Targeting HER2 is Clinically Meaningful Even with Its Low Expression

HER2 Testing

Recognizing the significance of pathologically increased activity of signaling pathways derived from the HER2 receptor was a pivotal event for the development of targeted breast cancer therapy. In 15-20% of these tumors, the increased activity is caused by enhanced expression of the HER2 receptor, most commonly due to gene amplification for HER2.

The expression of HER2 receptors in tumor tissue is examined immunohistochemically (IHC). In the case of IHC 2⁺ expression, gene amplification needs to be confirmed by fluorescent in situ hybridization (FISH). Currently, tumors with IHC 3⁺ and IHC 2⁺ with positive FISH are considered positive. Other tumors were long considered HER2-negative until it was discovered in 2020 that tumors with IHC 1⁺ or 2⁺ and negative FISH (referred to as HER2-low) can also respond to some HER2-targeting drugs. To improve patients' access to potentially effective therapy, it is crucial to correctly detect low-level HER2 expressions.

Neither Positive Nor Negative

Thus, a group of tumors with low HER2 expression (HER2-low) was identified in pathological classification. These tumors represent more than 50% of breast cancer cases and generally correspond to luminal types. The clinical relevance of low HER2 expression has so far been determined mainly in retrospective cohorts with inconsistent results. However, most studies lean towards the conclusion that HER2-low tumors are associated with the same or slightly better prognosis than HER2-negative tumors.

They also differ in having a lower prevalence of BRCA gene mutations and mutations in signaling pathways associated with the protein p53, the cell cycle, immune checkpoints, or the PI3K-Akt pathway. The HER2 status can change over the course of the disease and also reacts to treatment. Increased expression has been described in response to hormonal therapy or radiotherapy.

Targeted Biodistribution

It currently appears that HER2 expression is not a driving factor of oncogenesis in tumors with low expression, and simply eliminating the HER2 receptor does not lead to clinical benefit, as shown by clinical trials with trastuzumab. However, if the HER2 receptor is used as a navigation tool to deliver potent cytostatics to the tumor cell, very interesting results can occur. This was demonstrated by the phase III clinical trial DESTINY-Breast04.

Clinical Trial

The study included patients with metastatic carcinoma with low HER2 expression (IHC 1⁺ or 2⁺ and negative FISH) who underwent ≤ 2 lines of chemotherapy. Patients with positive hormone receptor (HR+) expression had to be refractory to this therapy.

A total of 557 individuals (including 2 men) were randomized in a 2:1 ratio to treatment with trastuzumab-deruxtecan or chemotherapy chosen by the treating oncologist. After a median follow-up of 18.4 months, there was a 49% lower risk of progression and a 36% lower risk of death in HR+ patients treated with trastuzumab-deruxtecan compared to the control group. Similar results were achieved in the entire study population, as shown in the following table.

Table: Results of the DESTINY-Breast04 Study

Note: HR – hormone receptors; M – month; OS – overall survival; PFS – progression-free survival; T-DXd – trastuzumab-deruxtecan

New Generation of Antibody-Drug Conjugates

Trastuzumab-deruxtecan is an antibody-drug conjugate targeting HER2 and acting as a topoisomerase I inhibitor. Unlike previous conjugates, it has higher efficacy, as the cytostatic not only targets tumor cells expressing HER2 but also enters nearby cells (so-called bystander effect).

Currently, it is the only registered drug targeting HER2 suitable for patients with low expression of this receptor. In the current Czech guidelines for breast cancer treatment, it is listed as an option for tumors without HER2 gene amplification and with an HR+/HER2-low profile, or triple-negative tumors with HER2-low, in patients who have been treated with ≥ 1 chemotherapy regimen for metastatic disease or who have recurred during adjuvant chemotherapy or within 6 months of its completion.

What About Diagnostics?

Along with new treatment options, in the context of low HER2 expression, it will also be necessary to modify methods of examining tumor tissue. Current methods are not entirely suitable for detecting low levels of HER2 receptors. A 2022 study highlighted the low concordance (26%) among pathologists when classifying samples into HER2-negative and HER2 1⁺ and 2⁺ groups according to IHC.

To improve resolution capability, the American Society of Clinical Oncology (ASCO) in collaboration with the College of American Pathologists (CAP) recommends examining preparations at higher magnification (40×) and utilizing a second reading if the results are close to 0. New, more sensitive detection methods based on mass spectrometry or image analysis combined with machine learning (artificial intelligence) are under development.

Conclusion

Cancers with low HER2 expression form a large portion of breast cancer cases. With the discovery of the significant efficacy of the 3rd generation of HER2-targeting antibody-drug conjugates in this patient population, it is essential to refine pathological examination methods and continue studying the impact of HER2 expression levels on treatment outcomes and patient prognosis.

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Sources:
1. Shirman Y., Lubovsky S., Shai A. HER2-low breast cancer: current landscape and future prospects. Breast Cancer: Targets and Therapy 2023; 15: 605–616, doi: 10.2147/BCTT.S366122.
2. Modi S., Jacot W., Yamashita T. et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 2022; 387 (1): 9–20, doi: 10.1056/NEJMoa2203690.
3. Malignant breast neoplasm (C50). In: Kiss I. (ed.). Blue Book of the Czech Oncology Society, 30th update. Masaryk Memorial Cancer Institute, Brno, 1. 3. 2024. Available at: www.linkos.cz/lekar-a-multidisciplinarni-tym/personalizovana-onkologie/modra-kniha-cos/aktualni-vydani-modre-knihy/asd-12-zhoubny-novotvar-prsu-c50