Person: Rangachari, Deepa
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Rangachari
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Deepa
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Rangachari, Deepa
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Publication Experience with targeted next generation sequencing for the care of lung cancer: Insights into promises and limitations of genomic oncology in day-to-day practice(Elsevier BV, 2015) Rangachari, Deepa; Vanderlaan, Paul; Le, Xiuning; Folch, Erik; Kent, Michael; Gangadharan, Sidhu; Majid, Adnan; Haspel, Richard; Joseph, Loren; Huberman, Mark S.; Costa, DanielIntroduction Tumor genotyping using single gene assays (SGAs) is standard practice in advanced non-small-cell lung cancer (NSCLC). We evaluated how the introduction of next generation sequencing (NGS) into day-to-day clinical practice altered therapeutic decision-making. Methods Clinicopathologic data, tumor genotype, and clinical decisions were retrospectively compiled over 6 months following introduction of NGS assay use at our institution in 82 patient-tumor samples (7 by primary NGS, 22 by sequential SGAs followed by NGS, and 53 by SGAs). Results SGAs identified abnormalities in 34 samples, and all patients with advanced EGFR-mutated or ALK-rearranged tumors received approved tyrosine kinase inhibitors (TKIs) or were consented for clinical trials. NGS was more commonly requested for EGFR, ALK, and KRAS-negative tumors (p<0.0001). NGS was successful in 24/29 (82.7%) tumors. Of 17 adenocarcinomas (ACs), 11 (7 from patients with ≤15 pack-years of smoking) had abnormalities in a known driver oncogene. This led to a change in decision-making in 8 patients, trial consideration in 6, and off-label TKI use in 2. Of 7 squamous cell (SC) carcinomas, 1 had a driver aberration (FGFR1); 6 had other genomic events (all with TP53 mutations). In no cases were clinical decisions altered (p=0.0538 when compared to ACs). Conclusions Targeted NGS can identify a significant number of therapeutically-relevant driver events in lung ACs; particularly in never or light smokers. For SC lung cancers, NGS is less likely to alter current practice. Further research into the cost effectiveness and optimal use of NGS and improved provider training in genomic oncology are warranted.Publication Rapidly fatal advanced EGFR -mutated lung cancers and the need for rapid tumor genotyping in clinical practice(Elsevier BV, 2016) Rangachari, Deepa; Drake, Lauren; Huberman, Mark S.; McDonald, Danielle C.; Vanderlaan, Paul; Folch, Erik; Costa, DanielUse of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is associated with dramatic, durable, and tolerable responses and side effect profiles, respectively, when applied for palliation of advanced EGFR-mutated non-small-cell lung cancers (NSCLCs). Expert guidelines recommend that EGFR mutation testing results should be available within 10 working days of receipt of tumor specimen by the testing laboratory; in circumstances where the tumor specimen needs to be sent to an external laboratory for testing, the sample should be sent within 3 working days of receiving the request for testing. We report here 2 cases, out of 109 EGFR-mutated (exon 19 deletion or L858R) NSCLCs seen at our institution, experiencing rapid clinical deterioration and death within the window of time prescribed by consensus testing guidelines. We hypothesize that a faster turn-around time may have changed the clinical outcome. Improving rapid turnaround times for tumor genotyping may afford more optimal palliation vis-à-vis early initiation of oral targeted therapy in patients with advanced EGFR-mutated NSCLC.Publication Brain metastases in patients with EGFR -mutated or ALK -rearranged non-small-cell lung cancers(Elsevier BV, 2015) Rangachari, Deepa; Yamaguchi, Norihiro; Vanderlaan, Paul; Folch, Erik; Mahadevan, Anand; Floyd, Scott R.; Uhlmann, Erik; Wong, Eric; Dahlberg, Suzanne; Huberman, Mark S.; Costa, DanielIntroduction—Brain metastases (BM) are common in non-small-cell lung cancer (NSCLC). However, the baseline incidence and evolution of BM over time in oncogene-driven NSCLCs are seldom reported. In this study, we evaluated the frequency of BM in patients with epidermal growth factor receptor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Methods—The presence of BM, clinicopathologic data, and tumor genotype were retrospectively compiled and analyzed from a cohort of 381 patients. Results—We identified 86 EGFR-mutated (90.7% with metastatic disease; 85.9% received an EGFR inhibitor) and 23 ALK-rearranged (91.3% with metastatic disease; 85.7% received an ALK inhibitor) NSCLCs. BM were present in 24.4% of EGFR-mutated and 23.8% of ALK-rearranged NSCLCs at the time of diagnosis of advanced disease. This study did not demonstrate a difference in the cumulative incidence of BM over time between the two cohorts (EGFR/ALK cohort competing risk regression [CRR] coefficient of 0.78 [95% CI 0.44–1.39], p=0.41). In still living patients with advanced EGFR-mutated NSCLC, 34.2% had BM at 1 year, 38.4% at 2 years, 46.7% at 3 years, 48.7% at 4 years, and 52.9% at 5 years. In still living patients with advanced ALKrearranged NSCLC, 23.8% had BM at 1 year, 45.5% at 2 years, and 58.4% at 3 years. Conclusions—BM are frequent in advanced EGFR-mutated or ALK-rearranged NSCLCs, with an estimated >45% of patients with CNS involvement by three years of survival with the use of targeted therapies. These data point toward the CNS as an important unmet clinical need in the evolving schema for personalized care in NSCLC.Publication De novo pulmonary small cell carcinomas and large cell neuroendocrine carcinomas harboring EGFR mutations: Lack of response to EGFR inhibitors(Elsevier BV, 2015) Le, Xiuning; DeSai, Neelam; Majid, Adnan; Karp, Rebecca; Huberman, Mark S.; Rangachari, Deepa; Kent, Michael; Gangadharan, Sidhu; Folch, Erik; Vanderlaan, Paul; Costa, DanielIntroduction Epidermal growth factor receptor (EGFR) mutations are present in 10-20% of all non-small-cell lung cancers and predict for response to EGFR tyrosine kinase inhibitors (TKIs). However, the incidence of these mutations and their ability to predict response to TKIs in high-grade pulmonary neuroendocrine carcinomas [i.e. small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC)] is unknown. Methods The presence of EGFR mutations, clinicopathologic and anti-cancer therapy response data were retrospectively compiled and analyzed from a cohort of 608 patients-lung tumors to identify EGFR mutated high-grade pulmonary neuroendocrine carcinomas. We identified 126 EGFR-mutated (21.8% of 578 successful genotyped cases) lung cancers and only 2 (1.6%) were high-grade neuroendocrine carcinomas. Results Case one was of a 63 year-old white never smoker woman with extensive stage SCLC harboring EGFR-delL747_P753insS but without EGFR protein expression. After progression on carboplatin/etoposide, the patient was treated with erlotinib and developed progressive disease with a survival <3 months from start of erlotinib. Case two was of a 73 year-old Asian 30 pack-year smoker man with metastatic LCNEC harboring EGFR-delL747_P753insQS and also lacking EGFR protein expression. The patient received first line therapy with erlotinib and had progressive disease with a survival of 4 months. Conclusions The lack of response to EGFR TKIs in EGFR mutated de novo SCLC and LCNEC reported here may indicate that tumor differentiation affects tumor dependency on EGFR as a driver oncogene.