HER2

HER2 is the cell-surface protein encoded by ERBB2, a member of the EGFR/ERBB receptor tyrosine kinase family. Cancer can become HER2-driven through gene amplification, marked protein overexpression, or activating sequence variants. HER2 testing is therefore not one universal test: the clinically relevant alteration and scoring system depend on the tumor type and the therapy being considered. [H1-H5]

In breast and gastroesophageal cancers, IHC and ISH are established methods for identifying HER2-positive tumors. In lung cancer and some other solid tumors, activating ERBB2 mutations detected by NGS can be the more relevant alteration. New antibody-drug conjugates have also made lower levels of HER2 expression clinically relevant in selected breast-cancer settings, without changing the conventional ASCO-CAP definition of HER2-positive breast cancer. [H2-H4, H6-H10]

ERBB2 encodes a transmembrane receptor with an intracellular tyrosine-kinase domain. Unlike several related receptors, HER2 has no well-established direct ligand and is a preferred dimerization partner for other ERBB-family receptors. Dimerization activates downstream pathways including RAS-RAF-MEK-ERK and PI3K-AKT-mTOR, which regulate proliferation, survival, differentiation, migration, and tissue development. [H1]

Gene amplification can produce many ERBB2 copies and high membrane-protein expression. Activating kinase-domain or extracellular-domain mutations can signal without amplification. These are biologically distinct events and should be reported separately rather than collapsed into a generic "HER2 positive" label. [H1, H6, H10]

Clinically established HER2 alterations occur in subsets of breast, gastric and gastroesophageal-junction adenocarcinoma, non-small-cell lung cancer, and biliary-tract cancer. HER2 overexpression or amplification can also occur in colorectal, endometrial/uterine serous, ovarian, salivary-gland, bladder, and other solid tumors, although the clinical actionability, assay, and required threshold differ. [H2-H6, H10-H11]

The same label can represent different biology: breast and gastric treatment selection often centers on protein overexpression or amplification, whereas NSCLC treatment may center on an activating ERBB2 mutation. A tumor-agnostic U.S. FDA indication for trastuzumab deruxtecan uses IHC 3+ expression in previously treated unresectable or metastatic solid tumors with no satisfactory alternatives. [H6]

HER2 is generally not a stand-alone test for diagnosing malignancy. Histology establishes the cancer diagnosis. HER2 then refines tumor classification, supports staging or treatment planning in selected cancers, and identifies potential eligibility for HER2-directed therapy. In invasive breast cancer, HER2 is part of standard biomarker characterization; in advanced gastroesophageal adenocarcinoma, HER2 assessment is included in the diagnostic work-up for treatment selection. [H2-H5]

ERBB2 sequence testing can define a molecular subtype of NSCLC or another solid tumor. The report should distinguish amplification, overexpression, mutation, and low-level expression because they do not have interchangeable diagnostic or therapeutic meaning. [H6, H10]

Before effective HER2-directed therapy, HER2 overexpression or amplification in breast cancer was associated with a more aggressive natural history. Modern anti-HER2 treatment has substantially changed outcomes, so the biomarker's historical prognostic meaning cannot be applied without considering treatment. [H2, H5]

Outside breast cancer, the prognostic effect is inconsistent and depends on tumor type, stage, co-alterations, assay, and treatment exposure. HER2 should not be used alone to estimate an individual patient's survival or recurrence risk. [H4, H6]

HER2 is a strong predictive biomarker when a validated assay identifies the alteration specified in the therapy label or guideline. Established HER2-directed classes include monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, and small-molecule kinase inhibitors. [H2-H4, H6-H11]

Predictive interpretation must be exact. A breast tumor that is IHC 3+ or ISH amplified is conventionally HER2 positive. In selected metastatic breast-cancer settings, IHC 1+, IHC 2+/ISH-negative, or IHC 0 with detectable membrane staining can identify eligibility for trastuzumab deruxtecan under the relevant U.S. indication. These lower-expression categories do not imply classic HER2 pathway addiction and do not make all HER2-directed drugs appropriate. [H2, H7]

HER2 status may differ between a primary tumor and a recurrence or metastatic site and may change after treatment. Guidelines support testing metastatic tissue when available, particularly when the result could change management. [H2-H5]

Serial serum HER2 extracellular-domain testing is not a general substitute for tissue assessment. Plasma NGS may detect ERBB2 mutations or amplification, but a negative plasma result can reflect low tumor shedding and may require tissue testing. Longitudinal circulating-tumor-DNA approaches remain an active research area rather than a universal monitoring standard. [H6, H10]

IHC: detects HER2 membrane protein in fixed tissue and assigns an intensity/pattern score. It is the usual initial test in breast and gastric/GEJ cancer. [H2-H5]

ISH: fluorescence, chromogenic, or silver in situ hybridization measures ERBB2 copy number, often relative to a chromosome-17 control. In breast cancer, ISH is commonly used to resolve IHC 2+ cases and uncommon copy-number patterns under the ASCO-CAP algorithm. [H2-H3]

NGS: identifies activating ERBB2 substitutions, insertions, copy-number gain, and occasionally other alteration types. It is central for HER2-mutant NSCLC and broader solid-tumor profiling. [H6, H10]

Preanalytic controls: cold ischemic time, fixation, tumor cellularity, decalcification, assay validation, positive/negative controls, and pathologist review can materially affect results. [H2-H4]

Breast-cancer IHC is commonly reported as 0, 1+, 2+, or 3+ with staining pattern and percentage of invasive tumor cells. IHC 2+ is equivocal for conventional HER2 positivity and generally requires ISH. ISH reporting includes the assay method, HER2/CEP17 ratio when applicable, average HER2 signals per cell, interpretation, and any required concurrent IHC review. [H2-H3]

For lower-expression ADC eligibility, the report may add treatment-relevant wording such as IHC 1+, IHC 2+/ISH-negative, or IHC 0 with membrane staining, while avoiding creation of an unsupported new biological subtype. [H2, H7]

NGS reports should specify ERBB2, transcript, HGVS nucleotide and protein change, variant allele fraction, copy-number method, specimen, quality limitations, classification, and therapy-specific evidence. Gastric/GEJ and biliary reports should use their own validated scoring algorithms. [H4, H10-H11]

A "positive" result means only that the specimen met a defined assay and tumor-specific criterion. It does not guarantee response. A negative result does not exclude all HER2 biology: the wrong alteration may have been tested, the sample may be small or heterogeneous, or the current therapy may use a different threshold. [H2-H6]

Interpretation should answer four questions: What was measured? In which specimen? By which validated method? For which cancer and treatment context? The report should not use "HER2 positive" without clarifying whether it refers to IHC, ISH, or mutation status. [H2-H4]

HER2 is vulnerable to intratumoral heterogeneity, primary-metastatic discordance, small-biopsy sampling, fixation artifacts, decalcification, and interobserver differences near IHC boundaries. Gastric tumors are often more heterogeneous than breast tumors. [H2-H4]

Different antibody clones, platforms, ISH probes, NGS pipelines, and scoring rules are not automatically interchangeable. IHC 0 versus 1+ discrimination has become clinically important but can be difficult, especially in low-expression specimens. [H2, H7]

Copy-number gain detected by NGS may not equal high protein expression; a sequence mutation may not equal amplification; and HER2 expression alone may not identify the dominant driver in every tumor. [H6, H10]

Primary or acquired resistance can arise from heterogeneous or reduced HER2 expression, loss of amplification, receptor-domain changes that alter binding, impaired antibody internalization, altered lysosomal processing, drug-payload efflux, and changes in topoisomerase-I sensitivity for antibody-drug conjugates. [H6-H10]

Downstream PI3K-AKT-mTOR activation, PTEN loss, parallel signaling through other receptor kinases, hormone-receptor cross-talk, and immune-effector changes can allow survival despite HER2 blockade. After progression, reassessment may reveal a different dominant mechanism or loss of the original biomarker. These mechanisms are biologically plausible and documented in research, but no single resistance test is a universal standard. [H2, H6]

Monoclonal antibodies: trastuzumab, pertuzumab, and related products block or modulate HER2 signaling and can recruit immune effector mechanisms.

Antibody-drug conjugates: trastuzumab deruxtecan and trastuzumab emtansine deliver cytotoxic payloads to HER2-expressing cells; indication and expression threshold differ.

Bispecific HER2 antibodies: zanidatamab binds two HER2 epitopes and has a U.S. indication in selected HER2-positive biliary-tract cancer. [H11]

Tyrosine-kinase inhibitors: tucatinib, lapatinib, neratinib, zongertinib, and other agents inhibit HER-family kinases with different selectivity and indications. [H10]

Combination strategies: anti-HER2 therapy may be paired with chemotherapy, endocrine therapy, immunotherapy, or another HER2 agent. The biomarker requirement must be checked against the current local label. [H6-H11]

Expression has become a continuum for selected ADC use. In January 2025, the U.S. FDA expanded trastuzumab deruxtecan to certain HR-positive metastatic breast cancers categorized as HER2-low or HER2-ultralow by an authorized assay. This is treatment-selection language, not proof that HER2-low is a single stable biological disease. [H7]

Earlier-stage treatment is moving rapidly. In May 2026, the U.S. FDA approved two trastuzumab deruxtecan indications in HER2-positive early-stage breast cancer: a neoadjuvant sequence for stage II-III disease and adjuvant therapy for residual invasive disease after specified neoadjuvant treatment. [H9]

Mutation-directed lung therapy is expanding. In February 2026, the U.S. FDA expanded accelerated approval of zongertinib for unresectable or metastatic non-squamous NSCLC with activating ERBB2 kinase-domain mutations detected by an authorized test. [H10]

Pan-tumor and non-breast development continues. U.S. approvals include trastuzumab deruxtecan for previously treated IHC 3+ solid tumors and zanidatamab for selected HER2 IHC 3+ biliary-tract cancers. Research priorities include better low-expression reproducibility, spatial heterogeneity, resistance profiling, and ctDNA-guided reassessment. [H6, H11]

Regulatory statements describe U.S. FDA indications and should be checked against the current label for the user's country or region.