This podcast explores the expanding role of HER2-targeted ADCs across genitourinary, gastrointestinal, and gynecologic cancers. Experts discuss HER2 alterations, molecular testing strategies, and emerging clinical data.
In this episode, Zev A. Wainberg, MD; Funda Meric-Bernstam, MD; Alexandra Leary, MD, PhD; and Catherine Fahey, MD, PhD, explore testing for HER2 alterations and the incidence of HER2-positive disease in the treatment of genitourinary, gastrointestinal, and gynecologic malignancies.
Presenters:
Zev A. Wainberg, MD
Professor of Medicine and Surgery
Co-Director of GI Oncology
Director, Early Phase Clinical Research Program
Jonsson Comprehensive Cancer Center
UCLA School of Medicine
Los Angeles, California
Funda Meric-Bernstam, MD
Chair, Department of Investigational Cancer Therapeutics
Medical Director, Institute for Personalized Cancer Therapy
Nellie B. Connally Chair in Breast Cancer
The University of Texas MD Anderson Cancer Center
Houston, Texas
Alexandra Leary, MD, PhD
President, GINECO Group
Co-Director, Department of Medical Oncology
Medical Oncologist Gynecology
Team Leader, Gynecologic Translational Research Lab, INSERM u981
Institut Gustave Roussy
Villejuif, France
Catherine Fahey, MD, PhD
Assistant Professor
Division of Oncology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Link to full program:
https://bit.ly/42iEDjV
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Hello and welcome to the Clinical Care Options’ Oncology Podcast. I’m your host, Sharif Morsalin. Today’s episode features Dr Zev Wainberg from UCLA, Dr Funda Meric-Bernstam from MD Anderson Cancer Center, Dr Alexandra Leary from Gustave Roussy, and Dr Catherine Fahey from Massachusetts General Hospital. They will be discussing HER2-positive disease in genitourinary, gastrointestinal, and gynecological malignancies.
This episode is part of a larger educational program titled, “Emerging HER2-Targeted ADCs in Genitourinary, Gastrointestinal, and Gynecological Malignancies.” For more information on our presenters, along with a link to the full educational program, please visit the show notes for this episode.
Now, let’s get started and hear what the experts have to say.
Introduction
Dr Zev Wainberg (David Geffen School of Medicine at UCLA): Welcome to this podcast, From Concept to Clinical Reality: The Landscape of Emerging HER2-Targeted Antibody Drug Conjugate in Genitourinary, Gastrointestinal, and Gynecologic Malignancies.
Faculty
My name is Dr Zev Wainberg. I am a Gastrointestinal Medical Oncologist at UCLA. I am joined here today by specialists in their respective field.
Dr Funda Meric-Bernstam (MD Anderson Cancer Center): I am Funda Meric-Bernstam from MD Anderson Cancer Center. I run the phase I program, which is the Department of Investigational Cancer Therapeutics.
Dr Alexandra Leary (Gustave Roussy): I am Alexandra Leary. I am a Medical Oncologist Specializing in GYN tumors, so ovarian, cervical and uterine cancer. I am based at Gustave Roussy in Paris, France.
Dr Catherine Fahey (UNC Chapel Hill): Hi. I am an GU Medical Oncologist, so seeing prostate, kidney, and most relevant to this talk, seeing bladder cancer patients. I am at the University of North Carolina in Chapel Hill.
Introduction to ADC & HER2
Dr Wainberg: Welcome. Just to kick us off, we are all obviously familiar with antibody drug conjugates and HER2, but we will just talk high level at HER2.
I mean, we have known about HER2 for the better part of almost 30 years in beginning in breast cancer and then in gastric cancer secondarily. Now we learn more and more about it. In so far as prognosis, predictive value, I think about HER2 a lot because I am here at UCLA, where some of the early work in breast cancer was developed. I trained here and so I have heard about it since I was small.
The one thing I remember is that in the beginning it was a very poor prognostic sign and it was a very poor prognostic biomarker. On some level that seems to have changed because of effective anti-HER2 therapy.
Dr Meric-Bernstam: For advanced solid tumors, in our practice, we routinely offer next-generation sequencing and offer also immunohistochemistry for HER2. The rationale, of course, is that NGS can allow us to identify HER2 and other alterations and also of course can identify HER2 amplifications and mutations related to HER2.
HER2 amplification in NGS alone is not sufficient to identify all patients that may benefit from HER2-targeted therapy. HER2 immunohistochemistry allows us to expand the patients that may benefit.
Overall, the frequency of HER2 positivity or HER2 overexpression depends on tumor type. There is a little bit of a variability by practitioner, but in all comer setting the positivity rate is around 2% to 3% for 3+. But there are tumor types that seem to benefit from HER2-targeted therapy at lower expression, and we want to be able to identify patients that may also benefit in that setting.
Gastric Cancer
I will start with the gastric cancer. Gastric cancer, we think it represents somewhere around 15% to 18% of the disease. It is different than breast cancer in so far as it is a lot more heterogeneous and there is a lot more heterogeneity in GI cancers.
In GI cancers, there is a lot of heterogeneity in and of itself, but even within gastric cancer there is heterogeneity in the distribution of HER2 and in the frequency rates. But we think it is about 15% to 18%. I am curious, Dr Leary, if you could comment on that in your cancers of interest.
Dr Leary: We have known of HER2 amplifications in endometrial cancer for now quite some time, and it represents probably about 30% specifically enriched in certain histologies such as high-grade serous, potentially p53 mutated endometrial cancer. Again, here we are talking amplification.
The data gets a lot hazier as you start to say HER2 overexpression, where here it has been less well described in great detail in endometrial cancer. How many are 3+, 2+, even 1+ because some of these ADCs are going lower. There, the prevalence is still something we are really learning about.
In terms of other GYN malignancies, it is much more rare in ovarian cancer, especially in common ovarian cancers. It is a little more frequent in uncommon ovarian cancer such as clear cell, and also relatively rare in cervix. For now, the leading target for HER2 ADCs is endometrial cancer, but it is also being explored in ovarian cancer.
Dr Wainberg: Dr Fahey?
Dr Fahey: Yeah, I think when we are talking about urothelial carcinoma, we are seeing things pretty similar to the gastric level things in that 15% to 20%. I agree with Dr Leary's point that when we are defining what it actually means, this definition between HER2 1+, 2+, 3+ gets a lot more tricky.
I was reading an article recently where looking at the HER2-low population, they said in their particular urothelial subset, HER2-low was as high as 34%, that HER2 1+ I should be specific what I am talking about. In general, when we are talking about urothelial, we are talking about the 2+ IHC, FISH positive, or 3+. Everything that I found has been the 15% to 20% range.
Dr Wainberg: Yeah. Is there any frequency in any other GU malignancies of interest?
Dr Fahey: I am not aware of the rates for the other GU malignancies. It is not something that I have seen commonly come up in my other patients when I send genetic testing. I do not have the data there to make any strong comments.
Dr Wainberg: In GI, we do have expression by immunohistochemistry and usually associated with amplification and a few other GI cancers. We have probably 5% of colon cancer, which is almost exclusively on the amplification level. In that disease, it is usually a subset which is left-sided KRAS wild-type, where it seems to predominate. We actually have drugs approved now for HER2+ colorectal cancer, which we will talk about a little later.
In biliary tract cancers, it also represents perhaps up to 10%. There, it is often in gallbladders or extrahepatic cancers. There is this recurring theme, at least in GI cancers, where it is not uniform but it is reflected in different heterogeneity.
What is confusing is, I agree, this HER2-low question and what that really means that now seems to predominate the discussion in breast cancer. At least in gastric cancer, while there is the suggestion that this group represents a subset, we have not seen a lot of hard data yet. It is still emerging. Whereas in breast cancer now it seems the very large percentage of patients have some HER2 staining, which is, of course, only relevant in these antibody drug conjugates.
Dr Leary, do you test all of your patients for HER2?
Dr Leary: Not all of my patients. Endometrial cancer is getting increasingly common that people do test. As you just described, in GI cancer, in GYN cancers, HER2 overexpression or amplification is clearly enriched in certain histological subsets. Most people would agree that in endometrial cancer that it is useful to test for HER2 in high-grade serous or high-grade endometrioid or p53 mutated, the most aggressive subtypes actually.
In ovarian cancer, as I said, in the common ovarian cancers, we rarely see them. Outside of a clinical trial, it would not be done routinely. One exception, HER2 tends to be overexpressed in rare ovarian cancers. As I said, clear cell but also mucinous ovarian cancers.
In especially, mucinous, people do routinely test for HER2 because up to 30% of that specific histological subtype has 3+ or amplification. For cervix, we do not routinely test for HER2 outside the trial.
Dr Wainberg: You are doing focus testing basically, and high-grade serous, you are saying, yes, let us test for HER2. You are doing it on the amplification level.
Dr Leary: Yes. Again, this is in routine practice. It is very different once we are starting to think about clinical trials. As opposed to the US, our approvals in Europe are not quite where you are, so we do not have an approval across HER2 3+, but we can sometimes get it on exceptional basis if we negotiate well with our hospitals. That would be the cases where we would look for a routine and that is where we look in specific histological subtypes.
Dr Meric-Bernstam: This is an area that I think also is evolving. There is quite a bit of variability from institution to institution about how HER2 testing is done and how to scoring is implemented. For example, in the DESTINY-PanTumor02 study patients that had HER2 testing centrally in a quarter of the patients, and that was done using gastric cancer scoring.
The guidance for local testing also was to use gastric cancer scoring. But there are many institutions that actually use breast cancer scoring across tumor types. Definitely we need a little bit more information about how to best harmonize scoring system, antibodies used and reporting structure.
Dr Wainberg: Okay. Dr Fahey, how are you approaching which patients to test for bladder cancer?
Dr Fahey: If I can correct something I said earlier, we do see HER2 alterations in prostate cancer, but we are not routinely targeting them.
To answer your current question regarding bladder cancer, we are sending HER2 testing at diagnosis of locally advanced or metastatic urothelial. That is because we are sending genetic testing at that point anyway to look for FGFR3 alterations, which we do have additional medications for. We are sending the genetic testing again that information. We send the HER2 IHC at that point as well because it is very useful to know for our second-line therapies.
There are also a lot of trials that are opening up in the front-line setting or in the muscle-invasive bladder cancer setting. I anticipate we are going to be looking at this earlier for the majority of our patients. For now, I am sending it when I am seeing patients in that first clinic visit for metastatic urothelial carcinoma.
Dr Meric-Bernstam: I think in general, we should test when we think we will act on the result. Currently, there are certain diseases where early testing is logical. In the early stage breast cancer, for example, HER2 status will affect our treatment decisions. While for other diseases, HER2-target therapies will be the only approved in the advance setting that has been previously treated.
I do think in the advanced cancer setting, it makes sense to initiate both NGS and HER2 testing early so that even if there is a clearly active other first-line therapy that least we will know what the patient will be able to benefit from next line.
Dr Wainberg: I think in gastric cancer, for example, it is routine. It has been standard of care for about a decade, so we send every advanced patient. There is a big debate about, “Oh, should you start sending early stage gastric cancer?” We are not quite there yet. But we do send every advanced patient for HER2 immunohistochemistry, which comes back as pretty much the first biomarker of interest.
Then I would agree with the comments that both of you made, selectively send for HER2 colon cancer, and at least in our practice colon cancer and biliary tract cancer, where it almost always is linked to genomic expression. In that case, we often just send NGS to get it all captured together. I really think it is interesting, because you have to know what you are looking for and that we see subtle differences between our cancers about when the right time to send and how to send.
Across the board now we are sending it in a large percentage I would say, of advanced cancers. Even we know in lung cancer, there is some frequency there and our lung cancer colleagues are doing it. It seems to be the most common biomarker people check for.
Dr Meric-Bernstam: Thank you very much for listening to our podcast today. I hope that you were able to learn and gain some insights into the Landscape of Emerging HER2-Targeted ADCs in Genitourinary, Gastrointestinal and Gynecological Malignancies.
Thank you, Drs. Wainberg, Meric, Leary, and Fahey for a great discussion and for sharing your expertise with us. And many thanks to you, our listeners, for joining us today. As a reminder, to view the full program “Emerging HER2-Targeted ADCs in Genitourinary, Gastrointestinal, and Gynecological Malignancies,” please click the link in the show notes.
Be sure to check back soon for two more episodes from this program on: Episode 2: “Taking a New Path,” Evaluating Current and Emerging Clinical Data With HER2-Targeted ADCs in Genitourinary, Gastrointestinal, and Gynecological Malignancies, and Episode 3: “Uncovering Safety and Signposts to the Future,” Assessing Safety Profiles of HER2-Targeted ADCs and Future Applications.