Introduction
New therapeutic options—results of current clinical trials
Trial | Tumor Type | Study design | Outcome | Reference |
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Selected clinical trials in breast cancer | ||||
DESTINY-Breast01 Phase 2 | HER2-positive metastatic breast cancer | Phase 2 trastuzumab deruxtecan after previous therapy with T‑DM1 | 61% response | Modi et al., NEJM 2020 [15] |
DESTINY-Breast03 | Metastatic HER2-positive breast cancer | Trastuzumab deruxtecan vs. T‑DM1 | Positive study result PFS: 75.8% vs. 34.1% Overall response rate 79.7% vs. 34.2% | Cortes et al., NEJM 2022 [2] |
DESTINY-Breast04 | Metastatic HER2-low breast cancer (IHC1+ or 2+/SISHneg) | Trastuzumab deruxtecan (T-DXd) vs. physician’s choice chemotherapy (capecitabin, eribulin, gemcitabine, paclitaxel) | Positive study result (for details see text) The trial results are relevant for HER2 assessment in histopathological routine | Modi et al., NEJM 2022 [14] |
Daisy study | Metastatic breast cancer (HER2-positive, HER2-low, and HER2 negative) | Phase 2 Trastuzumab deruxtecan | Response rates: HER2 3+: 71% HER2-low: 37.5% HER2-neg: 30.0% | Mosele et al. ESMO breast 2022 [16] |
Selected trials in other types of tumors | ||||
DESTINY-Gastric01 | Advanced carcinoma of the stomach or gastroesophageal junction with classic definition of HER2 positivity, (3+ or 2+/FISH positive) | Phase 2 Trastuzumab deruxtecan (T-DXd) vs. chemotherapy | Objective response rate (ORR) and survival (OS) were significantly better than in the chemotherapy control arm (OS: 12.4 vs. 8.4 months) | Shitara et al., NEJM 2020 [26] |
DESTINY-CRC-01 | Colorectal carcinoma without RAS/BRAF mutations, classic HER2-positive and HER2-low positive | Phase 2 Trastuzumab deruxtecan | HER2 IHC3+ or IHC2+/ISH positive tumors: objective treatment response 45% Other results still pending | Siena et al. Lancet Oncol 2021 [27] |
DESTINY-Lung01 | Non-small cell lung cancer Activating ERBB2 mutation (independent of HER2 expression and ERBB2 amplification) | Phase 2 Trastuzumab deruxtecan | Response in 55% | Li et al., NEJM 2021 [12] |
Principles of HER2-low scoring
Step 1: Application of the “magnification rule” [23]
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Strong HER2 staining (IHC3+) can be seen as clear membrane staining even when using a 2 × or 5 × objective.
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Moderate-strength HER2 (IHC2+) staining is typically seen as linear membrane staining at the cell–cell contact sites only when using a 10 × or 20 × objective.
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Weak (IHC1+) staining is typically not clearly identified as membrane staining until the 40 × objective is used.
Step 2: Staining pattern—circularity of membrane staining
Step 3: Percentage of tumor cells with HER2 expression
Practice of HER2-low testing
Sample material
Antibodies, technical platforms, regulatory framework
T-DXd in other indications and in HER2 mutations
Current challenges and scientific questions
Conclusions for clinical practice
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A clear distinction between HER2 immunohistochemistry (IHC)0 and IHC1+ should be made in the histological report. The two groups should not be combined into a “HER2-negative” group in the report.
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The new group should be clearly identified in the pathology report. We recommend the use of the term “HER2-low.”
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The term “HER2-low” should currently only be used for breast cancer; the treatment option is currently only available for metastatic breast cancer. However, standardized evaluation with documentation of the individual IHC scores should be performed for all tumor types.
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Histological diagnosis is still based on the current ASCO/CAP guidelines for HER2 diagnosis. The evaluation of strongly HER2-positive tumors by immunohistochemistry (for IHC3+) or the combination of IHC and in situ hybridization (for IHC2+) also remain identical. The distinction between 0 and 1+ can only be made by IHC.
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For the evaluation of IHC, the standardized procedure described in this article (1: magnification rule; 2. staining pattern; 3. percentage) is recommended. The percentage of positive cells should be included in the diagnostic report. This is relevant for the differentiation between IHC0 (≤ 10% weak positive cells with incomplete membrane staining) and IHC1+ (> 10% weak positive cells with incomplete membrane staining). In this way, it is possible to directly identify which tumors are in the borderline area.
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The primary tumor or a re-biopsy of the metastasis can be used for the determination of HER2-low status; however, the current clinical guidelines recommend a re-biopsy with re-determination of the receptor status (including HER2) as standard in the case of tumor progression, if this is clinically possible.