KMT2C and KMT2D aberrations in breast cancer.

KMT2C and KMT2D are histone lysine methyltransferases responsible for the monomethylation of histone 3 lysine 4 (H3K4) residues at gene enhancer sites. KMT2C/D are the most frequently mutated histone methyltransferases (HMTs) in breast cancer, occurring at frequencies of 10-20% collectively. Frequent damaging and truncating somatic mutations indicate a tumour-suppressive role of KMT2C/D in breast oncogenesis. Recent studies using cell lines and mouse models to replicate KMT2C/D loss show that these genes contribute to oestrogen receptor (ER)-driven transcription in ER+ breast cancers through the priming of gene enhancer regions. This review provides an overview of the functions of KMT2C/D and outlines the recent clinical and experimental evidence of the roles of KMT2C and KMT2D in breast cancer development.

Neoadjuvant trastuzumab deruxtecan (T-DXd) with response-directed definitive therapy in early stage HER2-positive breast cancer: a phase II study protocol (SHAMROCK study).

BACKGROUND: The current standard of care in the neoadjuvant setting for high-risk HER2-positive (HER2 +) breast cancer is to combine systemic chemotherapy with dual HER2 blockade, trastuzumab and pertuzumab. Targeted therapies have significantly improved outcomes for patients with HER2-positive breast cancer. To improve treatment-associated toxicity, chemotherapy-sparing approaches are currently being investigated. Trastuzumab deruxtecan (T-DXd) is an HER2-directed antibody-drug-conjugate (ADC) with promising results in the metastatic setting for HER2-positive breast cancer. The SHAMROCK study investigates neoadjuvant T-DXd in early stage HER2-positive breast cancer, using pathological complete response (pCR) rate as the primary endpoint. METHODS: This is a phase II open-label, single arm, adaptive multi-centre trial of T-DXd in the neoadjuvant setting in stage 2-3 HER2-positive breast cancer. Eligible patients will receive 5.4 mg/kg of T-DXd intravenously every 3 weeks for up to 6 cycles. A repeat biopsy will performed after 2 cycles for the RNA disruption index (RDI) score assessment. According to their likelihood of pCR, as determined by the RDI score, patients will either undergo 4 or 6 cycles of T-DXd prior to imaging. Patients with imaging complete response (iCR) after either 4 or 6 cycles will proceed to surgery. Patients who do not achieve iCR will either undergo further systemic therapy or proceed to surgery. DISCUSSION: The SHAMROCK study is a chemotherapy-sparing approach to curative intent treatment, investigating neoadjuvant T-DXd. We hypothesise that neoadjuvant T-DXd will have a high pCR rate and be associated low toxicity in early stage HER2-positive breast cancer. TRIAL REGISTRATION: EudraCT Number: 2022-002485-32; ClinicalTrials.gov identifier: NCT05710666; Cancer Trials Ireland study number: CTRIAL-IE 22-01.

The gut microbiome, immune check point inhibition and immune-related adverse events in non-small cell lung cancer.

Systemic treatment options for patients with lung cancer have expanded in recent years, with a number of immunotherapeutic strategies now in our treatment armamentarium. Toxicity of and resistance to treatment hold a major stake in lung cancer morbidity and mortality. Herein, we summarise the background, current evidence and potential mechanisms underlying the role of the commensal gut microbiota in immunotherapy outcomes such as response and toxicity in patients with non-small cell lung cancer (NSCLC).

Systemic therapy for metastatic HER2-positive breast cancer.

The human epidermal growth factor receptor 2 (HER2), is amplified and/or overexpressed in approximately 15%-20% of breast cancers. Targeting of the HER2 receptor with the humanized monoclonal antibody trastuzumab in combination with chemotherapy has become the backbone of treatment for both early stage and metastatic breast cancer for the last 2 decades. Relapsed or de novo metastatic HER2-positive breast cancer essentially remains an incurable disease. Nonetheless, with advances in therapeutics, survival rates in this group continue to increase with median survival now in excess of 57 months. First line systemic therapy for HER2-positive metastatic breast cancer using taxane chemotherapy combined with trastuzumab and pertuzumab, and second line therapy with trastuzumab emtansine, are well established. Recent studies of small molecule oral tyrosine kinase inhibitors such as tucatinib and neratinib, and antibody drug conjugates such as trastuzumab deruxtecan further improve outcomes. Major treatment challenges remain in the areas of brain metastases and development of drug resistance. This review details an up to date analysis of current and emerging treatments of metastatic HER2-positive breast cancer.