The Role of PET Imaging in the Treatment of Metastatic Breast Cancer David A. Mankoff, MD, PhD Vice-Chair for Research, Department of Radiology, University of Pennsylvania & Komen Scholar Thanks; to: Erica Carpenter, Lewis Chodosh, Amy Clark, Angie DeMichele, Robert Doot, Lisa Dunnwald, Ken Krohn, Hank Kung, Brenda Kurland Hannah Linden, Bob Mach, Elizabeth McDonald, Lanell Peterson, Jennifer Specht, Mark Rosen, Mitch Schnall, Erin Schubert work supported by Komen SAC140060, NIH Grants CA42045, CA72064, CA12457, CA211337 S10 RR17229, DOE DE-SE0012476

What if… We could find metastatic breast cancer earlier and with more accuracy? We had scans that could determine whether a treatment for metastatic breast cancer was working early after treatment? We could use imaging to help guide treatment? We had a better way of learning about the biology of metastatic breast cancer in patients?

What if… Great idea – how can we do that? We could do a better job of treating metastatic breast cancer: Determine the location and extent of cancer sites to direct treatment Pick the treatment most likely to work best in an individual patient Decide quickly whether or not the treatment is working Direct the patient to more effective treatment when the treatment we picked is no longer effective Great idea – how can we do that?

Anatomic versus Functional Imaging Anatomic Imaging Relies on tumor size, shape, density e.g., mammography, CT Measures response by changes in size Functional/molecular imaging Relies on in vivo tumor biology: perfusion, metabolism, molecular features e.g., MRI, PET Measures response by changes in functional/molecular processes

Imaging Modalities Used for Cancer Anatomic Computed Tomography (CT) Ultrasound Magnetic Resonance Imaging (MRI) Optical Imaging Magnetic Resonance Spectroscopy (MRS) Radionuclide imaging Positron Emission Tomography (PET) Single-Photon Emission Computed Tomography (SPECT) Functional and Molecular

A Window on “In-the-Patient” Cancer Biology: Positron Emission Tomography (PET) Physics and Chemistry Meet Biology Cyclotron: Isotope Production PET Scanner: Takes Image of Tracer Electron-Positron Interactions 18F* O OH CH2OH 18F* PET Tracer Automated “Hot Cell”: Makes PET Tracer Image of Tracer Concentration 18F-Fluorodeoxyglucose (FDG): a tracer of sugar metabolism

PET/CT Combines Molecular and Anatomical Imaging (Alessio, Rad Clin N Amer, 2005)

What if… We could find metastatic breast cancer earlier and with more accuracy? We had scans that could determine whether a treatment for metastatic breast cancer was working early after treatment? We could use imaging to help guide treatment? We had a better way of learning about the biology of metastatic breast cancer in patients?

Breast CA Features Associated with FDG Uptake Associated with high uptake: High nuclear grade ER-negative (triple-negative) Proliferation Associated with low uptake: Well-differentiated (especially Grade I lobular) Low nuclear grade ER+ Prior (effective) therapy (Avril, J Nucl Med 42:9, 2001; Bos J Clin Oncol 20:379, 2002; Kumar Br Ca Res Treat, 98:267, 2006)

FDG PET/CT Detects Breast Cancer Outside the Breast and Axilla coronal axial

FDG PET Detects Lytic Bone Metastases Missed by Bone Scan Fluoride Bone Scan FDG PET

What if… We could find metastatic breast cancer earlier and with more accuracy? We had scans that could determine whether a treatment for metastatic breast cancer was working early after treatment? We could use imaging to help guide treatment? We had a better way of learning about the biology of metastatic breast cancer in patients?

Standard Imaging Has there been a response to Therapy? Post-Therapy (3 months) Pre-Therapy

PET Imaging Has there been a response to Therapy? (answer = Yes!) Post-Therapy (3 months) Pre-Therapy

FDG Uptake Predicts Outcome of Bone-Dominant Breast Cancer (Specht, Br Ca Res Treat, 2007) Time to Skeletal-Related Event Time to Progression > 41% < 41% % Decline in FDG SUV Initial SUV < 5.1 > 5.1

Can PET Measure Response Early? (answer = Yes!) 4 weeks of Therapy Pre-Therapy Sternum - with a max SUV of 7.2, previously 16.0 at baseline Sternum– max SUV 16.0 at baseline, 7.2 after 4 weeks

What if… We could use imaging to help guide treatment? We could find metastatic breast cancer earlier and with more accuracy? We had scans that could determine whether a treatment for metastatic breast cancer was working early after treatment? We could use imaging to help guide treatment? We had a better way of learning about the biology of metastatic breast cancer in patients?

Endocrine Therapy Response Rate: Targeted Breast Cancer Therapy: The Estrogen Receptor (ER) and Endocrine Treatment Endocrine Therapy Response Rate: ER - < 5% ER + 50% - 75% (Johnson and Dowsett, Nat Rev Cancer 3:821, 2002)

[F-18]-Fluoroestradiol (FES): PET Estrogen Receptor (ER) Imaging * Relative Binding (FES vs Estradiol) ER 0.9 SHBG 0.2 - 0.8 (Kieswetter, J Nucl Med, 1984)

18F-Fluoroestradiol (FES) PET Imaging of ER Expression in Breast Cancer Peterson, Mol Imag Biol 16:431, 2014 University of Washington, NCI CIP Phase I/II Program Patient A Biopsy = ER+ Patient B Biopsy = ER- FES FDG FES FDG Corresponding FDG and FES PET coronal slices are shown for two patients in the UW FES trial. Both patients have mediastinal nodal metastases from ER+ breast cancer. Both had biopsy of a metastatic site. Patient A has FES uptake at multiple sites, and, in fact, sites are more prominent on FES PET than FDG PET, as sometimes happens with well-differentiated breast cancer. Patient B has mediastinal disease clearly seen by FDG PET, but not seen on FES PET. Biopsy showed ER- breast cancer. Both are undergoing follow up to determine response to endocrine therapy. Estradiol Binding Glucose Metabolism Estradiol Binding Glucose Metabolism

Is the Target Present? FES Uptake Predicts Breast Cancer Response to Hormonal Therapy Pre-Rx Post-Rx Example 1 Recurrent sternal lesion ER+ primary Recurrent Dz strongly FES+ Excellent response after 6 wks Letrozole FES Example 2 FDG FDG No response to several different hormonal Rx’s Newly Dx’d met breast CA ER+ primary FES-negative bone mets University of Washington (Linden, J Clin Onc, 24:2793, 2006)

Serial FES PET Measures Endocrine Therapy Impact on Tumor Estrogen Binding (Linden, Clinical Cancer Res, 17:4799, 2011) Tamoxifen (blocks receptor) Letrozole (lower estrogen) Fulvestrant (blocks receptor)

FES PET Applied to a New ER-Targeted Agent: Novel Estogen Blocking Drug (SERD; ARN-810) Yang, Clinical Cancer Res, epub, 2017 Pre-therapy Post-ARN-810 (SRD)

What if… We could find metastatic breast cancer earlier and with more accuracy? We had scans that could determine whether a treatment for metastatic breast cancer was working early after treatment? We could use imaging to help guide treatment? We had a better way of learning about the biology of metastatic breast cancer in patients?

Breast Cancer Can Use Fuels other Than Glucose (Dang, Cancer Res 70:859, 2010)

Pre-Clinical Imaging Labeled Glutamine in a Rat Model [18F](2S,4R)-4F-Glutamine not metabolized therefore traces of tumor glutamine transport and pool size (Upper) small-animal PET images of l-[5-11C]-glutamine in xenografted 9L tumor of F344 rat after intravenous injection. Data represent images from summed 60-min scan. Images are shown in transverse, coronal, and sagittal views. Note areas of necrosis within 9L tumor (donut shape). Arrows correspond to organs and tissues of interest. (Lower) small-animal PET time–activity curve for l-[5-11C]-glutamine after intravenous injection into F344 rat. Xenografted 9L tumor was clearly visualized; however, there was necrotic tissue in middle of tumor, which does not show glutamine uptake (donut shape). Heart, liver, and pancreas uptake was also prominent, as is consistent with biodistribution data. (Lieberman, J Nucl Med 52:1947, 2011) (courtesy of Hank Kung and Bob Mach, U Penn)

Glutamine Kinetics & Impact of Blocking Glutaminase (GLS) Block GLS Glutamate Zhou, Pantel, Mankoff

Glutamine Pool Size by 1H NMR [18F]Fluoroglutmaine PET Uptake [18F]Fluoroglutamine to Measure GLS Inhibition in Triple Negative Breast Cancer Mouse Model Zhou, Cancer Research, 2017 Glutamine Pool Size by 1H NMR [18F]Fluoroglutmaine PET Uptake

What if… We could find metastatic breast cancer earlier and with more accuracy? We do that! We had scans that could determine whether a treatment for metastatic breast cancer was working early after treatment? We do that! We could use imaging to help guide treatment? We can do that but FDA approval and clinical trial validation is needed. We had a better way of learning about the biology of metastatic breast cancer in patients? We can do that and Komen funding is helping move it to patients.

Acknowledgements Grants Organizations University of Pennsylvania Komen SAC140060, CA42045, CA72064, CA12457, S10 RR17229, P50CA138293,, DOE DE-SE0012476, CA211337 Organizations ECOG-ACRIN, NCI CIP, NCI QIN University of Pennsylvania Erica Carpenter, Lewis Chodosh, Amy Clark, Chi Dang, Angela DeMichele, Robert Doot, Hank Kung, Camilla Lynch, Bob Mach, Elizabeth McDonald, Karen Palmer, Austin Pantel, Dan Pryma, Mark Rosen, Mitch Schnall, Erin Schubert, Julia Tchou, Rong Zhou University of Washington Janet Eary, Paul Kinahan, Hannah Linden, Mark Muzi, Lanell Peterson, Jennifer Specht, Others Brenda Kurland (Pitt), Ken Krohn and Jeanne Link (OHSU)

US Dept. of Energy Susan G. Komen Translational Radiochemistry Research and Training Center (Mach/Mankoff) University of Pennsylvania Susan G. Komen Komen Leadership Grant