In women with metastatic breast cancer (MBC), introduction of the anti-HER2 (human epidermal growth factor receptor-2) directed therapies including trastuzumab, pertuzumab, lapatinib, and/or trastuzumab-DM1 has markedly improved overall survival. However, not all cases of HER2-positive breast tumours derive similar benefit from HER2-directed therapy, and a significant number of patients experience disease progression because of primary or acquired resistance to anti-HER2-directed therapies. We integrated genomic and clinicopathological analyses in a cohort of patients with refractory breast cancer to anti-HER2 therapies to identify the molecular basis for clinical heterogeneity. To study the molecular basis underlying refractory MBC, we obtained 36 MBC tumours tissues and used next-generation sequencing to investigate the mutational and transcriptional profiles of 83 genes. We focused on HER2 mutational sites and HER2 pathways to identify the roles of HER2 mutations and the HER2 pathway in the refractoriness to anti-HER2 therapies. Analysis using massively parallel sequencing platform, CancerSCAN™, revealed that HER2 mutations were found in six of 36 patients (16.7%). One patient was ER (estrogen receptor)-positive and HER2-negative and the other five HER2 mutated patients were HER2-positive and HR (hormone receptor)-negative. Most importantly, four of these five patients did not show any durable clinical response to HER2-directed therapies. The HER2 pathway score obtained through transcriptional analyses identified that Growth Receptor Biding protein 2 (GRB2) was the most significantly down regulated gene in the HER2 mutated samples. Detection of HER2 mutations using higher deep DNA sequencing may identify a predictive biomarker of resistance to HER2-directed therapy. Functional validation is warranted.
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http://dx.doi.org/10.18632/oncotarget.5184 | DOI Listing |
Discov Oncol
January 2025
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.
Monotherapy with anti-programmed cell death protein 1 (PD-1) monoclonal antibody has been approved for the treatment of advanced non-small cell lung cancer with positive programmed cell death-ligand 1 (PD-L1) expression and oncogene wild type, which revealed survival benefit compared with chemotherapy. Nevertheless, certain patients develop rapid progression on anti-PD-1 inhibitor monotherapy. This novel pattern is called hyperprogressive disease (HPD), and the underlying mechanism and molecular characteristics still leaves not clear.
View Article and Find Full Text PDFZhonghua Jie He He Hu Xi Za Zhi
January 2025
National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou510120, China.
This paper reviews the clinical progress achieved in 2024 in the field of advanced non-small cell lung cancer (NSCLC), both nationally and internationally. In the area of targeted therapy, particularly for rare mutations, new targets beyond EGFR, ALK, and ROS1 mutations, such as KRAS G12C, HER2, and MET, have gained more clinical validation and approval for targeted drugs in 2024. KRAS G12C inhibitors have also shown significant improvements in disease control rates for patients.
View Article and Find Full Text PDFGastric Cancer
January 2025
Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Avenida Menendez Pelayo nro 4 accesorio, Valencia, Spain.
Introduction: Gastric cancer (GC) burden is currently evolving with regional differences associated with complex behavioural, environmental, and genetic risk factors. The LEGACy study is a Horizon 2020-funded multi-institutional research project conducted prospectively to provide comprehensive data on the tumour biological characteristics of gastroesophageal cancer from European and LATAM countries.
Material And Methods: Treatment-naïve advanced gastroesophageal adenocarcinoma patients were prospectively recruited in seven European and LATAM countries.
Breast J
January 2025
Department of Oncology University Hospital Center Split School of Medicine University of Split, Split, Croatia.
Cancer Res Commun
December 2024
Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Intratumor heterogeneity (ITH) presents challenges for precision oncology, but methods for its spatial quantification, scalable at population levels, do not exist. Based on previous work showing that admixture of PAM50 subtype can be measured from bulk tissue using transcriptomic data, we trained a deep neural network (DNN) to quantify subtype ITH in Luminal A (LumA) breast cancer from routinely-stained whole slide images. We tested the hypothesis that subtype admixture detected in images was associated with tumor aggressiveness and adverse outcome.
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