Jeremy Force, DO, assistant professor of medicine, in the Department of Medical Oncology, Duke Health, a member of the Duke Cancer Institute, and an oncologist at the Duke Cancer Center Breast Clinic, discusses the efficacy of fam-trastuzumab deruxtecan-nxki (Enhertu) in pretreated patients with HER2-positive breast cancer on the phase 3 DESTINY-Breast02 trial (NCT03523585).

The study investigated the use of the antibody-drug conjugate (ADC) trastuzumab deruxtecan compared with investigator's choice of treatment in patients with unresectable, metastatic HER2-positive breast cancer that has been previously treated with ado-trastuzumab emtansine (Kadcyla). Physician’s choice of treatment included trastuzumab (Herceptin) plus capecitabine or lapatinib (Tykerb) plus capecitabine.

Findings from DESTINY-Breast02 presented at the 2022 San Antonio Breast Cancer Symposium showed that trastuzumab deruxtecan led to a clinically meaningful improvement in the progression-free survival (PFS) and overall survival (OS) compared with physician’s choice of treatment. Patients treated with trastuzumab deruxtecan experienced a median PFS of 17.8 months compared with 6.9 months for those in the control arm. The median OS was 39.2 months and 26.5 months in the trastuzumab deruxtecan and the control arm, respectively.

Additionally, patients in the trastuzumab deruxtecan arm experienced an improvement in overall response rate at 69.7%, compared with 29.2% for the physician’s choice of treatment arm.

Data surrounding trastuzumab deruxtecan from DESTINY-Breast02 and other clinical trials have continued to show the positive benefit of the ADC for patients with HER2-positive breast cancer, Force says. As trastuzumab deruxtecan moves forward into earlier lines of therapy and potentially into the adjuvant setting, addressing interstitial lung disease associated with the ADC will be important in the adverse effect management of these patients, Force notes.

Along with DESTINY-Breast02, the phase 3 DESTINY-Breast03 (NCT03529110) and DESTINY-Breast04 (NCT03734029) trials have demonstrated the ability of trastuzumab deruxtecan to improve outcomes for patients with HER2-positive and HER2-low breast cancer, Force concludes.

Videos

Jeremy Force, DO, discusses the efficacy of trastuzumab deruxtecan in pretreated patients with HER2-positive breast cancer on the phase 3 DESTINY-Breast02 trial.


Dr. Force on the Efficacy of Trastuzumab Deruxtecan in the DESTINY-Breast02 Trial for HER2+ Breast Cancer

 With that, Dr Ulaner and I would like to take some questions and answers. Please do submit those in the Q & A box, so that we can answer them. It looks like there are 2 that I see here. Dr Ulaner, I would like to ask you this one question. Where is the FES-PET [F-18 fluoroestradiol-positron emission tomography] scan available? I’m assuming that means perhaps worldwide; as you mentioned, it is FDA approved in the United States. But what about the rest of the world in case this is a global audience?

 Thanks, Jeremy, and I’d like to say, your 3 cases are textbook examples for FES. In the first, the patient was FES negative, and they essentially did not respond to ER [estrogen receptor]-targeted therapy. The second was FES positive and responded very well to ER-targeted therapy. And the third was FES negative, so you purposely made the decision, don’t use ER-targeted therapy, use something else, which the patient responded so well to. Thus, really classic examples. 

Now, the question being, where is FES-PET available? I’ll start within the United States, this is FDA-approved, so this is available at any hospital in the United States that chooses to offer this agent. It takes time for technology to disseminate. Maybe not all medical centers are using FES-PET currently because it’s only recently been FDA approved. But the same thing could’ve been said about FDG [fluorodeoxyglucose] 10 or 15 years ago. It was only used in a few sites initially, and then when people realized how valuable it was, it disseminated, and now it’s available virtually at any hospital that has a PET scanner. FES is available anywhere that wishes to utilize FES in the United States, and I hope there will be a growing number of centers that will be using it. Of course, at academic centers like Dr Force at Duke University, and myself at a tertiary care center, the Hoag Family Cancer Institute, we have it probably a little earlier than many other centers. I expect many others to jump on board and use it just as much as we do in the near future.

As far as worldwide, again, each country will have its own regulatory agencies. FES is approved in the European Union, so it’s available in those countries. Then, I’m afraid I am not so knowledgeable about other areas in the world at the moment. But again, I do expect, as soon as people realize how valuable this is for many potential applications, that it will become more and more available throughout the world.

 I think that’s a great answer. Looking through some of these questions here, there’s another great question for you, Dr Ulaner. I think this is really an important, short question, will it be covered by insurance?

 This is a great question, which kind of blurs into another question of, do we need both PET scans? The answer is yes, I think we need both, and I think, yes, it will be covered by insurance providers for the appropriate applications. It all comes back to these scans, even though they’re both called PET scans, they are really individual scans. The FDG-PET scan finds metabolism and is predominantly used to evaluate extent of disease, whereas the FES finds estrogen receptor and is used for different applications, I think primarily to help you determine whether you should use ER-targeted therapies. Thus, while the FDG is very good at extent of disease, it doesn’t often help you choose what therapy you should use. And the FES is not going to find some diseases at all. But in the right diseases, like ER-positive breast cancer, it can be very valuable for helping you select what therapies you want. Hence, use the individual studies for the appropriate clinical indications. 

Then for insurance coverage, this will come with the appropriate clinical indications. If you’re ordering an FES-PET scan to try to determine extent of disease, it may not be covered. But if you explain to an insurance company in the case of a patient who may be on a first-line ER-targeted therapy and is progressing, and you say, “I want to decide whether I’m going to move to a second-line ER-targeted therapy or if I’m going to use chemotherapy instead.” It’s a very smart use of money to run a single imaging test that can help you determine whether estrogen receptor-targeted therapy is going to be effective. Because if it’s not FES avid, and therefore ER-targeted therapy is not going to be effective, why spend tens of thousands of dollars and waste months of a patient’s time receiving an ineffective therapy? Thus, I think we do need both scans; we need them for their own appropriate indications, and insurance providers will likely pay for them when used appropriately.

Jeremy, let me shoot a question back to you. There is a specific question here asking, what is your approach to a patient who’s ER+ and HER2+ [human epidermal growth factor receptor 2-positive] who develops an ER+, HER2-negative recurrence during anti-HER2–targeted therapy? Should we escalate the ER-targeted therapy arm or add fulvestrant or add your own recommendations for therapy in this particular patient?

 Yes, that’s an excellent question, and I think that the FES-PET has some clinical utility here, especially since they were receiving an AI [aromatase inhibitor] in that setting. As Dr Ulaner mentioned, if this patient was receiving tamoxifen or fulvestrant, the FES-PET may not be as effective or might not have as much clinical utility. This is a really challenging situation. I think the FES-PET can provide utility, first and foremost, to describe what is the burden of disease. Is that really the only recurrence? I think that would be first off. Secondly, if they had an isolated recurrence, I would try to aggressively approach that in various forms, whether it be SBRT [stereotactic body radiation therapy] and the SABR-COMET study really identified that there can be an overall survival advantage. Granted, there was a paucity of patients with breast cancer in the SABR-COMET study. But it did show that SBRT can provide a benefit in the oligometastatic or oligoprogressive setting.

Thirdly, obtaining an FES-PET to identify the ER negativity would be helpful, but one would question the HER2 status. And that’s where I think an FES-PET may not be helpful in that situation to determine HER2 positivity or negativity, for that matter, because that is not the point of what the FES-PET is providing. In this situation, though, if they have an isolated recurrence, and it’s hormone-positive, HER2- by biopsy, I think an aggressive approach with SBRT, resection, cryoablation, or radiofrequency ablation, followed by an endocrine therapy-focused approach would be pretty reasonable.

 Yes. Let me shoot you back a question here. Are there specific precautions for using FES-PET for patients? I think that’s a great question for you, Dr Ulaner.

 Thanks, Jeremy, for that question. In general, imaging agents have very low adverse effects. This isn’t a therapy, per se, that is going to have adverse effects that you need to be very aware of in using in patients who may have borderline organ function. The main precaution to keep in mind is really with tamoxifen and fulvestrant, drugs that bind to the estrogen receptor to have their effect. Those drugs can interfere with the proper results, the proper interpretation of the FES-PET scan. Patients who are using tamoxifen or fulvestrant will need to withdraw from those medications prior to using FES-PET as a diagnostic imaging agent. And for patients with fulvestrant, where they recommend 4 or 5 months of withdrawal, I think this is probably going to exclude using FES-PET in these patients because no one is going to want to wait 4 or 5 months off therapy, in order to get a diagnostic scan. That’s just the unfortunate part of it. You have to keep that in mind. 

But as for precaution, there’s very little. These diagnostic agents are very well tolerated with minimal adverse effects. From the FDA approval, they note that less than 1% of patients who undergo FES-PET scans have adverse effects like pain at the injection site, which you can imagine, because there’s an IV [intravenous] catheter in your arm. And less than 1% of patients have changes or alterations in their sensation of taste for about 1 to 2 days. I think in the current climate with COVID-19, it’s important for patients to know because if after their scan, they go home and they can’t taste their dinner, they might be worried that’s being caused by COVID-19, when in reality, it’s being caused as a rare adverse effect of the FES. But other than those 2 minor adverse reactions that have been noted, there are virtually no other adverse reactions, and the studies show they are very well tolerated, and no specific precautions need to be taken with specific patient populations.

Let me ask you, Jeremy, if we can look toward primary treatment where the tumor markers change. There’s a question here, what you do in the instance where the primary tumor doesn’t necessarily match, the tumor markers don’t match what you find subsequently in the patient’s care?

 Yes, it’s a great question. It’s something that we’re actively studying at Duke University and putting together trials to further investigate this, utilizing the FES-PET as a key component to identifying the estrogen receptor status. I’m assuming that you’re performing primary treatment and then the markers change after surgery, so they may have been getting neoadjuvant therapy, they went to surgery, and then those markers were checked again, and they were indeed nowhormone receptor negative. In those situations, we would offer somebody adjuvant chemotherapy if they didn’t already receive it in the neoadjuvant setting. It could be that that person was getting neoadjuvant endocrine therapy with an aromatase inhibitor. And if the biomarkers changed, I would certainly utilize the FES-PET, first as a way to determine has it spread anywhere else. As Dr Ulaner pointed out nicely, there was the patient who had stage III disease, and the FES-PET depicted that this patient had de novo metastatic disease.

I think the FES-PET will provide clarity to determine the bulk or burden of disease. And if the biomarkers have changed from a primary cancer, I think providing chemotherapy in the adjuvant setting; if this is metastatic disease, which we know that the biomarkers can change not infrequently, I think again, consideration of moving forward with the chemotherapy route would be imperative. The risk-benefit ratio of moving forward with endocrine therapy has been laid out nicely in the literature, that there’s a lack of benefit, and this is already declared itself as basically endocrine-therapy resistant. I think, again, the FES-PET will provide some clarity in that regard.

Dr Ulaner, I would like to ask this question about the processing of bone biopsies. This is a common problem, as you know, that we have in hormone-positive metastatic disease. Can you talk a little about the processing of bone metastases, and will there be any false negatives for estrogen receptor positivity or negativity?

 Thanks, Jeremy, for that question. I’ll preface the answer by saying I’m not a pathologist. They will be the most knowledgeable. But having encountered this problem before, I can give some perspective. In general, the processing for estrogen receptor status, the immunohistochemistry is pretty robust. I’ve seen this be more a problem with HER2 status, where the processing of the bone samples prior to HER2 sampling can cause a false reduction in what we see on the immunohistochemistry. So the HER2 status is false negative, essentially, on the pathology because of the processing of the bone. But I have not heard of that error occurring so commonly with respect to estrogen receptor.

 If I can hit one question here, this person gets right to the point and asks, why do we need this? We already have ER and PR status, and I think that’s right to the point, a critical question. And the answer being that the immunohistochemistry doesn’t always predict how patients are going to respond to therapy. To go back to this slide, the patient on top and the patient on the bottom are both ER+. They’ve had their immunohistochemistry determined, and they were both estrogen receptor positive. But they have very different results on their FES-PET scan. And that difference, despite the fact that they’re both ER+, the FES-PET is far more predictive in determining whether the patients are going to respond to ER-targeted therapy. Yes, it’s an incredibly valuable tool to have a biopsy and ER and PR immunohistochemistry. But this is a strong example of how the whole-body imaging can help you decide what therapies you want to utilize for your patients and be more accurate in predicting treatment outcome than immunohistochemistry from single sight biopsies.

 Yes. Dr Ulaner, that was really well said.

We all thank you for your attention and participation tonight. On behalf of Dr Ulaner and myself, I would like to thank you for joining us in the 

webinar on radiopharmaceuticals-based imaging in breast cancer. We hope you found this discussion to be informative and valuable in the treatment of your patients with breast cancer. We thank you for your time.

Dr Gary Ulaner and Dr Jeremy Force answer questions submitted by attendees of the live webinar discussing the role of various strategies to detect estrogen receptor (ER)-positive breast cancer, with particular focus on the role of 18-F FES-PET imaging in diagnosis and treatment of ER-positive breast cancer.

Question and Answer Session

 The next case that we have is case 3, with a 72-year-old female with early stage ER+ [estrogen receptor-positive], PR+ [progesterone receptor-positive], HER2- [human epidermal growth factor receptor 2-negative] invasive ductal carcinoma. She had surgery, it was a T1C lesion, grade 2. She had a high oncotype. She received adjuvant chemotherapy and 5 years of an aromatase inhibitor. She then came into my clinic complaining of new chest pain and dyspnea. She was found to have a new internal mammary lymph node based on a CT chest scan that was done in the emergency department. A biopsy was performed during her hospitalization, confirmatory of metastatic breast cancer, at least locally recurrent breast cancer to this internal mammary lymph node. Not metastatic disease, excuse me. But there wasn’t enough tissue for a biomarker assessment.

The FDG [fluorodeoxyglucose]-PET [positron emission tomography] scan you can see here. There was activity. But the FES-PET [F-18 fluoroestradiol-PET] was completely negative. From one study that came out of South Korea showing that when we see FES-negative disease, it’s 100% a negative predictive value that this will be estrogen receptor negative with biopsy. I think there is a lot of clinical utility with that in hand. We did encourage her to biopsy this again. As you can see, it’s right behind the sternum so it was slightly challenging to biopsy. But we were able to achieve that. It showed that it was triple-negative breast cancer. Thus, this was an isolated internal mammary lymph node recurrence.

We decided to move forward with curative intent. This was recently. She received dose-dense AC [doxorubicin, cyclophosphamide], carboplatin/Taxol with pembrolizumab. Basically, she didn’t participate in it, but we went off of the KEYNOTE-522 trial. She had a radiographic complete response and then subsequently received comprehensive radiation therapy and adjuvant pembrolizumab. She’s in follow-up and has no evidence of disease recurrence.

Dr Jeremy Force illustrates how FES-PET aids in the treatment of patients with breast cancer through a clinical case.

FES-PET in the Treatment of Patients With Breast Cancer: Clinical Case 3

 For case No. 2, we have a 60-year-old female with, again, hormone-positive, HER2 [human epidermal growth factor receptor 2]-negative metastatic breast cancer. She had received adjuvant dose-dense AC [doxorubicin, cyclophosphamide], weekly paclitaxel for a T2 N2 grade 2 invasive ductal carcinoma. This was about 8 years ago. She subsequently completed 5 years of an aromatase inhibitor about 3 years ago. Then she came into my clinic complaining of lower back pain. We obtained a PET [positron emission tomography]/CT scan showing that there was what appeared to be oligorecurrent metastatic breast cancer. This was the only lesion that was identified in her vertebrae.

If you see here, it is FES [F-18 fluoroestradiol]-positive. The uptake for this was not complete, meaning that there was some tumor heterogeneity. We biopsied this area, and it was ER+ [estrogen receptor-positive], PR- [progesterone receptor-negative], HER2-negative breast cancer. We discussed it with our spine metastasis tumor board. SBRT [stereotactic body radiation therapy] was applied in her situation. Then she was initiated on a different CDK4/6 inhibitor with a selective estrogen receptor degrader. We had to dose reduce the CDK4/6 inhibition by 1 dose reduction. She has had no evidence of gross disease for over a year.

FES-PET in the Treatment of Patients with Breast Cancer: Clinical Case 2

 For the first case, we have a 48-year-old female. She was newly diagnosed with de novo stage IV ER+ [estrogen receptor-positive], PR+ [progesterone receptor-positive], HER2 [human epidermal growth factor receptor 2]-negative disease. It was clinically T1C, grade 2 invasive ductal carcinoma. She presented to her primary care physician with difficulty walking and hip pain. The primary breast mass was biopsied, and a CT scan showed a left acetabular lesion, but the patient was hesitant about biopsy. She was initiated on a CDK4/6 inhibitor and aromatase inhibitor with her local oncologist and came to see me at Duke [Cancer Institute] for a second opinion. We subsequently reviewed the imaging that was done at the outside hospital, but I thought there may be utility to identify is this lesion in the left acetabulum estrogen receptor-positive or not. Dr Ulaner spoke pretty eloquently about the need to determine ER positivity and the potential benefit, especially from the Netherlands study showing that there were even subsets of this disease that may respond better or worse to CDK4/6 inhibition combined with endocrine therapy.

Indeed, this patient, when looking at the left acetabular lesion, you can see quite nicely on the right that the FES [F-18 fluoroestradiol] is negative for the estrogen receptor, while it is FDG [fluorodeoxyglucose] positive, so it is an active cancer but FES negative. I did express to her that we really needed to get a biopsy to confirm this diagnosis because it would change her prognostic components and also potential therapeutic interventions. Thankfully, we have a very robust interventional radiology group here. We discussed her case at our spine metastasis center. It was decided that we would not only biopsy the left acetabulum, but also simultaneously use cryoablation.

That biopsy did show that it was triple-negative breast cancer. It was 1+ score by HER2, so we did double check with fluorescence in situ hybridization. That was not amplified. We also sent out for genomic sequencing, and there was no actionable mutation. We did feel that given she was at a younger age, it would be reasonable to perform a lumpectomy with sentinel lymph node biopsy. That confirmed the ER+ primary breast cancer with now a triple-negative isolated bone lesion. She wished to avoid chemotherapy at all costs, and there were various reasons for that. Through a shared informed decision-making process, she decided to continue with the CDK4/6 inhibitor and aromatase inhibition. She did stay on this for about a year before there was progression in her lungs. While I don’t have that imaging, we did follow up with another FES-PET [positron emission tomography], and those lung lesions were also negative. She has now moved on to chemotherapy at this point.

Dr Jeremy Force illustrates how FES-PET aids in the care of patients with breast cancer through a clinical case.

FES-PET in the Care of Patients With Breast Cancer: Clinical Case 1

 A second potential application for an FES-PET [F-18 fluoroestradiol-positron emission tomography] scan is the ability to assess estrogen receptor [ER] status in lesions that you may find difficult or impossible to biopsy. The best example of this possibly is brain metastases. This was published from the University of Washington in Seattle. This is a patient with an estrogen receptor-positive breast cancer who unfortunately developed a lesion in the brain on MR [magnetic resonance] as shown in the image on the left. If you want to see if this is a lesion that’s being caused by metastasis from the ER+ breast cancer, one way to do that is to do a biopsy. But obviously, that’s quite invasive, putting a needle into the skull into the brain parenchyma in order to sample this deep lesion. Instead of doing that, an FES-PET scan can be performed, which demonstrates indeed this lesion is avid for the ER-targeting FES-PET agent, confirming with very high confidence that this is a metastasis from the estrogen receptor-positive breast cancer that the patient unfortunately suffers from.

A third potential application for FES-PET CT is helping to solve clinical dilemmas, inconclusive results on other imaging modalities. This is a manuscript out of a group from the Netherlands in which they followed a hundred patients that had inconclusive imaging on what we consider standard of care bone scans or CT scans. For example, this patient had some slight uptake on their bone scan in the spine. It was unclear whether this represented metastases or whether these were benign degenerative changes. The FES-PET scan that was subsequently performed in this patient could demonstrate multiple sites of disease within bones, providing strong confidence that this was representative of disease rather than benign degenerative changes, and greatly influencing the patient’s future course of treatment. For over 85% of patients who had inconclusive imaging results on CT or bone scan, the FES PET could more accurately define the extent of malignancy in these patients.

Finally, the FES-PET scan is being looked at for the evaluation of extent of disease. Now, extent of disease has predominantly been the role of FDG [fluorodeoxyglucose]-PET, as we’ve shown previously. But certain breast cancers are not particularly metabolically active. They don’t pick up a lot of FDG. Many of those tumors happen to be very strongly estrogen receptor-positive. Thus, using an agent that can detect the estrogen receptor may be more valuable for evaluating extent of disease than the metabolic tracer FDG-PET.

At the Hoag Family Cancer Institute, we have a prospective clinical trial evaluating FES-PET versus standard of care FDG-PET or CT bone scan to evaluate whether the FES-PET can provide value in assessing extent of disease, in 2 groups of patients. The first patients were newly diagnosed with locally advanced disease, so there is enough disease that there is a risk for distant metastasis but not proven to be distant metastasis. In these patients, the patients received both standard of care imaging as well as the FES-PET CT. And then, lesions that are suspicious undergo biopsy for pathological confirmation. As we have seen in several patients, whereas standard of care imaging like CT bone scan might fail to detect distant metastasis, in this patient with presumed locally advanced disease, the FES-PET identified bone metastases in multiple sites, which demonstrated this patient was de novo metastatic, so metastatic at diagnosis. That made a huge impact in their care. If they were locally advanced, then their treatment would likely be neoadjuvant chemotherapy or systemic therapy followed by surgery for a curative intent. But now with the knowledge that the patient is already metastatic, the likelihood of a mastectomy providing value is greatly decreased. And this patient’s plan changed from surgical management to systemic therapy in order to try to control the disease.

The second cohort of patients where the FES-PET trial is active is patients who have had disease that has been treated, and now has for some reason, like an elevated tumor marker or an inconclusive image finding, suspicion for breast cancer recurrence. Here is a patient who has suspicion of a recurrence in the left chest wall. Standard of care FDG-PET to evaluate the extent of disease found a solitary focus in the chest wall. However, the FES-PET unfortunately identified multiple osseous and soft tissue lesions, which were not apparent on the FDG-PET. Thus, the FES-PET evaluating estrogen receptor was much more accurate in identifying the extent of disease than the metabolic tracer FDG.

Now, both of these patients I just described had invasive lobular breast cancer. These tumors are known to be harder to find than the more common ductal malignancy. Lobular breast cancers are molecularly distinct from ductal malignancies. They tend to have lost a gene called 

 which encodes for E-cadherin, a cell adhesion molecule. While ductal tumors that have E-cadherin tend to grow in balls of tumors, lobular breast cancer that lacks this adhesion tends to grow out in sheets and lines, providing fewer tumor cells per unit volume of tissue and making it more difficult to detect on imaging studies like mammography, ultrasound, MR, and FDG-PET. These lobular tumors being more difficult to find by current imaging modalities need a new method of evaluating disease extent.

It so happens that lobular breast cancers are almost all estrogen receptor-positive. This estrogen receptor-positive imaging agent, FES, may be a valuable method for evaluating these patients. Indeed, in a retrospective study that needs to be confirmed in a prospective study of patients on clinical trials who underwent both FDG as well as FES-PET, the FES-PET in the patients with lobular breast cancer identified the extent of disease much more accurately than FDG. We are very excited to be evaluating FES-PET in patients with lobular breast cancers as well as other less metabolically active breast cancers. And hopefully, we’ll be able to advance the field in detection of disease for these patients.

A comprehensive analysis of the potential role of FES-PET imaging in assessing ER status in tumors that are difficult to biopsy and in evaluating the extent of disease.

Is There a Role for FES-PET Imaging in Assessing ER Status and Extent?

 Now, that we’ve introduced what FES is—a radiotracer composed of estrogen that’s bound to something, that emits radiation and allows us to noninvasively evaluate estrogen receptor [ER]—let’s talk about a few potential applications of this technology. The first to note, and potentially the most important, is that it helps you determine estrogen receptor status in metastatic lesions and helps you determine whether estrogen receptor–targeted therapies are going to be valuable in an individual patient.

Normally, imaging is used to detect the lesion and then determine if the lesion is getting bigger or smaller on treatment. But FES is not being used to determine whether lesions are getting bigger or smaller. Rather, it’s specifically being used to help medical oncologists, like Dr Jeremy Force, determine whether they should or should not use estrogen receptor–targeted therapies on this patient. Even if the patient is ER-positive on immunohistochemistry, if they don’t have enough FES uptake, then we can reliably predict that this patient will not respond to estrogen receptor–targeted therapy and that these patients should receive another form of therapy, such as chemotherapy.

Let’s look at a few examples of how this is applied in clinical practice. These are patients with metastatic ER-positive breast cancer receiving modern therapy, including an AI [aromatase inhibitor] and a CDK4/6 inhibitor. The FDG [fluorodeoxyglucose]–PET scan is the furthest on the left. Let’s look at the patient on the top. The FDG-PET shows us that there are FDG-avid sites of malignancy in this patient. The FES-PET, which is done before treatment shows that these lesions are FES avid. If we look back to that diagram that I showed on the prior slide, the patients are above the cutoff of FES avidity.

This predicts a good chance that the patient will respond to estrogen receptor–targeted therapy. Indeed, this patient received the estrogen receptor targeted therapy. And the post-treatment FDG, demonstrates a marked reduction in the amount of detectable disease. That’s a win both for the FDG-PET, which can measure the extent of disease, as well as for the FES-PET, which was used to help select estrogen receptor–targeted therapy for this patient.

Now, let’s look at the patient on the bottom. This patient also has FDG-avid malignancy. But the FES-PET is essentially predominantly negative. This patient is down below our cutoff, our threshold for FES PET-avidity. It predicts this patient will not respond to endocrine therapy. This patient in this clinical trial, and all patients, did go on to endocrine therapy. As expected, patients with low FES-avidity did not respond to estrogen receptor–targeted therapy. This patient has the same or even slightly more disease after a course of therapy than previously. This is a modern adaptation of the initial study that I showed, and it was performed at Washington University, confirming that even in modern ER-targeted therapy, we can use the FES-PET to help us determine whether patients will respond to estrogen receptor–targeted therapy. It’s a very useful scan for these patients.

Expert perspective on the applications of FES-PET imaging in treatment decision-making in patients with breast cancer.

Applications of FES-PET Imaging in Breast Cancer Treatment Decision-Making

 It’s important to clarify that FES–PET [positron emission tomography] is different from what we consider PET imaging. PET is mostly FDG [fluorodeoxyglucose]–PET. FDG is a glucose molecule, so the FDG-PET scan allows us to evaluate metabolism. Because cancer cells are often very metabolically active, we can use FDG-PET to detect cancer cells. FES-PET is an entirely distinct examination. It uses the same scanner, a PET scanner, but the agent that’s administered to the patients is entirely different. It is this fluorinated estrogen that finds the estrogen receptor [ER].

Lesions on FES-PET show us estrogen receptor. It’s not going to find estrogen receptor–negative breast cancer. It’s not going to find other types of cancers that are estrogen negative. It’s going to specifically allow us to visualize estrogen receptor–positive breast cancers, whereas FDG allows us to see metabolism. Keeping this in mind, there’s going to be a growing number of these agents that we’re using with PET scans. It’s going to be important to identify what type of PET scan we’re performing. When someone says, “We should order a PET scan,” it’s going to be important to know, “Do you want an FDG-PET scan to evaluate metabolism? Do you want a FES-PET scan to evaluate the estrogen receptor? Do you want some of the other types of PET scans that are being developed?”

Let’s talk a little more about the FES-PET scan, what it can do, and then what are some of the potential applications in patients with estrogen receptor–positive breast cancer. Importantly, this FES molecule that finds estrogen receptor can demonstrate metastases that we can’t see on anatomic imaging like CT [computed tomography] scans. On this slide, on the left slide, you see an image of the whole-body FES-PET scan, known as a MIP image, a maximum intensity projection image.

The image on the right is an axial image from a CT scan, which is anatomic imaging. It has an overlay of both, so you’re looking at the CT scan overlaid with the information that you’re getting from the FES-PET scan. It’s important. As you can see on the right image, there’s a lesion in a bone on the CT scan, which we don’t see on the FES-PET scan. There’s also a focus on the FES-PET overlay with no correlative anatomic finding on the CT scan. These images provide different information, and we have to bring them together to accurately determine the diagnosis in an individual case. For the lesion on the CT scan—what we’ve seen on the CT scan is a sclerotic lesion, but we don’t see it on the FES-PET scan because this is a patient with ER+ breast cancer. This is probably an old treated lesion, where there was a metastasis previously, but there’s no active estrogen receptor in the lesion. This is a treated site of disease. But the focus on the FES-PET scan demonstrates an active site of estrogen receptor–positive tumor, even though you can’t see it on the CT scan.

Another important issue to raise in comparing the FES-PET scan with the more common FDG-PET scan is that these 2 scans can work cooperatively to demonstrate heterogeneity of individual lesions in a single patient. We can see some lesions, such as the images on the left, on the FES-PET scan that are showing estrogen receptor. They aren’t seen on the images on the right, which are the FDG-PET images of metabolism. These are sites of malignancy that happen to express a lot of available estrogen receptor but are not metabolically active.

There are also lesions seen on the FDG-PET scan that aren’t seen on the FES-PET scan. These are sites of disease as well. But these sites of disease are much more metabolically active and maybe more aggressive, whereas the estrogen receptor is either not available for us to visualize or not present at all. These are breast cancer metastases, but there are different types of breast cancer metastases being visualized by the different imaging agents. Some are very FES-avid, very estrogen receptor–positive, and not very metabolically active. Others are very metabolically active and potentially more aggressive, but these do not show estrogen receptor availability.

I want to take a moment to note that, because this is a molecular imaging agent that finds the estrogen receptor, patients using drugs that affect the estrogen receptor will need to be withdrawn and paused before a FES-PET scan will give valid results. Patients on tamoxifen or fulvestrant may need to pause use of those agents prior to 1 FES-PET scan to be accurate. This is what a FES-PET scan looks like on imaging. The agent is excreted in the liver, into the biliary tree and the bowel, so we’ll often see the liver and the bowel as either what are called hot spots or, in a black-and-white image, very black.

The agent is also excreted to a lesser extent through the kidney into the ureter and the bladder, so we may see those organs as well. The agent is extensively excreted through the liver, so it may be hard to visualize lesions in the lever, particularly on a standard, what we call PET window. On the left, this is a PET window going from 0 to 10 SUV [standardized uptake value] units. If you expand the PET window, the image on the right is from 0 to 30 SUV. Now you might begin to see through the liver and may be able to find lesions in a way that you can’t on the standard window.

Dr Gary Ulaner compares the role of FDG-PET and FES-PET imaging in ER+ Breast Cancer and the ability of each of the 2 techniques in assessing ER status.

Role of FDG-PET Vs FES-PET in ER+ Breast Cancer

 Thanks for that excellent introduction to estrogen receptor–positive breast cancer and the ways that we would typically evaluate the estrogen receptor status, such as through biopsy. As you said, biopsy is not always attainable or desired, so it would be great if we had a noninvasive way to assess estrogen receptor status. What we have is called molecular imaging and therapy, and it’s developing into a tremendous field for medicine. Imagine, on the right, we see a cancer cell such as the breast cancer cell, and each cancer cell expresses unique targets, either on the surface or within the cell. We’re able to design binding agents that bind to that target much like a key fitting into a lock. And if we linked to that binding agent a radioisotope, something that emits a small amount of radiation, we’re able to build the keys that act as imaging agents for us to identify and localize where specific targets are on a cancer cell.

We’re going to be talking about estrogen receptor–positive breast cancer imaging, where the cancer cell is the breast cancer cell, the target is the estrogen receptor, which is found within about 75% to 80% of breast cancer cells. The binding agent is estradiol, in the upper left. Estradiol is estrogen, which is already found physiologically in our bodies. A radioisotope has been linked to estrogen, the radioisotope called fluorine-18, which emits a positron, which we’re able to visualize and localize in a PET [positron emission tomography] scanner.

Thus, we’re able to develop this key, which consists of estrogen as its binding agent, and fluoroestradiol as the radioisotope that allows us to image the estrogen and produce exquisite images of where estrogen receptor is within the body, such as the example on the lower right of the screen, demonstrating the sites of estrogen receptor–positive breast cancer in a way that is first a whole body. You can image from head to toe if you want to.

Second, it’s noninvasive—no biopsy, no needle required. This FES key we’re using for molecular imaging has been studied for quite some time, and data have been able to demonstrate that this allows us the noninvasive, whole-body assessment of estrogen receptor expression that we can use in lieu of biopsy to evaluate estrogen receptor. This compilation of work has led to FDA [Food and Drug Administration] approval of FES as an agent known as Cerianna for the whole body, noninvasive evaluation of estrogen receptor.

Experts provide an overview of the imaging modalities that can detect estrogen receptor status in patients with breast cancer.

Overview of Estrogen Receptor-Targeted Imaging

 Hello, my name is Dr Gary Ulaner, and I’m the James and Pamela Muzzy Endowed Chair of Molecular Imaging and Therapy at the Hoag Family Cancer Institute in Irvine, California. It’s my pleasure, on behalf of 

®, to welcome you to this webinar, titled “Optimizing Imaging in ER-positive Metastatic Breast Cancer to Improve Clinical Outcomes.” It’s my pleasure to introduce my copresenter, Dr Jeremy Force.

Hi, everyone. Thank you for allowing us this opportunity. I’m Dr Jeremy Force. I’m an assistant professor of medicine at Duke University School of Medicine in Durham, North Carolina. I focus on breast cancer and functional precision medicine, and we’re excited to talk to you about the use of functional imaging for ER [estrogen receptor]–positive breast cancer. When looking at the ER+ breast cancer landscape, we know that 70% to 75% of breast cancers diagnosed annually are hormone receptor positive or ER+, mPR [membrane progesterone receptor] positive.

This proportion of patients continues to increase because of therapeutic advancements we’ve made in breast cancer in terms of the prevalence of this disease. Breast cancer is the largest cancer among women in the entire world. This is clearly a problem, and this is clearly an issue for which we need to come up with better therapies and better diagnostics for these women and men with breast cancer, to aid the therapeutic endeavors that they’ll embark on.

The 5-year breast cancer specifics survival rate is still excellent. That also means that more patients may develop metastatic disease as time moves on. In respect to the progress we’ve made from a therapeutic advancement—going back to the 1890s with Sir George Beatson, with oophorectomy, and Dr Elwood Jensen, who discovered the estrogen receptor in the 1950s—there has been a large advancement over the last several decades, moving all the way forward with CDK4/6 pathway. We’ll get into some of the advancement and some of the data around functional imaging, not only the CDK4/6 inhibition pathway but also from an endocrine therapy perspective.

In totality, these drugs have revolutionized the field of ER+ metastatic breast cancer, which is equally great for our patients. When testing for ER+ disease, the hormone receptors that many medical oncologists and other oncologists will refer to are paramount. We’re able to identify the estrogen receptor status of tumors based on biomarkers from immunohistochemistry that we will commonly obtain from biopsies.

Those biopsies may come from primary breast masses or, in this situation, ER+ disease from metastatic sites. These help clarify the hormone receptor status but also delineate and further allow for us to determine which therapies may be appropriate for our patients. These are clearly diagnostic, and they’re predictive of endocrine therapy advantage. In that regard, there are many times that biopsies are challenging to get to. They’re validated, especially immunohistochemistry, and it’s the gold standard of predicting benefit from endocrine therapy. These core biopsies can be challenging, depending upon where they’re at.

Receptions also could be offered to patients, but it depends on which clinical situation and where the disease may lie. PET [positron emission tomography] scans—FDG [fluorodeoxyglucose]–PET scans, specifically—have shown utility in ER+ breast cancers. However, there are subsets for whom there’s a disadvantage using FDG-PET. Also, for indolent disease in general, it might not pick up all the disease that we would see in a metastatic case. Hence, our main discussion will be about the FES-PET, which has…clinical utility, and we’ll move into that moving forward. I’d like to hand this off to my esteemed colleague Dr Ulaner to take us through some of the FES-PET molecular imaging therapies.

Gary Ulaner, MD, PhD and Jeremy Force, DO review estrogen receptor (ER)-positive breast cancer and the various strategies available for diagnosing estrogen receptor (ER)-positive breast cancer.

Jeremy Force, DO

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