Catch up on some of the latest research and discussion around HER2-positive and HER2-negative breast cancer.
Immunotherapy has been shown to be effective in HER2-positive breast cancer patients, while HER2-negative breast cancer patients may need to be re-tested.
The hormone receptor and human epidermal growth factor 2 (HER2) expression of breast cancer tumours guides treatment decisions and can potentially predict clinical outcomes.
Patients with HER2-positive tumours can be treated with a range of targeted drugs including tremelimumab (an anti-CTLA-4 blocker) and durvalumab (an anti-PD-L1 inhibitor). But using these drugs in combination had never been prospectively tested in HER2-positive breast cancer.
Enter the DIAmOND study, a non-randomised phase II study that tested whether using tremelimumab and durvalumab in combination with trastuzumab, a monoclonal antibody that targets the HER2 receptor, could improve outcomes for men and women with HER2-positive metastatic breast cancer.
Professor Sherlene Loi, a consultant medical oncologist and head of the translational breast cancer genomics and therapeutics laboratory at the Peter MacCallum Cancer Centre, developed and led the new trial, presenting the results at the recent ESMO Breast Cancer congress in Germany.
Almost two thirds of breast cancer patients that were HER2-positive and had high levels of tumour infiltrating lymphocytes responded to the combination treatment, with some patients experiencing up to 30 months of durable cancer control.
“[The] median duration of the response in this study was impressive, highlighting that when responses occur, they can be durable. Toxicity was manageable, but grade 3/4 adverse events occurred in roughly 60% of patients – which is expected for CTLA-4/PD-L1 combinations – and less in the single dose tremelimab priming schedule cohort,” Professor Loi explained.
“These data were viewed as encouraging but early, [and] most questions centred on biomarker selection and how the regimen might compete with trastuzumab-deruxtecan (T-DXd).”
Professor Loi told Oncology Republic that as the DIAmOND trial collected sequential tumour biopsies from patients, analyses of T-cell clonality, TIL density, PD-L1 dynamics and HER2-specific antibodies are ongoing to refine predictive biomarkers.
Elsewhere, a recent review published in JCO Oncology Practice has called for improved HER2 testing after discussing how HER2 classification has changed following the development of novel antibody-drug conjugates such as T-DXd.
“Until recently, HER2 status was classified dichotomously as positive or negative on the basis of treatment indications. HER2-low expression was disregarded in clinical practice, as these tumours were considered ineligible for anti-HER2 therapies,” the authors wrote.
“[But] the development of a new generation of anti-HER2 ADCs has reshaped this paradigm, leading to the recognition of low HER2 expression as a targetable subgroup of [breast cancers].”
The review described the now five different HER2 categories, defined on the basis of their immunohistochemistry staining:
- HER2-0: No observable membrane staining
- HER2-0+: Incomplete and faint or barely perceptible membrane staining in ≤10% of tumour cells
- HER2-1+: Incomplete and faint or barely perceptible membrane staining in >10% of tumour cells
- HER2-2+: Weak-moderate complete membrane staining in >10% tumour cells OR intense membrane staining in ≤10% of tumour cells
- HER2-3+: Complete and intense membrane staining in >10 of tumour cells.
Around 15% of breast cancers are HER2-0, 10% are HER2-0+, 55% are HER2-1+ and 20% are HER2+/3+.
Data from clinical trials, including the phase III DESTINY-Breast04 and DENSITY-Breast06 trials, suggest that the majority of breast cancers – even if they have been classified as HER2-negative – exhibit a detectable amount of HER2 on their cell membranes that can be targeted by novel ADCs such as T-DXd (i.e., the HER2-0+ category).
“The phase III DESTINY-Breast04 trial… established that TDXd’s benefit over single-agent chemotherapy in chemotherapy pre-treated patients with HER2-low metastatic breast cancer,” the review authors explained.
“T-DXd significantly improved both progression-free survival and overall survival across all prespecified subgroups, including hormone receptor status and HER2 immunohistochemistry expression levels.
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“On the basis of these data, T-DXd has become a standard of care for patients with HER2-low metastatic breast cancer after one line of chemotherapy.”
The new drugs – at least eight different anti-HER2 drugs have been approved by the FDA and/or the European Medicines Agency – have a range of unique features that accounts for their activity in HER2-low breast cancers, “including a distinct mechanism of action of the cytotoxic payload, higher drug-to-antibody ratio or the ability to elicit the bystander effect”.
“Some characteristics, such as a hydrophobic payload or a cleavable linker, seem to play a major role in the latter effect, allowing the killing of neighbouring cells regardless of HER2 expression and resulting in clinical activity even in cases of low or heterogeneous antigen expression,” the authors wrote.
The authors go on to discuss how “the clinical landscape of HER2 testing has fundamentally shifted following the introduction of T-DXd, making the distinction between HER2 IHC 0 and 1+ clinically relevant”.
“This challenges current diagnostic practices for HER2 evaluation and emphasises the need for accurate and reproducible HER2 assessment. This is especially critical as ADCs move into the early, curative setting, where risk benefit considerations are paramount,” they said.
Consequently, the current HER2 testing approach may no longer be fit for purpose.
“The current IHC assay faces limitations in discriminating HER2 IHC from 0, as well as true HER2-0 (i.e., HER2-null, no staining) from ultralow expression (faint/barely perceptible membrane staining in ≤10% of invasive tumour cells). A critical concern is that what is classified as IHC 0 may often reflect technical limitations rather than true biological absence of HER2,” they wrote.
“Exploring innovative approaches, such as developing quantitative metrics for HER2 evaluation or leveraging the transformative potential of liquid biopsy, could further refine HER2 testing and ensure all eligible patients receive the most effective therapies.”
Professor Loi recommended that all patients who had previously been categorised as HER2-negative should be reassessed so as to not miss out on receiving T-DXd if required.
