Adjuvant Endocrine Therapy: How Long is Long Enough?

Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute

Harvard Medical School Boston, Massachusetts

hburstein@partners.org

• I have no conflicts to disclose.

Early vs Late Recurrence

Jatoi I et al. JCO 2011;29:2301-2304

Time Dependence of Breast Cancer Recurrence in

Subsets Defined by Genomic Assays

Intrinsic/

PAM50

MammaPrint

OncotypeDX

It is tautological to say, but the sine qua non for a late

recurrence is not having an early recurrence

Coates, A. S. et al. J Clin Oncol; 25:486-492 2007

BIG 1-98 DFS OS

Predictors of Early Recurrence

(first 2 years)

Mauriac Ann Oncol 2007:18:859

T stage

N stage

LVI

HER2+

ER or PR neg

Grade

Note: lots of these correlate with

ER expression

• Just because patients are at jeopardy for late recurrence does not necessarily mean that additional treatment will help

• Examples:

• HERA (2 vs 1 year of trastuzumab)

• Adjuvant Chemo (12 m vs 6 m)

Tamoxifen

Why did we stop at 5 years anyway?

Tamoxifen 5 yrs vs. Not

EBCTG

Overview

2000

Tam

Nil

Duration of Tamoxifen: NSABP B-14

Placebo

Placebo

n=579

Tamoxifen x 5 years

n=593

Disease Free at 5 yrs

n=1172

Tamoxifen x 5 yrs

NSABP B-14

ER+, LN neg

Fisher, et al. JNCI 2001

Duration of Tamoxifen: NSABP B-14 Fisher, et al. JNCI 2001;

median f/u 7 years post-rerandomization

Scottish Trial of Extended Tamoxifen

Stewart HJ, et al. Brit J Cancer 1996;74:297-299.

ECOG Trial of Extended Tamoxifen Beyond 5 Years

Tormey DC, et al. JNCI 1996;88:1828-33.

TAM

AI

TAM

AI

Plac

AI

TAM

TAM

0 5 2 3 10

Years After Diagnosis

Upfront

ATAC

BIG 1-98

ABCSG 12

TEAM

Sequential

BIG 1-98

IES

ITA

NSAS BC-03

ARNO 95

ABCSG 8*

Extended

MA.17

ABCSG 6a

NSABP B-33

ER+ Breast Cancer

What happens in years 6 to 10?

MA 27: Letrozole or Placebo after 5 years of Tamoxifen

Goss PE et al. N Engl J Med 2003;349:1793-1802.

Late Introduction of AI Therapy in MA17

Goss P E et al. JCO 2008;26:1948-1955

DFS

DDFS

Late switchers were:

Younger

Higher stage (N+, T2/T3)

Had more adj chemo

MA17: DFS by treatment and menopausal status (at time of diagnosis).

Goss P E et al. Ann Oncol 2013;24:355-361

NSABP B-33:

disease-free survival with exemestane versus placebo (intent-to-treat)

Mamounas E P et al. JCO 2008;26:1965-1971

©2008 by American Society of Clinical Oncology

Sites of first event with exemestane versus placebo.

Mamounas E P et al. JCO 2008;26:1965-1971

©2008 by American Society of Clinical Oncology

Cumulative incident plots of contralateral breast cancers according to initial randomization to

letrozole or placebo on MA.17.

Ingle J N et al. Ann Oncol 2008;19:877-882

ATLAS population

Disease-free Survival Overall Survival

Richard Gray, Daniel Rea, Kelly Handley & 17 others

on behalf of the

aTTom Collaborators

aTTom: Long-term effects of continuing adjuvant

tamoxifen to 10 years versus stopping at 5 years in 6,953

women with early breast cancer

10 vs 5 years of tamoxifen: Recurrence by treatment ASCO 2013

580 vs 672 recurrences RR=0.85 (95%CI 0.76-0.95)

p=0.003

An additional 143 vs 216 recurrences since 2008

10 vs 5 years of Tamoxifen: Breast Cancer Death by Treatment Allocation

404 vs 452 breast cancer deaths

RR=0.88 (95%CI 0.77-1.01; p=0.05) p=0.06

10 year EFS by stage, grade, and age for ER+ breast cancers not relapsing by year 5 from diagnosis:

British Columbia Data. Lohrisch et al. SABCS 2013 Stage

and

grade

Age > 50 years at Diagnosis Age

Late recurrence in endocrine-treated cancers. Cuzick et al. SABCS 2013 ATAC

N=9366 ABCSG-8 N=3714

PAM50 N=1007

Excluded: -Insufficient residual RNA -Failed PAM50 QC

PAM50 N=1478

Excluded: -Insufficient residual RNA -Failed PAM50 QC

Excluded: -Not recurrence free at 5 years (N=145)

Excluded: -Not recurrence free at 5 years (N=203)

Combined dataset N=2137

N=862 N=1275

Excluded: -Combination arm -Chemotherapy -No blocks received -Insufficient tumour material

transATAC* N=1125

Tissue database N=1620

Excluded: -No tissue specimen -No consent

*RNA extracted by GHI

Luminal A vs Luminal B HR (95% CI) P-value

Luminal A (N=1530 (71.6%)) - -

Luminal B (N=542 (25.4%)) 2.89 (2.07- 4.02)

WHY NOT JUST TREAT EVERYONE FOREVER, ANYWAY?

Patient-reported Reasons for Stopping Endocrine Therapy (N = 77)

%

Patient-related

Side effects

Concern about adverse effects from therapy

Cost

Dislike of having to be on medications

Wanted to move on from the cancer

27

16

18

17

11

Doctor-related

Told to stop by doctor

Completion of recommended course of treatment

16

9

(Not mutually exclusive)

Pini, ASCO 2011

Persistent Risks of Therapy

• Tamoxifen

• Uterine cancer

• Thromboembolism

• Aromatase Inhibitors

• Osteoporosis

• Myalgias/arthralgias

ATAC: annual bone fracture rates

ATAC Trialists, Lancet Oncology 2008;9:45

Real Choices I

• Premenopausal

• Start with tamoxifen

• At 5 years

– If premenopausal, continue tamoxifen

– If postmenopausal (for sure), continue tamoxifen or switch to an AI

Real Choices II

• Postmenopausal

• Start with tamoxifen or an AI

• If starting with tamoxifen, option of extended adjuvant treatment with either tamoxifen or an AI

• If starting with an AI, data may be available in 5 years to guide your choice at that timepoint

Real Choices III

• Patients can usually tell you their preference

The spectrum of patients on tamoxifen

Real Choices III

• Patients can usually tell you their preference

• Benefits of extended adjuvant therapy are relatively modest, and baseline risk probably is relevant

• Low threshold for discontinuing treatment if not well tolerate

Final Point

• After decades, we are still optimizing adjuvant endocrine therapy

• There is a movement to minimize the relationship between oncologists and breast cancer “survivors” by shifting care to other clinicians or survivorship clinics

• Ironically, in the largest population of cancer survivors, we are still amending treatment plans 5+ years out from diagnosis.