HER-2 mutation

NSCLC patients with oncogenic TKD HER2 mutations had different characteristics and genetic features than patients with non-TKD mutations. Real-world outcomes with first- and second-line standard-of-care treatment were suboptimal, highlighting the need for new treatment options for patients with advanced HER2-mutant NSCLC.

The temporal relationship between molecular and radiologic findings observed here suggests potential value for earlier detection of disease activity, although whether such lead time translates into improved clinical outcomes requires prospective validation. The findings support prospective evaluation of this approach, including the ongoing TROPHY trial investigating this therapeutic approach.

Performing molecular testing (in the absence of adequate tumor tissue with liquid biopsy) as early as possible is already an integral part of the treatment pathway planning for CCA patients. Early molecular testing may therefore lead to the possibility of administering targeted therapy in the first-line setting within this patient group, pending the outcomes of clinical trials.

Therapeutic progress in this population has accelerated over the past several years, first with trastuzumab deruxtecan and more recently with selective HER2 tyrosine kinase inhibitors (TKIs). Zongertinib demonstrates that selective HER2 inhibition can achieve durable responses in HER2 -mutant NSCLC with a favorable safety profile. However, optimal treatment sequencing, resistance mechanisms, and biomarker-guided patient selection remain to be defined.

p53 IHC, particularly using a ≥40% cut-off at 3+ intensity, is an accurate and accessible surrogate for TP53 mutation detection in LUAD patients. This method facilitates rapid molecular stratification, optimal resource utilization and informed prognostic and therapeutic decision-making in routine pathology practice.

These results demonstrate that both dPCR and NGS-based liquid biopsy workflows can be successfully implemented for ESR1 mutation testing in routine clinical practice using locally validated assays. This multicentre verification study provides practical guidance on assay verification, DNA input requirements, and key analytical parameters required to ensure reliable ESR1 mutation detection across different European laboratories. Robust analytical verification of ESR1 testing may improve diagnostic reliability and support personalized treatment strategies for patients with hormone receptor-positive, HER2-negative metastatic breast cancer.

Due to limited germline and epigenetic data, MSI-H tumors could not be classified as Lynch-associated or sporadic. Overall, MSI-H and MSS CRCs in the Chinese population demonstrate distinct molecular landscapes in terms of TMB, HRD, EBV status, and driver gene alterations, underscoring the molecular heterogeneity of MSI-H CRC and the need for future studies integrating germline and epigenetic data to refine subtype classification.

The patient underwent neoadjuvant chemothera- py, right-sided mastectomy, and trastuzumab therapy, achieving complete pathological regression (pCR) with no recur- rence after ten months of follow-up. Although the CASR p.Glu755Asp variant's pathogenic role is unproven, emerging evidence links CASR overexpression with hER2-positive breast cancers, promoting tumor progression via calcium- dependent signaling pathways (PI3K/AKt, MAPK). This case highlights the potential role of CASR as a low-penetrance susceptibility gene in breast cancer and supports further functional and genomic studies to clarify its clinical impact.

P2, N=60, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

Concerning treatment, in advanced HER2-positive, Non-Squamous NSCLC tumors, the first-line treatment is Platinum-based + Pemetrexed chemotherapy, with or without immunotherapy, because no HER2-targeted antibody therapy has yet been approved for initial treatment. After progression, HER2-targeted antibody-drug conjugates like Trastuzumab-Deruxtecan and Ado Trastuzumab-Emtansine may offer patients clinical benefits. New HER2-selective tyrosine kinase inhibitors, such as zongertinib and sevabertinib, have shown promising results, including patients previously treated with antibody-drug conjugates (ADCs). Recent advances, including next-generation ADCs such as SHR-A1811 and A166, and bispecific antibodies, such as zenocutuzumab for NRG1 fusion-positive disease, which are also expanding treatment options. Overall, advances in diagnostics and new targeted therapies are changing how HER2-altered NSCLC is treated and are helping to make care more personalized.

The LiBRA study supports liquid biopsy as a prognostic and monitoring tool in BRAF V600E-mutated NSCLC undergoing targeted therapy.

P1, N=108, Recruiting, Daiichi Sankyo | Active, not recruiting --> Recruiting