HER-2 mutation

MTT was the most common second-line treatment, however, outcomes were generally poor, emphasizing the unmet need for effective second-line treatments for HER2-mutant NSCLC.

DS-8201 demonstrates potential as one of the effective salvage therapies following RC48 failure in HER2 altered solid tumors, showing significantly better disease control and a distinct, manageable toxicity profile. These findings highlight the importance of selecting personalized ADCs based on molecular subtypes and toxicity factors and provide a basis for future, larger-scale prospective studies.

This real-world study demonstrates the low frequency of HER2 testing and potential poor prognosis for patients diagnosed with LAM HER2m NSCLC in France between 2015 and 2020. Despite the low prevalence of HER2m NSCLC, these data highlight the importance of routine HER2 testing to enable patients with HER2m NSCLC to receive treatments that can improve clinical outcomes.

P1, N=108, Active, not recruiting, Daiichi Sankyo | N=78 --> 108 | Trial completion date: Jun 2026 --> May 2030 | Trial primary completion date: Jun 2026 --> May 2030

Antibody-drug conjugates (ADCs), led by trastuzumab deruxtecan, have established clinically meaningful activity across multiple solid tumors in HER2 IHC 3+ populations and have further expanded into HER2-low and ultralow expression settings, supporting the concept of HER2 as a biological continuum rather than a binary biomarker...In gastroesophageal adenocarcinoma, treatment options beyond trastuzumab-based regimens continue to diversify: ADC-based standards in later lines are being complemented by next-generation HER2 antibodies, inclu ding recent phase Ⅲ evidence supporting anbenitamab after prior trastuzumab exposure, which may further inform sequencing decisions. Collectively, these advances highlight an emerging precision model in which therapeutic selection and rational sequencing are guided by integrated assessment of HER2 protein expression, ERBB2 genomic status, prior HER2-directed exposure, and toxicity risk (notably ADC-associated interstitial lung disease). Standardization of high-fidelity diagnostic workflows-spanning IHC/ISH quality assurance, re-biopsy when feasible, and context-appropriate use of circulating tumor DNA-will be essential to ensure consistent patient identification and to enable optimal deployment of ADCs, TKIs, and antibody-based therapies across histologic boundaries.

Methods We derived a novel PDX from a patient with hormone receptor negative, HER2-positive IBC refractory to neoadjuvant chemotherapy with Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab (TCHP)...We performed short-tandem repeat (STR) profiling, plotted tumor growth curves for mice treated with alpelisib/everolimus vs. untreated, and immunohistochemistry (IHC), and performed clinical genomic assays...Conclusion We established a PDX of a HER2-positive IBC tumor with a PIK3CA hotspot mutation (H1047R) refractory to TCHP. Targeting the PI3K/mTOR pathway may be useful to overcome resistance in HER2-positive IBC with a H1047R mutation in PIK3CA.

In this small case series, T-DXd demonstrated encouraging antitumor activity and manageable safety in heavily pretreated patients with HER2 mutated, metastatic NSCLC. Although selected patients had durable benefits, the findings are anecdotal and should be interpreted with caution. Larger real‑world cohorts and prospective studies are needed to validate the consistency, durability, and safety of T‑DXd in routine clinical practice.

Metastatic EMPD exhibits distinct clinicopathologic and molecular features, including high AR and HER2 expression, TP53 and CDKN2A/B alterations, and similarity to systemic HER2+ malignancies. The observed activity of HER2-directed therapies in this cohort suggests the potential value of further investigating biomarker-guided treatment strategies in metastatic EMPD. NGS-guided profiling may inform precision treatment strategies, including AR-targeted therapy and emerging MTAP-directed approaches.

P1, N=16, Recruiting, Memorial Sloan Kettering Cancer Center

P=N/A, N=170, Recruiting, AstraZeneca | N=70 --> 170

Emerging approaches, including liquid biopsy, AI, and multi-omics integration, offer dynamic insights but require prospective validation. Future progress depends on assay standardization, equitable access, and validation within adaptive clinical trial frameworks, supporting integrated molecular - clinical and AI-enhanced models for personalized therapy.

In CRC, TAT was 4.1, 5.3, and 10.2; QNS 0%, 0%, 7.5%; detection 63.9%, 62.5%, and 57.1%. OPA provides faster TAT and lower QNS rates with comparable detection of actionable alterations, supporting its use for community-based molecular testing in NSCLC and CRC.