EGFR-mutated lung cancer as a secondary neoplasm in a patient with Li-Fraumeni syndrome: case report

Introduction

In 1969, while working at the National Cancer Institute, Dr. Frederick Li and Dr. Joseph Fraumeni described four families with numerous early-onset malignancies in young adults and children (1). In 1990, a multi-institutional research team headed by Drs. Stephen Friend and David Malkin discovered inherited germline mutations of tumor protein p53 (TP53) as the primary cause of Li-Fraumeni syndrome (LFS) (2).

LFS is a rare inherited disorder caused by mutations in the TP53. It is an autosomal dominant disease that causes a predisposition for the development of multiple malignancies, primarily including breast cancers, sarcomas, central nervous system tumors, adrenocortical carcinomas, and osteosarcomas (3). It has been suggested that there may be a link between the TP53 mutation and lung cancer with epidermal growth factor receptor (EGFR) mutation. However, despite advancing knowledge about LFS, we still lack literature concerning the association between EGFR lung cancers and TP53 pathways (4,5). Here, we present a case of a woman with EGFR lung adenocarcinoma in an LFS patient with multiple previous malignancies in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-23-206/rc).

Case presentation

A 47-year-old non-smoker woman with a confirmed diagnosis of LFS by a hereditary genetic panel that identified a variant of the TP53 gene c.771_782+13del in a heterozygous state. She has a significant family history that revealed a high occurrence of neoplasms at a young age. Her mother was diagnosed with leukemia at age 36 years, her maternal grandmother with breast cancer at age 47 years, and other relatives on her mother’s side were also affected: her female cousin with sarcoma in her adolescence and breast cancer at 26 years, her uncle with sarcoma at 60 years, and her male cousin with sarcoma at age 51 years. With her personal and family history, the patient meets the classical clinical criteria of LFS. Nevertheless, the patient had no family history of lung cancer.

Her extensive pathological background began in when she was 28 years, with human epidermal growth factor 2 positive (HER2⁺) bilateral breast cancer treated with bilateral mastectomy, and AC chemotherapy (doxorubicin, hydrochloride and cyclophosphamide). Herceptin adjuvant (HERA) protocol was available at our hospital, but she refused this treatment. At the age of 38 years, a perivascular epithelioid cell tumor (pecoma) in her liver was detected, for which she underwent a partial hepatectomy in January 2014. Five months later, two more malignancies were detected: a grade three pleomorphic spindle cell sarcoma in her right thigh and a grade three infiltrating ductal carcinoma (IDC) in the right breast. She was treated with resection of the sarcoma with adjuvant radiotherapy and mastectomy of the right breast, TCH regimen (docetaxel, carboplatin, and trastuzumab) for 1 year and tamoxifen for 5 years. The involvement of radiotherapy for the sarcoma was decided through a multidisciplinary team due to its size, depth, and grade.

At the age of 44 years, she presented three recurrent pleomorphic sarcoma lesions of the right thigh that were subsequently resected. A full body computed tomography scan performed as a follow-up surveillance of the sarcomas detected a 1.4 cm nodule in the lung’s lingula when she was 46 years. She was not undergoing Toronto protocol screening due to lack of resources in the institution. The patient denied the presence of any symptomology. There were no evident abnormalities in the physical examination. A biopsy was performed, which led to the diagnosis of lung adenocarcinoma (Figure 1). Further genetic testing detected a deletion of EGFR exon 19. She was treated with a left inferior lobectomy, followed by pemetrexed and cisplatin. Mutation analysis in peripheral lymphocytes was also performed, and EGFR mutations were not detected. The patient had a good response to treatment and is currently free of relapse 2 years after treatment.

Figure 1 Infiltrating adenocarcinoma with lepidic and acinar pattern (hematoxylin and eosin stain, ×10). Source: Pathology Service of National Oncologic Institute, Panama.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying image. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

We report a case of a non-smoker woman with LFS detected with an EGFR-mutated lung cancer. There are currently very few cases reported in the literature (Table 1) that involve this condition together, and even fewer cases of patients with such an extensive background of previous tumors.

The TP53 gene is located on chromosome 17p13.1. In the absence or malfunction of the standard TP53 protein, cells with defective deoxyribonucleic acid (DNA) do not go through repair or apoptosis, which leads to a predisposition to malignant cell formation (6). EGFR is a transmembrane protein that, upon ligand binding, increases intracellular activity through tyrosine kinase activity that through phosphorylation activates pathways related to phospholipase C-y, mitogen-activated protein kinase (MAPK) and the ras GTPase-activating protein (GAP) that promote cell proliferation.

Wild-type p53 (TP53) binds to the EGFR promoter region, increasing its activity. Similarly, the tumor-associated mutant transcription factor p53 also binds to the EGFR promoter but at a different site than wild-type p53, resulting in dysregulation of this receptor and increased cell proliferation and mutational load that may contribute to carcinogenesis (6). Also, lung cancer cell line studies have suggested that lung cancer cells with TP53 mutations overexpress EGFR, leading to tumor formation (5).

The TP53 gene has different variations, including NM_000546.6, due to alternative promoters and splicing. It is located on the negative strand of chromosome chr17 and covers 19,070 base pairs, including introns, at position 7668421 (14). The messenger ribonucleic acid (mRNA) resulting from transcription and splicing has 2,512 bases, with only 1,182 translated into a protein. Alternative isoforms can arise from exon 7 of 11 position 99 of 110 to intron 7 of 10 position 13 of 343 (splicing, splicing, intronic, coding), where identical transcript variants have alternative translation start codons (15).

Loss of function is a disease mechanism that affects this gene, and there are 540 reported ClinVar null pathogenic variants in ten different exons, with 56 variants in exon 7. The genome aggregation database (gnomAD) observed/expected score for these variants is 0.449. The coding chain is on the reverse chain, and exon skipping can lead to altered reading frames. ClinGen has assigned the Null classification as a loss-of-function mechanism for ten exons, including exon 6. The skipped exon is a crucial region for the protein’s function and has several pathogenic missense variants (16).

In the case presented, EGFR mutation was only identified in malignant cells in the lung since peripheral blood tests were also performed, and this mutation was not found. This opens a hypothesis that TP53 mutations in LFS may contribute to developing somatic EGFR mutations, which results in EGFR-mutant lung cancer. According to an international project led by the Clinical Lung Cancer Genome Project, tumoral somatic TP53 mutations and EGFR mutations co-occurrence have been found in 34% of lung adenocarcinomas (17).

Most of the reported cases of patients who have lung cancer with EGFR mutation and mutated TP53 LFS have been women, many without smoking history (4). Our case supports this tendency, as shown in the reported cases shown in Table 1. But this is yet to be supported by studies that include a representative sample of all individuals with LFS.

Lopes et al. published the largest cohort of lung cancer patients with the TP53 R337H mutation (28 patients), representing 16% of the 175 cases with tumors diagnosed in the Brazilian Li-Fraumeni Syndrome Study (BLISS) database, among these cases 14 were presented EGFR alterations located in the exon 19. In this research, lung adenocarcinoma was the first neoplasm diagnosed in 78.6% of the cases, reinforcing the hypothesis of potential interactions between the TP53 R337H variant and the ERBB family for the carcinogenesis of lung adenocarcinoma. Thus, proposing that lung cancer may be the first manifestation of LFS in non-smoking women over 50 years of age (18). This pattern was described by Barbosa et al. where in their case series 4 of 9 patients presented lung cancer as the first neoplasm diagnosed. In these tumors, 89% frequency of EGFR activating mutations was identified (19). Results published by Mezquita et al. in patients with non-small cell lung cancer (NSCLC) and pathogenic germline TP53 variant where molecular screening was performed in 21 tumors, somatic oncogenic alterations were detected in 90% of the tumors (19/21), with 18 cases of somatic mutation of the EGFR gene (20). In a single-institution case series, of 91 patients in the LFS cohort, 6.6% (6 patients) were diagnosed with lung cancer. All diagnosed cases were stage I–III adenocarcinomas, 80% of the patients had never smoked, 60% were women, and the mean age at diagnosis was 48 years. A significant proportion of these patients had other cancer diagnoses, and none had received previous thoracic irradiation treatment. Genetic analysis revealed that 40% of the patients had common EGFR mutations (21).

Currently, EGFR tyrosine kinase inhibitors (TKIs) are considered the first line of treatment for patients with NSCLC with EGFR mutations; they have demonstrated high efficacy and tolerability. There are three generations of EGFR-TKIs, but the preferred choice for patients with advanced or metastatic NSCLC is osimertinib, a potent third-generation irreversible inhibitor (22). In the case of our patient, she was not treated with Osimertinib due to unavailability in our institution, and a surgical approach was opted for.

This patient was treated with radiotherapy for her sarcoma. Even though use of radiation is typically avoided in patients with LFS, some studies have shown that the frequency of radiotherapy-related malignancies is lower than reported in the literature. Hendrickson conducted a study evaluating forty patients with LFS who received radiotherapy with curative intent where 4 (10%) developed malignancies following radiotherapy. Still, none can be stipulated to be associated with radiotherapy because they have the same histology as the primary tumor, suggesting a local recurrence. The authors comment that radiotherapy can be considered part of the treatment after a multidisciplinary discussion and when clinically indicated (23). Another retrospective study by Le et al. identified 51 patients diagnosed with breast cancer and LFS, 27 of these patients received adjuvant radiotherapy in the curative setting, of all patients 1 (6%) developed thyroid cancer and 1 (6%) developed sarcoma in the radiation field. Despite the potential risk of inducing sarcomas and other secondary cancers, the benefits of radiotherapy in reducing the risk of recurrence and improving overall survival outweighs the risk (24).

This case is another example of LFS with EGFR-mutated lung cancer. Further research should be carried out in search of the possible association between these two pathologies and, thus, evaluate the risk posed by LFS for the development of EGFR-mutated lung cancer.

Conclusions

This specific type of lung cancer has been understudied in the LFS spectrum. The complex interconnection between LFS and EGFR-mutant lung cancer represents an area that has received insufficient exploration in current research endeavors. The lack of in-depth investigation into this particular subtype amidst the broader spectrum of LFS and emphasizes the imperative need for forthcoming studies.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-23-206/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-23-206/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-23-206/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying image. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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