Clinicaloptions.com/oncology FRANCESCO BOCCARDO Professore Ordinario di Oncologia Medica, Università di Genova Direttore Oncologia Medica B IST.Genova

clinicaloptions.com/oncology

FRANCESCO BOCCARDO

Professore Ordinario di Oncologia Professore Ordinario di Oncologia Medica, Università di GenovaMedica, Università di Genova

Direttore Oncologia Medica BDirettore Oncologia Medica BIST .GenovaIST .Genova

Presidente NazionalePresidente Nazionale Associazione Italiana Oncologia Medica Associazione Italiana Oncologia Medica

INIBITORI DELL’AROMATASI(back from San Antonio)


Initial diagnosis 2-3 years after Tam or AI

5 years after Tam or AI

Beyond 10 years?

Tam

oxife

nA

rom

atas

e in

hibi

tor

5 years total 10 years total > 10 years

Decision Points

?

?

?

?

?

1

2

34

4?3

Initial diagnosis 2-3 years after Tam 5 years after Tam or AI More

Tam

oxi

fen

Aro

mat

ase

in

hib

ito

r


Decision Points:after 2-3 yrs of Tam

?

?IESABCSG8/ARNO95ITA

1

The Lancet 9561:533-5, 2007

The Lancet 9561:533-5, 2007

The Lancet 9561:533-5, 2007


AIOG Metanalysis




……….back from San Antonio 2008: take home #1

“There is a clear benefit (including a S benefit) in switching women already on treatment with Tam to an AI (anastrozole,exemestane) unless AI therapy is contraindicated”

Decision Points: Initial choice

?

?

?

?

Initial diagnosis 2-3 years after Tam


Beyond 10 years?

Tam

oxife

nA

rom

atas

e in

hibi

tor


ATACBIG 1-98 monotherapy TEAM 2.75 yr

?

2


ATAC:100 mos median follow-up , Lancet Oncology 2007


AIOG Metanalysis





: TEAM trial





“Three drugs now available as front line

treatment:

Which drug or which patients?”

ATAC:100 mos median follow-up , Lancet Oncology 2007

Predicting the benefit and the risks. Tamoxifen vs Ais:

Tumor Profile

– ERPgR

– HER2

– Recurrence Score

– Cyclin E

– uPA/uPAI-1

– Bcl-2

– ER-beta

Patient Profile

– Osteoporosis

– Hypercholesterolemia

– CV risk factors

– Endometrial pathologies

– DVT & TE risk factors

– SSRI use

– CYP 19 Genotype

– CYP2D6 Genotype


•TRANSACT




•ABCSG 8





“Starting with an Ai is a reasonable choice especially in certain patient subsets (i.e. PgRneg,HER2 pos,HRScore Node neg,poor metabolizers of CYP2D6….!):however:

1) no major mortality advantge

2) No over rate in selecting patients “


Initial diagnosis 2-3 years after Tam or AI


Beyond 10 years?

Tam

oxife

nA

rom

atas

e in

hibi

tor


Decision Points:sequencing

?

?

?

?

?

1

2

34

4?3

ABCSG8TEAM 5-yr: n.a. yet

BIG-1-98

Primarysurgery

Randomize Anastrozole

(3 years)

Switching period

Sequencing period

Switch point

Tamoxifen(3 years)

Tamoxifen (2 years)

Jakesz R, et al. Lancet. 2005;366:455-462.

Tamoxifen (2 years)

ABCSG Trial 8

Sequencing versus TAM

0

75

80

85

90

95

100

0 12 24 36 48 60 72

HR

0.76Events

P Value

.068

T

101

T A

79

94.4%

92.9%

ABCSG 8 seq:Event-Free Survival following surgery (n = 2926)

T A

T

EF

S (

%)

Time Since Surgery (Months)Jakesz R, et al. 2005 SABCS. Abstract 13


Sequencing versus LTZ






Take home #3

Primarysurgery

Randomize LTZ/ANA

(3 years)

Switching period

Sequencing period

Switch point

Examestane(3 years)

LTZ/ANA

(2 years)

LTZ/ANA(2 years)

DOUBLE TRIAL

……….back from S. Antonio 2008: Take home #4

“sequencing TAM with an Ai is probably better

than TAM alone,but does not offer major

advantages vs Ai alone; switching from an

Ai to TAM is possible if required… “


Tam

oxi

fen

Aro

mat

ase

in

hib

ito

r


Decision Points:after 5 yrs of Tam

MA.17ABCSG6a

NSABP B-42

?

?

NSABP B-14

DFS

Years

OS

Years

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

100

90

80

70

60

50Per

cen

tag

e o

f P

atie

nts

0 5

PlaceboTamoxifen

7

82%

78%P = .03

1 2 4 63 0 5

100

90

80

70

60

507

Per

cen

tag

e o

f P

atie

nts

PlaceboTamoxifen

94%

91%P = .07

1 32 4 6

Fisher B, et al. J Natl Cancer Inst. 2001;93:684-690.

NSABP B-14: No Benefit of Extending Tamoxifen Beyond 5 Years

DFS*Distant*

DFS

Node*pos

Node* pos

Node* neg

Node neg

Node neg

Node* pos

*non statistically significant

HR: 0.61(0.45-0.84)

HR: 0.45(0.27-0.75)

HR: 0.63(0.31-1.27)

HR: 0.53(0.36-0.78)

HR: 1.52(0.76-3.06)

HR: 0.61(0.38-0.98)

HR: 0.58(0.45-0.76) HR: 0.61

HR: 0.82(0.57-1.19)

OS

Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271.

Preplanned analysis (n = 5187)

MA.17: Key Endpoints in Nodal Subgroups

Adjusted HR (PLAC-LET to PLAC) for Efficacy Outcomes :postumblinding

Goss PE, et al. SABCS 2005. Abstract 16.

p<0.0001

p=0.002

p=0.05

p=0.012

0.310.28

0.53

0.23

0

0.1

0.2

0.3

0.4

0.5

0.6

PLAC-LET to PLAC

Disease-free survival Distant disease-free survival

Overall survival Contralateral breast cancer

Haz

ard

Rat

io

P < .0001P = .002

P = .05

P = .012

………back from S.Antonio 2008: Take home #5

“ Late switching after 5 yrs of TAM: no news “


Tam

oxi

fen

Aro

mat

ase

in

hib

ito

r


Decision Points:after 5 yrs of AIs

MA.17

MA.17-RNSABP B-42

?

?

NSABP B-14

AI x 5 yrs

AI x 3-2 yrs

Tam x 2-3 yrs

Letrozole x 5 yrs

Placebo x 5 yrs

Letrozole vs placebo after 5 years; not yet enrolling

NSABP B-42: Study Design

Primary endpoint: DFS

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

MA.17R: Design

Rerandomization (Disease-free)

Letrozole

Placebo qd

Letrozole 2.5 mg qd

5 years’ early adjuvant 5 years’ extended adjuvant

…….back from S. Antonio 2008: Take home #6

“ are trials concerning Ai optimal duration still

justified? “


•ZO-FAST



Immediate Therapy With Zoledronic Acid Prevents Bone Loss and Improves DFS in Women With Early Breast Cancer Receiving Letrozole

Zometa-Femara Adjuvant Synergy Trial (ZO-FAST): 36-month follow-up results of multicenter, randomized phase III trial[1]

…….back from S. Antonio 2008: Take home #7

“ the seed and soil theory likely to work: data

from ABCSG 12 confirmed!”

EARLYSWITCHING : 1) the new standard for the patients already on treatment with TAM from 2 or 3 yrs 2) switching from LTZ to TAM after 2-3 yrs possible if requiredLATE SWITCHING : a reasonable option for patients at the completion of 5 yrs of

TAM, namely for N pos (no news from San Antonio)

UPFRONT : the choice for the patients who have contraindications to the use of TAM. A reasonable choice for the patients at higher risk of relapse (HR score) or for whom a suboptimal response to TAM might be predicted (CYPD26) : cost/benefit to be defined in the individual patient (no S advantage on the average)

SEQUENCING : 1) no better /no worse than LTZ 2) no evidence yet in respect to TAM

AIs IN THE ADJUVANT SETTING,back from AIs IN THE ADJUVANT SETTING,back from San Antonio 2008:San Antonio 2008:

………back from S.Antonio 2008: Take home #8

“ THANK YOU! ”

Documents

Clinicaloptions.com/oncology FRANCESCO BOCCARDO Professore Ordinario di Oncologia Medica, Università di Genova Direttore Oncologia Medica B IST.Genova