the value of amh in assessing ovarian function and damage ... · amh reflects the number of small...
TRANSCRIPT
The value of AMH in assessing ovarian function and damage in
women with cancer
Richard A AndersonElsie Inglis Professor of Clinical Reproductive Science
University of Edinburgh
Chemotherapy: immediate and late effects on the ovary
• Depletion of growing folliclesHimelstein-Braw R, Peters H and Faber M (1978)
Morphological study of the ovaries of leukaemic children.
Br J Cancer 38, 82-87
• Premature ovarian failureChapman RM, Sutcliffe SB and Malpas JS (1979)
Cytotoxic-induced ovarian failure in women with Hodgkin's disease. I. Hormone function.
JAMA 242, 1877-1881
Effects of cancer therapy on the ovary
Cancer
Bloodvessels
PrimordialFollicles AMH
Estrogendeficiency
Infertility
Potentialfertility/subfertility
Treatment
GrowingFollicles
Post treatmentamenorrhoea
Recovery, of variable duration
Premature ovarianinsufficiency
AMH
AMH
Jayasinghe, Wallace and Anderson 2018 Expt Rev Endo Metab
Biomarkers: AMH, AFC, mensesClinical outcomes: fertility, age at menopause
Letourneau et al 2012 Cancer 118, 1710
Pregnancy: HR 0.87 (0.81-0.94)
Alkylators only at highest doseBusulfan and Lomustine
Live birth to female childhood cancer survivors: chemo only
Chow et al Lancet Oncol 2016
Hazard ratio for menopause <40 yrs in Hogdkin Lymphoma
0 5 10 15 20 25 30 35 40
No alkylating, no pelvic RT
Pelvic RT
Alkylating, no pelvic RT
Alkylating, pelvic RT
ABVD
ABVD with pelvic RT
Swerdlow AJ et al 2014, J Natl Cancer Inst
All adjusted for age, overall n=2127 (though data only from 50%)
Age-related changes in the ovarian reserve
Wallace and Kelsey 2010 PLoS One 5; e8772
Which stages of follicle growth are key targets of cancer therapies?
Loss of growing follicles may increase growth activation?
Focal cortical fibrosis in ovaries exposed to chemotherapy
Meirow D et al. Hum. Reprod. 2007;22:1626-1633
The ovarian stroma and vasculature are also targets
Normal controlGreen: Masson stain for collagenAfter chemotherapy
Prominent thickening and hyalinization, with narrowing
/obliteration of the lumen
Effects of cancer therapy on the ovary
Cancer
Bloodvessels
PrimordialFollicles AMH
Estrogendeficiency
Infertility
Potentialfertility/subfertility
Treatment
GrowingFollicles
Post treatmentamenorrhoea
Recovery, of variable duration
Premature ovarianinsufficiency
AMH
AMH
Jayasinghe, Wallace and Anderson 2018 Expt Rev Endo Metab
Biomarkers: AMH, AFC, mensesClinical outcomes: fertility, age at menopause
The variability in ovarian activity after cancer treatment
Ovari
an
Activity
CancerDiagnosis
Onset ofdisease
Age-relatedDecline
TreatmentTime
POIThreshold
Recovery Period
Key variables: age and treatment
Jayasinghe, Wallace and Anderson 2018 Expt Rev Endo Metab
AMH reflects the number of small growing follicles
Inhibin B, estradiol
AMH
Anderson RA 2012 Clin Endocrinol 77, 652
>60% from 3-8 mm antral follices
Jepperson, Anderson et al 2013 MHR 19, 519
Altered AMH to primordial relationship:IllnessAgeTreatment
AMH reveals ovarian damage in childhood cancer survivors despite regular cycles
Controls
Cancer survivors
Inhibin B
0
100
200pg/ml
FSH
0
4
8
12
IU/L
E2
0
100
200
pmol/L pmol/L
AMH
0
10
20
30
*
Bath LE et al 2003 Human Reprod 18 2368
AC 3CMF 3A-CMF 7E-CMF 18 FECT-T (TACT) 9TANGO 2
Post chemoTamoxifen 26 Goserelin + Tam 8Arom inhib 11None 4
6-9 months
Recruited n=56
No chemoGoserelin + Tam 8Tamoxifen 5Gos + anastrozole 1
Chemotherapy 42
Surgery
‘Late’ analysis35 at 4 years33 at 5 years (79%)(recurrence, TAH/BSO)
USS:27 pretreatment21 at 5 years
Effect of chemotherapy in eBC:acute toxicity and long-term prediction
Analyse ovarian activity here
In relation to predictive markers here
Anderson RA et al 2006 Human Reprod 21, 2583
Effect of chemotherapy in eBC:acute toxicity
0
10
20
30
40
50
0 3 6 9 12
FSH and LHIU/L
Months Months
0
200
400
600
800
0 3 6 9 12
Estradiolpmol/L
0
20
40
60
80
0 3 6 9 12
Inhibin Bng/ml
0.0
0.4
0.8
1.2
0 3 6 9 12
AMH
ng/ml
n=42
Anderson RA et al 2006 Human Reprod 21, 2583
Effect of chemotherapy in eBC:long-term prediction
*
Inhibin B
0
20
40
60
80
100
CRA Menses
AMH
0.0
1.0
2.0
3.0
4.0
CRA Menses
E2
0
100
200
300
CRA Menses
Anderson and Cameron 2011 JCE&M 96, 1336
AMH at diagnosis of early breast cancer is higher in those women who will still be having menses 5 years later
0
10
20
30
40
50
60
70
80
90
100
0 20 40 60 80 100
AMH
Age
Prediction of amen
AMH AUC 0.91 (0.870-1.01)
Pretreatment hormones vs late ovarian function
Clinical application:predictive mosaic chart in eBC
Anderson et al 2013 Eur J Cancer
sensitivity 98.2% specificity 80.0%for correct classification of amenorrhoea
n=75
Pretreatment AMH is reduced in girls with childhood cancer
van Dorp W et al. Hum. Reprod. 2014;29:337-342
n=208Temperature and CRP inversely correlated with AMHHb positively correlated
AMH profiles after chemotherapy
Are AMH levels here discriminatory?
Is AMH a good diagnostic here?
Leonard et al 2017 Ann Oncol
227 women with breast cancer, randomised to ± goserelin during chemotherapy
AMH as a diagnostic test in POI?
Contr
ol
WHO 1
WHO 2
(PCOS)
WHO
2 (a
ll)
WHO 3
HPR
L
0
25
50
75
100175
200 ** **
*
DIAGNOSIS
Se
rum
AM
H (p
mo
l/l)
Li et al 2011 Fertil Steril 96, 774
• Not part of the diagnosis at present
• Will increased assay sensitivity help?
• Useful in ‘fluctuant’ stage of condition when E2 and FSH very variable?
• But value post chemo excluded in STRAW+10
0
50
100
150
200
E2 p
mol/l
Baseline EoT 12 mo 24 mo
0
20
40
60
80
100
FS
H (
IU/L
)
Baseline EoT 12 mo 24 mo
0
1
2
3
4
6
8
10
AM
H (
pm
ol/l
)
Baseline EoT 12 mo 24 mo
Serum FSH and AMH by POI at 24 months. Data from all women from OPTION
Roche automated AMH assay
Red, not POI
Blue: POI (amenorrhoea plus FSH >25IL/L).
N=96 and 28 respectively; median ± 95% confidence intervals.
Can AMH diagnose POI after chemo?
ROC AUC of 0.86
sensitivity 100%
specificity 73%, LR 3.7
So YES at 24 months
Anderson et al 2017 Eur J Cancer
Importance of age for recovery of ovarian function after chemotherapy
0
1
2
3
4
5
AM
H (
pm
ol/l
)
EoT 12 mo 24 mo
0
20
40
60
80
FS
H (
IU/L
)
EoT 12 mo 24 mo0
50
100
150
200
250
Estr
adio
l (pm
ol/l
)
EoT 12 mo 24 mo
Women aged ≤ 40 (purple) vs >40 years (orange)
n=62 and 81, median ± 95% CI.
Anderson RA et al 2017 Eur J Cancer
Data from
OPTION trial
EOT predictive analysis in women >40 yrs
0 25 50 75 1000
25
50
75
100
100% - Specificity%
Sensiti
vity%
0 25 50 75 1000
25
50
75
100
AMH and FSH at end of treatment for
prediction of POI at 24 months
OPTION control group, n=32 months
undetectable detectableAMH at
EOT
E2
@12
mo
AM
H-v
e
E2
@24
mo AM
H-v
e
E2
@12
AM
H+
E2
@24
AM
H+
0
500
1000
1500
100
Estr
adio
l pm
ol/l
12 12 2424
AMH AUC 0.89
sensitivity 91%, specificity 82%
FSH AUC 0.77
sensitivity 100%, specificity 55%
Anderson RA et al 2017 Eur J Cancer
AMH and ovarian function after chemotherapy
AMH for• Pre chemo prediction• Post chemo diagnosis of POI• Immediate post chemo prediction?
The AMH normal rangefrom birth to menopause
Kelsey et al 2011 PLoS One 6: e22024
0 10 403020 50
AMHng/ml
Key featuresDetectable in girls of all agesRise through childhoodPeak at 24 yrs
Pre
Cyc
le 1
Cyc
le 2
Cyc
le 3
Cyc
le 4
Cyc
le 5
Cyc
le 6
0.0
0.5
1.0
1.5
2.0
2.5
****
*** ***
AM
H (n
g/m
l)
AMH: application in childhood cancer
Pre End Recovery0
1
2
3
* **
AM
H (n
g/m
l)
High risk
Pre End Recovery0
1
2
3**
AM
H (n
g/m
l)
Medium/low risk
22 girls age 0.3-15yr17 prepubertal
Brougham et al 2012 JCE&M 97, 2059
AMH in 3 girls with cancer
0 50 100 1500.0
0.5
1.0
1.5
2.0
Weeks
Age 14.6: Hodgkin’s lymphoma
Brougham et al 2012 JCE&M 97, 2059
0 25 50 750.0
0.2
0.4
0.6
0.8
1.0
Weeks
AM
H (n
g/m
l)
Age 1.2; neuroblastoma
Pre End Recovery0
1
2
3
* **
AM
H (n
g/m
l)
0 50 100 150 2000.0
1.0
2.0
3.0
Age 2.4; rhabdomyosarcoma
Pre End Recovery0
1
2
3**
AM
H (n
g/m
l)
How predictive is this?
Sowers MR et al. J Clin Endocrinol Metab 2008;93:3478-3483
Does AMH predict natural menopause?
50 women followed prospectively(Michigan Bone Health and Metabolism Study)6 annual assessments
Mean initial age 42 yr
AMH related to both time to and age at FMP
Inhibin B less predictive of both
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0 1 2 3 4 5 6
Cum
ula
tive
pro
po
rtio
n o
f w
om
en
ach
ievin
g p
regn
an
cy
Time from cessation of birth control (cycles)
0
10
20
30
40
50
60
70
19 21 23 25 27 29 31 33 35
AM
H (
pm
ol/L
)
Age (years)
AMH and fecundability
Hagen et al 2012 Fertil Steril
AMH quintiles, middle 3 combined
981 women aged 30 to 44, trying to conceived max 3 months at study entry
Steiner AZ et al, 2017, JAMA
Adjusted for age, smoking, contraception, BMI, race, prev pregnancy
AMH and fertility in older women
What about low toxicity regimens?RATHL trial in Hodgkin Lymphoma
2 cycles ABVD
Full dose, on schedule
PET 2 -vePET 2 +ve
4 cycles ABVD
PET2
PET 1(Staging)Stage II (adverse),III,IV,IPS 0-7
Over 18PS 0-3
Randomise
4 cycles AVD
Follow-up (no RT)
4 cycles BEACOPP-14
or 3 eBEACOPP
PET3
PET 3 -vePET 3 +ve
RT or salvageregimen
2 cycles BEACOPP-14 or 1 eBEACOPP
No RT
Ovarian substudy method
Women aged 18-45 were recruited(ethics approval/consent)
Blood samples:• Pre-treatment• After 2 cycles ABVD• End of chemo• 1, 2, 3 years later
• Analysed for AMH, FSH (Roche)
Johnson P et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma.N Engl J Med. 2016; 374: 2419-29
Pre
treat
men
t
2 cy
cles
End
of t
reat
men
t1
yr2
yr3
yr0.01
0.1
1
10
100
AM
H (
pm
ol/L
) Blue: ABVDRed: BEACOPP(after 2 cycles of ABVD)
Effects of A(B)VD and BEACOPP on ovarian function
Anderson RA et al 2018 Lancet Oncol
Hazard ratio for menopause <40 yrsin treatment of HL
0 5 10 15 20 25 30 35 40
No alkylating, no pelvic RT
Pelvic RT
Alkylating, no pelvic RT
Alkylating, pelvic RT
ABVD
ABVD with pelvic RT
Swerdlow AJ et al 2014, J Natl Cancer InstAll adjusted for age, overall n=2127 (though data only from 50%)
Main relationships: AMH, age, recovery
0
20
40
60
80
100
15 20 25 30 35 40 45 50
AM
H p
retr
ea
tme
nt
Age (years)
AMH pretreatment vs age
0
20
40
60
80
100
0 20 40 60 80
AM
H a
t 2
ye
ars
AMH pretreatment
AMH pretreatment vs 2 yr levels
Spearman r=0.71, p=0.0002slope =1.05Overall, AMH at recovery reflects pretreatment level
Anderson RA et al 2018 Lancet Oncol
Is AMH recovery always good?
0
100
200
300
400
500
15 20 25 30 35 40 45 50
AM
H r
eco
ve
ry (
%)
Age (years)
AMH recovery by age
r=-0.48, p=0.001
Older women show reduced recovery
0
100
200
300
400
500
0 20 40 60 80
AM
H r
eco
ve
ry (
%)
AMH pretreatment
AMH recovery by pretreatment AMH
r=-0.02, p=0.9
Women with low AMH show full recovery
Anderson RA et al 2018 Lancet Oncol
Confirmation of impact of age on recovery
0
20
40
60
80
100
120
140
160
Age <35 Age 35+
% r
eco
very
P<0.0001
By age
Multiple linear regression analysis vs AMH recovery:age (beta -0.43, p=0.004) pretreatment AMH (beta -0.15, p=0.3)
0
20
40
60
80
100
120
140
1 2Above Below
By median AMH (9.8 pmol/l)
ns
Anderson RA et al 2018 Lancet Oncol
Different to breast cancer data: older population, more toxic treatment
FSH recovery after A(B)VD is also dependent on age
Anderson RA et al 2018 Lancet Oncol
recovery to <25IU/L
Pre
trea
tmen
t
EOT
1 ye
ar
2 ye
ars
0
25
50
75
FS
H (
IU/L
)
FSH: effect of age with ABVD treatment
ABVD <35
ABVD 35+
*
*
* *
Age <35Age 35+
% recovered Age <35 35+
At 1 year 83% (77 – 88) 54% (43 – 66)
At 2 years 96% (93 – 98) 83% (73 – 91)
At 3 years 98% (95-99) 93% (85-97)
Mean±sem
Conclusions
Need for accurate, patient-specific risk to fertility and ovarian function
Extrinsic issues: proposed treatmentIntrinsic issues: age and ovarian reserve
Rational and effective use of FP techniquesTruly informed consent for interventions
AMH is a valuable index of ovarian function in oncology patientsPretreatment assessmentPost treatment: immediate, and long term
Key collaborators and funding
Hamish Wallace, and colleagues, Paediatric oncology, Edinburgh
David Cameron and colleagues, Edinburgh Breast Unit
Bob Leonard and OPTION investigators
Peter Johnson and RATHL investigators
Tom Kelsey, Mathematician, St Andrews University
Beckman Coulter and Roche Diagnostics for assay reagents