Premature ovarian failure in breast cancer How …BMS April 2013 Premature ovarian failure in breast...

BMS

April 2013

Premature ovarian failure in breast cancerHow definitive? Measurement & Prognosis

Patrick Neven, MD PhDGynaecologic Oncology

Multidisciplinary Breast Center UZ Gasthuisberg

Katholieke Universiteit Leuven

Hormones play a critical role in breast cancer carcinogenesis: Aromatase

Androstenedione↔ Testosterone

Estrone ↔ Estradiol

Estronesulfate

↔ ↔

↔AROMATASE

Premenopausal OvariesCyclical Changes

Postmenopausal women- Subcutaneous fatBreast: -Normal tissue-Tumor

SHBG

SHBG

Premenopause FP Free E2 ~ ERPR+ BrCa risk (Eliassen NHS-II JNCI 2006)- 1996-1999 2003 : 197/18521 women developed breast cancer Q1-Q4 RR: 2.8

Postmenopause Free E2 ~ ERPR+ BrCa risk up to 20 yrs (Zhang NHS-I BCRT 2013)

-1989-1990 2010: 707/32826 women developed breast cancer Q1-Q4 RR: 2.8

How do we interfere in estrogen binding in ER-positive breast cancer?

How frequent? Chemotherapy-induced amenorrhea

Tamoxifen-induced amenorrhea

Post LHRH-induced amenorrhea

Post R*-castration induced amenorrhea

Post BSO induced amenorrhea

Post-pil amenorrhea, stress, low BMI

How measure if definitive ?

Issues if no definitive menopause?

Tamoxifen

Oral aromatase inhibitors

Extended anti-E therapy

Premature Ovarian Insufficiency in breast cancer

EfficacyToxicityContraceptive needs

]For >12 monthsDefinitive?…

How frequent? More data for vaginal bleeding than for FSH, E2

Chemotherapy-induced amenorrhea ~ Age, type, duration, tam Tamoxifen without previous CT: >12 months amenorrhea = rare

“> 12 months” amenorrhea in breast cancerDefinitive? Measurement & Prognosis

Petrek J A et al. JCO 2006;24:1045-1051


Chemotherapy-induced amenorrhea ~ Age, type, duration, tam Tamoxifen without previous CT: >12 months amenorrhea = rare


Cave comparison of rates of CIA across different studies-Considerable differences in treatments used, -Addition of anti-E, -Follow-up duration,-Variability in the definition of CIA (3 m. - 1 yr no menses)-Biochemical bias (what is a high FSH and low E2?)-Amenorrhea and LNG-IUD

Follicular phase chemotherapyInhertitable factors

Specific genesBreast cancer ‘per se”


Chemotherapy-induced amenorrhea ~ Age, type, duration, tam Tamoxifen & no previous CT: >12 m. amenorrhea = rare


Petrek J A et al. JCO 2006;24:1045-1051

↑FSH elevated

E2: LowSymptoms

↑FSH lowE2: HighProg: ~

Ovarian CystsNo Symptoms

Tamoxifen-induced amenorrhea~ AGE

No CT; after LHRH-agonist only: irregular cycles, oligomenorrhea, no effect on age menopause

After CT: decreases bleeding between months 12 and 24 after chemotherapy with 15% fewer women having bleeding.

After CT OS with LHRH-agonist: prolongs CIA and chance to develop definitive menopause but date for the last statement arecontroversial

However, how tamoxifen influences CIA/CIM remains unclear.

Suggested has made that it increases plasma E2 and Prog & interferes with endometrial decidualisation and the hypothalamic–ovarian feedback loop that regulates E-synthesis

How frequent? How insufficient is insufficient? Chemotherapy-induced amenorrhea






How best to measurement definitive menopause?

How insufficient is insufficient?


Tamoxifen

Oral aromatase inhibitors Extended anti-E therapy



]For >12 months and than…

HOW INSUFFICIENT IS INSUFFICIENT?

THERE IS NO CLINICAL MARKER

THERE IS NO RELIABLE BIOCHEMICAL MARKER

Reliable assessment E2 is mostly lacking

THERE IS NO TVU MARKER (AFC)

Tam & AIs are able to induce follicles….

6 casesBiochemicalMenopause

AI-InducedOvarian Recovery

AS DieudonnéeMenopause 2011

AMH of no help

A special case Mrs S; °1945

1986: R. breast cancer: WE and ALND + RT. 2001: L. breast cancer: WE + ALND + RT + Tam

2002: Typical menstrual cycles (EB: proliferative)

2002: LHRH ag 6m + Anastrozole

2002: Anastrozole and postmenopausal E2 levels 2003: PMB and high E2 levels (327 pg/mL)

US: follicle and thickened endometrial (EB: proliferative)

2004: Tamoxifen : menorraghia.

D&C: Proliferative changes in endometrium. Progesterone ~ 4 .7 µg/L

follicular: 0.2 - 1.5 µg/L; ovulatory: 0.8 - 3.0 µg/Lluteal: 1.7 - 27.0 µg/L; postmenopausal: 0.1 - 0.8 µg/L

18 enrolled subjects

4 with BL elevated E2

14 subjects initiatedanastrozole

4 subjects without increased E2 at

wk 48

2 withdrawals:Subject preferenceNoncompliance

8 (57%) subjects withincreased E2

by wk 48

51 enrolled subjects

4 with BL elevated E22 withdrawals

45 subjects initiatedanastrozole

19 subjects without increased E2 at

wk 48

13 withdrawals:Toxicity (n=9)Subject/physician preference (n=2)Noncompliance (n=2)

13 (29%) subjects withincreased E2

by wk 48

EnrolledN=69 CIA

Part 1 Part 2

Michigan University : APPEL Trial Schema

Henry et al, Ann Oncol, in press

Characteristic All patients (N=45)

Ovarian function recovery (N=13)

No ovarian function recovery

(N=19)

Median age at chemotherapy, yrs (range) 48 (40-55) 43 (40-51) 49 (44-52)

Median age at AI therapy, yrs (range) 50 (40-56) 45 (40-56) 50 (46-55)

Mean BMI (SD) 27.6 (7.8) 29.2 (12.1) 26.7 (4.8)Prior chemotherapy regimen-No taxane-Taxane-based

9 (20%)36 (80%)

2 (15%)13 (85%)

3 (16%)16 (84%)

Median time since chemotherapy, yrs 1.4 (0.3-5.9) 0.6 (0.4-4.8) 2.0 (0.4-5.9)

Prior tamoxifen, no (%) 28 (62%) 7 (54%) 14 (74%)Mean baseline estradiol, pg/ml (SD) 8.4 (7.8) 9.5 (8.5) 8.4 (8.4)

Mean baseline FSH (SD)- prior tamoxifen- no prior tamoxifen

56.4 (31.1)43.3 (23.1)78.5 (29.4)

55.8 (28.4)51.7 (30.7)80.3 (14.8)

54.2 (28.2)44.9 (24.5)78.4 (24.1)

Mean baseline AMH <0.17 <0.17 <0.17Mean baseline Inhibin B 10.1 (0.4) 10.3 (0.8) <10Time to primary endpoint, months 2.1 (0.6-11.9) NA

Patient Characteristics


APPEL Trial: Results

• 45 women who developed chemotherapy-induced ovarian failure defined by all means possible were enrolled and treated with anastrozole for 18 months– Recovered ovarian function: 28.9%

– Did not recover ovarian function: 42.2%

– Discontinued AI for other reason: 28.9%• Primarily due to toxicity

RecoveredOvarian Function

RemainedPostmenopausal

Age at Chemotherapy Initiation

Recovery of Ovarian Function During AI Therapy By Age


Multivariable Analysis of Predictors of Ovarian Function Recovery

Predictor Odds Ratio P value

Age at chemotherapy 0.48 (0.30-0.77) 0.0022

Time since chemotherapy 0.90 (0.35-2.28) 0.81

BMI 25-30 vs <25

>30 vs <25

1.91 (0.16-23.22)

1.50 (0.13-17.87)

0.61

0.75

Menses at chemotherapy (irregular vs regular)

0.21 (0.01-5.60) 0.35

Prior Tamoxifen (yes vs no) 0.29 (0.02-5.62) 0.41

Baseline estradiol 0.91 (0.74-1.11) 0.34


How frequent? Chemotherapy-induced amenorrhea






How best to measurement definitive menopause?


Tamoxifen

Oral aromatase inhibitors

Extended anti-E therapy



]For >12 months and than…

Fertility: Proper Contraception! Contraceptive needs: Always up to what age?

Two pregnancies on AI: 37 yrs M* / 46 yrs Adj

Safety endometrium: Unopposed estrogen Cyclical progestins? LNG-IUD? OS?

Ov Insufficiency ~ amenorrhea in breast cancerWhat if no definitive menopause?

Who should not use LNG IUS?• Has an untreated pelvic infection now

• Has had a serious pelvic infection in the past 3 months after a pregnancy

• Can get infections easily

• Has or is suspected to have cancer of the uterus or cervix

• Has unexplained bleeding from the vagina

• Has liver disease or liver tumor

• Has or has had breast cancer

• Has a condition of the uterus that changes the shape of the uterine cavity, such as large fibroid tumors

A woman should not use LNG IUS if she:

Mirena prescribing information March 22, 2011

The system contains 52 mg of the hormone levonorgestrel and releases 20µg/24h in the “uterus” for up to five years of protection

Fertility: Proper Contraception! Safety endometrium: Unopposed estrogen

Cyclical progestins? LNG-IUD? OS?

Efficacy tamoxifen? Independent of menopausal status

Should we suppress ovaries?

Value of OS + Tam vs Tam (toxicity)

ZIPP, ABC: controversial outcome Value LHRH-meta-analysis

Ov Insufficiency ~ amenorrhea in breast cancerWhat if no definitive menopause?

Small subset :Tamoxifen ± LHRH (n=1013)

RECURRENCERECURRENCE DEATH AFTER RECURRENCEDEATH AFTER RECURRENCE

010

2030

4050

Dea

th a

fter r

ecur

renc

e (%

)

0 1 2 3 4 5 6 7 8 9 10Years since randomisation

HR=0.84, 95% CI = [0.59-1.19], P=0.33

TamoxifenLHRH + tamoxifen

010

2030

4050

Rec

urre

nce

(%)

0 1 2 3 4 5 6 7 8 9 10Years since randomisation

HR=0.85, 95% CI = [0.67-1.09], P=0.20

TamoxifenLHRH + tamoxifen

8.8% vs. 7.3%1.5% reduction

22.8% vs. 18.2%4.6% reduction

Do we need OS if Tam?Meta-Analysis ‘LHRH’-agonists

7,3 yrs of FU

J. Cuzick in Lancet 2007

SOFT TRIAL-Tamoxifen-OS + Tamoxifen-OS + Exemestane

QOL- endpointEfficacy endpoint

Many clinicians meanwhile continue to add OS …

QOL & LONG – TERM TOXICITY

CIA vs no-CIAPrognostic Importance After CT

Swain et al NEJM 2010

HR Recurrence Death

ER-positive 0.51 0.52

ER-negative 0.96 1.08

This clearly reflects importance of ovarian targetted effect of CTNo hit to ovary ~ No hit to subclinical breast cancer

Not necessary via hormonal effect This therefore doesn’t mean one can reduce relapse/death risk by + OS

5228 women with node-pos disease AC vs ACT vs ACTCIA = prognostic if ER-pos breast cancer

ASCO ENDORSEMENT OF CANCER CARE ONTARIO GUIDELINES REGARDING OS by GRIGGS et al. JCO 2011

Adjuvante hormonale therapie ER positive breast cancer:

The Leuven Guidelines45-52 yrs of age

TAMOXIFEN at least 5 yearsExtended: Tam or AI

LONGER IS BETTER!

Not <50 yrs

Extended adjuvant – MA.17 study

Peri-menopausal: 45 - 52 yrsIntermediate or high risk for relapse

[AI] or [Tamswitch] bij CT-amenorrhea– Amenorrhea 12 m ≠ Menopauze (Tam, AI)

• Contraception• Switch to AI

– FSH, Oestradiol, very variable» AI: high FSH, low E2 = temporarely

» Tam: “low” FSH, low E2 can be menopause*Hypogonadotrophe hypo-oestrogenic amenorrhea» Exemestane false positive E2 and ProgHigh FSH and E2 likely to be menopauseAromasin

FSH: 99.2 IU/L Estradiol 32 ng/L

TamoxifenFSH: 37.8 IU/L FSH: 8 IU/L*Estradiol 8 ng/L

Anastrozole/ LetrozoleFSH: 99.2 IU/L Estradiol <5 ng/L

SHOULD WE add OS to safely give AI?

Med FU 62 monthsJCO 2011

WORSE OS AI>TAMHR: 1.75 (1.08-2.83) TEXT TRIAL

Conclusion:Breast Cancer Therapy –

Induced Prolonged AmenorrheaImportant topic: Many premenopausals get CT

Ovarian Insufficiancy differs from menopause

Definition & Measurement impossible!

Many consequences

Avoid AI therapy if CIA < 52 yrs of age

Promote extended anti-E (Tam or AI ~age)

Important Prognostic Factor after CT

Also predictive for adding OS? Await SOFT

Premature ovarian failure in breast cancer How …BMS April 2013 Premature ovarian failure in breast...

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