The Role of Next-Generation Sequencing in Precision Medicine: A Review of Outcomes in Oncology

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Abstract

Precision medicine seeks to use genomic data to help provide the right treatment to the right patient at the right time. Next-generation sequencing technology allows for the rapid and accurate sequencing of many genes at once. This technology is becoming more common in oncology, though the clinical benefit of incorporating it into precision medicine strategies remains under significant debate. In this manuscript, we discuss the early findings of the impact of next-generation sequencing on cancer patient outcomes. We investigate why not all patients with genomic variants linked to a specific therapy receive that therapy and describe current barriers. Finally, we explore the current state of health insurance coverage for individual genome sequencing and targeted therapies for cancer. Based on our analysis, we recommend increased transparency around the determination of “actionable mutations” and a heightened focus on investigating the variations in health insurance coverage across patients receiving sequencing-matched therapies.

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Most cited references 31

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Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.

Christophe Le Tourneau, Jean-Pierre Delord, Anthony Goncalves … (2015)

Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed.

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Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative.

Apostolia-Maria Tsimberidou, Nancy G Iskander, David S. Hong … (2012)

We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations. Patients with advanced cancer were treated in the Clinical Center for Targeted Therapy. Molecular analysis was conducted in the MD Anderson Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Patients whose tumors had an aberration were treated with matched targeted therapy, when available. Treatment assignment was not randomized. The clinical outcomes of patients with molecular aberrations treated with matched targeted therapy were compared with those of consecutive patients who were not treated with matched targeted therapy. Of 1,144 patients analyzed, 460 (40.2%) had 1 or more aberration. In patients with 1 molecular aberration, matched therapy (n = 175) compared with treatment without matching (n = 116) was associated with a higher overall response rate (27% vs. 5%; P < 0.0001), longer time-to-treatment failure (TTF; median, 5.2 vs. 2.2 months; P < 0.0001), and longer survival (median, 13.4 vs. 9.0 months; P = 0.017). Matched targeted therapy was associated with longer TTF compared with their prior systemic therapy in patients with 1 mutation (5.2 vs. 3.1 months, respectively; P < 0.0001). In multivariate analysis in patients with 1 molecular aberration, matched therapy was an independent factor predicting response (P = 0.001) and TTF (P = 0.0001). Keeping in mind that the study was not randomized and patients had diverse tumor types and a median of 5 prior therapies, our results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials. ©2012 AACR.

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Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER).

Fabrice André, Thomas Bachelot, Frédéric Commo … (2014)

Breast cancer is characterised by genomic alterations. We did a multicentre molecular screening study to identify abnormalities in individual patients with the aim of providing targeted therapy matched to individuals' genomic alterations. From June 16, 2011, to July 30, 2012, we recruited patients who had breast cancer with a metastasis accessible for biopsy in 18 centres in France. Comparative genomic hybridisation (CGH) array and Sanger sequencing on PIK3CA (exon 10 and 21) and AKT1 (exon 4) were used to assess metastatic biopsy samples in five centres. Therapeutic targets were decided on the basis of identified genomic alterations. The primary objective was to include 30% of patients in clinical trials testing a targeted therapy and, therefore, the primary outcome was the proportion of patients to whom a targeted therapy could be offered. For the primary endpoint, the analyses were done on the overall population registered for the trial. This trial is registered with ClinicalTrials.gov, number NCT01414933. 423 patients were included, and biopsy samples were obtained from 407 (metastatic breast cancer was not found in four). CGH array and Sanger sequencing were feasible in 283 (67%) and 297 (70%) patients, respectively. A targetable genomic alteration was identified in 195 (46%) patients, most frequently in PIK3CA (74 [25%] of 297 identified genomic alterations), CCND1 (53 [19%]), and FGFR1 (36 [13%]). 117 (39%) of 297 patients with genomic tests available presented with rare genomic alterations (defined as occurring in less than 5% of the general population), including AKT1 mutations, and EGFR, MDM2, FGFR2, AKT2, IGF1R, and MET high-level amplifications. Therapy could be personalised in 55 (13%) of 423 patients. Of the 43 patients who were assessable and received targeted therapy, four (9%) had an objective response, and nine others (21%) had stable disease for more than 16 weeks. Serious (grade 3 or higher) adverse events related to biopsy were reported in four (1%) of enrolled patients, including pneumothorax (grade 3, one patient), pain (grade 3, one patient), haematoma (grade 3, one patient), and haemorrhagic shock (grade 3, one patient). Personalisation of medicine for metastatic breast cancer is feasible, including for rare genomic alterations. French National Cancer Institute, Breast Cancer Research Foundation, Odyssea, Operation Parrains Chercheurs. Copyright © 2014 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): J Pers Med

Journal ID (iso-abbrev): J Pers Med

Journal ID (publisher-id): jpm

Title: Journal of Personalized Medicine

Publisher: MDPI

ISSN (Electronic): 2075-4426

Publication date (Electronic): 17 September 2018

Publication date Collection: September 2018

Volume: 8

Issue: 3

Electronic Location Identifier: 30

Affiliations

[1 ]Division of Health Informatics, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY 10065, USA; ham2026@ 123456med.cornell.edu (H.M.); jyp2001@ 123456med.cornell.edu (J.P.)

[2 ]Division of Medical Oncology, Weill Cornell Medicine and New York-Presbyterian Hospital, New York, NY 10065, USA; hip9004@ 123456med.cornell.edu

[3 ]Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; ole2001@ 123456med.cornell.edu

[4 ]Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY 10065, USA

[5 ]Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA

Author notes

[* ]Correspondence: morash.maggie@ 123456gmail.com ; Tel.: +1-646-962-9409

Article

Publisher ID: jpm-08-00030

DOI: 10.3390/jpm8030030

PMC ID: 6164147

PubMed ID: 30227640

SO-VID: eded6403-f092-4d6e-b2fd-eb0f1ab8860f

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

The Role of Next-Generation Sequencing in Precision Medicine: A Review of Outcomes in Oncology

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Abstract

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Karger: Oncology

Most cited references 31

Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.

Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative.

Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER).

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