NGS in Gallbladder Cancer and Response to Treatment

Official title

Genetic Mutations and Response to Treatment in Gallbladder Cancer: A Hospital Based Cohort Study

Overview

Evidence suggests distinct models of molecular and pathologic progression, and a growing body of genetics data points to a heterogeneous collection of underlying mutations in key oncogenes and tumor suppressor genes. Although tumor genetics have been used to tailor individual treatment regimens and guide clinical decision making in other cancers, these principles have not been applied in gallbladder malignancy. Recent clinical trials with targeted therapies seem promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored.

Detailed description

Gallbladder carcinoma (GBC) is the most common type of biliary tract carcinoma and the third commonest digestive tract malignancy in India. GBC arises in the setting of chronic inflammation and the commonest source is cholesterol gallstones (in more than 75% patients). Other causes of chronic inflammation include primary sclerosing cholangitis, ulcerative colitis, liver flukes, chronic Salmonella typhi and paratyphi infections, and Helicobacter infection. Many other factors have also been identified such as ingestion of certain chemicals, exposures through water pollution, heavy metals and radiation exposure. Only a small fraction of GBC are associated with hereditary syndromes like Gardner syndrome, neurofibromatosis type I and hereditary non-polyposis colon cancer.

Of the multiple molecular alterations observed in GBC, it has not yet been possible to pinpoint which ones are the "driver" genes or controllers of the neoplastic process and to differentiate them from the "passenger" genes, those observed mainly in sporadic malignant tumors like GBC in which epigenetic alterations predominate. The most frequently mutated genes in GBC are: TP53 (41%), CDKN2A (28%) KRAS (19%), TERT (8%), CTNNB1 (8%) and PI3K (7%). The signalling pathway of the ERBB family is one of the most frequently mutated in GBC. These receptors participate in regulating cell proliferation, differentiation and survival. Their amplification mainly translates into protein over expression. The receptor HER2/NEU, after dimerization activates a large variety of downstream pathways such as RAS-RAF-MEK-ERK1/2 or PI3k-AKT-MTOR with great influence on cell proliferation. On the other hand, PTEN (phosphatase and tensin homolog) is a tumor suppressor gene that encodes a protein with phosphatase function that inactivates substrates like PI3K The absence of the PTEN functional protein permits the activation of PI3k with an even greater intensity than the activating mutation of PI3K itself. The uncontrolled production of PIP3 is one of the most important effectors of the PI3K/AKT pathway with mTOR stimulating protein synthesis that regulate apoptosis. The immunohistochemical expression of the PTEN protein is considered a good way to evaluate the functional state of the gene.

1. Comprehensive history and physical examination of the patients and all the details will be recorded in the preset proforma. All routine investigations as indicated including a biopsy to establish a diagnosis and CT/MRI/MRCP of the abdomen to measure the tumor dimensions and stage the disease before initiation of treatment will be recorded. 2. The archival tissue will be studied for expression of gene mutation by molecular analysis using Next Generation Sequencing. Patients treated between 2017-2020 where NGS information is available will also be included in retrospect. Their data will be extracted from the Medical records, and attempts will be made to contact them for follow-up.

Interventions

• Diagnostic test Next generation sequencing
  NGS is carried out on DNA isolated from paraffin embedded tissue

Primary outcome measures

• Response to treatment [Time frame: 1 year]
• Overall Survival [Time frame: 5 year]

Secondary outcome measures (2)

• PFS [Time frame: 5 yers]
• RFS [Time frame: 5 year]

Eligibility criteria

Inclusion criteria

• Treatment naïve patients with histologically proven carcinoma of the gallbladder.

Exclusion criteria

• No histological evidence of malignancy
• Pregnant and lactating women

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

India · 1 center

• Banaras Hindu University — Varanasi

Publications

• Sanders G, Kingsnorth AN. Gallstones. BMJ. 2007 Aug 11;335(7614):295-9. doi: 10.1136/bmj.39267.452257.AD. No abstract available. PMID 17690370
• Hsing AW, Gao YT, Han TQ, Rashid A, Sakoda LC, Wang BS, Shen MC, Zhang BH, Niwa S, Chen J, Fraumeni JF Jr. Gallstones and the risk of biliary tract cancer: a population-based study in China. Br J Cancer. 2007 Dec 3;97(11):1577-82. doi: 10.1038/sj.bjc.6604047. Epub 2007 Nov 13. PMID 18000509
• Ishiguro S, Inoue M, Kurahashi N, Iwasaki M, Sasazuki S, Tsugane S. Risk factors of biliary tract cancer in a large-scale population-based cohort study in Japan (JPHC study); with special focus on cholelithiasis, body mass index, and their effect modification. Cancer Causes Control. 2008 Feb;19(1):33-41. doi: 10.1007/s10552-007-9067-8. Epub 2007 Sep 30. PMID 17906958
• Trajber HJ, Szego T, de Camargo HS Jr, Mester M, Marujo WC, Roll S. Adenocarcinoma of the gallbladder in two siblings. Cancer. 1982 Sep 15;50(6):1200-3. doi: 10.1002/1097-0142(19820915)50:63.0.co;2-a. PMID 7104965
• Weiss KM, Ferrell RE, Hanis CL, Styne PN. Genetics and epidemiology of gallbladder disease in New World native peoples. Am J Hum Genet. 1984 Nov;36(6):1259-78. PMID 6517051
• Begnami MD, Fukuda E, Fregnani JH, Nonogaki S, Montagnini AL, da Costa WL Jr, Soares FA. Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J Clin Oncol. 2011 Aug 1;29(22):3030-6. doi: 10.1200/JCO.2010.33.6313. Epub 2011 Jun 27. PMID 21709195
• Tafe LJ, Tsongalis GJ. The human epidermal growth factor receptor 2 (HER2). Clin Chem Lab Med. 2011 Sep 15;50(1):23-30. doi: 10.1515/CCLM.2011.707. PMID 21919545
• Ocana A, Vera-Badillo F, Al-Mubarak M, Templeton AJ, Corrales-Sanchez V, Diez-Gonzalez L, Cuenca-Lopez MD, Seruga B, Pandiella A, Amir E. Activation of the PI3K/mTOR/AKT pathway and survival in solid tumors: systematic review and meta-analysis. PLoS One. 2014 Apr 28;9(4):e95219. doi: 10.1371/journal.pone.0095219. eCollection 2014. PMID 24777052

Identifiers

NCT: NCT05404347 · NGSGB1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗