Profili Genici e

Personalizzazione del

trattamento adiuvante nel

carcinoma mammario

G. RICCIARDI

UOC Oncologia Medica,

A.O. Papardo, Messina

Dir. Prof. V. Adamo

“Adjuvant” Medical Therapies

Lung

Liver

Bone

Brain

Localized Disease

Curable

Generalized Disease

Very difficult to cure

But risk of:

•Overtreatment

•Undertreatment

•Wrog treatment

•Suboptimal treatment

Adapted by M. Piccart AACR 2016

BREAST CANCER

100 BC patients 20% HER2+ BC 15% TN BC 65 HR+/HER2- BC patients 5% >4 Node positive 2-3% too frail for CT 50 HR+/HER2- BC PATIENTS POTENTIALLY CANDIDATE TO ADJUVANT CHEMOTHERAPY BENEFIT/NO TOXICITY BENEFIT/TOXICITY NO BENEFIT/NO TOXICITY NO BENEFIT/TOXICITY

Treatment Individualization

G1, T≤2,

N -; ER & PgR +

HER2 –; LVI Absent

Age <35, G2-3; T>2, Node – or Node + (1-3), ER & PgR+,

HER2 -

Node + (1-3), HER2+, Node + (>4)

R

I

S

k

R

I

S

k

Low

Intermedie

High

Only 20% of patienst!

Most difficult

group for CT

decision!

St Gallen Definition Risk

Benefit Increase Survival

(2 to12%)

Long-Term Risks Secondary Cancer

Cardiac toxicity

Early Menopause

Reduction cognitive function

… and Socio-Economic Burden

Adpted by M. Piccart AACR 2016

Adjuvant Chemotherapy in Early Breast

Cancer: Benefit/Risk Balance

WHO CAN BE SPARED TREATMENT? WHO SHOULD RECEIVE TREATMENT? QUESTION

TOOL

CLINICAL PROBLEM

AVOID UNNECESSARY Tx MAXIMIZE BENEFIT

PROGNOSTIC MARKERS PREDICTIVE MARKERS

INDIVIDUALIZED TREATMENT CHOICE

The Road To Treatment Individualization

Clinical validity

Clinical utility

Correlation of score with outcome

Evaluation of Gene-Expression Profiles

Kwa M, Nat Rev Clin Oncol 2017

Analytic Validity Refers to the ability to accurately and

reliably measure the genotype of

interest.

is the ability of a test result to divide a

population into two or more groups

that differ either biologically or

clinically

Refers to whether using the test leads to an

improvement in clinical decision-making,

with measurable improvements in clinical

outcomes compared with those observed

when the test is not used

Most Common Commercially Available

Prognostic Gene Signatures for Breast Cancer

Kwa M, Nat Rev Clin Oncol 2017

*FDA Approval: Mammaprint & PAM50 ROR

¿ We can identify a subset of

patients who do not require

adjuvant chemotherapy?

YES!

Early Breast Cancer HR+/HER2-

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

MammaPrint OncotypeDX PAM50 ROR EndoPredict

(include tumor size+nodal status)

Analytical Validation of Decentralized

Gene Expression-based tests

(only EndoPredict and PROSIGNA)

Predicting Baseline Prognosis

All tests have at least level IB evidence for HR+/HER2-, T1-2 and N0-1

early BC

DATA FROM PROSPECTIVE

RANDOMIZED TRIALS

ONCOTYPE DX

It was developed on the basis of the NSABP B-20 and B-14 trials.The

RS is a continuous variable, ranging from 0 to100,and classified the pts

into three categories, ilow risk (RS,18),intermediate risk(RS18-31),and

high risk(RS.31), The optimal management of the intermediate-risk

group is uncertain and is being studied in the TailorX trial, in which

patients with ER+ N0 were assigned to low-risk (RS , 11), intermediate-

risk (RS 11-25), and high-risk groups(RS.25).The main results of the

intermediate-risk score group are eagerly awaited.

1. Paik S, NEJM 2004, 2.Sparano JA, NEJM2015; 3.Paik S, JCo2006; 4. Albain

KS, Lancet 2010; 5.Dowsett M, JCO 2010; 6. Kraw, Nat Rev Clin Oncol 2017

Trial Assigning Individualized Options

for Treatment or TAILORx

Sparano JA et al. N Engl J Med 2015

TailorX: prognosis of RS low patients

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)

PlanB: Translational subprotocol <br />5-year DFS in per-protocol population<br />(no chemotherapy in pN0-1 and Recurrence Score 0-11)

MAMMAPRINT

“…The MammaPrint, was the first microarray-based

prognostic signature to be approved by the U.S. FDA.

The 70-gene profile may be used for determining the

prognosis of patients with stage I and/or II, N0 as well as

for nodes 1 to 3 positive disease.This gene profile was

first established using RNA from fresh, frozen tumor

tissues;however from 2012 onward, It is also evaluable

in formalin-fixed, paraffin-embedded tumor tissue. A list

of 70 genes that could accurately predict poor versus

good prognosis for these patients was identified by a

supervised analysis of 25,000 genes included in the

microarrays. The true clinical utility of MammaPrint is

being tested in a randomized prospective phase III trial:

MINDACT…”

1. Sapino A, J Mol Diagn 2014; 2.Mook S, Breast Cancer Res Treat 2009; 3.Knauer M, Breast Cancer Res Treat 2009; 4 Van de Vijver NEJM 2012., 5.

Knaw Nat Rev Clin Oncol 2017

MINDACT

Cardoso F, NEJM 2016

The primary end point was survival

without distant metastasis (event-free rate at 5 years)

“…Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for

recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of

survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy.

Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might

not require chemotherapy…”

Survival without distant metastasis of 94.7% among

pts who did not received chemotherapy 95% CI: 92.5

-96.2); thus, the primary objective of the study (i.e.,

to show whether the lower boundary of the 95% CI

for the rate of survival without distant metastasis

would be at least 92%) was achieved.

Cardoso F, NEJM 2016

Tryfonidis K, ESMO 2017

DMFS at 5-years DFS at 5-years OS at 5-years

Tryfonidis K, ESMO 2017

PAM50 (PROSIGNA)

“…PAM 50 was originally developed for intrinsic subtyping of breast cancer, but later it started to be used to predict

recurrence. Its score, PAM 50 ROR is calculated by using the expression profile of 50 selected genes from four intrinsic

subtypes, a proliferation score (18-gene subset), and pathologic tumor size and nodal status. It can be used with formalin-

fixed, paraffin-embedded tissue samples and was approved by the U.S. FDA in 2013.. The results of ATAC and ABCSG-8

meet this high level of evidence (Level I) for clinical validity using archived specimens . It is, therefore, a more useful

signature to predict late distant relapses compared with Oncotype DX or MammaPrint.…”

1. Parker JS, JCO 2009; 2.Gnant M, Ann of Oncol 2014; Filipits M, Clin Cancer Res 2014; Coates, Ann of Oncol 2015.

ENDOPREDICT

“The Endopredict analyzed 12 genes with the qRT-PCR for the classification

of patients into two recurrence risk groups. The assay was validated in the

ABCSG-6 and ABCSG-8 trials. Additionally, EndoPredictClin, which

combines the EndoPredict score with tumor size and nodal status in a linear

model, identified a subgroup of pts with an excellent long-term prognosis

after a standard 5 years of endocrine therapy, thus making it useful for

evaluating risk of late elapse.Relative gene expression levels are used to

calculate the EndoPredict score (EP score) ranging from 0 to 15. Patients

with a score below or equal to 5 are classified as low risk for distant

recurrence under endocrine therapy, those with a score above 5 as high risk”

.

1. Filiptis M, Clin Cancer Res 2011; 2. Dubsky P, Br J Cancer. 2013

*could be considered in low burden nodal status. 1.Harris L. J Clin Oncol 2016;

2. Krop I., J Clin Onco 2017

MINDACT :

MammaPrint

assay may be

used in those

with high

clinical risk

HR+/HER2-neg and NODE-negative

INDICATION Evidence Quality Recommendation Strenght

OncotypeDX YES HIGH STRONG

PAM50 ROR YES HIGH STRONG

EndoPredict YES INTERMEDIATE MODERATE

MammaPrint NO INTERMEDIATE MODERATE

HR+/HER2-neg and NODE-positive

INDICATION Evidence Quality Recommendation Strenght

OncotypeDX NO INTERMEDIATE MODERATE

PAM50 ROR NO INTERMEDIATE MODERATE

EndoPredict NO INSUFFICIENT MODERATE

MammaPrint NO INTERMEDIATE MODERATE

YES HIGH STRONG

¿ we can identify with the Ki-67

a low-risk group that does not

need chemotherapy?

NO

Early Breast Cancer HR+/HER2-

Ki67 was not taken into account

Goldhirsch A, Ann of Oncol 2009

St Gallen 2009

St Gallen 2011 Goldhirsch A, Ann of Oncol 2011

A majority of the Panel voted that a threshold of

≥14% was indicative of ‘high’ Ki-67 status

St Gallen 2013

Goldhirsch A, Ann of Oncol 2013

A majority of the Panel voted that a threshold of

≥20% was indicative of ‘high’ Ki-67 status

Ki-67 scores should be interpreted in the light of local

laboratory values: as an example, if a laboratory has a

median Ki-67 score in HR+ disease of 20%, values of

30% or above could be considered clearly high; those

of 10% or less clearly low

St Gallen 2015 Coates A, Ann of Oncol 2015

Confusion Regarding Ki67 Scoring in the

Clinical Setting

St Gallen 2017 The Panel raised an issue of caution about

reproducibility of IHC for Ki67 and its use to make

clinical decisions, due to the variability of this assay Curigliano G, Ann of Oncol 2017

J Clin Oncol 2016

Guide choice on adjuvant chemotherapy

INDICATION Evidence Quality Recommendation Strenght

Ki67 IHC NO INTERMEDIATE MODERATE

IHC4 NO INTERMEDIATE MODERATE

“…IHC for Ki-67 analysis lacks reproducibility across

laboratories and, therefore, cannot be consistently interpreted

when performed in a broad range of laboratories…”

¿ Changes the choice of

adjuvant treatment?

What if the Prognostic Gene Signatures

are inserted into clinical practice?

“…After receiving the

GEP results, treatment

recommendations were

changed for 40 patients

(20%)…”

“…After receipt of the Prosigna results, physician confidence increased in 41.6% of cases.

The Prosigna results reinforced the confidence of clinicians in the accuracy of adjuvant therapy selected for

the pts…”.

Martin M & Prat A, CMRO 2015

¿Can we safely identify patients

who do not need endocrine

therapy beyond 5 years?

Early Breast Cancer HR+/HER2-

To identify a group of patients (T1-2/N0-N+ with HR+/HER2- disease

• That may be spared extended endocrine therapy (5-10 years) due to

their low risk of recurrence

Sestak JCO 2015 Sestak JNCI 2013

Dubsky BJC 2013

PAM50 ROR EndoPredict

(include tumor size+nodal status)

Predicting Late Recurrence

“…ROR was the strongest molecular prognostic factor in predicting late recurrence and

discriminating patients into low and high risk for late distant recurrence.

However, the St Gallen 2017 did not recommend the use of gene expression signatures for

choosing whether to recommend extended adjuvant endocrine treatment, as no

prospective data exist and the retrospective data were not considered sufficient to justify

the routine use of genomic assays in this setting. …”

1. Prat A Ann Oncol 2012; 2. Sestak I J Natl Cancer Inst 2013 ; 3. Curigliano G. Ann of Oncol 2017

Predicting Late Recurrence

• All provide prognostic information independent of traditional factors

• 4 tests based on gene expression (Oncotype DX®, PAM50 / Prosigna ™, Endopredict® and

MammaPrint®) are available in the clinic.

• They have proven to be highly reproducible :

• 2 have been accredited FDA/510(k) (PAM50 y MammaPrint).

• 2 may be performed in local laboratories(PAM50 y EndoPredict).

• Majority validated in ER+/HER2-, N- BC patients, some also found to be prognostic in N1 pts

• Only OncotypeDx and Mammaprint have been tested in prospective randomized trials (some

studies ongoing for other tests).

• The Ki67 IHC NO has shown the same evidence to identify low-risk patients who do not

require adjuvant chemotherapy and another problem related to Ki67 is that of reproducibility

• IMPORTANT: They should be used with integration of clinical and pathological data (tumor

size and lymph node involvement).

PAM50 and EndoPredict integrate these data in the report.

Oncotype DX does not consider this data in the report.

• It is unclear whether routine use is improving patients outcome, but data are emerging

Multigene Tests: Summary of Evidence

GRAZIE!