Breast Cancer Subtype Characterization Through Patient's Derived Organoids.

NCT06315868 | Recruiting

• 1 other identifier: 5590
• Study Type: observational
• Target: 306
• Locations: 1 country
• Sites: 1

Brief Summary

Development of tools to predict patients chemo-sensitivity and identification of corresponding biomarkers is an urgent challenge for BC patients lacking targeted therapies, such as TNBC, or for patients experiencing relapse after adjuvant chemotherapy or targeted therapies. The refinement of 3D-cultivation techniques, experienced in the last decade, has allowed cultivation of patients-derived cancer cells in organotypic structures, named patient-derived organoids (PDO), which preserve histologic, genomic and transcriptomic features of primary tumors. PDO allow propagation, pharmacological treatment and genetic manipulation of patients-derived cancer cells in a close to physiology setting, thus representing a promising tool in the development of personalized therapies

Conditions

Breast Cancer; Organoids

Keywords

breast cancer; new drugs; organoids

Outcome Measures

Primary Outcomes (2)

• evaluate the histological and molecular conformity (yes/no) between PDO and matched primary and/or recurrent BC sample, in order to develop a live biobank of ER/PR+, HER2+ and TNBC PDO.

  Part of each surgical specimen will be used to obtain PDOs according to established procedures, part will be fixed and paraffin embedded for histological analysis and part will be flash-frozen for DNA, RNA and protein analyses. At first passages, organoids will be characterized for histologic and cytologic features. PDOs that faithfully recapitulate features of the matched primary tumor will be analysed for genomic features and splicing-sensitive transcriptomic signatures by next generation sequencing (NGS). Dichotomic variable: Yes (conform)/No (not conform)

  36 months

• evaluate the sensitivity of ER/PR+, HER2+ and TNBC PDO to novel therapeutic agents in clinical trials for BC or other cancer types

  PDO will be tested for their susceptibility to the therapeutic agents administered to the corresponding patients and/or to novel therapeutic agents in clinical trials for BC or other cancer types by performing cell viability assays and clonogenic potential assay before and after treatments. Sensitivity to the tested drugs will be evaluated on the basis of the known maximal plasma concentration of the drug (Cmax): sensitive if survival is \<50% at Cmax dose; resistant if survival is \>50% at Cmax dose. Dichotomic variable: Yes (sensitive)/No (resistant)

  42 months

Secondary Outcomes (2)

• test the sensitivity of PDO to splicing-targeting treatments, either alone or in combination with other therapies

  42 months

• test the synergizing effects of agents splicing-targeting treatments to immunotherapies by co-culture experiments with autologous immune cells

  42 months

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Eligible population includes women diagnosed with primary BC, eligible for surgical resection of the tumor according to national and international guidelines. Each case will be discussed, before surgery, at the multidisciplinary tumor board for BC of the Fondazione Policlinico A. Gemelli, IRCCS. All women will be required to sign written informed consent to enter the study. The study design has considered following inclusion criteria: age between 18 and 70 years; newly diagnosed breast neoplasms, tumor size of at least 1.5 cm diameter.

You may qualify if:

• women diagnosed with primary BC, eligible for surgical resection of the tumor according to national and international guidelines.
• age between 18 and 70 years; newly diagnosed breast neoplasms, tumor size of at least 1.5 cm diameter.

You may not qualify if:

• breast cancer diagnosed during pregnancy, neoadiuvant chemotherapy

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Study Sites (1)

IRCCS Fondazione Policlinico A. Gemelli

Roma, 00168, Italy

RECRUITING

Related Publications (13)

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• Garrido-Castro AC, Lin NU, Polyak K. Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discov. 2019 Feb;9(2):176-198. doi: 10.1158/2159-8290.CD-18-1177. Epub 2019 Jan 24.

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  PMID: 27939063 BACKGROUND

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  PMID: 18250347 BACKGROUND

• Kornblihtt AR, Schor IE, Allo M, Dujardin G, Petrillo E, Munoz MJ. Alternative splicing: a pivotal step between eukaryotic transcription and translation. Nat Rev Mol Cell Biol. 2013 Mar;14(3):153-65. doi: 10.1038/nrm3525. Epub 2013 Feb 6.

  PMID: 23385723 BACKGROUND

• Pagliarini V, Naro C, Sette C. Splicing Regulation: A Molecular Device to Enhance Cancer Cell Adaptation. Biomed Res Int. 2015;2015:543067. doi: 10.1155/2015/543067. Epub 2015 Jul 26.

  PMID: 26273627 BACKGROUND

• Chabot B, Shkreta L. Defective control of pre-messenger RNA splicing in human disease. J Cell Biol. 2016 Jan 4;212(1):13-27. doi: 10.1083/jcb.201510032.

  PMID: 26728853 BACKGROUND

• Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol. 2007 Mar;14(3):185-93. doi: 10.1038/nsmb1209. Epub 2007 Feb 18.

  PMID: 17310252 BACKGROUND

• Hsu TY, Simon LM, Neill NJ, Marcotte R, Sayad A, Bland CS, Echeverria GV, Sun T, Kurley SJ, Tyagi S, Karlin KL, Dominguez-Vidana R, Hartman JD, Renwick A, Scorsone K, Bernardi RJ, Skinner SO, Jain A, Orellana M, Lagisetti C, Golding I, Jung SY, Neilson JR, Zhang XH, Cooper TA, Webb TR, Neel BG, Shaw CA, Westbrook TF. The spliceosome is a therapeutic vulnerability in MYC-driven cancer. Nature. 2015 Sep 17;525(7569):384-8. doi: 10.1038/nature14985. Epub 2015 Sep 2.

  PMID: 26331541 BACKGROUND

• Chan S, Sridhar P, Kirchner R, Lock YJ, Herbert Z, Buonamici S, Smith P, Lieberman J, Petrocca F. Basal-A Triple-Negative Breast Cancer Cells Selectively Rely on RNA Splicing for Survival. Mol Cancer Ther. 2017 Dec;16(12):2849-2861. doi: 10.1158/1535-7163.MCT-17-0461. Epub 2017 Sep 6.

  PMID: 28878028 BACKGROUND

• Stricker TP, Brown CD, Bandlamudi C, McNerney M, Kittler R, Montoya V, Peterson A, Grossman R, White KP. Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression. PLoS Genet. 2017 Mar 6;13(3):e1006589. doi: 10.1371/journal.pgen.1006589. eCollection 2017 Mar.

  PMID: 28263985 BACKGROUND

• Trincado JL, Sebestyen E, Pages A, Eyras E. The prognostic potential of alternative transcript isoforms across human tumors. Genome Med. 2016 Aug 17;8(1):85. doi: 10.1186/s13073-016-0339-3.

  PMID: 27535130 BACKGROUND

• Kahles A, Lehmann KV, Toussaint NC, Huser M, Stark SG, Sachsenberg T, Stegle O, Kohlbacher O, Sander C; Cancer Genome Atlas Research Network; Ratsch G. Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients. Cancer Cell. 2018 Aug 13;34(2):211-224.e6. doi: 10.1016/j.ccell.2018.07.001. Epub 2018 Aug 2.

  PMID: 30078747 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Bioptic samples of Breast Cancer

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Central Study Contacts

Alba Di Leone, Doc

CONTACT

0039 3474980503; alba.dileone@policlinicogemelli.it

Chiara Naro, Doc

CONTACT

0039 3495087203; chiara.naro@unicatt.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 5 Years
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 11, 2023
• First Posted: March 18, 2024
• Study Start: June 15, 2023
• Primary Completion (Estimated): June 15, 2026
• Study Completion (Estimated): June 15, 2027
• Last Updated: March 18, 2024

Record last verified: 2023-06

Locations

IT (1)