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Circulating Tumor Cells in Individualizing Breast Cancer Therapy
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
James M. Reuben, Massimo Cristofanilli
The process of sorting cancer cells from other cellular components (e.g., blood and stromal cells) in clinical samples is fundamentally important for the future of genomic and proteomic analysis (43–45). Collecting representative tissue from solid tumor metastases usually requires more invasive procedures that increase the risk of complications and discomfort. Furthermore, these procedures may not provide an adequate specimen for detailed analysis and typically cannot be repeated for dynamic evaluation of the biologic changes during treatments. Theoretically, CTC detection would allow specific genes [e.g., c-erbB-2, epidermal growth factor receptor (EGFR), and mammaglobin B (MGB)] or more global gene expression to be analyzed while using specific targeted treatments for MBC based on the expression of the CTCs (29,46–48). This information could then be used to design specific treatments that more appropriately reflect the dynamics and heterogeneity of MBC.
The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
NICE also recommended a similar intraoperative test known as the “Metasin Test” which was developed in the NHS. This uses qRT-PCR (Quantitative Reverse Transcription Polymerase Chain Reaction) to simultaneously detect two predictive markers of metastasis, CK19 and mammaglobin. Mammaglobin is expressed mainly by breast epithelial cells, and high levels are associated with breast cancer. A reference gene (porphobilinogen deaminase; PBGD) is used to confirm the validity of the mRNA used in the test, and two other controls (positive and negative) are included. The test runs on commercially available instruments (e.g., originally the Cepheid SmartcyclerTM but now the later GeneXpert OmniTM systems) and it takes approximately 32 minutes to extract and purify mRNA from the tissue and produce results. In 2016 a report was published of a multicenter validation of the Metasin test for the intraoperative assessment of sentinel lymph nodes (SLNs) from breast cancer patients. RNA from 3,296 lymph nodes from 1,836 patients undergoing SLN assessment was analyzed with the Metasin test, and alternate slices of tissue were examined in parallel by histology. A concordance between Metasin and histology was observed in 94.1% of cases (92% sensitivity and 97% specificity), and over half of the discordant cases (4.4%) were ascribed to tissue allocation bias (TAB). Based on these results, the investigators concluded that the test is sufficiently sensitive and specific for use in the intraoperative setting and could replace postoperative histopathology. However, the need to extract RNA makes the test more complex compared to the RD-100i OSNA System.
Ultrastaging of the sentinel node
Published in Charles F. Levenback, Ate G.J. van der Zee, Robert L. Coleman, Clinical Lymphatic Mapping in Gynecologic Cancers, 2022
Celien P.H. Vreuls, Ate G.J. van der Zee, Paul J. van Diest
Different studies have evaluated the usefulness of RT-PCR for detecting SN metastases. Schoenfeld et al.70 compared keratin 19 RT-PCR with histopathologic results (H&E and IHC) in axillary lymph nodes of breast cancer patients and found all 18 histopathologically involved lymph nodes to be positive by RT-PCR. Of the 39 lymph nodes that were histologically negative, 14 were positive by RT-PCR. Noguchi et al.68,71 compared MUC1 and keratin 19 RT-PCR and found all ten lymph nodes that were histopathologically positive to be also positive by RT-PCR and that three (6%) and five (9%) of histopathologically negative (H&E only) lymph nodes expressed MUC1 and keratin 19, respectively, indicating the presence of metastases. Hoon et al.69 found occult metastases by beta–human chorionic gonadotropin (ß-HCG) RT-PCR in 25% of patients that were histopathologically lymph node negative, and Kataoka et al.72 found conversion percentages of 25% for CEA and 21% for mammoglobin in an H&E-only study. In this last study, RT-PCR improved the prediction of axillary lymph node status to 98.5%. In a study on breast and gastrointestinal cancer, Mori et al.73 detected metastases by CEA RT-PCR in 47/87 (54%) lymph nodes that were negative on regular histology. Wascher et al.,74 using MAGE-A3 RT-PCR, found 28 of 73 (38%) histopathologically negative SNs to be RT-PCR positive. Manzotti et al.75 found a high prevalence of positive RT-PCR in histologically uninvolved SNs when considering single markers, but when at least two of three markers (maspin, cytokeratin 19, and mammaglobin) were expressed, the concordance with either SN or axillary lymph node status was highest.75 Some authors76 use RT-PCR routinely. For vulvar cancer, there are at present no data on the value of RT-PCR. Van Trappen et al.77 applied a fully quantitative, real-time RT-PCR assay to document absolute copy numbers of the epithelial marker cytokeratin 19 in primary tumors, 156 lymph nodes from 32 patients with cervical cancer (stages IA2, IB1, and IB2), and 32 lymph nodes from nine patients with benign disease. All primary tumors and histologically involved lymph nodes (six) had increased expression of cytokeratin 19 mRNA, while lower expression of cytokeratin 19 was detected in 66 (44%) of 150 histologically uninvolved lymph nodes and in nodes from 16 of 32 patients with cervical cancer. Fifteen of these 16 patients with evidence of micrometastases had the highest cytokeratin 19 transcription level in a first lymph node drainage station. Transcription of cytokeratin 19 was found at a low level in just 1 of 32 lymph nodes obtained from nine patients with benign disease. The median copy number of cytokeratin 19 transcription was significantly higher in association with adverse prognostic features. These results suggest that about 50% of early-stage cervical cancers shed tumor cells to the pelvic lymph nodes, and the amount of cytokeratin 19 expression was related to clinicopathologic features. However, further studies are required to document the clinical implications of molecular micrometastases.77
Modulating multidrug resistance to drug-based antitumor therapies through NF-κB signaling pathway: mechanisms and perspectives
Published in Expert Opinion on Therapeutic Targets, 2023
Dapeng Wu, Sai Tian, Wenjing Zhu
As a significant pathway in cancer, NF-κB signaling pathway may act as a compensatory pathway to modulate drug resistance. Previous studies have demonstrated osimertinib resistance is attributed to mutations of EGFR C797 and L792, amplifications of MET and FGFR, etc. A recent study showed the osimertinib-resistant NSCLC cells are addictive to the NF-κB pathway independent of EGFR, indicating the resistance could also be dependent on the NF-κB pathway [129]. Other studies showed the resistance to gefitinib and osimertinib could be enhanced by activating the IRAK1/NF-κB signaling pathway, and cosuppression of NF-κB and AICDA could reverse EGFR-TKI resistance in NSCLC [130,131]. In clear cell renal cell carcinoma, two studies both indicated NF-κB p65 is involved in sunitinib resistance, and both PPARα and Lefty A could regulate sunitinib resistance through NF-κB signaling pathway [132,133]. Moreover, Mammaglobin 1 could promote aggressiveness of trastuzumab-resistant breast cancer cells through regulating NF-κB [134]. In oral squamous cell carcinoma, a study reported enhanced NF-κB expression could promote resistance to the combination therapy of paclitaxel and cetuximab, and the NF-κB inhibitor bortezomib could increase the sensitivity to the combination of chemotherapy and targeted therapy [135]. These above studies indicated NF-κB pathway may play a synergistic role in the resistance to targeted therapy in some cancer types.
Cancer vaccines as a targeted immunotherapy approach for breast cancer: an update of clinical evidence
Published in Expert Review of Vaccines, 2022
Maryam Abbaspour, Vajihe Akbari
Mammaglobin-A (Mam-A) is a secretory protein overexpressed in 40–80% of BCs. In a phase I clinical study (NCT00807781) safety and biological efficacy of MAM-A DNA was evaluated. The results confirmed that the vaccine was well tolerated and had no severe adverse events. They concluded that the improved overall survival compared to the unvaccinated group was due to increased production of specific Mam-A CD8 + T cells and IFN-γ production, reduced production of Tregs and IL- 10. These promising results indicate that Mam-A DNA vaccine can increase survival and antitumor immunity in patients with BC [129–131]. A phase Ib clinical trial (NCT02204098) is underway to evaluate Mam-A DNA vaccine safety and immune response in HER2 negative BC patients following neoadjuvant endocrine therapy or chemotherapy.
Tear film, contact lenses and tear biomarkers
Published in Clinical and Experimental Optometry, 2019
Tears might contain biomarkers for ocular or non‐ocular diseases. The proteome of reflex tears contains the protein lacryglobin that has high similarity to another protein mammaglobin, that is associated with breast cancer.1997 Tears were collected from individuals with breast, lung, colon, ovary and prostate cancer and they were compared for the presence of lacryglobin in tears of these individuals with controls. There was an increased frequency of lacryglobin in tears from breast, lung, colon and prostate cancer compared to controls with no family history of cancer.2001 At a similar time, research in the laboratory was comparing the tear proteome of humans with animals, including dogs.2000 Tears from dogs with cancer contained elevated amounts of a protein that may be analogous to lacryglobin.2008 Further research has demonstrated that the lactoferrin concentration in tears does not change between controls and men with benign prostate hyperplasia or prostate cancer.2016 This is important as it provides a stable protein in tears which can be used to compare with changes of other potential marker proteins.