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2. Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival.

Author

Magbanua, MJM, Swigart, LB, Wu, H-T, Hirst, GL, Yau, C, Wolf, DM, Tin, A, Salari, R, Shchegrova, S, Pawar, H, Delson, AL, DeMichele, A, Liu, MC, Chien, AJ, Tripathy, D, Asare, S, Lin, C-HJ, Billings, P, Aleshin, A, Sethi, H, Louie, M, Zimmermann, B, Esserman, LJ, and van 't Veer, LJ

Subjects
Humans, Breast Neoplasms, Neoplasm, Residual, Neoadjuvant Therapy, Mutation, Biomarkers, Tumor, Circulating Tumor DNA, breast cancer, circulating tumor DNA, neoadjuvant chemotherapy, pathologic complete response, Cancer, Genetics, Clinical Research, Prevention, Breast Cancer, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundPathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence.Patients and methodsCell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years.ResultsAt T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5).ConclusionsLack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

Published
2021

12. Evaluation of the teaching recovery techniques community-based intervention for accompanied refugee children experiencing post-traumatic stress symptoms (Accompanied refugeeS In Sweden Trial; ASsIST) : study protocol for a cluster randomised controlled trial

Author

Warner, G., Durbeej, N., Salari, R., Fängström, K., Lampa, E., Baghdasaryan, Z., Osman, F., Gupta Löfving, S., Perez Aronsson, A., Feldman, I., Sampaio, F., Ssegonja, R., Bjärtå, Anna, Rondung, Elisabet, Leiler, Anna, Wasteson, Elisabet, Calam, R., Oppedal, B., Keeshin, B., Sarkadi, A., Warner, G., Durbeej, N., Salari, R., Fängström, K., Lampa, E., Baghdasaryan, Z., Osman, F., Gupta Löfving, S., Perez Aronsson, A., Feldman, I., Sampaio, F., Ssegonja, R., Bjärtå, Anna, Rondung, Elisabet, Leiler, Anna, Wasteson, Elisabet, Calam, R., Oppedal, B., Keeshin, B., and Sarkadi, A.

Abstract

BACKGROUND: Refugee children have often experienced traumas and are at significant risk of developing mental health problems, such as symptoms of post-traumatic stress disorder (PTSD), depression and anxiety, which can continue for years after resettlement. The Accompanied refugeeS In Sweden Trial (ASsIST) aims to evaluate a community-based intervention, called 'Teaching Recovery Techniques' (TRT), for accompanied refugee minors experiencing PTSD symptoms. METHODS/DESIGN: A cluster randomised controlled trial will be conducted in which participants will be randomly allocated to one of the two possible arms: the intervention arm (n=113) will be offered the TRT programme and the waitlist-control arm (n=113) will receive services as usual, followed by the TRT programme around 20 weeks later. Outcome data will be collected at three points: pre-intervention (T1), post-intervention (T2; c.8 weeks after randomisation) and follow-up (T3; c.20 weeks after randomisation). ETHICS AND DISSEMINATION: Ethical approval was granted by the Regional Ethical Review Board in Uppsala (Ref. 2018/382) (24th February 2019). Results will be published in scientific journals. TRIAL REGISTRATION DETAILS: ISRCTN17754931. Prospectively registered on 4th June 2019.

Published
2020
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19. Herbal medicines for suppressing appetite: A systematic review of randomized clinical trials

Author

Sahebkar-Khorasani, M, Jarahi, L, Cramer, H, Safarian, M, Naghedi-Baghdar, H, Salari, R, Behravanrad, P, Azizi, H, Sahebkar-Khorasani, M, Jarahi, L, Cramer, H, Safarian, M, Naghedi-Baghdar, H, Salari, R, Behravanrad, P, and Azizi, H

Abstract

© 2019 Elsevier Ltd The suppression of appetite with herbal medicines has become very popular in recent years. We conducted this systematic review to evaluate the recent scientific evidence regarding herbal medicines that are used to suppress appetite. We retrieved clinical trials from PubMed, Cochrane Central Register of Controlled Trials, Web of Science, Scientific Information Database, and IranMedex from January 1, 2013 to April 24, 2018. English and Persian language randomized clinical trials that used herbal medicines to suppress appetite in healthy or obese or overweight individuals were included. Risk of bias was assessed using Cochrane methodology. Out of 591 articles, 22 trials with 973 participants were included. One study on the Meratrim formulation which contained the Sphaeranthus indicus flower heads extract and Garcinia mangostana fruit, revealed longer-term evidence; while 6 studies on Ilex paraguariensis, Spinacia oleracea, Phaseolus vulgaris, Secale cereale, Sorghum bicolor and Plantago showed short-term evidence for suppressing appetite. No serious adverse events were reported. Despite some methodological concerns in the included studies, there is promising evidence for suppressing appetite with herbal medicines that needs to be confirmed in long-term clinical trials with adequate sample size and higher methodological quality with more attention to safety, effective dose and side effects.

Published
2019

20. Analysis of circulating tumour DNA for early relapse detection in stage III colorectal cancer after adjuvant chemotherapy

Author

Jacobs, S.A., primary, Sethi, H., additional, Kolveska, T., additional, George, T.J., additional, Shchegrova, S., additional, Tin, T., additional, Lee, J., additional, Olson, A., additional, Renner, D., additional, Kalashnikova, E., additional, Yothers, G., additional, Wolmark, N., additional, Pogue-Geile, K.L., additional, Srinivasan, A., additional, Kortmansky, J., additional, Louie, M., additional, Salari, R., additional, Zimmermann, B., additional, Aleshin, A., additional, and Allegra, C.J., additional

Published
2019
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21. Presence of circulating tumour DNA in surgically resected renal cell carcinoma is associated with advanced disease and poor patient prognosis

Author

Correa, A., primary, Connolly, D.C., additional, Balcioglu, M., additional, Wu, H.-T., additional, Dashner, S., additional, Shchegrova, S., additional, Kalashnikova, E., additional, Pawar, H., additional, Uzzo, R.G., additional, Gong, Y., additional, Kister, D., additional, Collins, M., additional, Donovan, M., additional, Winters, R., additional, Aleshin, A., additional, Sethi, H., additional, Salari, R., additional, Louie, M., additional, Zimmermann, B., additional, and Abbosh, P., additional

Published
2019
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22. Abstract P4-01-02: Early detection of residual breast cancer through a robust, scalable and personalized analysis of circulating tumour DNA (ctDNA) antedates overt metastatic recurrence

Author

Coombes, RC, primary, Armstrong, A, additional, Ahmed, S, additional, Page, K, additional, Hastings, RK, additional, Salari, R, additional, Sethi, H, additional, Boydell, A-R, additional, Shchegrova, SV, additional, Fernandez-Garcia, D, additional, Gleason, KL, additional, Goddard, K, additional, Guttery, DS, additional, Assaf, ZJ, additional, Balcioglu, M, additional, Moore, DA, additional, Primrose, L, additional, Navarro, SL, additional, Aleshin, A, additional, Rehman, F, additional, Toghill, BJ, additional, Louie, MC, additional, Zimmermann, BG, additional, Lin, C-HJ, additional, and Shaw, JA, additional

Published
2019
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23. Characterization of Encapsulated Berberine in Yeast Cells of Saccharomyces cerevisiae

Author

Salari, R., Rajabi, O., zahra khashyarmanesh, Najafi, M. F., and Fazly Bazzaz, B. S.

Subjects
yeast cells, Berberine, kinetic, microencapsulation, Original Article, MIC
Abstract

Berberine was loaded in yeast cells of Saccharomyces cerevisiaeas a novel pharmaceutical carrier to improve the treatment ofmany diseases. The yeast-encapsulated active materialsshowedhigh stability and bioavailability due to the enhanced solubility and sustained releasing. In this study, different characteristics of prepared berberine loaded yeast cells (loading capacity, release kinetic order, MIC and stability) were evaluatedby different analytical methods (fluorescence spectroscopy, HPLC and SEM).The loading capacity was about 78% ± 0.6%.Berberine release patterns of microcapsules happened in two different stages and followed by zero and first-order kinetic,respectively. About 99% of all active material released during 34 h. MIC was improved by berberine loaded microcapsules in comparison withberberine powder. The microcapsules were completely stable. Berberine loaded Sac. Cerevisiae could be considered as a favorite sustained release drug delivery system. The yeast would be applied as an efficient carrier to improve various properties of different active materials.

Published
2015

24. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution

Author

Abbosh, C, Birkbak, NJ, Wilson, GA, Jamal-Hanjani, M, Constantin, T, Salari, R, Quesne, JL, Moore, DA, Veeriah, S, Rosenthal, R, Marafioti, T, Kirkizlar, E, Watkins, TBK, McGranahan, N, Ward, S, Martinson, L, Riley, J, Fraioli, F, Bakir, MA, GrÖnroos, E, Zambrana, F, Endozo, R, Bi, WL, Fennessy, FM, Sponer, N, Johnson, D, Laycock, J, Shafi, S, Czyzewska-Khan, J, Rowan, A, Chambers, T, Matthews, N, Turajlic, S, Hiley, C, Lee, SM, Forster, MD, Ahmad, T, Falzon, M, Borg, E, Lawrence, D, Hayward, M, Kolvekar, S, Panagiotopoulos, N, Janes, SM, Thakrar, R, Ahmed, A, Blackhall, F, Summers, Y, Hafez, D, Naik, A, Ganguly, A, Kareht, S, Shah, R, Joseph, L, Quinn, AM, Crosbie, P, Naidu, B, Middleton, G, Langman, G, Trotter, S, Nicolson, M, Remmen, H, Kerr, K, Chetty, M, Gomersall, L, Fennell, DA, Nakas, A, Rathinam, S, Anand, G, Khan, S, Russell, P, Ezhil, V, Ismail, B, Irvin-sellers, M, Prakash, V, Lester, JF, Kornaszewska, M, Attanoos, R, Adams, H, Davies, H, Oukrif, D, Akarca, AU, Hartley, JA, Lowe, HL, Lock, S, Iles, N, Bell, H, Ngai, Y, Elgar, G, Szallasi, Z, Schwarz, RF, Herrero, J, Stewart, A, Quezada, SA, Van Loo, P, Dive, C, Lin, CJ, Rabinowitz, M, Aerts, HJWL, Hackshaw, A, Shaw, JA, Zimmermann, BG, Swanton, C, Bosshard-Carter, L, Goh, G, Gorman, P, Murugaesu, N, Hynds, RE, Wilson, G, Horswell, S, Al Bakir, M, Mitter, R, Escudero, M, Xu, H, Goldman, J, Stone, RK, Denner, T, Biggs, J, Costa, M, Begum, S, Phillimore, B, Nye, E, Graca, S, Joshi, K, Furness, A, Aissa, AB, Wong, YNS, Georgiou, A, Quezada, S, Simeon, C, Hector, G, Smith, A, Aranda, M, Novelli, M, Forster, M, Papadatos-Pastos, D, Carnell, D, Mendes, R, George, J, Navani, N, Taylor, M, Choudhary, J, Califano, R, Taylor, P, Krysiak, P, Rammohan, K, Fontaine, E, Booton, R, Evison, M, Moss, S, Idries, F, Bishop, P, Chaturved, A, Marie Quinn, A, Doran, H, leek, A, Harrison, P, Moore, K, Waddington, R, Novasio, J, Rogan, J, Smith, E, Tugwood, J, Brady, G, Rothwell, DG, Chemi, F, Pierce, J, Gulati, S, Bellamy, M, Bancroft, H, Kerr, A, Kadiri, S, Webb, J, Djearaman, M, Fennell, D, Le Quesne, J, Moore, D, Thomas, A, Walter, H, Monteiro, W, Marshall, H, Nelson, L, Bennett, J, Primrose, L, Amadi, A, Palmer, S, Miller, J, Buchan, K, Lester, J, Edwards, A, Morgan, F, Verjee, A, MacKenzie, M, Wilcox, M, Smith, S, Gower, N, Ottensmeier, C, Chee, S, Johnson, B, Alzetani, A, Shaw, E, Lim, E, De Sousa, P, Tavares Barbosa, M, Bowman, A, Jordan, S, Rice, A, Raubenheimer, H, Proli, C, Elena Cufari, M, Ronquillo, JC, Kwayie, A, Bhayani, H, Hamilton, M, Bakar, Y, Mensah, N, Ambrose, L, Devaraj, A, Buderi, S, Finch, J, Azcarate, L, Chavan, H, Green, S, Mashinga, H, Nicholson, AG, Lau, K, Sheaff, M, Schmid, P, Conibear, J, Light, T, Horey, T, Danson, S, Bury, J, Edwards, J, Hill, J, Matthews, S, Kitsanta, Y, Suvarna, K, Fisher, P, Keerio, AD, Shackcloth, M, Gosney, J, Postmus, P, Feeney, S, Asante-Siaw, J, Constatin, T, Zimmermann, B, Dentro, S, Dessimoz, C, Shiu, K-K, Bridgewater, J, Hochauser, D, Beck, S, Parker, P, Walczak, H, Enver, T, Proctor, I, Sinclair, R, Lok, C-W, Mitchison, M, Trevisan, G, Lynch, M, Brandner, S, Gishen, F, Tookman, A, Stone, P, Sterling, C, Larkin, J, Attard, G, Eeles, R, Foster, C, Bova, S, Sottoriva, A, Chowdhury, S, Ashish, C, Spicer, J, Stares, M, Lynch, J, Caldas, C, Brenton, J, Fitzgerald, R, Jimenez-Linan, M, Provenzano, E, Cluroe, A, Stewart, G, Watts, C, Gilbertson, R, McDermott, U, Tavare, S, Maughan, T, Tomlinson, I, Campbell, P, McNeish, I, Biankin, A, Chambers, A, Fraser, S, Oien, K, Krebs, M, Marais, R, Carter, L, Nonaka, D, Dhomen, N, Shaw, J, Baijal, S, Tanchel, B, Collard, M, Cockcroft, P, Taylor, J, Colloby, P, Olisemeke, B, Wilson, R, Harrison, D, Loda, M, Flanagan, A, McKenzie, M, Lederman, J, Sharp, A, and Farrelly, L

Subjects
0301 basic medicine, Oncology, Lung Neoplasms, IMPACT, Biopsy, DNA Mutational Analysis, Drug resistance, Metastasis, 0302 clinical medicine, Limit of Detection, Carcinoma, Non-Small-Cell Lung, Medicine, Neoplasm Metastasis, Early Detection of Cancer, Multidisciplinary, medicine.diagnostic_test, Phylogenetic tree, DNA, Neoplasm, STATISTICS, 3. Good health, Tumor Burden, Multidisciplinary Sciences, Cell Tracking, PEACE consortium, 030220 oncology & carcinogenesis, Disease Progression, Science & Technology - Other Topics, medicine.medical_specialty, CARCINOMA, Tumour heterogeneity, General Science & Technology, Early detection, Evolution, Molecular, 03 medical and health sciences, Internal medicine, MD Multidisciplinary, Carcinoma, Humans, Cell Lineage, Lung cancer, Postoperative Care, Science & Technology, MUTATIONS, TRACERx consortium, business.industry, CIRCULATING TUMOR DNA, Reproducibility of Results, medicine.disease, R1, NEGATIVE BREAST-CANCER, Clone Cells, 030104 developmental biology, Drug Resistance, Neoplasm, UPTAKE RATIO, Immunology, FDG PET, Neoplasm Recurrence, Local, business, Multiplex Polymerase Chain Reaction
Abstract

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

Published
2017

25. Longitudinal assessment of multiplex patient-specific ctDNA biomarkers in bladder cancer for diagnosis, surveillance and recurrence

Author

Birkenkamp-Demtröder, K., primary, Christensen, E., additional, Sethi, H., additional, Sharma, S., additional, Wu, H.-T., additional, Taber, A., additional, Agerbæk, M., additional, Swenerton, R., additional, Salari, R., additional, Hafez, D., additional, Nordentoft, I., additional, Lamy, P., additional, Srinivasan, R., additional, Balcioglu, M., additional, Navarro, S., additional, Assaf, Z., additional, Zimmermann, B., additional, Lin, J., additional, Bjerggaard Jensen, J., additional, and Dyrskjøt, L., additional

Published
2018
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26. Serial circulating tumor DNA analysis for detection of residual disease, assessment of adjuvant therapy efficacy and for early recurrence detection in colorectal cancer

Author

Reinert, T., primary, Henriksen, T.V., additional, Rasmussen, M.H., additional, Sethi, H., additional, Salari, R., additional, Shchegrova, S., additional, Swenerton, R., additional, Wu, H.-T., additional, Sharma, S., additional, Christensen, E., additional, Natarajan, P., additional, Dashner, S., additional, Tin, T., additional, Olson, A., additional, Pawar, H., additional, Zimmermann, B., additional, Iversen, L.H., additional, Madsen, M.R., additional, Lin, J., additional, and Andersen, C.L., additional

Published
2018
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28. Lidocaine Cyclodextrin complex Ophthalmic Drop, a New Topical Anesthetic Choice

Author

Sabermoghadam Ranjbar, AA, Rajabi, O, Salari, R, and Ashraf, H

Subjects
Symblepharon, Ophthalmicdrop, Lidocaine, Cyclodextrin, Original Article, Dysport, Drug Delivery, Pterygium
Abstract

Background Topical anesthesia is a safe and cost-effective method considered as the first-choice in many procedures. Due to the physiological characteristics of eye, most of the local anesthetics cannot efficiently penetrate through the conjunctiva deep to tenon. The aim of this pilot study was to find a new form of lidocaine to give a sufficient level of anesthesia. Methods: Lidocaine Cyclodextrin complex ophthalmic drop was produced and its pharmacological properties were studied [tested] in standard temperature and pressure. 30 patients (18 males, 12 females) with the mean age of 30.68±8.02 years enrolled in this clinical trial. All the patients were fully informed and signed the ethics committee consent forms. The patients were given tetracaine drop as the anesthetic: 3 drops separated 2 minute apart 10 min before the intervention. If we achieved a sufficient level of anesthesia, the procedure was done after. If the patient could not tolerate the procedure, the method was changed to lidocaine drop (administered after wash-out period like the first drop).The last option was conventional injection method if the patient could not tolerate the procedure with the second method either.We used this type of anesthesia for conventional procedures such as forced duction test, symblepharon, pterygium, and disport injection into extra-ocular muscles. All the procedures were done by one surgeon in a university hospital. We used a 0 to 10 visual analogue scale for pain and two 0 to 4 patient and physician satisfaction scales designed for this study. Results The mean pain score was 7.53±0.90 in group 1 and 3.03±1.83 in group 2 (P=0.00). Patient and surgeon satisfaction in group 1 were 1.33±0.48 and 1.40±0.56 respectively; while 3.23±1.00 and 3.56±0.77 for group 2 (P=0.00). Tetracaine drop could not induce sufficient anesthesia for none of the patients. Cyclodextrin based lidocaine drop was successful except For two patients for whom we changed the anesthesia to Sub-conjunctival injection method. Conclusion Our newly manufactured cyclodextrin based lidocaine eye drop could successfully induce sufficient anesthesia for 28 of 30 patients. Further studies with larger sample sizes are now being designed to find more clinical evidence about this method.

Published
2012

34. 456PD - Serial circulating tumor DNA analysis for detection of residual disease, assessment of adjuvant therapy efficacy and for early recurrence detection in colorectal cancer

Author

Reinert, T., Henriksen, T.V., Rasmussen, M.H., Sethi, H., Salari, R., Shchegrova, S., Swenerton, R., Wu, H.-T., Sharma, S., Christensen, E., Natarajan, P., Dashner, S., Tin, T., Olson, A., Pawar, H., Zimmermann, B., Iversen, L.H., Madsen, M.R., Lin, J., and Andersen, C.L.

Published
2018
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46. Assessment of the Microbiological Quality and Mycotoxin Contamination of Iranian Red Pepper Spice.

Author

Salari, R., Habibi Najafi, M. B., Boroushaki, M. T., Mortazavi, S. A., and Fathi Najafi, M.

Subjects
*PEPPERS, *SPICES, *PRODUCT quality, *OCHRATOXINS, *MICROBIAL contamination, *MICROBIOLOGY, *PLANTS
Abstract

The objective of this study was to assess the microbial contamination of Razavi Khorasan (Iran) hot red pepper. The natural occurrence of aflatoxins and ochratoxin A in those samples was also investigated. For this purpose, 36 samples of this kind of pepper were collected from a farm and sun-dried. Standard and established methods were used for both microbiological analyses and mycotoxins identification. Total aerobic mesophilic counts of samples varied from 102 to 4×106 cfu g-1. Coliforms were present at high levels in all samples ranging from 1.9×102 to 3.52×106 cfu g-1that may indicate inappropriate hygienic quality of samples. 42% of the samples were of unsatisfactory quality due to the presence of E. coli. In all samples examined, sulphite-reducing clostridia (SRC) was below detection limit and Salmonella spp. was not detected. Fungi were found in all of the collected samples. Mold and yeast were generally high ranging from 2.4×103 to 4.6×106 cfu g-1and the most predominant fungal genera were Aspergillus spp., Penicillium spp and Rhizopus spp. Considering the results obtained, the samples analyzed contain a high level of microorganisms and only two samples (6%) had acceptable levels for all microbial factors according to EU Commission Recommendation (directive2004/24/EC). 69% and 17% of samples were found contaminated with total aflatoxins and ochratoxin A, respectively, that might contribute to health hazards for humans. Overall, The Razavi Khorasan hot red pepper samples collected for this study were contaminated with microorganisms and mycotoxins, which suggests that hygiene practice pre- and postharvesting must be improved if the region is to exploit fully the potential for this valuable product. [ABSTRACT FROM AUTHOR]

Published
2012

49. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

Author

Abbosh, C, Birkbak, NJ, Wilson, GA, Jamal-Hanjani, M, Constantin, T, Salari, R, Le Quesne, J, Moore, DA, Veeriah, S, Rosenthal, R, Marafioti, T, Kirkizlar, E, Watkins, TBK, McGranahan, N, Ward, S, Martinson, L, Riley, J, Fraioli, F, Al Bakir, M, Grönroos, E, Zambrana, F, Endozo, R, Bi, WL, Fennessy, FM, Sponer, N, Johnson, D, Laycock, J, Shafi, S, Czyzewska-Khan, J, Rowan, A, Chambers, T, Matthews, N, Turajlic, S, Hiley, C, Lee, SM, Forster, MD, Ahmad, T, Falzon, M, Borg, E, Lawrence, D, Hayward, M, Kolvekar, S, Panagiotopoulos, N, Janes, SM, Thakrar, R, Ahmed, A, Blackhall, F, Summers, Y, Hafez, D, Naik, A, Ganguly, A, Kareht, S, Shah, R, Joseph, L, Marie Quinn, A, Crosbie, PA, Naidu, B, Middleton, G, Langman, G, Trotter, S, Nicolson, M, Remmen, H, Kerr, K, Chetty, M, Gomersall, L, Fennell, DA, Nakas, A, Rathinam, S, Anand, G, Khan, S, Russell, P, Ezhil, V, Ismail, B, Irvin-Sellers, M, Prakash, V, Lester, JF, Kornaszewska, M, Attanoos, R, Adams, H, Davies, H, Oukrif, D, Akarca, AU, Hartley, JA, Lowe, HL, Lock, S, Iles, N, Bell, H, Ngai, Y, Elgar, G, Szallasi, Z, Schwarz, RF, Herrero, J, Stewart, A, Quezada, SA, Peggs, KS, Van Loo, P, Dive, C, Lin, CJ, Rabinowitz, M, Aerts, HJWL, Hackshaw, A, Shaw, JA, Zimmermann, BG, TRACERx Consortium, PEACE Consortium, and Swanton, C

Subjects
Postoperative Care, Lung Neoplasms, Biopsy, DNA Mutational Analysis, Reproducibility of Results, DNA, Neoplasm, 16. Peace & justice, 3. Good health, Clone Cells, Tumor Burden, Evolution, Molecular, Cell Tracking, Drug Resistance, Neoplasm, Limit of Detection, Carcinoma, Non-Small-Cell Lung, Disease Progression, Humans, Cell Lineage, Neoplasm Metastasis, Neoplasm Recurrence, Local, Multiplex Polymerase Chain Reaction, Early Detection of Cancer
Abstract

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

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