Leading healthcare experts Dr. Hannah Linden and Dr. Gary Ulaner offer their insights about a diagnostic imaging agent that may help inform physicians clinical decisions and treatment selection for people with recurrent or metastatic breast cancer. For more information, visit our website at sharecancersupport.org or call our Helpline at 844.ASK.SHARE (844.275.7427).

1. The Impact of Targeted Estrogen Receptor (ER) Imaging on Patients
with Breast Cancer
Gary Ulaner, MD, PhD, FACNM
James and Pamela Muzzy Endowed Chair of Molecular Imaging & Therapy
Hoag Family Cancer Institute
Professor of Radiology and Translational Genomics
University of Southern California

2. DISCLOSURES
Research Grants
• NIH R01 (#CA204167, #CA248398)
• Department of Defense (#W81XWH-14-1-0444)
• Komen for the Cure Foundation (#KG110441)
• Leukemia & Lymphoma Society (#RTF6004-19)
Consultant/Advisory Board/Lecturer
• GE Healthcare/Zionexa
• Siemens
• Genentech
• Sanofi
• Novartis
• Puma biotechnology
• ImaginAb
• Progenics/Lantheus

3. Estrogen Receptor (ER) targeted imaging
FES PET

4. FES PET ≠ FDG PET
FES PET measures available ER FDG PET measures metabolism

5. “Normal” distribution of FES PET/CT
Injection
drainage
Liver
Renal
collecting
system
bowel
Bladder
Ulaner, Seminars in Nuclear Medicine 2022

6. Scenario number Description Appropriateness Score
Diagnosis
1 Diagnosing primary breast cancer Rarely appropriate 2
2 Diagnosing malignancy of unknown primary when a biopsy is not feasible or is nondiagnostic May be appropriate 5
Staging
3 Routine staging of the primary tumor (T staging) Rarely appropriate 1
4 Routine staging of axillary nodes Rarely appropriate 3
5 Routine staging of extra-axillary nodes and distant metastases May be appropriate 5
6 Staging invasive lobular carcinoma and low-grade invasive ductal carcinoma May be appropriate 5
Biopsy
7 Assessing ER status, in lieu of biopsy, in lesions that are easily accessible for biopsy May be appropriate 5
8 Assessing ER status in lesions that are difficult to biopsy, or when biopsy is nondiagnostic Appropriate 8
Selection of therapy
9 After progression of metastatic disease, for considering second line of endocrine therapy Appropriate 8
10 At initial diagnosis of metastatic disease, for considering endocrine therapy Appropriate 8
11 At initial diagnosis of primary breast cancer, for considering endocrine therapy Rarely appropriate 1
Other
12 Measuring response to therapy Rarely appropriate 1
13 Detecting lesions in patients with suspected/known recurrent or metastatic breast cancer May be appropriate 5
14 Detecting ER status when other imaging tests are equivocal or suspicious Appropriate 8
SNMMI Appropriate Use Criteria (AUC) in development

7. Mortimer, Dehdashti, et al, J Clinical Oncology 2001
FES PET predicts response of ER+ breast cancer to endocrine therapy
Cerianna SUV
Before Therapy
-----------------------------------------------------
Locally advanced or
metastatic breast cancer;
Therapy with tamoxifen
Responders Non-
Respondersrs

8. Boers et al, Eur J Cancer 2020
FES PET predicts response of ER+ breast cancer to endocrine therapy
Metastatic breast cancer; Therapy with letrozole and palbociclib
FDG pre Tx FES pre Tx
---------------------------
---------------------------
FDG post Tx

9. Authors Year # subjects Therapy
Mortimer et al. 1996 43 unspecified hormonal therapy or chemotherapy
Dehdashti et al. 1999 11 tamoxifen
Mortimer et al. 2001 40 tamoxifen
Linden et al. 2006 47 unspecified hormonal therapy after discontinuing tamoxifen
Dehdashti et al. 2009 51 fulvestrant or AI
Linden et al. 2011 30 tamoxifen, fulvestrant, or AI
Peterson et al. 2014 19 tamoxifen, fulvestrant, or AI±fulvestrant
Van Kruchten et al. 2015 16 fulvestrant
Van Kruchten et al. 2015 19 estradiol post ≥ 2 lines of endocrine therapy
Park et al. 2016 24 letrozole + lapatinib
Kurland et al. 2017 90 tamoxifen, fulvestrant, or AI±fulvestrant
Chae et al. 2017 26 neoadjuvant chemotherapy or letrozole
Boers et al. 2020 30 letrozole + palbociclib
He et al. 2020 36 fulvestrant
Liu et al. 2020 12 fulvestrant
Peterson et al. 2021 23 vorinostat + AI
Su et al. 2021 30 high-dose tamoxifen
FES PET predicts response of ER+ breast cancer to endocrine therapy

10. Patient: Metastatic ER+ Breast Cancer. Progressing on 1st line ER-targeted therapy. Should a
2nd line ER-targeted therapy be used?
Importance: ER-targeted
therapy will not be effective
---------------------------------
FDG PET F18 Fluoroestradiol PET

11. Patient: Metastatic ER+ Breast Cancer. Should ER-targeted therapy be used?
Importance:
Appropriate for ER-targeted therapy.
-------------------------------

12. Scenario number Description Appropriateness Score
Diagnosis
1 Diagnosing primary breast cancer Rarely appropriate 2
2 Diagnosing malignancy of unknown primary when a biopsy is not feasible or is nondiagnostic May be appropriate 5
Staging
3 Routine staging of the primary tumor (T staging) Rarely appropriate 1
4 Routine staging of axillary nodes Rarely appropriate 3
5 Routine staging of extra-axillary nodes and distant metastases May be appropriate 5
6 Staging invasive lobular carcinoma and low-grade invasive ductal carcinoma May be appropriate 5
Biopsy
7 Assessing ER status, in lieu of biopsy, in lesions that are easily accessible for biopsy May be appropriate 5
8 Assessing ER status in lesions that are difficult to biopsy, or when biopsy is nondiagnostic Appropriate 8
Selection of therapy
9 After progression of metastatic disease, for considering second line of endocrine therapy Appropriate 8
10 At initial diagnosis of metastatic disease, for considering endocrine therapy Appropriate 8
11 At initial diagnosis of primary breast cancer, for considering endocrine therapy Rarely appropriate 1
Other
12 Measuring response to therapy Rarely appropriate 1
13 Detecting lesions in patients with suspected/known recurrent or metastatic breast cancer May be appropriate 5
14 Detecting ER status when other imaging tests are equivocal or suspicious Appropriate 8
SNMMI Appropriate Use Criteria (AUC) in development

13. Kurland…Linden, The Oncologist, 2020
FES may evaluate ER status in lesions difficult to biopsy

14. Scenario number Description Appropriateness Score
Diagnosis
1 Diagnosing primary breast cancer Rarely appropriate 2
2 Diagnosing malignancy of unknown primary when a biopsy is not feasible or is nondiagnostic May be appropriate 5
Staging
3 Routine staging of the primary tumor (T staging) Rarely appropriate 1
4 Routine staging of axillary nodes Rarely appropriate 3
5 Routine staging of extra-axillary nodes and distant metastases May be appropriate 5
6 Staging invasive lobular carcinoma and low-grade invasive ductal carcinoma May be appropriate 5
Biopsy
7 Assessing ER status, in lieu of biopsy, in lesions that are easily accessible for biopsy May be appropriate 5
8 Assessing ER status in lesions that are difficult to biopsy, or when biopsy is nondiagnostic Appropriate 8
Selection of therapy
9 After progression of metastatic disease, for considering second line of endocrine therapy Appropriate 8
10 At initial diagnosis of metastatic disease, for considering endocrine therapy Appropriate 8
11 At initial diagnosis of primary breast cancer, for considering endocrine therapy Rarely appropriate 1
Other
12 Measuring response to therapy Rarely appropriate 1
13 Detecting lesions in patients with suspected/known recurrent or metastatic breast cancer May be appropriate 5
14 Detecting ER status when other imaging tests are equivocal or suspicious Appropriate 8
SNMMI Appropriate Use Criteria (AUC) in development

15. FES may be used to solve clinical dilemmas in recurrent or MBC cases
Retrospective study: F18 fluoroestradiol PET
solved 87/100 imaging dilemmas, including:
- Inconclusive imaging finding (n = 52)
- which tumor caused a metastasis (n=17)
- unclear ER status of tumor (n=31)
15

16. Scenario number Description Appropriateness Score
Diagnosis
1 Diagnosing primary breast cancer Rarely appropriate 2
2 Diagnosing malignancy of unknown primary when a biopsy is not feasible or is nondiagnostic May be appropriate 5
Staging
3 Routine staging of the primary tumor (T staging) Rarely appropriate 1
4 Routine staging of axillary nodes Rarely appropriate 3
5 Routine staging of extra-axillary nodes and distant metastases May be appropriate 5
6 Staging invasive lobular carcinoma and low-grade invasive ductal carcinoma May be appropriate 5
Biopsy
7 Assessing ER status, in lieu of biopsy, in lesions that are easily accessible for biopsy May be appropriate 5
8 Assessing ER status in lesions that are difficult to biopsy, or when biopsy is nondiagnostic Appropriate 8
Selection of therapy
9 After progression of metastatic disease, for considering second line of endocrine therapy Appropriate 8
10 At initial diagnosis of metastatic disease, for considering endocrine therapy Appropriate 8
11 At initial diagnosis of primary breast cancer, for considering endocrine therapy Rarely appropriate 1
Other
12 Measuring response to therapy Rarely appropriate 1
13 Detecting lesions in patients with suspected/known recurrent or metastatic breast cancer May be appropriate 5
14 Detecting ER status when other imaging tests are equivocal or suspicious Appropriate 8
SNMMI Appropriate Use Criteria (AUC) in development

17. If malignancy is confirmed, patients will be managed accordingly.
Treatment will not be a component of this protocol.
Pathology will be used to confirm presence or absence of malignancy
If lesions suspicious for distant metastases (cohort 1) or recurrent disease (cohort 2)
are detected on either study, then a suspicious lesion will be selected for biopsy
Interpretation of FES PET/CT and standard of care imaging by separate radiologists,
blinded to the results of the other modality
Research FES PET/CT and standard-of-care imaging (Either CT/bone scan or FDG
PET/CT) within 14 days of each other
Prospective trial of 124 subjects with ER+ breast
cancer
- Cohort 1: 62 with newly diagnosed stage 2B-3C
- Cohort 2: 62 with suspected recurrence
Patients undergo both a standard-of-care imaging
(CT/bone scan or FDG PET/CT) and FES PET/CT.
Image guided biopsy is obtained as the gold
standard.
FES PET/CT Trial at Hoag (NCT04883814)

18. FDG
FES
Patient: Locally advanced (stage 3B) ER+ lobular breast cancer.

19. Patient: ER+ Lobular Beast Cancer post mastectomy. Left chest wall recurrence on FDG PET/CT.
FDG
PET/CT
Importance:
More than 20 bone and thoracic soft
tissue metastases seen on Cerianna PET.
Cerianna
PET/CT

20. Lobular Breast Cancers (ILC) are harder to find than other breast cancers
• ILC accounts for ~15% of breast cancers
• ILC is a clinically and molecularly distinct disease from
IDC
• ILCs show loss of a gene called CDH1, which encodes
for E-cadherin, a cell adhesion molecule
• Lobular breast cancers grow in less tightly packed
tumors, which make them harder to detect on imaging
(mammography, ultrasound, MR, and FDG PET).

21. Cerianna may detect metastatic ILC better than FDG
1 2 3 4 5
Cerianna
FDG
8
0
8
0
Ulaner et al, Journal of Nuclear Medicine, 2020

22. Summary
• 18F-Fluoroestradiol (FES) is a radiolabeled estrogen that is FDA-
approved for the detection of Estrogen Receptor-positive (ER+) breast
cancer by PET imaging
• There are Appropriate Use Criteria (AUC) in development by the
Society of Nuclear Medicine and Molecular Imaging (SNMMI) stating
FES PET is appropriate:
• When considering endocrine therapy (at initial metastases or
progression)
• When lesions are difficult to biopsy or biopsy is nondiagnostic
• When other imaging tests are equivocal
• Additional uses of FES are being evaluated in clinical trials

23. Thank you!!
MSKCC
Sarat Chandarlapaty
Chris Reidl
Serge Lyashchenko
Jason Lewis
Audrey Maugnen
Mithat Gönen
Darra Ross
Adriana Corben
Hoag
Beth Thomsen
Mel Silverstein
Heather McDonald
Colleen Coleman
Louis Vandermolen
Chaitali Nangia
Merry Tetef
U Illinois
John Katzenellenbogen
U Pennsylvania
David Mankoff
Washington University of St Louis
Farrokh Dehdashti
University of Washington
Hannah Linden
• NIH R01 #CA204167
• NIH R01 #CA248398
• Department of Defense (#W81XWH-14-1-0444)
• Komen for the Cure Foundation (#KG110441)

24. The Impact of Targeted Estrogen Receptor (ER) Imaging on Patients
with Breast Cancer
Gary Ulaner, MD, PhD, FACNM
James and Pamela Muzzy Endowed Chair of Molecular Imaging & Therapy
Hoag Family Cancer Institute
Professor of Radiology and Translational Genomics
University of Southern California