e-learning gene expression signature to inform on adjuvant ......mindact: study design cardoso f, et...

GENE EXPRESSION SIGNATURE TO INFORM ON ADJUVANT TREATMENT

Maria Vittoria Dieci

Department of Surgery, Oncology and Gastroenterology – University of Padova, Italy

Medical Oncology 2 – Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy

OUTLINE

Introduction

Clinical utility of gene expression signatures

◆ Prognostic role: who can be spared CT?

◆ Predictive role: CT benefit

◆ Extended adjuvant

Optimising the use of gene expression signatures

◆ Are all tests the same?

◆ Classic prognostic features

◆ Impact on clinical practice

TREATMENT INDIVIDUALISATION FOR

EARLY HR+/HER2– BC PATIENTS

100 BC pts

20% HER2+ BC

15% TN BC

65 HR+/HER2– BC pts candidate to HT

5% ≥4 node positive

2–3% too frail for CT

50 HR+/HER2– BC patients

potentially candidate CT + HT

(5 years or more)

Type of biomarker Clinical question

Prognostic biomarker

Predictive biomarker

Who can be spared further treatment (i.e. chemotherapy or extended

endocrine therapy?)

Who benefits from a specific treatment (i.e. chemotherapy or extended

endocrine therapy?)

CLINICAL UTILITY OF A BIOMARKER AND LEVEL

OF EVIDENCE 1

Simon RM, et al. J Natl Cancer Inst 2009;101(21):1446–52

Analytical validation

Clinical validation

Clinical utility

Level of evidence Tumour marker study

1A PROSPECTIVE: Prospective clinical trial specifically

designed to test the marker

1B PROSPECTIVE USING ARCHIVED SPECIMENS:

Consistent results from ≥2 prospective clinical trials not

designed to test the marker, but design accommodates

tumour marker utility (preplanned analysis)

OUTLINE

Introduction









USE OF BIOMARKERS TO GUIDE DECISIONS ON

ADJUVANT SYSTEMIC THERAPY

For women with early-stage invasive breast cancer:

American Society of Clinical Oncology Clinical Practice Guideline

CT produces the same proportional risk reduction in all patients (EBCTCG)

This translates into different degrees of absolute benefit, depending on the individual estimate of absolute risk

of recurrence

What is the threshold of absolute risk of recurrence that defines patients that can be safely spared CT?

Harris LN, et al. J Clin Oncol 2016:34(10):1134–50. ASCO Special Article

Absolute distant

recurrence risk at baseline

Relative risk

reduction with CT

Absolute risk

reduction from CT

Risk of fatal, life-threatening,

permanent CT toxicity

50–60% 30% 15–20% 2–3%

10–15% 30% 2–3% 2–3%

Level 1A: data from prospective randomised trials

designed to test the marker

MammaPrint1 OncotypeDX2 PAM50 ROR3 EndoPredict4

(include tumour size + nodal status)

GENOMIC PROFILING AND PROGNOSIS FOR

HR+/HER2- PATIENTS

All tests have at least level 1B evidence for HR+/HER2–, T1–2 and N0–1 early BC

1. From N Engl J Med 2002, van de Vijver M, et al. A Gene-Expression Signature as a Predictor of Survival in Breast Cancer; 347:1999–2009. Copyright © 2002 Massachusetts Medical Society. Reprinted with permission

from Massachusetts Medical Society; 2. From N Engl J Med 2004; Paik S, et al. A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer; 351:2817–26. Copyright © 2004 Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society; 3. Nanotring Prosgina Package Insert. Prosigna® Breast Cancer Prognostic Gene Signature Assay. Version 10, Sept 2019. ©2012-2019

NanoString Technologies Inc., Seattle, USA. Reproduced with permission from NanoString; 4. Reprinted (or adapted) from Clin Cancer Res, Copyright 2011, 17(18), 6012–20, Filipits M, et al. A New Molecular Predictor of

Distant Recurrence in ER-Positive, HER2-Negative Breast Cancer Adds Independent Information to Conventional Clinical Risk Factors, with permission from AACR.

MINDACT: STUDY DESIGN

Cardoso F, et al. N Engl J Med 2016;375(8):717–29; Piccart M, et al. Presented at AACR 2016.. With permission from Prof M. Piccart.

Clinical low:

◆ T≤1 cm & G3

◆ T 2 cm & G2

◆ T 3 cm % G1

Clinical high: others

Clinical risk (c)

Adjuvant online

Enrolled N=6,693

Primary endpoints: Distant metastasis-free survival (DMFS) at 5 years

Null hypothesis: 5-year DMFS rate in PT population = 92%

Genomic risk (g)

70-gene signature or MammaPrint®

N=644

c-Low/g-Low

Discordant

c-High/g-Highc-Low/g-High c-High/g-Low

No chemotherapy Chemotherapy

R-T

N=2745N=592 N=1550

N=1806

32%

MINDACT: CHARACTERISTICS OF CLINICAL

HIGH-RISK PATIENTS

Cardoso F, et al. N Engl J Med 2016;375(8):717–29.

cH/gL (n=1550) cH/gH (n=1806) All cH (n=3356)

Age <50y

Age >50y

534 (34.5%)

1016 (65.5%)

716 (39.6%)

1090 (60.4%)

1250 (37.2%)

2106 (62.8%)

T<1 cm

T1-2 cm

T >2 to 5 cm

T>5 cm

38 (2.5%)

610 (39.4%)

843 (54.4%)

58 (3.7%)

29 (1.6%)

914 (50.6%)

843 (46.7%)

20 (1.1%)

67 (2.0%)

1524 (45.4%)

1686 (50.3%)

78 (2.3%)

N0

N1

>4 N pos

812 (52.4%)

731 (47.2 %)

6 (0.4%)

1329 (73.6%)

475 (26.3%)

2 (0.1%)

2141 (63.8%)

1206 (35.9%)

8 (0.2%)

G1

G2

G3

98 (6.3%)

995 (64.2%)

443 (28.6%)

15 (0.6%)

421 (23.3%)

1365 (75.6%)

113 (3.4%)

1416 (42.2%)

1808 (53.9%)

HR+/HER2-

HR+/HER2+

HR-/HER2+

HR-/HER2–

1402 (90.5%)

115 (7.4%)

9 (0.6%)

20 (1.3%)

895 (49.6%)

222 (12.3%)

122 (6.8%)

566 (31.3%)

2297 (68.4%)

337 (10.0%)

131 (3.9%)

586 (17.5%)

Patients Events 5-year DMFS (95% CI)

644 38 94.7 (92.5-96.2)

Patients Events 5-year DMFS (95% CI)

644 78 95.1 (93.1-96.6)

Median FU 5 years Median FU 8.7 years

MINDACT: PRIMARY ENDPOINT

Distant metastasis-free survival in clinical high/genomic low (no CT)

Cardoso F, et al. N Engl J Med 2016;375(8):717–29; Piccart M, et al. Presented at AACR 2016; with permission from Prof M Piccart; Cardoso F, et al. J Clin Oncol 38: 2020 (suppl; abstr

506). Presented at ASCO 2020; with permission from Prof F Cardoso.

95% CI excludes 92%: primary endpoint met

TAILORx: STUDY DESIGN

HR+/HER2–, N-negative, T1c-2 any grade or T1b and G2/3

Primary analysis: non-inferiority (iDFS) of HT vs. CT+HT in women in the RS 11–25 group

Sparano JA, et al. N Engl J Med 2015;373(21):2005–14.

RS <11

Oncotype DX® assayEnrolled 10,071 pts (2006–2010) 900 sites, 6 countries

Primary study group

RS 11-25RS >25

RandomiseARM A: endocrine

therapy alone

ARM D: CT plus

endocrine therapy

ARM B: endocrine

therapy alone

ARM C: CT plus

endocrine therapy

N=6897 (67.3%)

N=1626 (15.9%) N=1730 (16.9%)

All RS 0-10 RS 11-25 RS>26

All 9719 1619 (16.7%) 6711 (69.0%) 1389 (14.2%)

Age <50y 2694 (31.4%) 429 (26%) 2216 (33%) 409 (29%)

Postmenoapausal

Premenopausal

6419 (66%)

3300 (34%)

1141 (70%)

478 (30%)

4296 (64%)

2415 (36%)

982 (71%)

407 (29%)

T, median (range) NA 1.5 (1.2-2.0) 1.5 (1.2-2.0) 1.7 (1.3-2.3)

G1

G2

G3

2512 (27%)

5242 (55%)

1676 (18%)

530 (34%)

931 (59%)

111 (7%)

1893 (29%)

3721(57%)

884 (14%)

89 (7%)

590 (43%)

681 (50%)

PgR neg

PgR pos

951 (10%)

8571 (90%)

28 (2%)

1555 (98%)

518 (8%)

6061 (92%)

405 (30%)

948 (70%)

Clin low risk

Clin high risk

6615 (70%)

2812 (30%)

1227 (78%)

345 (22%)

4799 (74%)

1697 (26%)

589 (43%)

770 (57%)

TAILORx: PATIENTS’ CHARACTERISTICS


5yrs rate 94.0% ±0.6

9yrs rate 84.0% ±1.3

5yrs rate 99.3% ±0.62

9yrs rate 96.8% ±0.7

5yrs rate 98.8% ±0.3

9yrs rate 95.0% ±0.8

5yrs rate 98.0% ±0.4

9yrs rate 93.7% ±0.8

iDFS event (NEJM 2018) n=185:

Nonbreast primary cancer n=75

Contralateral invasive BC n=29

Death without another event n=33

Distant recurrence n=28

Local/regional recurrence n=20

TAILORX: PROGNOSIS OF RS LOW PATIENTS

From N Engl J Med, Sparano JA, et al. Prospective Validation of a 21-

Gene Expression Assay in Breast Cancer, 373(21), 2005–14. Copyright ©

2015 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society.

Invasive disease-free survival Freedom from recurrence of breast cancer at distant site

Freedom from recurrence at any site Overall survival

RECURRENCE SCORE:

PROGNOSTIC ROLE FOR N+ PATIENTS

WSG-PlanB: Trial design

*Endocrine and radiotherapy according to national guidelinesNitz U, et al. SABCS 2014; Poster P4-11-01; Nitz U, et al. Breast Cancer Res Treat 2017;165(3):573–83

*pT >2 cm

G2-3

uPA/PAI-1 high

HR–

≤35 years

HR–

Pts qualifying for chemotherapy by

◆ HER2–

◆ pN+

◆ pN0 high risk

Recurrence score

HR+

0-3 LNand

RS >11or

≥4 LN

0-3 LNand

RS ≤11

Randomisation

DOC75C600 x 6*

E90C600 x 4 →DOC100 x 4*

Endocrine therapy*

WSG PlanB: 5-YEAR DFS ACCORDING TO RS

Nitz U, et al. Breast Cancer Res Treat 2017;165(3):573–83; reproduced under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (available at: http://creativecommons.org/licenses/by-

nc/4.0/. Accessed Aug 2020)

pN0 5-yrs DFS rate

RS 0-11 94.2% (90.4-98.0)

pN1 5-yrs DFS rate

RS 0-11 94.4% (89.5-99.3)

http://creativecommons.org/licenses/by-nc/4.0/

Patients treated with ET alone

BREAST CANCER-SPECIFIC MORTALITY

In patients with node-negative and node-positive breast cancer guided by the

21-gene assay: A SEER-Genomic population-based study

Hortobagyi G, et al, Presented at SABCS 2018; poster P3-11-02; with permission from Dr G Hortobagyi.

N0 N1

OUTLINE

Introduction









MINDACT: CT VS. NO CT IN CH/GL

(SECONDARY ENDPOINT)

Absolute difference in DMFS between CT and no CT

groups:

◆ At 5 years: 0.9 ± 1.1% points

◆ At 8 years: 2.6 ± 1.6% points

Type of first event (n=150)

◆ Distant recurrences: 74.7%

◆ Death of any cause: 25.3%

Cardoso F, et al. J Clin Oncol 38: 2020 (suppl; abstr 506). Presented at ASCO 2020; with permission from Prof F Cardoso.

Distant metastasis free survival (DMFS)

MINDACT: CT VS. NO CT IN CH/GL, HR+/HER2–

PATIENTS, STRATIFIED BY AGE


Age ≤50 years Age >50 years

5% difference No difference

TAILORx (N0): RS 11–25, PRIMARY ENDPOINT

RS 11–25, randomised to CT+ET or ET alone n=6711

From N Engl J Med; Sparano JA, et al., Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer, 379:111–21, Copyright © 2018. Massachusetts Medical Society. Reprinted with permission from


CT+ET

ET

A 5-year rate of invasive disease–free survival of 90% with chemoendocrine therapy and of 87% or less with endocrine therapy alone, which

corresponds to a 32.2% higher risk of an invasive disease recurrence, second primary cancer, or death as a result of not administering

chemotherapy (hazard ratio, 1.322)

iDFS 5 years % 9 years %

ET 92.8 ± 0.5 83.3 ± 0.9

CT+ET 93.1 ± 0.5 84.3 ± 0.8

CT + ET:

86.8%

ET:

96.8%

ET: 94.5%

CT: 95.0%

ET:

98.5%

ET: 93.6%

CT+ET: 95.2%

ET: 86.9%

CT+ET: 93.4%

CT+ET:

88.7%

ET: 97.2%

CT+ET: 98.0%

TAILORx: FREEDOM FROM RECURRENCE FROM

BREAST CANCER AT A DISTANT SITE, 9-YEAR RATES


All patients

Young patients (≤50 yrs), n=2216

0–11 ≥2611–25

0–11 11–15 16–20 21–-25 ≥26

EFFECT OF AGE AND MENOPAUSAL STATUS

ON CT BENEFIT (RS 16–25)

From N Engl J Med; Sparano JA, et al. Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer, 380:2395–405. Copyright © 2019, Massachusetts Medical Society. Reprinted with permission from


In T1/T2, N0 cancers, genomic assays are valuable for determining whether to recommend chemotherapy:

Yes 93.6%, No 4.3%, Abst 2.1%

In T3, N0 cancers, genomic assays are valuable for determining whether to recommend chemotherapy:

Yes 74.5%, No 21.3%, Abst 4.3%

In (T any), N1-3+ cancers, genomic assays are valuable for determining whether to recommend chemotherapy:

Yes 78.7%, No 17.0%, Abst 4.3%

EARLY BREAST CANCER

ESMO Clinical Practice Guidelines for diagnosis treatment and follow-up

Validated gene expression profiles may be used to gain additional prognostic and/or predictive information to

complement pathology assessment and help in adjuvant ChT decision making [I, A].

USE OF BIOMARKERS TO GUIDE DECISIONS ON

ADJUVANT SYSTEMIC THERAPY

For women with early-stage invasive breast cancer: ASCO Clinical

Practice Guideline update – Integration of results from TAILORx

Andre F, et al. J Clin Oncol 2019;37(22):1956–64. ASCO Special Article.

Group Recommendation Evidence rating

ER+/HER2–

N0

Clinicians may use the 21-gene RS to guide decision for adj CT Quality: high, Strength: strong

>50 years with RS <26 and ≤50 yrs with RS <16: may offer endocrine therapy Quality: high, Strength: strong

≤50 years with RS 16-25: may offer chemoendocrine therapy Quality: intermediate, Strength: moderate

RS >30: should be considered candidates for chemoendocrine therapy Quality: high, Strength: strong

RS 26-30: may offer chemoendocrine (panel consensus) Quality: insufficient, Strength: moderate

ER+/HER2–

N+Clinicians should not use the 21-gene RS to guide decision for adj CT Quality: intermediate, Strength: moderate

OUTLINE

Introduction









EXTENDED ADJUVANT THERAPY FOR HR+ BC

After 5 years of adjuvant ET, recurrences continue to occur steadily up to 20 years1

The risk of distant recurrence ranges from 10 to 41%, depending on TN stage and tumour grade1

Impact of extended AI therapy depends on prior endocrine therapy, with larger risk reduction in patients with

prior tamoxifen2

Absolute benefit varies across N categories: Nneg <1-3 pos nodes <4+ pos nodes2

Careful consideration of potential side effects (risk of bone fracture increased by 25%)2

The majority of the trials reported substantial discontinuation rate

1. Pan H, et al. N Engl J Med 2017;377(19):1836–46; 2. Gray R, et al. (EBCTCG), SABCS 2018.

PROGNOSTIC ROLE OF GENE EXPRESSION

SIGNATURES FROM YEAR 5 TO 10

Sestak I, et al. JAMA Oncol 2018;4(4):545–53.

Gene signature

Patient group

Node-negative disease (n=535) Node-positive disease (n=154)

HR (95% CI)a C Index (95% CI) HR (95% CI)a C Index (95% CI)

CTS 1.95 (1.43-2.65) 0.721 (0.654-0.788) 1.61 (1.05-2.47) 0.644 (0.534-0.753)

IHC4 1.59 (1.16-2.16) 0.660 (0.576-0.745) 1.20 (0.79-1.81) 0.579 (0.460-0.697)

RS 1.46 (1.09-1.96) 0.585 (0.467-0.702) 1.24 (0.81-1.90) 0.555 (0.418-0.693)

BCI 2.30 (1.61-3.30) 0.749 (0.668-0.830) 1.60 (1.04-2.47) 0.633 (0.514-0.751)

ROR 2.77 (1.93-3.96) 0.789 (0.724-0.854) 1.65 (1.08-2.51) 0.643 (0.528-0.758)

EPclin 2.19 (1.62-2.97) 0.768 (0.701-0.835) 1.87 (1.27-2.76) 0.697 (0.594-0.799)

PREDICTIVE ROLE OF BCI IN THE

TRANS-ATTOM STUDY

Bartlett JMS, et al. Ann Oncol 2019;30(11):1776–83. Reproduced under the terms of the Creative Commons Attribution Non-Commercial License (available at: http://creativecommons.org/licenses/by-nc/4.0/; accessed

August 2020).

Relative benefit Absolute benefit

http://creativecommons.org/licenses/by-nc/4.0/

OUTLINE

Introduction









AGREEMENT AMONG TESTS

Summary of head to head comparisons of risk classifications by 6 prognostic signatures

Varga Z, et al. Int J Cancer 2019;145(4):882–93. © 2019 UICC. Reproduced with permission from John Wiley and Sons.

52.6 56.6

39.0 37.0

51.6 54.2

35.9 27.3

30.3

11.5 16.2

30.7

63.0

48.4 45.8

0

20

40

60

80

100

RS BCI ROR EP Epclin MMP

Pat

ient

s pe

r ris

k gr

oup

(%)

High risk

Intermediate risk

Low risk

PERFORMANCE OF 6 PROGNOSTIC SIGNATURES

IN TRANSATAC

Sestak I, et al. JAMA Oncol 2018;4(4):545–53. Reproduced under the terms of the CC-BY License (available at: https://creativecommons.org/licenses/. Accessed August 2020). © 2018.

◆ Differences may be related, at least in part, to: clinicopathological features in EpClin, differing ability to predict late recurrences

◆ Potential selection bias can not be excluded (n=928 out of the n=9366 enrolled in ATAC)

◆ Comparison studies on different clinical platforms may be useful

https://creativecommons.org/licenses/

OUTLINE

Introduction









MINDACT: EFFECT OF CLINICAL RISK ON PROGNOSIS


Distant metastasis free survivalWithin the same clinical risk category, genomic risk

discriminates groups at different prognosis

Within the same genomic risk category, clinical risk

discriminates groups at different prognosis

TAILORx: EFFECT OF CLINICAL RISK ON PROGNOSIS



TAILORx: EFFECT OF CLINICAL RISK ON PREDICTION

OF CT BENEFIT (RS 11-25)



TAILORx: EFFECT OF CLINICAL RISK ON PREDICTION

OF CT BENEFIT (DISTANT RECURRENCE RATES)

<50 years, RS 16-25

Sparano JA, ASCO 2019; Sparano JA, et al. N Engl J Med;2019;380:2395–405.

Estimated absolute chemo benefit

not stratified by clinical riskClinical risk No.

Estimated absolute chemo

benefit stratified by clinical risk

RS 16-20 (N=886)Δ +1.6%

(±SE 1.9%)

Low 671 (76%)Δ -0.2%

(±SE 2.1%)

High 215 (24%)Δ +6.5%

(±SE 4.9%)

RS 21-25 (N=476)Δ +6.5%

(±SE 3.7%)

Low 319 (67%)Δ +6.4%

(±SE 4.9%)

High 157 (33%)Δ +8.7%

(±SE 6.2%)

ER expression

Time since random assignment (years)

100

80

60

40

20

0

BC

FI (

%)

6543210

≥50%

20% to 49%

<20%

No. of

patients

3,892

400

509

Events

293

66

103

5-year BCFI

(% ± SE)

92.6 ± 0.5

85.9 ± 1.8

81.4 ± 1.8

More than 10% difference in the 5-year BCFI

according to the level of ER expression

REFINING THE RISK ASSESSMENT:

THE TEXT-SOFT ADJUVANT TRIAL ANALYSIS

Regan MM, et al. J Clin Oncol 34(19), 2016: 2221–3. Reprinted with permission. © (2016) American Society of Clinical Oncology. All rights reserved.

PERFORMANCE OF CLINICAL SELECTION

From N Engl J Med; Francis PA, et al. Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer, 379:122–37. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts

Medical Society

OUTLINE

Introduction









GENE EXPRESSION SIGNATURES IN CLINICAL PRACTICE

1. Curtit E, et al. Breast 2019;44:39–45; 2. Albanell J, et al. Eur J Cancer 2016;66:104–13; 3. Dieci MV, et al. Oncologist 2019;24(11):1424–31.

CharacteristicsPONDx1

(N=866), n (%)Pooled European2

(n=565), n (%)ROXANE3

(n=251), n (%)

Age >50 yrsAge ≤50 yrs

633 (73)233 (27)

>55: 394 (70)<55: 171 (30)

159 (63)92 (37)

Pre/peri-menopausalPostmenopausal

283 (32)579 (67)

NA105 (43)142 (57)

T ≤2cmT >2cm

570 (66)296 (34)

397 (70)167 (30)

171 (69)77 (31)

N0N1

613 (71)253 (29)

565 (100)0

152 (61)99 (39)

Grade 1Grade 2Grade 3

120 (14)589 (68)157 (18)

99 (18)387 (69)75 (13)

17 (7)142 (57)92 (37)

PgR posPgR neg

744 (86)122 (14)

489 (87)71 (13)

211 (84)40 (16)

CT indication 66% 45% 52%

Treatment change 44% 32% 30%

CT net reduction 37% 30% 16%

Clin Low: 73 (29.1%)

Clin High: 178 (70.9%)

OPTIMISING THE USE OF GENOMIC

PROGNOSTIC TESTS

Decision on adjuvant CT for HR+/HER2- BC: clinical utility demonstrated

Decision on extended adjuvant endocrine tx: clinical validity demonstrated (Endopredict, prosigna, BCI), clinical utility to be proved

Regulatory restrictions still limit the use outside clinical studies in many countries.

Classic clinicopathological features still matter!

It is challenging to provide a universally accepted definition of the patients for whom the test would be most useful:

◆ Avoid offering the test to patients not suitable for chemotherapy

◆ Avoid offering the test to patients for whom the decision is highly unlikely to change (clinical judgement)

Avoid multiple testing for the same patient

Once you have the results (i.e. RS for N0):

◆ RS<16: avoid CT

◆ RS 16-25: decision based on age and clinical risk

◆ RS>26: consider CT

◆ Word of caution on substituting CT with OFS in young patients: compliance, OFS was beneficial in SOFT patients who

remained premenopausal after CT

THANK YOU!

e-learning gene expression signature to inform on adjuvant ......mindact: study design cardoso f, et...

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