adjuvant endocrine therapy for postmenopausal breast cancer

Adjuvant Endocrine Therapy For Hormone Positive Breast Cancer

Postmenopausal WomenEmad Shash MBBCh., MSc., MD.

Medical Oncology Department

National Cancer Institute, Cairo University

Female Menstrual & Reproductive Period Definitions

Menarche Menopause

Premenopausal Period Postmenopausal PeriodPerimenopausal Period

Menopause is diagnosed after 12 months of

amenorrhea 1, 2

NCCN Definition (Aimed to standardize definition across Clinical trials initially) 3: • Prior bilateral oophorectomy.• 60 or older.• If Age < 60 years, the female should be:

• Amenorrhea for 12 or more months in the absence of: • chemotherapy• tamoxifen, toremifene, or ovarian suppression

• If receiving cancer directed therapy: follicle-stimulating hormone (FSH) and plasma estradiol in the postmenopausal range.

• It is not possible to assign menopausal status to women who are receiving LHRH agonist or antagonist.

• In women premenopausal at the time of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status.

1 Butler L, Santoro N. Steroids 20112 Santoro N, Randolph JF Jr. Obstet Gynecol Clin North Am 2011

3 NCCN Guidelines version 1.2017 [accessed April 2017]

A female Life Time Story

Breast Cancer Snapshot

SEER 18 2009-2013, All Races, Females

Median Age at Diagnosis

62 years old

Age at Diagnosis by Menopausal Status

Premenopausal

Perimenopausal

Postmenopausal

More than 90% of patients are either postmenopausal or will

get menopausal

seer.cancer.gov [accessed April 2017]

Breast Cancer & Hormonal Status

• Around 60-70% patients diagnosed to have breast cancer are Estrogen receptor-positive

(65% of these are also positive for Progesterone receptors)

• Patients with (ER+) tumours have a better survival than (ER-) tumours

• Patients with ER + tumours are candidates for hormonal therapy

1896 19751896 1904 1912 1920 1928 1936 1944 1952 1960 1970

First Use of Hormonal Therapy in Cancer Treatment

Tamoxifen (ICI-46474) First Development

1st Clinical Study of Tamoxifen in Advanced Breast Cancer

Tamoxifien Dose Optimization

1st Work done on AI in Breast Cancer

Surgical Oopherectomy for Advanced Breast Cancer

1896 – Dr George Beaston• Significant tumor regression• Sense of well being• Reduction in cutaneous metastases• No effect on osseous metastases• Best above age of 40 years

1941 – Dr Charles Higgins

1966 – Dr Arthur L Walpole/Dr Dora Richardson

Developed Tamoxifen (ICI-46474) as a Contraceptive “Morning After Pill”Never proved useful in human contraception

History & Evolution

Endocrine Therapies Development for Breast Cancer

Lim E, et al. Oncology (Williston Park) 2012. Croxtall JD, et al. Drugs. 2011.

Rationale for Endocrine Therapy

• Estrogen: • Steroid hormone

• Profound proliferative effect on normal human mammary epithelium through its activation of ER-alpha, a classic nuclear hormone receptor

• Estrogen promotes the growth of breast cancer by binding to and activating the Estrogen Receptor (ER)

3 possible ways to interrupt this process

Reduce estrogen production

Down regulate receptor

Interfere with

receptor binding

Tamoxifen & SERMs

Fulvestrant

Premenopausal (LHRH)Postmenopausal (AI)

But we need to understand how to use them wisely!!

Case Presentation: Postmenopausal Patient

• 62 year old female with suspicious micro calcifications on screening mammography

• Biopsy: • IDC grade 2, hormone +with high grade DCIS. • Patient underwent lumpectomy with SLN

• Final pathology: • 1.2 cm grade 2 IDC with high grade DCIS. • SLN 0/1 T1cN0 Stage IA

• Oncotype Dx Recurrence Score – low risk

Considerations in Postmenopausal Patients(What will be discussed today?)

• Peripheral conversion of androgen to estrogen by aromatase - main source of estrogen and primary target of therapy

• Questions:• Should she receive an AI or Tamoxifen?

• Should she receive monotherapy (AI or Tamoxifen alone) or sequential therapy using both?

• 5 vs 10 years of therapy?

• If More than 5 years of endocrine therapy, which class to be used?

Tamoxifen for 1, 2 or 5 years!What the Historical Data tells us? “Recurrence”

Early Breast Cancer Trialists' Collaborative Group. Lancet 2011

∆ 8 % ∆ 8.8 % ∆ 14.2 %

Tamoxifen for 1, 2 or 5 years!What the Historical Data tells us? “Mortality”


∆ 5.8 % ∆ 6.1 % ∆ 7.2 %

Tamoxifen “5years” Long Term Effect: Perimenopausal & Postmenopausal


Can we do better than TAM For 5 years?

Quantity of life

Quality of life

0 2 3 5 10

RTAM

AI

UpfrontATACBIG 1-98ABCSG 12TEAM

Questions addressed in Randomized Clinical Trials (Can we do better than TAM X 5 years)?

A Breast Cancer female Life Time Story

# 1st Question

ATAC Trial (AI Superiority over Tamoxifen in postmenopausal females)

Ran

do

miz

e Tamoxifen 20 mg X 5 Years (N: 3116)

Anastrazole 1 mg X 5 Years (N: 3125)

Tamoxifen + Anastrazole X 5 Years (N: 3125)

Postmenopausal women with

histologically proven operable invasive breast cancer who

had completed primary surgery and

chemotherapy (where given), and were candidates to receive hormonal adjuvant therapy*

(N = 9366)

Baum M, et al. Lancet 2002Cuzick et al. Lancet Oncol 2010

* At the time the ATAC trial was started, patients with negative or unknown hormone-receptor status were included because hormone-receptor-negative patients were thought to derive benefit from adjuvant therapy with a hormonal agent.

time to recurrence in hormone-receptor-positive patientsFirst reported results

time to recurrence in hormone-receptor-positive patientsUpdated 10 years results

BIG 1-98 Study Design

Thurlimann B et al. N Eng J Med 2005

0 2 3 51 4

Tamoxifen Letrazole

TamoxifenLetrazole

Letrazole

Tamoxifen

4 arm option (1999-2003)

A

B

C

D

Letrazole

Tamoxifen

2 arm option (1998-2000)

A

B

N= 911

N= 917

N= 1548

N= 1546

N= 1548

N= 1546

• 1ry endpoint: disease-free survival (DFS) • 2ry endpoints: overall survival (OS),

invasive breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI)

Randomized, phase III, double-blind trial that recruited 8010 postmenopausal Hormone positive women early breast cancer.

AI Superiority Confirmed with BIG 1-98 (Long Term Benefit)

Thurlimann B et al. N Eng J Med 2005 Thurlimann B et al. SABCS 2016

Confirmed Benefit at 10 years updated analysis!

5 Years AI Vs. TamoxifenMeta-analysis Conclude & Consolidate Evidence


0 2 3 5 10

RTAM

AI

TAM RTAM

AITAM


SequentialBIG 1-98IESITANSAS BC-03ARNO 95ABCSG 8



# 1st Question

# 2nd Question

Switching to AI (Anastrazole) after 2-3 years of TAM better than 5 years Tamoxifen

Jonat W et al. Lancet Oncol 2006

These findings gives a clear message to clinicians “consider switching postmenopausal women who have taken adjuvant tamoxifen for 2–3 years

to anastrozole”

BIG 1-98: Sequential Strategy is not bad VS Letrazole Monotherapy!

There were no statistically significant differences in OS, DRFI, or BCFI for either sequence compared with letrozole monotherapy

Regan MM et al. Lancet Oncol 2011

Switching strategy: starting with Tamoxifen is equal to an upfront AI

No significant difference in DFS between the arms

Tamoxifen Exemestane

TEAM trial

Tamoxifen Exemestane Adjuvant Multinational Trial

Van de Velde et al. Lancet 2011

9775 postmenopausal hormone positive patients randomized to Aromasin vssequential TAM/Aromasin

Exemestane

0 2 3 51 4

0 2 3 5 10

RAI

AI

RTAM

AI

TAM RTAM

AITAM



AI CompMA27FACE



# 1st Question

# 2nd Question

# 3rd Question

Which AI should be used upfront?With All the Respect to both Trade Name Companies & Lovers

NCIC CTG MA.27 Phase III Trial

Post-menopausal women HR +VE

Underwent adequate Surgery.

Adjuvant chemotherapy and radiation are allowable.

– Chemotherapy must be completed before randomization.

(N = 7,576 women median age, 64.1 years)

Follow-up

Follow-up

Exemestane 25 mgX 5 years

Anastrazole 1 mgX 5 years

1. Lymph node status at diagnosis (negative, positive or unknown)2. Prior adjuvant chemotherapy (yes, no)

3. Current low dose prophylactic aspirin use, < 81 mg/day (yes, no)

R ± celecoxib 200 mgX 3 years

Goss PE et al. JCO 2013

• 1ry Endpoint: event free survival (EFS)• 2ry Endpoints: overall survival, time to distant recurrence, incidence

of contralateral breast cancer, long-term clinical and laboratory safety

• Exemestane & Anastrazole have equivalent efficacy.

• Different Side effect profile.

FACE Phase IIIb Trial

Postmenopausal women with HR + ve & node-positive eBC (stage IIA to IIIC invasive cancer) who were within 12 weeks after breast surgery or completion of adjuvant chemotherapy.

Patients who received neoadjuvant chemotherapy or adjuvant treatment with trastuzumab were also eligible

(N = 4,136 women)

Letrazole 2.5 mgX 5 years

Anastrazole 1 mgX 5 years

1. Number of lymph nodes (one to three or four or more2. Human epidermal growth factor receptor 2 (HER2)

R

Smith I et al. JCO 2017

• 1ry Endpoint: disease free survival (DFS)• 2ry Endpoints: overall survival, time to development of distant

metastases, distant disease-free survival and safety

• Letrozole did not provide statistically superior efficacy over anastrozole for both the 1ry & 2ry

endpoints • Different Side effect profile.

Which AI should be used? What we have learned?

• The benefits of AI therapy appears to be a “class effect”

• The different AIs appear to have equivalent efficacy (MA-27 & FACE)

• How to choose: Safety profile & Patients preference??

0 2 3 5 10

RAI

AI

RTAM

AI

TAM RTAM

AITAM



AI CompMA27FACE



# 1st Question

# 2nd Question

# 3rd Question

# 4th Question Do we have a benefit from Extended Hormonal Therapy?

Are we happy with the 5 years of adjuvant endocrine therapy?If not:

• why???

• How shall we proceed?

• For how long?

Optimal duration of therapy in Postmenopausal Patients

Predictors of recurrence during years 5-14 in 46,138 women with ER+ breast cancer allocated 5 years only of endocrine therapy (ET)

Pan et al. ASCO 2016

Other Predictors?

• High Ki 67• Higher Tumor Grade• Non Luminal A subtypes• Age???• Risk Recurrence Scoring

(need to be further validated)

Are we happy with the 5 years of adjuvant endocrine therapy?If not:

• why???

• How shall we proceed?

• For how long?

Optimal duration of therapy in Postmenopausal Patients

Proposed Strategies

0 2 3 5 10

Tamoxifen AI

Aromatase Inhibitor (AI)

Tamoxifen


Tamoxifen



ATLASaTTom

MA 17

MA 17RIDEALDATA

NSAPB B-42

ATLAS Trial Adjuvant Tamoxifen Longer Against Shorter

Davies C et al. Lancet 2013

Ran

do

miz

e

Discontinue tamoxifen

(5 years total therapy)

Continue tamoxifen for

10 years total therapy

6846 patient

After Completion of 5 Years of

Adjuvant Tamoxifen

ATLAS Results: Recurrence and breast cancer mortality

3.7% reduction in recurrence2.8% reduction in breast cancer mortality

MA-17**

**883 (out ~ 5000 enrolled) were premenopausal at diagnosis and became postmenopausal (oophorectomy or secondary to chemotherapy) after 5 years of tamoxifen

• Significantly improved DFS with Letrazole vs Placebo

• But wasn’t reflected on OS

• QoL???

Goss PE et al. N Eng J Med 2003

Postmenopausal women with

primary breast cancer who had

completed approximately 5

years (4.5 to 6) of adjuvant tamoxifen

therapy

Letrazole 2.5 mg

For 5 years

Placebo

For 5 Years

Extended duration with AI (>5 years)

AI > 5 Years?

MA 17R

DATA

NSAPB B-42

IDEAL

MA.17R: Study Design

• Primary endpoint: DFS (from randomization)

• Secondary endpoints: OS, CBC, safety, QoL

Postmenopausal pts with ER+ and/or PgR+ breast cancer who completed

4.5-6 yrs of letrozole2.5 mg PO QD ± prior

tamoxifen (N = 1918)

Goss PE, et al. ASCO 2016. Abstract LBA1.

Stratification by lymph node status at diagnosis, prior adjuvant chemotherapy,

interval between last AI dose and randomization, duration of prior tamoxifen

Ran

do

miz

e

Letrazole 2.5 mg PO QD

for 5 years

(n = 959)

Placebo

for 5 years

(n = 959)

Follow-up

Follow-up

Median follow-up: 6.3 yrs

MA.17R: DFS and OS After Median Follow-up of 6.3 Yrs

• MA.17R first study to demonstrate benefit of extending AI treatment beyond 5 years• Letrazole treatment for 10 years decreased risk of disease recurrence by 34%

• Majority of benefit in reduction of contralateral breast cancer

• OS not improved by extending Letrazole beyond 5 years

DFS Outcomes Letrozole Placebo HR (95% CI) P Value

Overall 5-yr DFS, % 95 910.66

(0.48-0.91).01

Events, n (%) 67 (7.0) 98 (10.2)

New contralateral breast cancers, n (%)

13 (1.4) 31 (3.2) .007

Locoregional recurrences, n 19 30

Distant recurrences, n 42 53

Bone recurrences, n 28 37

Goss PE, et al. ASCO 2016. Abstract LBA1.

NSAPB B-42: Study Design

0 2 3 5 10

Tamoxifen AI


R

Letrazole 2.5 mg

Placebo

Mamounas EP P et al. SABCS 2016

NSAPB B-42: Results

Mamounas EP P et al. SABCS 2016

Didn’t reach Statistical Significance for DFS ??? Cumulative incidence for DR Benefit

IDEAL* & DATA**

0 2 3 5 10

Tamoxifen AI


Tamoxifen

R

Letrazole 2.5 mg

Letrazole 2.5 mg

*Blok EJ J et al. SABCS 2016**Tjan-Heijnen VC C et al. SABCS 2016

0 2 3 5 10

Tamoxifen

R

Anastrazole 1 mg

Anastrazole 1 mg

IDEAL* DATA**

These findings do not yet support the use of extended adjuvant AI prescription after 5 years of sequential endocrine therapy for postmenopausal patients with hormone receptor-positive breast

cancer

0 2 3 5 10

RAI

AI

RTAM

AI

TAM RTAM

AITAM



AI CompMA27FACE

How to Conclude?


# 4th Question Do we have a benefit from Extended Hormonal Therapy?

Postmenopausal Take Home Message“5 years of Endocrine Therapy”

• 5 years of adjuvant AI better than 5 years of TAM (ATAC, BIG 1-98 monotherapy arm)

• Switching to AI after 2-3 years of TAM is better than 5 years of Tam (ARNO, IES, ABCSG 8)

• Switching to AI after 2-3 years of TAM is equivalent to 5 years of AI (TEAM, BIG 1-98)

• Switching to an AI after 5 years of TAM is better than placebo (MA 17)

• Endocrine therapy should include AI but sequencing with tamoxifen is acceptable

Postmenopausal Take Home Message“Extended Endocrine Therapy Beyond 5 years”

• Late Recurrences are real accounting for > 50% of events• Baseline Stage, grade, and other prognostic markers……….

• Treatment Pros/Cons• Benefits include: lower distant recurrences & secondary prophylaxis• Side Effects include: ongoing familiar side effects & bone health risks

• When to consider Extended adjuvant endocrine therapy?• Women with Stage 3 • Women with stage 2 at higher risks especial node positive• Women with stage 1 (still need to be more personally individualized)

• Women who had tolerated and willing to continue!• Women had started with Tamoxifen!!• Duration not to exceed 10 years (lesser attempts: data are not mature to give a definitive answer)

adjuvant endocrine therapy for postmenopausal breast cancer

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