Research ArticleExperimental Studies

A Rare Presentation of a Non-Asian Female With Metastatic Non-small-cell Lung Cancer Harboring EGFR L747P Mutation With Clinical Response to Multi-targeted Epigenetic and EGFR Inhibition

SAMIA S. MESSEHA, MOHAMMAD A. NEZAMI, STEVEN HAGER and KARAM F.A. SOLIMAN
Anticancer Research January 2022, 42 (1) 441-447; DOI: https://doi.org/10.21873/anticanres.15502

Abstract

Background: Activating mutations of the epidermal growth factor receptor (EGFR) gene have been utilized to predict the effectiveness of EGFR tyrosine kinase inhibitor (TKI) therapy. The most common EGFR mutations are exon 19 deletion and exon 21-point mutation, which are sensitive to EGFR TKI. However, rare/complex EGFR mutations still exist, data of which are scarce and controversial. Hence, their role in response to standard therapy remains uncertain. Case Report: We present the case of a patient diagnosed with stage IV lung adenocarcinoma for whom standard chemotherapies, including platinum agents, had failed. The patient was found to have an EGFR exon 19 (L747P) mutation, as evident in her liquid biopsy. This alteration has not been described before in the literature on non-Asian females. Data from the current case study highlight the aggressive nature of this type of EGFR mutation as indicated by the complete resistance to erlotinib. Using standard first-generation EGFR inhibitors in treating this point mutation was considered inadequate. However, this patient showed a substantial response when treated with erlotinib combined with epigenetic therapies, consisting of DNA methyltransferase and histone deacetylase inhibitors. For more than 8 years, the patient has been responding to combination therapy with a normal quality of life. Conclusion: This case represents a possible novel approach to reducing resistance in patients harboring this rare EGFR mutation which may translate to better outcomes.

Key Words:

In multicellular organisms, the epidermal growth factor (EGF) family of receptor tyrosine kinases maintains homeostasis by regulating cell proliferation, differentiation, and migration (1). EGF receptors (EGFR) regulate intrinsic tyrosine kinase function (2). The seven growth factor ligands that characterize EGFR (also known as ERBB1 and HER1) are EGF, heparin-binding interleukin, transforming growth factor-α, amphiregulin, betacellulin, epigen, and epiregulin (2). During resting conditions, EGFR exists in an auto-inhibited form. The formation of an asymmetric dimer of kinase domains enhances the activation of this receptor (3). Oncogenic EGFR and its ligands have been implicated in multiple aspects of tumor progression (4) for maintaining cell growth, resisting cell death, and reconstituting the metabolic networks. The active role of EGFR in metastasis has recently attracted attention, and various studies have shed light on the involvement of EGFR and its ligands in cancer progression (2, 4).

In the United States, lung cancer (LC) is the leading cause of cancer-related death (5). Non-small cell lung cancer (NSCLC) accounts for almost 80% of all LC cases diagnosed (6). Mutations in the gene encoding EGFR (7, 8), the important driving event in the growth of NSCLC (9), were found in 10-28% of patients with NSCLC; however, NSCLC is very common in non-smoker patients. The presence of EGFR gene mutation predicts the sensitivity of NSCLC to various EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, or afatinib (6, 8, 10-12). Mutations of the EGFR gene are mainly exhibited in exons 18-21 (13). According to relevant studies, exon 21-point mutation, L858R mutation, and exon 19 deletion account for 85% of all EGFR alterations (11-14). However, rare EGFR mutations linked to gene sequencing also exist (10, 15). The prevalence of EGFR mutations varies among different populations, with ~10-12% of Caucasian patients with LC expressing mutated EGFR, while the proportion is increased to 40% in East Asians, especially in pathologically diagnosed lung adenocarcinoma and non-smoking women. Moreover, it is known that Asians are more sensitive to EGFR-TKIs as compared to their Caucasian counterparts (2, 6).

Compared with traditional platinum-containing chemotherapy, patients with NSCLC with specific EGFR-sensitive mutations showed higher clinical response to EGFR-TKIs, as confirmed by a series of phase III clinical trials WJTOG3405 (16), OPTIMAL (17), and LUXLUNG6 (18). Still, the overall survival rate among patients with the most perturbed targets (typical exon 21 deletions) does not exceed 3 years. Nevertheless, three EGFR mutations (Gly719Xaa, Leu861Gln, and Ser768Ile) conferred an excellent response to the second generation of EGFR-TKIs. Treatment responses associated with other mutations have not been identified (19, 20). Hence, more studies are needed to explore therapeutic outcomes, specifically in the case of EGFR L747P mutations, since the current standard care is certainly challenging in finding a treatment with predictable, sustained results (21-25). While there have been significant efforts in trying different targeted drugs from the first to the second generation, we present a case that represents a resistant tumor type with expected poor outcomes, regardless of the drug used for this category of patients (26-28).

Case Report

According to the regional legislation and the principles of the declaration of Helsinki, an official written consent form was obtained from the patient. Treatment was also given following the standards of good clinical practice and compassionate basis. Three drugs were prescribed: Erlotinib at 25 mg on day 1 and thereafter increased to 50 mg/day, afatinib at 20 mg/day, and osimertinib at 40 mg once a day. The selected epigenetic therapies (ET), a combination of flavonoid and phenylbutyrate, were injected intravenously.

A 57-year-old non-Asian female was diagnosed in August 2013 with oligometastatic NSCLC. During the period from November 2013 to January 2014, the patient went through a series of treatments, including right middle lobectomy/radiation for stage 1 adenocarcinoma (T1, N0, and M0), stereotactic radiation to a paraspinal mass, and four cycles of chemotherapy, consisting of carboplatinum and Alimta. Despite these therapies, the disease had progressed, as evidenced in her positron-emission tomography (PET) scan before her referral on 16th December 2014. Initial evaluation revealed lactate dehydrogenase had increased to 280 IU. Furthermore, Biofocus Laboratory (Recklinghausen, Germany) confirmed the presence of circulating tumor cells, in addition to mRNA positivity for the oncogene protein MYC proto-oncogene bHLH transcription factor (MYC), and histone deacetylase (HDAC). Immediately, the patient was started ET on a daily basis, five times/week. Interestingly, the patient was asymptomatic through the treatment, except for the expected feeling of nausea. By the end of the first 2-week course, a significant drop in lactate dehydrogenase was found from 280 to a normal level of 216 IU. Meanwhile, the patient did not change her diet nor receive any other conventional or alternative therapies. Furthermore, measuring the circulating tumor cells after 2 weeks of therapy (10 treatments) showed complete eradication of this biomarker (first sample on 15th January 2015 and the second on 15th February 2015, as shown in (Table I).

View this table:
Table I.

Results of the evaluation of molecular markers for circulating tumor cells at initial presentation before and after a 2-week course of therapy.

ET showed a clinically promising outcome regarding the eradication of CTCs and normalized cMyc and HDAC markers. Combining targeted EGFR-inhibitory drugs with ET was initiated, and she received erlotinib on 5th April 2015 at 25 mg/day. Erlotinib was subsequently given at a lower dose (less than 25-50 mg/day) to avoid the synergistic effects of combining epigenetic protocol, targeting heat-shock protein 27 and chaperone molecules related to the EGFR target. On 20th April 2015, she was restaged with another PET/computed tomography, which showed a significant response to the therapy, resolution of hilar lymph nodes, along with a significant decrease in both size and activity of all pulmonary lesions/nodules and lymph nodes. In addition, there was a significant drop in the PET/computed tomography standardized uptake value (SUV) from 8 to 2.0. All the samples of her circulating DNA (cDNA) evidenced the positive response to EGFR-inhibitory drugs in addition to ET (12th June 2015), with the disappearance of R507G and P512S mutations of BRCA2 DNA repair associated (BRCA2) from cDNA.

By July 10th, 2015, the patient had returned home and was unable to receive further ET. Analysis of her cDNA showed disease recurrence with mutated allele frequency (MAF) of 73% on July 10, 2018, as a sign of resistance to erlotinib. Due to difficulty traveling, the patient preferred to continue her therapy by receiving an EGFR inhibitor alone; she then received osimertinib instead of erlotinib for 3 years, which showed a promising outcome. Unfortunately, by July/2020, osimertinib caused an increase in her cDNA, which necessitated another switch to afatinib. The MAF increased to 57%; her tumor had progressed in PET scan, with evidence of increased SUV and size of diffuse metastatic lesions when measured in July 2020.

Again, the patient was referred to us in July 2020 and received localized radiation to the pulmonary lesions, however, without noticeable recovery at this time. The progressive disease was evident by fluorodeoxyglucose-avid mediastinal and axillary nodes, a paratracheal node with SUV of 4.3 increased from background activity, left lower lobe node with an SUV of 5.8 (2.1×1.2 cm) from no activity, and left upper lobe node with an SUV of 4.5 from not active. During this time, the patient was treated with osimertinib (Tagrisso) at 80 mg/day. Immediately, the patient was placed on an ET protocol after her initial laboratory tests revealed increased tumor markers and liquid biopsy confirming the increased MAF. Upon completing her predesigned course of therapy, the laboratory results showed a substantial decrease in carcinoembryonic antigen from 16 to 10.5 ng/ml when measured on the 19th and 20th of August 2020, respectively. Her MAF on cDNA dropped dramatically from 73.8% in July 2018 to 3.9% in July 2020 (Table II), then declined to 0.7% on the 28th of October 2020.

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Table II.

The circulating DNA (cDNA) profile of the patient after treatment with osimertinib (Tagrisso) at 80 mg/day in addition to the epigenetic therapy protocol. Upon completing her predesigned course of therapy, the laboratory results showed that the mutated allele frequency for cDNA dropped dramatically from 73.8% to 3.9%.

The patient was restaged with a PET scan which showed response to the interim therapy, with reduced sizes and metabolic activities of all metastatic disease. For example, the SUV of the left lower lobe lesion dropped from 4.5 to 1.7, that of the pericardial lymph node dropped from 9.6 to 8.5, and that of the cephalad node dropped from 11.9 to 7.7. Furthermore, the axillary and mediastinal nodes were resolved. Unfortunately, the patient’s decision to taper ET to once a month and receive afatinib alone led to another episode of disease progression, as evidenced by her cDNA and scan. Moreover, a core biopsy of the supraclavicular lymph node had shown positive uptake in the PET scan when she was treated with afatinib.

The growth of this lymph node was suggested to represent treatment resistance, and biopsy confirmed lung adenocarcinoma. Furthermore, molecular profiling and analysis of the tissue, performed by the Foundation Laboratory (Sahel Oncology, Orange Coast Medical Center of Hope, Newport Beach, CA, USA) on June 16th, 2021, showed amplification of EGFR L747P as well as amplification of cyclin E1 (CCNE1), AKT serine/threonine kinase 2 (AKT2), activating mutation of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) E81K, retinoblastoma1 (RB1) loss, tumor protein P53 (TP53) mutation, alpha-thalassemia/mental retardation, X-linked (ATRX) mutation and tuberous sclerosis 1 (TSC1) splice site. The presence of ATRX mutation denoted a possible advantage from HDAC inhibitors; likewise, demethylation might have been a mediator in RB1 loss.

Consequently, afatinib was stopped, and the patient decided to re-start ET, along with dacomitinib at 45 mg/day on a 5-days on/off schedule. The scheduled dose was selected based on her reported side-effects from prior EGFR inhibitors and previous literature for cases with uncommon EGFR-mutated LC (17). Previous literature (29) supported our choice of perphenazine treatment prescribed upon her arrival in April 2021, suggesting its promising role in reversing drug resistance. The patient was receiving ET daily, four times/week for 6 weeks. Upon completing the treatment protocol, laboratory investigations were conducted on April 23rd, 2021 (Table III) and June 15th, 2021. The obtained results confirmed the profound reduction of both carcinoembryonic antigen (from 17 to 11.4 ng/ml) and transforming growth factor β1 from 9,498 to 6,749 pg/mg. The level of the prognostic marker in lung cancer, CYFRA 21.1 (normally less than 2.3 ng/ml), also dropped from 2.9 ng/ml on 3rd May 2021 to 2.0 ng/ml on July 22nd, 2021. On June 14th, 2021, her cDNA investigation showed a dramatic response compared with the results obtained on April 23rd, 2021. The significant reduction of cDNA MAF for mutant EGFR from 57% to 1.2% was also noted. Various alterations, such as those of CCNE1, TP53, PI3KCA, cyclin-dependent kinase 6 (CDK6), and BRCA1/2 DNA repair associated (BRCA1/2) had also disappeared.

View this table:
Table III.

Circulating DNA (cDNA) profile before re-initiation of therapy and analysis of tissue.

The patient was restaged on 16th July 2021 with PET/computed tomography, which confirmed the positive response to therapy with resolution of several metastatic sites and significant response in both size and metabolic activities. For example, right lower cervical and supraclavicular lymph nodes had improved. Remarkable shrinkage in nodal size was detected, in addition to the reduced SUV activity, from 4.7 to 1.6 in level 5 nodes and 10.7 to 5.0 in the right lower paratracheal node. Interval resolution of sub-centimeter in fluorodeoxyglucose-avid right hilar nodes, along with several pulmonary nodules, were also reported to have decreased in size and activity; for instance, the SUV decreased from 10.6 to 5.4 in left lung nodes. Surprisingly, the previously measured SUV of 10.9 in the subcarinal lymph node was resolved entirely.

Discussion

DNA methylation and histone alterations that regulate gene transcription play an essential role in cancer (30, 31). Furthermore, studying cDNA has become a tool for monitoring therapy response in patients with LC with actionable targets. Recently, our team has shown the correlation between MAFs and the response to the therapy in a series of 374 cases of longitudinal liquid biopsy assays (32). Here, we reported a patient with stage 4 chemoresistant lung adenocarcinoma with a rare EGFR L747P mutation. In parallel with other EGFR mutations, this uncommon mutation drives oncogenesis (32). At the same time, limited and controversial literature revealed diverse responses to EGFR-TKI therapy among patients with lung adenocarcinoma harboring rare EGFR L747P mutation (32, 33). Hence more studies are suggested to shed light on the precise mechanism of these agents.

Patients with c19 deletion-EGFR mutations have shown an extended response to TKI therapy (8, 12, 34); however, progression-free survival infrequently exceeds 12 months, in addition to varying degrees of side-effects, such as diarrhea, fatigue, pneumonitis, and rash, associated with receiving the standard doses. The aggressive nature of this rare type of mutation is evidenced by its profound resistance to erlotinib (35). One mechanism suggested concerning resistance is methylation of the target, which has been investigated in LC (31) and other types of cancer, such as colorectal cancer (36). Epigenetic modifiers, including hypomethylating agents, HDAC inhibitors, microRNA modulators, and decitabine, act as demethylators of EGFR to reverse this resistance. Other mechanisms of resistance include chaperon molecules such as HSP, and again the combination of HSP inhibitors with EGFR targeted drugs had been emphasized in the literature, and a series of HSP90 inhibitors have been investigated as effective molecular-targeted therapy tactics against LC (37, 38).

Recently, extensive studies have positioned HDAC and DNA methyltransferase (DNMT) inhibitors as potential anticancer agents (39-42). Indeed, HDAC inhibitors increase histone acetylation and enhance expression of specific genes, mediating apoptosis and growth arrest (43). On the other hand, DNMT inhibitors have been paid specific attention due to their unique mechanism for activating tumor-suppressor genes (42). The combination of DNMT/HDAC inhibitors with other traditional therapeutic agents is highly recommended as a promising molecular-targeted therapeutic regimen (40, 44). Others reported the combination of DNMT and HDAC to induce an apoptotic effect in various cancer models, including LC (39, 41, 42).

ET has shown an excellent therapeutic outcome in treating patients with various types of cancer in many clinical trials (40, 45, 46). However, more drugs and combined therapies still need to be investigated. Although only a single case, co-treating our patient with ET and low-dose EGFR-targeted treatment had achieved a remarkable progression-free survival with maximum quality of life for more than 8 years, without experiencing any severe side-effects. Compared to the standard of care protocols, the therapeutic outcome in this study sheds light on the value of treating such patients with ET in conjunction with different EGFR inhibitors.

Conclusion

To our knowledge, this case is the first report of a rare EGFR mutation traditionally reported as a type of disease resistant to standard EGFR inhibitors. Combined epigenetic and biological response modifiers with targeted therapies might be feasible and effective in patients with rare EGFR mutations where targeted drugs alone generally fail. Figure 1 summarizes the proposed mechanisms associated with the treatment of NSCLC with EGFR L747P mutation. This report can generate interest in establishing further randomized control trials to prove the concept and ultimately provide a therapy approach with meaningful survival benefit to patients with advanced NSCLC.

Figure 1.
Figure 1.

Summary of the therapy sequence of a patient with non-small cell lung cancer with epidermal growth factor receptor (EGFR) L747P mutation.

Acknowledgements

This research was partially funded by an NIH grant from the National Institute on Minority Health and Health Disparities (NIMHD), U54 MD007582.

Footnotes

  • Authors’ Contributions

    Conceptualization, methodology, and validation, MN, and SH; writing MN, SH, KFAS, and SSM; review and editing, KFAS, SM, MN, and SH. All Authors have read and agreed to the published version of the article.

  • Conflicts of Interest

    The Authors declare no conflicts of interest.

  • Received September 29, 2021.
  • Revision received October 27, 2021.
  • Accepted November 13, 2021.

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A Rare Presentation of a Non-Asian Female With Metastatic Non-small-cell Lung Cancer Harboring EGFR L747P Mutation With Clinical Response to Multi-targeted Epigenetic and EGFR Inhibition
SAMIA S. MESSEHA, MOHAMMAD A. NEZAMI, STEVEN HAGER, KARAM F.A. SOLIMAN
Anticancer Research Jan 2022, 42 (1) 441-447; DOI: 10.21873/anticanres.15502
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