Summary Deregulated HER2 is a target of many approved cancer drugs. We analyzed 111,176 patient tumors and identified recurrent HER2 transmembrane domain (TMD) and juxtamembrane domain (JMD) mutations, including G660D, R678Q, E693K and Q709L. Using a saturation mutagenesis screen and testing of patient-derived mutations we found several activating TMD and JMD mutations. Structural modeling and analysis showed that the TMD/JMD mutations function by improving the active dimer interface or stabilizing an activating conformation. Further, we found that HER2 G660D employed asymmetric kinase dimerization for activation and signaling. Importantly, anti-HER2 antibodies and small molecule kinase inhibitors blocked the activity of TMD/JMD mutants. Consistent with this, a G660D germline mutant lung cancer patient showed remarkable clinical response to HER2 blockade.

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Introduction. Brain metastasis is a poor prognostic marker in lung cancer. However it is not known whether amongst patients with EGFR mutation those with brain metastases have a worse outcome. Methods. We compared the survival outcomes between EGFR mutation positive patients with and without brain metastases. In this retrospective analysis of prospective database of all metastatic lung cancer patients at our centre between July 2009 and December 2012, patients were treated with either combination chemotherapy or oral TKI. All patients with brain metastases received whole brain radiation. Kaplan Meier method was used for survival analysis and compared using log rank test. Results. 101 patients with EGFR mutated, metastatic lung cancer were studied. Fourteen had brain metastases and 87 did not. The common EGFR mutations were exon 19 deletion (61.3%) and exon 21 L858R mutation (28.7%). Overall response was 64% in extracranial metastasis group as compared to 50% in brain metastasis group. There was a significant worsening of median OS in the patients with brain metastases (11.6 months) compared with only extracranial metastases (18.7 months), P = 0.029. Conclusion. Amongst patients with EGFR mutant NSCLC, the presence of brain metastases leads to a worse outcome as compared to patients with extracranial metastases alone.

Introduction ROS1 oncogenic fusion, which was first identified by Rikova et al, is reported to be present in 1%–2% of non-small cell lung cancers (NSCLCs) and is defined as a distinct molecular sub-group. Crizotinib is very effective in ROS1-positive patients and is now Food and Drug Administration (FDA) approved for the treatment of patients with advanced ROS1-positive NSCLC. We report our experience in a tertiary cancer care hospital in India in ROS-1 positive patients. Materials and method The present series is a retrospective analysis of 22 patients from the prospectively maintained lung cancer audit. Demographic data were collected which included age, performance status, gender, stage, co-morbidities, sites of metastasis and smoking history. Data were also collected regarding the source of financing for crizotinib whether self-financed, through insurance or Non-Governmental Organisation (NGO) sponsored. Patients who had tested negative for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) and were subsequently found to be ROS1-mutation negative by fluorescence in situ hybridization (FISH) were evaluated on similar lines. All the data were entered and statistical analyses were performed using the SPSS software version 22.0. Response evaluation was done by RECIST 1.1 criteria. Results Between January 2015 and December 2017, there were 22 patients who were ROS1 positive from a total of 535 patients in whom ROS1 testing was performed. A total of 16 patients could receive crizotinib and 6 patients were never exposed to crizotinib. Among the 16 patients who received crizotinib, 2 (12.5%) achieved complete response (CR) as their best response and continue to remain in CR at follow-up. 13 (81%) had a partial response as best response and of which on follow-up 5 (38%) have progressed, while 8 (62%) continue to maintain response. The patients who were on crizotinib had good tolerance with none experiencing any grade 3/4 toxicity. The median follow-up of the entire cohort was 15.2 months in ROS1-positive cohort and 11.4 months in ROS1-negative cohort. In ROS1-positive cohort median, progression-free survival (PFS) was not reached and the estimated 2-year PFS was 54% and in ROS1-negative cohort, it was 5.1 months. The median overall survival of the entire ROS1-positive cohort was not reached and the estimated 1- and 2-year overall survival (OS) was 72% and 54%, respectively, and was 8.8 months in ROS1-negative cohort. Conclusion ROS1 rearrangement with an incidence of 4% of lung adenocarcinoma which is EGFR and ALK negative represents an important targetable driver mutation in the Indian population. Crizotinib also represents an effective treatment option with outcomes similar to those reported. Access to treatment remains an important roadblock to improve outcomes but innovative methods may improve access to these drugs.

Objective To assess the ability of 68Ga DOTA-NOC PET/computed tomography (CT) to differentiate dural metastases from meningioma. Patients and methods Patients who underwent a 68Ga DOTA-NOC PET/CT for differentiating meningiomas from dural metastases were included in the study. A visual score was assigned to the dural lesions (visual score – 1 to 3) in relation to the uptake in liver and spleen and variation in the visual score was evaluated. SUVmax of the dural lesions was also noted and difference in the values of the two pathologies were compared for statistical significance using nonparametric statistical tests. Final diagnosis was decided by histopathological confirmation whenever available. Results Imaging, histopathology or follow-up data of 42 patients was available for analysis. Meningioma was the final diagnosis in 31 (73.8%) patients, whereas dural metastases were diagnosed in 9 (21.4%) patients. In two patients, histopathology revealed inflammatory pseudotumor and hemangioblastoma. Meningiomas showed intense tracer uptake in 30/31 patients (visual score 3). All metastatic lesions showed some degree of tracer uptake though the intensity was lesser compared to meningioma (visual score 1, 2). Meningiomas showed a significantly higher median SUV max value compared to metastases (12.7 vs. 6.0, P = 0.001). Conclusion Meningiomas can be differentiated from dural metastases by virtue of their higher uptake of 68Ga-labeled DOTA peptides reflecting higher SSTR expression. An asymptomatic meningeal based lesion with a high visual score (Visual score 3) has a very high probability to be a meningioma rather than dural metastasis.