Updated 30 April 2009

POLICY ON DEFINED USE OF UP-FRONT AROMATASE INHIBITOR THERAPY FOR ADJUVANT HORMONAL MANAGEMENT OF HIGH RISK ER+ BREAST CANCER

Rationale:
Multiple different strategies for incorporation of aromatase inhibitors (anastrazole, letrozole, exemestane) into adjuvant hormonal therapy have now been studied or are the subject of ongoing studies.  The ASCO expert panel on technology has published a review of the subject, indicating that an aromatase inhibitor should be considered as part of the standard adjuvant hormone therapy of newly diagnosed postmenopausal women with breast cancer.; The optimal strategy has not yet been determined: upfront use of an AI for 5 years vs. 2-3 years of tamoxifen followed by an AI for 3-2 years, vs. 5 years of tamoxifen followed by 3-5 years of an AI.  No studies have yet determined the optimal duration of an AI, but some studies are currently planned or underway to assess the effects of >5 years of AI therapy.  No study has established one AI is superior to another.

The strategy of a sequential approach, incorporating tamoxifen first for some period, followed by an AI, has some theoretic advantages compared to monotherapy with either tamoxifen or an AI alone.  This strategy allows for two treatments with differing mechanisms of action, thus potentially superior in overcoming treatment resistance.  Also, the osteoporosis risk produced by prolonged use of an AI may be offset by the prior use of tamoxifen.  The cumulative risks of uterine hyperplasia and malignancy and thrombosis related to tamoxifen may be limited by switching after 2-3 years to an AI.  For those women completing adjuvant chemotherapy with loss of menses during therapy, upfront use of tamoxifen allows hormone therapy to proceed while the impact of adjuvant chemotherapy on ongoing menstrual status is determined.

The theoretic disadvantage of using tamoxifen for 2-3 years followed by an AI is that some patients with higher risk disease may relapse while on tamoxifen prior to the switch in therapy.  It is impossible to know at this time whether early relapsers would have a different survival outcome ultimately by use of an AI upfront. ; The various AI adjuvant studies have uniformly demonstrated an improvement in disease-free survival (DFS), but an overall survival (OS) difference is not yet clearly apparent.  The studies have included a majority of low risk patients.  There is a possibility that DFS and OS impact would be greater in patients at high risk for early relapse or with relative tamoxifen resistance.

Early data has been obtained from a review of BCCA treatment data, and analysis continues.  This indicates that women with N2 disease or higher, high grade breast cancer, or low ER+ (1+) are at higher than average risk (>10%) for relapse within the first 2.5 years.   PR status and her2neu status will also be analyzed in the near future.

More data is anticipated from longer term follow-up of studies including ATAC, IES, MA17, BIG 1-98, and others (see references), and may affect future policy decisions.   In the interim the breast systemic tumour group proposes the following treatment guideline for use of AI in the setting of therapy for ER+ breast cancer in women:

GENERAL POLICY: (ALL ER+ DISEASE):
Premenopausal women:
Tamoxifen for 5 years (BRAJTAM), unless they become post-menopausal during therapy (no menses>12 months and FSH/LH in postmenopausal range), then see strategy C below. Note: It is not recommended to switch patients to AI after only 1 year of tamoxifen, as there is no data to guide this approach, and some patients may yet recover menstrual function beyond 1 year post chemotherapy.

Postmenopausal women:

Strategy A: Tamoxifen monotherapy:  Low grade T1N0 tumours: Tamoxifen for 5 years (BRAJTAM). Substitution of AI allowed if intolerant or if serious complications or contraindications exist.

Strategy B:  AI monotherapy (BRAJANAS, BRAJEXE, BRAJLET): High risk for early relapse, defined as:

• high grade, or
• Low ER (1+), or
• Stage III ( Includes any N2/N3, T4, or T3N+)

May consider using AI upfront for 5 years, or strategy C below, at discretion of treating oncologist.  

Strategy C:  All other tumours: Sequential therapy preferred for most postmenopausal women, other than as defined above.

Tamoxifen for 2-3 years followed by AI (BRAJANAS, BRAJEXE, BRAJLET) for 3-2 years, for total 5 years of hormone therapy ("early switch")

or

Tamoxifen for 5 years followed by AI for 3 years, for women who have finished >3 years of tamoxifen already at this time, or who become postmenopausal AFTER completing 3 years of tamoxifen ("late switch").

1. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350(11):1081-92.
2. The ATAC Trialists' Group. Anastrozole Alone or in Combination with Tamoxifen versus Tamoxifen Alone for Adjuvant Treatment of Postmenopausal Women with Early-Stage Breast Cancer. Cancer 2003;98:1802-10.
3. The ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359(9324):2131-39.
4. The ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet Published online December 8, 2004;364(9451).
5. Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005;23(3):619-29.
6. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349(19):1793-802.