Mechanisms of Response and Resistance to Innovative Treatments in Patients With Locally Advanced or Metastatic Breast Cancer

NCT07066917 | Recruiting

• 1 other identifier: HE_11PDR/24
• Study Type: observational
• Target: 150
• Locations: 1 country
• Sites: 5

Brief Summary

Ample evidence has highlighted the significant clinical benefit of novel therapies for many patients with advanced breast cancer (aBC). The use of CDK inhibitors, antibody-drug conjugates (ADCs), immune checkpoint inhibitors (ICIs), and PARP inhibitors as first-line or subsequent treatments has improved progression-free survival (PFS) rates compared to conventional therapies. In selected cases, these treatments have also increased overall survival (OS), reshaping the therapeutic landscape for advanced breast cancer. However, several key questions remain unanswered. For example, what should be the first-line treatment when multiple effective options are available? Determining the optimal sequence of drugs in successive lines of therapy is another major challenge. Furthermore, the development of resistance to treatment and the occurrence of severe adverse events that may lead to early discontinuation or fatal outcomes are pressing concerns. That said, identifying robust predictive biomarkers of response or resistance is crucial for ensuring that patients receive the most effective treatment while avoiding unnecessary exposure to therapies that could cause harm without benefit. Additionally, when multiple effective options exist, selecting the optimal treatment algorithm for each patient based on clinical, pathological, and molecular biomarkers is essential. We herein, aim at employing high throughput methodologies, such as Whole Exome Sequencing, circulating tumour DNA (ctDNA) analysis, digital pathology and radiomics analyses, as well as real-world data obtained both from patients records for the training of a ML-based algorithm that can predict response or resistance to a specific treatment, based on the genetic make-up of the patient and the molecular profile of the tumour.

Conditions

Metastatic Breast Cancer

Keywords

mBC; biomarkers; ADCs; immunotherapy; PARPi; Breast Cancer

Outcome Measures

Primary Outcomes (3)

• Progression-free survival (PFS)

  Correlation of genetic and molecular/circulating biomarkers with PFS, with PFS defined as the time from enrollment to disease progression or death

  Through study completion, 5 years

• Overall Survival (OS)

  Correlation of genetic and molecular/circulating biomarkers with OS, with OS defined as the time from date of metastatic diagnosis to last follow-up (36 months, post enrollment) or death

  Through study completion, 5 years

• Objective Response Rate (ORR)

  Correlation of genetic and molecular biomarkers with response to treatment

  Through study completion, 5 years

Secondary Outcomes (1)

• Evaluation of AI-predictive algorithm

  Through study completion, 5 years

Study Arms (3)

ADCs

Patients receiving treatment with an Antibody-Drug conjugate (e.g Trastuzumab-Deruxtecan, Sacituzumab-Govitecan)

ICIs

Patients receiving treatment with an immune checkpoint inhibitor (ICI) (e.g pembrolizumab)

PARPi

Patients receiving treatment with a PARP inhibitor (e.g Olaparib)

Eligibility Criteria

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

Study Population

The study will include patients with histologically confirmed, advanced breast cancer of one of the following subtypes: i) Hormone receptor positive and/or ii) HER2-positive or -low or iii) triple negative breast cancer (TNBC)

You may qualify if:

• Eligible patients will be 18 years of age and older
• Histologically confirmed, advanced breast cancer.
• Diagnosis of i) hormone receptor positive and/or ii) HER2-positive or -low or iii) triple negative breast cancer (TNBC).
• Patients will be included in the analysis after receiving at least one treatment cycle.

You may not qualify if:

• Diagnosis of early breast cancer at time of enrollment
• Unwillingness to provide informed consent
• Unwillingness to provide biological specimen
• Lack of comprehensive clinical data

Sponsors & Collaborators

• Hellenic Cooperative Oncology Group: lead

Study Sites (5)

University General Hospital "ATTIKON", 2nd propedeutic dept. of Internal Medicine

Athens, GR 12462, Greece

RECRUITING

"MITERA" Hospital, Dept. of Medical Oncology

Athens, GR 15123, Greece

RECRUITING

Metropolitan Hospital, 2nd Dept. of Medical Oncology

Athens, GR 18547, Greece

RECRUITING

Metropolitan Hospital, 4th Dept. of Medical Oncology

Athens, GR 18547, Greece

RECRUITING

St. Luke's Hospital, Dept. of Medical Oncology

Thessaloniki, GR 55236, Greece

RECRUITING

Related Publications (12)

• Schwartzberg L, Kim ES, Liu D, Schrag D. Precision Oncology: Who, How, What, When, and When Not? Am Soc Clin Oncol Educ Book. 2017;37:160-169. doi: 10.1200/EDBK_174176.

  PMID: 28561651 BACKGROUND

• D'Arienzo A, Verrazzo A, Pagliuca M, Napolitano F, Parola S, Viggiani M, Caputo R, Puglisi F, Giuliano M, Del Mastro L, Arpino G, De Laurentiis M, Montemurro F. Toxicity profile of antibody-drug conjugates in breast cancer: practical considerations. EClinicalMedicine. 2023 Jul 27;62:102113. doi: 10.1016/j.eclinm.2023.102113. eCollection 2023 Aug.

  PMID: 37554126 BACKGROUND

• Guidi L, Pellizzari G, Tarantino P, Valenza C, Curigliano G. Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges. Cancers (Basel). 2023 Feb 10;15(4):1130. doi: 10.3390/cancers15041130.

  PMID: 36831473 BACKGROUND

• Fenton MA, Tarantino P, Graff SL. Sequencing Antibody Drug Conjugates in Breast Cancer: Exploring Future Roles. Curr Oncol. 2023 Nov 29;30(12):10211-10223. doi: 10.3390/curroncol30120743.

  PMID: 38132377 BACKGROUND

• Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roche H, Im YH, Quek RGW, Markova D, Tudor IC, Hannah AL, Eiermann W, Blum JL. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018 Aug 23;379(8):753-763. doi: 10.1056/NEJMoa1802905. Epub 2018 Aug 15.

  PMID: 30110579 BACKGROUND

• Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017 Aug 10;377(6):523-533. doi: 10.1056/NEJMoa1706450. Epub 2017 Jun 4.

  PMID: 28578601 BACKGROUND

• Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA; IMpassion130 Trial Investigators. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018 Nov 29;379(22):2108-2121. doi: 10.1056/NEJMoa1809615. Epub 2018 Oct 20.

  PMID: 30345906 BACKGROUND

• Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Perez-Garcia J, Iwata H, Masuda N, Torregroza Otero M, Gokmen E, Loi S, Guo Z, Zhou X, Karantza V, Pan W, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022 Jul 21;387(3):217-226. doi: 10.1056/NEJMoa2202809.

  PMID: 35857659 BACKGROUND

• Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortes J, O'Shaughnessy J, Dieras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021 Apr 22;384(16):1529-1541. doi: 10.1056/NEJMoa2028485.

  PMID: 33882206 BACKGROUND

• Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, Tredan O, Ciruelos E, Dalenc F, Gomez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1423-1433. doi: 10.1016/S0140-6736(23)01245-X. Epub 2023 Aug 23.

  PMID: 37633306 BACKGROUND

• Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I; DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):610-621. doi: 10.1056/NEJMoa1914510. Epub 2019 Dec 11.

  PMID: 31825192 BACKGROUND

• Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5.

  PMID: 35665782 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Peripheral blood will be collected for ctDNA analysis and germline mutation testing before initiation of treatment and at disease progression. FFPE tissue and H\&E slided will be collected for whole exome sequencing and digital pathology respectively at diagnosis and at disease progression

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

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

Study Officials

• Elena Fountzilas, MD, PhD

  Hellenic Cooperative Oncology Group

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Electra Sofou, PhD

CONTACT

+302106912520; e_sofou@hecog.ondsl.gr

Elena Fountzilas, MD, PhD

CONTACT

+302106912520; elenafou@gmail.com

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 2 Years
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 4, 2025
• First Posted: July 15, 2025
• Study Start: October 15, 2024
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2029
• Last Updated: July 15, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

GR (5)