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Update: Testing and Treatment
Recent Developments in Testing for and Targeting HER2, HER3, and TROP2 in Patients With Advanced Breast, GI, and Other Solid Cancers

Released: July 23, 2020

Expiration: July 22, 2021

Mark D. Pegram
Mark D. Pegram, MD
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With a wealth of targeted therapeutics now available to treat many solid and hematologic malignancies, optimal biomarker testing and interpretation are essential. In this commentary, I review recent developments and data surrounding HER2, HER3, and TROP2 testing in breast, gastrointestinal, and other solid tumors and how this testing may inform treatment options now or in the future.

Updates in HER2 Testing in Breast Cancer
HER2 testing has informed breast cancer prognosis and use of targeted therapy for the past 20 years. Recently, the treatment armamentarium for HER2-positive breast cancer has been expanded with the approvals of 2 HER2-targeted TKIs, neratinib and tucatinib, and the HER2-targeted antibody–drug conjugate (ADC) trastuzumab deruxtecan. Several additional agents, including trastuzumab duocarmazine (SYD985) and margetuximab, are currently in later-phase clinical trials.

Guidance in testing continues to be refined. In 2018, ASCO and the College of American Pathologists released updated guidelines for HER2 testing that differed from historical versions in these key ways.

  • The definition of “IHC2 positive” (equivocal) was revised back to the original FDA-approved criteria.
  • Repeat HER2 testing on a surgical specimen is no longer considered mandatory if the initial tested core biopsy is negative.
  • For less common patterns of HER2 aberrant amplification (ISH groups 2-4, where classical HER2 gene amplification may not be observed but there may be an increase in HER2 copy number by other mechanisms eg, DNA ploidy), interpretation criteria have been made more stringent.
  • Dual-color FISH assays are now preferred over single-probe ISH assays. This is particularly important because several single-probe assays are now commercially available, and although many have regulatory approval in different parts of the world, they are not ideal for some cases of HER2 gene amplification, in particular, those where the copy number may be low.

HER2 Gene Amplification: Beyond Breast Cancer
It is important to recognize that HER2 gene amplification is observed outside of breast cancer, having been described in salivary gland cancer, ovarian cancer, endometrial cancer, gastric and gastroesophageal junction cancers, colorectal cancer, and lung cancer. HER2 gene amplification is often detected by next-generation sequencing (NGS), either with tumor tissue or circulating tumor DNA. A recent study tested more than 5000 different nonbreast solid tumors and found that 2.4% exhibited HER2 gene amplification, with HER2-targeted therapy significantly associated with an increased OS. This parallels with findings from a key trial in which HER2-targeted therapy was used to treat non–breast cancer patients with HER2 gene amplifications: the pivotal TOGA study, which found that the addition of trastuzumab to chemotherapy significantly improved survival in patients with advanced HER2-positive gastric cancer, leading to trastuzumab becoming a standard of care for these patients.

As such, although HER2 gene amplifications may not be common in many solid tumors, testing for this alteration may reveal an actionable therapeutic path, depending on the tumor type. Numerous HER2-targeting agents are currently in clinical trials for treating nonbreast HER2-positive solid tumors, including trastuzumab deruxtecan and tucatinib for advanced colorectal cancer.

Beyond HER2 Gene Amplification: HER2 Point Mutations
In general, HER2 gene amplification is what we test for in breast cancer and other solid tumors. However, data have suggest that specific point mutations in the genomic sequence of the coding regions of the HER2 gene may also have prognostic and therapeutic significance. A recent study that assessed data from more than 100,000 tumors encompassing 400 cancer types or subtypes found that somatic substitution mutations were commonly found in or near the transmembrane or juxtamembrane domains of the protein, including G660D, V659E, R678Q, and Q709L. Functional analysis of these mutations demonstrated that most are likely to be driver mutations. Somatic HER2 mutations are relatively rare, occurring in 1% to 3% of patients across multiple malignancies. The phase II SUMMIT basket study treated patients with solid cancers (breast, bladder, colorectal, lung, and biliary tumors) with HER2 mutations with neratinib and found overall response rates of up to 32%.

This is an emerging story. These point mutations are rare, and as yet, there are not a lot of data in this space, but I would say that it is not only important to look for HER2 gene amplification but also to look for mutations in HER2, particularly those that affect the juxtamembrane or tyrosine kinase domains. NGS assays are able to detect amplifications as well as point mutations, so we are starting to see these more often in multiple tumor types. It is notable that when HER2 substitution mutations are found in breast cancers, there is often no concomitant HER2 gene amplification; these cancers would be classified as HER2 negative by conventional IHC or FISH measurements but potentially include deleterious HER2 substitution mutations.

TROP2 and HER3: Emerging Biomarkers for Solid Tumors
TROP2 is a cell surface protein anchored to the membrane by a single transmembrane domain. TROP2 is overexpressed in a number of different types of cancer cells, making it a viable therapeutic target. Indeed, sacituzumab govitecan, a TROP2-directed ADC with a topoisomerase 1 inhibitor payload, recently received accelerated FDA approval for the treatment of patients with metastatic triple-negative breast cancer. It should be noted that the indication for sacituzumab govitecan is independent of TROP2 testing, so it is not necessary to test patients for this biomarker in advance of treatment.

There are numerous ongoing trials with sacituzumab govitecan outside of breast cancer, as TROP2 can be expressed on a variety of epithelial carcinomas, including endometrial, bladder, and prostate cancer. Several other TROP2-targeted ADCs are also in development for breast cancer, including DS-1062a, which is currently being investigated in a phase I trial for treating unresectable small-cell lung cancer and triple-negative breast cancer.  

HER3 is another biomarker of interest across solid tumor types and has been implicated in the acquisition of cancer characteristics. A recent study found that HER3 was mutated in 3.8% of 844 solid tumor samples screened. Most identified HER3 mutations occur in the extracellular domain and often occur at the dimerization interface of HER3.

The days are still early in terms of HER3-targeted therapeutics. Data have suggested that HER2-targeted agents like pertuzumab can block the HER2/HER3 dimerization interface, thus blocking engagement of HER2 with HER3, either in wild-type or mutant forms. However, further clinical investigation is required to determine if this is a viable strategy for patients with HER3-mutated cancers. Several HER3-targeted agents are in early-phase clinical trials, including U3-1402, an anti-HER3 antibody, which is currently being assessed in metastatic breast cancer and non-small-cell lung cancer.

Your Thoughts
What are your best practices for HER2 testing in breast cancer? Do you test for HER amplifications/alterations in nonbreast solid cancers? If so, how do test results influence your management of these cancers? Please share your thoughts in the comments box and answer the polling question on your screen.

Want to know more? Sign up here to attend one or more of the following online Webinars:

  • “Diagnostic Testing for HER2, HER3, and TROP2 in Breast, GI, and Lung Cancers” on Thursday, July 30, 2020, with expert pathologist faculty Michael F. Press, MD, PhD;
  • “Targeting HER, HER3, and TROP2 in Breast Cancer” on Friday, August 21, 2020, with me, Mark D. Pegram, MD
  • “Assessment of HER2 Status and Targeting HER2 in Gastrointestinal Cancers” with Axel Grothey, MD; date TBD
  • “Experts Answer Your Questions on Diagnostic Testing for HER2, HER3, and TROP2 and Treatment Implications in Breast, GI, and Lung Cancers” with multidisciplinary expert panel; date TBD
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