The Relationships Between Radiation Dosage and Long-term Swallowing Kinematics and Timing in Nasopharyngeal Carcinoma Survivors.

This study aimed to investigate the relationship between intensity-modulated radiation therapy (IMRT) dosimetry and swallowing kinematic and timing measures. Thirteen kinematic and timing measures of swallowing from videofluoroscopic analysis were used as outcome measures to reflect swallowing function. IMRT dosimetry was accessed for thirteen swallowing-related structures. A cohort of 44 nasopharyngeal carcinoma (NPC) survivors at least 3 years post-IMRT were recruited. The cohort had a mean age of 53.2 ± 11.9 years, 77.3% of whom were male. There was an average of 68.24 ± 14.15 months since end of IMRT; 41 (93.2%) had undergone concurrent chemotherapy. For displacement measures, female sex and higher doses to the cricopharyngeus, glottic larynx, and base of tongue were associated with reduced hyolaryngeal excursion and pharyngeal constriction, and more residue. For timing measures, higher dose to the genioglossus was associated with reduced processing time at all stages of the swallow. The inferior pharyngeal constrictor emerged with a distinctly different pattern of association with mean radiation dosage compared to other structures. Greater changes to swallowing kinematics and timing were observed for pudding thick consistency than thin liquid. Increasing radiation dosage to swallowing-related structures is associated with reduced swallowing kinematics. However, not all structures are affected the same way, therefore organ sparing during treatment planning for IMRT needs to consider function rather than focusing on select muscles. Dose-response relationships should be investigated with a comprehensive set of swallowing structures to capture the holistic process of swallowing.

Molecular subtyping of cancer: current status and moving toward clinical applications.

Cancer is a collection of genetic diseases, with large phenotypic differences and genetic heterogeneity between different types of cancers and even within the same cancer type. Recent advances in genome-wide profiling provide an opportunity to investigate global molecular changes during the development and progression of cancer. Meanwhile, numerous statistical and machine learning algorithms have been designed for the processing and interpretation of high-throughput molecular data. Molecular subtyping studies have allowed the allocation of cancer into homogeneous groups that are considered to harbor similar molecular and clinical characteristics. Furthermore, this has helped researchers to identify both actionable targets for drug design as well as biomarkers for response prediction. In this review, we introduce five frequently applied techniques for generating molecular data, which are microarray, RNA sequencing, quantitative polymerase chain reaction, NanoString and tissue microarray. Commonly used molecular data for cancer subtyping and clinical applications are discussed. Next, we summarize a workflow for molecular subtyping of cancer, including data preprocessing, cluster analysis, supervised classification and subtype characterizations. Finally, we identify and describe four major challenges in the molecular subtyping of cancer that may preclude clinical implementation. We suggest that standardized methods should be established to help identify intrinsic subgroup signatures and build robust classifiers that pave the way toward stratified treatment of cancer patients.

Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Few studies have been conducted to compare the efficacies of stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA). Thus, in this multinational study, we compared the effectiveness of SBRT and RFA in patients with unresectable HCC. METHODS: The retrospective study cohort included 2,064 patients treated in 7 hospitals: 1,568 and 496 in the RFA and SBRT groups, respectively. More than half of the patients (56.5%) developed recurrent tumors, mainly after transarterial chemoembolization (44.8%). Propensity score matching was performed to adjust for clinical factors (n = 313 in each group). RESULTS: At baseline, the SBRT group had unfavorable clinical features compared to the RFA group, including BCLC stage (B-C 65% vs. 16%), tumor size (median 3.0 cm vs. 1.9 cm), and frequent history of liver-directed treatment (81% vs. 49%, all p <0.001). With a median follow-up of 27.7 months, the 3-year cumulative local recurrence rates in the SBRT and RFA groups were 21.2% and 27.9%, respectively (p <0.001). After adjusting for clinical factors, SBRT was related to a significantly lower risk of local recurrence than RFA in both the entire (hazard ratio [HR] 0.45, p <0.001) and matched (HR 0.36, p <0.001) cohorts. In subgroup analysis, SBRT was associated with superior local control in small tumors (≤3 cm) irrespective of location, large tumors located in the subphrenic region, and those that progressed after transarterial chemoembolization. Acute grade ≥3 toxicities occurred in 1.6% and 2.6% of the SBRT and RFA patients, respectively (p = 0.268). CONCLUSIONS: SBRT could be an effective alternative to RFA for unresectable HCC, particularly for larger tumors (>3 cm) in a subphrenic location and tumors that have progressed after transarterial chemoembolization. LAY SUMMARY: It is currently not known what the best treatment option is for patients with unresectable hepatocellular carcinoma. Here, we show that stereotactic body radiation therapy provides better local control than radiofrequency ablation, with comparable toxicities. Stereotactic body radiation therapy appears to be an effective alternative to radiofrequency ablation that should be considered when there is a higher risk of local recurrence or toxicity after radiofrequency ablation.

Prediction of sensitivity to gefitinib/erlotinib for EGFR mutations in NSCLC based on structural interaction fingerprints and multilinear principal component analysis.

BACKGROUND: Non-small cell lung cancer (NSCLC) with activating EGFR mutations, especially exon 19 deletions and the L858R point mutation, is particularly responsive to gefitinib and erlotinib. However, the sensitivity varies for less common and rare EGFR mutations. There are various explanations for the low sensitivity of EGFR exon 20 insertions and the exon 20 T790 M point mutation to gefitinib/erlotinib. However, few studies discuss, from a structural perspective, why less common mutations, like G719X and L861Q, have moderate sensitivity to gefitinib/erlotinib. RESULTS: To decode the drug sensitivity/selectivity of EGFR mutants, it is important to analyze the interaction between EGFR mutants and EGFR inhibitors. In this paper, the 30 most common EGFR mutants were selected and the technique of protein-ligand interaction fingerprint (IFP) was applied to analyze and compare the binding modes of EGFR mutant-gefitinib/erlotinib complexes. Molecular dynamics simulations were employed to obtain the dynamic trajectory and a matrix of IFPs for each EGFR mutant-inhibitor complex. Multilinear Principal Component Analysis (MPCA) was applied for dimensionality reduction and feature selection. The selected features were further analyzed for use as a drug sensitivity predictor. The results showed that the accuracy of prediction of drug sensitivity was very high for both gefitinib and erlotinib. Targeted Projection Pursuit (TPP) was used to show that the data points can be easily separated based on their sensitivities to gefetinib/erlotinib. CONCLUSIONS: We can conclude that the IFP features of EGFR mutant-TKI complexes and the MPCA-based tensor object feature extraction are useful to predict the drug sensitivity of EGFR mutants. The findings provide new insights for studying and predicting drug resistance/sensitivity of EGFR mutations in NSCLC and can be beneficial to the design of future targeted therapies and innovative drug discovery.

Long-term outcomes and recurrence pattern of 18F-FDG PET-CT complete metabolic response in the first-line treatment of metastatic colorectal cancer: a lesion-based and patient-based analysis.

BACKGROUND: 18F-FDG PET-CT is commonly used to monitor treatment response in patients with metastatic colorectal cancer (mCRC). With improvement in systemic therapy, complete metabolic response (CMR) is increasingly encountered but its clinical significance is undefined. The study examined the long-term outcomes and recurrence patterns in these patients. METHODS: Consecutive patients with mCRC who achieved CMR on PET-CT during first-line systemic therapy were retrospectively analysed. Measurable and non-measurable lesions identified on baseline PET-CT were compared with Response Criteria in Solid Tumors (RECIST) on CT on a per-lesion basis. Progression free (PFS) and Overall Survival (OS) were compared with clinical parameters and treatment characteristics on a per-patient basis. RESULTS: Between 2008 and 2011, 40 patients with 192 serial PET-CT scans were eligible for analysis involving 44 measurable and 38 non-measurable lesions in 59 metastatic sites. On a per-lesion basis, 46% also achieved Complete Response (CR) on RECIST criteria and sustained CMR was more frequent in these lesions (OR 1.727, p = 0.0031). Progressive metabolic disease (PMD) was seen in 12% of lesions, with liver metastasis the most common. Receiver operating characteristics (ROC) curve analysis revealed the optimal value of SUVmax for predicting PMD of a lesion was 4.4 (AUC 0.734, p = 0.004). On a per-patient basis, 14 patients achieved sustained CMR and their outcomes were better than those with PMD (median OS not reached vs 37.7 months p = 0.0001). No statistical difference was seen in OS between patients who achieved PR or CR (median OS 51.4 vs 44.2 months p = 0.766). CONCLUSION: Our results provided additional information of long-term outcomes and recurrence patterns of patients with mCRC after achieving CMR. They had improved survival and sustained CMR using systemic therapy alone is possible. Discordance between morphological and metabolic response was consistent with reported literature but in the presence of CMR the two groups had comparable outcomes.

Head and neck cancer in Hong Kong.

Head and neck cancer is a major cause of morbidity and mortality in Hong Kong. HNC is well-known for its heterogeneity in epidemiology, clinical behavior, clinic-pathological features and patient characteristics. Treatment strategies for this heterogeneous disease vary greatly in different parts of the world, depending on availability of resources, local expertise and experience. Extensive research in head and neck cancer, particularly nasopharyngeal carcinoma, has been conducted in Hong Kong in the past few decades. In this article, we will review the available local evidence and summarize common practice in management of head and neck cancer in Hong Kong.

Hyperfractionation compared to standard fractionation in intensity-modulated radiation therapy for patients with locally advanced recurrent nasopharyngeal carcinoma.

We prospectively studied the efficacy and safety of hyperfractionated intensity-modulated radiation therapy (HF-IMRT) and compared to a historical cohort treated with standard fractionation (SF-IMRT) in patients with locally advanced recurrent (rT3-T4, rN0-N1, M0) nasopharyngeal carcinoma (NPC). Ten patients were treated with induction chemotherapy followed by HF-IMRT (64.8 Gy/54 fr/5.5 weeks) concurrent with weekly cisplatin. They were compared to another ten patients treated with induction chemotherapy followed by SF-IMRT (60 Gy/30 fr/6 weeks) concurrent with weekly cisplatin. After a median follow-up duration of 44.6 months, we demonstrated that the median local failure-free survival (LFFS) showed a trend in favor of HF-IMRT (28.2 vs. 16.6 months, p = 0.164). Overall survival (OS) (34.8 vs. 35.5 months, p = 0.603) was not different between the two groups. Treatment-related hemorrhage was slightly less with HF-IMRT (30.0 vs. 0 %), reaching marginal significance (p = 0.060). Judging from our study results, HF-IMRT offered a marginally better LFFS and an apparently more favorable toxicity profile compared to SF-IMRT in locally advanced recurrent NPC.

Efficacy and safety of afatinib in Chinese patients with EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) previously responsive to first-generation tyrosine-kinase inhibitors (TKI) and chemotherapy: comparison with historical cohort using erlotinib.

BACKGROUND: Afaitnib has shown anti-tumor activity against metastatic EGFR-mutated NSCLC after prior failure to first generation EGFR-TKI and chemotherapy. We prospectively evaluated the efficacy and safety of afatinib in Chinese patients who previously failed first-generation TKI and chemotherapy under a compassionate use program (CUP) and compared to the erlotinib cohort. METHODS: Patients who suffered from metastatic EGFR-mutated NSCLC previously responsive to first-generation TKI and chemotherapy received afatinib until progression, loss of clinical benefits or intolerable toxicity. Treatment response, survival and safety were evaluated and compared to the erlotinib cohort. RESULTS: Twenty-five and 28 patients received afatinib and erlotinib respectively. More patients in the afatinib group had worse performance status (ECOG 2) than the erlotinib group (p = 0.008). After a median follow-up of 12.1 months, afatinib demonstrated comparable objective response rate (ORR) (20.0% vs. 7.1%, p = 0.17) but significantly higher disease control rate (DCR) (68.0% vs. 39.3%, p = 0.04) compared to erlotinib. Median progression-free survival (PFS) (4.1 months [95% CI, 2.7-5.5 months] vs. 3.3 months [95% CI, 2.2-4.3 months], p = 0.97) and overall survival (OS) were not different between the two groups (10.3 months [95% CI, 7.5-13.0 months] vs. 10.8 months [95% CI, 7.4-14.2 months], p = 0.51). Multivariate analyses revealed that age ≤ 70 years and time to progression (TTP) ≥ 18 months for the 1st TKI therapy were prognostic of PFS (p = 0.006 and p = 0.008 respectively). Afatinib caused less rash (60.0% vs. 67.9%, p = 0.04) but more diarrhea (60.0% vs. 10.7%, p = 0.002) compared to erlotinib. CONCLUSION: Afatinib produced encouraging clinical efficacy as 2nd TKI therapy with manageable safety profiles in our Chinese patients after failure to another TKI and systemic chemotherapy. This study was registered at ClinicalTrials.gov (NCT02625168) on 3rd December 2015.

EGFR Mutant Structural Database: computationally predicted 3D structures and the corresponding binding free energies with gefitinib and erlotinib.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation-induced drug resistance has caused great difficulties in the treatment of non-small-cell lung cancer (NSCLC). However, structural information is available for just a few EGFR mutants. In this study, we created an EGFR Mutant Structural Database (freely available at http://bcc.ee.cityu.edu.hk/data/EGFR.html ), including the 3D EGFR mutant structures and their corresponding binding free energies with two commonly used inhibitors (gefitinib and erlotinib). RESULTS: We collected the information of 942 NSCLC patients belonging to 112 mutation types. These mutation types are divided into five groups (insertion, deletion, duplication, modification and substitution), and substitution accounts for 61.61% of the mutation types and 54.14% of all the patients. Among all the 942 patients, 388 cases experienced a mutation at residue site 858 with leucine replaced by arginine (L858R), making it the most common mutation type. Moreover, 36 (32.14%) mutation types occur at exon 19, and 419 (44.48%) patients carried a mutation at exon 21. In this study, we predicted the EGFR mutant structures using Rosetta with the collected mutation types. In addition, Amber was employed to refine the structures followed by calculating the binding free energies of mutant-drug complexes. CONCLUSIONS: The EGFR Mutant Structural Database provides resources of 3D structures and the binding affinity with inhibitors, which can be used by other researchers to study NSCLC further and by medical doctors as reference for NSCLC treatment.

Clinical utility of plasma Epstein-Barr virus DNA and ERCC1 single nucleotide polymorphism in nasopharyngeal carcinoma.

BACKGROUND: Single nucleotide polymorphism (SNP) of the excision repair cross-complementing group 1 (ERCC1) gene has been linked with sensitivity to platinum and radiation. The authors hypothesized that the ERCC1 genotype for the SNPs cytosine-to-thymine substitution at codon 118 (C118T) and cytosine-to-adenine substitution at codon 8092 (C8092A) is prognostic in patients with nasopharyngeal carcinoma (NPC) who receive either radiotherapy (RT) or cisplatin plus RT. METHODS: The authors tested their hypothesis using biomarker screening samples from the Hong Kong NPC Study Group 0502 trial, which was a prospective, multicenter clinical trial that used post-RT plasma Epstein-Bar virus (EBV) DNA (pEBV) levels to screen patients with high-risk NPC for adjuvant chemotherapy. RESULTS: ERCC1 SNPs were analyzed in 576 consecutive patients who were screened by pEBV. In the total biomarker population, there was no significant association of ERCC1 C118T or C8092A genotype with relapse-free survival (RFS) or overall survival (OS). There also was no correlation between ERCC1 genotype and ERCC1 protein or messenger RNA expression in a subset of patients who had available paired biopsies. Post-RT pEBV status was the only independent prognosticator for RFS and OS in multivariate analyses. However, there was a significant interaction between ERCC1 C118T genotype and post-RT pEBV status (RFS, P = .0106; OS, P = .0067). The ERCC1 C118T genotype was significantly associated with both RFS (hazard ratio, 1.67; 95% confidence interval, 1.07-2.61; P = .024) and OS (hazard ratio, 2.31; 95% confidence interval, 1.22-4.40; P = .0106) in the post-RT pEBV-negative population, but not in the pEBV-positive population. CONCLUSIONS: The current results prospectively validate pEBV as the most significant prognostic biomarker in NPC that can be used to select high-risk patients for adjuvant therapy. The ERCC1 C118T genotype may help to identify a favorable subgroup (approximately 7%) of pEBV-negative patients with NPC who have an excellent prognosis and can be spared the toxicities of further therapy.

Antifungal susceptibility and phenotypic characterization of oral isolates of a black fungus from a nasopharyngeal carcinoma patient under radiotherapy.

BACKGROUND: During a research project on fungal Candida species in patients wearing obturator treated with radiotherapy for their recurrent nasopharyngeal carcinoma, we serendipitously observed the presence of black fungus in two consecutive samples from a patient. CASE PRESENTATION: The samples were collected from a 57 year-old Hong Kong gentleman who diagnosed to have undifferentiated type of nasopharyngeal carcinoma. He was treated with definitive concurrent chemoradiotherapy followed by adjuvant chemotherapy and then received a second-course radiotherapy with IMRT. 18S rDNA sequencing revealed that the isolates belong to Exophiala dermatitidis which was susceptible to fluconazole, itraconazole, ketoconazole and voriconazole. Interestingly, E. dermatitidis isolates were resistant to caspofungin and one isolate was resistant to amphotericin B. Both isolates formed biofilms comparable to that of Candida albicans. Single isolate of E. dermatitidis showed hemolysin and proteinase ability comparable to C. albicans whilst the other isolate was not. CONCLUSION: We, for the first time, reported the discovery of a black fungus-E. dermatitidis isolates derived from a patient with nasopharyngeal carcinoma treated with radiotherapy. These isolates were shown to be resistant to caspofungin, a major antifungal agent for systemic candidiasis. As little is known about the black fungus in the clinical setting, it is important that clinicians must keep abreast of the new discovery in this field.

Effectiveness and cost-effectiveness of erlotinib versus gefitinib in first-line treatment of epidermal growth factor receptor-activating mutation-positive non-small-cell lung cancer patients in Hong Kong.

OBJECTIVE: To compare the effectiveness and cost-effectiveness of erlotinib versus gefitinib as first-line treatment of epidermal growth factor receptor-activating mutation-positive non-small-cell lung cancer patients. DESIGN. Indirect treatment comparison and a cost-effectiveness assessment. SETTING: Hong Kong. PATIENTS: Those having epidermal growth factor receptor-activating mutation-positive non-small-cell lung cancer. INTERVENTIONS: Erlotinib versus gefitinib use was compared on the basis of four relevant Asian phase-III randomised controlled trials: one for erlotinib (OPTIMAL) and three for gefitinib (IPASS; NEJGSG; WJTOG). The cost-effectiveness assessment model simulates the transition between the health states: progression-free survival, progression, and death over a lifetime horizon. The World Health Organization criterion (incremental cost-effectiveness ratio <3 times of gross domestic product/capita:

The Role of Natural Killer Cells in the Tumor Immune Microenvironment of EBV-Associated Nasopharyngeal Carcinoma.

Endemic nasopharyngeal carcinoma (NPC) is closely associated with the Epstein-Barr virus (EBV), which contributes to tumor development and influences the tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells, as part of the innate immune system, play a crucial role in responding to viral infections and malignant cell transformations. Notably, NK cells possess a unique ability to target tumor cells independent of major histocompatibility complex class I (MHC I) expression. This means that MHC I-deficient tumor cells, which can escape from effective T cell attack, are susceptible to NK-cell-mediated killing. The activation of NK cells is determined by the signals generated through inhibitory and activating receptors expressed on their surface. Understanding the role of NK cells in the complex TIME of EBV+ NPC is of utmost importance. In this review, we provide a comprehensive summary of the current understanding of NK cells in NPC, focusing on their subpopulations, interactions, and cytotoxicity within the TIME. Moreover, we discuss the potential translational therapeutic applications of NK cells in NPC. This review aims to enhance our knowledge of the role of NK cells in NPC and provide valuable insights for future investigations.

Dosimetric parameters predict radiation-induced temporal lobe necrosis in nasopharyngeal carcinoma patients: A systematic review and meta-analysis.

This systematic review examines the role of dosimetric parameters in predicting temporal lobe necrosis (TLN) risk in nasopharyngeal carcinoma (NPC) patients treated with three-dimensional conformal RT (3D-CRT), intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). TLN is a serious late complication that can adversely affect the quality of life of NPC patients. Understanding the relationship between dosimetric parameters and TLN can guide treatment planning and minimize radiation-related complications. A comprehensive search identified relevant studies published up to July 2023. Studies reporting on dosimetric parameters and TLN in NPC patients undergoing 3D-CRT, IMRT, and VMAT were included. TLN incidence, follow-up duration, and correlation with dosimetric parameters of the temporal lobe were analyzed. The review included 30 studies with median follow-up durations ranging from 28 to 110 months. The crude incidence of TLN varied from 2.3 % to 47.3 % and the average crude incidence of TLN is approximately 14 %. Dmax and D1cc emerged as potential predictors of TLN in 3D-CRT and IMRT-treated NPC patients. Threshold values of >72 Gy for Dmax and >62 Gy for D1cc were associated with increased TLN risk. However, other factors should also be considered, including host characteristics, tumor-specific features and therapeutic factors. In conclusion, this systematic review highlights the significance of dosimetric parameters, particularly Dmax and D1cc, in predicting TLN risk in NPC patients undergoing 3D-CRT, IMRT, and VMAT. The findings provide valuable insights that can help in developing optimal treatment planning strategies and contribute to the development of clinical guidelines in this field.

Effectiveness and safety of continuous low-molecular-weight heparin versus switching to direct oral anticoagulants in cancer-associated venous thrombosis.

Given the existing uncertainty regarding the effectiveness and safety of switching from low-molecular-weight heparin (LMWH) to direct oral anticoagulants (DOACs) in patients with cancer-associated venous thrombosis (CAT), we conducted a comprehensive population-based cohort study utilizing electronic health database in Hong Kong. A total of 4356 patients with CAT between 2010 and 2022 were included, with 1700 (39.0%) patients switching to DOAC treatment. Compared to continuous LMWH treatment, switching to DOACs was associated with a significantly lower risk of hospitalization due to venous thromboembolism (HR: 0.49 [95% CI = 0.35-0.68]) and all-cause mortality (HR: 0.67 [95% CI = 0.61-0.74]), with no significant difference in major bleeding (HR: 1.04 [95% CI = 0.83-1.31]) within six months. These findings provide reassurance regarding the effectiveness and safety of switching from LMWH to DOACs among patients with CAT, including vulnerable patient groups.

Direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer-associated venous thrombosis: a cost-effectiveness analysis.

Background: Direct oral anticoagulants (DOACs) have demonstrated clinical benefits and better patient adherence over low-molecular-weight heparin (LMWH) in treating patients with cancer-associated venous thrombosis (CAT). We aimed to compare the cost-effectiveness of DOACs against LMWH in patients with CAT from the perspective of the Hong Kong healthcare system. Methods: A Markov state-transition model was performed to estimate the incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) for DOACs and LMWH in a hypothetical cohort of 10,000 patients with CAT over a 5-year lifetime horizon. The model was primarily based on the health states of no event, recurrent venous thromboembolism, bleeding, and death. Transition probabilities, relative risks, and utilities were derived from the literature. Resource cost data were obtained from the Hong Kong Hospital Authority. Deterministic and probabilistic sensitivity analyses tested the robustness of the results. Results: Relative to LMWH, DOACs were associated with increased QALYs (1.52 versus 1.50) at a lower medical cost of USD 2,232 versus 8,224 in five years. The cost of LMWH was the main contributor to the outcome. Out of 10,000 simulated cases, DOACs were dominant in 15.8% and cost-effective in 42.1%, at the willingness-to-pay threshold of USD 148,392 per additional QALY. Conclusions: DOACs were associated with greater QALY improvements and lower overall costs compared to LMWH. Accounting for uncertainty, DOACs were between cost-effective and dominant in 57.9% of cases. DOACs are a cost-effective alternative to LMWH in the management of CAT in Hong Kong.

Computational Methods for the Analysis and Prediction of EGFR-Mutated Lung Cancer Drug Resistance: Recent Advances in Drug Design, Challenges and Future Prospects.

Lung cancer is a major cause of cancer deaths worldwide, and has a very low survival rate. Non-small cell lung cancer (NSCLC) is the largest subset of lung cancers, which accounts for about 85% of all cases. It has been well established that a mutation in the epidermal growth factor receptor (EGFR) can lead to lung cancer. EGFR Tyrosine Kinase Inhibitors (TKIs) are developed to target the kinase domain of EGFR. These TKIs produce promising results at the initial stage of therapy, but the efficacy becomes limited due to the development of drug resistance. In this paper, we provide a comprehensive overview of computational methods, for understanding drug resistance mechanisms. The important EGFR mutants and the different generations of EGFR-TKIs, with the survival and response rates are discussed. Next, we evaluate the role of important EGFR parameters in drug resistance mechanism, including structural dynamics, hydrogen bonds, stability, dimerization, binding free energies, and signaling pathways. Personalized drug resistance prediction models, drug response curve, drug synergy, and other data-driven methods are also discussed. Recent advancements in deep learning; such as AlphaFold2, deep generative models, big data analytics, and the applications of statistics and permutation are also highlighted. We explore limitations in the current methodologies, and discuss strategies to overcome them. We believe this review will serve as a reference for researchers; to apply computational techniques for precision medicine, analyzing structures of protein-drug complexes, drug discovery, and understanding the drug response and resistance mechanisms in lung cancer patients.