Qualitative and Quantitative Image-Based Biomarkers of Therapeutic Response for Triple-Negative Breast Cancer

Daniel I. Golden, Ja A. Lipson, Melinda L. Telli, James M. Ford, Daniel L. Rubin

Department of Radiology, Stanford University Daniel Rubin Laboratory

AMIA Joint Summits on Translational Bioinformatics March 1822, 2013

Quantitative Imaging Laboratory

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Motivation
Triple-Negative Breast Cancer 15% of all breast cancers; 30,000 annual diagnoses; 8000 deaths Lacks estrogen, progesterone, HER2 receptors Response to chemo is mixed

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Motivation
Triple-Negative Breast Cancer 15% of all breast cancers; 30,000 annual diagnoses; 8000 deaths Lacks estrogen, progesterone, HER2 receptors Response to chemo is mixed Critical Need A way to predict in advance whether patients will respond: Precision Medicine

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Motivation
Triple-Negative Breast Cancer 15% of all breast cancers; 30,000 annual diagnoses; 8000 deaths Lacks estrogen, progesterone, HER2 receptors Response to chemo is mixed Critical Need A way to predict in advance whether patients will respond: Precision Medicine
Known Malignancy Selection of Optimal Treatment

???
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Treatment A Treatment B

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Motivation
Dynamic Contrast-Enhanced MRI (DCE-MRI) Acquires multiple images before and after contrast injection Whole tumor, minimally-invasive (unlike biopsy) Reveals tumor kinetic phenotype: morphology and texture Hypothesis: Features can predict treatment response

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Motivation
Dynamic Contrast-Enhanced MRI (DCE-MRI) Acquires multiple images before and after contrast injection Whole tumor, minimally-invasive (unlike biopsy) Reveals tumor kinetic phenotype: morphology and texture Hypothesis: Features can predict treatment response
Known Malignancy Selection of Optimal Treatment

???
Daniel Golden (dgolden1@stanford.edu) Breast Cancer Imaging Biomarkers

Treatment A Treatment B

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Motivation
Dynamic Contrast-Enhanced MRI (DCE-MRI) Acquires multiple images before and after contrast injection Whole tumor, minimally-invasive (unlike biopsy) Reveals tumor kinetic phenotype: morphology and texture Hypothesis: Features can predict treatment response
Known Malignancy MRI Features Selection of Optimal Treatment

???
Daniel Golden (dgolden1@stanford.edu) Breast Cancer Imaging Biomarkers

Treatment A Treatment B

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Outline

Imaging Biomarkers

Modeling and Results

Conclusion and Future Work

Daniel Golden (dgolden1@stanford.edu)

Breast Cancer Imaging Biomarkers

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Outline

Imaging Biomarkers

Modeling and Results

Conclusion and Future Work

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List of Features

Semantic Imaging Breast Imaging Reporting and Data System (BI-RADS) Quantitative Imaging Lesion kinetic texture via the Gray-Level Co-Occurrence Matrix (GLCM) Both assessed prior to chemotherapy

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List of Features

Semantic Imaging Breast Imaging Reporting and Data System (BI-RADS) Quantitative Imaging Lesion kinetic texture via the Gray-Level Co-Occurrence Matrix (GLCM) Both assessed prior to chemotherapy

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Semantic Imaging Features

BI-RADS Checklist of descriptors of lesion shape, margins, enhancement

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Semantic Imaging Features

BI-RADS Checklist of descriptors of lesion shape, margins, enhancement

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Tumor Spatial Heterogeneity

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Tumor Spatial Heterogeneity

Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor.

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Dynamic Contrast-enhanced MRI

0.7 min 2.5 min 14.9 min

10 mm

1000
Image 800 Intensity 600

Wash-Out Wash-In

400 0 2 4 6 8 Minutes 10 12 14
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Breast Cancer Imaging Biomarkers

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Dynamic Contrast-enhanced MRI

0.7 min 2.5 min 14.9 min

10 mm

1000
Image 800 Intensity 600

Wash-Out Wash-In

trans

(min )

2 1.5 1

400 0 2 4 6 8 Minutes 10 12

140.5
9 / 14

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Breast Cancer Imaging Biomarkers

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Quantitative Texture via the GLCM

The Gray-Level Co-Occurrence Matrix (GLCM) Based on kinetic texture (rate of contrast uptake) Gray Level = pixel value

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Quantitative Texture via the GLCM

The Gray-Level Co-Occurrence Matrix (GLCM) Based on kinetic texture (rate of contrast uptake) Gray Level = pixel value

Quantized Lesion Kinetic Image

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Quantitative Texture via the GLCM

The Gray-Level Co-Occurrence Matrix (GLCM) Based on kinetic texture (rate of contrast uptake) Gray Level = pixel value

Pixel and Quantized Lesion Neighbor Values Kinetic Image

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Quantitative Texture via the GLCM

The Gray-Level Co-Occurrence Matrix (GLCM) Based on kinetic texture (rate of contrast uptake) Gray Level = pixel value
Count and Sum
GLCM
2000

Pixel Amplitude

4 6 8 2

Pixel and Quantized Lesion Neighbor Values Kinetic Image

Pixel Amplitude

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Num Pixels

Quantitative Texture via the GLCM

The Gray-Level Co-Occurrence Matrix (GLCM) Based on kinetic texture (rate of contrast uptake) Gray Level = pixel value
Count and Sum
Number of pixels with value 4 neighboring pixels with value 1

Pixel Amplitude

4 6 8 2

Pixel and Quantized Lesion Neighbor Values Kinetic Image

Pixel Amplitude

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Num Pixels

GLCM

2000

Quantitative Texture via the GLCM

The Gray-Level Co-Occurrence Matrix (GLCM) Based on kinetic texture (rate of contrast uptake) Gray Level = pixel value
Count and Sum
Number of pixels with value 4 neighboring pixels with value 1

Pixel Amplitude

4 6 8 2

Pixel and Quantized Lesion Neighbor Values Kinetic Image

Pixel Amplitude

Scalar measures of image texture

Contrast Correlation Energy Homogeneity

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Num Pixels

GLCM

2000

Outline

Imaging Biomarkers

Modeling and Results

Conclusion and Future Work

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Example Model Results

Modeling Methodology Cohort: 60 neoadjuvant triple-negative BC patients Lasso logistic regression (includes feature selection) Performance assessed via cross-validated ROC curves

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Example Model Results

Modeling Methodology Cohort: 60 neoadjuvant triple-negative BC patients Lasso logistic regression (includes feature selection) Performance assessed via cross-validated ROC curves
Pathologic Complete Response

Residual Tumor

Residual Nodes

Resid Tumor + Nodes

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Example Model Results

Modeling Methodology Cohort: 60 neoadjuvant triple-negative BC patients Lasso logistic regression (includes feature selection) Performance assessed via cross-validated ROC curves
Pathologic Complete Response
BIRADS (n=59) GLCM (n=53) 95% CI

Residual Tumor

Residual Nodes

Resid Tumor + Nodes 0.5 0.6 0.7 ROC AUC 0.8 0.9 1

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Example Model Results

Modeling Methodology Cohort: 60 neoadjuvant triple-negative BC patients Lasso logistic regression (includes feature selection) Performance assessed via cross-validated ROC curves
Pathologic Complete Response
BI-RADS
BIRADS (n=59) GLCM (n=53) 95% CI

GLCM

Residual Tumor

Residual Nodes

GLCM BI-RADS

Resid Tumor + Nodes 0.5 0.6 0.7 ROC AUC 0.8

0.9

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Outline

Imaging Biomarkers

Modeling and Results

Conclusion and Future Work

Daniel Golden (dgolden1@stanford.edu)

Breast Cancer Imaging Biomarkers

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Conclusion and Future Work

Conclusion Contrast-enhanced MRI can predict treatment response Both morphological and texture features effective for different response denitions Future Work Improve model
Extend features to 3D New quantitative features (e.g., wavelets, region clustering via superpixels) Combine imaging with other biomarkers (e.g., genomics)

Sensitivity analysis Validate in independent cohort

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Conclusion and Future Work

Conclusion Contrast-enhanced MRI can predict treatment response Both morphological and texture features effective for different response denitions Future Work Improve model
Extend features to 3D New quantitative features (e.g., wavelets, region clustering via superpixels) Combine imaging with other biomarkers (e.g., genomics)

Sensitivity analysis Validate in independent cohort

Daniel Golden (dgolden1@stanford.edu)

Breast Cancer Imaging Biomarkers

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Thank You
Mentor Daniel Rubin Collaborators Ja Lipson Melinda Telli Jim Ford Katie Planey Nick Hughes Funding Stanford SCIT Program (NIH T32 CA009695) NIH U01 CA142555
Daniel Golden (dgolden1@stanford.edu) Breast Cancer Imaging Biomarkers Mar 1822, 2013 15 / 14

Breast DCE-MRI Heterogeneity Review

Malignancy Sinha et al., 1997; Chen et al., 2007; Woods et al., 2007; Kale et al., 2008; Nie et al., 2008; Agner et al., 2011; Karahaliou et al., 2012 Hauth et al., 2008; Preim et al., 2011

Survival

Type

Treatment Response

Texture

Holli et al., 2010 Chang et al., 2004; Padhani et al., 2009

Histogram

Johansen et al., 2009

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Breast DCE-MRI Heterogeneity Review

Malignancy Sinha et al., 1997; Chen et al., 2007; Woods et al., 2007; Kale et al., 2008; Nie et al., 2008; Agner et al., 2011; Karahaliou et al., 2012 Hauth et al., 2008; Preim et al., 2011

Survival

Type

Treatment Response You Are Here Chang et al., 2004; Padhani et al., 2009

Texture

Holli et al., 2010

Histogram

Johansen et al., 2009

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Example Selected Features

good response
BIRADS NonMass BIRADS Mass Margin Spiculated BIRADS Mass Enhancement Homogeneous BIRADS Mass Shape Round 1 0.5 0 b*std

poor response

0.5

BI-RADS to predict residual tumor + nodes

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Data Set

The Triple-Negative Breast Cancer (TNBC) Trial Clinical trial run by Melinda Telli and Jim Ford at Stanford 93 patients with triple-negative or BRCA-mutated breast cancer 69 patients available for analysis This imaging study: retrospective and proof-of-concept

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Non-Imaging Features
Clinical Age at diagnosis Tumor stage (IAIIIA) Tumor grade (II or III) T and N stage from TNM (T0T4, N0N3) ER/PR percent (for non-triple-negative) Ki67 percent Cycles of treatment received (4 or 6) Genomic BRCA 1/2 mutation status

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Kinetic Modeling
t=1.5 min

1 cm

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Kinetic Modeling
t=1.5 min

3
Fractional enhancement

2 1 0 1 0

Data Model

1 cm

Minutes

10

15

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Kinetic Modeling
t=1.5 min

3
Fractional enhancement

2 1 0 1 0
K (min1)
ep

Data Model

1 cm Ktrans (min1)

Minutes

10
ve (unitless)

15
3

2 1.5 1 0.5

2 1.5 1 0.5
0 2

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Lasso

Feature Sets
All Clinical All Clinical but Ki67 Ki67 GLCM Pre GLCM Post GLCM Pre and GLCM Post Patterns of Response BIRADS GLCM Pre and BIRADS

Lasso Model

Response
Residual Tumor Residual Lymph Nodes Residual Tumor and Nodes

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All Model Results

a) Predict pCR
All Clinical All Clinical but Ki67 GLCM Pre GLCM Post GLCM Pre and GLCM Post Patterns of Response BIRADS GLCM Pre and BIRADS

b) Predict residual tumor

junk junk junk

n=46 n=60 n=53 n=46 n=42 n=57 n=59 n=53

junk junk

junk junk

junk junk junk 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

c) Predict residual nodes

All Clinical All Clinical but Ki67 GLCM Pre GLCM Post GLCM Pre and GLCM Post Patterns of Response BIRADS GLCM Pre and BIRADS
Daniel Golden (dgolden1@stanford.edu)

d) Predict residual tumor and nodes

AUC 95% CI

junk junk

junk

junk

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

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Breast Cancer Imaging Biomarkers

Model Features
Relevant features for predicting Residual Tumor
PostChemotherapy GLCM 0.5 0.75 1 AUC

Postchemo GLCM Kep Correlation Postchemo GLCM Ktrans Correlation Postchemo GLCM ve Homogeneity Postchemo GLCM WashIn Energy Postchemo WashOut Average 1 0 b*std 1

GLCM Pre and PostChemotherapy 0.5 0.75 1 AUC

Postchemo GLCM Kep Correlation Postchemo GLCM Ktrans Correlation Postchemo GLCM WashIn Energy Postchemo GLCM Kep Contrast Postchemo WashOut Average 1
Daniel Golden (dgolden1@stanford.edu)

0 b*std

1
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Breast Cancer Imaging Biomarkers

Model Features
Relevant features for predicting Residual Lymph Nodes
Clinical All 0.75 GLCM Pre and PostChemotherapy 0.5 0.75 1 AUC

0.5 AUC Tumor Stage IIIA BRCA1 Negative Treatment Cycles: 4 Age Tumor Grade II TNM: N1 Treatment Cycles: 6 BRCA1 Positive Ki67 percent TNM: N0 1

Prechemo GLCM Kep Homogeneity Postchemo Lesion Area Postchemo GLCM Ktrans Correlation Prechemo GLCM Kep Contrast 1 0 b*std
BIRADS 0.75

0 b*std

0.5 AUC BIRADS NonMass BIRADS Mass Margin Spiculated BIRADS NonMass Segmental BIRADS Mass Enhancement Homog. BIRADS Mass Margin Smooth BIRADS Mass Shape Round 1

0.5 AUC Tumor Stage IIIA BRCA1 Negative Age Treatment Cycles: 4 TNM: N1 TNM: N0 1

Clinical Except Ki67 0.75 1

0 b*std

0 b*std

PreChemotherapy GLCM and BIRADS 0.5 0.75 1 AUC

PreChemotherapy GLCM 0.5 0.75 1 AUC

Prechemo GLCM Kep Energy Prechemo GLCM Contrast AUC Energy Prechemo GLCM Ve Contrast Prechemo GLCM Kep Contrast 2 0 b*std 2

BIRADS NonMass Prechemo GLCM Contrast AUC Energy Prechemo GLCM Kep Energy Prechemo GLCM Kep Homogeneity Prechemo GLCM Ktrans Homogeneity BIRADS Mass Margin Spiculated BIRADS NonMass Enhancement Homog. BIRADS NonMass Segmental BIRADS Mass Shape Round Prechemo GLCM Kep Contrast 2 0 b*std 2

PostChemotherapy GLCM 0.5 0.75 1 AUC

Postchemo GLCM Ktrans Correlation Postchemo Lesion Area 1 0 b*std 1

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Model Features
Relevant features for predicting Residual Tumor and Lymph Nodes
Clinical All 0.75 BIRADS 0.75

0.5 AUC Tumor Stage IIIA Treatment Cycles: 4 Tumor Grade II BRCA1 Negative TNM: N1 Age Treatment Cycles: 6 TNM: N0 Ki67 percent 1

0.5 AUC BIRADS NonMass BIRADS Mass Margin Spiculated BIRADS NonMass Enhancement Homog. BIRADS NonMass Segmental BIRADS Mass Enhancement Homog. BIRADS Mass Shape Round 1

0 b*std

0 b*std

PostChemotherapy GLCM 0.5 0.75 1 AUC

PreChemotherapy GLCM and BIRADS 0.5 0.75 1 AUC

Postchemo GLCM Ktrans Correlation Postchemo Lesion Area 1 0 b*std 1

GLCM Pre and PostChemotherapy 0.5 0.75 1 AUC

BIRADS NonMass BIRADS Mass Margin Spiculated Prechemo GLCM Contrast AUC Energy Prechemo GLCM Ktrans Homogeneity Prechemo GLCM Kep Energy Prechemo GLCM Kep Homogeneity Prechemo GLCM Ktrans Energy BIRADS NonMass Segmental BIRADS NonMass Enhancement Homog. Prechemo Contrast AUC Average BIRADS Mass Enhancement Homog. BIRADS Mass Shape Round 1 0 b*std 1

Postchemo GLCM Ktrans Correlation Postchemo Lesion Area Prechemo GLCM Kep Energy 1 0 b*std 1

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Model Features
Relevant features for predicting No Residual Tumor
GLCM Postchemotherapy 0.5 0.75 1 AUC

0.5 AUC ki67 percent 0.5

Ki67 0.75

GLCM Ktrans correlation postchemo GLCM wash out slope contrast postchemo avg wash out postchemo 1 0 b*std 1

0 b*std

0.5

GLCM Pre and GLCM Postchemotherapy 0.5 0.75 1 AUC

GLCM Ktrans correlation postchemo GLCM AUC contrast prechemo GLCM kep contrast postchemo GLCM wash out slope contrast postchemo avg wash out postchemo 1 0 b*std 1

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Residual Cancer Burden

1
Cumulative Distribution Function

0.8 0.6 0.4 0.2 0 0

3 2.5 2 1.5
3 3 2 4

RCB>2.5 (12, 21%) 0<RCB<2.5 (26, 46%)

Natural separation points

RCB=0 (pCR) (19, 33%)

2 3 RCB Value
5 4

5
6 5
5

Residual Nodes (3, 5%)

Term 2 (Positive Nodes)

4
RCB

3
2 3 2 1 4

1 1 0.5 0 0

2 1

Residual Tumor (22, 39%)

pCR (19, 33%)

Tumor + Nodes (13, 23%)

1 2 Term 1 (Primary Tumor)

0 3 Only 1 case with residual tumor and nodes and RCB<2.5

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