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HER2 ADCs: GU Malignancies

CME

Emerging HER2-Targeted Antibody–Drug Conjugates in Genitourinary Malignancies

Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™

Released: April 08, 2024

Expiration: October 07, 2024

Elizabeth R. Plimack
Elizabeth R. Plimack, MD, MS, FASCO
CME/CE Information

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HER2 Targeted ADCs in the Setting of Advanced Urothelial Cancer

As a GU medical oncologist at Fox Chase Cancer Center with a focus on novel therapies for advanced bladder cancer, it has been exciting to see all the recent data on HER2targeted ADCs in the setting of advanced UC. This is a hot topic at this moment and healthcare professionals (HCPs) need to be aware of the emerging data in this setting. 

HER2 Receptor Signaling Pathway

HCPs and researchers alike are very familiar with the HER2 proto-oncogene because of its role in tumor progression, survival, and the available targeted therapies for breast cancer. However much less is known about the role of HER2 in UC.  

A reminder, the HER2 gene—often called ERBB2—belongs to a family of epithelial growth factors receptors, including HER1, HER2, HER3 and HER4.1,2 In normal and cancerous cells, the HER2 protein functions as a transmembrane tyrosine kinase receptor that, when activated, sends downstream signals to the Ras, PI3-kinase and AKT, and the mTOR pathways. In tumor cells, constitutive HER2 activation and downstream signaling can aberrantly stimulate cell survival/proliferation, differentiation, and angiogenesis leading to metastatic disease.  

It is important to note for the context of this discussion that approximately 17% to 20% of UC harbors HER2 gene alterations. 

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HER2 Alterations and Testing in Muscle Invasive BC

I would like to briefly go over the different types of HER2 alterations that have been identified in patients with bladder cancer or UC. We often find HER2 gene alterations in the form of single nucleotide point mutations.3 

The figure on the upper left of the slide shows a dataset of patients with bladder cancer from the Cancer Genome Atlas (TCGA). Here we can see that investigators determined that approximately 11%—or 45 patients—in that cohort had mutations in ERBB2, the gene encoding HER2. Some of the point mutations were determined to be located in the extracellular domains and some were located within the intracellular domain. Of note, HER2 gene alterations and expression changes seem to be mostly correlated with gene copy number variance and where the mutation was located, with intracellular mutations correlating with somewhat mRNA expression and reverse phase protein array.  

A key next question is whether amplifications in HER2 mRNA translate into protein overexpression in the tumor. The panel on the right shows that, as measured by IHC or fluorescence in situ hybridization (FISH), patients with muscle invasive bladder cancer can exhibit gene amplification and higher than normal HER2 protein levels, but we should note this is not always the case.

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Tumor Agnostic Prevalence of HER2 Alterations (Mutations and Amplifications) 

Of interest, recent molecular analysis data for several solid tumors show that HER2 gene alterations (eg, mutations, amplification, or multiple alterations) are most prevalent in bladder cancer when compared to a list of other solid tumors shown here on the right.2 I think this is interesting because HER2-directed therapy is not often thought of for bladder cancer the way that it is for other cancers on this list. Notwithstanding, HER2 gene mutations can be common in bladder cancer, and that is reflected here in the high rate of HER2 alterations depicted in the graph. 

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Molecular Alterations and Genetic Testing in Bladder Cancers 

It is important for us to test for different molecular alterations in bladder cancer to be able to recommend the most appropriate therapy for our patients. HCPs can test for genetic alterations in FGFR3 and PD-L1 status because there are approved therapies that target these mutations.4,5 More recently, HCPs have been considering testing bladder tumors for other alterations for potential consideration of a clinical trial. HER2 testing will be folded into that paradigm throughout this discussion.  

Some HER2 mutations may result in a constitutively active receptor, promoting oncogenesis through constant activation of HER2 downstream pathways.6 Some HER2 mutations, on the other hand, can be silent. The most prevalent single-base substitutions found in urothelial tumors is HER2 S310F (3.92%). Other low-incidence mutations include R103Q, D277Y, G292R, S310Y, F595L, R678Q, I767M, V777L, V842I, D933N. However, not every tumor has the same alterations in HER2.3,7   

The generally accepted cutoff for assigning HER2 positivity in UC by IHC is 30% strong or complete basolateral or lateral staining (IHC 3+), and for FISH (gene amplification) the cutoff is a HER2/CEP17 ration ≥2.0.5 I think the IHC parameter is familiar to most pathologists because it is used in other tumor types as well.8 

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Role of HER2 in Kidney and Penile Cancers Remains Unclear 

Despite the known association between HER2 gene alterations and tumor progression for various GU tumors, at this time, there is no defined role for HER2 testing or any available HER2-targeted therapies for renal or penile cancers.9  

HER2 mutations in renal cancers are rare, and the role of HER2 testing in renal cancer remains unclear.10 Slightly more is known about HER2 mutations in penile cancer. Approximately 24% of patients with penile cancer exhibit elevated HER2 positivity by IHC.11 I think there might be potential to direct some of these patients to a clinical trial for HER2-directed therapy if available.  

ASCO/CAP Guidelines for HER2 Classification

The American Society of Clinical Oncology and the College of American Pathologists provide guidelines on HER2 classification by IHC.12 Although this is something that a pathologist will typically work on, I think it is something that would be helpful for all HCPs to visualize as they think through emerging HER2-directed therapies in development for bladder cancer.   

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Guideline and Expert Recommendations for Type and Frequency of HER2 Testing in Genitourinary Cancers 

Unfortunately, at this time, there are no HER2-targeted therapies approved for clinical use, therefore testing for HER2 biomarker status is currently recommended specifically for the purpose of matching a patient to a clinical trial. For this reason, HER2 testing—either via IHC, FISH, or next-generation sequencing (NGS)—may not be routinely done in clinical practice, particularly when a matching trial is not readily available. HER2 alterations may be “picked up” in the context of standard of care NGS panel testing, which is done for currently actionable biomarkers (eg, FGFR, PD-L1), although we could use the HER2 results to inform options for our patients at a later point. Beyond NGS, HER2 protein testing via IHC may be a consideration in patients with advanced or recurrent disease who are being considered for enrollment on clinical trials evaluating anti-HER2‒targeted ADCs in bladder cancers. Approximately 17% to 20% of GU tumors harbor HER2 gene mutations. A recent survey conducted by CCO found that 6% to 8% of HCPs are currently performing HER2 testing for GU cancers, presumably for the purpose of clinical trial enrollment. Moreover, there is no evidence to support routine HER2 testing for patients with renal cell carcinoma or penile cancer.9

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