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Advanced Non-Small Cell Lung Carcinoma (NSCLC) patients with ROS1 gene rearrangement have shown significant therapeutic responses to tyrosine kinase inhibitors approved by the US Food and Drug Administration, with approximately 40 fusion partners documented in the existing literature. Our report highlights a novel fusion partner of ROS1 that has demonstrated a conclusive response to the current standard of treatment.

Summary: Lung cancer varies between Caucasians and Asians. There have been differences recorded in the epidemiology, genomics, standard therapies and outcomes, with variations according to the geography and ethnicity which affect the decision for optimal treatment of the patients. To better understand the profile of lung cancer in Southeast Asia, with a focus on India, we have comprehensively reviewed the available data, and discuss the challenges and the way forward. A substantial proportion of patients with lung cancer in Southeast Asia are neversmokers, and adenocarcinoma is the common histopathologic subtype, found in approximately a third of the patients. EGFR mutations are noted in 23–30% of patients, and ALK rearrangements are noted in 5–7%. Therapies are similar to global standards, although access to newer modalities and molecules is a challenge. Collaborative research, political will with various policy changes and patient advocacy are urgently needed.

Executing global clinical trials for cancer is a long, expensive, and complex undertaking. While selecting countries global studies, sponsors must consider several aspects including patient pool, quality of trained investigators, competing trials, availability of infrastructure, and financial investment versus returns. With a large, often treatment-naïve, and diverse patient pool, relatively low cost, good quality health care facilities in urban areas, and a robust and well-trained workforce, India offers several advantages for conducting oncology clinical trials. However, there remains challenges, including a shifting regulatory environment in recent decades. With the implementation of the New Drugs and Clinical Trial Rules in 2019, India's regulatory atmosphere seems to have stabilized. In this article, we present a review of the evolving clinical trial landscape in India, highlight the current regulatory scenario, and discuss the advantages and challenges of selecting India as a potential location for conducting global oncology clinical trials.

Background: Endobronchial ultrasound-guided transbronchial fine-needle aspiration (EBUS-TBNA) has replaced mediastinoscopy as the preferred investigation for evaluating mediastinum in staging lung cancer. There is little evidence of mediastinal staging by EBUS-TBNA from India. Objectives: To study endobronchial ultrasound's diagnostic accuracy in staging lung cancer. Methodology: We retrospectively analysed patients operated on for lung cancer where EBUS was performed preoperatively for mediastinal staging. We compared the histological findings obtained from different mediastinal lymph nodes (LNs) by EBUS-TBNA with the pathology of the same LNs obtained after surgical dissection as the reference standard. Results: Seventy-six patients underwent curative surgery for lung cancer. The diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of EBUS-TBNA in predicting mediastinal metastasis were 93.9%, 40%, 99%, 80% and 94.6%, respectively. Of the 115 LNs sampled, EBUS-TBNA was false negative in six nodes, resulting in an up-staging of six patients. Conclusions: EBUS-TBNA has a high diagnostic accuracy for lung cancer staging.

The most common oncogenic driver in non-small-cell lung cancer (NSCLC) is the epidermal growth factor receptor (EGFR) gene mutations that occur more frequently among Asians (30%–50%) as opposed to Caucasians (10%–15%). Lung cancer is one of the most prevalent cancers in India, with a reported adenocarcinoma positivity ranging between 26.1% and 86.9% in NSCLC patients. The prevalence of EGFR mutations in adenocarcinoma patients (36.9%) in India is higher than that of Caucasian patients and lower than that of East Asian patients. The exon 19 deletion (Ex19del) is more common than exon 21 L858R mutations in Indian patients with NSCLC. Studies have shown that the clinical behaviour of patients with advanced NSCLC differs between EGFR Ex19del and exon 21 L858R mutation status. In this study, we investigated the differences in clinicopathological features and survival outcomes after first line and second-line treatment with EGFR tyrosine kinase inhibitors (EGFR TKIs) in NSCLC patients with Ex19del and exon 21 L858R EGFR mutation status. This study also focuses on the role and potential benefits of dacomitinib, a second-generation irreversible EGFR TKI, in patients with Ex19del and exon 21 L858R EGFR mutation-positive advanced NSCLC in Indian settings.

Abstract Background Angiosarcoma is an uncommon and highly aggressive malignant tumor. Angiosarcoma presenting as diffuse alveolar hemorrhage (DAH) is rare. Case presentation A young female who presented with history of dyspnea was found to have features of DAH on radiological evaluation. Angiosarcoma was confirmed from the histopathological examination of the underlying lung nodule. Management with the palliative chemotherapy showed clinical improvement, and resolution of changes of DAH on imaging. Conclusion Angiosarcomas are not usually listed in the causes of DAH. It must be considered in the differentials of DAH after ruling out the common causes.

Abstract Background KRAS, although a common variant of occurrence (~20% of non‐small‐cell lung carcinoma [NSCLC]) has been untargetable, owing to the molecular structure which inherently prevents drug binding. KRAS mutations in NSCLC are associated with distinct clinical profiles including smokers and mucinous histology. KRAS G12C mutations account for ~40% KRAS altered NSCLC, but NSCLC being a geographically diverse disease, the features may be distinct in this part of the world. This is a single‐center experience of KRAS‐mutated NSCLC including clinical, imaging, pathologic features, and treatment patterns and outcomes. Methods This is a single‐center retrospective study of KRAS‐mutated NSCLC. The clinicopathological features and outcomes were retrieved and collated from the medical record archives of the hospital. Results Fifty (30.6%) patients with advanced‐stage NSCLC with alterations in the KRAS gene were enrolled in the 163 patients who were tested for KRAS alterations. The median age was 61 years. Molecular detection revealed three main types of KRAS mutations viz‐a‐vis: G12C in 17 (34%), G12V in 9 (18%), and G12D in 6 (12%) patients. Comparing G12C versus the non‐G12C mutated cases, co‐mutations were common in the non‐G12C subgroup (p

Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is a molecularly distinct subgroup of oncogene-addicted NSCLC, accounting for 3-5% of cases. These are mainly genomic rearrangements resulting in a fusion oncoprotein, thus causing persistent constitutive signaling. Recent developments and approvals of various generations of ALK inhibitors have revamped the therapeutic and prognostic landscape of this disease entity. For the preparation of this review, we searched various databases such as PubMed, Embase, and Scopus, using the keywords “ALK,” “ALK crizotinib,” “Oncogene NSCLC,” and “Alectinib,” and we finally included 46 articles. In this review, we describe the molecular biology and pathologic and clinical characteristics of ALK-rearranged NSCLC. The detection methods, therapeutic strategies, and trials will be discussed in the next part of this biomarker review series.

Anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC) comprises a distinct molecular entity with a reported global prevalence of 5–7%. The development and rapid approvals of small molecule ALK tyrosine kinase inhibitors (TKIs) have led to the development of diagnostic strategies with robust methodology and superior attributes. Owing to myriad alterations which can be present in the ALK gene in NSCLC, it is important to understand the principal attributes as well as limitations of each to aid in optimal therapeutic decision making. To prepare this review, we used the keywords, “ALK detection,” “ALK NGS,” “ALK TKI,” and “EML4 (echinoderm microtubule-associated protein-like 4)-ALK,” to search within scientific databases like Scopus, PubMed, and Embase. We chose 55 articles that we identified from this search. Detection of ALK is an essential frontline diagnostic test as per all international and national recommendations. The various modalities available include immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and DNA/RNA-based next-generation sequencing. Each has its own advantages and limitations with respect to test metrics like sensitivity and specificity, as well as ease of use, availability, and cost. This is a detailed review of these various techniques and their attributes.

Background: The purpose was to determine whether tumor response to CPI varies by organ and to characterize response patterns in a group of surgically treated metastatic RCC patients treated with Nivolumab. Methods: A retrospective analysis was undertaken between January 2016 and March 2020 on patients receiving Nivolumab for metastatic RCC, following first-line therapy and having at least one baseline and two follow-up scans. A Fisher’s exact test was used to compare categorical variables, and a Kruskal–Wallis test was used to compare continuous variables. Results: Twenty-one out of thirty patients evaluated were eligible, and they were divided into two groups: responders (n = 11) and non-responders (n = 10). According to all iRECIST standards, 18 (85.7 percent) of the 21 patients had PD (10 patients), PR (3 patients), or SD (8 patients). At baseline, 7, 15, 4, 13, 7, and 7 patients, respectively, had detectable hepatic metastasis and lung, brain, lymph node, soft tissue, and other intra-abdominal metastases; these patients were evaluated for organ-specific response. The ORRs for hepatic metastasis and lung, brain, lymph node, soft tissue, adrenals, and other intraperitoneal metastases were correspondingly 10%, 20%, 35%, 0%, and 25%. In total, 13 (61.9%) of them demonstrated varied responses to CPI therapy, with 6 (28.5%) demonstrating intra-organ differential responses. The lymph nodes (35%) had the best objective response (BOR), followed by the adrenals and peritoneum (both 25%), the brain (20%), and the lung (20%). The response rate was highest in adrenal gland lesions (2/4; 50%), followed by lymph nodes (13/19; 68.4 percent) and liver (5/10; 50%), whereas rates were lowest for lesions in the lung (9/25; 36%), intraperitoneal metastases (1/4; 25%), and brain (1/5; 20%). Conclusions: In renal cell carcinoma, checkpoint inhibitors have a variable response at different metastatic sites, with the best response occurring in lymph nodes and the least occurring in soft tissue.

ROS1 rearranged non-small-cell lung cancer (NSCLC) is a distinct molecular subtype of NSCLC, accounting for 2% of cases. Typically, these are genomic rearrangements resulting in a fusion oncoprotein that causes unabated constitutive signaling. Patients with ROS1 rearranged NSCLC have distinct clinical and histologic profiles and show excellent outcomes with various small molecule tyrosine kinase inhibitors. For the preparation of this review, we searched the literature in databases like PubMed, Embase, and Scopus with keywords such as “ROS1”, “ROS1 crizotinib”, and “Oncogene NSCLC.” We included 72 articles. This is a narrative review of the molecular biology, clinical, and pathologic characteristics, detection methods, and management of ROS1 rearranged lung cancer.

Abstract Vikas Ostwal Background Ramucirumab is considered a standard of care as second-line therapy (CT2) in advanced gastric cancers (AGCs). The aim of this study was to assess practice patterns and outcomes with ramucirumab among Indian patients with AGCs. Materials and Methods A computerized clinical data entry form was formulated by the coordinating center's (Tata Memorial Hospital) medical oncologists and disseminated through personal contacts at academic conferences as well as via email for anonymized patient data entry. The data was analyzed for clinical characteristics, response rates, and survival outcomes. Results A total of 26 physicians contributed data, resulting in 55 patients receiving ramucirumab and being available for analysis. Median age was 53 years (range: 26–78), 69.1% of patients had greater than two sites of disease, and baseline Eastern Cooperative Oncology Group's performance score (ECOG PS) ≥ 2 was seen in 61.8% of patients. Ramucirumab was used as monotherapy in 10.9% of patients, while the remaining 89.1% received ramucirumab combined with chemotherapy. Median event-free survival (EFS) and median overall survival (OS) with ramucirumab were3.53 months (95% CI: 2.5–4.57) and 5.7 months (95% CI: 2.39–9.0), respectively. Common class specific grade adverse events seen with ramucirumab included gastrointestinal (GI) hemorrhage (9.1% - all grades) and uncontrolled hypertension (Grade 3/4 - 3.6%). Conclusions Ramucirumab appears to have similar efficacy in Indian AGC patients when compared with real-world data from other countries in terms of median EFS, but OS appears inferior due to more patients having borderline ECOG PS and high metastatic disease burden. GI hemorrhages appear more common than published data, although not unequivocally related to ramucirumab.

Abstract The combination of cyclin dependent kinase 4/6 inhibitors with endocrine therapy is the standard therapy in hormone receptor positive HER-2 negative metastatic breast cancer (HR+/HER2− MBC). Several randomized trials have shown the benefits of this combination, however, real world evidence in the Indian patients is warranted. The present study reports the largest real world multicentric data from Indian population on the use of Palbociclib in HR+/HER2− MBC. A multicentric study on the HR+/HER2− MBC patients who received palbociclib with hormonal agent (Aromatase inhibitors/Fulvestrant) between February 2017 and May 2020 was conducted. Clinical and demographic information and survival data was retrieved from the Hospital medical records. Among a total of 188 patients, 57% patients were premenopausal and 17% patients had bone only disease. Altogether, 115 (61%) patients received palbociclib with Aromatase inhibitors in the first line whereas 73 (39%) patients received it in the second line with Fulvestrant. The median follow up period with advanced disease was 13 months. The median progression free survival in the first line and second line was 20.2 months and 12 months, respectively (p-value

Background: Epidermal growth factor receptor (EGFR) is one of the driver mutations in advanced Non – Small Cell Lung Carcinoma (NSCLC) and is prominently chosen to advocate personalized treatment approaches. The advancing field of molecular pathology along with the introduction of the EGFR TKIs has profoundly changed the therapeutic landscape of the NSCLC. But therapeutic decision might be challenging when different testing methods yield non-identical results. Method: A patient diagnosed with lung carcinoma negative for ALK and ROS1 rearrangements was subjected to EGFR testing by Therascreen, plasma based genotyping by Roche cobas V2 and bioRAD droplet digital PCR. Taking into consideration the variant results, both Therascreen and Roche cobas V2 testing was again performed on fresh biopsies. Result: Single gene testing of EGFR by Therascreen was negative. Plasma based genotyping for EGFR mutations using the Roche cobas V2, yielding a del19 mutant whereas, bioRAD droplet digital PCR revealed del19 wild type along with small clone of T790M. The Therascreen assay was negative, whereas the Roche cobas V2 yielded a positive del19 mutant. The T790M clone was not detected by cobas neither in plasma nor in tissue. Conclusion: In view of the absence of T790M mutant, the patient was planned first line therapy of Osimertinib. The choice of testing modality decides the suitable therapy for the patient to a great extent. Although tissue genotyping is still the gold standard, using liquid biopsy genotyping in addition to tissue genotyping improves the discovery of sensitizing mutations in targetable genes, ultimately leading to better patient outcomes.

Lung cancer being a molecularly distinct entity in the female population, multiple primary tumors including the genital and urinary tract malignancies with lung carcinoma is rare and constitutes a unique set of patient population. This case report serves to illustrate the rarity of multiple primary tumor involving ovarian carcinoma with ALK positive lung cancer. Additionally high throughput sequencing revealed a germline BRCA2 mutation causing alteration of splice site. This report highlights the occurrence of multiple primary tumors in this patient possibly due to BRCA2 predisposition.

Introduction The increased use of new checkpoint inhibitors in cancer therapy has led to the discovery of new unconventional responses, like pseudoprogression and hyperprogression disease (HPD). The study documents imaging findings of HPD and analyzes the growth kinetics in advanced metastatic cancers patients treated with immunotherapy. Methods We retrospectively reviewed patients treated with anti-PD-1 (anti-progressive disease-1) antibody therapy (nivolumab) between January 2017 and December 2017 at our institute. The patients who exhibited early and rapid progression rates after initiation of immunotherapy were further analyzed for tumor growth kinetics (TGKs) and imaging findings. All prebaseline, baseline, and post nivolumab imaging were retrospectively reviewed to assess the TGKs, time to treatment failure (TTF), and rate of progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Results Four patients with HPD had peculiar imaging appearance of unilateral circumferential nodular pleural thickening along with conglomerate pleural masses and effusions. Both primary and secondary sites progressed along with the appearance of new lesions in all these patients. The mean progression-free survival (PFS) was 32 days using Kaplan Meier analysis. Conclusion The unique and recurring imaging pattern of disease progression in patients with HPD as reported in our case series in addition to TGK ratio, and TTF may prove to be of additional help in early identification of this unique and ghastly outcome.

Hepatoid adenocarcinoma of lung is a rare entity, accounting for 5% of all hepatoid adenocarcinoma. Distinguishing it from metastatic hepatocellular carcinoma is essential, but occasionally can be very challenging, especially with concurrent liver mass. A judicious immunohistochemical panel is warranted for accurate diagnosis and subsequent preservation of tissue for molecular testing. There is limited data on the mutational status, behavior and management strategies of this type of lung adenocarcinoma. We report largest series of six cases of hepatoid adenocarcinoma of lung citing the clinical, histopathological, immunohistochemical and molecular parameters including PD-L1 immunoexpression as a predictive biomarker for immunotherapy. None of the evaluated cases showed targetable mutation; however, four out of six cases showed significant PD-L1 expression. All the cases presented with advanced stage and received chemotherapy, however overall prognosis was dismal. In view of significant PD-L1 expression in these tumors and poor response to conventional chemotherapy, these cases might be considered for upfront immunotherapy.

Lung cancer diagnostics and therapeutics have witnessed a paradigm shift in the last decade because of the discovery of targetable biomarkers and rapid approvals of the corresponding targeted therapies. The prognosis of biomarker-driven tumors has improved, and hence, testing for the presence of targetable biomarkers is now a mandate according to both national and international recommendations. Apart from the common and canonical alterations in the epidermal growth factor receptor, anaplastic lymphoma kinase, and ROS1 genes, NTRK fusions, although rare, are gaining clinical importance as targetable alterations. With entrectinib and larotrectinib making their way into the phase III trials, a comprehensive knowledge about the biology, molecular diagnostic techniques, ongoing trials, and available drugs for NTRK-fusion-positive lung cancers is essential. Therefore, we performed a narrative review of the already published literature. The PubMed, Embase, and Scopus databases were searched using the keywords “biology of NTRK,” “TRK,” “NTRK” and “NSCLC.” A total of 32 relevant articles were reviewed. In this review, we have described the biology, signaling pathways, detection methods, and treatment for NTRK-fusion-positive cancers.

Non-small cell lung cancer (NSCLC) has emerged as the poster child of molecular medicine. Kirsten rat sarcoma (KRAS)-mutated NSCLC is a common yet heterogeneous entity with distinct clinical and prognostic characteristics. Therapeutically, targeting the KRAS mutation in NSCLC has been the most difficult challenge faced by scientists and drug developers and after decades of efforts, a final breakthrough in the form of KRAS G12C inhibitors has emerged. In this edition of the biomarker series, we review KRAS, its biology, clinical features, and the therapeutic options in KRAS-mutant NSCLC. We performed a thorough search in PubMed, Embase, and Scopus and finally included 59 articles to write this review.

The unprecedented growth of the high-throughput next-generation sequencing has facilitated the identification of rare oncogene fusions such as ROS1 for NSCLC. ROS1 rearrangement has been observed in only 2% of cases of NSCLC and has been successfully targeted using various tyrosine kinase inhibitors including crizotinib. However, the on-target and off-target mechanisms of the resistance are still vague. Here, we report a case of a patient with ROS1 rearranged NSCLC presenting primary resistance to crizotinib.

Objective The aim of this study is to investigate the effects of gemcitabine maintenance on progression-free survival (PFS) in patients with metastatic gallbladder cancer (GBC). Materials and Methods Sixty patients with unresectable or metastatic GBC having ongoing response to treatment with initial six cycles of gemcitabine and a platinum-based doublet chemotherapy were prospectively randomized on day 21 of the 6th cycle in 1:1 fashion to receive either maintenance gemcitabine 1 g/m2 intravenously on day 1 and day 8 of three weekly cycle or observation. Survival analysis was performed using the Kaplan–Meier method and comparisons by the log-rank test. A p-value < 0.05 was considered as statistically significant. Results Of 60 patients, a total of 56 were available for final analysis. The median PFS was 4.7 months (3.1–6.3) in gemcitabine arm and 2.6 months (2.4–2.8) in observation arm, hazard ratio (HR) 0.196 (95% confidence interval [CI]: 0.1–0.39), p < 0.001. Median overall survival in gemcitabine arm was 12.4 months (9.15–15.6) as opposed to 9.9 months (8.29–11.5) in observation arm, HR 0.76 (95% CI: 0.43–1.35), p = 0.354. The grade 3 or 4 side effects in maintenance arm were transaminitis (17.9%), thrombocytopenia (17.8%), neutropenia (14.2%), and febrile neutropenia (7.1%). Conclusions Maintenance gemcitabine therapy in unresectable/metastatic GBC patients responding to first-line gemcitabine and platinum treatment contributes to increase PFS with minimal and manageable side effects.

Background: Biomarker-driven lung adenocarcinomas involving alterations in oncogenic drivers such as EGFR, ALK, ROS1, and NTRK have witnessed a dramatic shift in the therapeutic and prognostic landscape owing to the development of molecular targeted therapies. The recent approval of the selective RET inhibitor, selpercatinib, has led to an ardent interest in RET-rearranged non-small cell lung carcinoma (NSCLC). However, sequential single-gene testing cannot detect RET rearrangements accurately or characterize the fusion partners. Objectives: We aimed to determine the incidence and types of RET alterations in our patients with NSCLC, and to describe the demographic and clinical profile of our patients with RET-driven NSCLC. In addition, our aim was to highlight the advantages of broader panel-based testing by the next generation sequencing (NGS) over single-gene assays. Materials and Methods: This is a retrospective, case series of patients with advanced NSCLC who underwent testing by NGS between December 2018 and August 2020 at our center, with a focus on the cases who were found to have the RET gene rearrangement. The demographic, clinicopathological profiles, and treatment details were retrieved from the medical record archives. Statistical analysis was performed using the Statistical Package for the Social Sciences software version 23 for Windows. Results: A total of 169 patients were enrolled in the study. RET rearrangement was detected in 2.9% (n = 5) of the patients in our cohort. Four cases had the KIF5B-RET fusion, and one case had the CCDC6-RET fusion. The median age of the patients was 55 years (range, 45–82), with a slight female preponderance (men: 2 and women: 3). The RET fusions were detected using an NGS-based assay. Four out of the five patients were administered pemetrexed-carboplatin-based chemotherapy and are alive and on regular follow-up. One patient did not receive any treatment and has succumbed to the disease. One patient has been administered selpercatinib after failing many lines of chemotherapy. Conclusions: The emergence of newer molecular targets necessitates the use of an broader panel-based NGS testing to detect oncogene addiction in NSCLC. This case series highlights the importance of NGS-based testing in the light of the recent approval of selpercatinib for RET-rearranged NSCLC.

Introduction: Whereas interpatient heterogeneity in clinical characteristics and treatment outcomes of NSCLC harboring a KRAS mutation is recognized, the characterization of these patients in Asia has been limited. Methods: A multicenter, retrospective cohort study was conducted in eight academic centers across Asia. Patients diagnosed with advanced NSCLC harboring a KRAS mutation and who had received at least one line of anticancer therapy between January 2014 and December 2018 were included. Modified time to next treatment (TTNT) was adopted as a proxy for progression-free survival. Results: A total of 216 patients were analyzed. The median age at diagnosis of advanced NSCLC was 63.3 years, 70.8% were men and 89.8% had adenocarcinoma. KRAS G12D was the most common subtype (25.5%), followed by G12C (24.5%), and G12V (19.4%) The proportion of current or former smokers was 65.7% in the overall population, with 86.8% in G12C and 58.9% in non-G12C subgroups. For all treatments combined for the total population, the first-line duration of therapy, modified TTNT, and TTNT were 4.5 (95% confidence interval: 3.4–5.9), 6.2 (4.9–8.8), and 9.5 (7.1–11.4) months, respectively. The median overall survival for the total population was 10.3 (6.9–12.4) months and was prolonged in patients ever treated with immunotherapy (14.6 [8.6–19.1] versus 7.0 [5.9–10.6] mo, hazard ratio = 0.54, p < 0.001), with left truncation to account for the time of KRAS testing. Conclusions: Whereas treatment outcomes with conventional anticancer therapy are reasonable and immunotherapy looks promising, the unmet need remains high for patients with KRAS-mutated NSCLC in Asia, underscoring the need for novel therapeutic approaches.

Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma arising from peripheral nerves. They can be found in isolation, but about half of the cases are associated with neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder. They usually arise from the nerve plexus in extremities and trunk. MPNSTs arising from the viscera or internal organs are very rare. We hereby report a rare case of sporadic MPNST arising from pleural surface in a middle-aged male. The diagnosis of such a rare entity involved multimodal investigations with consideration of wide differential diagnosis.

Myoepithelial tumor of lung is a rare tumor; the histopathological findings resemble the myoepithelial tumors of the salivary gland. Distinguishing low-grade nonmetastatic myoepithelial carcinoma from benign myoepithelioma can be challenging both radiologically and histomorphologically. We present a case report of a low-grade myoepithelial carcinoma of lung with contralateral lung metastasis which was treated with low-dose external beam radiotherapy

The treatment of advanced non-small-cell lung cancer (NSCLC) has undergone a paradigm shift since the early part of this millennium. The knowledge and detection of molecular subtypes of this entity based on the phenomenon of oncogene addiction like ALK rearrangement, has led to the emergence of an era of precision and personalized medicine. Since its discovery, many molecular targets have been developed for ALK rearranged NSCLC which have rapidly transitioned from bench to bedside, with fast approvals for clinical use. This has increased the outcome in ALK rearranged patients dramatically; however the emergence of resistance to ALK TKI is inevitable and is fundamental to ongoing research and every day clinical practice. We herein report two interesting cases of ALK rearranged NSCLC who developed resistance to second generation ALK TKI, due to the development of new KRAS mutations. By far, this mechanism in the context of alectinib has not been reported in literature and this report may stimulate further studies into the same

Multiple primary malignancies have been reported in anecdotal case reports and series in literature. The de novo occurrence poses diagnostic and therapeutic challenges. The co-occurrence of lung adenocarcinoma with acute myeloid leukemia synchronously has been reported in one small series in literature. There is limited data available regarding the treatment and response outcomes in such cases, where both malignancies are molecularly and therapeutically distinct. Hence, a comprehensive workup including a complete molecular profiling is necessary to render appropriate therapy to the patient. This report elucidates the same in a case of concurrent de novo lung adenocarcinoma and acute myeloid leukemia, where complete molecular workup culminated in a successful treatment outcome.

The knowledge of oncogene addiction in non small cell lung carcinoma (NSCLC) involving EGFR, ALK and ROS1 genes has changed the therapeutic and prognostic landscape of NSCLC. ALK rearranged NSCLC accounts for 10% of these cases, and with the development and approval of ALK TKIs (tyrosine kinase inhibitors) like crizotinib, it is imperative to detect the same. Various ALK variants are known to occur resulting in differential sensitivities to TKIs because of different protein stabilities. The precise characterization hence is important which can be achieved only by high throughput next generation sequencing (NGS) based assays. Immunohistochemistry and FISH (fluorescence in situ hybridization) although considered gold standards cannot define the breakpoints and length of the fusion transcripts. We herein report a novel EML4-ALK variant in a case of advanced NSCLC which plausibly is inherently resistant to crizotinib because of the breakpoints involved.

ABSTRACT Single gene assays for variants in Epidermal Growth Factor Receptor (EGFR) demonstrate actionable and sensitising mutations in majority of the cases. However, the emergence of next generation sequencing platforms has facilitated the detection of newer variants in the already known drivers of lung carcinomas, which may be clinically actionable. Mutations in exons 18 to 21 of EGFR are widely characterised in literature, and rare unusual mutations in these regions are constantly being demonstrated recently. This report describes a rare exon 18 insertion variant in EGFR gene in a 61-year-old patient of non-small cell lung carcinoma, which is potentially actionable, thus highlighting the need of next generation sequencing based platforms in this era of precision medicine.

Aims: The anaplastic lymphoma kinase (ALK) Break Apart FISH Probe Kit and Ventana anti-ALK (D5F3) CDx immunohistochemistry (IHC) assay are the Food and Drug Administration-approved companion diagnostic for targeted therapy with the ALK inhibitor crizotinib in lung cancers. The aim of this study was to assess the efficacy and safety of twice daily crizotinib tablet (250 mg) in IHC-proven echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene among Indian patients with adenocarcinoma lung in the routine clinical practice. Subjects and Methods: Patients with nonsmall cell lung cancer (NSCLC), adenocarcinoma histology, whose tumors were found to be positive for EML4-ALK fusion gene using IHC, were considered for this study. IHC analysis was performed using a Ventana automated immunostainer (Benchmark XT). Detection was performed using Optiview DAB detection and amplification kit. Results: A total of 25 NSCLC adenocarcinoma patients were included in the study. There were 14 (56%) women and 10 (44%) men with a median age of 53 years. All patients had Stage IV disease at the time of initiation of crizotinib therapy. One patient achieved complete response and 20 achieved response rate (PR) for an overall PR of 84%. The median progression-free survival (PFS) was 11.8 months and median overall survival (OS) was 20.6 months. Two (8%) patients experienced severe hepatotoxicity requiring permanent discontinuation of crizotinib therapy. Conclusions: A very high PR, PFS, and OS achieved in our study population indicates that IHC can accurately identify EML4 ALK fusion gene mutations in lung adenocarcinoma patients who are responsive to ALK inhibitors such as crizotinib. IHC should be considered as a cost-effective alternative to FISH, especially in low-resource countries.

Background: We share our experience of using droplet digital polymerase chain reaction (DdPCR) in liquid biopsy specimens for detecting primary and secondary epidermal growth factor receptor (EGFR) mutations among patients with nonsmall-cell lung cancer who had tissue biopsy initially analyzed for del19, L858R and T790M. Materials and Methods: Three groups of patients were chosen: Group 1: patients positive for EGFR mutation (del 19 or L858R) by conventional tissue biopsy that were treatment naïve, Group 2: patients positive for EGFR mutation (del 19 or L858R) by conventional tissue biopsy with acquired resistance to tyrosine kinase inhibitor (TKI) therapy, documented by radiology, and Group 3: no known EGFR mutation detected on primary tissue biopsy and treatment naive. Results: One hundred and thirty-three patients were included in the study. Group 1 had 40 cases, of which 21 (52.5%) and 19 (47.5%) were positive for del19 and L858R mutations, respectively, by tissue biopsy. DdPCR detected primary mutation in all but 5 cases. DdPCR additionally found four patients to have T790M mutation. Group 2 had 73 cases and DdPCR detected T790M mutation in 39 (53.4%) cases. Liquid biopsy also picked the original primary mutation in 56/73 cases. Secondary tissue biopsy for T790M mutation status was performed in 11 patients and while it detected mutation in 2 out of 11 cases, DdPCR detected the same in 7 cases, thus providing significantly superior yield (46% difference, McNemar's test, P value 0.063). Tissue biopsy additionally detected c-MET amplification in a patient who had T790M mutation on liquid biopsy. Group 3 had 20 patients and none were falsely positive for EGFR mutation on liquid biopsy. Overall, DdPCR had a Cohen's kappa of 0.82 (standard error 0.074, 95% CI 0.68–0.97) indicating “very good agreement” with conventional tissue biopsy. Conclusion: DdPCR demonstrated 87.5% sensitivity and 100% specificity in detecting primary EGFR mutations in patients who were treatment naïve with overall positive and negative predictive value of 100% and 80%, respectively. DdPCR demonstrated T790M mutation postprogression on TKI therapy in 53.4% patients.

This is a case report of a 60-year-old diabetic, hypertensive male with a good performance status and a history of bilateral interstitial lung disease with a left upper lobe lung mass diagnosed to be a Stage IIB mixed small-cell/squamous cell carcinoma which was refractory to carboplatin- and etoposide-based chemotherapy. The patient was then taken up for adaptive intensity-modulated radiotherapy with tighter margin under image guidance with a mid-treatment replanning done at 25#. Acute toxicities were assessed weekly and showed no Grade 3 or more reactions. Pulmonary function test showed no detrimental changes during or after radiation. Response assessment at 12 and 20 weeks showed a partial response with decrease in metabolic activity on serial scans.

Aim: The aim of this study is to determine the incidence of T790M mutations after progression on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) and median duration on TKI before progression on TKI. Methods: Records of Rajiv Gandhi Cancer Institute and Research Centre, of patients who were diagnosed with metastatic adenocarcinoma of the lung and progressed on oral EGFR TKIs and underwent T790M mutation analysis in the last 6 months were retrospectively reviewed. The incidence of T790M positivity, sites of progression, and median duration of TKI treatment before progression was calculated. Results: Among 31 patients, 10 patients have undergone rebiopsy, and 24 patients had undergone liquid biopsy by Droplet Digital polymerase chain reaction (ddPCR), and three patients had undergone both tests. Among all, the rate of T790M positivity was 54.8%. Among these 17 patients positive for T790M, seven patients were positive by biopsy, and 11 patients were positive by ddPCR. Among three patients who underwent both, one was positive by both. The most common site of progression among all patients is pleura, and 10% of patients progressed in brain post-TKI. Median progression-free survival on TKI before progression is 289.7 days, highest being 1290 days, and lowest 45 days. Conclusions: Exact incidence of T790M mutations after progression on TKI s in Asian population is not exactly known and requires large data, as incidence may be different than reported in the Western population. Rebiopsy and ddPCR help to determine the most common type of resistance after progression on TKI, for which effective targeted therapy is available.

Background: The frequency of ROS1 rearrangement in non-small cell lung cancers has been reported from 1.6% to 2.3%. Materials and Methods: We examined 105 lung adenocarcinoma patients for ROS1 rearrangement which were negative for EGFR and anaplastic lymphoma kinase. Clinical characteristics of ROS1 rearranged patients and their responses to crizotinib therapy were studied. Results: Of the 105 patients, three cases were positive for ROS1 rearrangement by fluorescence in situ hybridization analysis. All of them showed heterogeneous pattern. All the 3 ROS1-positive patients were females in their forties and started on crizotinib. All of them responded to treatment. One of them developed resistance after 3 months. Another one showed marked systemic response but central nervous system lesions progressed. The third case is doing well till date with inactive lesions on positron emission tomography scan. Conclusions: The frequency of ROS1 rearrangement is low in non-small cell lung carcinoma, but their diagnosis offers patients an opportunity to receive highly effective targeted therapies.

Background: With fluorescence in situ hybridization (FISH) as the main-stay for the detection of anaplastic lymphoma kinase (ALK) rearrangements, the ALK Break Apart FISH Probe Kit has become a Food and Drug Association-approved companion diagnostic for targeted therapy with the ALK inhibitor crizotinib in lung cancers. The objective of this molecular epidemiological study was to estimate the prevalence of microtubule-associated protein-like 4-ALK (EML4-ALK) fusion gene using immunohistochemistry (IHC) as a cost effective alternative to FISH for Indian patients with nonsmall-cell cancer (NSCC)-adenocarcinoma, favor adenocarcinoma lung and NSCC- Not otherwise specified (NOS). Materials and Methods: Patients with NSCC-adenocarcinoma, favor adenocarcinoma lung, and nonsmall cell lung cancer-NOS histology were considered for this study. Permission was obtained from the Ethics Committee before the start of the study. Clinical characteristics and treatment details were collected from the patient's medical records. IHC analysis was performed using a Ventana automated immunostainer (Benchmark XT). Detection was performed using OptiView DAB Detection and Amplification Kit. Results: A total of 200 NSCC-adenocarcinoma, favour adenocarcinoma and NSCC-NOS patients were included in the study. There were 122 (61%) men and 78 (39%) women with a median age of 57 years. Of the 200 patients, 43 (21.5%) were nonsmokers and 175 (87.5%) had Stage-IV disease at the time of initial diagnosis. 48 (24%) cases were positive for epidermal growth factor receptor mutations, whereas EML4-ALK fusion gene was present in 27 (13.5%) patients. 25 of the 27 patients with ALK positivity received crizotinib therapy. Conclusions: The incidence of EML4-ALK gene fusions (13.5%) in this Indian population is four-fold high than the previous reported incidences and supports the claim of several recent studies that a relatively new ALK clone, 5A4, and D5F3 from Leica/Novocastra and cell signaling technology/Ventana, respectively can accurately identify ALK rearranged lung adenocarcinoma. The inclusion of IHC for the detection of EML4-ALK gene fusions as a low cost alternative seems justified in low resource setting.

Introduction: The optimal management of neuroparenchymal lesions in cases of lung cancer is exigent as this frequent yet notorious complication negatively impacts the morbidity and mortality index. Aims: This study is aimed at recognizing various patterns of neuroparenchymal metastasis in patients of lung cancer with epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-positive mutations. Material and Methods: The radiological findings of the neuroparenchymal lesions were analyzed and the statistical data were charted. We identified two groups of patients with neuroparenchymal lesions among a cohort of 340 patients having EGFR-positive (68) and ALK-positive (24) mutations (total: 24 + 68 = 92). Results: We observed that among the ALK group, leptomeningeal spread was less compared to EGFR group (2/24 as opposed to 18/68). Morphological heterogeneity and central necrosis in the parenchymal lesion which were associated with unfavorable outcomes were predominant in ALK group (8/24) as opposed to EGFR group (2/68). Ancillary findings but pertinent to survival and morbidity such as presence of perilesional edema, hemorrhage, and hydrocephalus on magnetic resonance imaging were also analyzed. The mutation-specific differential imaging spectrum could be attributed to biological differences between these cancers.