Introduction to the 8th Edition of the AJCC Staging System ... · •Genetic counselling and...

9/12/2019

1

Christy A Russell, MD

Senior Director of Medical Affairs, Genomic Health

ASCO Update on Diagnosis and Treatment of Early Breast Cancer

Agenda

•Genetics vs Genomics•Genetic counselling and testing

•Genomics in breast cancer and other cancers

•Prognostic versus Predictive biomarkers

•Multigene assays of early breast cancer

2

Genetics and Genomics

9/12/2019

2

WHO Definitions: Genetics & Genomics

4

GENETICS: The study of heredity

GENOMICS: The study of genes and their functions

Genetics examines the function of a single gene (or

chromosome) while Genomics examines groups of genes and

their relationships in order to identify their combined influence on

an organism

Clinical Utility of Genetics in Oncology

• Can be used to predict risk of disease development

̶ BRCA1 & 2: Increased risk of breast, ovarian, and other

tumors

̶ APC (Adenomatous polyposis coli): Increased risk of

familial adenomatous polyposis/colon CA

• Can be used to locate “targets” for intervention

• Generally involves mutations, variations

5

Clinical Utility of Genomics in Oncology

• Early and accurate diagnoses

• Greater individualization of treatment decisions

• Targeted therapy based on individual disease

• Greater likelihood of clinical trial success

• More rational drug discovery

• Faster drug development

– Patient selection

– Trial design

Normal gene expression and interaction - BIOLOGY

6

9/12/2019

3

Let’s Start With Genetics

Slide 4

Breast Cancer Risk Factors

9/12/2019

4

The likelihood of having a BRCA mutation is:

Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

Current Guidelines

9/12/2019

5

Controversies to Consider

9/12/2019

9/12/2019

9/12/2019

6

9/12/2019

9/12/2019

7

Summary for Panel Testing

• Testing of BRCA1, BRCA2, and moderate risk predisposition genes may result in improved clinical management of patients

• Accurate population-based and family history-based risk estimates for each gene are needed.

• Age-related risks must be defined for improved medical management of mutation carriers.

Besides Early Diagnosis, Why Does Knowing Genetic Status Matter?

9/12/2019

8

Final Thoughts

Now on to Genomics!

One More Important Concept:Prognostic Versus Predictive Biomarkers

• Prognostic biomarkers: A prognostic biomarker provides information on a cancer outcome (eg,

disease recurrence, disease progression)

• Predictive biomarkers: A biomarker is predictive if the treatment effect is different for biomarker-

positive patients compared with biomarker-

negative patients

• At least 2 comparison groups are needed (eg, 2 different treatment arms in a randomized trial)

• Examples: HER2, ER

• To determine whether a biomarker is potentially predictive, a formal test for an interaction between

the biomarker, treatment group, and outcome must be statistically significant (P

9/12/2019

9

Contr

ol

Review of Prognosis Versus Prediction30%

25%

20%

15%

10%

5%

0%

0 5 10 15 20 25 30 35 40

30%

25%

20%

15%

10%

5%

0%

0 5 10 15 20 25 30 35 40

Prognostic biomarkers are measured before treatment to indicate long-term outcome for patients untreated or receiving standard treatment

Predictive biomarkers are measured before treatment to identify who will or will not benefit from a particular treatment

Treatme

nt

Contr

ol

Treatme

nt

Ris

k o

f R

ecurr

ence

Ris

k o

f R

ecurr

ence

Score

Score

Simon et al. J Natl Cancer Inst. 2009.

Patients

Receiving

Significant

Benefit

Patients

Receivin

g No

Benefit

No Differential Treatment

Benefit

Breast Cancer Mortality: Endocrine Therapy +/- Chemotherapy

26

Lancet 2012;379:432-44

Approximately 1/3 Reduction

In Br Ca Mortallity, Regardless

Of Subgroup

Moving from Empiric to Precision Medicine

27

9/12/2019

10

Early-stage Disease:

Answering the difficult question

Genomic (Multigene) Tools

Examples of Multigene Assays in Oncology

• INVASIVE BREAST CANCER

• Breast Cancer Index (Biotheranostics)

• Endopredict (Myriad Genetics)

• Mammaprint (Agendia)

• Oncotype DX (Genomic Health, Inc)

• Prosigna (Nanostring Technologies, Inc)

• COLON CANCER

• Coloprint (Agendia)

• Gene FX Colon (Helomics)

• Oncodefender (Everest Genomics)


• PROSTATE CANCER

• Decipher (Genome DX Biosciences)


• Prolaris (Myriad Genetics)

29

Precision Medicine: Role of Biomarkers in Breast Cancer

• 1st generation: protein expression ~ 1970• ER/PR IHC

• 2nd generation: gene amplification ~ 1990• HER2/neu FISH

• 3rd generation: gene expression ~ 2004• Oncotype DX, Mammaprint, BCI

• PAM50, Endopredict

• 4th generation: mutational profiling ~ 2010• Commercial and academic assays

9/12/2019

11

Microarray-based Technology

Gene Cluster Diagram

Sorlie T et al. PNAS. 2001;98(19):10869-10874Sørlie et al. Proc Natl Acad Sci U S A. 2003;100:8418.

Full genecluster diagramof 496 intrinsicgenes

Classification Based on Gene-Expression

Carey LA et al. J Am Med Assoc 2006:295(12):2492-2502.

9/12/2019

12

Copyright ©2003 by the National Academy of Sciences

Prognosis of Various Subsets

Sorlie et al PNAS 2003

van de Vijver MJ et al. N Engl J Med 2002;347:1999-2009.

Prognostic Factors in ER Positive Breast Cancer

Presented By Harold Burstein at 2019 ASCO Annual Meeting

9/12/2019

13

Slide 31

Slide 32

Moving Beyond a “One Size Fits All” Approach Management of ER+ Early Stage Breast Cancer

• Adjuvant chemotherapy reduces the 10-year mortality rate for breast cancer by about 30% as shown in multiple trials

• Decisions to give adjuvant chemotherapy were formerly based on level of inherent risk of recurrence (prognosis) rather than on factors predictive of response to therapy

• The relative risk reduction with chemotherapy is independent of patient age, nodal status, tumor size, or tumor grade

EBCTCG. Lancet. 2012.

9/12/2019

14

NIH Consensus Development Panel, 2001

• It is accepted practice to offer cytotoxic chemotherapy to node

negative women with primary breast cancers larger than 1 cm

in diameter

• For women with lymph node-negative cancers smaller than 1

cm in diameter, the decision to consider chemotherapy should

be individualized.

JNCI Monographs 2001: 30: 5-15

Most ER+ Node-negative Patients Don’t Recur:

Only ~4% Benefit from Addition of Chemotherapy

0 2 4 6 8 10 12

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

All Patients

Tam + ChemoTam P = 0.02

N Events

424 33

227 31 Pro

po

rtio

n w

ith

ou

t D

ista

nt

Recu

rren

ce

NSABP B-20: Tamoxifen vs Tamoxifen + Chemo – All 651 Patients

Paik et al. J Clin Oncol. 2006.

4.4%

absolute

benefit from

tam + chemo

at 10 years

At10 yr:92%

88%

9/12/2019

15

Agendia, Inc.

43

(70-Gene Test)

MammaPrint®: 70 Gene cDNA Microarray Expression Profile

No distant metastases

Group (< 5 yrs)

Full genome

gene

expression

analysis

Distant metastasesGroup (< 5 yrs) Prognosis reporter genes

Netherlands Cancer Institute

Frozen Tissue Bank

Tumor samples of

known clinical outcome

Prognostic Risk Assessment Data

MINDACT

45

9/12/2019

16

MINDACT: Study Design

EnrollmentN=6693

Clinical Risk (C)Adjuvant! Online

Genomic Risk (G)70-gene signature

C-low/G-low N=2745C-low/G-high

N=592C-high/G-low

N=1550C-high/G-high

N=1806

Discordant

Randomized ChemotherapyNo Chemotherapy

Modified from Cardoso et al. N Engl J Med. 2016.

“We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene

signature to standard clinical–pathological criteria in selecting patients for adjuvant chemotherapy.”

46

Clinical Risk Assessment in the MINDACT Trial

47

MINDACT: Enrollment and Risk Groups Included in the AnalysesOnly 644 out of 6693 Patients Were Used in the Primary Analysis

Modified from Cardoso et al. N Engl J Med. 2016.

EnrollmentN = 6693

344 assigned to receive chemo

346 not assigned to receive chemo

2634 had C-low and G-low at enrollment

(2745*)

690 had CLINICAL LOW RISK and genomic high risk at

enrollment (592*)

1497 had CLINICAL HIGH RISK and Genomic low risk at

enrollment (1550*)

1873 had C-high and G-high at enrollment

(1806*)

*Number of patients in this group after

lab error correction appliedR

749 assigned to receive chemo

748 not assigned to receive chemo

R

53 had a change

in risk

42 received

chemotherapy

4 were ineligible

57 had a change in risk

76 received chemotherapy

5 had unknown

chemotherapy status

4 were ineligible

26 had a change in

risk

128 received

chemotherapy

9 had unknown

chemotherapy status

11 were ineligible

21 had a change in

risk

85 received

chemotherapy

1 had unknown

chemotherapy status

12 were ineligible

224 were included in

the per-protocol

population

254 were included

in the per-protocol

population

592 were included

in the per-protocol

population

636 were included in

the per-protocol

population

644 were included

in the primary-test

population

Intent-to-treat population

Per protocol population

Genomic high (G-high): 70-gene assay high risk

Genomic low (G-low): 70-gene assay low risk

48

9/12/2019

17

Click to edit Master title style Click to edit Master title styleClick to edit Master title style Click to edit Master title style

MINDACT: Primary Objective Was Met5-Year Rate of Distant Metastasis–Free Survival (DMFS)

Primary Objective:

In patients with high clinical risk, low

genomic risk (no chemotherapy), is the lower

boundary of the 95% confidence interval (CI)

for the rate of 5-year DMFS 92% or higher?

Yes, patients not treated with chemotherapy

(CT) had a 5-year DMFS rate of: 94.7%

(95% CI, 92.5 to 96.2)

Heterogeneous primary test population:

• N0, N1, N2

• ER/PR+, ER-/PR-

• HER2+ & HER2-

Cardoso et al. N Engl J Med. 2016.; Piccart et al. AACR. 2016.

ER: estrogen receptor

HER2: human epidermal growth factor receptor 2

PR: progesterone receptor

CI: confidence interval

49

Hormone Receptor–Positive/Node-Negative and Positive Populations

MINDACT

50

MINDACT: 70-Gene Assay Has Not Been Show to be Predictive of Chemotherapy Benefit in Node-Negative Patients – ITT Population

Cardoso et al. N Engl J Med. 2016.

DMFS: distant metastasis–free survival

ITT: intent-to-treat population

CT: chemotherapy


N=666 patients

Despite high-risk 70-Gene Assay results, patients receive no benefit from

chemotherapy

Despite low-risk 70-Gene Assay results, patients show a trend towards

chemotherapy benefit (31% risk reduction)

N=787 patients

(70-Gene Assay Low) (70-Gene Assay High)

51

9/12/2019

18

Low-Risk 70-Gene Assay Patients Showed a Consistent Improvement When Randomized to Chemotherapy – ITT PopulationClinical High-Risk/Genomic Low-Risk (MammaPrint® Low)

29% relative risk reduction

Cardoso et al. N Engl J Med. 2016.

Chemotherapy

No Chemotherapy

Year Disease-Free Survival CTPatients

(N)Events

(O)% at 5 yr(95% CI)

Hazard Ratio (95% CI)

P-value

Clinical high-risk Yes 749 54 92.9 (90.5-94.7) 0.71 (0.50-1.01) 0.055

MammaPrint low-risk No 748 78 90.1 (87.5-92.1) 1.00

70-gene assay low-risk patients experience a disease-

free survival benefit from

chemotherapy

~3%

absolute benefit

ITT: intent-to-treat population

CT: chemotherapy

CI: confidence Interval

52

Patients With Low-Risk 70-Gene Assay Results Showed a Consistent Improvement When Randomized to Chemotherapy

Risk Group, Outcome,

and Treatment Strategy*Chemotherapy

No. of

Patients

No. of

Events

Percentage With Outcome

of 5 Years (95% CI)

Hazard Ratio

(95% CI)

P-

Value

Clinical high-risk and

genomic low-risk

DMFS35% relative risk

reduction



Disease-free survival



Overall survival



Adapated from Cardoso et al. N Engl J Med. 2016.

*Per-protocol population.


DMFS: distant metastasis-free survival

53

Hormone Receptor-Positive/Node-Positive Population

MINDACT

54

9/12/2019

19

MINDACT: Node-Positive PatientsWhy Did Node-Positive Patients Do Better Than Node-Negative Patients?

Node-Negative: Clinical High/Genomic Low Node-Positive: Clinical High/Genomic Low

Median follow-up for lymph node-positive patients is

9/12/2019

20

58

The 21-gene assay uses a genomic approach to predict recurrence risk and response to adjuvant therapy

RS = + 0.47 x HER2 Group Score

- 0.34 x ER Group Score

+ 1.04 x Proliferation Group Score

+ 0.10 x Invasion Group Score

+ 0.05 x CD68

- 0.08 x GSTM1

- 0.07 x BAG1

PROLIFERATION

Ki-67

STK15

Survivin

Cyclin B1

MYBL2

ESTROGEN

ER

PR

Bcl2

SCUBE2

INVASION

Stromelysin 3

Cathepsin L2

HER2

GRB7

HER2

BAG1GSTM1

REFERENCEBeta-actinGAPDH

RPLPOGUS

TFRC

CD68

16 Cancer and 5 Reference Genes From 3 Studies

Category RS (0 -100)

Low risk RS

9/12/2019

21

Rationale for Adjusting Breast Recurrence Score® Midrange to

11-25 for TAILORx Trial

NSABP B-20

61

Sparano et al. J Clin Oncol. 2008.

Significant chemotherapy benefit with Breast Recurrence Score (RS) results

≥ 26 similar to RS result ≥ 31

Patients 10-Year DRFS (%)Recurrence by Addition

of Chemotherapy

RS No. % TAM TAM + chemo HR 95% CI P

0-10 177 27 98 95 1.788 0.360 to 8.868 0.471

11-25 279 43 95 94 0.755 0.313 to 1.824 0.531

26-100 195 30 63 88 0.285 0.148 to 0.551 < 0.0001

DRFS: distant recurrence-free survival

RS: Breast Recurrence Score result

TAM: tamoxifen

Absolute Benefit = 25% Relative Risk Reduction = 71%

TAILORx Design: Treatment Assignment & Randomization

Accrued Between April 2006 – October 2010

62

HR+/HER2- Node Negative Breast Cancer

21-Gene RS

(N=10,273)

Arm A: Low RS 0-10

Endocrine Therapy (ET)

(N=1629)

Mid-Range RS 11-25

RANDOMIZE

(N=6711)

Arm D: High RS 26-100

ET + Chemo

(N=1389)

ARM B: Experimental ArmET Alone(N=3399)

ARM C: Standard ArmET + Chemo

(N=3312)

RS: Breast Recurrence Score® result

Stratification Factors:• Menopausal Status• Planned Chemotherapy• Planned Radiation• RS 11-15, 16-20, 21-25

TAILORx Results: Endocrine Therapy Alone Was Not Inferior to Chemoendocrine

Therapy in Patients With RS 11-25 (Arms B & C)

Primary Endpoint: 9-Year Invasive Disease-Free Survival (iDFS) in ITT Population

836 iDFS events after

median follow-up of 7.5

years

63

ITT: intent-to-treat

iDFS: invasive disease-free survival

RS: Breast Recurrence –Score® result

ET: endocrine therapySparano et al. N Engl J Med. 2018.

9/12/2019

22

TAILORx Results: Patients With RS 11-25 (Arms B & C) Have a Very Low Risk of Distant

Recurrence

Secondary Endpoint: 9-Year Distant Recurrence–Free Interval in ITT Population

199 of 836 (23.8%) were distant recurrences

64

Sparano et al. N Engl J Med. 2018.


DRFI: distant recurrence–free interval


ET: endocrine therapy

65

TAILORx – Exploratory Subgroup Analysis

TAILORx Results: Exploratory Analysis in Clinical Subgroups to Identify Chemotherapy Benefit in Recurrence Score® 11-25

• Exploratory interaction tests were performed for subgroups that may derive chemotherapy benefit in the Breast Recurrence Score 11-25 group (ITT population)

• Exploratory analysis subgroups:

• Recurrence Score subgroups 11-15 vs 16-20 vs 21-25; 11-17 vs 18-25

• Clinicopathologic subgroups: tumor size, tumor grade, clinical risk category

• Menopausal status

• Age

66

Sparano et al. N Engl J Med. 2018. ITT: intent-to-treat

9/12/2019

23

TAILORx Results: Exploratory Analysis of Chemotherapy Treatment Interactions in Recurrence Score® Results 11-25 Arms

67

Recurrence Score result11-15 vs 16-20 vs 21-25

11-17 vs 18-25

Tumor size (≤2 cm vs >2 cm)

Grade (low vs int vs high)

Menopausal status (pre vs post)

Clinical risk category (high vs low)


No statistically significant chemotherapy treatment interactions were found in any

of these subgroups

TAILORx Results – ITT Population: Exploratory Analysis of Chemotherapy Treatment Interactions in Recurrence Score (RS) 11-25 Arms

Statistically significant chemotherapy treatment interactions

• Age (≤50, 51-65, >65) and chemotherapy benefit• IDFS (p=0.003)

• RFI (p=0.02)

• Age (or menopause), RS (11-15, 16-20, 21-25), and chemotherapy benefit• IDFS - Age-RS (p=0.004)

• IDFS - Menopause-RS (p=0.02)

There was no statistically significant chemotherapy treatment interaction seen with patient age and RS for distant recurrence–free interval

68


IDFS: Invasive Disease Free Survival

RFI: Recurrence Free Interval

69

ET Alone ET Alone

CHEMO + ET CHEMO + ET


TAILORx Results: Association Between Continuous Recurrence Score® Results 11-25 and 9-Year Distant Recurrence Rate by Treatment Arms Stratified by Age


>50 Years (n=4495)≤50 Years (n=2216)

The magnitude of chemotherapy benefit in patients ≤50 years increases with increasing

Recurrence Score result, but was not statistically significant

9/12/2019

24

TAILORx Results: A Small Chemotherapy Benefit is Seen in Women≤50 Years (N = 3054) With Recurrence Score® Results 16-20 and 21-259-Year Freedom From Distant Recurrence

70




CT: chemotherapy

RS: Recurrence Score results

*These differences in distant recurrences, while not statistically significant, may be clinically significant.

* *

Clinical Risk*

Low High

Recurrence

Score

0-25(n = 8068)

75% 25%

26-100(n = 1359)

43% 57%

TAILORx Results: 21-Gene Assay Prevents Over- and Undertreatment of Patients

71


Would have been

overtreated

*low clinical risk defined by low grade and tumor size ≤ 3 cm, intermediate grade and tumor size ≤ 2 cm, and high grade and tumor size ≤ 1 cm;

high clinical risk defined as all other cases with known values for grade and tumor size

Would have been

undertreated

Consistent Inclusion of 21-Gene Assay in National Treatment GuidelinesNode-Negative, Hormone Receptor-Positive, HER2-Negative Invasive Breast Cancer

72

(pT1-3, pN0) Tumor >0.5 cmStrongly consider 21-

gene assay

RS* 0-25

RS 26-30

RS 31-100

Adjuvant endocrine therapy*

Adjuvant endocrine therapy

or

Adjuvant chemotherapy followed

by endocrine therapy

Adjuvant endocrine therapy +

adjuvant chemotherapy

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelinese for Breast Cancer V.3.2018. © 2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. NCCN does not endorse any product or therapy. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

*In the TAILORx study, exploratory analyses of patients ≤50 years with RS

16-25 revealed lower distant recurrence rates for those randomized to

chemoendorine therapy; adjuvant chemotherapy may be considered for

these patients.

*RS: Recurrence Score® result

ASCO® GuidelinesNCCN® Guidelines

RS 0-25, Age >50

RS 0-15, Age ≤50

RS 16-25, Age ≤50

RS 31-100, All Ages

May offer endocrine therapy alone

May offer chemoendocrine therapy

Should be considered for

chemoendocrine therapy

RS 26-30, All Ages May offer chemoendocrine therapy

Patients Recommendation

9/12/2019

25

TAILORx-Defined Cutoff By Age for Definitively Determining Chemotherapy Benefit with the 21-Gene Assay

(Node-negative, HR-positive, HER2-negative)

73

1. Sparano et al. J Clin Oncol. 2008.; 2. Genomic Health (data on file) RS distributions in tested US N-, HR+, HER2- patients in 2017

Subgroup Age >50 years

RS 0-10No CT Benefit




RS 26-100CT Benefit1

~85% of patients2 ~15% of patients2


TAILORx-Defined Cutoff By Age for Definitively Determining Chemotherapy Benefit with the 21-Gene Assay

(Node-negative, HR-positive, HER2-negative)

74

1. CT benefit for distant recurrence from Sparano 2018 ASCO presentation.; 2. Sparano et al. J Clin Oncol. 2008.; 3. Genomic Health (data on file) RS distributions in tested US N-, HR+, HER2- patients in 2017

Subgroup Age ≤50 years



RS 16-20~1.6% CT Benefit1

RS 21-25~6.5% CT Benefit1

RS 26-100CT Benefit2

~50% of patients3 ~23% of patients3 ~12% of patients3 ~15% of patients3


Using the 21-Gene Assay in Node-Positive Disease after TAILORx

75

9/12/2019

26

Oncotype DX Breast Recurrence Score® Test for Treatment Decisions in Node-Positive Disease: RxPONDER Trial Schema

76

pN1mic & pN1, HR+, HER2- breast cancer

Study-sponsored RS testing

RS already availableRS ≤25

RS ≤25RS >25

or

Discuss alternative

clinical trials

Randomize

Randomization stratification factors:

• RS

9/12/2019

27

61.4%

36.1%

82.1%

29.4%

38.6%

34.5%

17.9%

OPTIMA study stratified risk comparing Oncotype DX with prognostic MGAs in the same patients

Oncotype DXBreast Recurrence

Score® assay

0-25 26-100Recurrence Score® results:

Low Intermediate HighRisk categories:

Prosigna

MammaPrint

Adapted from: Bartlett et al. JNCI J Natl Cancer Inst, 2016, Vol. 108, No. 9

Data from Table 3, IHC4-AQUA and conventional IHC4 data not shown

Pooled risk group distributions, N=313 early breast cancer patients

Conclusions

Genetics and Genomics

• It is important to understand who is at risk for developing a hereditary breast cancer• Challenges:

There are many different multigene tests to choose from.

There are an inadequate number of genetic counsellors to screen and inform patients.

Results are not definitive with many VUS within each test.

There are deleterious genes which only slightly increase the risk of developing cancer.

• There are multiple multigene assays which aid in the assessment of prognosis of women with ER+, HER2- early breast cancer

• It is important to understand the concepts of prognostic genomic markers versus predictive markers

• These genomic assays have been instrumental in reducing the exposure of women with breast cancer to unnecessary chemotherapy and to identify those who will truly benefit.

• Of the 6 multigene assays commercially available, only two have been a part of larger randomized clinical trials

• Future studies will continue to define the best therapy for the right patient.

81

9/12/2019

28

82

Questions?

Introduction to the 8th Edition of the AJCC Staging System ... · •Genetic counselling and...

Documents

Transcript of Introduction to the 8th Edition of the AJCC Staging System ... · •Genetic counselling and...