treatment of perimenopausal women with breast cancer · definition of menopause1 menopause...

Treatment of Perimenopausal Women with Breast cancer

Alison L Jones

Royal Free and UCLH

November 2014

Oestradiol levels in a female lifetime

1000pmol

150pmol

12 years 36 years 51 years

Definition of menopause1

Menopause

Bilateral prior oophorectomy

Age >60 years Age <60 years

Amenorrhoea for

>12 months

Post-menopausal

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.

Many women fall into the perimenopausal range…

…and may become postmenopausal during their treatment Cancer Research UK http://www.cancerresearchuk.org/cancer-info/cancerstats/types/breast/incidence/uk-breast-cancer-incidence-statistics Last accessed 10 Jan 2013.

Average Number of New Cases Per Year and Age-Specific Incidence Rates per 100,000 Population, Females, UK, 2008–2010

http://www.cancerresearchuk.org/cancer-info/cancerstats/types/breast/incidence/uk-breast-cancer-incidence-statistics













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):5769-5779

Goodwin PJ, et al. J Clin Oncol. 1999;17(8):2365-2370.

Mathematical Model of Risk of Menopause:

First Year After Diagnosis

0.2

0.4

0.6

0.8

1.0

0.0

25 30 35 40 45 50 55

None

Horm Only

Chem Only

Both

Age at Diagnosis, years

Esti

mate

d P

rob

ab

ilit

y

Our patient

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.

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): 2444-2447.

Biochemical Monitoring of Ovarian Function in Perimenopause

• Single measurement of FSH, (LH), E2, beta inhibin reflects function only at that time point, but is not predictive

• Tests used for E2 measurements are highly unreliable in perimenopause, as they do not extract or purify E2 from plasma

• Measurement in patients receiving a steroidal AI cross-react even with most specialized immunoassays

Smith IE, et al. J Clin Oncol. 2006;24(16):2444-2447.

FSH, follicle-stimulating hormone; LH, luteinizing hormone

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

Mortality estimations with Adjuvantonline

Addition of Chemotherapy to Endocrine in ER+ EBC EBCTCG 2005

Mrs AF; Adjuvant treatment

• She receives 3 cycles of FEC (100)

followed by 3 cycles of docetaxel which

she tolerates well

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

44 years; Last menses < 9 months; pT2,N1, M0

IDC, Grade III, ER/PgR [+], HER2 negative

Tamoxifen Efficacy Does Not Differ

Significantly According to Patient Age

Annual Risk Ratio ± SE

Breast Cancer

Recurrence Rate

Breast Cancer

Death Rate

Risk Ratio SE Risk Ratio SE

For all age groups 0.59 0.03 0.66 0.04

Age, years

<40 0.56 0.10 0.61 0.12

40-49 0.71 0.07 0.76 0.09

50-59 0.66 0.05 0.76 0.07

60-69 0.55 0.05 0.65 0.06

≥70 0.49 0.12 0.63 0.15

Parton M, et al. J Clin Oncol. 2008;26(5):745-752 after Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2005:365(9472):1687-1717.

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

Patient case

30 months had gone

No relapse

Patient still on Tamoxifen

Good tolerance (Hot flashes first year)

Amenorrhea maintained (38 months)

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

Coombes RC et al, Eur J Cancer Suppl. 2009;7(2): Abstract 5010.

Tamoxifen

R A N D O M I

ZE

Exemestane

(2-3 years)

Tamoxifen

(2-3 years)

Post-treatment follow-up

Diagnosis

Median follow-up from randomization = 91

months (June 2009)

Start of

study

Total 5 years

endocrine therapy

Total follow-up available from randomization at June 2009 analysis = 32296 women years

2-3 years

Intergroup Exemestane Study Design

Long term results from the IES Study

Coombes RC et al, Eur J Cancer Suppl. 2009;7(2): Abstract 5010.

If Use of AIs Is Considered in Perimenopause (Age <55 Years)

• Serial monthly measurement of FSH and E2

– For at least 6 months – For AI after tamoxifen situation even longer

• If E2 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):2444-2447.

Normal menopausal transition

• 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.

TREATMENT-NAÏVE:

NATURAL MENOPAUSAL

TRANSITION

TREATMENT-INDUCED AMENORRHOEA

Women of uncertain menopausal status who may be or may become eligible for an

adjuvant AI

CHEMOTHERAPY- INDUCED

WHILE ON TAMOXIFEN

AGE < 40: AI ALONE IS

CONTRAINDICATED

AGE > 40

Start with tamoxifen

Monitor E2 and FSH every

3-6 months

Consider an AI as soon as

menopausal status is confirmed

If E2 and FSH levels are post-menopausal 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

Chemotherapy-induced amenorrhea (<40)

TREATMENT-NAÏVE: NATURAL MENOPAUSAL

TRANSITION

TREATMENT-INDUCED

AMENORRHOEA


adjuvant AI

CHEMOTHERAPY-

INDUCED

WHILE ON TAMOXIFEN

AGE < 40:

AI ALONE IS

CONTRAINDICATED

AGE > 40


Monitor E2 and FSH every 3-6 months

Consider an AI as soon as menopausal status is confirmed



• 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


TRANSITION

TREATMENT-INDUCED

AMENORRHOEA


adjuvant AI

CHEMOTHERAPY-

INDUCED

WHILE ON TAMOXIFEN


CONTRAINDICATED

AGE > 40






Chemotherapy-induced amenorrhea (>40)

• 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


adjuvant AI

Cessation of menses on tamoxifen


TRANSITION

TREATMENT-INDUCED

AMENORRHOEA

CHEMOTHERAPY- INDUCED

WHILE ON

TAMOXIFEN


CONTRAINDICATED

AGE > 40






Issues for ‘perimenopausal’ women started

on an aromatase inhibitor

• Contraception

• Hot flashes

• Sexual dysfunction and dyspareunia

• Bone Heath

Serum estradiol levels in women receiving concurrent aromatase inhibitors and Vagifem.

Kendall A et al. Ann Oncol 2006;17:584-587

Avoid use of vaginal oestrogen preparations in women on aromatase inhibitors

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 (400-800 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, 2008.

P Hadji et al. Annals of Oncology 2008; 19: 1407-1416.

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.

treatment of perimenopausal women with breast cancer · definition of menopause1 menopause...

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