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Home , Anastrozole, Aromatase inhibitor, Letrozole

H.F. Kennecke, MD, MHA, FRCPC, S. Ellard, MD, FRCPC, S. O’Reilly, MB, FRCPC, K.A. Gelmon, MD, FRCPC

New guidelines for treatment of early hormone-positive with and inhibitors

Three strategies can be used to incorporate aromatase inhibitors in adjuvant therapy for postmenopausal breast cancer patients.

ABSTRACT: The Breast Tumour Group he Breast Tumour Group, a petitive antagonism of at its of the British Columbia Cancer Agency provincial multidisciplinary receptor. Daily tamoxifen for 5 years has developed new treatment guide- T committee of the British Co- reduces the risk of breast cancer death lines for the use of tamoxifen and lumbia Cancer Agency (BCCA), has by 31%, regardless of age or use of the aromatase inhibitors , 1,2 developed new guidelines for the use chemotherapy. This benefit is sus- , and . These of tamoxifen and aromatase inhibitors tained even at 15 years from initial guidelines are based on recent evi- 2 (AIs) in adjuvant therapy for early hor- diagnosis. dence about the role of these agents mone-positive breast cancer in post- Although well toleratedby the ma- in adjuvant therapy for women with menopausal women. Physicians are jority of women, tamoxifen is associ- hormone-positive breast cancer. Phy- encouragedto adhere to these treatment ated with a number of side effects that sicians should be aware of the data Figure 1 protocols (see )andshould are relatedto its dual agonist andantag- supporting the adjuvant use of tamo- request undesignated approval prior to onist activity. Side effects include hot xifen and aromatase inhibitors and prescribing tamoxifen or AIs outside flushes, gynecological symptoms such the new policies regarding their use. of the guidelines. When prescribed as vaginal discharge, risk of uterine Depending on the grade and size of within the guidelines, these medica- cancer (1%), thromboembolic disease, the tumor and the number of posi- tions are all funded by the BCCA. and stroke. The absolute risk of death tive nodes, postmenopausal women from thromboembolic anduterine can- with early invasive breast cancer Hormone-positive cer due to tamoxifen is 0.2% per may receive tamoxifen monothera- breast cancer decade, which is small compared with py, monothera- 2 In British Columbia, every primary the absolute benefits. In post- py, or sequential therapy. The BC breast cancer is tested for estrogen re- menopausal women only, tamoxifen Cancer Agency has informed pa- ceptor (ER) positivity and approxi- is associated with beneficial effects on tients and health care providers of mately 70% are ER-positive. Hor- these policies by letter. Further in- Dr Kennecke is a medical oncologist at the monal therapy and, possibly, radiation formation is available under “Cancer BC Cancer Agency,Vancouver Cancer Cen- and chemotherapy, are offered after Management Guidelines” at www tre. Dr Ellard is a medical oncologist at the surgery to women with ER-positive .bccancer.bc.ca. Cancer Clinic of the Southern Interior and tumors with a risk of recurrence. head of the Breast Systemic Committee. Since its introduction in the Dr O’Reilly is a medical oncologist at the 1970s, tamoxifen has been the most Vancouver Cancer Clinic and leader of the important advance in the management Provincial Systemic Program. Dr Gelmon is of ER-positive breast cancer. Tamox- a medical oncologist at the Vancouver ifen is a selective Cancer Clinic and head of the Breast modulator (SERM) and inhibits the Tumour Group. growth of breast cancer cells by com-

VOL. 48 NO. 3, APRIL 2006 BC MEDICAL JOURNAL 121 New guidelines for treatment of early hormone-positive breast cancer with tamoxifen and aromatase inhibitors

Strategies for incorporating aromatase inhibitors in Initial studies compared AIs with me- adjuvant therapy for breast cancer gestrol, , and tamo- xifen in patients with metastatic breast n Postmenopausal women cancer and showed superior efficacy Strategy A: Tamoxifen monotherapy and tolerance, leading to approval for this indication in the 1990s. For patients with low-grade node-negative tumors <2 cm and no evidence AIs are categorized as steroidal of lymphatic or vascular invasion (exemestane) and (anas- • Tamoxifen for 5 years trozole and letrozole). All are potent • Substitution of an AI allowed if patient is intolerant of tamoxifen or if inhibitors of aromatase and vary only serious complications occur or if contraindications exist minimally in their level of estrogen Strategy B: AI monotherapy suppression and side-effect profiles. Aromatase inhibitors are significantly For patients at high risk of early relapse, defined as having breast cancer more expensive than tamoxifen, cost- that is: ing on average $1800 per year of ther- • High grade (grade 3/poorly differentiated) or apy versus approximately $80 for • Low ER-positive (1+) or tamoxifen. Inevitably, cost is a con- • Stage III (includes breast cancers with four or more nodes positive, or sideration when evaluating province- large node-positive tumors, or that present with locally advanced breast wide implementation of a new thera- cancer) py, particularly as significant benefit • May consider using first-line AI therapy for 5 years in overall survival has not yet been Strategy C: Sequential therapy widely demonstrated when AIs are compared with tamoxifen. The current For patients with all other tumors review is only of the effects of aro- • Tamoxifen for 2–3 years followed by AI for 2–3 years, for total 5 years matase in early invasive breast cancer. of hormonal therapy (“early switch”) The use of aromatase inhibitors for For patients who have finished >3 years of tamoxifen already at this time, noninvasive in situ disease or for pri- or who become postmenopausal after completing 3 years of tamoxifen mary prevention of breast cancer is not • Tamoxifen for 5 years followed by AI for 3–5 years (“late switch”) proven and clinical trials are ongoing. In contrast to tamoxifen, AIs lack n Premenopausal women partial estrogen agonist activity and • Tamoxifen for 5 years unless patient becomes postmenopausal during are thus not associated with the unde- therapy (no menses >12 months andFSH/LH in postmenopausal range), sirable increased risks of thromboem- in which case, see Strategy C above bolism, gynecological symptoms, and uterine cancer. However, adverse ef- Figure 1. Summary of BCCA Breast Tumour Group guidelines. fects ofAIs include an increasedrisk of and osteoporotic frac- tures, myalgia and , and an bone health and on lipid profile. conversion of androgenic substrates adverse impact on the lipid profile, all , also a SERM, has been into estrogen. Aminoglutethimide, an thought to be related to the profound studied in breast cancer prevention but adrenal suppressant, was the original reduction of serum estrogen. Vaginal not in the treatment of breast cancer aromatase inhibitor used to treat breast dryness and decreased libido have been and is not approved in Canada for this cancer. Aminoglutethimide’s toxicity reported. In two separate analyses, no indication. and lack of selectivity prompted the significant differences in overall qual- Aromatase inhibitors development of modern aromatase ity of life were observed between inhibitors, which were introduced into women taking tamoxifen and women 3,4 The aromatase is found in clinical trials in the late 1980s. AIs taking anastrazole or exemestane. , fat, muscle, andbreast tissue and cause marked suppression of plasma Due to their mode of action, aro- is responsible for most estrogen syn- estrogen levels in postmenopausal matase inhibitors are only effective in thesis in postmenopausal women by women by inhibition of aromatase. postmenopausal women with breast

122 BC MEDICAL JOURNAL VOL. 48 NO. 3, APRIL 2006 New guidelines for treatment of early hormone-positive breast cancer with tamoxifen and aromatase inhibitors

Table 1. Summary of evidence for therapy with the aromatase inhibitors anastrozole, women were randomly assigned to 5 exemestane, and letrozole for postmenopausal women with ER-positive breast cancer.8-12, 15 years of anastrozole or tamoxifen or a 8,9 combination of the two. After 5.5 Aromatase inhibitor Administration Benefit years, women treated with anastrozole Anastrozole 1 mg/day8,9 Given for 5 years after • Reduced risk of breast cancer hada 17% reduction in the relative risk Letrozole 2.5 mg/day10 diagnosis instead of recurrence by approximately 20% of breast cancer occurrence (disease- tamoxifen • Absolute risk reduction of 3% in free survival) compared with those clinical trials treated with tamoxifen. This translat- Exemestane 25 mg/day11 Given for 2–3 years after • Reduced risk of recurrence by ed into only a 3% absolute improve- 12 Anastrozole 1 mg/day 2–3 years of tamoxifen approximately 30% - 40% ment in disease-free survival between (total duration of hormonal • Absolute risk reduction of 3% - 5% therapy was 5 years) in clinical trials the anastrozole and tamoxifen groups and there was no difference in risk of 15 Letrozole 2.5 mg/day Given for at least • Reduced risk of recurrence by 40% death. There was no advantage to com- 3–5 years after 5 years of and risk of death by 40% in node- tamoxifen positive patients bination therapy with anastrozole and • Absolute risk reduction of 6% in tamoxifen over tamoxifen alone. clinical trials In asecondlargeadjuvant trial (BIG 1-98), first-line therapy with letrozole was compared with tamoxifen and 10 found similar results. With a shorter cancer. In premenopausal women, the with hormone-positive breast cancer. follow-up time there was a 19% dif- reduced feedback of estrogen to the Three strategies have been studied, ference in disease-free survival and pituitary leads to as follows: between the two groups, but overall increased production and • First-lineAI therapy insteadof tamo- survival was not significantly differ- an increase in ovarian estrogen pro- xifen. ent. With longer follow-up, a reduc- duction, thereby rendering therapy • AI therapy after 2 to 3 years of tion in mortality may be observed in ineffective and potentially harmful, as tamoxifen. both of these trials as women with ovarian tissue may hypertrophy and • AI therapy at the end of a 5-year recurrent breast cancer have a signifi- uterine bleeding may increase. Many course of tamoxifen. cantly shortened life expectancy. premenopausal women who are treated It has not yet been determined Trials of AIs after 2 to 3 with chemotherapy become clinically which of these three strategies is the years of tamoxifen and serologically postmenopausal. optimal algorithm, and no one thera- The risk of chemotherapy-induced peutic strategy is advocated over anoth- Shortly after the results of first-lineAI increases with age, and er in the 2004 American Society of therapy were reported, the results of a women older than 40 have a greater Clinical Oncology guidelines. Howev- second strategy to incorporate an aro- than 50% risk of being rendered meno- er, the role of aromatase inhibitors has matase inhibitor into adjuvant therapy 5,6 pausal. If menstruation does resume, been acknowledged with the recom- were released. In this case, tamoxifen it usually does so within 12 months, mendation that optimal adjuvant hor- was prescribedas initial therapy andan but may not do so for up to 24 months. monal therapy for postmenopausal AI was substituted after 2 to 3 years to As AIs are not effective and may be women with ER-positive breast can- complete a total of 5 years of hormonal harmful to premenopausal women cer include an aromatase inhibitor as therapy. with breast cancer, they should not be initial therapy or after treatment with There are several potential advan- 7 considereduntil at least 1 to 2 years after tamoxifen. A summary of the evi- tages to this strategy. First, women chemotherapy-induced menopause. dence for therapy with AIs is provided are exposedto two treatments with dif- Table 1 Evidence of superiority of in . fering mechanisms of action. Second, AIs over tamoxifen First-line AI therapy the inherent risk of AI therapy, includ- ing osteoporosis, may be reduced by a Anumber of well-designedrandomized In the ATAC (Arimidex, Tamoxifen shorter duration of exposure and the trials have sought to evaluate the effect Alone or in Combination) Trial, the prior use of tamoxifen. Third, the cu- of aromatase inhibitors as adjuvant largest randomized adjuvant trial in mulative risks of tamoxifen therapy, treatment for postmenopausal women breast cancer, 9366 postmenopausal including uterine malignancy and

VOL. 48 NO. 3, APRIL 2006 BC MEDICAL JOURNAL 123 New guidelines for treatment of early hormone-positive breast cancer with tamoxifen and aromatase inhibitors

Other uses of AIs thrombosis, are also limited by a ed with a 3% absolute increase in 9 shortened duration of tamoxifen thera- Outside the realm of oncology, AIs osteoporotic fractures, whereas 2 to 3 py. have been used for treatment of severe years of AI therapy after tamoxifen In the International Exemestane . In a randomized trial was associated with a 1% absolute Study (IES), women who had received of anastrozole plus (a increase in osteoporotic fractures and 2 to 3 years of tamoxifen were ran- gonadotropin-releasing hormone a 2% absolute increase in osteoporo- 5,11 domly assigned to receive exemestane analog, also known as a luteinizing- sis. An adverse effect on lipid pro- or to continue on tamoxifen to com- hormone-releasing hormone or file was observed in one trial with plete 5 years of adjuvant hormonal LHRH) versus goserelin alone, AI use letrozole, and in two trials there was a 11 therapy. At a median follow-up of 31 resulted in a significant reduction in questionable trendof increasedserious 16 9,10 months, women who switched to recurrent . AIs have also been cardiovascular events. The extent exemestane hada 32% reduction in the used for ovarian stimulation for wo- and significance of cardiovascular risk risk of recurrence, and a corresponding men undergoing in vitro fertilization. associated with AIs is being investi- 5% absolute improvement in disease- It shouldbe noted, however, that when gated. free survival at 3 years. There was no aromatase inhibitors are used for these Risk of recurrence difference in overall survival but a indications, they are not paid for by with tamoxifen use trend was reported. the BCCA. In a second, smaller trial, post- Side effects of AIs Two recent studies of the BCCA menopausal women were switched to versus tamoxifen Breast Cancer Outcomes Database anastrozole after 2 years of adjuvant have sought to estimate risk of recur- tamoxifen, resulting in a 40% relative In the trials referred to here, hot flush- rence of breast cancer in postmeno- risk reduction and 3% absolute risk es were commonly reported (40% to pausal women treated with tamox- 12 17,18 reduction. 60%) and occurred with similar fre- ifen. In the first study, the risk of quency in women takingAIs or tamox- early recurrence of breast cancer was Trial of letrozole after 8,11,15 5 years of tamoxifen ifen. In the MA 17 trial, even determined among postmenopausal women who were on no hormonal women in British Columbia treated Previous evidence suggested that 5 treatment after 5 years of tamoxifen with tamoxifen alone or in addition to years of adjuvant hormonal therapy had a 54% incidence of low-grade hot chemotherapy for breast cancer. Early provides optimal benefit, with a longer flushes. A reduction in gy- recurrence was defined as relapse oc- duration of tamoxifen use possibly necological side effects (such as vagi- curring within 2.5 years of initial diag- associated with worse survival out- nal discharge or bleeding) with aro- nosis with breast cancer. Results indi- 13 comes. Yet, half of breast cancer matase inhibitors was most notable cate that women who have more than relapses occur later than 5 years after when an AI rather than tamoxifen was three nodes positive, or who have 1,2,14 diagnosis. In the NCIC MA17 used as first-line therapy. Rates of high-grade breast cancer (grade 3) or trial, the benefit of letrozole after 5 vaginal bleeding (5% versus 10%) and low ER-positive (1+) breast cancer are years of tamoxifen was evaluated. hysterectomy (1% versus 5%) were at significantly greater risk of recur- Women who were cancer-free after tak- both significantly less with anastro- rence within the first 2.5 years after 9 17 ing 5 years of tamoxifen were treated zole than tamoxifen. The difference in diagnosis with an intended 5 years of letrozole gynecological side effects between While it is not yet known if first- 15 versus placebo. After only 2.4 years tamoxifen and AIs are less apparent line treatment with AIs will reduce the follow-up there was a 40% decrease in after 2 years of tamoxifen use, as risk of death from breast cancer, cur- breast cancer occurrence in women tamoxifen-induced gynecological rent BCCAguidelines recommendthat treated with letrozole, which translat- symptoms predominate in the initial women at high risk of early recurrence ed into a benefit of 6% in absolute years of therapy. Although low in both and no contraindications to AIs be terms. In patients with node-positive groups, a reduction in the thrombo- treated with an AI instead of tamox- breast cancer there was also a 40% embolic events andrisk of uterine can- ifen. For postmenopausal women who reduction in risk of death, making this cer was observed with AIs versus do not meet these criteria, BCCA rec- the first of the AI trials to show a sur- tamoxifen. ommends initial therapy with tamox- vival benefit. Regarding other side effects, 5 ifen followedby a switch to an AI after years of anastrozole use was associat- 2 to 5 years.

124 BC MEDICAL JOURNAL VOL. 48 NO. 3, APRIL 2006 New guidelines for treatment of early hormone-positive breast cancer with tamoxifen and aromatase inhibitors

Table 2. Risk of breast cancer death and breast cancer occurrence 6 to 10 years after Patients with node-negative and diagnosis if disease-free after 5 years of tamoxifen. low-grade disease (grade 1) have a 18,19 Risk of breast cancer Risk of breast cancer favorable prognosis and are gener- Nodal involvement and Number of death between years occurrence between ally adequately treated with 5 years of tumor size patients 6 and 10 (%) years 6 and 10* (%) tamoxifen alone and no AI therapy. Low-grade breast cancer accounts for Node-negative, 418 4 10 approximately 16% of all breast can- all grades 2 cer. Node-negative, grade 1 42 0 3 For premenopausal women with ER-positive breast cancer, tamoxifen 1–3 nodes positive 380 9 15 remains the standard therapy. These patients are not candidates for aro- 4–9 nodes positive 109 22 30 matase inhibitor therapy. For women * Defined as cancer recurrence or second primary breast cancer who become menopausal after chemo- therapy and remain so for 1 to 2 years, a switch to an AI may be optimal. In an attempt to estimate the risk pausal women receiving adjuvant hor- There is not yet any evidence for the of late breast cancer relapse, breast can- monal therapy for early breast cancer. use of an LHRH agonist such as cer event rate and mortality were deter- There are three different AIs and three goserelin with an AI. mined in postmenopausal women different strategies to incorporate AIs It is recommended that physicians treated in British Columbia with 5 into adjuvant therapy. The question of assess a woman’s risk of osteoporosis 18 years of tamoxifen. Risk of breast which strategy is superior in terms of when considering AI therapy. If there cancer events (definedas recurrence and efficacy and side effects has not yet are any risk factors for osteoporosis, a second breast cancers) and mortality been answered. baseline test should be Table 2 20 are provided in . For postmenopausal women with performed. AIs may also have an In this study, nodal involvement breast cancer who are at high risk of adverse effect on lipid profile and there was the most important predictor of early relapse, first-line therapy with 5 is a possible but not yet quantifiedcar- breast cancer events or death after 5 years of AIs is recommended. Women diovascular risk. A baseline lipid pro- years of tamoxifen. Women with 1 to are considered at high risk if they have file should be performed at the time of 3 nodes positive had a 15% risk, and more than three nodes positive, have initiating AI therapy. women with 4 to 9 nodes positive had high-grade disease (grade 3), or low The recommendations described a 30% risk of breast cancer occurrence. ER-positive (1+) disease. Otherwise, here will be updated as the results of Women who had low-grade node-neg- first-line therapy with tamoxifen for 2 new trials become available and cur- ative disease had a very low risk (3%) to 3 years remains the standard. After rent trials continue. For now, BCCA of breast cancer occurrence after 5 years 2 to 3 years of tamoxifen, physicians recommends the exclusive use of first- of tamoxifen. Current BCCA guide- are asked to consider switching wo- line AI therapy for some postmeno- lines recommend that women with men to AI therapy for 2 to 3 years to pausal women and the sequential use node-positive or with high-grade node- complete a total of 5 years of hormonal of tamoxifen followed by an AI for negative breast cancer be considered treatment. It is recommended that most postmenopausal women with for another 3 to 5 years of therapy with women who have already received early stage hormone-positive breast letrozole after 5 years of tamoxifen. more than 3 years of tamoxifen con- cancer. The BCCA does not recommend Women with low-grade node-negative tinue on tamoxifen for a total of 5 the use of AI therapy for premeno- breast cancer should not routinely years, after which they should consid- pausal women with breast cancer. receiveletrozoleafter 5 years of tamox- er the option of 3 to 5 more years of ifen, since the overall risk of recur- AI therapy. Women with initially rence is very low. node-positive breast cancer or high- Full guidelines The full guidelines can be viewed at Guidelines for AI use grade node-negative breast cancer anda reasonable 5-year life expectancy www.bccancer.bc.ca. Aromatase inhibitors represent a new shouldbe consideredfor 3 to 5 years standard of care for many postmeno- of AI therapy.

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Competing interests Status report 2004. J Clin Oncol 2005; Updated findings from the National Sur- In the last 5 years Dr Kennecke has received 20;23:619-629. gical Adjuvant Breast and Bowel Project fees for speaking and fees from consultan- 8. Baum M, Buzdar A, Cuzick J, et al. Anas- B-14 randomized trial. J Natl Cancer Inst cy from AstraZeneca, Novartis, and Pfizer. trozole alone or in combination with 2001;93:684-690. tamoxifen versus tamoxifen alone for 14. Saphner T,Tormey DC, Gray R. Annual References adjuvant treatment of postmenopausal hazard rates of recurrence for breast can- 1. Early Breast Cancer Trialists’ Collabora- women with early-stage breast cancer: cer after primary therapy. J Clin Oncol tiveGroup.Tamoxifenforearlybreastcan- Results of the ATAC (Arimidex,Tamoxifen 1996;4:2738-2746. cer: An overview of the randomized tri- Alone or in Combination) trial efficacy and 15. Goss PE, Ingle JN, Martino S, et al. A ran- als. Lancet 1998;351:1451-1467. safety update analyses. Cancer 2003; domized trial of letrozole in postmeno- 2. Early Breast Cancer Trialists’ Collabora- 98:1802-1810. pausal women after five years of tamox- tive Group. Effects of chemotherapy and 9. Howell A, Cuzick J, Baum M et al. Results ifen therapy for early-stage breast cancer. hormonal therapy for early breast cancer of the ATAC (Arimidex, Tamoxifen, Alone N Engl J Med 2003;349:1793-1802. on recurrence and 15 years survival: An or in Combination) trial after completion 16. Soysal S, Soysal ME, Ozer S, et al. The overview of the randomized trials. Lancet of 5 years’ adjuvant treatment for breast effects of post-surgical administration of 2005:365:1687-1717. cancer. Lancet 2005;365:60-62. goserelin plus anastrozole compared to 3. Fallowfield L, Cella D, Cuzick J, et al. Qual- 10. Thurlimann BJ, Keshaviah A, Mouridsen goserelin alone in patients with severe ity of life of postmenopausal women in H, et al. BIG 1-98: Randomized double endometriosis: A prospective random- theArimidex,Tamoxifen,AloneorinCom- blind phase III study to evaluate letrozole ized trial. Hum Reprod 2004;19:160-167. bination (ATAC) Adjuvant Breast Cancer versus tamoxifen as adjuvant endocrine 17. McArthur HL, Olivotto I, Gelmon KA, et Trial. J Clin Oncol 2004;22:4261-4271. therapy for postmenopausal women al. Risk of early relapse in post-meno- 4. Fallowfield LJ, Price MH, Hall E, et al. with receptor-positive breast cancer. Pre- pausal women with early stage, estro- Intergroup exemestane study: Results of sented at the Symposium of the Ameri- gen receptor positive (ER+) breast can- the quality of life sub-protocol. Presented can Society of Clinical Oncology, Orlan- cer on tamoxifen. Breast Cancer Res at the San Antonio Breast Cancer Sym- do, FL, May 2005. Abstract 511. Treat 2005;94(1 suppl):s124. posium, San Antonio, TX, December 11. Coombes RC, Hall E, Gibson LJ, et al. A 18. Kennecke H, Speers C, Chia S, et al. 10 2004. Abstract 4. randomized trial of exemestane after two year event free survival in postmeno- 5. Swain SM, Land SR, Sundry M, et al. to three years of tamoxifen therapy in pausal women with early breast cancer Amenorrhea in premenopausal women postmenopausal women with primary during the second five years after tamox- on the ACT arm of NSABP B-30: Prelimi- breast cancer. N Engl J Med 2004; ifen. Presented at the SanAntonio Breast nary results. Presented at the Sympo- 350:1081-1092. Cancer Conference, San Antonio, TX, sium of the American Society of Clinical 12. Jakesz R, Kaufmann M, Gnant M, et al. December 2004. Abstract 1049. Oncology, Orlando, FL, May 2005. Ab- Benefits of switching postmenopausal 19. Chia SK, Speers CH, Bryce CJ, et al.Ten- stract 537. women with hormone-sensitive early year outcomes in a population-based 6. Goodwin PJ, Ennis M, Pritchard KI, et al. breast cancer to anastrozole after 2 years cohort of node-negative, lymphatic, and Risk of menopause during the first year adjuvant tamoxifen: Combined results vascular invasion-negative early breast after breast cancer diagnosis. J Clin from 3,123 women enrolled in the cancers without adjuvant systemic ther- Oncol 1999;17:2365-2370. ABCSGTrial 8 and the ARNO 95Trial. Pre- apies. J Clin Oncol 2004;22:1630-1637. 7. Winer EP,Hudis C, Burstein HJ, et al. sented at the San Antonio Breast Cancer 20. Brown JP,Josse RG; Scientific Advisory American Society of Clinical Oncology Symposium, San Antonio,TX, December Council of the Osteoporosis Society of technology assessment on the use of 2004. Abstract 2. Canada. 2002 clinical practice guidelines aromatase inhibitors as adjuvant therapy 13. Fisher B, Dignam J, Bryant J, et al. Five for the diagnosis and management of for postmenopausal women with hor- versus more than five years of tamoxifen osteoporosis in Canada. CMAJ 2002; mone receptor-positive breast cancer: for lymph node-negative breast cancer: 167(10 suppl):S1-34.

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