Background/Objectives: Circulating tumor-associated cells (CTACs) are rare among peripheral blood nucleated cells (PBNCs), creating a challenge for image-based multi-cancer detection. We evaluated a predefined CTAC-detection pipeline incorporating Attention U-Net segmentation, post-processing, cytological feature extraction, and Random Forest classification. Methods: Model suitability was explored in asymptomatic individuals and patients with advanced solid tumors. Clinical performance was assessed in a case-control cohort of therapy-naive stage I/II cancers, benign conditions, and asymptomatic individuals, followed by four prospective cohort evaluations performed within the same laboratory and imaging workflow: recurrent cancer with low radiological tumor burden, peri-operative solid tumors, suspected cancer, and asymptomatic screening. PBNCs were stained with EpCAM/Hoechst 33342 and imaged. Pathologists' review established ground truth annotations. Results: The model had 90.68% sensitivity and 99.53% specificity in the exploratory study. In the case-control cohort, sensitivity was 88.65% in therapy-naive stage I/II cancers, while specificity was 78.95% in benign conditions and >99.9% in asymptomatic individuals. In the prospective cohorts, CTAC detection sensitivity was 91.96% in pretreated low tumor burden cases; CTACs were detected in 100% of pre-surgery specimens and 29.41% of post-surgery specimens; and in suspected cancer cases, the Positive Predictive Value (PPV) and Negative Predictive Value (NPV) were 96.34% and 32.35%, respectively. In the asymptomatic screening cohort, 44/7183 participants were CTAC-positive; 16 had confirmed Stage I/II cancer, 10 had no radiologically detectable disease at the available assessment, and 18 remained unresolved. The conservative lower-bound PPV was 36.36%, and the NPV was 99.97%; estimates remain provisional pending complete follow-up. Conclusions: The integrated Attention U-Net/feature-based classification pipeline demonstrated consistent CTAC detection across the evaluated cohorts and supports its potential clinical utility for cancer detection.

BACKGROUND:Biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CCA), are rare but aggressive malignancies with distinct molecular landscapes and poor prognoses. Genomic profiling has revealed significant molecular alterations, but the genomic landscape of BTC in the Indian population remains underexplored. This study aims to comprehensively characterize the mutation landscape of BTC in the Indian population. METHODS:A total of 154 BTC cases, including 69 CCA and 85 GBC, were retrospectively analyzed using data collected from various targeted sequencing panels. Somatic mutations, copy number variations (CNVs), and gene fusions in key oncogenic and tumor suppressor genes were identified from these panel reports. Downstream analyses were performed to derive key biological insights, including pathway enrichment and mutual exclusivity and co-occurrence analyses of genomic alterations. RESULTS:TP53 was the most frequently mutated gene (53%), followed by KRAS (18%), ARID1A (9%), IDH1 (7%), and PIK3CA (7%). Recurrent amplifications were observed in MYC (12%) and ERBB2 (9%). Pathway enrichment analysis revealed significant dysregulation in the PI3K-AKT-mTOR, Notch, and Wnt/β-catenin signaling pathways. Notably, IDH1 mutations were primarily observed in CCA, while STK11 mutations were exclusive to GBC, highlighting distinct molecular characteristics between the two subtypes. PD-L1-negative tumors exhibited distinct genomic alterations, notably SMAD4 mutations, which were associated with reduced PD-L1 expression. This loss of SMAD4, involved in TGF-β signaling, could impair immune response regulation and facilitate immune evasion. CONCLUSIONS:This study provides a comprehensive molecular profiling of BTCs in the Indian population, revealing key genomic alterations, subtype-specific differences, and associations with immune features. The findings underscore the importance of molecular profiling in guiding personalized treatment strategies.

4151 Background: Biliary tract cancers (BTCs), comprising gallbladder cancer (GBC) and cholangiocarcinoma (CCA), are rare but highly aggressive malignancies with limited therapeutic options. While genomic profiling has identified actionable alterations in BTC, data from the Indian population remain underexplored. We characterized the mutational and pathway landscape of BTCs in Indian patients and identified subtype-specific and immune-relevant genomic features. Methods: We retrospectively analyzed 154 BTC tumors, including 69 CCA and 85 GBC cases, using data from targeted next-generation sequencing panels. Somatic single-nucleotide variants, copy-number variations (CNVs), and gene fusions in oncogenic and tumor suppressor genes were curated. Pathway enrichment analysis (Hallmark MSigDB database ( p < 0.05 )), and mutual exclusivity/co-occurrence testing (gene pairs selected based on Benjamini-Hochberg-corrected q-values < 0.05.) were performed to identify biologically relevant genomic signatures. Genomic alterations were correlated with PD-L1 status when available. Results: TP53 was the most frequently mutated gene (53%), followed by KRAS (18%), ARID1A (9%), IDH1 (7%), and PIK3CA (7%). Recurrent amplifications were observed in MYC (12%) and ERBB2 (9%). Pathway enrichment analysis revealed significant dysregulation in the PI3K-AKT-mTOR, Notch, and Wnt/β-catenin signaling pathways (p-value <0.05). IDH1 mutations were predominantly observed in CCA, supporting a clinically actionable subgroup amenable to IDH1-targeted therapy, whereas ERBB2 alterations were enriched in GBC, identifying HER2 as a key therapeutic target in this subtype. Importantly, PD-L1-negative tumors showed a higher frequency of SMAD4 mutations (Fisher’s exact test, p = 0.71), implicating disruption of TGF-β signaling in immune evasion and reduced tumor immune activation. Conclusions: This comprehensive genomic analysis of BTC from the Indian population delineates distinct molecular landscape between GBC and CCA. The subtype-specific actionable alterations, including IDH1 mutations in CCA and ERBB2 alterations in GBC, highlights clinically relevant opportunities for precision therapy. SMAD4 alterations are associated with an immune-cold, poorly immunogenic tumor subtype in BTCs and warrant further investigation as a predictive biomarker for patient stratification in immunotherapy-based treatment strategies. These findings support the utility of molecular stratification in BTC and provide a rationale for integrating targeted and immunotherapy-based approached in Indian patients.

Cervical cancer is highly prevalent in India, with most cases being diagnosed at advanced stages. Despite the standard concurrent chemoradiotherapy (CCRT), 30–40% of patients' experience treatment failure, underscoring the need for improved therapeutic strategies. Understanding resistance mechanisms and identifying predictive biomarkers are crucial to improve treatment efficacy and enable personalized medicine. We conducted a comprehensive genomic and proteomic analysis to identify molecular signatures associated with CCRT. We identified recurrent mutations in phosphatidylinositol 4,5‐bisphosphate 3‐kinase catalytic subunit alpha isoform (PIK3CA) and histone‐lysine N‐methyltransferase 2D (KMT2D), with mutation signature analysis revealing a prevalent DNA dC‐ > dU‐editing enzyme, APOBEC mutagenesis signature. Distinct genomic alterations, including epidermal growth factor receptor (EGFR) amplification and serine/threonine kinase 11 (STK11) deletion, were exclusively observed in the chemoradiation‐resistant cohort. Proteomic analysis identified 73 significantly dysregulated proteins, with syntaxin‐3 (STX3), SERPINB7, lipopolysaccharide‐binding protein (LBP), EMILIN2, and ribosyldihydronicotinamide dehydrogenase (quinone) (NQO2) being the top five upregulated proteins. Integrative pathway analysis highlighted an active DNA repair pathway in the resistant cohort. This study presents the first proteogenomic profiling of cervical cancer in the Indian population, linking molecular alterations to CCRT response. STK11 and STX3 emerged as predictive biomarkers for poor response, whereas EGFR presents as a promising therapeutic target in the resistant group.

Gingivobuccal mucosal squamous cell carcinoma (GBMSCC) is a distinct head and neck cancer subtype strongly linked to areca nut and smokeless tobacco, often arising in a background of oral submucous fibrosis. Multiomics studies reveal recurrent mutations (TP53, FAT1, CASP8, PIK3CA, and AAM pathway genes), characteristic copy number alterations, and transcriptomic programs driven by extracellular matrix remodeling, epithelial-mesenchymal transition, and immune evasion. The tumor microenvironment is enriched with exhausted T cells, macrophages and cancer-associated fibroblasts. These insights support subsite-specific strategies incorporating targeted therapy, immunotherapy, chemoprevention, and saliva-based biomarkers for early detection, prognostication, surveillance, and improved clinical outcomes in GBMSCC.

Liquid biopsy, specifically circulating tumor DNA (ctDNA) analysis, has emerged as a transformative tool in precision oncology, providing real-time, minimally invasive characterizations of the tumor and tumor dynamics. While tissue biopsy is a critical tool for baseline diagnosis of malignancy, it is often limited by sampling constraints and an inability to capture tumor heterogeneity. In this study, we explored the clinical utility of serial ctDNA testing in guiding therapeutic decisions across a cohort of 30 patients with diverse solid tumors. Our real-world analysis demonstrates that ctDNA profiling meaningfully influenced treatment escalation, de-escalation, disease monitoring, and early relapse prediction. Cases where ctDNA positivity indicated minimal residual disease prompted timely escalation of therapy, while ctDNA clearance allowed safe treatment de-intensification, minimizing toxicity without compromising outcomes. Longitudinal ctDNA monitoring provided a dynamic, non-invasive method for assessing treatment response and detecting recurrence months before radiological progression. Our study highlights the potential of integrating liquid biopsy into routine clinical practice to enable dynamic treatment monitoring, early detection of therapeutic resistance, and more informed, personalized decision-making across various cancer types.

Salivary ductal carcinoma is a rare, aggressive salivary gland carcinoma with poor prognosis and high relapse rate. In recurrent metastatic cases, the median survival is only 5 months. Despite the treatment with multimodal therapeutic strategies, conventional treatments demonstrate a limited effect on long-term survival of the patients. In this study we report two cases of salivary ductal carcinoma patients managed with precision-directed, biomarker-guided therapeutic approaches. In the first case androgen receptor (AR) and HER2 positivity by immunohistochemistry analysis were detected. The patient was treated with AR directed targeted therapy enzalutamide and Leuprolide as maintenance therapy. Disease progression with an emergent HER2 expression by immunohistochemistry led to the inclusion of trastuzumab and pertuzumab. While in the second case the patient progressed on neoadjuvant chemotherapy and the subsequent molecular analysis revealed high expression of PD-L1 and was treated with pembrolizumab in combination with chemotherapy. Follow up assessment revealed treatment durable responses and disease control in both the patients. These cases underscore the potential role of comprehensive molecular profiling-guided personalised therapeutic approaches in the management of advanced SDC patients.

e16043 Background: Patients with advanced esophageal squamous cell carcinoma (ESCC) have dismal survival outcomes post-progression on standard first-line chemoimmunotherapy. The median overall survival (OS) is usually less than a year. Patients receiving subsequent line treatment options experience significant treatment related toxicities (> 50-60% develop > grade 3 toxicities), are frail, and have a poor ECOG Performance Status (> 30% have ECOG-PS >2). Triple oral metronomic chemotherapy (triple-OMCT) is an efficacious and cost-effective treatment option in patients with locally advanced head and neck SCC. We aimed to explore the role of triple-OMCT in patients of advanced ESCC treated at our institute. Methods: This was a retrospective observational study conducted at our institute between 28.05.2019 to 09.01.2025 Patients of advanced esophageal SCC who had progressed on prior lines of systemic treatment were treated with triple-OMCT (tablet methotrexate 9mg/m 2 per week, tablet erlotinib 150mg once daily, capsule celecoxib 200mg twice daily). The addition of immunotherapy was permitted with this regimen. We assessed treatment efficacy [objective response rate (ORR)], safety, and survival outcomes [progression-free (PFS), OS] in these patients. Results: The data of 57 consecutively evaluated patients was analyzed. Median age was 59 years (IQR, 52.5-63.0), 54.4% (n = 31) were females, and 86.0% (n = 49) had an ECOG-PS of 0-1. Prior treatment in the curative or palliative setting was received by 64.9% (n = 37) patients, and the median number of prior lines of treatment was 2 (IQR, 1-2). At OMCT initiation, 68.4% (n = 39) patients had metastatic disease, with 54.4% (n = 31) patients having metastasis to non-regional lymph nodes. Immunotherapy was added to triple-OMCT in 47.4% (n = 27) patients. Amongst response evaluable patients (59.6%, n = 34/57), the objective response was 14.7% (five partial response), and disease control rate was 47.1% (n = 16/34, eleven stable disease). > Grade 3 toxicity was seen in 17.5% (n = 10) patients. Median follow-up of the cohort was 28.8 months (95%CI, 18.7-39.1). The median PFS and OS with the use of triple-OMCT was 3.4 months (95%CI, 2.8-3.9) and 9.7 months (95%CI, 6.6-12.8) respectively. With the addition of immunotherapy, the median PFS and OS was 3.4 months (95%CI, 2.4–4.5) and 11.4 months (95%CI, 8.8-14.0) respectively, compared to 3.0 months (95%CI, 2.5-3.6, p = 0.618) and 7.6 months (95%CI, 4.1-11.2, p = 0.386) without immunotherapy. Conclusions: Triple-OMCT is safe and has activity in patients with advanced esophageal SCC. This regimen is worthy of exploration in resource-limited settings. Best Overall Response, n (%) Patients, n (%)N=34 Complete Response (CR) 0 (0.0) Partial Response (PR) 5 (14.7) Stable Disease (SD) 11 (32.3) Progressive Disease (PD) 18 (52.9) Objective Response Rate (ORR) 14.7% Disease Control Rate (DCR) 47.1%

Background:Liquid biopsy assays are an important tool for non-invasive detection of genetic alterations, providing an effective alternative to traditional tissue biopsies. The study aimed to investigate the utility of ctDNA based next generation sequencing for clinical management of lung cancer patients from India. Methods:We conducted ctDNA targeted sequencing on 425 lung cancer patients from India using 50 gene oncomine precision assay. The assay was validated employing 7 controls and 77 clinical samples, and the performance of the assay was evaluated. The concordance analysis with matched tissue biopsy samples was performed on 162 cases. Results:Among the 425 lung cancer samples, 47 % harbored at least one mutation. EGFR was the most frequently altered gene (25.2 %), followed by TP53 (19.8 %) and KRAS (4.5 %). Concordance with tissue biopsy data was 77 % for EGFR, 79 % for TP53 and above 97 % for low frequency mutations. The assay demonstrated 100 % specificity and around 60 % sensitivity for the majority of clinically relevant genetic alterations including EGFR, KRAS and BRAF. Notably ERBB2 alterations were detected with 100 % sensitivity and specificity. Conclusion:The ctDNA assay demonstrates high accuracy and specificity, for both prevalent and rare genetic alterations. While further advancements are needed to enhance sensitivity and routine clinical application, our ctDNA profiling assay offers a reliable alternative for detecting genetic alterations in lung cancer patients, with significant potential for clinical integration in the Indian healthcare context.

Cisplatin-based concurrent chemoradiotherapy (CCRT) is the standard treatment for cervical patients with locally advanced disease. Despite the improved survival rates and prognosis observed in patients undergoing CCRT, over 30-40% do not achieve complete response and are at risk of locoregional recurrence. Targeting crucial molecules that confer resistance may improve the clinical outcomes of the treatment resistant patient cohort. Herein, we employed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based phosphoproteomic approach to identify the altered phosphophorylation events, activated kinases and dysregulated pathways involved in treatment resistance. We quantified 2531 unique phosphopeptides mapping to 1099 proteins of which 74 proteins were differentially phosphorylated between the cohorts. Pathway analysis revealed dysregulation of the DNA repair pathway and the proteins involved in DNA repair in the non-responder cohort. Additionally, we identified kinase signature associated with CCRT resistance. Kinases such as CSNK2A1, PRKDC, PLK-1, NEK2, ATM and CDK1 are predicted to be activated in non-responders. In particular, we showed that CSNK2A1 is involved in oncogenesis of cervical cancer and pharmacological inhibition led to reduced cell proliferation, migration and colony formation. Moreover, the combination of the CSNK2A1 inhibitor, silmitasertib with cisplatin demonstrated synergism (combination index < 1) and yielded a beneficial reduction in dosage. The dose reduced combination potentially reduced the proliferative, migratory and colony formation ability in vitro. Our findings highlight the potential of phosphoproteomics to identify clinically significant targets and pathways implicated in CCRT resistance. Our study also indicates that combination therapy could serve as an effective treatment strategy to improve the efficacy of patients undergoing CCRT.

The Excellence in Oncology Care (EIOC) 2023 Congress, held in Dubai as a hybrid event, brought together oncologists from the Middle East and the Indian subcontinent. Two panels, comprising 33 experts, developed the first region-specific consensus guidelines to address critical issues in non-small cell lung cancer (NSCLC), particularly focusing on the roles of liquid biopsy and targeted therapies in early-stage cancer. These guidelines, created through surveys and preparatory meetings, were presented and discussed at the congress, both in person and online. While tissue biopsies remain the gold standard, liquid biopsies are emerging as a promising, minimally invasive alternative, though they are hampered by a lack of standardization and logistical challenges in the region. Liquid biopsy supports follow-up by accessing circulating tumor DNA, though its utilization is limited by infrastructure and costs. In the Middle East and the Indian subcontinent, the adoption of liquid biopsy is constrained by logistical hurdles, financial limitations, and inadequate infrastructure. The EIOC panels provided consensus statements on employing liquid biopsy and integrating targeted therapy in early-stage and locally advanced NSCLC for this region. The consensus highlighted the importance of combining liquid and tissue biopsies, especially for detecting resistance mutations and driver alterations, such as EGFR and ALK, with recommendations for incorporating targeted therapy and chemotherapy. This consensus aims to assist regional clinicians in navigating the evolving landscape of NSCLC management.

Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non-small cell lung cancer (NSCLC) with limited treatment options and poor prognosis. EGFR mutations generally respond to tyrosine kinase inhibitors (TKIs)-based targeted therapy but are typically associated with resistance to immunotherapy. We report a case of oligometastatic PSC harboring compound EGFR mutations (p.G719C and S768I). The patient exhibited disease progression despite sequential treatment with EGFR TKIs, including osimertinib, afatinib, and mobocertinib, in combination with chemotherapy. The treatment strategy was then shifted to immunotherapy with pembrolizumab alongside carboplatin and paclitaxel, leading to a remarkable response. Given the oligometastatic nature of the disease and the sustained response, bilateral adrenalectomy was performed, revealing a complete pathological response. The patient remains disease-free posttreatment, with no evidence of recurrence on follow-up imaging. This case challenges the conventional paradigm that EGFR-mutated NSCLC does not benefit from immunotherapy, highlighting the potential for an alternative treatment approach in rare subtypes such as PSC. Our findings emphasize the importance of comprehensive molecular profiling and a personalized treatment strategy to optimize outcomes in aggressive and refractory lung cancers.

The validation and clinical utility of Comprehensive Genomic Profiling (CGP) for identifying somatic genomic mutations have been challenging within the Indian Oncology practice. The primary obstacles to establishing clinical utility are cost, availability, lack of expertise in testing, adoptability and implementation of therapeutic recommendations. However, the absence of standardized laboratory methods in Indian cases has not been previously addressed. We validated a widely applied CGP assay, TruSight Oncology 500, in a reference laboratory. Subsequently, the clinical utility in a series of 192 cases comprising late-stage tumor specimens from common solid cancer types was examined. The identified somatic variants were classified based on the AMP Tier classification to determine their clinical utility. Lung adenocarcinoma was the most common, followed by breast and gastrointestinal cancers. The most common genes with mutations were TP53 (36.5 %), MYC (29.7 %), EGFR (20.8 %), KRAS (16 %), PIK3CA (20.6 %), BRAF (11 %), and ERBB2 (10 %). Therapeutic recommendations based on AMP Guidelines Tier 1A were found in 33 % of cases, Tier 1B in 49 %, and Tier IIC in 83 % of cases. TMB-high (>10muts/Mb) in 21.5 % of cases, TMB-Low (<= 9 muts/Mb) in 77.6 % of cases, MSI-L (1-30 %) was identified in 85.4 % of cases, and MSS (<1 %) in 14 % of cases. Overall, we identified therapeutically actionable mutations in 83 % of cases of solid tumors that had undergone CGP.

We thank Das et al.[1] for the invaluable insights on our molecular tumor board article, "NUT-midline carcinoma of the lung with rare BRD3–NUTM1 fusion."[2] Das et al.[1] highlighted the immunohistochemical (IHC) phenotypes of nuclear protein in testis (NUT) carcinoma. In our case presentation, IHC positivity of NUT confirmed the histopathologic diagnosis of NUT midline carcinoma of the lung. NUT expression is a hallmark of NUT carcinoma.[3,4] P40 is highly sensitive and specific for squamous cell carcinoma. However, its presence alone does not conclusively confirm squamous cell carcinoma (SCC), like other cancers, may also express P40. In the case described, the tumor cells were positive for both P40 and NUT. While P40 positivity might suggest squamous differentiation, the concomitant strong positivity for NUT is more indicative of NUT carcinoma over squamous cell carcinoma as the final diagnosis. Typically, NUT carcinomas usually occur in the midline structures of the body such as the head, neck, and mediastinum; however, they can also manifest in the non-midline areas. Recognition of NUT carcinoma in the non-midline areas is crucial for timely diagnosis and treatment. The authors' insight is quite compelling in emphasizing the distinctive features of the primary histomorphological examination to identify NUT carcinomas. They also highlighted how identification is more common when it occurs in the non-midline regions. The main histopathologic indications of NUT carcinoma are undifferentiated or poorly differentiated histology and atypical nuclear morphology. In addition, high mitotic index, diffuse growth pattern, elevated Ki-67 proliferation index, and absence of squamous differentiation markers (e.g. CK5/6, p63) in cases with squamous differentiation give strong attestation of NUT carcinoma.[3,5] Similarly, a conjecture of NUT carcinoma should be raised in non-midline regions when there are atypical clinical presentations, rapid tumor growth, characteristic histologic features, young age of onset, failure to respond to standard treatments, or evidence of metastasis. The confirmation of NUT carcinoma is reinforced by IHC staining and positivity for NUT protein, or next-generation sequencing (NGS). We strongly concur with the use of NGS, as it confirms the presence of NUT fusion and opens an avenue for the discovery of new therapeutic targets, deepening our understanding of the complex and aggressive biology exhibited by these tumors. However, NUT carcinoma poses a significant clinical challenge due to its status as an orphan disease, lacking established treatment protocols, and typically presenting a bleak prognosis. Das et al.[1] have provided a holistic overview of therapeutic options for these aggressive cancers. The available sparse information also indicates these tumors may be amenable to treatment with immune checkpoint inhibitors, warranting further investigation.[6] To summarize, an accurate diagnosis of NUT carcinoma requires a comprehensive evaluation by a multidisciplinary team, including pathologists who could employ clinicopathologic correlation for the advanced interpretation of the cases. NUT carcinoma remains a unique challenge in the landscape of solid cancers, with limited treatment options and a generally dismal outlook, making the search for effective therapies for the management of this rare and aggressive cancer more important than ever before. Financial support and sponsorship Nil. Conflicts of interest Kumar Prabhash is a member of the editorial board of Cancer Research, Statistics and Treatment. As such, he may have had access to information and/or participated in decisions that could be perceived as influencing the publication of this manuscript. However, he recused himself from the peer review, editorial, and decision-making process for this manuscript, to ensure that the content is objective and unbiased.

The objective of the study was to provide a comprehensive genomic landscape of Indian lung cancer patients. Our findings highlight a high prevalence of actionable alterations in lung adenocarcinoma and the novel discovery of frequent EGFR alterations in lung squamous carcinoma. Thus, this study underscores the potential for implementation of precision medicine and the need for novel therapeutic strategies tailored to Indian population. Background: The genomic landscape of non-small cell lung cancer (NSCLC) in the Indian patients remains under- explored. We revealed distinctive genomic alterations of Indian NSCLC patients, thereby providing vital molecular insights for implementation of precision therapies. Methods: We analyzed the genomic profiles of 325 lung adenocarcinoma and 81 lung squamous carcinoma samples from Indian patients using targeted sequencing of 50 cancer related genes. Correlations between genomic alterations and clinical characteristics were computed using statistical analyses. Additionally, we identified distinct features of Indian NSCLC genomes by comparison across different ethnicities. Results: Our genomic analysis revealed several noticeable features of Indian NSCLC patients. Alterations in EGFR (45.8%), TP53 (27.4%), ALK (11.4%) and KRAS (10.2%) were predominant in adenocarcinoma, with 68% eligible for targeted therapies. Squamous carcinoma exhibited prevalent alterations in TP53 (40.7%), PIK3CA (17.3%), and CDKN2A (8.6%). We observed higher frequency of EGFR alterations (18.5%) in lung squamous carcinoma patients, significantly distinct from other ethnicities reported till date. Beyond established correlations, we observed 60% of PD-L1 negative squamous patients harbored TP53 alterations, suggesting intriguing therapeutic implications. Conclusions: Our data revealed unique genomic variations of adenocarcinoma and squamous carcinoma patients, with significant indications for precision medicine and clinical practice of lung cancers. The study emphasizes the importance of clinical utility of NGS for routine diagnostics.

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer. Among NSCLC, lung adenocarcinoma is majorly characterized by driver activating mutations in the EGFR (Epidermal growth factor receptor) gene, covering exons-18, 19, and 21. The most frequently observed mutations are the classical mutations Exon–19 E746_A750 deletion, and Exon - 21 L858R, EGFR exon-18 G719X than the rare variants of these genes. Besides classical mutations and other rare mutations, compound mutations are not very profound. Here, in this present case report, we identified the rare occurrence of EGFR E709A and L858R in tissue and liquid biopsy sample of the patient. The identified compound mutation had been validated in FFPE (formalin fixed paraffin embedded) tissue sample by Sanger sequencing. In addition, the concordance of the rare variants in tumor tissue as well as liquid biospy strongly suggests the clinical utility of liquid biopsy. The patient had been treated with single agent gefitinib which showed mixed response and later treatment had been upgraded to pemetrexed + carboplatin + gefitinib. The sensitivity and specificity of NGS technology provide an opportunity to identify uncommon variants, which opens up a wider avenue for targeted therapeutics.

Head and neck cancer (HNC) is a diverse group of malignancies arising in the mucosal linings of the oral cavity, pharynx, and larynx, influenced by factors such as tobacco use, alcohol consumption, and human papillomavirus (HPV) infection. This study conducts a comprehensive meta-analysis of the mutational landscape of HNC across Asian cohorts, encompassing India, Korea, Japan, China, Singapore, and Saudi Arabia. The analysis highlights distinct genetic profiles influenced by environmental exposures, lifestyle habits, and genetic predispositions. Notably, the RAF family proteins, enriched in both Indian and Chinese cohorts, present potential therapeutic targets for RAF inhibitors like Vemurafenib. Additionaly, specific mutations like MET in Singaporean patients can be effectively addressed with drugs like Crizotinib, leading to rapid responses in HNSCC. Smokers exhibited high frequencies of CASP8 and FAT1 mutations. Novel driver genes, including RYR2 and ANK2, emerged with significant mutational frequencies in smokers. The RAS signaling pathway was identified as a prominent driver in HNC, contrasting with the globally prevalent PIK3CA/MTOR pathway. This study also underscores the high prevalence of HRAS mutations in Indian and Saudi cohorts. The study emphasizes the necessity for region-specific data to understand the unique molecular differences and develop effective therapies. The identification of NBEA and ANK2 as potential novel driver genes in HNC highlights new avenues for research and targeted therapeutic interventions tailored to the genetic profiles of Asian HNC patients.