Test genomici e Medicina PersonalizzataValentina GuarneriIstituto Oncologico Veneto IRCCS

Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche –

DiSCOG, Università di Padova

• Understand tumor biology• Dissect tumor heterogeneity

• Determine pathways driving cancer growth and

treatment resistance

• Identify potential targets in tumor cells or the

microenvironment

• Assess the risk of recurrence

• Assess treatment benefit

Goals of personalized medicine

Prognostic factors

Risk Assessment

Prognostic factorsAge, T, N, histology, grade, LVI, Ki-67, HR, HER2

Predictive factorsHR, HER2

Proportional

benefit

Absolute benefit

Adjuvant Rx of EBC - Decision-making Algorithm

Short- and Long-

term toxicities

Patient

Characteristics

and preference

Adjuvant medical treatments

Reis-Filho J, Lancet 2011

Class discovery

Mammaprint

Endopredict

GGI

BCI

OncotypeDX

Top-Down

approach

Bottom-up

approach

Candidate gene

approach

PAM50 - ROR

� Same entity of proportional risk reductions

across age, nodal status, T size and ER

status groups.

� The same proportional risk reduction

translates into different absolute

reductions according to absolute risk

without chemotherapy.

EBCTCG, Lancet 2012

Anthracycline-based CT vs no CT

Can we define a very-low risk group that,

whatever the relative benfit is, could be

spared adjuvant chemotherapy?

Clinical validity Predict baseline prognosis

Clinical utility Who can be spared a more aggressive treatment?

An ABSOLUTE issue: Prognosis is so good that the relative

benefit, if any, would translate into an unrelevant absolute

gain

Target pts (VERY) LOW RISK

(don’t mind what the relative benfit would be)

Paik NEJM 2006 Vijver NEJM 2002Dowsett JCO 2013 Filipits CCR 2011

MammaPrintOncotypeDX PAM50 ROR EndoPredict

(include tumor size+nodal status)

Genomic profiling predicting baseline prognosis for HR+/HER2- patients

Van’t Veer L. et al, Nature 2002

Relapse

No relapse

70 genes identified after supervised

analysis of 250000 genes

Independent cohort:295

consecutive patients with stage I or

II breast cancer, < 53 years old; 151

had lymph-node-negative disease,

and 144 had lymph-node-positive

disease

Van de Vijver MJ, et al, NEJM 347:1999-2009, 2002

Mammaprint: 70-genes prognostic signature

MINDACT Trial design (n=6000)

Node negative & 1-3 positive nodes

Primary objective:

• Confirm that CLINPATH HIGH / MammaPrint LOW

patients can safely avoid chemotherapy

Null hypothesis: 5-yrs DMFS for CLINPATH HIGH /

MammaPrint LOW pts randomized to NO CHEMO is 92%;

reject the null hypothesis if DMFS 95%.

16 Cancer and 5 Reference Genes From 3 Studies

PROLIFERATION

Ki-67

STK15

Survivin

Cyclin B1

MYBL2

ESTROGEN

ER

PR

Bcl2

SCUBE2

INVASION

Stromolysin 3

Cathepsin L2

HER2

GRB7

HER2

BAG1GSTM1

REFERENCE

Beta-actin

GAPDH

RPLPO

GUS

TFRC

CD68

Paik S, NEJM 351(27):2817, 2004

RS = + 0.47 x HER2 group core

- 0.34 x HR group score

+ 1.04 x proliferation group score

+ 0.10 x invasion group score

+ 0.05 x CD 68

- 0.08 x GSTM1

- 0.07 x BAG1

RS < 18 RS 18-30 RS > 31

The Oncotype DX® 21 Gene Recurrence Score (RS) Assay: continuous predictor

Distant recurrence over time

10-Year rate of recurrence = 6.8%*95% CI: 4.0%, 9.6%

0 2 4 6 8 10 12 14 16

Years

Paik S, et al. N Engl J Med. 2004;351:2817-2826.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Pro

po

rtio

n w

ith

ou

t d

ista

nt

rec

urr

en

ce

RS < 18, n = 338

RS 18-30, n = 149

RS ≥ 31, n = 181

All Patients, n = 668

P < 0.001

10-Year rate of recurrence = 14.3%95% CI: 8.3%, 20.3%

10-Year rate of recurrence = 30.5%*95% CI: 23.6%, 37.4%

*10-Year distant recurrence comparison between low- and high-risk groups: P < 0.001

RS, Recurrence Score® result

Clinical validation study including 668 pts

from the NSABP B-14 trial (stage I-II, N-,

ER+ treated with 5 yrs of TAM)

Oncotype DX® Clinical Validation:

Prognosis in N- ER+ TAM-treated (NSABP B14)

Oncotype DX® assayOncotype DX® assay

Primary study group

RS 11–25

Primary study group

RS 11–25RS >25RS >25RS <11RS <11

RandomizeRandomizeARM D: CT plus

endocrine therapy

ARM D: CT plus

endocrine therapy

ARM A: endocrine

therapy alone

ARM A: endocrine

therapy alone

ARM C: CT plus

endocrine therapy

ARM C: CT plus

endocrine therapy

ARM B: endocrine

therapy alone

ARM B: endocrine

therapy alone

N=1626 (15.9%)

N=6897 (67.3%)

N=1730 (16.9%)

Enrolled 10,071 pts

(2006-2010) 900 sites, 6 countries

Sparano JA et al. N Engl J Med 2015

Designed to determine whether HT is not inferior to CT+HT in women whose tumors fall in the Primary

Study Group category (RS 11-25). The primary study endpoint is disease-free survival. Other co-primary

endpoints include distant recurrence-free interval, recurrence-free interval, and overall survival.

Trial Assigning IndividuaLized Options

for Treatment (Rx), or TAILORx

RS 0-10 RS 11-25 p

All 1626 (15.9%) 6897 (67.3%)

Age, median (range) 58 (50-64) 55 (48-62) <0.001

Menopausal

post

pre

1143 (70%)

480 (30%)

4396 (64%)

2477 (36%) <0.001

T, median (range) 1.5 (1.2-2.0) 1.5 (1.2-2.0) 0.31

G1

G2

G3

530 (34%)

937 (59%)

111 (7%)

1941 (29%)

3812 (57%)

912 (14%) <0.001

PgR neg

PgR pos

28 (2%)

1562 (98%)

528 (8%)

6224 (92%) <0.001

TailorX: RS low patients’ characteristics

Sparano J, et al. N Engl J Med 2015

5yrs rate 93.8%

(95% CI, 92.4 to 94.9)

5yrs rate 99.3%

(95% CI, 98.7 to 99.6)

5yrs rate 98.7%

(95% CI, 97.9 to 99.2)

5 yrs rate 98.0%

(95% CI, 97.1 to 98.6)

TailorX: prognosis of RS low patients

Sparano J, et al. N Engl J Med 2015

TailorX: prognosis of RS low patients

Sparano J, et al. N Engl J Med 2015

Clinical validity Predict benefit of chemotherapy

Clinical utility Who need (or not need) a more aggressive treatment?

A RELATIVE and BALANCE issue

- Determine the relative benefit and the prognosis,

then balance for absolute gain and toxicity.

Target pts ALL PATIENTS, EXCLUDING VERY LOW

AND VERY HIGH RISKS

Paik S JCO 2006

RS<18

RS 18-30 RS ≥31

RS: prediction of chemotherapy benefit in ER+/N-

NSABP B-20 trial - (ER+, node negative) - Tamoxifen versus CMF/TAM

Albain K, Lancet Oncol 2010

RS: prediction of chemotherapy benefit in ER+ N+

Benefit of chemo is the same in both

stage-defined risk groups, provided the

RS is high � predictive effect of RS above

underlining risk?

Albain K, Lancet Oncol 2010

RS: prediction of chemotherapy benefit in ER+ N+

Oncotype DX® assayOncotype DX® assay

Primary study group

RS 11–25

Primary study group

RS 11–25RS >25RS >25RS <11RS <11

RandomizeRandomizeARM D: CT plus

endocrine therapy

ARM D: CT plus

endocrine therapy

ARM A: endocrine

therapy alone

ARM A: endocrine

therapy alone

ARM C: CT plus

endocrine therapy

ARM C: CT plus

endocrine therapy

ARM B: endocrine

therapy alone

ARM B: endocrine

therapy alone

N=1626 (15.9%)

N=6897 (67.3%)

N=1730 (16.9%)

Enrolled 10,071 pts

(2006-2010) 900 sites, 6 countries

Sparano JA et al. N Engl J Med 2015

Designed to determine whether HT is not inferior to CT+HT in women whose tumors fall in the Primary

Study Group category (RS 11-25). The primary study endpoint is disease-free survival. Other co-primary

endpoints include distant recurrence-free interval, recurrence-free interval, and overall survival.

Trial Assigning IndividuaLized Options

for Treatment (Rx), or TAILORx

A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/-

Chemotherapy in Patients with 1-3 Positive Nodes, HR+/HER2-negative and

HER2-Negative Breast Cancer With Recurrence Score (RS) of 25 or Less.

ClinicalTrials.gov Identifier: NCT01272037

Opened 2011, Estimated Accrual = 4000

Primary Objective:

• To find a significant interaction between Recurrence

Score (as a continuous variable) and treatment

• DFS

• Type 1 error: 5% ; 80% power

Biology vs Stage: is the verdict already clear?

Is there a simpler and cheaper method to

capture the same biologic features as GEP?

GEP vs clinicopathological classical parameters in

predicting baseline prognosis

10

0

9-Y

ea

r ri

sk o

f d

ista

nt

recu

rre

nce

(%

)

Recurrence Score

Node negative

n = 872

1-3 Positive nodes

n = 243

≥ 4 Positive nodes

n = 63

01

02

03

04

05

06

07

08

09

0

0 5 10 15 20 25 30 35 40 45 50

95% CI

Mean

Low Recurrence Score suggests a low risk of recurrence for patients with 1-3 positive nodes.

Dowsett M, et al. J Clin Oncol. 2010;28(11):1829-1834.24

Trans ATAC: rate of distant recurrence increases

with number of positive nodes

for all RS values

Tang G JCO 2011

• Pathologic variables (i.e. grade, tumor size and nodal status) retained

an independent prognostic value which is not captured by the

molecular signature.

Pathologic variables still matter

(6%-11%)

(13%-24%)

T, N and G need to be accurately determined!!!

Dowsett M, et al. J Clin Oncol. 2013

Dowsett M, et al. J Clin Oncol. 2013

Ki67: high intralaboratory concordance but low interlaboratory concordance

100 cases, 8 laboratories

Each laboratory: 2 sets of TMA with the same 100 cases

1. Centrally stained, locally scored 2. Locally stained, locally scored

Polley MC, JNCI 2013

Ki67: reproducibility

Breast-DX Italy: Impact of the Oncotype DX® Breast Cancer Assay on

Resources Optimization and Treatment Decisions for Women with

Estrogen Receptor-Positive, Node-Negative and Node-Positive Breast

Carcinoma: a prospective Italian multicenter study.

PROGRAMMA PER LA RICERCA INNOVAZIONE E HTA (PRIHTA) – REGIONE DEL VENETO

Coordinatore: Istituto Oncologico Veneto IRCCS, Padova PI: Prof. PierFranco Conte

- Prospective, multicenter study (ROV)

- To evaluate the impact of Oncotype DX® on thedecision making processes of physicians inrecommending adjuvant therapy and on resourcesoptimization in an Italian setting

OBSERVATIONAL PHASE:

ALL CONSECUTIVE ER+, HER2-, N0-3, T1-3 PATIENTS

Low-Risk at least 4

of the following:

-Data collection

-Physician’s perception of Oncotype DX utility

-Pre-test Physician decision

-Test

-Post-test Physician decision + post-test

perception of utility

-Treatment started

High-Risk at least 4

of the following:CLINICAL PHASE:

SUBGROUP OF PTS FROM THE

OBSERVATIONAL PHASE

Oncotype DX Request for pts not eligible for the Clinical Phase will not be processed by GH.

�G1

�T1a-b

�Ki67 <15%

�N negative

�ER >80%

EXCLUDED

�G3

�T>2

�Ki67 >30%

�N pos

�ER <30%

EXCLUDED

Breast-DX Italy

Centres PI

Oncologia medica 2, Istituto Oncologico Veneto IRCCS - Padova P. Conte

Oncologia Medica, Ospedale di Camposampiero M. Mion

Oncologia Medica, Ospedale dell’Angelo - Mestre P. Morandi

Oncologia Medica, Ospedale di Montecchio Maggiore C. Oliani

Oncologia Medica, Ospedale Borgo Roma - Verona G. Tortora

UOC Oncologia Medica, Ospedale Sacro Cuore don Calabria - Negrar S. Gori

UOC Oncologia Medica, Ospedale di Vicenza L. Merlini

Oncologia Medica, Ospedali di Este e Monselice G. Bonciarelli

Oncologia Medica, Ospedale di Rovigo F. Pasini

Breast-DX Italy: participating centres