Tumor-microenvironment Spatial Interaction to Identify Markers of Resistance to Therapy in HER2+ Breast Cancer Patients

A Retrospective Observational Study Characterizing Tumour-microenvironment Spatial Interaction Aimed at the Identification of New Markers of Resistance to Therapy in HER2-positive Breast Cancer Patients

This retrospective observational study aims at the comparison of the tumour-microenvironment tissue architecture before and after neo-adjuvant therapy in samples from HER2-positive (HER2+) breast cancer (BrCa) patients that display residual invasive disease in the breast/lymph node at surgery after standard-of-care combined chemotherapy and trastuzumab treatment.

The working hypothesis of the investigators is that:

Therapy imposes a selective pressure on tumour-microenvironment features promoting resistance to treatment.

Participant that have already undergone neo-adjuvant treatment as part of their regular medical care for HER2-positive breast cancer will provide access to formalin-fixed paraffin-embedded (FFPE) samples taken before and after therapy.

Tumoral, peri-tumoral and stromal regions of each specimen will be analyzed with the ultimate goal to identify new biomarkers (and putative targets) of resistance to therapy.

Study Overview

• Status: Recruiting
• Conditions: HER2-positive Breast Cancer

• Study Type: Observational
• Enrollment (Estimated): 10

Contacts and Locations

• Study Contact: Name: Tiziana Daniele, PhD; Phone Number: +39 02 2643 6381; Email: daniele.tiziana@hsr.it

Study Locations

• Italy
  • Lombardy
    • Milan, Lombardy, Italy, 20132
      • Recruiting
      • IRCCS San Raffaele Hospital
      • Contact: Giampaolo Bianchini, MD; Phone Number: +39 02 2643 6530; Email: bianchini.giampaolo@hsr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

HER2+ Breast Cancer patients displaying residual invasive disease in the breast/lymph node at surgery after neo-adjuvant treatment [sequential chemotherapy comprising treatment with antracyclines (AC/EC q21, 4 cycles) followed by taxanes (paclitaxel 1,8,15 q21 for 12 weeks) in combination with the anti-HER2 antibody trastuzumab].

Description

Inclusion Criteria:

1. Participant is willing and able to give informed consent for participation in the study.
2. Patient underwent the following procedure before surgery: biopsy, sequential chemotherapy comprising treatment with antracyclines (AC/EC q21, 4 cycles) followed by taxanes (paclitaxel 1,8,15 q21 for 12 weeks) in combination with the anti-HER2 antibody trastuzumab.
3. Specimen collected at surgery display residual invasive disease in the breast/lymph node.

Exclusion Criteria:

1. pre-existing conditions or concurrent diagnoses;
2. concomitant use of other medications during neo-adjuvant treatment;
3. quality of stored specimen does not meet the standard for Imaging Mass Cytometry analysis.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
number of different cells per each phenotype	Cell types will be classified based on the expression of specific lineage/phenotype markers.	before and within 3 months from neo-adjuvant therapy (at surgery)
density of each phenotype	Cell phenotype densities will be calculated by dividing the number of total cells counted by the total area of the tissue acquired.	before and within 3 months from neo-adjuvant therapy (at surgery)
fraction of proliferative/active cells of each phenotype	The proportion of cells positive for the proliferation marker Ki67 will be assessed per cell phenotype. To assess the proportion of active immune cells, we will quantify the expression level of activation markers.	before and within 3 months from neo-adjuvant therapy (at surgery)
frequency of interactions	Cells will be defined as partaking in an interaction if their whole-cell profiles are in direct contact (contiguous pixels). Cell phenotypes will be mapped to cell-cell interaction masks, and for each specimen proximity events (cell-cell interactions) will be classified as homotypic or heterotypic proximity events	before and within 3 months from neo-adjuvant therapy (at surgery)
frequency of functional crosstalk events	Cells will be defined as participating in a functional crosstalk event if the proximal (contiguous pixels) cells express functional pairs (receptor/ligand) of markers (e.g. PD1/PDL1). The frequency of functional crosstalk events will be computed as the number of interactions between cells expressing functional pairs divided by the total number of cells expressing one of the markers (receptor, e.g. PD1) in the specimen.	before and within 3 months from neo-adjuvant therapy (at surgery)

Collaborators and Investigators

• Sponsor: Giampaolo Bianchini
• Investigators: Principal Investigator: Giampaolo Bianchini, MD, Head Breast Cancer Group - Department of Medical Oncology - IRCCS San Raffaele Hospital

Publications and helpful links

General Publications

• Wang XQ, Danenberg E, Huang CS, Egle D, Callari M, Bermejo B, Dugo M, Zamagni C, Thill M, Anton A, Zambelli S, Russo S, Ciruelos EM, Greil R, Gyorffy B, Semiglazov V, Colleoni M, Kelly CM, Mariani G, Del Mastro L, Biasi O, Seitz RS, Valagussa P, Viale G, Gianni L, Bianchini G, Ali HR. Spatial predictors of immunotherapy response in triple-negative breast cancer. Nature. 2023 Sep;621(7980):868-876. doi: 10.1038/s41586-023-06498-3. Epub 2023 Sep 6.

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: July 16, 2024
• First Submitted That Met QC Criteria: July 23, 2024
• First Posted (Actual): July 24, 2024

Study Record Updates

• Last Update Posted (Actual): April 15, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: TaME-HER2BrCa

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