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Thoracic Oncology Group, Cancer Medicine Department, Gustave Roussy, Villejuif, FranceTranslational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, SpainMedical Oncology Department, Hospital Clínic, Barcelona, Spain
Medical Oncology Department, Catalan Institute of Oncology-Badalona (ICO-Badalona), Institut Germans Trias i Pujol (IGTP), Badalona Applied Research Group in Oncology (B-ARGO), Universitat Autònoma de Barcelona (UAB), Medicine Department, Badalona, Spain
Department of Respiratory Medicine, Pontchaillou Hospital, Rennes, FranceUniversity of Rennes, Rennes, FranceChemistry, Oncogenesis, and Stress Signaling, INSERM, Centre Eugène Marquis, Rennes, France
Medical Oncology Department, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, FranceCancer Research for PErsonalized Medicine (CARPEM), Paris, FranceParis Descartes University, USPC, Paris, France
Department of Respiratory Medicine, Pontchaillou Hospital, Rennes, FranceUniversity of Rennes, Rennes, FranceChemistry, Oncogenesis, and Stress Signaling, INSERM, Centre Eugène Marquis, Rennes, France
Medical Oncology Department, Catalan Institute of Oncology-Badalona (ICO-Badalona), Institut Germans Trias i Pujol (IGTP), Badalona Applied Research Group in Oncology (B-ARGO), Universitat Autònoma de Barcelona (UAB), Medicine Department, Badalona, Spain
Normandie Univ, UNIROUEN, INSERM, and Rouen University Hospital, Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
Corresponding author. Address for correspondence: Olivier Caron, MD, Department of Medicine, Institut Gustave Roussy, 14 Rue Edouard Vaillant, 94800 Villejuif, France.
Thoracic Oncology Group, Cancer Medicine Department, Gustave Roussy, Villejuif, FranceINSERM, Gustave Roussy Cancer Campus, Université Paris Saclay, Saint-Aubin, France
Actionable somatic molecular alterations are found in 15% to 20% of NSCLC in Europe. NSCLC is a tumor observed in patients with germline TP53 variants causing Li-Fraumeni syndrome (LFS), but its somatic molecular profile is unknown.
Methods
Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants.
Results
Among 22 patients with NSCLC and LFS (n = 23 lung tumors), 64% were women, median age was 51 years, 84% were nonsmokers, 73% had adenocarcinoma histological subtype, and 84% were diagnosed with advanced-stage disease. These patients harbored 16 distinct germline TP53 variants; the most common was p.R158H (5/22; three in the same family). Personal and family histories of cancer were reported in 71% and 90% of patients, respectively. In most cases (87%, 13/15), lung cancer was diagnosed with a late onset. Of the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19 of 21 (90%), EGFR mutations in 18 (exon 19 deletion in 12 cases, L858R in three cases, and G719A, exon 20 insertion, and missing mutation subtype, each with one case), and ROS1 fusion in one case. A PI3KCA mutation was concurrently detected at diagnosis in three EGFR exon 19-deleted tumors (3/12). The median overall survival was 37.3 months in 14 patients treated with EGFR inhibitors; seven developed resistance, five (71%) acquired EGFR-T790M mutation, and one had SCLC transformation.
Conclusions
Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations; one ROS1 fusion was also observed. The germline TP53 variants and lung cancer carcinogenesis driven by oncogenic processes need further evaluation.
Li-Fraumeni syndrome (LFS), resulting from germline pathogenic TP53 variants, is a rare autosomal dominant inheritance condition characterized by the early onset of different cancer types, including breast cancer, bone and soft tissue sarcomas, central nervous system tumors, and adrenocortical carcinoma.
which is currently considered the third most frequent tumor in adults with LFS. In a cohort of 552 patients with LFS, 17 who were diagnosed with lung cancer had a median age of 45 years.
Caron et al. reported that lung adenocarcinoma was found in five of 107 germline TP53 variant carriers screened with whole-body magnetic resonance imaging.
Although previous articles have reported individuals with LFS and lung cancer harboring EGFR-sensitizing mutations (Supplementary Table 1), the clinical phenotype has not been well characterized, and the molecular profile of LFS lung tumors remains unknown.
The aim of this study was to describe the clinical presentation of 22 patients with LFS and lung cancer and the molecular phenotype of their tumors.
Materials and Methods
Patients with histologically confirmed NSCLC and pathogenic germline TP53 variants were included. Samples were collected from May 2002 to November 2017 in two academic centers (Gustave Roussy, France; Catalan Institute of Oncology, Spain). Clinical and molecular data were retrospectively extracted from electronic medical records.
Germline TP53 screening, interpretation of TP53 variants, and the somatic molecular profile of NSCLC were determined according to standard procedures (Supplementary Material). The institutional review boards of both centers approved this study.
Results
Baseline characteristics of the 22 patients and germline variants are summarized in Table 1 and Table 2, respectively. Overall, the median age was 51 years, 84% were nonsmokers, 64% were women, 73% had adenocarcinoma histology, and 76% were diagnosed with an advanced stage.
Table 1Baseline Characteristics of the Study Population
One patient presented two synchronous lung adenocarcinoma (no. 10; no. 11) with different pathologic and molecular characteristics and stages at diagnosis.
a One patient presented two synchronous lung adenocarcinoma (no. 10; no. 11) with different pathologic and molecular characteristics and stages at diagnosis.
Table 2Clinical, Pathologic, and Molecular Characterization of Patients With Lung Cancer and Germline TP53 Pathogenic Variant (n = 22 Tumors, 21 Patients)
The most common germline TP53 variant was p.R158H (5/22 patients), including three cases in the same family (Supplementary Fig. 1). The p.R248W variant was observed in two unrelated patients, and the p.R196∗ variant was found in one patient with two synchronous lung tumors.
Previous personal and family cancer histories were reported in 71% and 90% of the patients, respectively (Table 1). Breast cancer was the most common cancer type, affecting 67% of women (14/22). Breast (41%), lung (27%), and adrenal (18%) were the most common tumors diagnosed in the families (Table 2) (Supplementary Table 2).
Among patients who had previously developed another cancer, lung cancer was often the second or later event (13/15; 87%) (Fig. 1). The median time that elapsed between the first cancer and the subsequent lung cancer diagnosis was 7 years (range, −3 to 23 y). The most common first tumors identified were breast cancer (9/10) and mesenchymal tumors (3/5) in women and men, respectively. All four patients with breast cancer had HER2 amplification as per available analyses.
Figure 1Timeline of the personal cancer history of germline TP53-mutant cases with lung cancer and at least one additional cancer diagnosis. ∗Carcinoma in situ; Esophag, esophageal cancer; Sarc, sarcoma; Melan, melanoma; GBM, multiforme glioblastoma; H&N, head and neck squamous cell carcinoma.
Molecular screening was performed for 21 tumors, and next-generation sequencing target panel for lung cancer was performed for 12 tumors (Supplementary Table 3). Somatic oncogenic driver alterations were detected in 90% of the tumors (19/21), with 18 cases of somatic EGFR mutation and one case of ROS1 fusion (Supplementary Fig. 2). Two tumors did not harbor any EGFR mutation or other molecular alterations (in one, only EGFR-sensitizing mutations were sequenced), but the fusions were not tested. PI3KCA mutations were concomitantly detected in three EGFR exon 19-deleted tumors (3/11). Three patients belonged to the same family, with two of them harboring an EGFR exon 19 deletion and one an EGFR exon 21 mutation (#appsec1).
Among patients with EGFR-mutant tumors, 14 received an EGFR tyrosine kinase inhibitor (TKI) and 11 were evaluable for survival. Median progression-free survival was 25.9 months (95% confidence interval [CI]: 8.4‒not reached [NR]). With a median follow-up of 56.6 months (95% CI: 31.5–NR), seven patients had disease progression. The mechanisms of acquired resistance are displayed in Supplementary Figure 3. Five tumors developed EGFR-T790M resistance mutation (71%), and one case had SCLC transformation (14%). The emergence of the EGFR-T790M mutation on circulating tumor DNA in case no. 13 is represented in Supplementary Figure 4. The patient detected with the ROS1 fusion received ROS1 TKI (crizotinib) as a second-line therapy, after progression to platinum-based chemotherapy, with partial response as best response; at this moment, the patient is still under crizotinib after 18 months.
The median overall survival was 46.3 months (95% CI: 35.0–NR) in the overall population, and 31.9 months (95% CI: 24.4–NR) in the metastatic EGFR-mutant population (Supplementary Fig. 5A and B).
Discussion
Here, we present the largest series of patients with LFS and lung cancer in which we identified a high rate of targetable oncogenic drivers, most of them EGFR mutations. This is consistent with previously published case reports (Supplementary Table 1). In addition, we report, for the first time, the occurrence of ROS1 fusion in a patient with NSCLC and LFS.
have reported, very recently, a case series of nine patients with lung cancer harboring the known founder germline TP53 p.R337H variant (Supplementary Table 1). Of these nine cases, eight had an EGFR mutation and one had a KRAS mutation (EGFR wildtype, KRAS subtype not described); however, no next-generation sequencing was performed for testing other somatic mutations or fusions. In our cohort, we described one case harboring the germline TP53 p.R337H variant, but no tissue was available for molecular testing.
In never smokers, who are more susceptible to lung cancer with somatic oncogene driver alterations, the reported distribution in Europe of the altered genes is 44% for EGFR, 14% for ALK, and 3% for ROS1.
Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
In contrast, 90% were EGFR-mutant and 5% ROS1-positive in our LFS series. It has been described that breast tumors associated with LFS are enriched in HER2-positive subtype, which is in line with our data.
These observations suggest that the development of tumors in TP53 variant carriers requires somatic driver alterations, with TP53 variants acting not as oncogenic but as permissive events. This oncogenic addiction might be specific of an EGFR and HER2 pathway belonging to the HER family. In this sense, enhanced chromosomal instability has been previously related to EGFR/HER2-driven carcinogenesis in the context of TP53 mutations.
Other epithelial tumors related to LFS should be investigated to check the activation of other HER family protein kinases. Some authors have presented the hypothesis that the oncogenic potential of certain genomic drivers may also be context-dependent, and thus potentially organ-dependent, with early compensatory mechanisms that could moderate the oncogenic potential of the alteration.
In NSCLC with germline TP53 variant and somatic EGFR mutation, a important benefit from EGFR TKI was observed, comparable to the benefit reported in the general population.
In our NSCLC case with germline TP53 variant and somatic ROS1 fusion, we observed similar efficacy to crizotinib, as reported in the ROS1-positive population with unknown LFS status.
More preclinical studies are needed to study the link between germline and somatic driver alterations in the carcinogenesis processes in lung cancer.
To date, no lung cancer risk factors have been identified in patients with LFS. Nevertheless, patients with LFS have a higher risk of developing cancers related to radiation exposure, such as radon gas, considered by the WHO as the second cause of lung cancer and the first in never smokers. Therefore, a study of environmental factors combined with germline predisposition could help to better assess cancer risk and the molecular profile associated in these patients. Although data are limited, it is expected that smoking in patients with LFS might increase the risk of lung cancer even more when compared with those with NSCLC who do not harbor germline TP53 mutations.
Given that metastatic lung cancer conveys high mortality rates, optimizing screening techniques is required to detect lung cancers at earlier stages. The potential predisposition to somatic driver mutations in individuals with LFS could lead to integration of molecular tools in the follow-up, such as circulating tumor DNA, to detect cancer early.
Our study has several limitations including sample size, lack of a systematic comprehensive tumoral somatic molecular screening, particularly for fusion testing, and incomplete clinical-familial data from old cases. Despite these limitations, we observed a clinically relevant association between LFS and driver oncogene mutations in lung cancer, which warrants further studies.
In conclusion, we report a high prevalence of somatic driver oncogenic alterations, mainly EGFR mutations but also the first case of ROS1 fusion associated with LFS, in patients with lung cancers and germline TP53 variants in the largest series of LFS lung cancer reported to date. Our data support the concept of oncogene addiction in TP53 variant carriers and should prompt extensive screening for oncogenic alterations in other LFS tumors.
Acknowledgments
Information Commissioner’s Office grant support: Supported by the Carlos III National Health Institute funded by the Federación Española de Enfermedades Raras (FEDER) funds—a way to build Europe—(PI19/00553; PI16/00563; PI16/01898; and Centros de Investigación Biomédica en Red Cáncer) and the Government of Catalonia (2017SGR448; 2017SGR1282; and 2017SGR496). Ernest Nadal received support from the SLT006/17/00127 grant, funded by the Department of Health of the Generalitat de Catalunya by the call “Acció instrumental d’intensificació de professionals de la salut.” This study has been funded by the Sociedad Española de Oncología Médica through the “Proyectos de Investigación para Grupo Emergente.” We thank the Centers de Recerca de Catalunya Program, Generalitat de Catalunya for their institutional support. Dr. Maria Jové is supported by a Rio Hortega contract (CM17/00008) from the Carlos III Institute. Gustave Roussy: Dr. Laura Mezquita received support from the 2018 International Association for the Study of Lung Cancer Research Fellowship Award, European Society for Medical Oncology Translational Research Fellowship 2019, and Sociedad Española de Oncología Médica Retorno de Investigadores 2019.
Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
Drs. Mezquita and Jové contributed equally to this work.
Disclosure: Dr. Mezquita is sponsored by Bristol-Myers Squibb and Boehringer Ingelheim; has consulting and advisory roles for Roche Diagnostics, Takeda, and Roche; provides lectures and educational activities for Bristol-Myers Squibb, Tecnofarma, and Roche; has travel, accommodations, and expenses funded by Bristol-Myers Squibb and Roche; and provides mentorship program with key opinion leaders funded by AstraZeneca. Dr. Jové has consulting and advisory roles for Boehringer Ingelheim; provides lectures and educational activities for Roche; and has travel, accommodations, and expenses funded by Roche, Takeda, and Bristol-Myers Squibb. Dr. Nadal is sponsored by Roche and Pfizer; has consulting and advisory roles for Bristol-Myers Squibb, Merck Sharp & Dohme (MSD), Roche, AstraZeneca, Eli Lilly, Takeda, Boehringer Ingelheim, Pfizer, Novartis, and Amgen; and has travel, accommodations, and expenses funded by Roche, MSD, and Eli Lilly. Dr. Morán provides lectures and educational activities for Bristol-Myers Squibb, Roche, Eli Lilly, Boehringer Ingelheim, and AstraZeneca. Dr. Léna is funded by AstraZeneca, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Roche, Novartis, and AstraZeneca and has travel accommodations funded by Pfizer, Roche, Pierre Fabre Oncologie, Bristol-Myers Squibb, Amgen, and Takeda. Dr. Teulé is sponsored by Novartis and Innovation for patient care - Ipsen (IPSEN); has consulting and advisory roles for Novartis, IPSEN, Pfizer, and Advanced Accelerator Applications Iberica Sl (ADACAP); and has travel, accommodations, and expenses funded by Novartis, IPSEN, Pfizer, ADACAP, Roche, and AstraZeneca. Dr. Álvarez provides lectures and educational activities for Roche and has travel, accommodations, and expenses funded by Roche and Pfizer. Dr. Auclin has travel and expenses funded by Mundipharma and provides lectures and educational activities for Sanofi Genzymes. Dr. Adam serves on the advisory board of AstraZeneca and Bayer and receives honorarium from MSD and Bristol-Myers Squibb. Mrs. Green is an INIVATA employee and shareholder. Dr. Planchard has consulting and advisory roles or provides lectures for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, CME Peer Review, and Roche; receives honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, CME Peer Review, and Roche; has clinical trial research funded by AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, and Daiichi Sankyo; and has travel, accommodations, and expenses funded by AstraZeneca, Roche, Novartis, prIME Oncology, and Pfizer. Dr. Rouleau has consulting and advisory roles or provides lectures for AstraZeneca, Roche, and Bristol-Myers Squibb. Dr. Lázaro has consulting and advisory roles or provides lectures for AstraZeneca and Roche. Dr. Caron has travel, accommodations, and expenses funded by AstraZeneca and has consulting and advisory roles or provides lectures for AstraZeneca and IPSEN. Prof. Besse is sponsored by the Gustave Roussy Cancer Center, Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, Bristol-Myers Squibb, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, PharmaMar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma. The remaining authors declare no conflict of interest.
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