Synergistic Effects of the Combination of Alpelisib (PI3K Inhibitor) and Ribociclib (CDK4/6 Inhibitor) in Preclinical Colorectal Cancer Models.

The CDK4/6 inhibitor Ribociclib has shown limited efficacy as a monotherapy in colorectal cancer (CRC). However, combining Ribociclib with targeted therapies could present a viable strategy for treating CRC. This study evaluated the combination of Ribociclib and the PI3K inhibitor Alpelisib across four distinct cell lines representing different mutational statuses ( wild-type, -mutated, -mutated, and -mutated).

Neratinib plus dasatinib is highly synergistic in HER2-positive breast cancer in vitro and in vivo.

Background: HER2-targeted therapies have revolutionised the treatment of HER2-positive breast cancer. However, de novo resistance or the emergence of acquired resistance is a persistent clinical problem. Here we report that neratinib, an irreversible pan-HER inhibitor, in combination with the multi-kinase inhibitor dasatinib, currently used to treat certain leukemias, has strong anti-proliferative effects against models of HER2-positive breast cancer that are innately resistant to trastuzumab or have acquired resistance to neratinib.

Receptor Discordance in Metastatic Breast Cancer; a review of clinical and genetic subtype alterations from primary to metastatic disease.

Purpose: Receptor and subtype discordance between primary breast tumours and metastases is a frequently reported phenomenon. The aim of this article is to review the current evidence on receptor discordance in metastatic breast cancer and to explore the benefit of performing a repeat biopsy in this context.

Methods: Searches were undertaken on PubMed and Clinicaltrials.

Chromosomal copy number and mutational status are required to authenticate ovarian cancer cell lines as appropriate cell models.

Background: The mutational status of ovarian cancer cell line IGROV-1 is inconsistent across the literature, suggestive of multiple clonal populations of the cell line. IGROV-1 has previously been categorised as an inappropriate model for high-grade serous ovarian cancer.

Methods: IGROV-1 cells were obtained from the Netherlands Cancer Institute (IGROV-1-NKI) and the MD Anderson Cancer Centre (IGROV-1-MDA).

Predictive value of pretreatment circulating inflammatory response markers in the neoadjuvant treatment of breast cancer: meta-analysis.

Background: Systemic inflammatory response markers have been found to have a prognostic role in several cancers, but their value in predicting the response to neoadjuvant chemotherapy in breast cancer is uncertain. A systematic review and meta-analysis of the literature was carried out to investigate this.

Methods: A systematic search of electronic databases was conducted to identify studies that explored the predictive value of circulating systemic inflammatory response markers in patients with breast cancer before commencing neoadjuvant therapy.

Genome Sequencing of Multiple Primary Lung Cancers Harbouring Mixed Histology and Spontaneously Regressing Small-Cell Lung Cancer.

Up to 15% of lung cancer patients present two or more anatomically separate primary lung lesions, known as multiple primary lung cancers (MPLCs). While surgical resection or stereotactic body radiation therapy (SBRT) is the standard of care for most early-stage lung cancer cases, this may not be an option for patients with widespread tumours, highlighting the need for the improved targeted management of MPLC patients, which remains challenging. Moreover, the spontaneous regression (SR) of small-cell lung cancer (SCLC) is rare, with only four cases accounted for between 1988 and 2018.

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.

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.

Efficacy and Safety of Trastuzumab Deruxtecan in Breast Cancer: A Systematic Review and Meta-Analysis.

Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug-conjugate (ADC), primarily used in the treatment of HER2-positive breast cancer. This study aimed to conduct a systematic review to evaluate the efficacy and safety of T-DXd in treating breast cancer, based on clinical trials. A systematic search of the literature was conducted to identify clinical trials investigating the efficacy and safety of T-DXd in breast cancer.

Predictive modelling of response to neoadjuvant therapy in HER2+ breast cancer.

HER2-positive (HER2+) breast cancer accounts for 20-25% of all breast cancers. Predictive biomarkers of neoadjuvant therapy response are needed to better identify patients with early stage disease who may benefit from tailored treatments in the adjuvant setting. As part of the TCHL phase-II clinical trial (ICORG10-05/NCT01485926) whole exome DNA sequencing was carried out on normal-tumour pairs collected from 22 patients.

Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes.

Purpose: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer.

Methods: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm.

Protein Tyrosine Phosphatase Non-Receptor 11 (/Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC).

encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of and MEK. /Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated in lung cancer tumourigenesis and its utility as a therapeutic target has not been fully addressed. We applied mass-spectrometry-based genotyping to DNA extracted from the tumour and matched the normal tissue of 356 NSCLC patients (98 adenocarcinomas (LUAD) and 258 squamous cell carcinomas (LUSC)).

Preclinical evaluation of the CDK4/6 inhibitor palbociclib in combination with a PI3K or MEK inhibitor in colorectal cancer.

Background: Studies have demonstrated the efficacy of Palbociclib (CDK 4/6 inhibitor), Gedatolisib (PI3K/mTOR dual inhibitor) and PD0325901 (MEK1/2 inhibitor) in colorectal cancer (CRC), however single agent therapeutics are often limited by the development of resistance.

Methods: We compared the anti-proliferative effects of the combination of Gedatolisib and Palbociclib and Gedatolisib and PD0325901 in five CRC cell lines with varying mutational background and tested their combinations on total and phosphoprotein levels of signaling pathway proteins.

Results: The combination of Palbociclib and Gedatolisib was superior to the combination of Palbociclib and PD0325901.

Comparative analysis of deeply phenotyped GBM cohorts of 'short-term' and 'long-term' survivors.

Background: Glioblastoma (GBM) is an aggressive brain cancer that typically results in death in the first 15 months after diagnosis. There have been limited advances in finding new treatments for GBM. In this study, we investigated molecular differences between patients with extremely short (≤ 9 months, Short term survivors, STS) and long survival (≥ 36 months, Long term survivors, LTS).

Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer.

Purpose: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC.

Patients And Methods: Analysis of a prospectively collected clinical database was performed.

An observational study of dose dense chemotherapy with lipegfilgrastim support in early breast cancer.

Purpose: Breast cancer is one of the most prevalent malignant diseases in women. The development of dose dense chemotherapy regimens has improved clinical outcomes but has been associated with increased hematological toxicity. Currently there is a paucity of data on the use of lipegfilgrastim in dose dense AC treatment in early breast cancer.

Review of the status of neoadjuvant therapy in HER2-positive breast cancer.

Purpose: The development of human epidermal growth factor receptor 2 (HER2)-directed therapies has revolutionized the treatment of HER2-positive breast cancer. The aim of this article is to review the continually evolving treatment strategies in the neoadjuvant setting of HER2-positive breast cancer, as well as the current challenges and future perspectives.

Methods: Searches were undertaken on PubMed and Clinicaltrials.

The SARS-CoV-2 Pandemic and Cancer Trials Ireland: Impact, Resolution and Legacy.

Background: Cancer Trials Ireland (CTI) is the national cooperative group in Ireland. The SARS-CoV-2 pandemic led to significant ongoing disruptive change in healthcare from March 2020 to the present day. Its impact and legacy on a national clinical trials organisation was assessed.

Exhaled Breath Condensate (EBC) analysis of circulating tumour DNA (ctDNA) using a lung cancer specific UltraSEEK oncogene panel.

Introduction: Small diagnostic tissue samples can be inadequate in testing an expanding list of validated oncogenic driver alterations and fail to reflect intratumour heterogeneity (ITGH) in lung cancer. Liquid biopsies are non-invasive and may better reflect ITGH. Most liquid biopsies are performed in the context of circulating tumour DNA (ctDNA) in plasma but Exhaled Breath Condensate (EBC) shows promise as a lung-specific liquid biopsy.

BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors.

Background: We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors.

Methods: The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors.