Editor(s): Stephen B. Edge, M.D. Reviewers: Monica Morrow, MD, S. Eva Singletary, MD, David P. Winchester, MD, Hiram S. Cody, III, MD, Patrick I. Borgen, MD, J. Dirk Inglehart, MD.

Screening

Kerlikowske K, et al. Efficacy of screening mammography: A meta-analysis. JAMA 1995;273:149-54.

Rajkumar SV, Hartman LC. Screening mammography in women aged 40-49 years. Medicine 1999;78:410-16.

These papers examine the data addressing the efficacy of mammography at reducing mortality from breast cancer

Kuhl CK, Schmutzler RK, Leutuner CC, et al. Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: Preliminary results. Radiology 2000;215:267-79.

Screening technologies to complement mammography are needed, especially in young women at high risk. Magnetic resonance imaging is increasingly being shown to be useful in staging known breast cancer. Breast MRI may detect occult cancers not seen on mammography in women with mammographically dense breasts. However, the sensitivity, specificity, and clinical utility of screening breast MRI are unknown. This report from Germany is one of the first series reporting the use of screening MRI. There were 5 cancers detected among 192 high risk women with negative mammograms. There is currently a large multicenter trial of screening MRI ongoing in the United States targeted at high risk women (Gail model risk >25% lifetime). At the current time, this data is intriguing, but the use of screening breast MRI must still be considered purely investigational.

Breast cancer risk and genetics

Gail MH et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;1879-86.

This is original report of the Gail Model. This model provides an estimate of breast cancer risk based on the known risk factors of age, menstrual and child bearing history, family history, and history of prior benign breast biopsies. It is based on the Breast Cancer Detection and Demonstration Project, a large mammography study from the 1970's. It was subsequently modified to account for prior atypical hyperplasia and is used to determine eligibility for the NSABP breast cancer prevention studies. [Also see: Costantino JP, Gail MH, Pee D, et al. Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst. 1999;91:1541-8].

Bodian CA et al. Prognostic significance of benign proliferative breast disease. Cancer 1993;71:3896-907.

An excellent study of the risks associated with benign findings on breast biopsy, complementing the original work of Page and Dupont demonstrating increased long-term breast cancer risk with some benign histologies.

Armstrong K, Eisen A, Weber B. Assessing the risk of breast cancer. New Engl J Med. 2000;342:564-71.

Martin AM, Weber BL. Genetic and hormonal risk factors in breast cancer. J Natl Cancer Inst. 2000;92:1126-35.

Two recent reviews, the first of which is on the issues of assessing risk, counseling women about the use of preventive measures, and the appropriate application of breast cancer risk models (Gail and Claus models). The second is a review of the current state of knowledge of breast cancer-associated susceptibility genes and factors affecting expression of these genes, including BRCA1 and 2, and the less well known and low penetrance genes.

Struewing JP, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New Engl J Med. 1997;336:1401-8.

The report of a large scale screening of Ashkenazi Jews for mutations in BRCA1 and BRCA2. It demonstrates the frequency of mutations (2.5%) and risk of ovarian and breast cancer associated with these mutations.

Robson M, Levin D, Federic M, et al. Breast conservation therapy for invasive breast cancer in Ashkenzi women with BRCA gene founder mutations. J Natl Cancer Inst. 1999;91:2112-7.

This paper reports a retrospective review of women treated with breast conservation therapy for invasive breast cancer who were later proven to carry one of the founder mutations in BRCA genes carried in Ashkenazi populations. These women have a higher rate of ipsilateral recurrence and contralateral breast cancer compared to women without a known mutation. However, breast conserving therapy is appropriate and reasonable in this group.

Harding C, Osundeko O, Tetlow L, et al. Hormonally-regulated proteins in breast secretions are markers of target organ sensitivity. Br J Cancer 2000;82:354-60.

There is a need to develop reliable markers of breast cancer risk, and markers as intermediate end-points for evaluating the efficacy of chemopreventive agents. There is increasing interest in studying markers in cells present in breast ductal fluid obtained by nipple aspiration or ductal lavage (see ASCO Proceedings 2000;19:17a). This paper reports on the effect of goserelin and tamoxifen on the expression of estrogen-modulated secretory proteins in nipple aspirate fluid, demonstrating that there is sufficient material in NAF for marker analysis. Given that the cellular yield of ductal lavage is up to an order of magnitude greater, this strategy holds great future promise.

Ductal Carcinoma in situ

Morrow M, Schnitt SJ. Treatment selection in ductal carcinoma in situ. JAMA 2000;283(4):453-455.

Winchester DP, Jeske JM, Goldschmidt RA. The diagnosis and management of ductal carcinoma in-situ of the breast. CA: A Journal for Clinicians. 2000;50:184-200.

These papers provide a concise review and a detailed thoroughly referenced review article addressing all major issues in diagnosis and management of DCIS.

Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 1998;16:441-52.

This is the most recent report of the NSABP B-17 trial demonstrating that radiation after excision reduces the risk of ipsilateral recurrence in ductal carcinoma in situ, and that there is no subgroup that does not benefit from radiation.

Julien, J-P, Bijker N, Fentiman IS, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomized phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 2000;355;528-33.

The initial report of the European study comparing excision alone with excision plus radiation therapy for DCIS.

Silverstein MJ, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer 1996;77:2267-74.

Silverstein MJ, et al. The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med. 1999;340:1455-61.

Schnitt SJ, Harris JR, Smith BL. Developing a prognostic index for ductal carcinoma in suit of the breast. Are we there yet? (editorial) Cancer 1996;77(11):2189-2192.

In the NSABP was unable to identify any subsets of women in the B-17 study for which radiation did not reduce the rate of local failure. Conversely, analysis of a large cohort of women with DCIS suggests that there is little or no clinically significant benefit to radiation after excision in some cases. This is codified in the Van Nuys Prognostic Index, based on tumor size, width of surgical margins, and pathologic features (tumor grade and presence of necrosis). The second paper from this group suggests that margin width alone may be used as a surrogate of the index to determine the need for radiation with DCIS.

Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999;353:1993-2000.

The NSABP B-24 study evaluated the effectiveness of tamoxifen in women treated with wide excision and radiation for DCIS. The rate of breast events (ipsilateral and contralateral) at 5 years was reduced from 13.4% to 8.2% (p=.0009).

Cox CE, Nguyen K, Gray RJ, et al. Importance of lymphatic mapping in ductal carcinoma in situ (DCIS): why map DCIS? American Surgeon 2001;67(6):513-519

The rate of lymph node metastases with DCIS has generally been reported as extremely low and may only be associated with cases likely to harbor an invasive cancer. The widespread use of sentinel node biopsy in breast cancer has led some groups to perform sentinel node biopsy in women with DCIS, and to examine these nodes with immunohistochemistry for cytokeratin to identify otherwise unrecognizable metastatic deposits. There are now a number of reports of series of cases with rates as high as 13% (the reported rate in this series). Many were defined only by IHC. While it is intuitive that those tumors with poor prognositc features (e.g. high grade, necrosis, large size) would be more likely to harbor nodal metastases, Dr. Cox's group could not confirm this or define a "high risk" group. Dr. Cox's group recommends sentinel node staging in all cases of DCIS for this reason, and because of the high rate of invasive cancer found on final sectioning of lesions diagnosed as DCIS only on core biopsy (11G core or vacuum assisted biopsy). Most authorities do not consider axillary staging in DCIS to an appropriate standard at this time. However, ongoing critical analysis of this emerging literature is important, including investigation of the clinical significance of cytokeratin-detected micrometastases.

Local therapy of breast cancer - breast conserving surgery vs mastectomy

Landmark studies in the 1970's in Europe and North America demonstrated that breast conserving therapy provides long-term outcome equivalent to mastectomy. Remaining indications for mastectomy include multi-centric disease, locally advanced cancers precluding satisfactory lumpectomy and some forms of active collagen vascular disease. The risk of local recurrence after breast conserving therapy is minimized by use of radiation, and further reduced by addition of appropriate adjuvant systemic therapy. The risk of local-regional recurrence after mastectomy is stage-dependent, and is as high as 20% for women with node-postive disease. Radiation may be indicated in women with positive nodes treated by mastectomy.

Fisher B, Anderson S, Redmond CK, et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. New Engl J Med. 1995;333:1456-61.

This is the most recent published update of the seminal NSABP B-06 study. This 3-armed study compared mastectomy with lumpectomy plus radiation and with lumpectomy alone.

Morrow M, Harris JR, Schnitt SJ. Local control following breast-conserving surgery for invasive cancer: Results of clinical trials. J Natl Cancer Inst. 1995;87:1669-1673.

An excellent overview of the clinical trials of breast conserving surgery and the risk of local recurrence.

Veronesi U, Marubini E, Del Vecchio M, et al. Local recurrences and distant metastases after conservative breast cancer treatments: Partly independent events. J Natl Cancer Inst. 1995;87:19-27.

This paper summarizes the experience of the National Cancer Institute in Milan, Italy with a detailed examination of the factors affecting local and distant recurrence after breast conserving treatment.

Fowble B. The significance of resection margin status in patients with early-stage invasive cancer treated with breast-conservation therapy. The Breast Journal. 1998;4:126-131.

Park CC, Mitsumori M, Nixon A, et al. Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence. J Clin Oncol. 2000;18(8):1668-1675.

Fowble presents an excellent review of the literature on resection margins with breast conserving surgery. Park et al present the long-term follow-up data from the Joint Center for Radiation Therapy at Harvard examining the impact of margin status on the rate of local recurrence.

Morrow M, White J, Moughan J, et al. Factors predicting the use of breast-conserving therapy in stage I and II breast carcinoma. J Clin Oncol 2001;19(8):2254-2262.

This paper examines factors associated with the use of breast conserving therapy using data from the National Cancer Data Base. In the study time frame, the majority of women with Stage I/II cancer continued to be treated with mastectomy, and factors predicting the use of breast conserving therapy did not correspond to guidelines.

Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997;337:949-55.

27. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen. Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353(9165):1641-1648.

In 1997, two groups reported that chest wall and nodal radiation after mastectomy improved survival in women receiving chemotherapy for node-positive breast cancer. This paper is the larger of the two studies (the other is published in the same issue of the NEJM). The results of both studies were questioned because the node dissection in each was limited (median 7 and 11 nodes, respectively), potentially under staging some cases, and adversely affecting the rate of locoregional failure. These findings led to critical analysis of American data (see next paper by Recht et al), the development of practice guidelines (ASCO and ASTRO), and the development of a SWOG-sponsored randomized trial of post-mastectomy radiation for women with 1-3 positive nodes (opened in 2000 and available through SWOG, ACOSOG, CALGB, RTOG and ECOG).

Recht A, et al. Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol. 1999;17:1689-700.

This study assessed patterns of failure and factors affecting locoregional failure after mastectomy without radiation in breast cancer patients with positive nodes treated with chemotherapy on ECOG clinical trials. The risk of locoregional failure was 12.9% with 1-3 positive nodes and 28.7% with four or more positive nodes.

Recht A, Edge SB, Solin LJ, et al. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19(5):1539-1569.

In response to the debate over post-mastectomy radiation, the American Society of Clinical Oncology empanelled a guideline committee to establish standards for PMRT. Using the rigorous requirements for establishing an evidence-based guideline, the panel concluded that there was insufficient evidence to support or not support the use of PMRT for women with 1-3 positive nodes, and concluded that the American oncology community should strongly support the ongoing SWOG / Intergroup trial of PMRT in such cases. This article provides an exhaustive review of the relevant literature.

Early Breast Cancer Trialists' Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early-breast cancer: An overview of the randomised trials. Lancet 2000;355:1757-70

The EBCTCG at Oxford University performs rigorous meta-analysis of all the available randomised clinical trials in many aspects of breast cancer. This paper is the report on the use of radiation therapy. Overall in the reported series, radiation reduced the rate of local failure by 2/3. Radiation also reduced the breast cancer-specific mortality, but the benefit was offset by an increase in non-breast cancer mortality. Since the data on long term mortality necessarily is mostly derived from treatment 10-30 years ago, and since current radiation therapy planning techniques allow for much lower doses administered to the heart and lungs, it is possible that this increased non-breast cancer mortality with radiation is no longer an issue. However, this will need to be demonstrated by long term follow-up in studies such as the SWOG S9927 study of post-mastectomy radiation (see clinical trials review below).

Tran NV, Chang DW, Gupta A, Kroll SS, Robb GL. Comparison of immediate and delayed free TRAM flap breast reconstruction in patients receiving postmastectomy radiation therapy. Plastic Reconstruc Surg 2001;108(1):78-82.

Mastectomy is necessary in some circumstances, and when mastectomy is performed breast reconstruction is an important consideration. Reconstruction itself carries some risks related to wound and flap complications, and may be influenced by the use of post-mastectomy radiation. This paper reports the risk of short and long-term complications for women 32 women with TRAM flap reconstruction before radiation compared to 70 who had TRAM flap reconstruction after radiation. They found a marked increase in late complications that required surgical revision in the women who had pre-radiation TRAM flap reconstruction.

Role of axillary staging in breast cancer / breast cancer prognostic factors

Axillary staging is an integral part of breast cancer treatment. The purpose of axillary staging is to provide prognostic information and determine optimal adjuvant systemic therapy. The therapeutic benefit of axillary dissection may be limited to local control, though it may have a small direct impact on survival. Non-operative techniques to stage the axilla are of insufficient accuracy. The new technique of sentinel lymph node biopsy provides accurate staging of the axilla and may replace axillary dissection in women with clinically negative nodes. Emerging data suggests that bone marrow micrometastases are of more prognostic value than axillary lymph node status, and may supplement or even replace axillary staging in breast cancer treatment.

Isaacs C, Stearns V, Hayes DF. New prognostic factors for breast cancer recurrence. Seminars in Oncology 2001;28(1):53-67.

This paper reviews the current state of knowledge about standard prognostic factors (node status, size, grade), and biologic factors and puts these factors into the context of treatment decision making. It also addresses methodological issues in defining the utility of a prognostic factor and highlights issues in standardization of measurement of these factors.

Fisher B, et al. Comparison of radical mastectomy with alternative treatments for primary breast cancer. A first report of results from a prospective randomized clinical trial. Cancer 1977;39:2827-39.

This paper is the first report of the landmark NSABP B-04 study that challenged the Halstedian hypothesis that breast cancer spreads in an orderly fashion from cancer to nodes to distant sites. This study demonstrated that the extension of local surgery does not alter survival and set the stage for our current understanding and approach to breast cancer treatment.

Recht A, Houlihan MJ. Axillary lymph nodes and breast cancer. A review. Cancer 1995;76:1491-512.

An excellent review article including data and references from the large body of literature on the impact of axillary surgery and radiation on local failure and survival.

Gann PH, Colilla SA, Gapstur SM, et al. Factors associated with axillary lymph node metastasis from breast carcinoma: Descriptive and predictive analyses. Cancer 1999;86:1511-9.

This recent analysis from a large population demonstrates that while there are many factors associated with a lower likelihood of lymph node metastases (older age, white race, inner quadrant location, special histologic features, negative ER/PR status), it is difficult to accurately predict those patients where axillary dissection is not necessary if axillary staging will affect therapy.

Diel IJ, Kaufmann M, Costa SD, et al. Micrometastatic breast cancer cells in bone marrow at primary surgery: Prognostic value in comparison with nodal status. J Natl Cancer Inst. 1996;88:1652-8.

Braun S, Pantel K, Muller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. New Engl J Med. 2000;342:525-33.

There is an extensive literature demonstrating that bone marrow micrometastases are present at the time of breast cancer diagnosis in about 1/3 of women with Stage I/II breast cancer. These two large studies provide strong support to the hypothesis that bone marrow micrometastases have significant prognostic implications, independent of and possibly more powerful than the presence of axillary node metastases. This concept is being tested further in the sentinel node trial of the American College of Surgeons Oncology Group sentinel node study (see below for summary of ACOSOG Z0010 and Z0011 trials).

Krag D, et al. The sentinel node in breast cancer, a multicenter validation study. N Engl J Med. 1998;339:941-6.

McMasters KM, Tuttle TM, Carlson DJ, et al. Sentinel lymph node biopsy for breast cancer: a suitable alternative to routine axillary dissection in multi-institutional practice when optimal technique is used. J Clin Oncol 2000;18(13):2560-1566.

Krag conducted the first muticenter study of sentinel node biopsy in breast cancer. This critical paper describes the accuracy of the technique and the inter-surgeon variability of sentinel node biopsy. McMasters reports a later large multicenter experience.

Giuliano AE, Haigh PI, Brennan MB, et al. Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer. J Clin Oncol. 2000 Jul;18(13):2553-9.

Cox CE, Bass SS, Boulware D, et al. Implementation of new surgical technology: outcome measures for lymphatic mapping of breast carcinoma. Ann Surg Oncol 1999;6:553-61.

These two articles describe the technique of sentinel node biopsy and the results of the large series of cases at the John Wayne Cancer Center and the H. Lee Moffitt Cancer Center. Giuliano et al specifically address the low complication and axillary recurrence rate (no axillary recurrences with a median 39 month follow-up). Cox et al specifically address the critical issues of training and implementation of the technique (see also Reintgen D, Modarelli C, Cox C. The Training of Surgeons in America. Ann Surg Oncol. 2001;8:1-2).

Veronesi U, Marubini E, Mariani L, et al. The dissection of internal mammary nodes does not improve the survival of breast cancer patients: 30-year results of a randomised trial. Eur J Cancer 1999;35:1320-5.

While the lymphatic drainage from the majority of breast cancers is solely to the ipsilateral axilla, it is to the ipsilateral internal mammary chain in many cases. Internal mammary node dissection was abandoned many years ago as it carries substantial morbidity and does not improve survival. While this study clearly demonstrates that IMA dissection does not itself improve outcome, it also shows that internal mammary node involvement is a prognostic factor. Sentinel node biopsy provides the ability to perform directed sampling of the internal mammary nodes in those with internal mammary drainage. Data from this and other studies support the need for investigation of the internal mammary sentinel node biopsy.

Cote RJ, Peterson HF, Chaiwun B, et al. Role of immunohistochemical detection of lymph node metastases in management of breast cancer. Lancet 1999;354:896-900.

The clinical significance of micrometastases detected my serial sectioning and / or immunohistochemical staining of lymph nodes classified as negative by standard pathologic examination is uncertain. This study evaluated axillary nodes from 736 women staged as node-negative and treated on Trial V of the International Breast Cancer Study Group. Previously unrecognized micrometastases were detected in 7% of cases by serial sectioning and 20% by immunohistochemistry. This rate of unrecognized micrometastases is similar to other reported series. Importantly, the presence of micrometastases was associated with significantly worse disease-free and overall survival. Both the NSABP and the ACOSOG sentinel node trials (see clinical trial summaries below) are addressing the prognostic significance of micrometastases in the sentinel lymph node. However, because the use of this data in making treatment decisions is considered investigational, the data on the results of IHC on the nodes is not given to the patient or treating physicians.

Locally Advanced Breast Cancer / Neoadjuvant chemotherapy / ABMT

Fisher B. et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672-85.

The NSABP B-18 study evaluated the effect on local therapy and survival of preoperative chemotherapy with the same chemotherapy administered post-operatively. Pre-operative chemotherapy allowed more women to have breast conserving therapy, but did not improve survival over the use of post-operative chemotherapy.

Kuerer HM, Newman LA, Smith TL, et al. Clinical course of breast cancer with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 1999;17;460-9.

MD Anderson Cancer Center experience in two trials of neoadjuvant chemotherapy with locally advanced breast cancer demonstrating that patients with complete clinical response have a significantly improved disease-free survival.

Kuerer HM, Hunt KK, Newman L, et al. Neoadjuvant chemotherapy in women with invasive breast carcinoma: conceptual basis and fundamental surgical issues. J Am Coll Surg 2000;190:350-63.

Recent review article from MD Anderson group on neoadjuvant therapy.

Stadtmauer EA, O'Neill A, Goldstein LJ, et al. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hempatopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone marrow Transplant Group. New Engl J Med. 2000;342:1069-1076.

This is the most recent and well-designed study of the use of high dose chemotherapy with AMBT in breast cancer. This study addresses its use in metastatic disease. The studies of HDC / ABMT in the adjuvant setting also fail to show an advantage to this approach, but to date are only published in abstract form (Proceeding ASCO, 1999).

Brito RA, Valero V, Buzdar AU, et al. Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The Universityof Texas MD Anderson Cancer Center Experience. J. Clin Oncol 2001;19(3):628-633.

The presence of supraclavicular nodes at diagnosis is currently staged as M1 (distant metastases). This paper demonstrates that treatment of patients with M1 disease whose only metastases is supraclavicular nodes results in an outcome equivalent to locally advanced (Stage IIIB) disease without S.C. nodes.

Adjuvant Systemic Therapy

Hortobagyi GN, Buzdar AU. Current status of adjuvant systemic therapy for primary breast cancer: Progress and controversy. CA Cancer J Clin 1995;45:199-226.

An excellent review article with good references addressing all the major issues in the adjuvant therapy of breast cancer.

Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 1998;352:930-42.

Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 1998;351:1451-67.

The Early Breast Cancer Trialists' Collaborative Group in England performs rigorous meta-analysis of treatment of breast cancer. These two important papers are the most recent analysis of the use of adjuvant systemic therapy in breast cancer. An updated metaanalysis from the ECBCTG on adjuvant systemic therapy is currently under review and should be published in late 2001, or 2002. The ECBCTG separately performed a metaanalysis on the use of radiation, published in 2000.

National Institutes of Health Consensus Development Conference Statement: Adjuvant Therapy for Breast Cancer. November 1-3, 2000. http://odp.od.nih.gov/consensus/cons/114/114_statement.htm

The NIH periodically convenes consensus panels to review the data on treatment of specific diseases. In November, 2000, a consensus panel reviewed the use of adjuvant systemic and radiation therapy for breast cancer. This document is accessible over the internet from the NCI website listed. It should be read by all physicians treating women with breast cancer.

Muss HB, et al. C-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. NEJM 1994;330:1260-6.

In addition to providing prognostic information, biologic properties of breast cancer may provide information that predicts response to therapy. The most widely used predictive factor in breast cancer is hormone receptor status to predict benefit from tamoxifen. Other factors may predict benefit from specific chemotherapy agents or strategies. Data from the CALGB trial that examined dose intensity of doxorubicin provided the first large scale study demonstrating that overexpression of Her2-neu (c-erbB-2) affects response to doxorubicin adjuvant therapy. These finding have since been confirmed by the NSABP.

Recht A, et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. NEJM 1996;334:1356-61.

This is a randomized clinical trial examining the optimal sequencing of chemotherapy and radiation in women with node-positive breast cancer.

Buchholz TA, Tucker SL, Erwin J, et al. Impact of systemic treatment on local control for patients with lymph node-negative breast cancer treated with breast conserving therapy. J Clin Oncol 2001;19(8):2240-2246.

While the choice of local therapy is generally not driven the use of systemic therapy, local control is improved by the use of systemic chemotherapy or hormonal therapy.

Barakat RR, Gilewski TA, Almadrones L, et al. Effect of adjuvant tamoxifen on the endometrium in women with breast cancer: A prospective study suing office endometrial biopsy. J Clin Oncol 2000;18:3459-63.

An infrequent, but serious side effect of tamoxifen is the development of endometrial cancer. It is important to include questioning about abnormal vaginal bleeding or pelvic discomfort in every follow-up visit for women taking tamoxifen. It has been questioned whether routine endometrial biopsy or ultrasound could detect endometrial cancer sooner, and when more treatable. Two studies published in the Journal of Clinical Oncology in October, 2000 demonstrate that these studies are not necessary. The paper cited above examines the use of periodic endometrial biopsy. No endometrial cancers were identified in a cohort of 159 women followed annually with endometrial biopsies. In the other paper (Gerber B, et al, J Clin Oncol 2000;18:3464-70), ultrasound was examined for endometrial cancer screening. The ultrasound prompted invasive diagnostic studies in 52 / 247 women resulting in 4 uterine perforations, and the discovery of one asymptomatic endometrial cancer.

Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol. 2001;19(3):881-894.

Agents that antagonize the effects of estrogen on breast cancers are useful in treating advanced disease, and as adjuvant therapy. Classes of such agents include the more familiar selective estrogen receptor modulators, including tamoxifen. Another class of agents block the synthesis of estrogen via an aromatase at the final conversion from androstenedione and testosterone to estrone and estradiol. Aromatase inhibitors have been shown to be active as first line and second line hormonal therapy for advanced breast cancer, and are under investigation in the adjuvant setting in comparison to tamoxifen. This article reviews the rationale for use of aromatase inhibitors, and the current state of knowledge about their effectiveness.

Prevention / Prophylactic surgery

Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-88.

Day R, Ganz PA, Costantino J, et al. Health related quality of life and tamoxifen in breast cancer prevention: a report from the NSABP P-1 study. J Clin Oncol 1999;17:2659-2569.

This is the landmark study reporting the findings of the NSABP Breast Cancer Prevention Trial in which 13,3000 women at high risk of breast cancer were randomized to tamoxifen vs. placebo. The study demonstrated a 50% reduction in breast cancer risk for those treated with tamoxifen.

Jordan VC, Morrow M. Tamoxifen, raloxifene, and the prevention of breast cancer. Endocrine Reviews. 1999;20(3):253-78.

This is a detailed review of laboratory and clinical evidence supporting the use of estrogen receptor modulators in the prevention of breast cancer.

Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 1999;340:77-84.

The largest case control study demonstrating that prophylactic mastectomy reduces the risk of breast cancer in high risk women by about 90%.

46. Eisen A, Rebbeck TR, Wood WC, Weber BL. Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer. J Clin Oncol. 2000;18:1980-95.

Detailed review article addressing medical, genetics and social issues in the use of prophylactic mastectomy and oophorectomy.

Biopsy of mammographically-detected breast lesions

Dershaw, DD Liberman, L. Stereotactic breast biopsy: indications and results. 1998;Oncology (Huntingt) 1998;12:907-16 (Discussion 916, 921-2).

An overview of the techniques and indications for stereotactic breast biopsy.

Lymphedema: Incidence, prevention and treatment

Erickson VS, Pearson ML, Ganz PA, Adams J, Kahn KL. Arm edema in breast cancer patients. J Natl Cancer Inst. 2001;93:96-111.

Petrek JA, Pressman PI, Smith RA. Lymphedema: current issues in research and management. CA Cancer J Clin 2000;50:292-307.

Lymphedema is a chronic and potentially disabling complication of axillary therapy for breast cancer. After standard Level I/II axillary dissection, it occurs in up to 20% of cases. The rate of lymphedema is much higher when axillary radiation is given after axillary dissection. It may occur anytime after treatment, and is permanent. The only effective treatment is comprehensive physiotherapy with manual lymphatic drainage. While the incidence of lymphedema is likely to drop over the coming decades because of sentinel node biopsy, it is important for surgeons to be aware of the causes, prevention and treatment of lymphedema. These two excellent review articles have been published in the last year.

Follow-up of patients with breast cancer

Edge SB, Levine E, Arredondo M, et al. Breast Cancer. In Johnson F and Virgo K (eds), Cancer Surveillance After Primary Treatment. Mosby; St. Louis; 1997:290-336.

A detailed review of the literature on the efficacy of follow-up testing in breast cancer. The primary chapter written by a multidisciplinary team at Roswell Park Cancer Institute is followed by reviews from experts at other major cancer centers in the United States and abroad.

Treatment of cancer in the elderly

Martelli G, DePalo G, Rossi N, et al. Long-term follow-up of elderly patients with operable breast cancer treated with surgery without axillary dissection plus adjuvant tamoxifen. Br J Cancer 1995;72:1251-5.

This study reports about 350 women over age 70 treated with wide excision plus tamoxifen, but without radiation or axillary node dissection.

Extermann M, Balducci L, Lyman GH. What threshold for adjuvant therapy in older cancer patients? J Clin Oncol 2000;18:1709-17.

This paper examines the issues of benefit of adjuvant therapy for older cancer patients using life tables to examine the benefit in terms of added life for people with different states of health.

Estrogen replacement therapy

A critical and confusing issue for all women is long-term management of the symptoms and complications of menopause. Hormone replacement therapy after menopause relieves menopause symptoms, prevents progressive osteoporosis, and may reduce the rates of early heart disease and stroke. However, the cardiac benefit is less well proven than initially believed. Long term estrogen replacement increases the risk of breast cancer by 30-40%. The combination of estrogen and progestin may increase the rate of breast cancer a bit more, especially after 5 - 10 years of risk. Combined with the finding that tamoxifen reduces breast cancer risk, with some benefit in osteoporosis benefit, this data leaves many women and even their doctors at a loss for the correct answer. An even more complex issue is that of long term menopause management in women previously treated for breast cancer. This is especially important given that breast cancer is detected at earlier stages, and many more women live long lives without cancer recurrence. It is important for surgical oncologists to be expert in this area that affects a large portion of their patients.

Manson JE, Martin KA. Clinical practice. Postmenopausal hormone-replacement therapy. New Engl J Med. 2001;345(1):34-40.

This is a comprehensive review of the benefits and risks of hormone-replacement therapy.

Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-91.

A recent report from the follow-up of the mammography Breast Cancer Detection Demonstration Project (BCDDP) showing that estrogen alone increases breast cancer risk, and that the combination increases it somewhat more.

SELECTED ABSTRACTS

Peters WP, Rosner G, Vredenburgh J, Shpall E, Crump M, Marks L, et al. Updated results of a prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): CALGB 9082/SWOG9114/NCIC Ma-13. Proc ASCO 2001;20:21a.

This is the most recent update on the findings of the randomized trial examining the role of high dose consolidation therapy with bone marrow rescue as adjuvant therapy for women with 10 or more involved lymph nodes. The study now has a median 5.1 years follow-up. Event-free survival is 61% for the high dose vs. 60% for intermediate dose (no transplant). Overall survival is 70% for high dose and 72% for intermediate dose. There were 32 treatment-related deaths in the high dose group (5% mortality for women under age 40; 14% mortality for women over age 50).

Mass RD, Press M, Anderson S, Murphy M, Slamon D. Improved survival benefit from Herceptin (Trastuzumab) in patients selected by fluorescence in situ hybridization. Proc ASCO 2001;20:22a.

This is part of an increasing body of data showing that HER2/neu gene amplification is more predictive of response to traztuzumab than overexpression determined by immunohistochemistry.

Hughes KS, Schnaper L, Berry D, Cirrincione C, McCormick B, Shank B, et al. Comparison of lumpectomy plus tamoxifen with or without radiotherapy (RT) in women 70 years of age or older who have clinical Stage I, estrogen receptor positive (ER+) breast carcinoma. Proc ASCO 2001;20:24a.

This study directed by the Breast Surgery Committee of the CALGB examined the role of RT after lumpectomy in women with tumors under 2 cm, over age 70, treated with tamoxifen after lumpectomy. At the first analysis with only 28 months median time on study, local failure rates were extremely low, and there was no difference seen between the group that received radiation and the group that did not. There were 6 locoregional recurrences (4 breast, 2 axillary) among 319 who did not get RT, and 0 recurrences among the 317 who did not. If this finding persists with longer follow-up, the role of radiation in this population should be questioned.

Fyles A, McCready D, Manchul L, Trudeau M, Olivotto I, Merante P, et al. Preliminary results of a randomized study of tamoxifen +/- breast radiation in T1/2 N0 disease in women over 50 years of age. Proc ASCO 2001;20:24a.

This study randomized 769 women over age 50 with T1/2 N0 cancers to tamoxifen without RT vs. tamoxifen with RT after lumpectomy. With 3.1 years median followup, the local recurrence rate was 5.7% in the tamoxifen alone group, and 0.5% in the tamoxifen plus RT group. There is no difference in the distant relapse rate (2% in both groups) or survival.

Albain K, Green S, Ravdin P, Cobau C, Levine E, Ingle J, et al. Overall survival after cyclophosphamide, adriamycin, 5-FU, and tamoxifen (CAFT) is superior to T alone in postmenopausal, receptor (+), node (+) breast cancer: New findings from Phase III Southwest Oncology Group Intergroup Trial (S8814 (INT-0100). Proc ASCO 2001;20:24a.

This study with long-term followup shows that the addition of chemotherapy to tamoxifen in postmenopausal women with node-positive breast cancer improves survival. The adjusted hazard ratio for deat with T vs. CAFT is 1.29. CAFT provides a 5% absolute survival benefit over tamoxifen alone (84% vs. 79%). Chemotherapy was well tolerated in postmenopausal women.

Ravdin PM, Siminoff L, Hewlett J, Parker H, Mercer M, Davis G. Evaluation of impact of communication tool generated by the computer program, Adjuvant!, on patients with early breast cancer and their doctors. Proc ASCO 2001;20:31a.

Understanding the benefits and risks of adjuvant therapy is difficult for many patient, and difficult for physicians to fully convey. Tools to assist the communication of information to help patients make good choices are increasingly available, and are being increasingly shown to improve quality of life and patient satisfaction. This program can be found on the Web.

Hansen NM, Grube BJ, Te W, Brennan ML, Turner R, Giuliano AE. Clinical significance of axillary micrometastases in breast cancer: How small is too small?

The clinical significance of axillary micrometastases, especially those detected by immunohistochemistry alone, is unclear. The group at the John Wayne Cancer Institute examined the 5 year DFS and OS in women with sentinel node biopsy based on the extent of sentinel node metastases. They concluded that micrometastases detected by immunohistochemistry or by H&E have little or no impact on survival, and that IHC to detect micrometastases should not be performed on sentinel nodes outside of investigational trials. Group n 5 yr DFS 5 yr OS Negative 425 95.1% 99.7% IHC positive/H&E negative 56 98.3% 100% H&E micromets (<2mm) 76 94.5% 100% H&E macromets (>2mm) 139 75.2% 96.5%

Wayne JD, Albo D, Hunt K, Lee J, Myers J, Gershenwald J, et al. Anaphylactic reaction to isosulfan blue dye (IBD) during sentinel lymph node biopsy (SLNB) is more common in breast cancer than in melanoma. Proc ASCO 2001;20:38a.

Anaphylactic reactions to isosulfan blue occur but are rare. This is the first very large report on this in breast cancer and melanoma. The rate of anaphylactic reactions was 1.1% (7 / 639) breast cancer patients, and 0.13% (2 / 1492) melanoma patients. Onset of the reaction was within 15-30 minutes, and symptoms included hypotension, tachycardia, and urticaria. Awareness of the potential for this, and rapid and vigorous response are key to dealing with this uncommon but serious reaction to isosulfan blue.

CLINICAL TRIALS

NSABP P-02: Study of tamoxifen and raloxifine

The objective of the Study of Tamoxifen and Raloxifene (STAR) is to determine if raloxifene is as effective or more effective in preventing breast cancer as tamoxifen. The study opened to patient accrual at over 190 clinical centers in North America. The study is only open to post-menopausal women with a 5 year risk of breast cancer of 1.67% of greater (by Gail Model analysis). Participants are randomized to take tamoxifen (20 mg / d) or raloxifene (60 mg / d) for 5 years. As of June, 2001, about 10,200 women have entered the trial, an accrual on target for 22,000 in 5 years of accrual.

American College of Surgeons Oncology Group Z0010 / Z0011

The ACOSOG is addressing the role of sentinel lymph node biopsy in node negative and node positive breast cancer through paired studies: Z0010: Women with T1 or T2 cancer and clinically negative nodes undergo sentinel lymph node biopsy. If the sentinel node is negative, they are registered and followed without further axillary dissection. Patients receive stage appropriate adjuvant systemic therapy and radiation. The end points of the study are axillary recurrence and morbidity. If the sentinel node is positive, women are eligible to participate in Z0011 (if they elect not to participate in Z0011, axillary node dissection is recommended). The sentinel node is examined only by H&E at the local institution. Tissue blocks are sent to a central laboratory for cytokeratin immunohistochemistry. The results of IHC are not provided to the surgeon or the patient so that the long term significance of IHC-detected metastases can be determined. In addition, women undergoing sentinel node are asked to allow bilateral iliac crest bone marrow aspiration biopsy. The bone marrow is stained by H&E at the treating institution. The remainder of the specimen is analyzed centrally by IHC. The IHC results are not provided to the patient or the surgeon. Z0011: This study addresses the need for axillary dissection in women with a positive sentinel node. Women with a positive sentinel node in Z0010 are offered entry into Z0011. Participants are then randomly assigned to have no further lymph node surgery or to undergo standard axillary lymph node dissection. They then receive stage appropriate adjuvant systemic therapy, followed by breast radiation (using standard tangent beam radiation). The primary endpoint is survival. The secondary endpoint is axillary recurrence.

NSABP B-32: Phase III Randomized Study of Sentinal Node Dissection with or without Conventional Axillary Dissection in Women with Clinically Node Negative Breast Cancer

The NSABP sentinel node trial is open to women with T1 or T2 breast cancer with clinically negative nodes undergoing breast conserving surgery. Participants undergo sentinel lymph node biopsy. If the node is negative, they are randomly assigned to undergo 1) sentinel lymph node biopsy or 2) sentinel node biopsy plus axillary dissection. The primary endpoint of the study is survival. Like the ACOSOG, the NSABP performs central pathology lab IHC analysis of the sentinel node(s) and blinds the patient and physician to the results. NSABP is considering adding analysis of peripheral blood for circulating cancer cells to the B-32 study to examine its prognostic value. Surgeons may participate in NSABP B-32 after documenting as few as 5 cases. An NSABP surgeon-trainer will then visit the site, review the procedure with the staff, and proctor 1 - 3 cases.

RTOG 98-04 (also CALGB): Phase III Randomized Study of Tamoxifen With or Without Radiotherapy in Women With Ductal Carcinoma In Situ (DCIS) of the Breast

The objectives of the RTOG 98-04 trial are to compare the efficacy of tamoxifen with or without whole breast radiation, in decreasing or delaying the appearance of local failure, both invasive and in situ, and preventing the need for mastectomy in women with ductal carcinoma in situ (DCIS) of the breast, and to compare distant disease free survival of these patients in these treatment arms. The study is open to women with ductal carcinoma in situ of the breast detected by mammogram at the time of diagnosis. Eligibility criteria are: Unicentric DCIS; Lesions no greater than 2.5 cm; Low or intermediate grade; Inked margins at least 3 mm; Clinically node negative; No suspicious areas on post-operative mammogram taken within 12 weeks after final surgery. Patients are stratified according to age (under 50 vs 50 and over), final path margins (negative vs 3-9 mm vs at least 10 mm), and mammographic size of primary (no greater than 1 cm vs greater than 1 cm). Patients are randomized to: Arm I: Patients receive oral tamoxifen twice daily for 5 years. Arm II: Patients receive tamoxifen as in arm I. Concurrent radiotherapy is given once daily 5 times a week for 5.5 weeks.

E1199: A Phase III Study of Doxorubicin-cyclophosphamide therapy followed by paclitaxel or doxetaxel given weekly or every 3 weeks in patients with axillary node-positive or high-risk node-negative breast cancer. (ECOG, CALGB, NCCTG, SWOG)

This study compares the two taxanes (paclitaxel and doxetaxel) in two dosing schemes (weekly vs. every 3 weeks) in women with node positive breast cancer.

NSABP B-30: A three-arm randomized trial to compare adjuvant adriamycin and cyclophosphamide followed by taxotere (AC-T); adriamycin and taxotere (AT); and adreiamycin, taxotere and cyclophosphamide (ATC) in breast cancer patients with positive axillary lymph nodes.

The study compares three regimens containing doxorubicin (adriamycin) and doxetaxel (taxotere) in women with positive nodes.

NSABP B-31: Phase III Randomized Study of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With or Without Trastuzumab in Women With Node Positive Breast Cancer That Overexpresses HER2

Objectives: (1) Compare the cardiotoxicity of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in patients with operable, node positive breast cancer that overexpresses HER2. (2) Compare the effect of these regimens, with or without tamoxifen, on disease free and overall survival of these patients. Protocol Entry Criteria: Stage I, IIA, IIB, or IIIA (T1-3, N0-1, M0); At least 1 axillary node histologically positive; HER2 positive; Must have undergone axillary dissection and either total mastectomy OR lumpectomy; resection margins must be clear. Patients are stratified according to number of positive nodes (1-3 vs 4-9 vs 10 or more), administration of tamoxifen (yes vs no), surgery/radiotherapy (lumpectomy plus breast irradiation vs lumpectomy plus breast irradiation plus regional irradiation vs mastectomy without radiotherapy vs mastectomy with radiotherapy), and center. Patients are randomized to one of two treatment arms. Arm I: AC (q3wk x 4); Paclitaxel (q3wk x 4); follow-up monitoring. Arm II: AC (q3wk x 4); Paclitaxel (q3wk x 4); Trastuzumab (q wk x 52 starting concomitantly with paclitaxel); follow-up monitoring.

NCCTG N9831). Phase III Trial of doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel with or without Trastuzumab as adjuvant treatment for women with HER-2 overexpressing node positive breast cancer. (NCCTG, CALGB, ECOG, SWOG, EEP

This is an Intergroup study with a similar design and objectives to the NSABP B-31 study. Women are eligible if they have node positive breast cancer which overexpresses HER-2. After surgery and determination of eligibility, they are randomized to one of three treatment arms: Arm I: AC (q3wk x 4); Paclitaxel (qwk x 12); follow-up observation Arm II:AC (q3wk x 4); Paclitaxel (qwk x 12); Trastuzumab (q wk x 52); follow-up monitoring Arm III: AC (q3wk x 4); Paclitaxel + Trastuzumab (qwk x 12); Trastuzumab (q wk x 40); followup monitoring. Radiation is administered after completion of paclitaxel and tamoxifen is administered to all women with hormone receptor-positive tumors.

SWOG S9927 (also in ACOSOG, RTOG, ECOG, NCCTG). Evaluation of the role of postmastectomy radiation therapy for pre- and post-menopausal women with 1-3 positive axillary lymph nodes.

This phase III trial of postmastectomy radiation for women with 1-3 axillary nodes is opening in June, 2000 in SWOG. The other cooperative groups will activate this study over the following months. Women with T1 and T2 cancer with 1-3 positive nodes (by H&E) treated by mastectomy with Level I/II axillary dissection are eligible. They must undergo surgery, followed by chemotherapy with or without tamoxifen (women may participate in cooperative group clinical trials for adjuvant systemic therapy as well). After chemotherapy is completed, women are registered onto this study. They are then randomized to receive radiation or no radiation. Radiation must be started within 6 weeks of completion of chemotherapy. Radiation is administered to the chest wall, internal mammary nodes, and supraclavicular fossa. The endpoints are survival, local recurrence and toxicity.

JMA.17: A Phase III randomized double blind study of letrozole versus placebo in women with primary breast cancer completing five or more years of adjuvant tamoxifen (NCI-Canada; CALGB, ECOG, NCCTG, SWOG).

The current standard is to stop tamoxifen after 5 years because longer duration therapy does not further reduce the risk of recurrence. The objective of this study is to determine the impact of the aromatase inhibitor letrozole on long term recurrence in women who have completed 5 years of tamoxifen.

NSABP B-34: A clinical trial comparing adjuvant clodranate therapy versus placebo in early-stage breast cancer patients receiving systemic chemotherapy and/or tamoxifen or no therapy.

Bisphosphantes used in women with bony metastases of breast cancer reduce the risk of progression of metastases and of fracture. Data from Germany suggests that the oral bisphosphante Clodranate improves survival when used in conjunction with adjuvant chemotherapy. The study is a randomized trial of chemotherapy vs. chemotherapy plus clodranate in breast cancer.

S0012: A randomized comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus G-CSF as neoadjuvant therapy for inflammatory and estrogen-receptor negative locally advanced breast cancer (SWOG).