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Updates found with 'dna mismatch repair'

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Updates found with 'dna mismatch repair'

Maintenance with PARP inhibitor is the way forward in ovarian cancer:Median PFS in platinum sensitive relapse carcinoma ovary is approximately 10 months.20% of high grade serous carcinoma ovary have somatic or germline mutation in BRCA gene.Single stranded DNA breaks are repaired Base excision repair pathways of which PARP ( poly ADP ribose polymerase) enzymes are one of the key members.In presence of PARP inhibitors these single stranded breaks are converted into double stranded breaks and the repair of these double stranded breaks require intact Homologous recombination repair pathway. BRCA proteins are integral part of these Homologous recombination pathway.In presence of BRCA gene muatation the double stranded breaks produced in presence of PARP inhibitor bring about lethal damage to the cancer cells.Olaparib is the most extensively studied PARP inhibitor and it is approved in BRCA mutation positive relapse high grade carcinoma ovary as single agent after 3 or more lines of chemotherapy. Also Olaparib has been approved as maintenance in both BRCA mutated and wild type patients in relapse platinum sensitive high grade carcinoma ovary who attain CR or PR to last line platinum doublet.The reported PFS in this setting is around 18 months in BRCA mutated (SOLO-2 trial-using tablet olaparib 300mg twice daily) v/s 9 months in BRCA wild type based on STUDY- 19 Trial (Capsule Olaparib 400mg twice daily).It is important to note that about 15% patients remain progression free at 5 years in study-19 trial on Olaparib ( these long term progression free survival benefited both BRCA wild type and BRCA mutated subgroup) .Niraparib based on the result of NOVA trial (300 mg once daily) got approval in maintenance for both BRCA mutated and wild type patients in relapse platinum sensitive high grade carcinoma ovary who attain CR or PR to last line platinum doublet. Rucaparib at a dose of 600mg twice daily awaits its approval in similar setting with the promising results of the ARIEL3 presented in ESMO 2017.Main toxicity of Olaparib is anemia, nausea and fatigue. (Discontinuation rate 6%)Main toxicity of Niraparib is nausea and haematological (Thrombocytopenia> Anemia>Neutropenia) (Discontinuation rate 15%)Main toxicity of Rucaparib is anemia and elevation of liver enzyme (Discontinuation rate 13%)
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Decoding Lynch syndrome -- Colorectal cancer(CRC)Lynch syndrome is the most common cause of inherited Colorectal cancer (CRC-large intestine cancer). It constitutes 3% of all newly diagnosed colorectal cancer burden.In lynch syndrome there is germline mutation in DNA mismatch repair (MMR) genes.It has a autosomal dominant pattern of inheritance.MLH1; MSH2; MSH6; PMS-2 are genes that are commonly mutated which results in changes in repetitive nucleoside sequences known as microsatellite.These changes in microsatellites ie microsatellite instability (MSI) result in change of expression of genes involved in cell growth.MSI is not specific for Lynch syndrome but can be seen in other sporadic CRC patients.Progression of adenoma to carcinoma in these families and patients takes 3 years as compared to a decade or longer in sporadic cancers.Screening for Lynch syndrome is done using IHC or MSI testing from tumor tissue but are confirmed by gene sequencing in somatic or germline specimen.Life time risk of developing CRC in lynch family is 10-47% depending on the gene mutated.CRC in lynch involve usually right colon and the survival in patients with lynch syndrome developing CRC is better.Screening strategy for lynch family include Colonoscopy (every 1-2 years) beginning 5 years prior to the age of the earliest diagnosed CRC patient in family. Prophylactic hysterectomy and bilateral salphingo-oopherectomy after age of 40 years is recommended for preventing endometrial cancer.
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