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HER2 Targeted ADCs: GI Cancers

CME

Emerging HER2-Targeted Antibody Drug Conjugates in Gastrointestinal Malignancies

Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™

Released: April 09, 2024

Expiration: October 08, 2024

Zev A. Wainberg
Zev A. Wainberg, MD
CME/CE Information

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Tumor-Agnostic Prevalence of HER2 Alterations (Mutations and Amplifications) in GI Cancers

For a number of years now, it has been well documented that the HER2 protooncogene plays an active role in GI cancers. Approximately 15% to 25% of esophagogastric cancers harbor mutations, amplifications, or multiple alterations in the HER2 gene. In other GI cancers—such as colorectal cancer (CRC), GI neuroendocrine cancer, and pancreatic cancer—the incidence of HER2 alterations is much lower and ranges from approximately 3% to 10%, but it can lead to overexpression of HER2 protein nonetheless.1

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Guideline Recommendations for HER2 Testing

In GI cancers, we have considerable data supporting the use of HER2 testing, as this is an actionable biomarker for us, particularly for gastric and GEJ tumors.

The National Comprehensive Cancer Network (NCCN) guidelines have a uniform recommendation for HER2 testing in all GI cancers at diagnosis, which includes HER2 testing for advanced/metastatic GI disease. HER2 testing is recommended in gastric and GEJ adenocarcinomas via immunohistochemistry (IHC) and in situ hybridization (ISH) first, but next-generation sequencing (NGS) may be considered.2

In patients with CRC, HER2 testing is recommended via IHC, ISH, or NGS, unless they are known to have a RAS gene or RAF gene mutation. In biliary tract cancers (BTCs), HER2 testing is recommended in all patients (IHC, fluorescence in situ hybridization [FISH], or NGS).3,4  

HER2 testing in pancreatic cancer is recommended using NGS under circumstances where one would be considering anti‑HER2 therapy.5 NGS often is used while assessing for other alterations beyond HER2.

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Molecular Subtypes of Gastric Cancer  

Gastric and GEJ tumors can be subclassified into 4 molecular subtypes.6

  • Chromosomal instability (CIN: with intestinal histology, TP53, and RTK-RAS alterations)
  • Epstein-Barr virus (EBV: with PI3KCA, PD-L1/2 overexpression, EBV-CpG island methylation phenotype, CDKN2A gene silencing, and immune signaling)
  • Genomically stable (GS: with diffuse histology, CDH1 and RHOA mutations, CLDN18-ARHGAP gene fusion, and cell adhesion
  • Microsatellite instability (MSI: with hypermutation, Gastric-CpG island methylation phenotype, MLH1 gene silencing, and mitotic pathways)

These 4 subtypes represent not only molecular alterations, but also a unique pathology, intestinal vs diffuse distinctions, varying tumor locations in either the cardia body or pylorus, and distinct epidemiologic risk factors.6 Thus, it is not surprising to find different degrees of HER2 expression in gastric cancer.

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Molecular Subtypes of Gastric Cancer 

CIN tumors often have the highest HER2 expression (16%-34%), are habitually found in the cardia and GEJ, and are less common in the body of the stomach. Histology wise, there is a higher incidence of HER2-positive disease in the intestinal subtype of gastric cancer than in the diffuse subtype.7,8

Looking at all-comers with a diagnosis of gastric or GEJ cancers, approximately 20% or more in the United States are HER2-positive.9

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Intratumoral Heterogeneity and Incomplete Membrane Staining of HER2

Intratumoral heterogeneity and incomplete membrane staining have been documented extensively for HER2 testing globally and according to current guidelines.10 Moreover, we have learned that HER2 testing in GI cancers is not the same as testing for HER2 in breast cancer because of unique idiosyncrasies for HER2 testing in gastric cancer. For example, based on some of the largest studies done to date, HER2 testing in GI cancers is quite complex, and if we biopsy 2 different locations in the tumor, we may end up with 2 different results.

Co-occurring alterations (ie, with EGFR, MET, FGFR) are extremely uncommon in gastric cancers compared with breast cancers.10

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HER2 Immunohistochemistry Scoring: ToGA Study

The table shows HER2 IHC scoring for GI tumors based on the randomized phase III ToGA study protocol.11

In that study, surgical specimens were considered positive, or HER2 IHC 3+, if they had a strong complete basolateral or lateral membranous reactivity in ≥10% of tumor cells; HER2 IHC 2+ if weak to moderate basolateral or lateral membranous staining in ≥10% of tumor cells; and HER2 IHC 1+ if faint or barely perceptible membranous reactivity in ≥10% of tumor cells. If cancer cells had no reactivity or membranous reactivity in <10% of cancer cells, those were considered negative, or HER2 IHC 0. Of importance, if the HER2 IHC score is 2+, or weak to moderate staining in ≥10% of cells—also known as equivocal—the sample scoring undergoes reconfirmation via FISH or ISH testing.

Regarding HER2 testing in other GI cancers, we often think about the less common tumors to harbor HER2 positivity—for example, CRC and BTCs. In my opinion, it is worth testing those cases, and we are starting to see additional data supporting this approach.12,13

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Types of HER2 Testing: NCCN Recommendations

HER2 testing in gastric cancer and CRC has been adopted by the NCCN guidelines, the College of American Pathologists, and the American Society of Clinical Oncology, such that we now have a fairly uniform recognition of what is considered HER2 positive in gastric and GEJ tumor samples.2,3,14

It is important to remember that there are other recent changes that may include NGS and assessment of circulating tumor DNA (ctDNA)—this can be one of the fastest ways to get an IHC test back after a cancer diagnosis.15

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Loss of HER2 on Disease Progression After Trastuzumab: ctDNA Profiling

There are a handful of nuances in gastric cancer that also must be addressed regarding current challenges in HER2 testing upon disease relapse. Researchers have established a body of literature suggesting that heterogeneity is not the only challenge for HER2 testing in GI tumors, but we also may encounter HER2 loss, particularly in patients with progressive disease who previously received trastuzumab plus chemotherapy. In those patients, the recurrent disease may no longer express HER2 after progression. This has been demonstrated using ctDNA liquid biopsies after trastuzumab resistance in patients with metastatic HER2-positive gastric cancer.16

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Loss of HER2 on Disease Progression After Trastuzumab: Second-line Trial Outcomes

HER2 loss at disease progression also was observed in the randomized phase II T‑ACT (WJOG7112G) trial of weekly paclitaxel with or without trastuzumab in patients with HER2-positive advanced gastric or GEJ cancer refractory to trastuzumab plus fluoropyrimidine and platinum-based chemotherapy (N = 91).17

As shown on the progression-free survival (PFS) curve, investigators showed a lack of benefit with the addition of trastuzumab to weekly paclitaxel (median PFS: 3.68 vs 3.19 months; HR: 0.906; P = .334), which correlated with a lower proportion of patients (31% vs 100%) who tested positive for HER2 at recurrence compared with baseline (n = 16).

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Several Emerging Gene Alterations After Trastuzumab

The discovery of HER2 loss has led to extensive research that suggests there is a degree of emerging gene alterations following trastuzumab exposure leading to the emergence of HER2‑negative clones that become predominant and therefore more relevant within the disease.18 This notion of decrease in relevance for HER2-positive status has been challenged more recently by emerging ADC data, which we will discuss later.

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Summary and Takeaways for HER2 Testing in GI Cancers

To summarize where we stand on HER2 testing in GI cancers, I would say that HER2 testing is complex and nuanced by key factors relating to the technique used for determining HER2 positivity and tumor evolution itself. In general terms, IHC and FISH are common methods for assessing HER2 status across GI tumors for either recommending anti-HER2 therapy or assessing eligibility for a clinical trial, although NGS maybe used, and testing on ctDNA also can be considered. In gastric and GEJ adenocarcinomas, we have a reasonable standard of IHC and/or FISH testing, which should be adopted based on clinical guideline recommendations. Lastly, receipt of HER2-targeted therapies does have the potential to change the biology of these tumors and consequently HER2 expression.

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