Treatment of Perimenopausal Women with Breast cancer. Alison L Jones Royal Free and UCLH

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1 Treatment of Perimenopausal Women with Breast cancer Alison L Jones Royal Free and UCLH November 2014

2 Oestradiol levels in a female lifetime 1000pmol 150pmol 12 years 36 years 51 years

3 Definition of menopause 1 Menopause Bilateral prior oophorectomy Age >60 years Age <60 years Amenorrhoea for >12 months Postmenopausal FSH and oestradiol concentrations Cannot assign menopausal status to women on LHRH analogue therapy Amenorrhoea menopause on chemotherapy 1. Breast cancer. NCCN practice guidelines in oncology v.3; 2012.

4 Many women fall into the perimenopausal range Average Number of New Cases Per Year and Age-Specific Incidence Rates per 100,000 Population, Females, UK, and may become postmenopausal during their treatment Cancer Research UK Last accessed 10 Jan 2013.

5 Chemotherapy - Induced Amenorrhea Rates Agents Younger Women ( 40 y) Older Women (>40 y) Alkylating 18% to 61% 61% to 97% Anthracyclines ~ 32% ~ 88% Taxanes (+Anthac.) ~ 61% ~ 84% Walshe JM, et al. J Clin Oncol. 2006;24(36):

6 Estimated Probability Mathematical Model of Risk of Menopause: First Year After Diagnosis Our patient None Horm Only Chem Only Both Age at Diagnosis, years Goodwin PJ, et al. J Clin Oncol. 1999;17(8):

7 NICE guidelines for endocrine therapy in pre/peri-menopausal ABC Offer tamoxifen and ovarian suppression as first-line treatment to premenopausal and perimenopausal women with ER-positive advanced breast cancer not previously treated with tamoxifen Offer ovarian suppression to premenopausal and perimenopausal women who have previously been treated with tamoxifen and then experience disease progression NICE clinical guideline 81, 2009.

8 Use of AIs in Perimenopause: Royal Marsden Experience 45 women Median age 47 (39-52) years with CT induced amenorrhea Treated with AIs (33 biochemically confirmed ovarian suppression) Recovery of ovarian function: 12 (27%) Pregnancies 1 Median duration of amenorrhea: 12 (4-59) months Median time on AI: 6 (3-18) months Smith IE, et al. J Clin Oncol. 2006;24(16):

9 Biochemical Monitoring of Ovarian Function in Perimenopause Single measurement of FSH, (LH), E 2, beta inhibin reflects function only at that time point, but is not predictive Tests used for E 2 measurements are highly unreliable in perimenopause, as they do not extract or purify E 2 from plasma Measurement in patients receiving a steroidal AI cross-react even with most specialized immunoassays FSH, follicle-stimulating hormone; LH, luteinizing hormone Smith IE, et al. J Clin Oncol. 2006;24(16):

10 Mrs A F (aged 49) 2010 Carcinoma right breast T2 N1 (2/9) M0 2.5 cm Grade 2 IDC with clear margins ER + Quick score 7/8 PR + Quick score 4/8 HER 2 Negative (IHC 0) No co-morbidities Mastectomy and axillary node clearance

11 Mortality estimations with Adjuvantonline

12 Addition of Chemotherapy to Endocrine in ER+ EBC EBCTCG 2005

13 Mrs AF; Adjuvant treatment She receives 3 cycles of FEC (100) followed by 3 cycles of docetaxel which she tolerates well

14 Q2: Initial Endocrine therapy option? 44 years; Last menses < 9 months; pt2,n1, M0 IDC, Grade III, ER/PgR [+], HER2 negative 1. Decision based on FSH/E1 levels 2. Tamoxifen started 3. An Aromatase Inhibitor started 4. A combination of LHRH-Ag and AI 5. A combination of LHRH-AG and Tamoxifen

15 Tamoxifen Efficacy Does Not Differ Significantly According to Patient Age Breast Cancer Recurrence Rate Annual Risk Ratio ± SE Breast Cancer Death Rate Risk Ratio SE Risk Ratio SE For all age groups Age, years < Parton M, et al. J Clin Oncol. 2008;26(5): after Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2005:365(9472):

16 Q2: Initial Endocrine therapy option? 1. Decision based on FSH/E1 levels 2. Tamoxifen started 3. An Aromatase Inhibitor started 4. A combination of LHRH-Ag and AI 5. A combination of LHRH-AG and Tamoxifen

17 Patient case 30 months had gone No relapse Patient still on Tamoxifen Good tolerance (Hot flashes first year) Amenorrhea maintained (38 months)

18 Q3: Is it time for switching endocrine therapy? 1. No discussion switch to Exemestane 2. Exemestane but measuring FSH/E1 levels 3. Tamoxifen maintained for 5 years and then we will see

19 Intergroup Exemestane Study Design Tamoxifen R A N D O M I ZE Exemestane (2-3 years) Tamoxifen (2-3 years) Post-treatment follow-up 2-3 years Median follow-up from randomization = 91 months (June 2009) Diagnosis Start of study Total 5 years endocrine therapy Total follow-up available from randomization at June 2009 analysis = women years Coombes RC et al, Eur J Cancer Suppl. 2009;7(2): Abstract 5010.

20 Long term results from the IES Study Coombes RC et al, Eur J Cancer Suppl. 2009;7(2): Abstract 5010.

21 If Use of AIs Is Considered in Perimenopause (Age <55 Years) Serial monthly measurement of FSH and E 2 For at least 6 months For AI after tamoxifen situation even longer If E 2 remains >10 pmol/l = AI is not fully effective Switch back to tamoxifen Surgical ovarian ablation Instruct patients to contact clinician if menstrual bleed recurs or hot flushes stop abruptly Adequate contraception should be practiced during monitoring period Anti Müllerian Hormone (AMH) is most reliable indicator of residual follicular function Smith IE, et al. J Clin Oncol. 2006;24(16):

22 Normal menopausal transition Women of uncertain menopausal status who may be or may become eligible for an adjuvant AI TREATMENT-NAÏVE: NATURAL MENOPAUSAL TRANSITION Start with tamoxifen Monitor E2 and FSH every 3-6 months AGE < 40: AI ALONE IS CONTRAINDICATED Consider an AI as soon as menopausal status is confirmed TREATMENT-INDUCED AMENORRHOEA CHEMOTHERAPY- INDUCED AGE > 40 WHILE ON TAMOXIFEN If E2 and FSH levels are postmenopausal by reliable & valid measure start AI Monitor hormones at 3, 6 months and q6 during treatment If postmenopausal status cannot be confirmed, treatment with AIs alone is contraindicated. Monitor E2 and gonadotrophin levels (ie, every 3-6 months) to allow an AI when postmenopausal status is confirmed. The added value of ovarian suppression remains to be defined.

23 Chemotherapy-induced amenorrhea (<40) Women of uncertain menopausal status who may be or may become eligible for an adjuvant AI TREATMENT-NAÏVE: NATURAL MENOPAUSAL TRANSITION Start with tamoxifen TREATMENT-INDUCED AMENORRHOEA CHEMOTHERAPY- INDUCED AGE < 40: AI ALONE IS CONTRAINDICATED Monitor E2 and FSH every 3-6 months Consider an AI as soon as menopausal status is confirmed AGE > 40 WHILE ON TAMOXIFEN If E2 and FSH levels are postmenopausal by reliable & valid measure start AI Monitor hormones at 3, 6 months and q6 during treatment The effects of chemotherapy on ovarian function vary The likelihood of resumed ovarian function diminishes as a woman approaches the mean age of natural menopause (51 years) Women with CIA who are younger than 40 are more likely to resume ovarian function and should not receive an AI alone

24 Chemotherapy-induced amenorrhea (>40) Women of uncertain menopausal status who may be or may become eligible for an adjuvant AI TREATMENT-NAÏVE: NATURAL MENOPAUSAL TRANSITION Start with tamoxifen AGE < 40: AI ALONE IS CONTRAINDICATED Monitor E2 and FSH every 3-6 months Consider an AI as soon as menopausal status is confirmed TREATMENT-INDUCED AMENORRHOEA CHEMOTHERAPY- INDUCED AGE > 40 WHILE ON TAMOXIFEN If E2 and FSH levels are postmenopausal by reliable & valid measure start AI Monitor hormones at 3, 6 months and q6 during treatment In older women if E2 and FSH levels are consistent with postmenopausal status, an AI can be started Undertake serial monitoring at 3 and 6 months and then at intervals of six months during treatment If reliable testing is not available, AIs should be used with great caution

25 Cessation of menses on tamoxifen Women of uncertain menopausal status who may be or may become eligible for an adjuvant AI TREATMENT-NAÏVE: NATURAL MENOPAUSAL TRANSITION Start with tamoxifen AGE < 40: AI ALONE IS CONTRAINDICATED Monitor E2 and FSH every 3-6 months Consider an AI as soon as menopausal status is confirmed TREATMENT-INDUCED AMENORRHOEA CHEMOTHERAPY- INDUCED AGE > 40 WHILE ON TAMOXIFEN If E2 and FSH levels are postmenopausal by reliable & valid measure start AI Monitor hormones at 3, 6 months and q6 during treatment If the patient is a candidate for switching to an AI first check E2 and FSH levels Measurements should be made at baseline and then serially (eg, every 3-6 months) during treatment

26 Issues for perimenopausal women started on an aromatase inhibitor Contraception Hot flashes Sexual dysfunction and dyspareunia Bone Heath

27 Serum estradiol levels in women receiving concurrent aromatase inhibitors and Vagifem. Avoid use of vaginal oestrogen preparations in women on aromatase inhibitors Kendall A et al. Ann Oncol 2006;17:

28 Bone health A baseline measurement of bone mineral density (BMD) is recommended to guide future management. Advice on exercise, cessation of smoking and moderation of alcohol should be provided. Adequate calcium (1g/day) and vitamin D ( i.u.) is advised in all postmenopausal women. Women with BMD T score of <-2 or <-1 and annual bone loss > 4%/year should be considered for bisphosphonate treatment DM Reid et al. Cancer Treatment Reviews 34, Suppl 1, S3-S18, P Hadji et al. Annals of Oncology 2008; 19:

29 Summary When menopausal status is uncertain, starting endocrine therapy with tamoxifen rather than an AI provides effective treatment while allowing a period during which the patient s menopausal status may become clearer. If in doubt wait! However, given the benefit certain women may gain from receiving an AI rather than continuing on tamoxifen, it is important regularly to monitor the hormonal status of perimenopausal patients so that treatment can be switched when appropriate.