These slides were released by the speaker for internal use by Novartis

Breast cancer recurrence: a continuing problem

Tanja Cufer (Institute of Oncology, Ljubljana, Slovenia)

ˇ

EBCTCG Lancet 2005;365:1687–717

NODE NEGATIVENODE NEGATIVE NODE NEGATIVENODE NEGATIVE

Breast cancer recurrence and mortality without adjuvant medication

Adjuvant tamoxifen

• 5 years of tamoxifen has been the gold standard for many years– Reduction in annual risk of recurrence by 41% and

death by 34%

EBCTCG Lancet 2005;365:1687–717

Breast cancer recurrence and mortality after 5 years of tamoxifen

EBCTCG Lancet 2005;365:1687–717

ControlAbout 5 years of tamoxifen

15-year gain 9.2% Logrank 2p < 0.00001

15-year gain 11.8%Logrank 2p < 0.00001

34.8

Breast cancer mortality

Bre

as

t c

an

cer

mo

rta

lity

(%)

0 10

20

0

30

40

60

50

10

5 15

Years

11.9

25.7

8.3

17.8

25.6

Re

cu

rren

ce

(%

)

0 10

20

0

30

40

60

50

10

5 15

Years

Recurrence

45.0

33.2

38.3

24.7

26.5

15.1

Adjuvant tamoxifen

• 5 years of tamoxifen has been the gold standard for many years– Reduction in annual risk of death by 34% and

recurrence by 41%1

• But, the risk of recurrences and breast cancer mortality remain substantial, despite adjuvant therapy2

– Risk of relapse, even while on adjuvant therapy, is highest in the first 2–3 years

1. EBCTCG Lancet 2005;365:1687–7172. Saphner et al. J Clin Oncol 1996;14:2738–46

Annual risk of recurrence by nodal status

Saphner et al. J Clin Oncol 1996;14:2738–46

Re

cu

rren

ce

ha

zard

ra

te

0

0.1

0.2

0.3N0N1–3N4+

0 1 2 3 4 5 6 7 8 9 10 11 12Years

• Patients receiving adjuvant chemotherapy or endocrine therapy

Annual risk of recurrence by ER status

Years

0

0.1

0.2

0.3

0 1 2 3 4 5 6 7 8 9 10 11 12

Rec

urr

ence

haz

ard

rat

e

ER– (n = 1305)

ER+ (n = 2257)

• Over half of breast cancer recurrences occur > 5 years post-surgery

• The annual risk of late recurrence is particularly high in ER+ tumors

Saphner et al. J Clin Oncol 1996;14:2738–46

Years from randomization0 2 3 4 51

Pro

po

rtio

n f

aili

ng

(%

)

LET

TAM

13.6%

10.2%

8.1%

6.2%

5-year difference (LET-TAM): –3.4%p < 0.001

0

5

10

15

20

*Breast cancer event defined as ipsilateral or distant recurrence, or new contralateral breast primary

Thürlimann et al. N Engl J Med 2005;353:2747–57

BIG 1-98: cumulative incidence of breast cancer relapse*

Letrozole is not licensed in all European countries for use in early adjuvant setting

Adjuvant tamoxifen

• 5 years of tamoxifen has been the gold standard for many years– Reduction in annual risk of death by 34% and

recurrence by 41%1

• But, the risk of recurrences and breast cancer mortality remain substantial, despite adjuvant therapy2

– Risk of relapse, even while on adjuvant therapy, is highest in the first 2–3 years

– Over half of all recurrences and deaths occur after completion of 5 years of tamoxifen

1. EBCTCG Lancet 2005;365:1687–7172. Saphner et al. J Clin Oncol 1996;14:2738–46

Recurrences Breast cancer deaths

Years

85.2

73.7

0

20

40

60

80

100

0 5 10 15

TamoxifenControl

15% 17%

0

20

40

60

80

100

0 5 10 15

87.8

Years

TamoxifenControl

9% 18%

91.4

% o

f p

atie

nts

% o

f p

atie

nts

54.9

68.2 73.0

64.0

More than half of all breast cancer recurrences and deaths occur post-

tamoxifen

EBCTCG Lancet 2005;365:1687–717

Meta-analysis: risk of recurrence remains high despite adjuvant tamoxifen therapy

05

101520253035404550

Tamoxifen Control

% o

f re

curr

enc

es

5 yearspost-diagnosis10 yearspost-diagnosis

15 yearspost-diagnosis

EBCTCG Lancet 2005;365:1687–717

Reducing late relapses: extending adjuvant therapy beyond 5 years

• Patients with ER+ breast cancer are at a particularly high risk of late (> 5 years after surgery) relapse*

• Such patients could benefit from further endocrine therapy• Option 1

– Give tamoxifen for longer

*EBCTCG Lancet 2005;365:1687–717

Randomized trials of extended adjuvant tamoxifen beyond 5 year

Study Patients N Follow-up

(median)

Outcome

Fisher et al. JNCI 2001;93:684

N negative

ER+

Premeno = 25%

1152 7.5 years Worse DFS

No difference in OS, RFS

Stewart et al. JCNI 2001;93:456

Mostly N neg.

Mostly ER?

Premeno=25%

342 6 years Suggestion of harm

Tormey et al. JNCI 1996;88:1828

N positive Mostly ER+

Premeno=53%

193 5-6 years Suggestion of benefit

NSABP B-14: no efficacy benefit of extending tamoxifen beyond 5 years

Fisher et al. J Natl Cancer Inst 2001;93:684–90

DFS OS

p = 0.07

PlaceboTamoxifen

Years after tamoxifen

p = 0.03

100

90

80

70

60

50

% o

f pa

tien

ts

0 5 7

82%

78%

1 2 4 63 0 5

100

90

80

70

60

507

% o

f pa

tien

ts

PlaceboTamoxifen

94%

91%

1 32 4 6Years after tamoxifen

• Tamoxifen demonstrated higher rates of endometrial cancer and more deaths from ischemic heart disease and cerebrovascular disease

Reducing late relapses: extending adjuvant therapy beyond 5 years

• Patients with ER+ breast cancer are at a particularly high risk of late (> 5 years after surgery) relapse*

• Such patients could benefit from further endocrine therapy• Option 1

– Give tamoxifen for longer• Option 2

– Give other endocrine therapy after 5 years of tamoxifen

*EBCTCG Lancet 2005;365:1687–717

MA.17: trial design

Goss et al. J Natl Cancer Inst 2005;97:1262–71Goss et al. N Engl J Med 2003;349:1793–802

Randomization(all patients disease-free)

Tamoxifen

Approx. 5 years’ adjuvant 5 years’ extended adjuvant

0–3months

Letrozole 2.5 mg qd (n = 2582)

Placebo qd † (n = 2586)

• Eligibility criteria: postmenopausal, HR+/unknown, recurrence-free, completed 4.5–6 years’ tamoxifen, ECOG PS 0–2

• Primary endpoint: DFS (breast-only events)

• Secondary endpoints: OS, rate of contralateral BC, safety, QoL

• Substudies:Substudies: BMD/bone markers, lipid profile

MA.17: HRs for DFS over follow-up period

Ingle et al. Breast Cancer Res Treat 2006; E-pub 16 March

0.0000

0.0005

0.0010

0.0015

0.0020

0.0025

0.0030

0.0035

0 6 12 18 24 30 36 42 48

Ha

zard

ra

te

Months after randomization

Letrozole

PlaceboPlacebo

Letrozole 2583 2531 2425 2060 1555 1110 768 464244

Placebo 2587 2528 2409 2020 1530 1075 723 436231

ABCSG-6a: EFS(Recurrence of BC or new primary BC)

Jakesz et al. J Clin Oncol 2005;23:10s(abstract 527)Anastrozole is not licensed in this indication

At median follow-up of 5 years:• 3 years of extended adjuvant treatment with anastrozole

reduced the risk of recurrence by 36%• No significant difference in overall survival

Anastrozole (n = 387)

No treatment(n = 409)

Hazard ratio (95% Cl) p value

5-year DFS rate NR NR0.64

(0.41–0.99) 0.047

Events 30 56 — —

Reducing late relapses: extending adjuvant therapy beyond 5 years

• Option 1

– Give tamoxifen for longer Option 2

– Give other endocrine therapy after 5 years of tamoxifen

? Option 3

• Extended treatment with AIs beyond 5 or even 10 years from diagnosis

• Life-long endocrine therapy

Long-term toxicities of extended endocrine therapies

Menopausal symptoms poorer quality of life

• Vasomotor symptoms (hot flushes, sweating)

• Decreased sexual functioning

• Vaginal complaints (dryness, discharge, itching)

• Insomnia

• Fatigue

• Mood disturbances – emotional distress, anxiety

Osteoporosis

? Cardiovascular adverse events

NSABP B-42: study designTrial still pending*

Letrozole vs placebo after 5 years of an AI or sequential tamoxifen / AI

AI x 5 years

AI x 2–3 yrs

Tam x 2–3 yrs

Letrozole x 5 years

Placebo x 5 years

5 years’ further adjuvant

Randomization (Disease-free)

*n = 5000; primary endpoint = DFS

MA.17R: design

Primary endpoint: DFSSecondary endpoints: OS, incidence of contralateral breast cancer, long-term clinical and laboratory safety, overall QoL, menopausal QoL

Rerandomization (Disease-free)

Letrozole

Placebo qd

Letrozole 2.5 mg qd

5 years’ extended adjuvant 5 years’ further extended adjuvant

EORTC-BIG MINDACT trial design6000 women with N– disease

Evaluate clinical-pathological risk and 70-gene signature risk

Clin-path and 70-gene both HIGH

risk

Discordant cases

Clin-path HIGH70-gene LOW

Clin-path LOW70-gene HIGH

Clin-path and 70-gene both LOW

risk

Use Clin-path risk to decide chemo or not

Use 70-gene risk to decide chemo or not

55% 32% 13%

R1

Chemotherapy

n = 3300 n = 780

Endocrine therapy

n = 1920

Tam x 2 y→ Let x 5 y Letrozole x 7 y

Summary (1): risk of recurrence in early breast cancer

• Risk of recurrence highest in first 2–3 years but remains substantial even 5–10 years after diagnosis, particulary in HR+ disease

• Adjuvant tamoxifen substantially reduces risk of recurrence but may be detrimental for > 5 years

• Large proportion of recurrences and > 50% of breast cancer deaths occur after completion of adjuvant tamoxifen

Extended adjuvant treatment with AIs after 5 years of tamoxifen improves DFS, with an OS benefit observed in N+ disease

Summary (2): risk of recurrence in early breast cancer

• Extended adjuvant therapy with an AI seems a reasonable treatment option, but the optimal duration of AI therapy or sequence of AI / tamoxifen is not yet known

• Life-long endocrine therapy is a potential treatment option that should be explored in clinical trials with emphasis on cost:benefit (late side effects) and translational research capable of identifing patients who may benefit most from extended treatment