An observational study in Early-stage Invasive Lobular Breast Carcinoma, sponsored by Hellenic Cooperative Oncology Group. Completed at 1 site in Greece. Open to female participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-25.
Sponsored by Hellenic Cooperative Oncology Group · Observational
Invasive lobular breast carcinoma (ILC), the second most common breast cancer type, represents approximately 15% of all breast cancer cases. Improvement in diagnostic modalities as well as growing evidence that hormone replacement therapy is associated with higher risk of both invasive lobular carcinoma (ILC) and invasive ductal-lobular mixed carcinoma (IDLC) have increased ILC incidence during last years.
Most risk factors for ILC, which is more frequently diagnosed in women over the age of 50, are related to increased hormone exposure, including earlier menarche, late menopause, late age at first birth, oral contraceptives, menopausal hormone therapy. Lifestyle factors, like alcohol intake, Western diet and postmenopausal obesity are also associated with lobular breast cancer.
Along with environment and lifestyle factors, genetic predisposition with germline mutations commonly found in CDH1 and FOXA1 are significant in ILC development. Other implicated genes include PIK3CA, PTEN, AKT1, and GATA3, while more than 50% of ILC harbor mutations in ERBB2, ESR1, FGF, or NF1, conferring endocrine therapy resistance. Interestingly, BRCA1 mutations are less frequent in ILC than in IDC, with similar frequencies of BRCA2, TP53, and CHEK2.
The predominant genetic mutation in CDH1 results in loss of expression of the cell-cell adhesion molecule E-cadherin, leading to a "discohesive" morphology of lobular cells. E-cadherin loss is commonly accompanied by abnormal expression of other parts of the cadherin-catenin complex, like membranous B-catenin and cytoplasmic p120-catenin. The characteristic "Indianfile" pattern of infiltration allows tumor cells to move through the extracellular matrix while causing a very little disruption of the underlying anatomic structures which frequently makes ILC difficult to detect through physical examination or imaging studies, like standard mammograms.
Patients with lobular carcinomas are generally diagnosed at a more advanced stage compared with invasive ductal carcinomas, with larger tumor sizes and more frequent lymph node invasion. Because these tumors are more likely hormone receptor positive and HER2 negative, endocrine therapy is the widely preferred therapeutic approach. Combining endocrine treatments with CDK4/6 inhibitors have shown promising results in HR+ breast cancer, in early as well as in a metastatic setting. However, since endocrine resistance is common in estrogen receptor-positive breast cancer, new therapeutic approaches are needed.
Recent studies have found bromodomain and extraterminal (BET) inhibition as well as FGFR inhibition, since ILC is known to have also FGFR-1 mutations causing resistance to BET inhibition, to be a potential therapeutic strategy for endocrine-resistant ILC cases.
Other promising potential therapies rely on the role of mTOR inhibitors since mutations in the PI3K/Akt signaling pathway are the second most common in ILC and acquired resistance to hormonal therapies is linked to PI3K/AKT/mTOR activation. Targeted immune checkpoint inhibitors therapy is also being investigated in a subset of ILC with higher tumor-infiltrating lymphocytes (TILs) and PD-L1 expression. Finaly, since ILCs seem to have a significant number of cases which are now classified as HER2-low the use of antibody drug conjugates needs to be studied in these cases, preferably by designing multicentric randomized control trials.
There is an urgent need to enhance our understanding of the clinicopathological and molecular features of invasive lobular breast cancer subtype with the goal of refining existing classifications and/or identifying potential biomarkers that could ultimately help improve therapeutic outcomes with established and novel therapies.
Conclusively, the ILC less aggressive biological profile (strong hormone receptor positivity, low proliferative activity, lower histological grade) does not reflect a better long-term outcome. ILC overall biological and clinical features entail a cautious diagnostic and therapeutic approach and as mentioned before, the fact that ILC cells spread in single-file patterns rather than forming distinct masses make them difficult to detect.
Digitalization and deep learning (DL) could definitely enhance ILC management. We intend to use a DL model in digitalized pathology slides and genomic data to improve ILC detection, predict recurrence risk, identify novel biomarkers and guide personalized treatments. Indeed, AI-driven models have been applied to whole-slide digital pathology images (WSIs) to predict CDH1 mutations from H\&E-stained slides. Moreover, a novel AI-derived tumour microenvironment risk score has been tested for long-term risk assessment supporting consideration of extended endocrine therapy in patients with ER+/HER2-, node-negative ILC.
From 1996 until 2022, 6,918 eligible patients with operable breast cancer of intermediate or high risk of relapse, according to St.Gallen criteria, were treated, within the context of 3 randomized and 5 observational clinical studies with dose-dense sequential adjuvant chemotherapy with epirubicin, cyclophosphamide, taxane (only one arm in HE_10/97 did not include a taxane) and "intensified" CMF. Adjuvant hormonal and radiation treatment were administered, as indicated.
IHC and FiSH data from patients enrolled in three randomized phase III trials conducted by the Hellenic Cooperative Oncology Group (HeCOG) (HE 10/97, HE 10/00, HE 10/05), a feasibility study (HE 10/04) and in four observational studies (HE 10/08, HE 10/10, HE10/13, HE10A/13) will be retrospectively reviewed.
All patients have signed a study-specific written informed consent before randomization, consenting for the trial and permitting the use of their biological material for future research purposes. All studies were conducted in accordance with the Declaration of Helsinki.
Tumor material is examined mainly on tissue microarrays (TMA). Although, there is a HER2 assessment from local pathology laboratories, all tumors are re-evaluated centrally for ER, PgR and HER2 in the laboratory of Molecular Oncology according to ASCO/CAP guidelines. Tumors are subtyped with immunohistochemistry (IHC4) for ER, PgR, HER2 and Ki67. FISH is performed for the assessment of HER2 gene status. IHC for EGFR and CK5 is used for the classification of basal-like tumors; the expression of CD8 on TILs is also evaluated. Moreover, we investigate the mutational profile of Greek women with breast cancer, via the application of DNA Next Generation Sequencing (NGS) technologies, relative also to patient outcome. All H\&E and IHC-stained slides will be digitalized for the investigation of the potential of a deep learning-based system for automated biomarker prediction.
Patient demographic, clinicopathological and treatment data are available in all cases.
69 studies on the registry are indexed under Carcinoma, Lobular; 18 are open to participants now.
This study's enrollment of 3,648 is above the median of 336 across 18 observational studies indexed under Carcinoma, Lobular.
Browse Carcinoma, Lobular studies →Hellenic Cooperative Oncology Group is the lead sponsor of 62 studies on the registry; 6 are open to participants now.
Counted across the registry records on this site, refreshed daily.
patients with operable breast cancer treated with dds-CT including taxanes and anthracyclines. Adjuvant hormonal and radiation treatment were administered, as indicated
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Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
Histologically or cytologically confirmed
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Adjuvant and neoadjuvant
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Overall Survival (OS)
Correlation of genetic and molecular biomarkers with OS. OS is defined as the time from diagnosis or surgery to death from any cause.
Time frame: Time from study entry to death from any cause, assessed up to 120 months
Progression-free survival (PFS)
Correlation of genetic and molecular biomarkers with PFS, with PFS defined as the time from enrollment to disease progression or death
Time frame: Time from study entry to first recurrence (local, regional, distant) or death from any cause, whichever comes first, assessed up to 120 months
Evaluation of AI-predictive algorithm
Evaluation of the efficiency of the AI-predictive algorithm, by determining key metrics such as sensitivity and specificity
Time frame: Through study completion, 2 years
Plan to share: No
Ran from Dec 1996 to primary completion in Jul 2026, 355 months.
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From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
This study is completed, as verified in Sep 2026. You cannot join it, but the record below documents what was studied.
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Hellenic Cooperative Oncology Group