"Observational, Retrospective and Prospective, Non-interventional, Multicentre National Registry-based Study to Collect Information on the Use of Genomic Testing in the Management of Early Stage HR+/HER2- Breast Cancer"
Conditions: Breast Cancer
Sponsor: Consorzio Oncotech

Protocol name: GIM29-GIMOMIC 
Version 2.0; Version Date: 21 Feb 2024  
 
 
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CLINICAL STUDY PROTOCOL 
 
 
GIM29-GIMOMIC 
TITLE: Observational, retrospective and prospective, non-interventional, multicentre national 
registry-based study to collect information on the use of genomic testing in the management of early 
stage HR+/HER2-  breast cancer 
 
 
 
Protocol code:  
 
 
GIM29- GIMOMIC 
Protocol version: 
 
 
2.0 
Protocol date: 
 
 
21/Feb/2024 
Sponsor: 
 
 
 
Consorzio Oncotech  
c/o Università degli studi di Napoli Federico II 
Dipartimento di Medicina Clinica e Chirurgia 
Via Pansini, 5 – 80131 - Napoli 
 
 
 
 
Not For Distribution – Do Not Copy  
This document is confidential and is to be distributed for review only to investigators, study staff, and 
applicable independent ethics committees or institutional review boards. The contents of this 
document shall not be disclosed to others without written authorization from Consorzio Oncotech, 
unless it is necessary to obtain informed consent from potential study participants 

Protocol name: GIM29-GIMOMIC 
Version 2.0; Version Date: 21 Feb 2024  
 
 
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SIGNATURE PAGE 
 
SPONSOR 
Consorzio Oncotech 
Via Pansini, 5, 80131 Napoli  
 
Legal Representative 
Prof. Sabino De Placido 
 
__________________________ 
 
SCIENTIFIC 
COORDINATORS AND 
PROTOCOL AUTHORS 
Alberto Zambelli 
Istituto Clinico Humanitas 
U.O. di Oncologia ed Ematologia 
via A. Manzoni, 56 
20089 Rozzano (MI) 
alberto.zambelli@hunimed.eu 
 
Mario Giuliano  
University of Naples Federico II 
via Sergio Pansini n. 5 – 80131 
m.giuliano@unina.it 
 
 
 
  
 
 
 

Protocol name: GIM29-GIMOMIC 
Version 2.0; Version Date: 21 Feb 2024  
 
 
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PROTOCOL APPROVAL 
 
 
CLINICAL STUDY PROTOCOL 
 
GIM 29- GIMOMIC  
Observational, retrospective and prospective, non-interventional, multicentre national 
registry-based study to collect information on the use of genomic testing in the management 
of early stage HR+/HER2- breast cancer 
 
I agree to the terms of this study protocol. I will conduct the study according to the procedures specified herein, 
and according to principles of Good Clinical Practices and local regulations and requirements. 
 
 
Investigator: 
 
Site Number:  ____________________________________ 
 
Name:   
____________________________________  
 
Signature:  
____________________________________  
 
Date:   
____________________________________ 
 
 

Protocol name: GIM29-GIMOMIC 
Version 2.0; Version Date: 21 Feb 2024  
 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ADCC 
Antibody-dependent Cell-mediated Cytotoxicity 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CE 
Conformitè Europëenne 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
eBC 
Early Breast Cancer 
CNS 
Central Nervous System 
DRFI 
Distant Recurrence-free Interval 
DFS 
Disease-free Survival 
ECD 
Extracellular Domain 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EoT 
End of Treatment 
FDA 
Food and Drug Administration 
FISH 
Fluorescence In Situ Hybridization 
GCP 
Good Clinical Practice 
GPP 
Good Pharmacoepidemiology Practices 
GVP 
Good Pharmacovigilance Practices 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HER2 
Human Epidermal growth factor Receptor 2 
HR 
Hazard Ratio 
ICH 
International Council for Harmonisation 
iDFS 
Invasive Disease-free Survival 
IEC 
Independent Ethic Committee 
Ig 
Immunoglobulin 
ISH 
In Situ Hybridization 
ITT 
Intention-to-treat 
IV 
Intravenous 

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IVD 
In Vitro Diagnostic 
KM 
Kaplan Meier 
LVEF 
Left Ventricle Ejection Fraction 
MAH 
Marketing Authorization Holder 
MCC 
4-[N-maleimidomethyl] Cyclohexane-1-carboxylate 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoH 
Ministry of Health 
MRI 
Magnetic Resonance Imaging 
MUGA 
Multiple-gated Acquisition 
NCI 
National Cancer Institute 
OS 
Overall Survival 
pCR 
Pathological Complete Response 
PET 
Positron Emission Tomography 
PgR 
Progestinic Receptor 
PI3-K 
Phosphatidylinositol 3-kinase 
PT 
Preferred Term 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
T-DM1 
Trastuzumab Emtansine 
WHO 
World Health Organization 
 
 
 

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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................................................. 6 
PROTOCOL SYNOPSIS ................................................................................................................................................. 7 
1 
BACKGROUND AND INTRODUCTION ................................................................................................................10 
2 
RATIONALE .......................................................................................................................................................11 
3 
OBJECTIVES OF THE STUDY ...............................................................................................................................11 
4 
ENDPOINTS ......................................................................................................................................................12 
4.1 
CO-PRIMARY ENDPOINTS .......................................................................................................................................... 12 
4.2 
SECONDARY ENDPOINTS ............................................................................................................................................ 12 
5 
PATIENT SELECTION CRITERIA...........................................................................................................................12 
5.1 
INCLUSION CRITERIA ................................................................................................................................................ 12 
5.2 
EXCLUSION CRITERIA ................................................................................................................................................ 13 
6 
STUDY DESIGN ..................................................................................................................................................13 
7 
STATISTICAL CONSIDERATION ..........................................................................................................................15 
7.1 
SAMPLE SIZE ........................................................................................................................................................... 15 
7.2 
STATISTICAL ANALYSIS .............................................................................................................................................. 15 
8 
FORMS AND PROCEDURES FOR COLLECTING DATA AND DATA MANAGING .....................................................15 
9 
QUALITY CONTROL ...........................................................................................................................................16 
10 
DATABASE RETENTION AND ARCHIVING OF STUDY DOCUMENTS ....................................................................16 
11 
ETHICAL CONSIDERATION .................................................................................................................................16 
11.1 
PATIENT PROTECTION .......................................................................................................................................... 16 
11.2 
INFORMED CONSENT ........................................................................................................................................... 17 
11.3 
INSURANCE ........................................................................................................................................................ 17 
12 
RISK/BENEFIT STATEMENT ...............................................................................................................................17 
13 
FARMACOVIGILANCE/ADVERSE REACTION REPORTING ...................................................................................18 
14 
STUDY TIMETABLE ............................................................................................................................................18 
15 
REFERENCES .....................................................................................................................................................19 
 
 
 

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PROTOCOL SYNOPSIS 
 
Study Title 
Observational, retrospective and prospective, non-interventional, multicentre 
national registry-based study to collect information on the use of genomic testing 
in the management of early stage HR+/HER2-  breast cancer 
Study ID 
GIM29-GIMOMIC 
Number of 
participating Sites 
Approximately 25 Italian sites 
Study aim 
The study aims to establish an Italian registry for the implementation of the use 
of genomic tests in patients with HR +/HER2- breast cancer at intermediate risk 
of recurrence after the entry into force of the Ministerial Decree of 18/05/2021.  
The decree has established the reimbursability of genomic testing for breast 
cancer patients, thereby influencing clinical decision-making and patient 
management within Breast Units. 
In addition, the study aims to evaluate the clinical impact of the use of genomic 
testing on the type of adjuvant treatment, in terms of change of treatment 
indication by breast units according to the test result. 
The retrospective cohort will contribute to expanding our knowledge of the 
clinico-pathological characteristics of patients who underwent genomic testing.   
This comprehensive understanding of the clinico-pathological profile of patients 
undergoing genomic testing will enable a more thorough assessment of the 
clinical dynamics and therapeutic decisions associated with genomic testing 
results, including the analysis of their possible evolution over the years. 
Study Design 
The study is a retrospective and prospective, non-interventional, observational 
registry-based study that will enroll all patients with ER +/HER2-negative, T1-3 
breast cancer with negative axillary lymph nodes or up to 3 positive axillary 
lymph nodes for whom Breast Units require genomic test to support adjuvant 
therapy decisions, according to current clinical practice.  
For prospective cohort: genomic tests will be performed on all patients who meet 
the criteria for access to testing as set out in the Ministerial Decree of 18/05/2021, 
unless otherwise agreed by the reference Breast Unit, in accordance with the 
specific diagnostic pathways activated by each site. 
For retrospective cohort: data for patient referred for genomic testing  following 
Ministerial Decree 18/05/2021 will be collected. 
The patient’s baseline demographic characteristics, tumor clinicopathological 
features, pre and post-test therapeutic indication (CET vs ET), the test results, the 
actual adjuvant treatment received and time around data will be recorded in a 
dedicated registry. 
Duration of the 
study 
18 months 
Primary endpoints 
1. Establishment of a prospective Italian observational registry for the 
implementation of genomic tests in patients with HR +/HER2- breast cancer at 

Protocol name: GIM29-GIMOMIC 
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intermediate risk of recurrence after the adoption of the Ministerial Decree of 
18/05/2021 
2. Measurement of the impact of genomic testing on adjuvant treatment choice 
(CET vs ET only) in terms of:  
- 
Rate of adjuvant treatment choice’s change following the genomic test 
result (Breast Unit’s pre-test vs post-test indication) 
- 
Saving in adjuvant chemotherapy compared to the pre-test indication 
- 
Addition of adjuvant chemotherapy to endocrine therapy alone compared 
to the pre-test indication 
- 
Type of adjuvant treatment the patient actually received 
Secondary 
Endpoints 
- 
Record the predominant demographic and clinical characteristics of the 
patients for whom genomic testing was indicated. 
- 
Describe which genomic tests are used and the factors involved in the 
selection of genomic tests. 
- 
Identify any inequalities in access to the genomic tests in different 
geographical areas of the country. 
- 
Analyse the prescriptive adequacy and the compliance with the inclusion 
criteria for genomic tests. 
- 
Record the distribution of demographic and clinical characteristics (e.g., 
patient age, comorbidities, tumour size, number of positive lymph nodes, 
tumour grade) in the group of patients with changed treatment 
recommendation compared to the group of patients with unchanged indication 
after genomic test. 
- 
Evaluate the impact of the test on the timing of activation of adjuvant 
treatment, in terms of: 
o Time from diagnosis to request for genomic test 
o Time from request for the genomic test to result 
o Time from test result to activation of adjuvant chemotherapy, if 
indicated 
o Time from diagnosis to activation of adjuvant chemotherapy, if 
indicated 
 
Patients number 
1.000 patients 
Study Population 
Inclusion Criteria 
All male and female patients meeting these criteria: 
1. Age ≥ 18 years 
2. PS ECOG 0-1 
3. Histologically confirmed early breast carcinoma with positivity for 
hormone receptors (ER+ IHC >10%) and HER2 negative (IHC value 0-
1+ and/or FISH not-amplified)  
4. Primary resective surgery for early breast cancer with adequate 
assessment of lymph node status (sentinel lymph node biopsy or 
complete axillary dissection), with one of the following diagnostic stages: 
• 
T1-3, N0, M0 
• 
T1-3, pN1mic, M0 
• 
T1-3, pN1a, M0 

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5. Indication for adjuvant treatment with endocrine therapy (ET) or chemo-
endocrine therapy (CET), according to the decision of the reference 
Breast Unit 
6. Meeting the criteria for "intermediate" risk, i.e., no “low” or “high” risk 
of recurrence, as defined in the ministerial decree of 18/05/21: 
• 
Low risk defined by at least 5 of the following: G1, T1a-b, KI67 < 15, 
N neg, ER > 80% 
• 
High risk, defined by at least 4 of the following: G3, T > 2, Ki67 > 30, 
N pos, ER < 30% 
7. Indication for genomic test (Oncotype DX®, Mammaprint®, PAM50-
Prosigna®, Breast Cancer Index®, EndoPredict®) by the Breast Unit  
8. Ability to provide written informed consent to participate in the registry 
study, approved by the local Ethics Committee. 
9. The patient underwent genomic testing starting from September 2021 
Exclusion criteria 
1. Low-risk and High-risk patients as defined in the Ministerial Decree of 
18/05/21 
2. ER negative and/or HER2 positive tumours 
3. More than 3 lymph nodes involved at clinical/pathological staging 
4. Invasive tumours <2mm evaluated by local pathologists 
5. Previous history of breast cancer 
6. Synchronous breast cancers 
7. Multifocal tumours 
8. Metastatic disease  
9. Contraindications to adjuvant treatments 
10. Performance status (PS ECOG) > 1 and / or other clinical factors that 
would make the patient a candidate and unsuitable for systemic adjuvant 
treatment or have received an exclusive indication for precautionary 
hormone therapy as part of the Breast Unit collegial assessment. 
11. Psychiatric diagnosis that may affect the ability to participate in this 
study 
Statistical methods 
Although the true nature of this registry does not define apriori the number of 
patients ultimately expected, one of the main factors driving the sample size of 
this study is the clinical impact analysis and focuses on the accuracy of the 
estimate of the proportion of changes in planned adjuvant therapy pre and post 
genomic results. 
Study Duration 
Duration of the Project: 18 months 
Ethics committee submission: June 2023 
Patient enrolment: May 2024-May 2025 
End of Follow-up:  November 2026 

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1 BACKGROUND AND INTRODUCTION 
Breast cancer (BC) is the most common cancer in women, with approximately 55,000 new diagnosed 
cases per year in Italy and 13,000 BC specific deaths. After BC surgery, adjuvant treatment with 
radiotherapy, endocrine therapy and chemotherapy in selected cases, represents the standard of care 
for hormone-positive (HR +), HER2-negative early breast cancer (eBC). 
The choice of the type of adjuvant treatment generally takes into account the clinicopathological 
characteristics of the patient and the tumour, including age, menopausal status, tumour size, grading 
and Ki67 labelling index, number of lymph nodes involved and hormone receptor expression. These 
characteristics configure specific and different BC risk profiles and drive the individual adjuvant BC 
treatment as for recommended international guidelines. 
However, some ambiguity still remains in the optimal adjuvant treatment in HR+/HER2- eBC, 
particularly regarding whether patients should receive or not adjuvant chemotherapy (CT) in addition 
to endocrine treatment (ET). Considering the absolute clinical benefit of adjuvant CT in addition to 
ET in HR + eBC with negative lymph nodes (N0) is modest (4% absolute recurrence risk reduction 
at 10 years), and considering that currently about 50% of patients with HR+/HER2- eBC still receive 
adjuvant CT, the proper patient selection for CT is a major clinical unmet need. The same applies to 
older patients (post-menopausal) with HR +/HER2- eBC with limited lymph node involvement 
(N1a), for whom the use of adjuvant CT is often associated with increase toxicity and avoidable side-
effects. 
Consequently, there is an urgent clinical need to support the optimal decision-making process for 
determining the best postoperative therapy, especially for "intermediate" risk patients for whom it is 
unclear whether they should receive endocrine therapy alone (ET) or chemotherapy (CT). 
In recent years, the role of molecular classifiers in prognosis and prediction has increased 
considerably. Indeed, several tests have been developed that assess the expression of panels of genes 
involved in the cellular replication of tumour cells and their metastatic ability, revealing specific 
genomic profiles associated with different risk of recurrence. Eventually, these tools can be used to 
refine the individual patients’ prognosis and to estimate the benefit expected of adjuvant treatment. 
Accordingly, these tests provide critical support for therapeutic choice in patients with HR +/HER2- 
eBC (stage I-IIIA) at intermediate risk of recurrence according to clinical and histopathological 
factors, and help define whether adjuvant chemotherapy is appropriate in addition to endocrine 
therapy alone. 
Several clinical trials have investigated the impact of these molecular classifiers on the choice of 
therapy. Multigenic tests have significantly changed the choice of treatment in a substantial 
proportion of patients, largely sparing the need for additional chemotherapy in favour of endocrine 
therapy alone. 
Currently, some of these classifiers are available for routine clinical use in Italy, including 
OncotypeDX, Endopredict, Prosigna and Mammaprint. In line with the growing scientific evidence, 
the Ministry of Health, by decree of 18 May 2021, recognised the utility of genomic breast genomic 
tests and established their reimbursement according to some clinical criteria that can define the 
intermediate risk of recurrence, as derived from the scientific literature and the results of 3 prospective 
Italian experiences with the use of OncotypeDX. 

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The Ministry estimates that approximately 10,000 patients per year are expected to have access to the 
tests, resulting in a potential saving in chemotherapy prescription > 50% compared to what is 
currently proposed. Conversely, it is estimated that in about 10% of patients eligible for adjuvant 
endocrine therapy alone, the genomic test result will change the therapeutic approach and indicate 
the need to associate chemotherapy. 
2 RATIONALE 
With the receipt of the ministerial decree, Italian Breast Units have made genomic tests available to 
patients according to national indications, although availability varies from region to region. 
Irrespective of the estimates of the expected use of genomic tests, it is crucial to assess the actual 
degree of implementation of the use of genomic tests in accordance with ministerial indications, their 
prescriptive suitability and, finally, the clinical-therapeutic impact since the decree came into force. 
Understanding the clinico-pathological characteristics of patients undergoing genomic tests is crucial 
for personalized cancer care. This understanding enables clinicians to tailor treatment plans 
effectively by identifying specific patient characteristics that correlate with certain genomic profiles. 
This approach improves treatment outcomes and reduces adverse effects. Additionally, integrating 
clinico-pathological characteristics with genomic data enhances prognostication, providing patients 
with more accurate prognostic information and enabling better long-term management strategies. 
Furthermore, this comprehensive understanding facilitates the identification of predictive biomarkers, 
guiding the selection of effective therapeutic interventions and driving the development of innovative 
targeted therapies. By assessing the evolution of clinico-pathological characteristics and treatment 
decisions over time, the study provides insights into the long-term effectiveness of genomic testing, 
allowing for continuous quality improvement and optimization of treatment protocols. 
Ultimately, findings from this study inform the development of clinical practice guidelines and health 
policies, guiding evidence-based decisions on resource allocation, reimbursement policies, and the 
integration of genomic testing into standard clinical practice. This comprehensive approach to 
understanding clinico-pathological characteristics in patients undergoing genomic testing contributes 
to the delivery of more effective, personalized cancer care, thereby improving patient outcomes and 
quality of life. 
3 OBJECTIVES OF THE STUDY 
The study aims to establish an Italian registry for the implementation of the use of genomic tests in 
patients with HR +/HER2- breast cancer at intermediate risk of recurrence after the entry into force 
of the Ministerial Decree of 18/05/2021. The decree has established the reimbursability of genomic 
testing for breast cancer patients, thereby influencing clinical decision-making and patient 
management within Breast Units. 
In addition, the study aims to evaluate the clinical impact of the use of genomic testing on the type of 
adjuvant treatment, in terms of change of treatment indication by breast units according to the test 
result. 
The retrospective cohort will contribute to expanding our knowledge of the clinico-pathological 
characteristics of patients who underwent genomic testing.   This comprehensive understanding of 
the clinico-pathological profile of patients undergoing genomic testing will enable a more thorough 
assessment of the clinical dynamics and therapeutic decisions associated with genomic testing results, 
including the analysis of their possible evolution over the years. 

Protocol name: GIM29-GIMOMIC 
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4 ENDPOINTS 
4.1 Co-primary endpoints 
1. 
Establishment of a prospective Italian observational registry for the implementation of 
genomic tests in patients with HR +/HER2- breast cancer at intermediate risk of recurrence after the 
adoption of the Ministerial Decree of 18/05/2021 
2. 
Measurement of the impact of genomic testing on adjuvant treatment choice (CET vs ET only) 
in terms of:  
- 
Rate of adjuvant treatment choice’s change following the genomic test result (Breast 
Unit’s pre-test vs post-test indication) 
- 
Saving in adjuvant chemotherapy compared to the pre-test indication 
- 
Addition of adjuvant chemotherapy to endocrine therapy alone compared to the pre-
test indication 
- 
Type of adjuvant treatment the patient actually received 
 
4.2 Secondary endpoints 
- 
Record the predominant demographic and clinical characteristics of the patients for 
whom genomic testing was indicated. 
- 
Describe which genomic tests are used and the factors involved in the selection of 
genomic tests. 
- 
Identify any inequalities in access to the genomic tests in different geographical areas 
of the country. 
- 
Analyse the prescriptive adequacy and the compliance with the inclusion criteria for 
genomic tests. 
- 
Record the distribution of demographic and clinical characteristics (e.g., patient age, 
comorbidities, tumour size, number of positive lymph nodes, tumour grade) in the 
group of patients with changed treatment recommendation compared to the group of 
patients with unchanged indication after genomic test. 
- 
Evaluate the impact of the test on the timing of activation of adjuvant treatment, in 
terms of: 
• 
Time from diagnosis to request for genomic test 
• 
Time from request for the genomic test to result 
• 
Time from test result to activation of adjuvant chemotherapy, if indicated 
• 
Time from diagnosis to activation of adjuvant chemotherapy, if indicated 
 
5 PATIENT SELECTION CRITERIA 
5.1 Inclusion Criteria 
All male and female patients meeting these criteria: 
1. Age ≥ 18 years 
2. PS ECOG 0-1 
3. Histologically confirmed early breast carcinoma with positivity for hormone receptors (ER+ 
IHC >10%) and HER2 negative (IHC value 0-1+ and/or FISH not-amplified)  

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4. Primary resective surgery for early breast cancer with adequate assessment of lymph node 
status (sentinel lymph node biopsy or complete axillary dissection), with one of the following 
diagnostic stages: 
T1-3, N0, M0 
T1-3, pN1mic, M0 
T1-3, pN1a, M0 
5. Indication for adjuvant treatment with endocrine therapy (ET) or chemo-endocrine therapy 
(CET), according to the decision of the reference Breast Unit 
6. Meeting the criteria for "intermediate" risk, i.e., no “low” or “high” risk of recurrence, as 
defined in the ministerial decree of 18/05/21: 
▪ Low risk defined by at least 5 of the following: G1, T1a-b, KI67 < 15, N neg, 
ER > 80% 
▪ High risk, defined by at least 4 of the following: G3, T > 2, Ki67 > 30, N pos, 
ER < 30% 
7. Indication for genomic test (Oncotype DX®, Mammaprint®, PAM50-Prosigna®, Breast 
Cancer Index®, EndoPredict®) by the Breast Unit 
8. Ability to provide written informed consent to participate in the registry study, approved by 
the local Ethics Committee. 
9. The patient underwent genomic testing starting from September 2021 
 
5.2 Exclusion criteria 
 
 
1. Low-risk and High-risk patients as defined in the Ministerial Decree of 18/05/21 
2. ER negative and/or HER2 positive tumours 
3. More than 3 lymph nodes involved at clinical/pathological staging 
4. Invasive tumours <2mm evaluated by local pathologists 
5. Previous history of breast cancer 
6. Synchronous breast cancers 
7. Multifocal tumours 
8. Metastatic disease  
9. Contraindications to adjuvant treatments 
10. Performance status (PS ECOG) > 1 and / or other clinical factors that would make the patient 
a candidate and unsuitable for systemic adjuvant treatment or have received an exclusive 
indication for precautionary hormone therapy as part of the Breast Unit collegial assessment. 
11. Psychiatric diagnosis that may affect the ability to participate in this study 
 
6 STUDY DESIGN 
The study is a retrospective and prospective, non-interventional, observational registry-based study 
that will enrol all patients with ER +/HER2-negative, T1-3 breast cancer with negative axillary lymph 
nodes or up to 3 positive axillary lymph nodes for whom Breast Units require genomic test to support 
adjuvant therapy decisions, according to current clinical practice.  
Only patients who fulfill certain criteria specified in Ministerial Decree 18/05/2021 will be included 
unless otherwise agreed by the reference Breast Unit, in accordance with the specific diagnostic 
pathways activated by each site. 

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Data will be collected from September 2021 onwards. The tests are conducted as part of routine 
clinical care, independent of this observational clinical study. 
The patient’s baseline demographic characteristics, tumour clinicopathological features, pre and post-
test therapeutic indication (CET vs ET), the test results, the actual adjuvant treatment received and 
time around data will be recorded in a dedicated registry.  
7 VISITS 
7.1 Schedule 
Due to the observational nature of the study, no predetermined visit schedule can be planned, as 
patients performed visits at the clinic according to common clinical practice as programmed with the 
study physicians and staff. 
Therefore, data from all assessments detailed in Section 7.2 will be collected if and where available 
at the study visits.  
7.2 Assessments 
The main data for this study will come from the medical records of each patient who participates. All 
information entered into the electronic Case Report Form (eCRF) should have corresponding 
documentation in the patients' medical records. 
 
Throughout the observational period, data collection will adhere to standard clinical practices, 
whenever possible. This includes tests, procedures, and visits, which are conducted based on the usual 
clinical protocols at each site and at the discretion of the site physician. 
 
Upon obtaining informed consent from the patients, the following data will be collected during the 
enrollment period, provided it is available: 
 
✓ Enrollment and screening 
 
- 
General demography: sex, date of birth, age at the time of signing the consent, region of origin; 
- 
Menopausal state, previous surgery, previous threpapies (including start and stop date, type 
of therapy). 
- 
Tumor characteristics: histology, grading, size of primary tumor, lymphnode status and 
number of metastatic lymphnodes, receptor status (ER, HER, PgR, Ki67) 
- 
Physical examination: weight, height, BMI  
- 
Prior and concomitant comorbities and medication. 
 
✓ Visit prior test 
 
- 
Therapy prior test 
 
✓ Visit prior test 
 
- 
Test Type, test result, post therapeutic recommendation, patient decision 
 
✓ End of study: specify reason 
 

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8 STATISTICAL CONSIDERATION 
Although the true nature of this registry does not define apriori the number of patients ultimately 
expected, one of the main factors driving the sample size of this study is the clinical impact analysis 
and focuses on the accuracy of the estimate of the proportion of changes in planned adjuvant therapy 
pre and post genomic results.  
8.1 Sample size 
For the clinical impact analysis, 1000 patients, stratified in 60% of N0 and 40% of N1a patients, 
corresponding to 600 node-negative and 400 node-positive patients were enrolled.  
After reaching the first 400 patients, an interim analysis is planned to check the accuracy of the 
assumed estimates and the feasibility of the study.  
Moreover, to increase the accuracy of the results of this registry, enrolment and data collection will 
continue beyond the planned number of 1000 participants and will include all patients who meet the 
inclusion criteria throughout the whole study period. 
8.2 Statistical analysis 
It is assumed that the proportion of patients changing from chemotherapy (CT) followed by endocrine 
therapy (ET) to ET alone may be 50%, while the proportion of patients who change from ET to CT 
(followed by ET) is 10%. Therefore, the net change from CT to ET is expected to be 40%.  
To demonstrate this expected impact in clinical practice, with a sample size of 1000 patients, the 
confidence intervals for these three estimates are expected to be 46.9%-53.1% (C.I. width of 6.2%) 
for changes from CT to ET; 8.3%-12.0% (C.I. width of 3.7%) for changes from ET to CT and 37.0%-
43.1% (C.I. width of 6.1%) for the net change from CT to ET.  
9 FORMS AND PROCEDURES FOR COLLECTING DATA AND 
DATA MANAGING 
All patient’s data will be recorded in a dedicated Case report form (CRF). All the information will be 
extracted from the medical records. 
CRF is the primary data collection instruments for the study. All data requested on the CRF must be 
recorded, and any missing data must be explained.  If a space is left blank because the procedure was 
not done or the question was not asked, “N/D” must be noted.  If the item is not applicable to the 
individual case “N/A” must be noted.   
The registry will be implemented on a web-based platform to capture and update patient recruitment 
in real time by regularly monitoring the number of patients enrolled as well as geographic and 
demographic information. In addition, the platform will be able to generate quarterly reports that will 
be available to those involved in the management and support of the study. 

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10 QUALITY CONTROL 
The Study will be conducted according to applicable ICH and GCP guidelines. The monitoring visits 
will be conducted to ensure protocol adherence, quality of data, and compliance with regulatory 
requirements. As required by GCP and local regulations, the investigator will provide direct access 
to source data / documents for trial-related monitoring, audit, review by representatives of the 
sponsor, to CE and for inspections by regulatory authorities. 
Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the course of the study and 
after the study has completed, if required. They can be both on-site and/or remote visits. During on-
site visits, eCRFs and supporting documentation related to the study will be reviewed and any 
discrepancies or omissions will be resolved. Furthermore, electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values and 
sent to the investigational site via the EDC system or via e-mail. 
11 DATABASE RETENTION AND ARCHIVING OF STUDY 
DOCUMENTS 
The investigator must retain all study records and source documents for the maximum period required 
by applicable regulations and guidelines, or institution procedures, or for the period specified by the 
sponsor (25 years), whichever is longer.  
The investigator must contact the sponsor prior to destroying any records associated with the study. 
Location of database and supporting documentation will be outlined in the final observational study 
report. 
12 ETHICAL CONSIDERATION 
This study will be conducted in agreement with either the Declaration of Helsinki (Tokyo, Venice, 
Hong Kong and Somerset West amendments) and the laws and regulations of the country, whichever 
provides the greatest protection of the patients. The protocol has been written and the study will be 
conducted according to the ICH guidelines for good clinical practice (ICH / GCP). 
12.1 Patient Protection 
All parties involved in the registry development will maintain the strict confidentiality to assure that 
neither the person nor the family privacy of the patient participating in the registries is violated.  
Data will be processed exclusively by authorized personnel who participate in the definition of the 
GIMOMIC Study (data processor will be identified in each HCP involved). Access to computer 
systems and premises where they are kept will be controlled by means of appropriate security 
measures that comply with the requirements of the privacy regulations. The processing of the personal 
data of patients taking part in the GIMOMIC Study, and in particular regarding data concerning 
consent, will comply with local law on the privacy and with the General Data Protection Regulation 
2016/679 (GDPR) of the European Union. 
The registry protocol will be submitted to the Ethic Committee (EC) of the HCPs involved. 
Furthermore, ECs of the HCP involved, will authorize in advance any research carried out with the 
GIMOMIC Study data. 

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12.2 Informed Consent 
The informed consent is the legal basis of the GIMOMIC Study. The investigator must explain to 
each patient (or legally authorised representative) the nature of the GIMOMIC Study, its purpose, the 
type of data collected, the expected duration, the potential risks and benefits involved. Each patient 
must be informed that consenting to have her/his data in the GIMOMIC Study is voluntary and that 
she/he may withdraw from the registry at any time and that withdrawal of consent will not affect 
her/his subsequent medical treatment or relationship with treating physician. The informed consent 
will be given by means of standard written statement, using non-technical language. The patient 
should read and consider the statement before signing and dating it, and should be given an original 
copy of the signed document. If the subject cannot read or sign the document, oral presentation may 
be made or signature given by the subject’s legally appointed representative, if witnessed by a person 
not involved in the registry, mentioning that the patient could not read or sign documents. Information 
about a patient cannot be entered in the GIMOMIC Study before her/his informed consent has been 
obtained. 
A separate informed consent for the analysis of biological samples, not mandatory to be part of the 
main study, will be signed by the patient. The informed consent must explain to the patient that no 
additional samples will be required for the purpose of GIMOMIC Study, but only results coming 
from the genomic test on biological samples already available at the site will be used.  
The informed consent is part of the protocol and must be submitted to the local ECs. 
The patient can withdraw the consent in any moment during the study. 
The investigator should maintain a copy of the informed consent in the Trial Investigator File of the 
study and he/she should release an original copy to the patient. 
For patients who will no longer be traceable, the data collected up to the last observation date will be 
analysed. 
12.3 Insurance 
Given the observational nature of the study, no additional insurance policy will be required compared 
to those already provided in normal clinical practice (AIFA Determination, 20 March 2008). The 
insurance is included in the general insurance coverage of the Hospital for clinical and research 
activities. 
13 RISK/BENEFIT STATEMENT 
There are no identifiable physical, psychological and/or social risks directly derived from the 
procedures that will be followed for the enrolment of patients in the study and the collection of the 
related data. 
This study does not represent a direct benefit for the patient involved, however the collection of 
information regarding breast cancer may help the future treatment of patients affected by this disease. 

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14 FARMACOVIGILANCE/ADVERSE REACTION REPORTING 
Since this is an observational study, medicinal products are prescribed in accordance with the terms 
of the marketing authorization (AIC) and in any case the assignment of the patient to a specific 
therapeutic strategy is not decided in advance by this trial protocol, but falls within current practice 
and the decision to prescribe the medicinal product is completely independent of that of including the 
patient in the study. No additional diagnostic or monitoring procedures should be applied to the 
patients and, and epidemiological methods will be used for the analysis of collected data, according 
to the provisions of AIFA Determination 20 March 2008 on “Guidelines for classification and 
conducting observational studies on medicinal products” published in the OJ 31 March 2008 No. 76. 
For these reasons, any adverse reaction must be notified to the local authority as required by Italian 
Legislative Decree no. 219 dated 24 April 2006, Implementation of directive 2001/83/EC (and 
subsequent amending directives) relating to a community code concerning medicinal products for 
human use, as well as directive 2003/94/EC, and subsequent amendments 
15 STUDY TIMETABLE 
Duration of the Project: 18 months 
Ethics committee submission: June 2023 
Patient enrolment: May 2024-May2024 
End of Follow-up: November 2026 
 
 

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