The Lobular Breast Cancer Alliance (LBCA) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) recently announced Marina Sharifi, MD, PhD, as the recipient of the inaugural SNMMI/LBCA Invasive Lobular Carcinoma (ILC) Imaging Research Fellowship. Dr. Sharifi is an assistant professor in the Department of Medicine, Division of Hematology, Oncology and Palliative Care at the University of Wisconsin, Madison. Dr. Sharifi was awarded the $100,000 grant based on her proposal, Integrating minimally invasive biomarkers of estrogen signaling to detect endocrine therapy resistance in metastatic invasive lobular cancer.

Dr. Sharifi recently took time to explain more about this research.

Q&A with Dr. Marina Sharifi

LBCA: Dr. Sharifi, we are so excited that you are focusing on improving imaging in the treatment of lobular breast cancer, which is such a huge need. We know that ILC poses particular imaging issues in both the early and metastatic stages. Can you explain in simple terms:

• What will this study do?
• What problem in imaging lobular breast cancer tumors does it tackle?
• What will it be adding to the ability to effectively treat metastatic lobular breast cancer?
• How the two tests will be used together in a new way?
• What you expect to have achieved or what new knowledge gained at the end of the two-year study?

Dr. Sharifi: Lobular breast cancer, which accounts for about 15% of breast cancer diagnoses, is almost always estrogen driven (ER+), and treated according to standard approaches for ER+ ductal breast cancers. However, the investigation of lobular breast cancer cells in the lab has suggested that they are less likely to respond well to anti-estrogen therapy than ductal breast cancers, suggesting patients with metastatic lobular breast cancer would be more likely to experience anti-estrogen therapy resistance. Unfortunately, we do not have current clinical diagnostic approaches for early identification of tumors that are insensitive to anti-estrogen therapy; instead, all patients receive this therapy empirically and it is only after repeat imaging at 3 or 6 months that patients with anti-estrogen-resistant disease can be identified and offered alternative treatment approaches.

To address the need for early detection of anti-estrogen therapy resistance in metastatic lobular breast cancer, we propose to evaluate an innovative approach combining two non-invasive tests to measure estrogen signaling in the breast cancer cells of patients while they are being treated with anti-estrogen therapy, to understand whether the treatment is effectively suppressing estrogen signaling to control or eradicate a patient’s breast cancer cells. The first is an imaging test similar to a CT scan that uses a special injected dye called FFNP to highlight areas of breast cancer in the body with high levels of estrogen signaling. The second is a test that measures estrogen signaling in cancer cells found in the blood of breast cancer patients via a simple blood draw. While both tests have been studied in ER+ metastatic breast cancer, neither has been studied specifically in lobular breast cancer. In this study, patients receiving standard anti-estrogen therapy for metastatic ER+ lobular breast cancer will undergo both the imaging and blood test for estrogen signaling before starting treatment, then again after four weeks of treatment.

The goals of this proposal are (1) to identify how tumor estrogen signaling changes on treatment via the imaging test (2) to identify how tumor estrogen signaling changes on treatment via the blood test (3) to understand whether the combination of the imaging and blood test can distinguish between patients whose cancers will respond to anti-estrogen therapy and patients whose cancers are resistant to this type of treatment. This pilot study will lay the groundwork for a larger phase I/II clinical trial testing this approach to identify patients with anti-estrogen resistance early and offer them an alternative, more effective treatment, minimizing exposure to side effects from a treatment that is not effective.

LBCA: What is the population of metastatic patients you will be studying? How many will be enrolled and what percentage will be newly diagnosed?

Dr. Sharifi: This will be a pilot study with 8-10 patients with newly diagnosed ER/PR positive/HER2 negative metastatic lobular breast cancer (the most common type of metastatic lobular breast cancer) who are starting our standard first treatment for this type of metastatic breast cancer, which is endocrine (anti-estrogen) treatment in combination with a CDK4/6 inhibitor targeted therapy.

LBCA: Dr Sharifi, can you please explain what FFNP is?

Dr. Sharifi: The overall concept is similar to a standard PET/CT scan, which uses an injected dye that highlights areas of rapid cell growth in the body, but FFNP is a special type of dye that specifically highlights areas of breast cancer in the body with high progesterone levels, which is a marker of estrogen signaling.

LBCA: If FFNP measures the progesterone receptor, how does it measure estrogen signaling? Do patients enrolled in the study need to be PR+ on histology?

Dr. Sharifi: The presence of progesterone receptor on breast cancer cells is actually driven by estrogen signaling, which is why measuring the progesterone receptor is a good downstream indicator of how active the estrogen receptor is in breast cancer cells.  This has some advantages over measuring estrogen receptor itself, as the estrogen receptor can in some cases be present but not active in driving breast cancer growth.  However, it is correct that in this study patients will need to be PR+ on histology, which is true of the majority of ER+ lobular breast cancers.

LBCA: Since the new tracer is progesterone receptor based, could you explain how that will help predict therapies designed to block estrogen receptors and how this will identify ER receptor activity?

Dr. Sharifi: Because progesterone receptor expression on breast cancer cells is driven by estrogen signaling, FFNP signal increases with stimulation of estrogen signaling and decreases when estrogen signaling is suppressed in estrogen-sensitive pre-clinical models. Therefore, we expect that FFNP signal will decrease in breast cancers where estrogen signaling is adequately suppressed by anti-estrogen therapy, which is what we will be testing in our study.

LBCA: Can you explain what type of blood test will measure endocrine signaling changes?

Dr. Sharifi:  The blood test measures the gene expression of a panel of estrogen-regulated genes in circulating tumor cells isolated from blood samples from patients with metastatic breast cancer. This complements the imaging by assessing not only progesterone receptor but a number of additional estrogen-regulated genes to get a broader assessment of estrogen signaling in the cancer cells in these samples and how it changes after patients start endocrine (anti-estrogen) treatment.

LBCA: Are there guaranteed to be enough circulating tumor cells (CTCs) in metastatic lobular breast cancer for sampling?

Dr. Sharifi:  Our microfluidic CTC isolation technology relies on a combination of techniques to enrich for CTCs, and in the previous studies we have done with this technology, we have able to detect CTCs in most patients with metastatic breast cancer, including lobular breast cancer.

LBCA: Can you explain the role of patient advocates in your work. How have they been involved so far and what will they do in the future?

Dr. Sharifi: The lobular breast cancer patient advocate we are working with on this study provided feedback on the relevance of the overarching question of early treatment response monitoring for patients, as well as the proposed design of the study, in particular in considering what barriers or concerns there might be for study participation from a patient perspective and how to address those successfully. Moving forward, our patient advocate will be involved in finalizing the study protocol, in providing input in the planned manuscript reporting the results of this study, and in helping with development of the next steps planned for this work after completion of this study.