1,721,134 research outputs found
Exploring the epigenetic susceptibility mechanisms of lung cancer through DNA methylation markers
No full textBiosimilars in oncology. Focus on SB3 studies [Biosimilars in oncology. Focus on SB3 studies]
No full textA phase III study compared SB3, a trastuzumab biosimilar, with trastuzumab originator in 800 HER2 positive breast cancer patients undergoing neoadjuvant chemotherapy. The aim of the study was to demonstrate the equivalence between the two drugs in terms of pathological complete responses. The total pathologic complete response rates were 51.7% and 42.0% with SB3 and trastuzumab, respectively. Equivalence for efficacy was demonstrated between SB3 and trastuzumab. Safety and immunogenicity were comparable
EGFR signaling pathway as therapeutic target in human cancers
No full text: Epidermal Growth Factor Receptor (EGFR) enacts major roles in the maintenance of epithelial tissues. However, when EGFR signaling is altered, it becomes the grand orchestrator of epithelial transformation, and hence one of the most world-wide studied tyrosine kinase receptors involved in neoplasia, in several tissues. In the last decades, EGFR-targeted therapies shaped the new era of precision-oncology. Despite major advances, the dream of converting solid tumors into a chronic disease is still unfulfilled, and long-term remission eludes us. Studies investigating the function of this protein in solid malignancies have revealed numerous ways how tumor cells dysregulate EGFR function. Starting from preclinical models (cell lines, organoids, murine models) and validating in clinical specimens, EGFR-related oncogenic pathways, mechanisms of resistance, and novel avenues to inhibit tumor growth and metastatic spread enriching the therapeutic portfolios, were identified. Focusing on non-small cell lung cancer (NSCLC), where EGFR mutations are major players in the adenocarcinoma subtype, we will go over the most relevant discoveries that led us to understand EGFR and beyond, and highlight how they revolutionized cancer treatment by expanding the therapeutic arsenal at our disposal
Monitoring of secondary drug resistance mutations in circulating tumor DNA of patients with advanced ALK positive NSCLC
No full textBackground
Disease progression in ALK positive NSCLC patients treated with crizotinib occurs after a median of 9–10 months of treatment. Several mechanisms of resistance were identified and include ALK gene mutations and amplification and activation of bypassing signaling pathways like EGFR, KRAS or c-KIT. Second-generation ALK-TKIs demonstrated an enhanced spectrum of activity in crizotinib-resistant patients. However, re-biopsy in NSCLC patients represents a critical issue and analysis of circulating cell-free DNA (cfDNA) has a promising role for the identification of mechanisms of resistance.
Methods
Sixteen patients progressed during ALK-TKI were enrolled. After progression, blood was collected and DNA was extracted from plasma using QIAamp circulating nucleic acid kit (Qiagen®) and tested for ALK secondary mutations and KRAS exon 12 mutations using the Digital Droplet PCR (ddPCR – BioRad®).
Results
All patients were stage IV adenocarcinoma; 11 female and 5 male. Nine were never-smokers and 7 former-smokers. Median age was 53 yrs (range 40–81). Fifteen patients received crizotinib and 1 ceritinib. ALK-TKIs was administered mainly as second-line, in 2 cases as first and in the remaining as third-line therapy. Twelve patients had partial response, 3 stable disease, one progressed. Median PFS was 8 months. In 12 cases brain was a site of progression and only 5 patients had a tumor site that could potentially undergo re-biospy. ALK secondary mutations were identified in 4 patients. One showed both p.L1196M and p.G1269A mutations which levels decreased after 2 months of therapy with second generation ALK-TKI, along with tumor response. The second and the third patient had p.L1196M and p.G1269A, respectively. The 4th patient showed p.F1174L after initiation of second generation ALK-TKI. A total of 9 patients KRAS mutations p.G12D or p.G12V appeared in cfDNA at the time of resistance to TKI, 3 of them presented both ALK and KRAS mutations.
Conclusions
ddPCR can detect resistance mutations in cfDNA of ALK+ NSCLC and is an effective alternative to re-biopsy. The assessment of mutant allele burden could be used for response monitoring during treatment. Moreover, KRAS mutations may play a role in resistance to ALK-TKIs
Covalent Bruton tyrosine kinase inhibitors across generations: A focus on zanubrutinib
Full text linkBruton tyrosine kinase (BTK), the primary target of BTK inhibitors, is a key enzyme in the proliferation and survival pathway of neoplastic B-cells. BTK inhibitors are approved in many hematologic malignancies: chronic lymphocytic leukaemia, mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinaemia and follicular lymphoma. Second-generation BTK inhibitors display high target selectivity thus resulting in a reduction in off-target and off-tissue effects, better therapeutic index and improved tolerability. This paper summarizes the mechanisms of action of first and second generation BTK inhibitors and elucidates results in any disease setting, with a precise focus on zanubrutinib
Empower the potential of trastuzumab deruxtecan with novel combinations
No full text: Trastuzumab deruxtecan (T-DXd) is reshaping the therapeutic landscape of HER2-positive tumors. A recent article reports on the preclinical activity of the combination of T-DXd plus adavosertib, WEE1 kinase inhibitor, which promises to expand the use of this antibody-drug conjugate in HER2-positive tumors with CCNE1 co-amplification
Circulating DNA in diagnosis and monitoring EGFR gene mutations in advanced non-small cell lung cancer
No full textEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are current treatments for advanced non-small cell lung cancer (NSCLC) harboring activating EGFR gene mutations. Histological or cytological samples are the standard tumor materials for EGFR mutation analysis. However, the accessibility of tumor samples is not always possible and satisfactory in advanced NSCLC patients. Moreover, totality of EGFR mutated NSCLC patients will develop resistance to EGFR-TKIs. Repeat biopsies to study genetic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumor heterogeneity. Thus, exploring accurate and less invasive techniques to (I) diagnosis EGFR mutation if tissue is not available or not appropriate for molecular analysis and to (II) monitor EGFR-TKI treatment are needed. Circulating DNA fragments carrying tumor specific sequence alterations [circulating cell-free tumor DNA (cftDNA)] are found in the cell-free fraction of blood, representing a variable and generally small fraction of the total circulating DNA. cftDNA has a high degree of specificity to detect EGFR gene mutations in NSCLC. Studies have shown the feasibility of using cftDNA to diagnosis of EGFR activating gene mutations and also to monitor tumor dynamics in NSCLC patients treated with EGFR-TKIs. These evidences suggested that non-invasive techniques based on blood samples had a great potential in EGFR mutated NSCLC patients. In this review, we summarized these non-invasive approaches and relative scientific data now available, considering their possible applications in clinical practice of NSCLC treatment
Pharmacogenetics of anti-estrogen treatment of breast cancer
No full textA major effort is underway to select genetic polymorphisms potentially relevant to the clinical efficacy and safety of endocrine treatment of breast cancer. Genetic factors of the host that affect the metabolism of tamoxifen, a widely used drug for the adjuvant treatment of breast cancer, have received particular attention. Cytochrome P450 isoform 2D6 (CYP2D6) is a key step in the metabolism of tamoxifen to its active moiety endoxifen. Women with functionally deficient genetic variants of CYP2D6 who are given drugs that inhibit CYP2D6 are exposed to low endoxifen plasma levels and may enjoy reduced benefits from tamoxifen treatment. Therefore, CYP2D6 status may be an important predictor of the benefits of tamoxifen to an individual; unfortunately, the data are not uniformly concordant, and definitive evidence that would suggest the routine analysis of CYP2D6 before commencing tamoxifen treatment is not yet available. Recent research has focused on the role UDP-glucuronosyltransferases, a family of metabolizing enzymes that play an important role in the metabolic clearance of tamoxifen and of the aromatase inhibitors as well, and how interindividual differences in these enzymes may play a role in the clinical outcome upon administration of anti-estrogen treatment. In conclusion, whether a pharmacogenetic profile should be obtained prior to initiating tamoxifen therapy is currently a matter of debate, although summing up all the scientific evidence available on this issue it appears that the genetic screening would be an useful support for clinical decision making in selected patients
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