Observational, Prospective, Multicentre Study to Investigate the Family History of Cancer in Patients With Non-small Cell Lung Cancer (FAHIC - Lung).
Conditions: Non Small Cell Lung Cancer
Sponsor: Fondazione Policlinico Universitario Campus Bio-Medico

 
  March 08, 2023 
 
 
 
 
 
PROTOCOL FAHIC – Lung 
OBSERVATIONAL PROSPECTIVE ACADEMIC TRIAL  
Observational, prospective, multicentre study to investigate the family history of 
cancer in patients with non-small cell lung cancer (FAHIC – Lung). 
 
 
Short Title  
Family history of cancer in NSCLC 
Title acronyms or Protocol Code: FAHIC – Lung  
Version and Date: V 1.0 08th March 2023 
 
 
Promotor: 
 
 
Coordinating Centre: 
Fondazione Policlinico Campus Bio-Medico, Vial 
Alvaro del Portillo 200, 00128, Roma, Italia 
 
Oncologia Medica, Fondazione Policlinico Campus 
Bio-Medico, Vial Alvaro del Portillo 200, 00128, 
Roma, Italia 
 
 
Principal Investigator:  
Dott. Alessio Cortellini MD PhD 
Oncologia Medica, Fondazione Policlinico Campus 
Bio-Medico, Vial Alvaro del Portillo 200, 00128, 
Roma, Italia 
0039 06225411244 
a.cortellini@policlinicocampus.it 
 
Other investigators: 
 
Dr Fabrizio Citarella  
Oncologia Medica, Fondazione Policlinico Campus 
Bio-Medico, Vial Alvaro del Portillo 200, 00128, 
Roma, Italia 
f.citarella@unicampus.it  
 
Prof Fiorella Gurrieri 
Genetica Medica, Fondazione Policlinico Campus Bio-
Medico, Vial Alvaro del Portillo 200, 00128, Roma, 
Italia 
 
Dott. Pierfilippo Crucitti 
Chirurgia Toracica, Fondazione Policlinico Campus 
Bio-Medico, Vial Alvaro del Portillo 200, 00128, 
Roma, Italia 
 
 
 
 

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Other Participating Centers: 
IRCCS Ospedale San Raffaele, Medical Oncology 
Department. 
Universitá Vita Salute San Raffaele, Milan 
Local-PI: Roberto Ferrara  
ferrara.roberto@hsr.it  
 
 
Ospedale le Molinette, Oncologia Medica 1U 
Universitá di Torino, Torino 
Local-PI: Massimo Di Maio 
Massimo.dimaio@unito.it  
 
Informazioni di Contatto 
 
Nome Contatto Promotore 
Dott. Alessio Cortellini MD PhD 
Oncologia Medica, Fondazione Policlinico 
Campus Bio-Medico, Vial Alvaro del Portillo 200, 
00128, Roma, Italia 
0039 06225411244 
a.cortellini@policlinicocampus.it 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document is confidential and the property of individual.  No part of it may be transmitted, reproduced, 
published, or used by other persons without prior written authorization from the author. 
 
 
 

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PAGINA DELLE FIRME DEL PROTOCOLLO   
 
      
 
 
DICHIARAZIONE DELLO SPERIMENTATORE: 
 
Codice del protocollo: FAHIC – Lung 
 
Dichiaro di aver letto il protocollo ed acconsento a condurre questo studio clinico in accordo a tutti 
i requisiti del protocollo e secondo le Linee Guida di Buona Pratica Clinica ed i principi della 
Dichiarazione di Helsinki. 
 
 
 
 
 
 
 
 
 
 
 
     29/08/2023 
 
(Sperimentatore)  
Dott. Alessio Cortellini 
firma  
 
data 
 
 
 

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1 Background and rationale 
Familial aggregation and inherited predisposition have been increasingly investigated in multiple 
cancer types. In breast, ovarian, prostate and colorectal malignancies, genetic counselling is 
recommended in patients showing risk criteria for syndromes of inherited susceptibility to 
cancer, as aggregations with other malignancies have been widely described within families of 
these patient populations [1–3].  
With a predicted number of death of about 160 000 cases in 2023  in Europe and 127 070 in US 
[4,5], Non-Small Cell Lung Cancer (NSCLC) still remains a leading cause of cancer death 
worldwide. A positive smoking history represents the main cause related to NSCLC (90% of 
cases)[6], while environmental factors such as exposure to radon, asbestosis and air pollution 
have been linked to lung cancer among never smokers [7–9]. However, few studies have 
investigated the impact of a positive family history of cancer (FHC) in patients with NSCLC, 
describing types of other malignancies that can co-occur within relatives of patients with NSCLC.  
In previous reports, the relative risk (RR) of developing lung cancer directly correlated with the 
number of lung cancer cases in fist-degree relatives y (RR= 2.57 for first-degree relative >= 1 to 
RR= 4.24 for first-degree relative affected ≥3), and a similar trend has been observed when taking 
into account second and third degrees [10]. Furthermore, RR of developing lung cancer has been 
estimated to be up to 1.89 among those having a first-degree relative with lung cancer as second 
primary malignancy [11]. However, all these studies were conducted using local national registry, 
with no additional info on potential within-families clustering of other risk factors, including 
tobacco smoking exposure and other geographical/epidemiological factors. In addition, 
retrospective approaches to this topic are heavily impacted by recall bias and misclassification 
[12-13]. 
More recently, a “high burden” of family history of cancer in patients with advanced stage NSCLC, 
has emerged as potential predictive factor for systemic treatment with PD-1/PD-L1 checkpoint 
inhibitors, but without showing enrichment of somatic DNA damage and repair (DDR) gene 
alterations in tumour samples [14]. In terms of germline genetic alterations, lung cancer risk has 
been associated with rare genetic syndromes such as the Li-Fraumeni syndrome [15]. 
Furthermore, in multiple genome-wide associations studies three main susceptibility loci have 
been associated with increased risk of developing NSCLC including 15q25, 5p15 and 6p21 regions, 
corresponding to CHRNA3, CHRNA5, and CHRNB4, TERT, CLPTM1L, APOM, BAG6 genes [7].  
To underline the importance and the potential clinical implications of investigating FHC in 
patients with NSCLC, a recent retrospective study conducted in a cohort of 7,7888 patients with 
NSCLC, undergoing to commercially available genetic germline testing, but with no information 
about their FHC, pathogenic germline variants (PGV) or likely PGV were found in 14.9% of cases 
and an additional 2.9% of cases carried a single PGV in a gene associated with autosomal 
recessive inheritance. Among these 14.9% PGV positive, 61.3% of them had a PGV in DDR/HRR 
genes and 95.1% of them harboured a PGV in clinically actionable genes, with BRCA2 (2.8%), 

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CHEK2 (2.1%), ATM (1.9%), TP53 (1.3%), BRCA1 (1.2%), and EGFR (1.0%) being the most 
commonly reported PGVs [16].  
Despite this few evidence, genetic causes of lung cancer still remain largely unknown, and 
FHC/potential within-family clustering of other risk factors need to be prospectively assessed.  
With the aim of individuating and describing FHC and potential within-family clustering of other 
risk factors in patients with NSCLC the FAHIC – Lung study will represent the firsts prospective 
observational study in this area.  
 
2 Study Objectives 
2.1 Primary Objectives: 
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.   
2.2 Secondary Objectives:  
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. 
3 Study design 
3.1 General Design 
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. 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; 

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- 
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, each patient will be given a minimum time of 4 weeks to gather 
family history information. The study-questionnaire will be then collected at the following clinical 
consultation as already planned per clinical practice, with no additional study-specific 
procedures. 
  
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, we will be able to reconstruct patients’ 
family three with additional information on how other potential risk factors, such as history of 

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smoking, exposure to professional/environmental carcinogens, segregate within the relatives 
with history of cancer. 
We 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, we will also investigate 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.  
 
3.2 Participants Selection 
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 
3.3  
3.4 Study flow-chart 
 
 

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3.5 Study duration 
 
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.  
4 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, we 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 study questionnaire to collect 
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). 
 
5 Data Management and confidentiality 
Data will be collected and retained in accordance with the European General Data Protection 
Regulation (GDPR) L119, 4 May 2016 and in compliance with other international data protection 
regulations, such as the title 21 CFR Part 11 of the Code of Federal Regulations, the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA), and the United Kingdom GDPR. 
Data will be collected by investigators at each participating site through a dedicated electronic 
case report form (eCRF) designed by the study staff with the Research Electronic Data Capture 
software (REDCap, Vanderbilt University, Nashville, TN, USA) using a GDPR-compliant secure 
server at the coordinating center (Fondazione Policlinico Universitario Campus Bio-Medico, 
Rome, Italy) and will be kept for 5 years after the study completion. 

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Access to the database will be given to authorized personnel only at each site, log of access will 
be kept in the study file by the Principal Investigator with a secure two factor authentication 
system for each investigator. 
A unique reference number will be assigned to each institution and a second-level unique and 
sequential ID number will be assigned to each participant.  
Each participating institution will ensure that all anamnestic, clinical and follow-up information 
will be collected after a complete anonymization process. Investigators at the coordinating center 
(Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy) will not be able to match 
participants’ ID with potentially identifiable information, which will be accessible to local 
investigators only at each participating site.  
Principal Investigator will ensure that the patient’s privacy is maintained at all times. On the Case 
Report Form (CRF) or other documents, patients will be identified by a study ID number only.  
Technical and organizational measures to ensure data protection will include: anonymization and 
encryption, confidentiality, integrity, availability and resilience of processes and services on a 
permanent basis, procedures for regularly testing, verifying and evaluating the effectiveness of 
technical and organizational measures in order to guarantee the security of the processing.  
The investigator shall permit direct access to study source document for the purposes of 
monitoring, auditing, or inspection by the Sponsor, authorized representatives of the Sponsor 
and Regulatory Authorities.  
6 Ethical consideration 
The study will be conducted in accordance with the principles of Good Medical Practice and the 
recommendations for physicians involved in research on human subjects adopted by the 18th 
World Medical Assembly, Helsinki 1964 and later revisions.   
A written informed consent to participate to the study and to personal data processing will be 
ask at each participating institution by local investigators to all patients. Study-related medical 
risks are the same as for clinical practice.  
The Investigators declares no direct conflicting interest for the proposed study.   
 
7 Fundings 
This is an academic study, which did not receive any direct funding.  
  
8 Publication policy 
A whole or part of the study results will be communicated, orally presented, and/or published 
in appropriate scientific journals. Full anonymity of subject’s details will be maintained 
throughout. Subjects wanting to see the results of the trial can request a copy of the article 
from the investigators once it has been published. 
 

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9 References 
1.  
Stjepanovic, N.; Moreira, L.; Carneiro, F.; Balaguer, F.; Cervantes, A.; Balmaña, J.; Martinelli, 
E. Hereditary Gastrointestinal Cancers: ESMO Clinical Practice Guidelines for Diagnosis, 
Treatment 
and 
Follow-Up†. 
Annals 
of 
Oncology 
2019, 
30, 
1558–1571, 
doi:10.1093/annonc/mdz233. 
2.  
Genetics of Prostate Cancer (PDQ®)–Health Professional Version - NCI Available online: 
https://www.cancer.gov/types/prostate/hp/prostate-genetics-pdq (accessed on 12 March 
2023). 
3.  
Guidelines Detail Available online: https://www.nccn.org/guidelines/guidelines-detail 
(accessed on 12 March 2023). 
4.  
Lung Cancer Statistics | How Common Is Lung Cancer? Available online: 
https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html (accessed on 12 
March 2023). 
5.  
Malvezzi, M.; Santucci, C.; Boffetta, P.; Collatuzzo, G.; Levi, F.; Vecchia, C.L.; Negri, E. 
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Malhotra, J.; Malvezzi, M.; Negri, E.; Vecchia, C.L.; Boffetta, P. Risk Factors for Lung Cancer 
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