controversies in adjuvant endocrine therapy aromatase inhibitors james f bishop md professor of...

CONTROVERSIES IN ADJUVANT ENDOCRINE THERAPY

AROMATASE INHIBITORS

JAMES F BISHOP MDPROFESSOR OF CANCER MEDICINE, UNIVERSITY

OF SYDNEYDIRECTOR, SYDNEY CANCER CENTRE

ROYAL PRINCE ALFRED HOSPITAL, SYDNEY

3RD GENERATION AROMATASE INHIBITORS

• Aromatase convert androgens to low level estrogen in PM women

• AI suppress estrogen levels to 1-10% pre-treatment levels with Letrozole > Anastrozole*

• Inadequate data in pre-menstrual women with hormone combination with LHRH analogue

* J Clin Oncol 20:751, 2002

AROMATASE INHIBITORS IN MBC

• All AI superior or equivalent to megestrol acetate as second line for efficacy and toxicity

• Anastrozole and Letrozole superior or equivalent to TAM for efficacy (TTP) and toxicity (fewer TE events)

• Exemestane vs TAM ongoing phase III trial

LESSONS FROM THE OVERVIEW

IMPACT OF TAMOXIFEN (5 YEARS) VS NONE

Recurrence Death

< 50 45 + 8% 32 + 10%

50 – 59 37 + 6% 11 + 8%

60 – 69 54 + 5% 33 + 6%

Age (Years)

Reduction In Annual Odds

Lancet 351:1451, 1998

NSABP B-24: TAMOXIFEN RISK REDUCTION

RiskNo of

Patients RR*95%

CI P

DCIS 1804 All breast ca 0.63 (0.47 – 0.83) 0.0009

Non-invasive 0.69 (0.46 – 1.04) 0.08

Invasive 0.57 (0.38 – 0.85) 0.004

* At 74 mos median follow up

Fisher et al Lancet 353:1993, 1999

LESSONS FROM THE OVERVIEW

OVARIAN ABLATION < 50 YEARS

Recurrence Mortality 15 Year Survival

Ovarian ablationvs none

18.5 (+ 5.5)% 18.4 (+ 5.7) % 6.3 (+ 2.3)%

Reduction In Annual Odds

Lancet 348:1189, 1998

Effect less in the presence of chemotherapy

* Surgery + radiotherapy + chemotherapy(Patients may start trial therapy while still receiving radiotherapy)

+

Postmenopausal women with invasive breast cancerPostmenopausal women with invasive breast cancer

Completion of primary therapy*Completion of primary therapy*

Randomization 1:1:1 for 5 yearsRandomization 1:1:1 for 5 years

Anastrozole 1mg od+

Tamoxifen placebo

Anastrozole placebo+

Tamoxifen 20mg od

Anastrozole 1mg od+

Tamoxifen 20mg od

Regular follow-up monitoring adverse eventsRegular follow-up monitoring adverse events

Trial endpointsTrial endpoints

ATAC TRIAL DESIGN

ATAC TRIAL – STUDY ENDPOINTS

Primary Endpoints• Disease-free survival

Loco regional or distant recurrence, new primary breast cancer, or death from any cause

• Safety/Tolerability

Secondary Endpoints• Incidence of new breast (contralateral) primaries • Time to distant recurrence• Survival (data will be mature in ~ 2 years)

• Hormone receptor-positive population (protocol-defined sub-group)

PATIENT CHARACTERISTICS

Mean age (years) 64.1 64.1 64.3

Mean weight (kg) 70.8 71.1 71.3

Receptor status (%)

Positive 83.7 83.3 84.0

Negative 7.4 8.0 6.9

Other 8.9 8.7 9.1

Primary treatment (%)

Mastectomy 47.8 47.3 48.1

Axillary surgery 95.5 95.7 95.2

Radiotherapy 63.3 62.5 62.0

Chemotherapy 22.3 20.8 20.8

Prior tamoxifen 1.6 1.7 1.7

Tamoxifen(n=3116)

Anastrozole(n=3125)

Combination(n=3125)

KAPLAN–MEIER CURVES OF DISEASE-FREE SURVIVAL IN ITT POPULATION

Curves truncated at 42 months

HR 95.2% CI p-value

AN vs TAM 0.83 0.71–0.96 0.0129Comb vs TAM 1.02 0.88–1.18 0.7718

Anastrozole

Tamoxifen

Combination

Time to event (months)

Pro

po

rtio

n e

ven

t fr

ee (

%)


Pro

po

rtio

n e

ven

t fr

ee (

%)

0

80

85

90

95

100

0 6 12 18 24 30 36 42

KAPLAN–MEIER CURVES OF DISEASE-FREE SURVIVAL IN RECEPTOR-POSITIVE POPULATION

Curves truncated at 42 months

HR 95.2% CI p-value



Pro

po

rtio

n e

ven

t fr

ee (

%)

Anastrozole

Tamoxifen

Combination

0

80

85

90

95

100

0 6 12 18 24 30 36 42

ANALYSIS OF THE INCIDENCE OF NEW (CONTRALATERAL) BREAST PRIMARIES

Time to first contralateral new primary (months) 0 6 12 18 24 30 36 42

0

98

99

100

Pro

po

rtio

n w

ith

ou

t C

L B

Ca

(%)

Anastrozole

Tamoxifen

Combination

OR 95% CI p-value


SIGNIFICANT DIFFERENCE IN PRE-DEFINED ADVERSE EVENTS

-10 -5 0 5 10

Difference between anastrozole and tamoxifen AEs (%)

(-5.4%)

(-1.8%)

(-3.6%)

(-8.6%)

(-1.1%)

(-1.4%)

(-0.7%)

Fractures of hip,spine, wrist

Fractures

MSK disorders

(-0.4%)

In favour of In favour of anastrozoleanastrozole

Hot flushes

Weight gain*

Vag. bleeding

(6.6%)

(2.1%)

(0.8%)

Endo Ca

ICVA

VTE

DVT

Vag. discharge

In favour of In favour of tamoxifentamoxifen

* proportion with 10% gain in body weight from baseline to year 2

ASCO TECHNOLOGICAL REPORT 2002

AIM:

• To define whether adjuvant AI should have broad based use in conventional practice

METHODOLOGY:

• Panel of experts

• Computerised searches of Medline/ASCO Jan 2002

• 3 companies invited to provide unpublished data


EVIDENCE:

• Long term adverse effects of TAM but not AI are known. Some concern about adverse bone effects

• Absolute differences in DFS are small, currently 2.02%• 5 years of TAM need to see full benefit but reported at

33 mos FU• No reported differences in survival• Optimal duration of AI not addressed in this trial• Possible optimal sequence of TAM and AI not

addressed• ATAC trial data not yet peer reviewed

IMPLICATIONS OF THE ATAC TRIAL


PANEL CONSENSUS:

• ATAC trial is preliminary

• 5 years of TAM remains standard of care

• Need for longer FU and other trial results

IMPLICATIONS OF THE ATAC TRIAL


EVIDENCE:

• Confined discussion to third generation anastrozole, Letrozole and Exemestane which may be equivalent in MBC

• Quoted RCT in 713 MBC Anastrozole vs Letrozole showing equivalence in TTP, response duration *

• Ongoing trials which will compare AI

PANEL CONSENSUS:

• Only adjuvant data is with Anastrozole• If AI to be used in an adjuvant setting should be Anastrozole

* Rose et al ASCO 2002

ARE ALL AROMATASE INHIBITORS EQUIVALENT?


EVIDENCE:

• Study of TAM vs TAM -> aminoglutethimide * with superiority for sequential arm

PANEL CONSENSUS:

• No data supporting substitution of TAM for AI• Intolerable SE from TAM, AI could be considered but

unproven

* Boccardo et al J Clin Oncol 19:4201, 2001.

WOMEN ALREADY ON ADJUVANT TAM


EVIDENCE:

• No data

PANEL CONSENSUS:

• After TAM for 5 years should not receive AI unless in a trial

SHOULD AI BE GIVEN AFTER 5 YEARS OF TAM


EVIDENCE:

• No trials• ATAC trial current report with FU 33 mos

PANEL CONSENSUS:

• Patients receiving adjuvant AI should receive 2-3 years

• Review as more data is available

DURATION OF ADJUVANT AI


EVIDENCE:

• AI no established role in pre-menopausal women• MBC trials with LHRH + AI show activity

PANEL CONSENSUS:

• AI alone is contra-indicated in pre-menopausal women

• Adjuvant Zoladex or oophorectomy plus AI not been reported

AROMATASE INHIBITORS IN PRE-MENOPAUSAL


EVIDENCE:

• Resumption of ovarian function frequently occurs especially in younger women

• Such resumption would render AI ineffective

PANEL CONSENSUS:

• Cautioned against use of AI in this setting because of the substantial probability of resumption of ovarian function

AROMATASE INHIBITORS AFTER CT INDUCED AMENORRHEA


EVIDENCE:

• Reduction in contralateral cancers in Anastrozole arm of ATAC

• No data on DCIS

PANEL CONSENSUS:

• Women with DCIS should not receive AI outside a clinical trial

AROMATASE INHIBITORS IN DCIS


EVIDENCE:

• TAM remains the only agent tested and approved by the FDA

• Reduction in contralateral breast cancer in Anastrozole arm of ATAC is insufficient evidence

PANEL CONSENSUS:

• Women with increased risk of breast cancer should not receive AI to reduce risk outside a clinical trial

AROMATASE INHIBITORS IN CHEMO-PREVENTION

EVIDENCE:

• Overwhelming evidence that adjuvant hormone therapy is effective only in ER positive patients

• No contradictory data with AI

PANEL CONSENSUS:

• Women with ER negative cancers should not receive AI as adjuvant therapy

AROMATASE INHIBITORS IN ER NEGATIVE CANCERS


EVIDENCE:

• Conflicting studies some suggest TAM is less beneficial in HER-2 positive cancers

• Many studies have methodological flaws

• NIH consensus conference recommended all ER positive patients receive TAM regardless of HER-2 status

AROMATASE INHIBITORS IN HER-2 POSITIVE CANCERS


R

OPR ErbB-1 +/or BreastErb-2 Positive Sparing

SurgeryTAM4mos 41% 21% 21%

Letrozole4mos 60% 86% 41%

AROMATASE INHIBITORS IN HER-2 POSITIVE CANCERS


ER +/ORPR

Positive

Ellis et al: J Clin Oncol 19:3808, 2001.

IRESSA RESTORES TAM SENSITIVITY IN HER-2 OVEREXPRESSING

TUMOURS

• MCF-7/HER2 overexpressing cells

• Given estrogen, TAM estrogren deprivation + Iressa

• Iressa restored TAM sensitivity

Massarweh: ASCO #130:2002.

PANEL CONSENSUS:

• Recommendation against use of HER-2 studies to make decisions about adjuvant hormone therapy

• Clinical data to support use of HER-2 status are inadequate

AROMATASE INHIBITORS IN HER-2 POSITIVE CASES



EVIDENCE:

• TAM is associated with increased risk of thrombo-embolic and cerebrovascular disease

PANEL CONSENSUS:

• Reasonable to use adjuvant AI with a relative or absolute contraindication to TAM

• Recommend careful consideration of the significance of the contraindication given the proven benefits with TAM

AROMATASE INHIBITORS WHEN TAM IS CONTRAINDICATED


EVIDENCE:

• In MBC AI are effective following progression on TAM• Role of AI following Raloxifen unknown• Evidence of cross resistance between Raloxifen and

TAM suggesting TAM may be ineffective after Raloxifen

PANEL CONSENSUS:

• Reasonable to use adjuvant AI although data are poor

AROMATASE INHIBITORS FOR INVASIVE BREAST CANCER WHILE ON TAM OR RALOXIFEN

ADJUVANT ANASTROZOLE TRIALS

Group Special Eligibility

Study Target Status

ATAC ER/PRUnknown

TAMAITAM + AI

9336 Completed

Austrian ABCSG Post-TAM (5y)

AI Control 1700 800

Austrian AU08 Post-TAM (2 y)

TAMAI

2500 2600

Austrian AU 12 Pre-M TAM + ZoladexAI + Zoladex

1250 600

German GR001 Post-TAM (2y)

TAMAI

1000 N/A

ItalianIT 02 Post-TAM (2y)

TAMAI

525 N/A

Total targets 16,311

ADJUVANT LETROZOLE TRIALS


Study Target Status

NCICMA-17

Post-TAM (5y)

AIPlacebo

4800 4100

IBCSG-1-18BIG-FEMTA

Post CT TAM (5y)AI (5y)TAM (2y) -> AIAI (2y) -> TAM

7900 5004

Total Target 12,700

ADJUVANT EXEMESTANE TRIALS


Study Target

NSABP B-33 Post-TAM (5y)

AIPlacebo

3000

BIG-9702 Post-TAM (2y)

TAMAI

4400

CRC-TU-TEAM

Prior CT TAMAI

4400

Total Target 11,800

Total target accrual for all adjuvant AI trials 40,811 women

1. ATAC Trial – not yet

2. Are all AI the same – Anastrozole now

3. If now on TAM – no

4. After 5 years of TAM – no

5. Duration of AI – don’t know

6. In pre-menopausal – no

7. After CT amenorrhoea – watch out!

SUMMARY OF ROLE OF ADJUVANT AI


8. DCIS – no

9. Chemo-prevention – no

10. ER/PR negative cancers – definitely no!

11. HER-2 positive cancers – no, but who knows

12. Women where TAM contraindicated – maybe

13. New invasive cancers after chemo-prevention - OK

SUMMARY OF ROLE OF ADJUVANT AI


controversies in adjuvant endocrine therapy aromatase inhibitors james f bishop md professor of...

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