The Detection of Cell-in-cell Structure (CICs) in Patients With Breast Cancer Undergoing Neoadjuvant Chemotherapy

Breast cancer is the most common malignant tumor in women worldwide and neoadjuvant therapy has been the standard care for local advanced breast cancer. Moreover, neoadjuvant therapy undoubtedly provides an ideal model to evaluate the response to therapy. Cell-in-cell structures (CICs) refer to the presence of one or more cells inside host cell, which generally leads to the death of inner cells. Notably, established evidences indicated that CICs were present in breast cancer and tend to impact patient survival. However, whether CICs profile could predict efficacy of therapy remains unclear. In this prospective cohort study, the CICs number and profile will be detected in tumor tissue before and after the neoadjuvant therapy. Then the association between CICs number including dynamic changing and response rate will be explored.

Study Overview

• Status: Recruiting
• Conditions: Breast Neoplasms
• Intervention / Treatment: Drug: Neoadjuvant therapy

• Study Type: Observational
• Enrollment (Anticipated): 175

Contacts and Locations

• Study Contact: Name: Hongyan Huang, PHD; Phone Number: +86 18911358631; Email: hhongy1999@126.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100038
      • Recruiting
      • Beijing Shijitan Hospital, Capital Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Patients with breast cancer treated with neoadjuvant therapy attending Beijing Shijitan Hospital from 2021-2023.

Description

Inclusion Criteria:

• Age 18-65, female;
• Pathological biopsy confirmed invasive ductal carcinoma;
• Karnofsky Performance Status (KPS)≥ 60, expected survival ≥4 months;
• Locally advanced breast cancer (HER2-positive disease and TNBC, ≥cT1c or ≥cN0； HER2-negative，HR positive disease，≥cT2 or ≥cN1；Large primary tumor relative to breast size in a patient who desires breast conservation) ;
• According to the RECIST1.1 standard, at least one measurable lesion exists;

Exclusion Criteria:

• Pregnant or lactating women;
• Left ventricular ejection fraction less than 50%;
• History of malignant tumor and concurrent occurrence of other tumors;
• Serious medical pathology, such as congestive heart failure; unstable angina; uncontrolled high risk arrhythmias, and other serious illness or medical condition that may interfere with the study;
• Refuse to participate in the study.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Single group assignment; Patients with invasive breast cancer who need neoadjuvant therapy.	Drug: Neoadjuvant therapy; all procedures is in accordance with international guidelines and domestic expert consensus on breast cancer.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pCR(complete pathological response)	no invasive malignant cells identifiable in sections from the site of the tumor（Miller-Payne grades 5） the Miller-Payne grades 4 and 5 patients are grouped as responders.	Up to 24 weeks.
Objective response rate (ORR)	Response Evaluation Criteria in Solid Tumors (RECIST)：Progressive Disease (PD); Partial Response (PR); Complete Response (CR); Stable Disease (SD) Objective response rate (ORR), defined as the proportion of patients with a complete response (CR) partial response (PR) to treatment.	Up to 24 weeks.
Quantification of CIC structure in tumor tissue	CICs number and subtypes in tumor tissue (Core needle biopsy specimens before and after neoadjuvant therapy and surgical specimens based on neoadjuvant therapy.)	Up to 24 weeks.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-free survival (DFS)	It refers to the length of time from the start of medication after enrollment to the death of the patient because of the recurrence, distant metastasis of the disease, invasive contralateral breast cancer, or any other cause.	Within 5 years after surgery
Overall survival (OS)	It refers to the length of time from the start of treatment to the death of the patient.	Within 10 years after surgery
CEA(carcinoembryonic antigen)	Counts of international units per milliliter (IU/mL) of tumor marker CEA	Up to 24 weeks.
CA125(Carbohydrate antigen125)	Counts of international units per milliliter (IU/mL) of tumor marker CA 125	Up to 24 weeks.
CA199(Carbohydrate antigen199)	Counts of international units per milliliter (IU/mL) of tumor marker CA 199	Up to 24 weeks.

Collaborators and Investigators

• Sponsor: Beijing Shijitan Hospital, Capital Medical University
• Investigators: Principal Investigator: Hongyan Huang, PHD, Beijing Shijitan Hospital, Capital Medical University

Publications and helpful links

General Publications

• Fais S, Overholtzer M. Cell-in-cell phenomena in cancer. Nat Rev Cancer. 2018 Dec;18(12):758-766. doi: 10.1038/s41568-018-0073-9.
• Overholtzer M, Mailleux AA, Mouneimne G, Normand G, Schnitt SJ, King RW, Cibas ES, Brugge JS. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell. 2007 Nov 30;131(5):966-79. doi: 10.1016/j.cell.2007.10.040.
• Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nunez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon HU, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012 Jan;19(1):107-20. doi: 10.1038/cdd.2011.96. Epub 2011 Jul 15.
• Schwegler M, Wirsing AM, Schenker HM, Ott L, Ries JM, Buttner-Herold M, Fietkau R, Putz F, Distel LV. Prognostic Value of Homotypic Cell Internalization by Nonprofessional Phagocytic Cancer Cells. Biomed Res Int. 2015;2015:359392. doi: 10.1155/2015/359392. Epub 2015 Oct 4.
• Schenker H, Buttner-Herold M, Fietkau R, Distel LV. Cell-in-cell structures are more potent predictors of outcome than senescence or apoptosis in head and neck squamous cell carcinomas. Radiat Oncol. 2017 Jan 18;12(1):21. doi: 10.1186/s13014-016-0746-z.
• Huang H, Chen A, Wang T, Wang M, Ning X, He M, Hu Y, Yuan L, Li S, Wang Q, Liu H, Chen Z, Ren J, Sun Q. Detecting cell-in-cell structures in human tumor samples by E-cadherin/CD68/CD45 triple staining. Oncotarget. 2015 Aug 21;6(24):20278-87. doi: 10.18632/oncotarget.4275.
• Ruan B, Niu Z, Jiang X, Li Z, Tai Y, Huang H, Sun Q. High Frequency of Cell-in-Cell Formation in Heterogeneous Human Breast Cancer Tissue in a Patient With Poor Prognosis: A Case Report and Literature Review. Front Oncol. 2019 Dec 19;9:1444. doi: 10.3389/fonc.2019.01444. eCollection 2019.
• Zhang X, Niu Z, Qin H, Fan J, Wang M, Zhang B, Zheng Y, Gao L, Chen Z, Tai Y, Yang M, Huang H, Sun Q. Subtype-Based Prognostic Analysis of Cell-in-Cell Structures in Early Breast Cancer. Front Oncol. 2019 Sep 20;9:895. doi: 10.3389/fonc.2019.00895. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2021
• Primary Completion (Anticipated): October 1, 2023
• Study Completion (Anticipated): October 1, 2024

Study Registration Dates

• First Submitted: November 2, 2022
• First Submitted That Met QC Criteria: December 6, 2022
• First Posted (Estimate): December 8, 2022

Study Record Updates

• Last Update Posted (Estimate): December 8, 2022
• Last Update Submitted That Met QC Criteria: December 6, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Breast Neoplasms; Neoadjuvant therapy; cell-in-cell structures
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: Z211100002921033

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No