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HER2 Pathology Insights
Expert Insights Into How Pathologists Can Guide Clinical Decision-making for HER2-Altered Solid Tumors

Released: April 23, 2024

Expiration: April 22, 2025

Katherine M. Bever
Katherine M. Bever, MD
Laura C. Collins
Laura C. Collins, MD
Tanya Gupta
Tanya Gupta, MD
Funda Meric-Bernstam
Funda Meric-Bernstam, MD
Elizabeth D. Thompson
Elizabeth D. Thompson, MD, PhD
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Key Takeaways
  • In breast cancer, pathologists are now challenged to identify HER2-low tumors, with their findings potentially influencing how patients are treated.
  • HER2 testing is essential in GI cancers to inform treatment choices, with the HER2 IHC labeling pattern and scoring systems differing from those in breast cancer.
  • Numerous HER2-targeted agents are in clinical development.

HER2 alterations, including amplification, overexpression, and activating mutations, are observed with different prevalence in solid tumors and can inform the use of approved and investigational HER2-targeted therapeutics. In this commentary, expert pathologists and oncologists answer key questions from a live symposium focused on how pathologists can help guide clinical decision-making in patients with HER2-altered solid tumors.

How does the concept of HER2-low or HER2-ultralow status expand the HER2 spectrum in breast cancer?

Laura C. Collins, MD:
How do we define HER2-low disease? Treatment response with antibody‒drug conjugates has been demonstrated among patients with HER2-low breast cancers, which are defined as IHC 1+ or 2+/ISH nonamplified. This definition requires pathologists to discriminate HER2 IHC 0 from HER2 1+ expression levels. As a review, HER2 IHC 0 tumors are those that have no staining or membrane staining that is incomplete, faint, or barely perceptible in ≤10% of tumor cells. Tumors that are HER2 IHC 1+ have that same level of expression in terms of intensity but in >10% of cells.

Pathologists are essentially being asked to differentiate 2 very similar IHC intensities, but right around that 10% threshold. This can be a difficult thing to do, and our interpretation can determine whether a patient will receive a potentially beneficial therapy. The need to classify HER2-low breast cancers has caused a shift from what was a 2-tier scoring system of HER2 positive vs negative to a 3-tier scoring system. There are now HER2-positive tumors, which are the IHC 3+ and the 2+/ISH-amplified tumors; HER2-low tumors; and HER2-negative/IHC 0 tumors.

We are now seeing an emergence of something that is being called HER2-ultralow disease. This is because of data suggesting clinical benefit with trastuzumab deruxtecan (T-DXd) among patients with HER2-ultralow breast cancer. The definition of HER2-ultralow disease is HER2 IHC 0 tumors that show some level of expression, such as weak or incomplete membranous staining in ≤10% of cells, as opposed to HER2-null tumors, which have no staining at all. Something to note: The HER2 IHC assay was designed and has dynamic range for identifying HER2 IHC 3+ disease, but it can lack reliability and reproducibility to distinguish IHC 0 cases from 1+ cases.

It is also worth mentioning that HER2-low expression can change over time. There are studies showing that tumors that were either HER2 IHC 0 or 1+ can change in subsequent specimens or sites; status can either move from IHC 0 to 1+ or from 1+ to 0. Often at an oncologist’s request, an IHC 0 result may prompt a test of either a subsequent specimen or a prior specimen to see if there is actually HER2-low expression.

How can we improve our ability to recognize these HER2-low breast cancers? Well, the American Society of Clinical Oncology and College of American Pathologists guidelines advise that pathologists should be examining a slide at 40x to see that weak incomplete membranous staining to enable us to discriminate IHC 0 from 1+. It is recommended that samples be reviewed by a second pathologist in cases that are close to that 10% threshold. It is also wise to have controls with a range of protein expression, especially 1+, to ensure that an assay has appropriate limits of detection, especially at that lower end of the range. Paying attention to preanalytic variables is also key.

What is an appropriate therapeutic approach for a patient with HER2-low metastatic breast cancer?

Tanya Gupta, MD:
In patients such as these, 1 specific treatment option is T-DXd, which is approved in the metastatic setting for patients who have HER2-low disease and have received at least 1 prior line of chemotherapy. This approval was supported by DESTINY-Breast04, a randomized phase III trial that evaluated T-DXd vs chemotherapy in patients with HER2-low disease. In this study, HER2-low disease was defined as IHC 1+ or 2+ with a negative FISH result. Eligible patients had received 1-2 prior lines of chemotherapy in the metastatic or locally advanced disease setting. When comparing patients who received T-DXd vs chemotherapy, median progression-free survival was 8.8 vs 4.2 months, respectively, with an HR of 0.36. There was also an improvement in overall survival with the use of T-DXd (23.9 vs 17.5 months).

Looking at HER2-ultralow breast cancer, the DESTINY-Breast06 study is a randomized phase III study evaluating T-DXd vs physician’s choice of chemotherapy in patients with advanced or metastatic HER2-low or HER2-ultralow (IHC >0 and <1+) breast cancer with progression on 2 previous endocrine therapies. We await the results of this study to better address the degree of benefit that patients may have from receiving T-DXd with HER2-ultralow status.

What are some of the key differences in HER2 testing between breast and gastrointestinal (GI) cancers?

Elizabeth D. Thompson, MD, PhD:
Major differences lie in the pattern of labeling, as well as the scoring systems. Final scoring categories historically have been the same, classifying tumors as HER2 negative, equivocal, and positive, both with the general testing strategy of IHC first, followed by reflex ISH testing when scoring is equivocal. The specific criteria for HER2 IHC 1+, 2+, and 3+ differ among gastric and breast cancers (as well as potentially between other GI cancers, as those scoring systems continue to evolve), and the percentages of HER2-positive cancers that we expect in these categories are also different.

The IHC pattern of HER2 labeling in gastroesophageal junction (GEJ) cancer and colorectal cancer (CRC) is different from breast cancer. Particularly in GEJ cancer, complete circumferential labeling is fairly rare. A basolateral pattern of labeling is much more common, and there is a lot more heterogeneity within individual tumors. This variability plays into how a GI tumor gets scored, particularly for biopsy vs resection specimens. This is different from breast cancer scoring, which uses the same criteria for all specimens.

What are some treatment options for HER2-mutated metastatic CRC?

Katherine M. Bever, MD:
Tucatinib plus trastuzumab was recently approved as HER2-targeted therapy for patients with RAS wild-type, HER2-positive unresectable or metastatic CRC that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This approval was supported by the phase II MOUNTAINEER study, which randomly assigned previously treated patients with HER2-positive/RAS wild-type metastatic CRC to receive tucatinib alone or in combination with trastuzumab. The results from the combination arm of this study showed an objective response rate of 38% and a 12.4-month median duration of response.

Numerous other HER2-targeted strategies also have shown activity in this setting, including trastuzumab plus lapatinib in the HERACLES study, trastuzumab plus pertuzumab in the MyPathway trial, and T-DXd in the DESTINY-CRC01 trial. These have all shown response rates in the ~25% to 45% range. Although these strategies are not yet approved by the FDA in the metastatic CRC setting, they are listed in US national guidelines as treatment options for patients with HER2-positive metastatic CRC after ≥1 line of prior therapy.

It should also be noted that since this live program, T-DXd has received a tumor-agnostic approval for patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

What are some novel HER2-targeted approaches in development?

Funda Meric-Bernstam, MD:
One novel HER2-targeted therapy is the biparatopic antibody zanidatamab. Zanidatamab binds HER2 in 2 domains and was assessed in a phase I study that had a large expansion in multiple cohorts; the objective response rate across tumor types for HER2-positive cancer was 37%. Zanidatamab also was evaluated in a phase IIb trial in HER2-amplified, locally advanced unresectable or metastatic biliary tract cancer after progressive disease with a gemcitabine regimen and demonstrated an objective response rate of 41%. This agent is currently being explored in phase III trials in advanced biliary tract and gastroesophageal cancers.

Another interesting agent is disitamab vedotin (DV), which is a HER2-targeted antibody (hertuzumab) coupled to monomethyl auristatin E via a cleavable linker. Initial studies of DV in urothelial cancer showed considerable activity, including in HER2-low disease. There is an ongoing phase II study looking at DV across tumor types and phase III trials in urothelial and breast cancers.

Of note, several other interesting HER2-directed therapies are in development, including strategies with vaccines, natural killer cell trials, chimeric antigen receptor strategies, and other immune-mediated mechanisms. HER2 is clearly a very important target that we need to keep an eye on and continue to identify best ways to assess.

Your Thoughts?
What challenges in HER2 testing have you encountered in your practice? What are some best practices you use in collaboration between pathologists and oncologists to inform treatment for patients with HER2-altered solid tumors? Join the discussion by posting a comment below.

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