Publications by authors named "Smreti Vasudevan"

8 Publications

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Rare epidermal growth factor receptor gene alterations in non-small cell lung cancer patients, tyrosine kinase inhibitor response and outcome analysis.

Cancer Treat Res Commun 2021 13;28:100398. Epub 2021 May 13.

Department of Research, Rajiv Gandhi Cancer Institute & Research Centre, Rohini, Delhi-110085, India. Electronic address:

Background: The predictive value of rare epidermal growth factor receptor gene (EGFR) mutations for non-small cell lung carcinoma (NSCLC) patients remain elusive. We evaluated the distribution, clinicopathological association, tyrosine kinase inhibitor (TKI) response, and outcome of NSCLC patients carrying uncommon EGFR aberrations in comparison to classical EGFR mutations.

Methods: Treatment naïve, advanced NSCLC cases tested by Next-Generation sequencing (NGS) method between 2015 and 2020 were included. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were analyzed.

Results: A total of 237 tumor samples were sequenced. Among the sixty-nine (29%) EGFR mutated cases, 41 (59.4%) harbored classical mutation (37.7% Del19, 21.7% p.L858R). Non-classical aberrations included missense mutations in exon 18/20/21 (15.9%), EGFR amplification (8.7%), exon 20 insertions (7.2%), EGFR Variant III (4.3%), exon 18 indel (2.9%), exon 21 missense (2.9%) and exon 19 missense mutation (1.4%). These occurred as complex mutations in 16% of cases. Oral TKI was administered in 66.7% cases. The patients harboring non-classical variants had a lower ORR and DCR (23.1% and 61.5%) than those carrying a common mutation (57.6% and 84.8%). Collectively, compared to the patients with common EGFR mutations, the uncommon group showed early disease progression and had shorter overall survival.

Conclusion: NGS testing has the capacity to reveal a diverse spectrum of uncommon EGFR variants. Our study can contribute to the database of uncommon EGFR mutations with a positive influence on evidence-based care of advanced lung cancer patients with EGFR mutations.
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http://dx.doi.org/10.1016/j.ctarc.2021.100398DOI Listing
May 2021

COVID-19 mortality in cancer patients: a report from a tertiary cancer centre in India.

PeerJ 2021 21;9:e10599. Epub 2021 Jan 21.

Department of Research, Rajiv Gandhi Cancer Institute & Research Centre, New Delhi, Delhi, India.

Background: Cancer patients, especially those receiving cytotoxic therapy, are assumed to have a higher probability of death from COVID-19. We have conducted this study to identify the Case Fatality Rate (CFR) in cancer patients with COVID-19 and have explored the relationship of various clinical factors to mortality in our patient cohort.

Methods: All confirmed cancer cases presented to the hospital from June 8 to August 20, 2020, and developed symptoms/radiological features suspicious of COVID-19 were tested by Real-time polymerase chain reaction assay and/or cartridge-based nucleic acid amplification test from a combination of naso-oropharyngeal swab for SARS-CoV-2. Clinical data, treatment details, and outcomes were assessed from the medical records.

Results: Of the total 3,101 cancer patients admitted to the hospital, 1,088 patients were tested and 186 patients were positive for SARS-CoV-2. The CFR in the cohort was 27/186 (14.52%). Univariate analysis showed that the risk of death was significantly associated with the presence of any comorbidity (OR: 2.68; (95% CI [1.13-6.32]); = 0.025), multiple comorbidities (OR: 3.01; (95% CI [1.02-9.07]); = 0.047 for multiple vs. single), and the severity of COVID-19 presentation (OR: 27.48; (95% CI [5.34-141.49]); < 0.001 for severe vs. not severe symptoms). Among all comorbidities, diabetes (OR: 3.31; (95% CI [1.35-8.09]); = 0.009) and cardiovascular diseases (OR: 3.77; (95% CI [1.02-13.91]); = 0.046) were significant risk factors for death. Anticancer treatments including chemotherapy, surgery, radiotherapy, targeted therapy, and immunotherapy administered within a month before the onset of COVID-19 symptoms had no significant effect on mortality.

Conclusion: To the best of our knowledge, this is the first study from India reporting the CFR, clinical associations, and risk factors for mortality in SARS-CoV-2 infected cancer patients. Our study shows that the frequency of COVID-19 in cancer patients is high. Recent anticancer therapies are not associated with mortality. Pre-existing comorbidities, especially diabetes, multiple comorbidities, and severe symptoms at presentation are significantly linked with COVID-19 related death in the cohort.
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http://dx.doi.org/10.7717/peerj.10599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827973PMC
January 2021

Clinical characteristics and survival profile of young versus old colorectal cancer patients at a tertiary cancer center in North India over a period of 5 years.

Indian J Cancer 2021 Jul-Sep;58(3):355-364

Department of Laboratory and Transfusion Services, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Delhi, India.

Background: Colorectal cancer (CRC) is mostly considered a disease of the elderly. But the rate is increasing among young adults and is associated with different clinical patterns. The objective was to study the frequency of CRC in young patients and compare the clinicopathological profile and survival with the older cohort.

Methods: Five-year (2012-2016) data of the 912 consecutive CRC cases treated at the center were analyzed. Clinical and histopathological characteristics were compared in young (≤40) and older (>40) patients. Descriptive statistics were used for data presentation. Categorical data were compared by the Chi-square test; survival analyses were performed by Kaplan-Meier method.

Results: In total, 231 (25.3%) and 681 (74.7%) cases were in the young and older age groups, respectively. Male predominance was noted. Young patients presented predominantly in stage III (46%). Majority of the young patients harbored left-sided tumors (75.8% vs 63.7% in old patients, P = 0.001) and rectum was the favored site in young patients (53.7% vs 37%; P < 0.001). Poorly differentiated adenocarcinoma was more common in the young age group (46.88% vs 24.16% in old patients, P < 0.001), also signet-ring cell morphology occurred more often in young patients (11.7% vs 4%, P < 0.001). Survival was inferior in the patients presenting at an advanced stage or with adverse histology or poor tumor grade. However, stage-specific survival showed no significant difference between both groups.

Conclusion: This study shows that though young CRC patients present with higher stage, aggressive morphology, and predominantly rectal localization, the overall survival and stage-specific survival did not differ significantly from the older patients.
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http://dx.doi.org/10.4103/ijc.IJC_246_19DOI Listing
January 2021

Predictive biomarkers in nonsmall cell carcinoma and their clinico-pathological association.

South Asian J Cancer 2019 Oct-Dec;8(4):250-254

Department of Molecular Diagnostics and Cell Biology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.

Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Genome-directed therapy is less toxic, prolongs survival and provides a better quality of life. Predictive biomarker testing, therefore, has become a standard of care in advanced lung cancers. The objective of this study was to relate clinical and pathological features, including response to targeted therapy (TT) and progression-free survival (PFS) with positive driver mutation.

Materials And Methods: Archival data of nonsmall cell carcinoma patients with Stage IV disease were retrieved. Those who tested positive for one of the four biomarkers (epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], MET, and ROS) were included. Patient demographics and clinical features were reviewed. Tumor histomorphology was correlated with oncological drivers. Treatment response, PFS, and overall survival were studied in three subcohorts of patients who received computed tomography (CT), CT followed by TT and those who received TT in the first line.

Results: A total of 900 patients underwent biomarker evaluation of which 288 tested positive. Frequency of the four biomarkers observed was 26.6% (229/860), 6.6% (51/775), 6.6% (5/75), and 5.1% (3/59) for EGFR, ALK, MET, and ROS-1, respectively. The median PFS for EGFR-mutated cohort was 12 months, whereas it was 21 months for ALK protein overexpressing cases. Patients treated with first-line tyrosine kinase inhibitors performed better compared to those who were switched from chemotherapy to TT or those who received chemotherapy alone ( < 0.05).

Conclusion: Biomarker testing has improved patient outcome. Genome-directed therapy accords best PFS with an advantage of nearly 10 months over cytotoxic therapy.
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http://dx.doi.org/10.4103/sajc.sajc_373_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852638PMC
December 2019

Germline and deleterious mutations and variants of unknown clinical significance associated with breast/ovarian cancer: a report from North India.

Cancer Manag Res 2018 30;10:6505-6516. Epub 2018 Nov 30.

Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Delhi 110085, India.

Background: The spectrum of BRCA mutations that predispose to development of breast/ovarian cancer in Indian population remains unexplored. We report incidence and various types of pathogenic, likely pathogenic and variants of unknown significance (VUS) mutations in and genes observed at a tertiary cancer center in North India.

Materials And Methods: A total of 206 unrelated breast and/or ovarian cancer patients, who met the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing, were screened for germline / mutations on high-throughput sequencing platform; large genomic rearrangements were assessed by multiple ligation probe assay. Mutations were mined in mutational databases, PubMed, and discerned into classes. Furthermore, the clinicopathological correlation of BRCA mutation status with prognostic markers in breast cancer and tumor histology in ovarian cancer was performed.

Results: In total, 45/206 and 17/206 cases showed positivity for and mutations, respectively, whereas 1/206 was positive for a mutation in both the genes. Altogether, 33 distinct mutations were observed, among which 27 were deleterious (12 frameshifts, 8 nonsense, 1 missense, 3 splice-site variants, 2 big deletions and 1 large duplication) and 6 were VUS. Five novel mutations (c.541G>T, c.1681delT, c.2295delG, c.4915C>T and exon 23 deletion) were identified. Seven mutations (c.2214_2215insT, c.2295delG, c.3607C>T,c.4158_4162delCTCTC, c.4571C>A, splicesite_3 (C>T) and exon 21-23 duplication) occurred more than once, whereas 16 distinct mutations were noted - 9 were lethal (6 frameshifts, 2 nonsense and 1 big deletion) and 7 VUS. One unique pathogenic mutation (c.932_933insT) was recognized. Two mutations (c.9976A>T and c.10089A>G) recurred twice. No significant difference in hormone receptor status was observed among carriers, carriers and noncarriers.

Conclusion: We have documented various pathogenic and VUS mutations in and genes observed in the cohort. Six novel mutations were identified. The knowledge shared would assist genetic testing in enabling more focused site-specific screening for mutations in biological relatives.
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http://dx.doi.org/10.2147/CMAR.S186563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280886PMC
November 2018

6-Shogaol Inhibits Breast Cancer Cells and Stem Cell-Like Spheroids by Modulation of Notch Signaling Pathway and Induction of Autophagic Cell Death.

PLoS One 2015 10;10(9):e0137614. Epub 2015 Sep 10.

Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram - 695014, India.

Cancer stem cells (CSCs) pose a serious obstacle to cancer therapy as they can be responsible for poor prognosis and tumour relapse. In this study, we have investigated inhibitory activity of the ginger-derived compound 6-shogaol against breast cancer cells both in monolayer and in cancer-stem cell-like spheroid culture. The spheroids were generated from adherent breast cancer cells. 6-shogaol was effective in killing both breast cancer monolayer cells and spheroids at doses that were not toxic to noncancerous cells. The percentages of CD44+CD24-/low cells and the secondary sphere content were reduced drastically upon treatment with 6-shogaol confirming its action on CSCs. Treatment with 6-shogaol caused cytoplasmic vacuole formation and cleavage of microtubule associated protein Light Chain3 (LC3) in both monolayer and spheroid culture indicating that it induced autophagy. Kinetic analysis of the LC3 expression and a combination treatment with chloroquine revealed that the autophagic flux instigated cell death in 6-shogaol treated breast cancer cells in contrast to the autophagy inhibitor chloroquine. Furthermore, 6-shogaol-induced cell death got suppressed in the presence of chloroquine and a very low level of apoptosis was exhibited even after prolonged treatment of the compound, suggesting that autophagy is the major mode of cell death induced by 6-shogaol in breast cancer cells. 6-shogaol reduced the expression levels of Cleaved Notch1 and its target proteins Hes1 and Cyclin D1 in spheroids, and the reduction was further pronounced in the presence of a γ-secretase inhibitor. Secondary sphere formation in the presence of the inhibitor was also further reduced by 6-shogaol. Together, these results indicate that the inhibitory action of 6-shogaol on spheroid growth and sustainability is conferred through γ-secretase mediated down-regulation of Notch signaling. The efficacy of 6-shogaol in monolayer and cancer stem cell-like spheroids raise hope for its therapeutic benefit in breast cancer treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137614PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565635PMC
May 2016

Diaminothiazoles evade multidrug resistance in cancer cells and xenograft tumour models and develop transient specific resistance: understanding the basis of broad-spectrum versus specific resistance.

Carcinogenesis 2015 Aug 25;36(8):883-93. Epub 2015 May 25.

Division of Cancer Research and Distributed Information Sub-Centre, Rajiv Gandhi Centre for Biotechnology, Trivandrum, India and Department of Chemistry, University of Kerala, Trivandrum, India

Acquired drug resistance poses a challenge in cancer therapy. Drug efflux is the most common mechanism of resistance displayed by hydrophobic drugs beyond a certain size. However, target specific changes and imbalance between the pro- and anti-apoptotic proteins are also found quite often in many tumours. A number of small antimitotic agents show high potential for multidrug resistant tumours, mainly because they are able to evade the efflux pumps. However, these compounds are also likely to suffer from resistance upon prolonged treatment. Thus, it is important to find out agents that are sensitive to resistant tumours and to know the resistance mechanisms against small molecules so that proper combinations can be planned. In this report, we have studied the efficiency of diaminothiazoles, a novel class of tubulin targeting potential anticancer compounds of small size, in multidrug resistant cancer. Studies in model cell lines raised against taxol and the lead diaminothiazole, DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino) thiazole], and the xenograft tumours derived from them, show that diaminothiazoles are highly promising against multidrug resistant cancers. They were able to overcome the expression of efflux protein MDR1 and certain tubulin isotypes, could sensitize improper apoptotic machinery and ablated checkpoint proteins Bub1 and Mad2. Further, we have found that the resistance against microtubule binding compounds with higher size is broad-spectrum and emerges due to multiple factors including overexpression of transmembrane pumps. However, resistance against small molecules is transient, specific and is contributed by target specific changes and variations in apoptotic factors.
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http://dx.doi.org/10.1093/carcin/bgv072DOI Listing
August 2015

Upregulation of DR5 receptor by the diaminothiazole DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino) thiazole] triggers an independent extrinsic pathway of apoptosis in colon cancer cells with compromised pro and antiapoptotic proteins.

Apoptosis 2013 Jun;18(6):713-26

Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Trivandrum 695014, India.

Mitochondria mediated signalling is the more common way of apoptosis induction exhibited by many chemotherapeutic agents in cancer cells. Death receptor mediated signalling for apoptosis in many cells also requires further amplification from the mitochondrial pathway activation through tBid. Thus the potential of most chemotherapeutic agents in tumours with intrinsic apoptosis resistance due to changes in molecules involved in the mitochondrial pathway is limited. Diaminothiazoles were shown earlier to bind to tubulin thereby exhibiting cytotoxicity towards different cancer cells. We observed that the lead diaminothiazole, DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino) thiazole] could induce apoptosis in the colon cancer cell line HCT116 by both pathways. However, in contrast to many other chemotherapeutic agents, DAT1 triggered apoptosis where the intrinsic pathway was blocked by changing the pro and antiapoptotic proteins. An independent extrinsic pathway activation triggered by the upregulation of DR5 receptor accounted for that. The induction of DR5 occurred in the transcriptional level and the essential role of DR5 was confirmed by the fact that siRNA downregulation of DR5 significantly reduced DAT1 induced apoptosis. HCT116 cells were earlier shown to have a type II response for apoptosis induction where extrinsic pathway was connected to the intrinsic pathway via the mediator protein tBid. Our finding thus indicates that the signalling events in the manifestation of apoptosis depend not only on the cancer cell type, but also on the inducer. Our results also place diaminothiazoles in a promising position in the treatment of tumours with compromised apoptotic factors.
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http://dx.doi.org/10.1007/s10495-013-0826-6DOI Listing
June 2013
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