Joan Albanell Servicio de Oncología Médica Implicaciones clínicas de los subtipos intrínsecos de...

Joan AlbanellServicio de Oncología Médica

Implicaciones clínicas de los subtipos intrínsecos de cáncer de mama

The intrinsic breast cancer subtypes

PAM50: intrinsic subtypes and ROR

Studies in Hormone Receptor positive disease

Studies in HER2 positive disease

Studies in Triple Negative disease

Summary

Molecular classification in breast cancer:The intrinsec subtypes

Sorlie, T et al. PNAS, 2001Perou, CM et al. Nature, 2000Perreard, L et al. Breast Cancer Res, 2006

Breast cancer intrinsic subtypes vary in subsets defined by ER and HER2

Prat, A & Perou, CM. Mol Oncol 2011

IHC-based definition of Luminal A is ER+ and/or PR+HER2-Ki67<14%PR>20%

IHC-based definition of Luminal B is ER+ and/or PR+ / HER2- / Ki67<14% / PR<20%orER+ and/or PR+ / HER2- / Ki67>14% or ER+ and/or PR+ / HER2+

IHC-based definition ofLuminal A versus Luminal B tumors

However, these definitions 1) do not fully recapitulate the intrinsic subtypes and 2) are technically challenging (i.e. precise scoring

of Ki-67 and PgR), and thus the Pathology Community needs to establish scoring standards and provide controls

Prat et al. J Clin Oncol 2013

Survival analyses within IHC-LumA tumors






Summary

Extract RNA from FFPE tumor sample

Run RNA & CodeSet on nCounter Analysis System

Intrinsic Subtype

Risk of Relapse (ROR)

RESEARCH

DIAGNOSTICS

FDA 510(k)

Prosigna test (PAM50)

Adapted from Aleix Prat

1. The qRT-PCR assay consists of 50 genes

2. The subtype classification accuracy of the 50 genes by qRT-PCR versus 2000 genes by microarray was 93%

3. The assay works using RNA from FFPE materials or fresh frozen tissues.

PAM50 Using nCounter Classifies Breast CancerInto Intrinsic Subtypes

Parker J Clin Oncol 2009

PAM50 Generates a Risk Of Relapse (ROR) Score Specific to Each Patient

• ROR is based on the similarity of the gene expression profile to intrinsic subtypes, proliferation score (i.e. mean expression prolif-related genes), nodes and tumor size.

• ROR ranges from 0 through 100 (ROR) indicating the probability of distant recurrence in a “training cohort” of patients with tumors representing all subtypes and patients that did not receive any adjuvant systemic therapy.

Patient expression

profile Lum

B

Lum

A

Basa

l-like

HER2

-enr

iched

PAM50 centroids

ROR = aRLumA+

bRLumB+

cRHer2e+

dRBasal+

eP+

fT

Pearson’s correlation to centroids

Proliferation scoreTumor size

Parker et al. JCO 2009; Nielsen et al. CCR 2010






Summary

ATAC studyPostmenopausal

women with invasive BC (N=9366)

Tam alone (N=3116)

Arimidex alone (N=3125)

Tam + Arimidex (N = 3125)

TransATAC study (N=1125 blocks)

ABCSG-8 studyPost-menopausal women with HR+

BC (N=3714)

Tamoxifen(N=1849)

Anastrozole (N=1865)

ABCSG-8 study (N = 1478 blocks)

Tam2-years 3 years

PAM50 (PROSIGNA®) Validation Studies

Primary Objective: Validate published observations that Prosigna/ROR Score provides additional prognostic information over and above standard clinical variables for DRFS at 10 yrs- Primary Analysis: All patients- Secondary Analysis: Node-

negative, node-positive, and HER2-negative patients

Secondary Objective: Validate observations that Luminal A and Luminal B patients have statistically significantly different DRFS at 10 yrs1

Findings From the Combined Analysis of >2400 Patient Samples

DRFS by Risk-Group for Node-negative Patients

DRFS by Risk-Group for Node-positive Patients (1-3 positive nodes)

1.0

0.9

0.8

0.7

0.6

1.0

0.9

0.8

0.7

0.60 2 4 6 810

Follow-Up Time (yrs)

Perc

ent W

ithou

t Dist

ance

Rec

urre

nce

Low-riskIntermediate-riskHigh-risk

0 2 4 68 10 Follow-Up Time (yrs)

Perc

ent W

ithou

t Dist

ance

Rec

urre

nce

Low-riskIntermediate-riskHigh-risk

1.0

0.9

0.8

0.7

0.6

1.0

0.9

0.8

0.7

0.6

Risk Group N (%) EventsThrough 10 Yrs

% Without Recurrence at 10 yrs [95% CI]

Low 875 (49%) 31 96%.2 [94.7% - 97.3%]

Intermediate

551 (31%) 53 89.2% [86.%1 - 91.7%]

High 360 (20%) 73 77.7% [72.8% - 81.95%]

Total 1,786 (100%)

157

Risk Group N (%) EventsThrough 10 yrs

% Without Recurrence at 10 yrs [95% CI]

Low 24 (4%) 2 91.7% [70.6% - 97.8%]

Intermediate

211 (36%) 18 90.4% [85.2% - 93.9%]

High 355 (60%) 87 71.8% [66.3% - 76.6%]

Total 590 (100%)

107

Prosigna Low Risk patients

remain Low Risk over

10yrs

Source: Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol. 2013;31(22):2783-2790: Gnant M, Filipits M, Greil R, et al; Austrian Breast and Colorectal Cancer Study Group. Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol. 2014;25(2):339-345.

Chana Lotan

in node positive graph (right), can you check the range of low risk? 70.6-97.8, is thia correct?

Pascale Morel

in node positive graph (right), can you check the range of low risk? 70.6-97.8, is thia correct?

Pascale Morel

Could we have one highlight on the fact that confidence intervals do not overlap and that therfore the assignement to a risk group is "precise" . See box added.

Knowledge of Luminal Status May Improve Disease Management

DRFS by Risk-Group for Node-Negative Patients

Risk Group N (%)

EventsThrough 10

yrs

% Without Recurrence at 10

yrs [95% CI]

Luminal A

1254 62 94.6% [93.1% – 95.8%]

Luminal B

460 75 81.9% [77.7% – 85.3%]

Total 1,714 137

Risk Group N (%)

EventsThrough 10

yrs

% Without Recurrence at 10

yrs [95% CI]

Luminal A

375 41 87.6% [83.5% – 90.8%]

Luminal B

186 52 68.3% [60.4% – 75.0%]

Total 561 93

DRFS by Risk-Group for Node-Positive Patients

(1-3 Positive Nodes)

Source: Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol. 2013;31(22):2783-2790: Gnant M, Filipits M, Greil R, et al; Austrian Breast and Colorectal Cancer Study Group. Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol. 2014;25(2):339-345.

Pascale Morel

The statement describing the results in the slide should be " Luminal A and Luminal B have different prognostic (or outcome) over time"

Pascale Morel

which would lead to an interest in knowing the Luminal status. But the statemet as it is here is would only derive from a DI study, not the references nor the result of the studies as shown below.

JCO 2013

• Discordance between ROR and RS groups of 43% at the

individual level

Prospective study of the impact of the Prosigna® assay on adjuvant clinical decision-making in an unselected population of women with ER+, HER2-negative, node-negative breast cancer: a GEICAM study

JNCI 2013

• TransATAC study• OncotypeDX RS, PAM50 ROR and IHC4 (Ki67, PgR, ER, HER2 status)

Ivana Sestak

Jack Cuzick, Mitch Dowsett, Martin Filipits, Peter Dubsky, J. Wayne Cowens, Sean Ferree, Carl Schaper, Christian Fesl, Michael Gnant

Centre for Cancer Prevention, Wolfson Institute of Prevention Medicine, Queen Mary University, London, UK Academic Department of Biochemistry, Royal Marsden Hospital, London, UK

Austrian Breast and Colorectal Cancer Study Group, Vienna, AustriaDepartment of Surgery and Comprehensive Cancer Centre, Medical University of Vienna, Vienna, Austria

NanoString Technologies, Seattle, WA, USAMyRAQA, Redwood Shores, CA, USA

San Antonio Breast Cancer – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013

Prediction of late distant recurrence after 5 years of

endocrine treatment: A combined analysis of 2137 patients from the ABCSG-8

and transATAC studies using the PAM50 Risk of Recurrence (ROR) score

Luminal A vs Luminal BHR (95% CI) P-value

Luminal A (N=1530 (71.6%)) - -

Luminal B (N=542 (25.4%)) 2.89 (2.07- 4.02) <0.0001


Sestak et al. SABCS 2013 and JCO 2014

05

10

15

5 6 7 8 9 10

Follow-up time [years]

Luminal B

Luminal A

Dis

tan

t re

curr

en

ce (

%)

4.1%

12.9%

05

10

15


Risk groups – ROR score (N=2137)HR (95% CI)

Low (N=1183 (55.4%)) -

Intermediate (N=538 (25.2%)) 3.26 (2.07-5.13)

High (N=416 (19.5%)) 6.90 (4.54-10.47)

2.4%

16.6%

8.3%

05

1015

20

5 6 7 8 9 10Follow-up time [years]

LowIntermediateHigh

Dis

tant

rec

urre

nce

(%)

05

1015

20

Sestak et al. SABCS 2013






Summary

The HER2-enriched subtype is associated wit higher responses and improved survival outcomes in

HER2+ breast cancer in the NOAH study

• Chemotherapy: AT x 3 T x 4 CMF x 3

• 156 (46.7%) pre-treatment samples were PAM50 profiled.

HER2+ HER2+/HR-

Prat et al. Clin Cancer Res 2014Note: interaction test between HER2E subtype and treatment was not statistically significant.

pCR Odds Ratio P-value

HER2+/HER2-E

No-trastuzumab (n=29) 27.6%

Trastuzumab (n=34) 52.9%

HER2+/nonHER2-E



HER2+/HR-/HER2-E



HER2+/HR-/nonHER2-E



0.002

2.4 0.582

Subtype

5.1 0.009

2.1 0.352

8.7

RESPONSE






Summary

Prat et al. BJC 2014

Summary

• The PAM50 assay provides better intrinsic subtype molecular (Luminal A and B, HER2-enriched and Basal-like) classification than current pathology-based surrogate definitions.

• PAM50 ROR provides robust prognostic information in ER+/HER2- early breast cancer and influenced systemic treatment recommendations in a prospective clinical impact study.

• PAM50 ROR and classification of luminal A vs B tumors may also help to estimate the risk of late recurrences (> 5 years) in ER+ disease.

• HER2+ disease includes all the intrinsic subtypes (i.e. not just Luminal B and HER2-enriched). HER2+enriched tumors appear to benefit the most from anti-HER2 treatments in combination with chemotherapy in the neoadjuvant setting. The role of HER2+ subtyping may vary by disease burden (neoadjuvant, micrometastasis, overt metastasis) and type of regimen.

• Within TNBC, distinguishing Basal-like vs. Other subtypes predicted benefit from chemotherapy and docetaxel vs. carboplatin benefit.

Joan Albanell Servicio de Oncología Médica Implicaciones clínicas de los subtipos intrínsecos de...

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