Molecular landscape of HER2-mutated non-small cell lung cancer in Northeastern Brazil: Clinical, histopathological, and genomic insights

Abstract

HER2 genomic alterations characterize a specific subset of NSCLC with potential therapeutic relevance. While most studies focus on populations from high-income countries, data from Latin America remains scarce. We retrospectively analyzed 13 HER2-mutated NSCLC cases from a single institution in Northeastern Brazil, integrating clinical, histopathological, immunohistochemical, and molecular findings. Predominant histological patterns included acinar and lepidic subtypes, with HER2 mutations primarily involving exon 20 insertions (A775_G776insYVMA) and frequent co-alterations in TP53, KRAS, and STK11. HER2 protein expression assessed by IHC showed low scores (0-2+) in most cases, while HER2 gene amplification was confirmed in one case by D-DISH and NGS. Tumor mutation burden was universally low. Treatment responses varied, with one patient receiving trastuzumab deruxtecan. Our findings highlight the molecular diversity and diagnostic challenges of HER2-mutated NSCLC in underrepresented populations, emphasizing the need for comprehensive molecular profiling and expanded access to targeted therapies.

Keywords: HER2 mutation; NSCLC; genomic profiling; lung cancer; targeted therapy.

Figure 1. Clinical, histological, and molecular features of 13 lung cancer cases with HER2 alterations.

The heatmap summarizes the clinical, histological, and molecular profile of 13 lung cancer patients with HER2 mutations. Key characteristics, including sex, smoking history, tissue origin (lung or pleura), histological subtype (acinar, lepidic, mucinous, or solid), HER2 status by IHC (0, 1+, 2+, or NA), PD-L1 status (positive, negative, or NA), and type of HER2 mutation (TKD or non-TKD), are depicted. The lower panel displays additional genomic alterations, including mutations, amplifications, deletions, and losses in frequently altered genes (e.g., ERBB2, EGFR, KRAS, TP53). The bar plot to the right indicates the frequency of alterations across the cohort. This comprehensive profile highlights the heterogeneity in clinical, immunohistochemical, and genomic features in HER2-mutated lung cancer cases.

Figure 2. Distribution of HER2 mutations, HER2 IHC expression, and PD-L1 status in a cohort of 13 lung cancer patients.

Sankey diagram illustrating the molecular and immunohistochemical landscape of HER2-mutated lung adenocarcinomas. This diagram visualizes the classification pathway of 13 lung cancer patients harboring HER2 alterations, highlighting the distribution and relationships among HER2 mutation variants, mutation domain (TKD vs. non-TKD), HER2 protein expression by immunohistochemistry (IHC), and PD-L1 expression status. The flow begins with 13 patients, of whom 12 harbored HER2 mutations alone and one presented with both HER2 mutation and amplification. Specific HER2 variants are shown, with the most common being A775_G776insYVMA. These variants are subsequently grouped by mutation location: tyrosine kinase domain (TKD) mutations (n = 10) and non-TKD mutations (n = 3). The next level displays HER2 IHC results (0, 1+, 2+, or not available (NA)), followed by PD-L1 status (positive, negative, or NA). The diagram highlights the heterogeneity of HER2-mutant tumors in terms of both protein expression and immune marker status. For instance, HER2 IHC scores were not consistently correlated with mutation type or PD-L1 expression. This comprehensive view underscores the complexity of biomarker interplay in HER2-altered non-small cell lung cancer (NSCLC) and supports the need for multi-modal molecular profiling in therapeutic decision-making. The width of each flow is proportional to the number of patients it represents. Each pathway from left to right shows how patients are distributed across molecular subtypes and immunohistochemical profiles.

Figure 3. Radiological, histopathological, and molecular features of a HER2-amplified lung adenocarcinoma.

(A) Chest computed tomography (CT) scan demonstrates a consolidative opacity with air bronchograms, surrounded by a faint ground-glass halo and lobulated margins, located in the visceral periphery of the apicoposterior segment of the left upper lobe. (B) Hematoxylin and eosin (H&E) staining reveals acinar-pattern adenocarcinoma with moderately differentiated tumor cells showing glandular architecture (scale bar = 200 μm). (C) Immunohistochemistry for HER2 (IHC) demonstrates a 2+ membranous staining pattern, focal basolateral and incomplete, moderate (scale bar = 100 μm). (D) Dual in situ hybridization (DISH) reveals HER2 gene amplification with an average of 4 HER2 gene copies per centromere (scale bar = 50 μm). These findings confirm the HER2-amplified status of the tumor and support its molecular characterization for targeted therapeutic strategies.

Figure 4. Radiological, histopathological, and molecular features of a HER2 non-amplified lung adenocarcinoma.

(A) Chest computed tomography (CT) scan reveals a solid nodular lesion with interspersed cystic areas and a subtle ground-glass halo, exhibiting spiculated margins with pleural impressions, located in the anterior segment of the right upper lobe. (B) Hematoxylin and eosin (H&E) staining shows a mixed acinar and papillary adenocarcinoma pattern, characterized by glandular and papillary structures lined by atypical epithelial cells (scale bar = 100 μm). (C) Immunohistochemistry for HER2 (IHC) demonstrates 1+ membranous staining, indicative of low HER2 expression., with weak incomplete staining in 10% of the tumor (scale bar = 20 μm). (D) Dual in situ hybridization (DISH) indicates a non-amplified HER2 gene status wi (scale bar = 20 μm).