As our understanding of the biology of breast cancer continues to improve, treatment of the disease continues to change. Although the ultimate goal of treatment remains improved survival, increasing emphasis is now put on less morbid treatments and improving quality of life. Prevention remains a major focus, particularly in women at high risk of developing breast cancer because of mutations in susceptibility genes. In this article, we review the current prevention strategies in carriers of BRCA1 and BRCA2 mutations, data on sentinel node biopsy for axillary staging, and trials of new endocrine treatments for advanced breast cancer.
Methods
We selected topics on the basis of their current or likely future impact on practice, with an emphasis on areas in which significant changes in our knowledge base have occurred in the past three to five years. We did English language Medline searches, giving priority to prospective randomised trials or large prospective multi-institutional studies when available. We also reviewed abstracts from meetings on breast cancer in the past three years.
Management of risk in carriers of BRCA1 and BRCA2 mutations
Mutations of the breast cancer susceptibility genes BRCA1 and BRCA2 are responsible for approximately 10% of breast cancers, and women with these mutations have a cumulative risk of developing breast cancer up to age 70 of 55-85%.1,2 The appropriate strategies for surveillance in these women and the efficacy of chemoprevention with tamoxifen and of prophylactic mastectomy are all controversial. Several recent studies provide new information that helps to clarify the outcomes of these approaches.
Chemoprevention
The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 prevention trial, which compared tamoxifen with placebo over five years, found that tamoxifen reduced the incidence of breast cancer by 49% in women at high risk.3 To assess the effect of tamoxifen in carriers of BRCA1 and BRCA2 mutations, DNA sequencing was performed on 288 of the 315 women who developed invasive breast cancer.4 Only 19 (6.6%) had mutations, eight in BRCA1 and 11 in BRCA2. The risk ratios for tamoxifen versus placebo were 1.67 (95% confidence interval 0.41 to 8.00) for BRCA1 and 0.38 (0.06 to 1.56) for BRCA2. The small number of cases and the wide confidence intervals do not allow any conclusions to be drawn from these data. Narod et al performed a case-control study of 593 carriers of BRCA1 and BRCA2 mutations with bilateral (cases) or unilateral (controls) breast carcinoma.5 The odds ratio for contralateral breast cancer in women taking tamoxifen was 0.50 (0.28 to 0.89). Benefit was seen for both BRCA1 and BRCA2 carriers, independent of age. The protective effect increased with duration of use of tamoxifen up to four years.
Recent developments
Prophylactic mastectomy reduces the risk of breast cancer by approximately 90% in women at high risk; short term follow up suggests similar benefits in carriers of BRCA1 and BRCA2 mutations
Reducing exposure to oestrogen by oophorectomy or tamoxifen also seems to reduce risk in this population
Women at risk should be the major decision makers in the selection of a strategy for reduction of risk
A sentinel node can be identified in more than 90% of patients with breast cancer; the false negative rate of sentinel node biopsy is less than 5%, but the long term rate of axillary recurrence is unknown
Anastrozole and letrozole are appropriate choices for first line treatment of hormone receptor positive, metastatic breast cancer in postmenopausal women
Fulvesterant is a new endocrine agent with a distinct mechanism of action that has antitumour activity equivalent to anastrozole
Non-steroidal and steroidal aromatase inhibitors are under evaluation as adjuvant treatment in patients with early stage breast cancer
Oophorectomy
Narod et al also noted a benefit for oophorectomy in women diagnosed with their first breast cancer before age 50.5 These findings are consistent with the observations of Rebbeck et al that oophorectomy reduces risk of breast cancer by approximately 50% in BRCA1 carriers,6 and with observations that a reduction in exposure to endogenous oestrogen, the number of ovulatory cycles, or both is protective. These findings indicate that a reduction in exposure to oestrogen by oophorectomy or tamoxifen is an alternative approach to managing risk in gene carriers who do not want prophylactic mastectomy.
Prophylactic mastectomy
Hartmann et al identified 6039 women with a family history of breast cancer who underwent prophylactic mastectomy.7 The reduction in adjusted cancer incidence, compared with the sisters of study participants, ranged from 90% to 94%, and the reduction in death from breast cancer ranged from 81% to 94%. Among a subset of 110 women with very strong family histories of breast cancer, 18 had deleterious mutations of BRCA1 and BRCA2. After a median follow up of 16 years, none of these women had developed breast cancer.8 Meijers-Heijboer et al prospectively studied 139 mutation carriers without a personal history of breast cancer.9 Seventy six underwent prophylactic mastectomy, and after a mean follow up of 2.9 years no cases of breast cancer were observed, compared with eight cancers in the surveillance group. Decision analysis has also been used to assess the survival benefits of prophylactic mastectomy in a theoretical cohort of 30 year old women carrying mutations.10,11 With lifetime risks of breast cancer ranging from 40% to 85%, survival was increased by 2.8 to 3.4 years. Minimal survival gains were seen for women having surgery after age 60.10
Attitudes towards prophylactic mastectomy vary widely, with some women and their physicians considering this an unacceptable intervention, and major variations in acceptance are seen around the world. However, psychological and social functioning in women who choose to have the procedure seem to be well maintained.12
Advising patients about risk reduction
As with any preventive interventions, the role of the physician is to inform women at high risk about the risks and benefits of prophylactic surgery (table 1). The decision to undertake a risk reducing strategy, whether prophylactic mastectomy, oophorectomy, or tamoxifen, ultimately rests with the woman at risk.
Table 1.
Strategies for managing women carrying mutations of BRCA1 or BRCA2
| Intervention | Benefits | Risks |
|---|---|---|
| Surveillance: mammography, clinical breast examination, breast self examination | Non-invasive; promising early data on magnetic resonance imaging in this population | Does not reduce cancer incidence; sensitivity of mammography lower in younger women; evidence of reduction in mortality in this population is lacking |
| Tamoxifen | 50% reduction in cancer incidence in women at high risk; case-control evidence of benefit in gene carriers; absence of major toxicity in premenopausal women | Effect on oestrogen receptor positive tumours only; duration of benefit uncertain; increased risk of thrombosis and endometrial cancer in postmenopausal women |
| Prophylactic oophorectomy | 50% reduction in cancer incidence in carriers of BRCA1 mutation | Long term sequelae of early menopause with increased risk of osteoporosis, cardiovascular disease, and reduced quality of life |
| Prophylactic mastectomy | 90% reduction in cancer incidence; preliminary data in carriers of BRCA1 or BRCA2 mutations similar | Major surgery, chest wall anaesthesia, need for multiple operations with reconstructive procedures; psychological sequelae |
Sentinel lymphadenectomy for breast cancer
Axillary dissection is considered a standard part of treatment for breast cancer. It provides prognostic information, maintains local control in the axilla, and in a minority of cases determines the need for adjuvant systemic treatment. The therapeutic value is controversial but would be limited to patients with nodal metastases. Lymphatic mapping and sentinel node biopsy is a new minimally invasive technique to identify patients with axillary node involvement. The sentinel node is defined as the first node to receive drainage from a tumour and is identified by injecting a vital blue dye, a radiocolloid, or both around the area of the primary tumour. A small incision is made in the axilla, and a hand held gamma probe or direct visual inspection is used to identify a radioactive node or blue stained lymphatic channels leading to a blue lymph node.
Individual investigators have reported identification of the sentinel lymph node in more than 95% of breast cancer patients, with false negative rates for prediction of axillary nodal metastases of less than 5%.13 Table 2 summarises the results of three large multi-institutional trials.14–16 The false negative rates were established by completing the axillary dissection after sentinel node biopsy. In all three studies, patient age over 50 was associated with a significant decrease in the ability to identify a sentinel node.14–16 There was no agreement on factors influencing the false negative rate.
Table 2.
Outcome of sentinel node biopsy in multi-institutional trials
| Author | No of surgeons | No of procedures | Technique | Sentinal node identified (%) | False negatives (%) |
|---|---|---|---|---|---|
| Krag et al14 | 11 | 443 | Radiocolloid | 91 | 11.4 |
| Tafra et al15 | 48 | 535 | Blue dye plus radiocolloid | 87 | 13.0 |
| McMasters et al16: | |||||
| 1-20 cases per surgeon | 226 | 1817 | Surgeon choice | 91.7 | 9.0 |
| >20 cases per surgeon | 28 | 331 | Surgeon choice | 96.7 | 1.9 |
Contraindications to sentinel node biopsy include suspicious palpable axillary adenopathy, pregnancy, and multicentric carcinoma. Few data exist on the accuracy of the procedure for patients with tumours larger than 5 cm, with features of locally advanced breast cancer, or who have received preoperative chemotherapy, and sentinel node biopsy should be considered investigational in these circumstances. How many cases of sentinel node biopsy followed by axillary dissection must be done before a surgeon is competent to perform axillary staging with sentinel node biopsy alone is uncertain. Simmons, in a review of this subject, suggested that an 85% rate of identification and a false negative rate of 5% are achieved after 10-20 cases on average.17
Sentinel node biopsy has several advantages over axillary dissection. It is a brief outpatient procedure requiring no drains and allowing a return to full activity in 2-3 days. In the first prospective comparison of sentinel node biopsy and axillary dissection, 3% of 67 patients having sentinel node biopsy experienced complications compared with 35% of 57 patients undergoing axillary dissection.18 In addition to decreasing morbidity, sentinel node biopsy may improve staging. It has been known for many years that lymph nodes found to be free of tumour cells by standard sectioning and haematoxylin and eosin staining will have microscopic tumour deposits identified in 10-25% of cases if multiple sections of the node are examined or immunohistochemical staining techniques are used.19 However, the reported impact of these micrometastases on survival is variable, and their detection in an entire axillary dissection specimen is time consuming and expensive. With the sentinel node technique, the pathologist is presented with a small number of nodes to which serial sections and immunohistochemical staining can be readily applied. Two large prospective trials are assessing the prognostic significance of micrometastases in the sentinel node (see table on bmj.com). Additional questions that will be answered by ongoing trials include the incidence of axillary recurrence after a negative sentinel node biopsy and the benefit of completion axillary dissection in patients staged as node positive with sentinel node biopsy.
Treatment of metastatic breast cancer in postmenopausal women
The goals of therapy for metastatic carcinoma are the prolongation of life and improvement of symptoms with low toxicity due to treatment. New endocrine treatments that meet these goals are now approved for clinical use.
Aromatase inhibitors
Tamoxifen was until recently the standard first line treatment of hormone receptor positive, metastatic breast cancer. In the past year randomised clinical trials have provided data supporting the use of the newer selective aromatase inhibitors as first line treatment of hormone receptor positive, metastatic breast cancer in postmenopausal women.20–22
The rationale for the use of aromatase inhibitors is to decrease the levels of circulating and intratumoural oestrogen by inhibiting the conversion of androstenedione and testosterone into oestrogen. Aromatase inhibitors are not effective in premenopausal women, as lower circulating levels of oestrogen result in increases in follicle stimulating hormone and luteinising hormone that stimulate the ovary to produce both androstenedione and the aromatase enzyme, resulting in maintenance of circulating oestrogen levels (see fig A on bmj.com). The primary source of oestrogen in postmenopausal women is the conversion of adrenal steroids (androstenedione and testosterone) into oestrogen by extra-ovarian sites of aromatase activity (liver, adipose tissue, muscle). Human breast tumours are also known to have aromatase activity.23
The currently available, third generation aromatase inhibitors can be categorised as reversible, non-steroidal inhibitors (anastrozole and letrozole) or irreversible, steroidal inhibitors (exemestane).23 The use of aromatase inhibitors as second line treatment for metastatic, hormone receptor positive breast cancer in postmenopausal women was established as a result of clinical trials comparing them with megestrol acetate. As summarised in table 3, the aromatase inhibitors were at least as effective as megestrol acetate and seemed to offer a survival advantage.24–26 The next step in assessing the role of the aromatase inhibitors was to evaluate them as first line treatment.
Table 3.
Comparison of aromatase inhibitors and megestrol acetate (MA)24-26
| Anastrozole 1 mg v MA | Letrozole 2.5 mg v MA | Exemestane 25 mg v MA | |
|---|---|---|---|
| No of patients | 263 v 253 | 174 v 189 | 366 v 403 |
| Response rate* | AN=MA | LET>MA | EXE=MA |
| Duration of response | Not reported | LET>MA | EXE=MA |
| Time to progression | AN=MA | LET>MA | EXE>MA |
| Overall survival | AN>MA | LET=MA | EXE>MA |
Objective response rate=complete response plus partial response.
The US Food and Drug Administration has approved both anastrozole and letrozole as first line treatment for hormone receptor positive, metastatic breast cancer in postmenopausal women. Both agents have been directly compared with tamoxifen in prospective randomised studies that showed relatively small but significant improvements in outcome for patients treated with aromatase inhibitors.20–22 No overall differences in toxicity were seen,20–22 but fewer thromboembolic events occurred in the patients treated with aromatase inhibitors.20,21 No association between the aromatase inhibitors and the risk of endometrial carcinoma has been found, but long term follow up is needed before definitive conclusions are drawn. A recently reported pilot study confirms the antitumour activity of exemestane in postmenopausal women with hormone receptor positive, metastatic breast cancer,27 and a large randomised clinical trial is under way.
Data are also available to support the use of the aromatase inhibitors as primary treatment for postmenopausal patients with hormone receptor positive breast cancer who are not candidates for immediate surgery, because of either size of tumour or presence of comorbidity. In pilot trials with anastrozole28 and exemestane27 a significant proportion of patients who would have needed mastectomies were able to undergo breast conservation. In a larger trial (337 patients) comparing four months of tamoxifen (20 mg/day) with letrozole (2.5 mg/day) the rate of breast conservation was 45% for patients receiving letrozole and 35% for those receiving tamoxifen.29 These results confirm that primary endocrine treatment is feasible in selected patients who are not candidates for surgery or may not be suitable for primary chemotherapy owing to refusal or comorbidity.
Several large randomised adjuvant clinical trials are now assessing whether the aromatase inhibitors add to the effects of tamoxifen or whether they are an alternative to tamoxifen in patients with early stage breast cancer.
Additional resources
Stefanek M, Hartman L, Nelson W. Risk reduction mastectomy: clinical issues and research needs. J Natl Cancer Inst 2001;17:1297-306
Gemignani ML, Borgen PI. Is there a role for selective axillary dissection in breast cancer? World J Surg 2001;25:809-18
Jordan VC, Gapstur SM, Morrow M. Selective estrogen receptor modulators for the prevention of breast cancer, osteoporosis, and coronary heart disease. J Natl Cancer Inst 2001;8:745-65
Buzdar A, Howell A. Advances in aromatase inhibition: clinical efficacy and tolerability in the treatment of breast cancer. Clin Cancer Res 2001;7:2620-5
Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182,780 (Faslodex): development of a novel, “pure” antiestrogen. Cancer 2000;89:817-25
Lonning PE. Aromatase inhibitors and inactivators in breast cancer. BMJ 2001;323:800-81.
Collected resources from BMJ.com
(www.bmj.com/cgi/collection/cancer%3Abreast?page=4)
The psychosocial impact of bilateral prophylactic mastectomy: prospective study using questionnaires and semi-structured interviews
How women with family history of breast cancer and their general practitioners act on genetic advice in general practice: prospective longitudinal study
General information on breast cancer on line
www.nci.nih.gov (Cancernet section)
Selective oestrogen receptor downregulators
Fulvesterant has properties distinct from those of tamoxifen and its analogues. These agents bind to the oestrogen receptor and block its activation, whereas the binding of fulvesterant to the oestrogen receptor results in rapid degradation and loss of oestrogen receptor protein (see fig B on bmj.com).30–32 Two randomised trials comparing fulvesterant and anastrozole were recently reported.31,32 In the European trial, 451 postmenopausal women with metastatic breast cancer previously treated with tamoxifen in the adjuvant or metastatic setting were randomised to fulvesterant or anastrozole. Time to progression of disease, time to treatment failure, objective response rate, and rate of clinical benefit did not differ between the two treatment arms.30 Both treatments were well tolerated. The North American trial was a randomised double blind trial in 400 postmenopausal women with metastatic disease recurring or progressing on tamoxifen.31 The time to disease progression, rate of clinical benefit, and duration of response all favoured patients who received fulvesterant.31
The results of these two trials establish fulvesterant as a treatment with equivalent activity to anastrozole in patients who have received tamoxifen. Data are now maturing from a completed clinical trial comparing fulvesterant with tamoxifen as first line endocrine treatment for patients with metastatic breast cancer.
Treatment options
The introduction of new endocrine agents has increased treatment options for women with metastatic hormone sensitive breast cancer. The figure summarises the current treatment algorithm for these patients. As additional data emerge from clinical trials, the use of these agents may expand to the adjuvant, and possibly the prevention, setting.
Supplementary Material
Figure.
Sequence of treatment for postmenopausal women with hormone receptor positive, metastatic breast cancer. Antioestrogens are tamoxifen or torimefene. Non-steroidal aromatase inhibitors are anastrozole and letrozole. When fulvesterant is available for routine clinical use, it will also be a second line treatment
Footnotes
Funding: MM and WG are supported by the Specialized Program of Research Excellence in Breast Cancer, P50-CA89018, and the Avon Products Foundation.
Competing interests: None declared.
An extra table and two figures appear on bmj.com
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