The Oncogenic Landscape of the Idiopathic Pulmonary Fibrosis: A Narrative Review

Giulia Maria Stella; Vito D'Agnano; Davide Piloni; Laura Saracino; Sara Lettieri; Francesca Mariani; Andrea Lancia; Chandra Bortolotto; Pietro Rinaldi; Francesco Falanga; Cristiano Primiceri; Angelo Guido Corsico; Andrea Bianco


Transl Lung Cancer Res. 2022;11(3):472-496. 

In This Article

Abstract and Introduction


Background and Objective: Translational research is a source of continuous innovation in medicine, more particularly for clinical research on new treatment modalities in idiopathic pulmonary fibrosis (IPF) patients. However, the heterogeneity of the disease is well recognized, and different pathological and molecular settings have been identified. The molecular mechanisms by which IPF proceeds in time and space remains poorly understood. Although some IPF features are reminiscent of cancer, the dynamics of malignant divergent clonal selective pressure and heterogeneity clearly differ from those occurring in IPF. This is reflected in the absence of patient proper selection and stratification to biological agents (pirfenidone, nintedanib) which limit therapeutic efficacy. Consequently, increased costs are related to the clinical management of advanced IPF patients. Steady collaboration and fluid communication between pneumo-oncologists, radiologists and molecular biologists is a clear priority for the correct interpretation of tests and the definition of effective personalized strategies against this orphan disease. The present work aims at providing the most relevant hints shared by cancer and IPF.

Methods: A systematic literature review was performed to identify all relevant data. The examined databases were Scopus, Web of Science, Cochrane, Google Scholar, and PubMed. The last search was run on January 5, 2022. We have primarily conducted separated research for lung cancer, IPF, genetics, epigenetics, surgery in IPF and cancer.

Key Content and Findings: The data here presented mainly focus on gene mutations, epigenetics and novel therapeutic approaches. Moreover, epidemiology, prognostic variables and in new treatment strategies adopted in patients with IPF and lung cancer are discussed as well.

Conclusions: Overall, the findings of this narrative review will be of help in defining the key molecular features that could applied in IPF setting with promising rationale to improve therapy and to better manage those cases carrying IPF and cancer concomitantly.


Idiopathic pulmonary fibrosis (IPF) is characterized by a proliferative landscape, which recalls—under several aspects—that of cancer. This critical issue has been already exploited for therapeutic purposes taking advantage from know-how and expertise from cancer pharmacology. Moreover, IPF diagnosis is associated to a significantly higher risk of lung cancer development.[1,2] Notably the coexistence of IPF is associated to a more unfavourable prognosis in lung cancer patients who generally experience severe disease exacerbation during antineoplastic therapy.[3–5] Others and we already described bio-molecular similarities and differences between IPF and cancer[6–10] (Figure 1), however some points need deeper clarification and update.

Figure 1.

IPF and cancer. The two diseases share common pathogenic pathways that should be exploited for novel therapeutic approaches. The oncogenic gain behaves as main driver of proliferative and invasive phenotypes. Heterogeneity which characterizes both diseases, refers to clonal selection (cancer) and histology (IPF). The specific IPF context impacts on the therapeutic exploitation of targeting oncogenes. IPF, idiopathic pulmonary fibrosis. IPF, idiopathic pulmonary fibrosis.

The concept that interstitial lung diseases (ILDs) represent a relevant risk factor for lung cancer development is well documented and known.[11–20] Within respect to IPF, reports indicated a cumulative incidence of cancer in IPF patients varying from 3.3%, 15.4%, and 54.7% after 1, 5, and 10 years of follow-up for IPF[21] to 41% and 82% at 1 and 3 years, respectively.[5] Age and smoking habit act as known confounding variables since they impact on both lung cancer and IPF onset.[19,20,22,23] Moreover, many occupational and environmental exposure toxics are common risks for the development of both the diseases. Notably, IPF patients are at higher risk of cancer development if compared to those affected by chronic obstructive pulmonary disease (COPD), another cancer predisposing pathologic entity.[24] The Japanese Hokkaido registry data reports an unadjusted risk ratio of 7.8 for lung cancer in IPF patients vs. COPD ones.[25,26] Most often tumors in IPF context arise in peripheral lung,[27,28] although these data need further confirmation.[19] The mechanistic explanation and the association between IPF and cancer are discussed in detail in the next sections of the manuscript. However, several issues deserve to be here underline. It is conceivable that the pro-proliferative landscape that characterizes IPF, should promote the selection of those cells carrying oncogenic mutations.[29–31] Pirfenidone and nintedanib act as antifibrotic drugs through different mechanisms. The first essentially acts by deregulating a series of cytokines, including transforming growth factor (TGF)-β1, connective tissue growth factor (CTGF), platelet-derived growth factors (PDGF), and tumor necrosis factor (TNF)-α. Moreover, it behaves as scavenger of reactive oxygen species (ROS) and downregulate angiotensin-converting enzyme (ACE) expression.[32,33] Nintedanib is a multikinase inhibitor which also down-regulates protein and mRNA expression of extracellular matrix (ECM) proteins, fibronectin, and collagen 1a1 and inhibits (TGF)-β1-induced myofibroblast differentiate.[34] Notably, both drugs inhibited collagen I fibril formation.[35] It should be underlined that a relationship exists between these main two treatments for IPF, namely pirfenidone and nintedanib, and lung as well. Several recent studies have shown a prophylactic effect of the use of pirfenidone perioperative setting against postoperative acute IPF exacerbations in patients with lung cancer.[36–40] Notably therapy with pirfenidone seems to be associated to lower incidence of lung cancer in IPF patients if compared to non-pirfenidone treated cases,[41] although this observation should be confirmed by more extensive analysis. Some recent observation also underlined a potential therapeutic role of pirfenidone against lung cancer. In detail, it has been reported in vitro and in vivo that it could suppressed activation of non-small-cell lung carcinoma (NSCLC) associated myofibroblasts,[42] which are known to be involved in tumor progression[43–45] and impairs epithelial–mesenchymal transition (EMT) by acting on exogenous TGF-β1 and on paracrine TGF-β produced from NSCLC cells.[46] Pirfenidone seems to play a synergic effect with conventional chemotherapy such as carboplatin,[47] whereas studies evaluating effects of combination with immune checkpoint (IC) inhibitors are ongoing (the NCT04467723 trial evaluating the combination of pirfenidone with the programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) inhibitor atezolizumab in second-line and beyond NSCLC, website at The antiproliferative effect of nintedanib derives to its ability to block the vascular endothelial growth factor (VEGF), PDGF and the fibroblast growth factor receptor (FGFR). Nintedanib in combination with docetaxel is approved as second-line therapy for advanced NSCLC.[48] It also promotes antitumor immunity and antitumor activity in combination with PD-1 blockade in mice by targeting cancer-associated fibroblasts (CAF) thus attenuating the immunosuppressive tumor microenvironment on one hand and promoting intratumoural activation of antitumor CD8+ T cells.[49] Although some reports suggesting a positive effect,[50–52] it is still unclear if nintedanib could play an effective role against lung cancer aroused in IPF patients. When associated with corticosteroids, it seems to be able to attenuate targeted drug[53] and IC inhibitor-related pneumonitis in cancer patients.[54,55] Thus, we—here—report and discuss more recent advances from multidisciplinary contexts that will result in significant changes in the diagnosis and treatment of IPF patients. We present the following article in accordance with the Narrative Review reporting checklist (available at