Rathi Pillai

Molecular Biology, Immunology, Cancer Research

27.05

Publications

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    ABSTRACT: We tested and clinically validated a targeted next-generation sequencing (NGS) mutation panel using 80 formalin-fixed, paraffin-embedded (FFPE) tumor samples. Forty non-small cell lung carcinoma, 30 melanoma, and 30 gastrointestinal (12 colonic, 10 gastric, and 8 pancreatic adenocarcinoma) FFPE samples were selected from laboratory archives. After appropriate specimen and nucleic acid quality control, 80 NGS libraries were prepared using the Illumina TruSight tumor (TST) kit and sequenced on the Illumina MiSeq. Sequence alignment, variant calling, and sequencing quality control were performed using vendor software and laboratory-developed analysis workflows. TST generated ≥500× coverage for 98.4% of the 13,952 targeted bases. Reproducible and accurate variant calling was achieved at ≥5% variant allele frequency with 8 to 12 multiplexed samples per MiSeq flow cell. TST detected 112 variants overall, and confirmed all known single-nucleotide variants (n = 27), deletions (n = 5), insertions (n = 3), and multinucleotide variants (n = 3). TST detected at least one variant in 85.0% (68/80), and two or more variants in 36.2% (29/80), of samples. TP53 was the most frequently mutated gene in non-small cell lung carcinoma (13 variants; 13/32 samples), gastrointestinal malignancies (15 variants; 13/25 samples), and overall (30 variants; 28/80 samples). BRAF mutations were most common in melanoma (nine variants; 9/23 samples). Clinically relevant NGS data can be obtained from routine clinical FFPE solid tumor specimens using TST, benchtop instruments, and vendor-supplied bioinformatics pipelines.
    No preview · Article · Jan 2016 · The Journal of molecular diagnostics: JMD
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    ABSTRACT: Background: The last 3 decades have witnessed limited therapeutic advances in small cell lung cancer (SCLC) management. This study evaluated real-world trends in the use of systemic therapies and the impact on patient outcomes in the United States. Methods: The Surveillance, Epidemiology, and End Results-Medicare database was used to find patients diagnosed with SCLC between 1985 and 2005. The 1985-1990 period served as the baseline for a temporal analysis conducted at 5-year intervals (1985-1990, 1991-1995, 1996-2000, and 2001-2005). Cox proportional models were used to estimate the effect of chemotherapy on survival. Results were validated with a propensity-matched analysis. Results: There were 47,351 eligible patients: 52% were male; the median age was 71 years; and 87% were white, 7% were black, and 1.4% were Asian. The proportion of patients treated with chemotherapy was low but increased over time (38%, 55%, 50%, and 53%; P < .001). Race, diagnosis period, age, stage, and location of residence significantly predicted chemotherapy use. Females (51%), Asians (53%), and rural residents (60%) were more likely to receive chemotherapy. The median overall survival with and without chemotherapy was 9.6 and 3.6 months, respectively. Linear trend analyses showed a modest reduction in the impact of chemotherapy on survival for patients treated with chemotherapy versus untreated patients (hazard ratios [HRs], 0.59, 0.61, 0.64, and 0.62; P < .001) but an overall trend of improved survival for treated (HRs, 1.0, 1.03, 1.00, and 0.96; P = .005) and untreated patients (HRs, 1.0, 0.99, 0.94, and 0.92; P < .001). There was no survival difference between patients treated with carboplatin and patients treated with cisplatin (HR, 0.99; confidence interval [CI], 0.81-1.19; P = .875). Additional therapy beyond platinum-based chemotherapy was associated with a survival benefit (HR, 0.78; CI, 0.75-0.81; P < .001). Conclusions: Chemotherapy use was associated with a survival benefit in Medicare patients with SCLC treated in a real-world setting. Cancer 2015. © 2015 American Cancer Society.
    No preview · Article · Oct 2015 · Cancer

  • No preview · Article · Aug 2015 · Cancer Research
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    ABSTRACT: In preclinical studies, the efficacy of the combination of antiangiogenic agents with chemotherapy seems to be dependent on the specific cytotoxic agent. We conducted a systematic review of the efficacy of bevacizumab in combination with taxane or non-taxane containing regimens for untreated, nonsquamous non-small-cell lung cancer patients. An extensive search of published clinical trials was conducted from electronic databases (MEDLINE, EMBASE, and Cochrane) and meeting proceedings using relevant search criteria. Phase 2 and randomized trials reporting on the efficacy of bevacizumab combined with taxane or non-taxane regimens were selected. A systematic analysis of extracted data was performed using Comprehensive Meta-Analysis (Version 2.2) software. Clinical outcome in patients treated with taxane versus non-taxane regimen was compared using point estimates for weighted values of median overall survival, progression-free survival, and response rate. Twenty-nine studies reported between 2005 and 2015 were eligible. A total of 5890 patients (2767 and 3123 in the taxane and non-taxane groups, respectively) were included. The taxane and non-taxane groups were comparable in patient characteristics: median age, 62.8 versus 61.2 years; males, 57% versus 58%; adenocarcinomas, 83% versus 83%; stage IV, 87% versus 82%; performance status 0/1- 45/55% versus 41/59%, respectively. The weighted median overall survival was 14.4 versus 13.7 months (p = 0.5); progression-free survival was 6.93 versus 6.99 months (p = 0.61); response rate was 41% versus 39% (p = 0.65) for taxane and non-taxane groups. The outcomes between taxane and non-taxane regimens when given in combination with bevacizumab for patients with nonsquamous non-small-cell lung cancer are comparable.
    No preview · Article · Aug 2015 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer

  • No preview · Article · Aug 2015 · Journal of Thoracic Oncology
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    ABSTRACT: Patients with lung cancer are at high risk of developing venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism. We sought to characterize the clinical factors associated with development of VTE and the impact of VTE on outcomes for hospitalized lung cancer patients. We analyzed data captured in the Nationwide Inpatient Sample (NIS) database of the Agency of Healthcare Research and Quality (AHRQ). The study included all lung cancer patients hospitalized between 2006 and 2010 who had VTE captured as one of the top three discharge diagnoses. Demographics and outcomes of this population were compared to those of inpatient lung cancer patients without a VTE diagnosis. All analyses were performed using SAS version 9.3. Out of 570,304 lung cancer hospitalizations, 20,672 had a clinically relevant diagnosis of VTE, accounting for 3.6% of all events. The median age of lung cancer patients with VTE was 68 years; 48% were females, 79% were Caucasians, and 43% had metastatic disease. When compared to a lung cancer cohort without VTE (n=502,153), patients with VTE had significantly longer length of stay (LOS) (7.15 days vs. 6.05 days, OR 1.12), higher inpatient mortality (10.03% vs. 8.69%, OR 1.06), higher total hospital charges ($43,800 vs. $37,800, OR 1.07), and greater likelihood of moderate to severe disability upon discharge (55% vs. 49%, OR 1.23). VTE in hospitalized lung cancer patients is associated with longer LOS, higher inpatient mortality rates, increased cost and greater disability upon discharge compared to other inpatient lung cancer patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Feb 2015 · Lung Cancer
  • Rathi N Pillai · Suresh S Ramalingam

    No preview · Article · Dec 2014
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    Full-text · Article · Nov 2014 · International journal of radiation oncology, biology, physics
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    ABSTRACT: Introduction: Use of postoperative radiotherapy (PORT) in non-small-cell lung cancer remains controversial. Limited data indicate that PORT may benefit patients with involved N2 nodes. This study evaluates this hypothesis in a large retrospective cohort treated with chemotherapy and contemporary radiation techniques. Methods: The National Cancer Data Base was queried for patients diagnosed 2004-2006 with resected non-small-cell lung cancer and pathologically involved N2 (pN2) nodes also treated with chemotherapy. Multivariable Cox proportional hazards model was used to assess factors associated with overall survival (OS). Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce selection bias. OS was compared between patients treated with versus without PORT using the adjusted Kaplan-Meier estimator and weighted log-rank test based on IPTW. Results: Two thousand and one hundred and fifteen patients were eligible for analysis. 918 (43.4%) received PORT, 1197 (56.6%) did not. PORT was associated with better OS (median survival time 42 months with PORT versus 38 months without, p = 0.048). This effect was significant in multivariable and IPTW Cox models (hazard ratio: 0.87, 95% confidence interval: 0.78-0.98, p = 0.026, and hazard ratio: 0.89, 95% confidence interval: 0.79-1.00, p = 0.046, respectively). No interaction was seen between the effects of PORT and number of involved lymph nodes (p = 0.615). Conclusions: PORT was associated with better survival for patients with pN2 nodes also treated with chemotherapy. No interaction was seen between benefit of PORT and number of involved nodes. These findings reinforce the benefit of PORT for N2 disease in modern practice using the largest, most recent cohort of chemotherapy-treated pN2 patients to date.
    Full-text · Article · Nov 2014 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer
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    ABSTRACT: Background: Atypical carcinoid (AC) of the lung is a rare form of thoracic malignancy. The limited knowledge of its biology and outcome stems largely from small, single institution experiences. We analyzed the Surveillance, Epidemiology, and End Results database (SEER) to better understand the clinical characteristics of this disease. Methods: Demographic, treatment, and outcome data on all patients with pulmonary AC were obtained from the SEER database with 18 reporting sites from 1973 to 2010 using SEER*Stat 8.1.2. Statistical analysis was performed using SAS 9.3 (SAS Institute, Inc., Cary, NC). Results: There were 947,463 patients diagnosed with lung and bronchus tumors in the SEER database, of which 441 had AC (0.05%). Median age of AC patients was 65 years; 69% were women and 87% of white ethnicity. Metastatic disease was present in 20% of patients at diagnosis. In terms of treatment, 78% of patients underwent resection and 12.5% received radiation. The overall 1-year and 3-year survival rates were 86% and 67%, respectively. The 3-year survival rates for distant (M1), regional (lymph node involvement), and localized (lung only) disease were 26% (13 of 50), 69% (50 of 72), and 85% (99 of 116), respectively. On univariate analysis, patients treated with surgery had reduced risk of death (hazard ratio, HR 0.19; p < 0.001), whereas radiation treatment was associated with increased risk of death (HR 2.45; p < 0.001). Conclusions: AC accounted for less than 1% of all lung cancers diagnosed and was more frequent in women. The best outcomes were observed with surgical resection for localized disease.
    Full-text · Article · Nov 2014 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer

  • No preview · Article · Nov 2014 · International journal of radiation oncology, biology, physics

  • No preview · Article · Nov 2014 · International journal of radiation oncology, biology, physics
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    Full-text · Article · Aug 2014 · Current Problems in Cancer
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    Full-text · Article · Aug 2014 · Current Problems in Cancer
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    ABSTRACT: Background: Patients with recurrent small-cell lung cancer (SCLC) have dismal outcomes. The failure of salvage therapy is due to the possible development of resistance mechanisms, such as the upregulation of the anti-apoptosis protein, Bcl-2. We conducted a phase II study to evaluate if modulation of Bcl-2 with 13-cis-retinoic acid (13-CRA) and interferon alpha could improve response rates when combined with paclitaxel in patients with recurrent SCLC. Methods: Patients with recurrent SCLC and measurable disease were treated with interferon alpha at 6 million units/m² subcutaneously and 13-CRA 1 mg/kg orally on days 1 and 2 and paclitaxel 75 mg/m² intravenously on day 2 of each week for 6 weeks of an 8-week treatment cycle. Treatment was continued until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was response rate with secondary endpoints of progression-free survival (PFS) and overall survival (OS). Bcl-2 levels were assessed in peripheral blood mononuclear cells (PBMCs). Results: Thirty-seven patients were enrolled; 34 were included in the intention-to-treat analysis as 3 patients were ineligible for the study. There were 3 partial responses (9 %), and 5 patients had stable disease (15 %) as best response. The median PFS was 2 months, and median OS was 6.2 months. Although mean Bcl-2 protein levels decreased with therapy in PBMCs, there was no association between Bcl-2 levels and response rate or survival. Conclusion: Despite sound pre-clinical evidence, the addition of 13-CRA and interferon alpha to paclitaxel did not improve outcomes for recurrent SCLC.
    No preview · Article · May 2014 · Cancer Chemotherapy and Pharmacology
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    Rathi N Pillai · Suresh S Ramalingam
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    ABSTRACT: The diagnostic and therapeutic landscape of non-small cell lung cancer (NSCLC) has changed dramatically in the past 50 years since the Surgeon General's report on smoking and lung cancer. Early detection is now a reality for lung cancer. The use of low-dose computed tomography scans for early detection decreases mortality and is beginning to be used in routine clinical practice. Technological advances such as positron emission tomography and endobronchial ultrasound have improved the accuracy of NSCLC staging. The cure rate for early-stage NSCLC has improved as a result of multimodality treatment approaches. The role of systemic therapy has also expanded to earlier stages of the disease. In recent years, the initial steps toward personalized medicine by utilization of targeted treatments based on tumor genotype have been undertaken. Emerging technological advances and greater insights into tumor biology are poised to greatly reduce the burden of lung cancer in the years to come. Mol Cancer Ther; 1-8. ©2014 AACR.
    Preview · Article · Feb 2014 · Molecular Cancer Therapeutics
  • Rathi N Pillai · Taofeek K Owonikoko
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    ABSTRACT: Small cell lung cancer (SCLC) remains a fatal disease due to limited therapeutic options. Systemic chemotherapy is the bedrock of treatment for both the limited and extensive stages of the disease. However, the established management paradigm of platinum-based chemotherapy has reached an efficacy plateau. A modest survival improvement, approximately 5%, was witnessed with the addition of cranial or thoracic radiation to systemic chemotherapy. Other strategies to improve outcome of platinum-based chemotherapy in the last two decades have met with minimal success. The substitution of irinotecan for etoposide in the frontline treatment of SCLC achieved significant efficacy benefit in Japanese patients, but similar benefit could not be reproduced in other patient populations. Salvage treatment for recurrent or progressive SCLC is particularly challenging, where topotecan remains the only agent with regulatory approval to date. Ongoing evaluation of biologic agents targeting angiogenesis, sonic hedgehog pathway, DNA repair pathway, and immune checkpoint modulators hold some promise for improved outcome in SCLC. It is hoped that the coming decade will witness the application of new molecular biology and genomic research techniques to improve our understanding of SCLC biology and identification of molecular subsets that can be targeted appropriately using established and emerging biological agents similar to the accomplishments of the last decade with non-small cell lung cancer (NSCLC).
    No preview · Article · Feb 2014 · Seminars in Oncology
  • Rathi N Pillai · Suresh S Ramalingam
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    ABSTRACT: Heat shock protein 90 (Hsp90) protects cellular proteins from degradation by the ubiquitin-proteasome system in conditions of stress. Many cancers have increased expression of Hsp90 to ensure their malignant phenotype of increased proliferation, decreased apoptosis, and metastatic potential by conservation of proteins like epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, anaplastic lymphoma kinase (ALK), v-Raf murine sarcoma viral oncogene homologue B1, AKT, B-cell lymphoma 2, and cell cycle proteins. This review discusses recent developments in the strategy of Hsp90 inhibition as a targeted therapy in nonsmall cell lung cancer (NSCLC). Hsp90 inhibitors result in growth inhibition and tumor regression in NSCLC cell lines and tumor xenograft models, both as monotherapy and in combination with other drugs. Hsp90 inhibition has particular efficacy in molecular subtypes of NSCLC, such as EGFR-mutated and ALK-rearranged NSCLC. IPI-504 and ganetespib have activity in NSCLC both as monotherapy and in combination with docetaxel. Preclinical studies and early clinical trials have confirmed the efficacy of Hsp90 inhibition as a targeted therapy in NSCLC. Ongoing trials will further define the utility of Hsp90 inhibitors in NSCLC.
    No preview · Article · Jan 2014 · Current opinion in oncology
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    ABSTRACT: Purpose: Currently, there is no clinically validated test for the prediction of response to tubulin-targeting agents in non-small cell lung cancer (NSCLC). Here, we investigated the significance of nuclear expression of the mitotic checkpoint gene checkpoint with forkhead and ringfinger domains (CHFR) as predictor of response and overall survival with taxane-based first-line chemotherapy in advanced stage NSCLC. Methods: We studied a cohort of 41 patients (median age 63 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. CHFR expression by immunohistochemistry (score 0-4) was correlated with clinical outcome using chi-square test and Cox proportional models. A cutoff score of "3" was determined by receiver operator characteristics analysis for "low" CHFR expression. Results were validated in an additional 20 patients who received taxane-based chemotherapy at Emory University Hospital and the Atlanta VAMC. Results: High expression (score = 4) of CHFR is strongly associated with adverse outcomes: the risk for progressive disease after first-line chemotherapy with carboplatin-paclitaxel was 52% in patients with CHFR-high versus only 19% in those with CHFR-low tumors (P = 0.033). Median overall survival was strongly correlated with CHFR expression status (CHFR low: 9.9 months; CHFR high: 6.2 months; P = 0.002). After multivariate adjustment, reduced CHFR expression remained a powerful predictor of improved overall survival (HR = 0.24; 95% CI, 0.1-0.58%; P = 0.002). In the validation set, low CHFR expression was associated with higher likelihood of clinical benefit (P = 0.03) and improved overall survival (P = 0.038). Conclusions: CHFR expression is a novel predictive marker of response and overall survival in NSCLC patients treated with taxane-containing chemotherapy.
    Full-text · Article · Feb 2013 · Clinical Cancer Research
  • Rathi N Pillai · Suresh S Ramalingam
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    ABSTRACT: The Insulin-like Growth Factor 1 (IGF-1) signaling pathway activates several downstream signals important to lung cancer development and survival. IGF-1R activation has been linked to cancer risk in epidemiological studies and tumorigenesis in preclinical models. Several inhibitors of the insulin-like growth factor 1 receptor (IGF-1R) have been tested in clinical trials. Despite promising data in early phase studies, most studies of IGF-1R antagonists in combination with chemotherapy or with epidermal growth factor receptor (EGFR) inhibitors in non-small cell lung cancer (NSCLC) yielded disappointing results. Biomarker studies of clinical trials have identified IGF-1 levels as a potential marker of sensitivity to IGF-1R inhibition. Further study will need to focus on selection of NSCLC patients most likely to benefit from the addition of IGF-1R antagonists to standard therapy and the development of rational strategies for combination therapy in NSCLC.
    No preview · Article · Feb 2013

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