Germline testing to find genetic alteration that can be linked to inherited susceptibility of developing the disease is recommended for patients diagnosed with certain solid cancers, such as breast, prostate and ovarian, due to strong association with inheritable mutations implying familiar counselling. Non-Small Cell Lung Cancer (NSCLC) is the leading cancer-related cause of death and smoking habitude is the main modifiable risk, while environmental factors, such as radon, asbestosis and fine polluting particles account for most diagnoses among never or light smokers. At the same time, the relative risk (RR) of lung cancer correlates with the number of relatives diagnosed with lung cancer.

A recent study of 7788 patients with NSCLC who receiving a germline testing described a prevalence of genetic alterations linked to inherited susceptibility of cancer in 14.9% of cases, highlighting the potential role of genetic However, all the available studies investigating the family history of cancer among patients with NSCLC are retrospective and do not consider modifiable risk factors such as smoking, working habits and geographical origins.

The objective of this study is the detailed description of the family history of cancer among patients with NSCLC and the description of distribution of other risk factors, such as smoking, among the study participants, in order to establish whether there are specific family history clusters that can help clinicians in directing patients to genetic counselling.

The study will enrol consecutive patients with NSCLC, independently from age, disease stage, smoking status, and clinic-pathological characteristics.

Participants will provide clinical anamnestic information filling an ad hoc self-reported study questionnaire, internally validated by the genetic expert of the steering committee. Data of interest include: Family history of cancer; Type of tumours/primary tumour site among relatives with history of cancer; Age at diagnosis among relatives with history of cancer; Biological sex of relatives with history of cancer; Exposure to tobacco smoking and smoking habits among relatives with history of cancer; Geographical origin of participants and relatives with history of cancer; Personal history of multiple malignancies; Potential professional and environmental exposure to carcinogens of participants and relatives with history of cancer; Ethnicity of both participants and relatives with history of cancer.

The study does not require any additional hospital access from the patients since the questionnaire will be returned at the following planned clinical consultation to minimize recall bias.

The investigators will collect the following clinic-pathologic characteristics: Smoking status (active/passive, package/year, total years of smoking); Eastern Cooperative Oncology Group Performance Status (ECOG-PS); Age at diagnosis; Tumour histology; Tumour stage at diagnosis according to the 8th edition of TNM staging system; Ethnicity; Professional and environmental exposure to carcinogens; Programmed death ligand-1 tumour proportion score (PD - L1 TPS); Any available oncogenic drivers including epidermal growth factor receptor (EGFR), Kirsten rat sarcoma virus (KRAS), BRAF, c-MET, mutations and Anaplastic lymphoma kinase (ALK), ROS-1, RET, neurotrophic tyrosine receptor kinase NTRK translocation/gene fusions; Personal history of other synchronous/metachronous primary malignancies.

This is a prospective, observational, multi-centre study. Our study population will be represented by consecutive patients with histologically diagnosed NSCLC, regardless of their age, TNM stage, smoking status, and other clinic-pathologic characteristics.

The primary objectives of this study will be:

• description of the FHC and potential within-family clusters of other risk factors among patients with NSCLC
• identification of potential FHC patterns and within-family clusters of other risk factors to address patient with NSCLC to systematic genetic counselling.

Secondary objectives include:

- description of clinic-pathological and oncological characteristics of patients with NSCLC of according to FHC patterns and within-family clusters of other risk factors.

Participants' history will be carefully collected by investigators through a dedicated self-reported study questionnaire, which has been developed for the purpose of this study (provided as Appendix 1) The ad-hoc study questionnaire has been validated by the genetic expert of the steering committee who will train each investigator to translate the returned questionnaire into standardized family trees.

Study questionnaire will focus on:

• Family history of cancer;
• Type of tumours/primary tumour site among relatives with history of cancer;
• Age at diagnosis among relatives with history of cancer;
• Biological sex of relatives with history of cancer;
• Exposure to tobacco smoking and smoking habits among relatives with history of cancer;
• Geographical origin of participants and relatives with history of cancer;
• Personal history of multiple malignancies;
• Potential professional and environmental exposure to carcinogens of participants and relatives with history of cancer;
• Ethnicity of both participants and relatives with history of cancer.

To minimize risks of recalling bias, patients will be followed up for 4 weeks through 2 study visits: the first study visit at enrolment and the follow-up study visit.

During the first study visit all patient's clinic-pathologic will be collected and study participants will be given the ad-hoc questionnaire, which will be returned to the study personnel at the follow-up study visit.

The following clinic-pathologic characteristics will be collected:

• Smoking status (active/passive, package/year, total years of smoking)
• Eastern Cooperative Oncology Group Performance Status (ECOG-PS)
• Age at diagnosis;
• Tumour histology;
• Tumour stage at diagnosis according to the 8th edition of TNM staging system;
• Ethnicity;
• Professional and environmental exposure to carcinogens;
• Programmed death ligand-1 tumour proportion score (PD - L1 TPS)
• Any available oncogenic drivers including epidermal growth factor receptor (EGFR), Kirsten rat sarcoma virus (KRAS), BRAF, c-MET, mutations and Anaplastic lymphoma kinase (ALK), ROS-1, RET, neurotrophic tyrosine receptor kinase NTRK translocation/gene fusions.

Personal history of other synchronous/metachronous primary malignancies.

Study data will be collected through dedicated electronic case report form (e-CRF). A full list of information that will be collected through the dedicated eCRF (provided as appendix 2).

Even though no established FHC criteria exists to refer patients with NSCLC to a genetic counselling for germ-line testing, investigators will assess participant questionnaire at the follow-up study visit and refer patients to genetic counselling when clinically indicated as per local routine practice.

Following collection of participants' questionnaires, the investigators will be able to reconstruct patients' family three with additional information on how other potential risk factors, such as history of smoking, exposure to professional/environmental carcinogens, segregate within the relatives with history of cancer.

The investigators will be able to describe whether recurrent family clusters of malignancies/risk factors are specifically associated with risk of lung cancer in order to individuate patients to specifically address to systematic genetic counselling, to assess eligibility for germ-line testing in clinical practice. Secondly, the investigators will also assess the distribution of participants clinic-pathologic characteristics to assess whether any patients and/or tumour-related feature is associated with patterns of FHC and within-family clustering of other risk factors.

The esteemed study duration is 24 months. Enrolment will start after protocol approval and will last for 12 months. Data analysis will last 12 months from the closure of data collection.

Statistical Plan and Sample Size

Given the descriptive nature of the study, and the lack of available data on the relationship between family history of cancer and NSCLC, the minimum sample size for the study has been established on the only study available to date which investigated distribution of FHC among unselected patients with stage IV NSCLC, which described a high familiar burden of cancer (i.e. especially enriched FHC with cases of cancer in both the collateral and lineal family lines) in up to the 6.8% of patients [14]. On the basis of this data, the investigators hypothesized a prevalence of 10% of participants with an especially enriched family history of cancer in our study population; assuming a confidence level of 95% with a total width for the confidence interval of 0.1 (precision of +/- 5%) and considering a 10% drop out, the minimum number of subjects that will need to be enrolled to properly describe the group of interest following a binomial "exact" calculation of the sample size is 175 Descriptive statistics will be used as appropriate to report FHC data, distribution of within-family other risk factors and baseline clinic-pathologic characteristics. The Fisher exact test and the χ2 test will be used as appropriate to compare categorical variables (e.g. distribution of baseline characteristics according to the personal/familial positive or negative history). Analyses were performed using the R-studio software, R Core Team (2021). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, and the MedCalc® Statistical Software version 20 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org; 2021).

Inclusion Criteria:

• Histopathological diagnosis of Non-Small Cell Lung Cancer (all stages)
• Age ≥ 18 years old
• Signed informed consent
• Availability of familiar and/or personal anamnestic data of cancer

Exclusion Criteria:

• Unavailability of familiar and/or personal anamnestic data of cancer
• Patient's refusal

This is a prospective, observational, multi-centre study. Our study population will be represented by consecutive patients with histologically diagnosed NSCLC, regardless of their age, TNM stage, smoking status, and other clinic-pathologic characteristics.

Patients' history will be carefully collected by investigators through a dedicated self-reported study questionnaire, which has been developed for the purpose of this study (provided as Appendix 1).

The ad-hoc study questionnaire has been validated by the genetic expert of the steering committee who will train each investigator to translate the returned questionnaire into standardized family trees.

IPD will not be shared and there is no plan at this stage. Future requests will be considered upon reasonable requests. Fully anonymised data will be considered for sharing after assessment of the study PI, data protection office of the sponsor and with a data trasnfer agreement in place.