15), 0.82 for survival (95% CI = 0.63--1.06; P =.14), and 0.80 for recurrence-free survival (RFS) (95% CI = 0.62--1.04; P =.10). Tests for interaction between treatment and HER2 status were suggestive but not statistically significant (P =.19 for DFS, P =.11 for survival, and P =.08 for RFS).

CONCLUSIONS: These results, together with overview results indicating minor overall superiority for anthracycline-based regimens relative to CMF, indicate a preference for the AC regimen in patients with HER2-positive tumors. Both AC and CMF regimens may be considered for patients with HER2-negative tumors.

Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial.

Fisher B, Dignam J, Bryant J, Wolmark N.

National Surgical Adjuvant Breast and Bowel Project, and Department of Surgery, University of Pittsburgh, PA 15212-5234, USA.

J Natl Cancer Inst 2001 May 2;93(9):684-90 Abstract quote

BACKGROUND: Previously reported information from B-14, a National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized, placebo-controlled clinical trial, demonstrated that patients with estrogen receptor (ER)-positive breast cancer and negative axillary lymph nodes experienced a prolonged benefit from 5 years of tamoxifen therapy. When these women were rerandomized to receive either placebo or more prolonged tamoxifen therapy, they obtained no additional advantage from tamoxifen through 4 years of follow-up. Because the optimal duration of tamoxifen administration continues to be controversial and because there have been 3 more years of follow-up and a substantial increase in the number of events since our last report, an update of the B-14 study is appropriate.

METHODS: Patients (n = 1172) who had completed 5 years of tamoxifen therapy and who were disease free were rerandomized to receive placebo (n = 579) or tamoxifen (n = 593). Survival, disease-free survival (DFS), and relapse-free survival (RFS) were estimated by the Kaplan-Meier method; the differences between the treatment groups were assessed by the log-rank test. Relative risks of failure (with 95% confidence intervals) were determined by the Cox proportional hazards model. P values were two-sided.

RESULTS: Through 7 years after reassignment of tamoxifen-treated patients to either placebo or continued tamoxifen therapy, a slight advantage was observed in patients who discontinued tamoxifen relative to those who continued to receive it: DFS = 82% versus 78% (P =.03), RFS = 94% versus 92% (P =.13), and survival = 94% versus 91% (P =.07), respectively. The lack of benefit from additional tamoxifen therapy was independent of age or other characteristics.

CONCLUSION: Through 7 years of follow-up after rerandomization, there continues to be no additional benefit from tamoxifen administered beyond 5 years in women with ER-positive breast cancer and negative axillary lymph nodes.

Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23.

Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB.

National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA 15212-5234, USA.

J Clin Oncol 2001 Feb 15;19(4):931-42 Abstract quote

PURPOSE: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor-negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study.

PATIENTS AND METHODS: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status.

RESULTS: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P =.96,.8, and.8, respectively), for those aged < or = 49 years (P =.97,.5, and.9, respectively), or for those aged > or = 50 years (P =.7,.6, and.6, respectively). A comparison between all CMF- and all AC-treated patients demonstrated no significant differences in RFS (87% at 5 years in both groups, P =.9), EFS (83% and 82%, P =.6), or S (89% and 90%, P =.4). There were no significant differences in RFS, EFS, or S between CMF and AC in patients aged < or = 49 or > or = 50 years. No significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM. RFS in both groups was 87% (P =.6), 87% in patients aged < or = 49 (P =.9), and 88% and 87%, respectively (P =.4), in those aged > or = 50 years.

CONCLUSION: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.

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