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Intratumor heterogeneity increases risk for NSCLC recurrence, death
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Intratumor heterogeneity mediated through chromosome instability increased risk for recurrence or death in patients with non–small cell lung cancer, according to results of the TRACERx prospective cohort study published in The New England Journal of Medicine.
This finding supports the potential value of chromosome instability as a prognostic predictor, according to the researchers.
“Large-scale sequencing studies have revealed the complex genomic landscape of NSCLC and genomic difference between lung adenocarcinomas and lung squamous cell carcinomas,” Charles Swanton, FRCP, BSc, PhD, research professor at The Francis Crick Institute in London, and colleagues wrote. “However, in-depth exploration of NSCLC intratumor heterogeneity — which provides the fuel for tumor evolution and drug resistance — and cancer genome evolution has been limited to small retrospective cohorts. Therefore, the clinical significance of intratumor heterogeneity and the potential for clonality of driver events to guide therapeutic strategies have not yet been defined.”
Swanton and colleagues performed multiregion, whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. Researchers analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and RFS.
Overall, researchers observed widespread intratumor heterogeneity for somatic copy-number alterations and mutations.
Researchers identified a median of 30% (range, 0.5-93) of somatic mutations as subclonal and a
median of 48% (range, 0.3-88) of copy-number alterations as subclonal.
“This finding suggests that genomic-instability processes at the mutational level are ongoing during tumor development,” the researchers wrote.
Researchers also observed considerable variation in intratumor heterogeneity among tumors, with the number of subclonal mutations ranging from two to 2,310 and the percentage of the genome affected by subclonal copy-number alterations ranging from 0.06% to 81%.
Clonal mutations were more prevalent in squamous cell carcinomas than adenocarcinomas (P = .003), which could be related to differences in smoking history. Subclonal mutations did not significantly differ between these two groups.
The proportion of subclonal mutations did not appear linked to RFS. However, results of a preliminary analysis showed patients with greater than the 48% cohort median of subclonal copy-number alterations had an increased risk for recurrence or death than those with a low proportion (HR = 4.9; 95% CI, 1.8-13.1). The median time to recurrence or death was 24.4 months in the higher-risk group and not reached in the lower-risk group.
This finding persisted in a multivariate analysis adjusted for age, pack-years of smoking, histologic subtype, adjuvant therapy and tumor stage (HR = 3.7; 95% CI, 1.29-10.65).
Researchers then evaluated cancer driver events, because whether they occur early or late can indicate whether the event is involved in tumor initiation or maintenance. They found 795 driver events (range in adenocarcinomas, 1-19; range in squamous cell carcinomas, 2-21). Of these, 219 in 77 tumors were subclonal and 576 were clonal.
Researchers found that driver mutations in EGFR, MET, BRAF and TP53 were usually clonal and occurring before genome duplication, suggesting involvement in tumor initiation.
Still, heterogenous driver alterations that occurred later in evolution were found in more than 75% of the tumors. These were common in PIK3CA and NF1, as well as in genes involved in chromatin modification and DNA damage response and repair.
Genome doubling and ongoing dynamic chromosomal instability appeared to be causes of intratumor heterogeneity, which resulted in parallel evolution of driver somatic copy-number alterations, including amplification in CDK4, FOXA1 and BCL11A.
“Whether noninvasive prognostic approaches, such as liquid biopsy, can be used to prospectively assess the levels of chromosomal instability in the clinical setting warrants further attention,” the researchers wrote. “In addition to ongoing efforts to target single genetic alterations, there is a need to develop a greater understanding of chromosomal instability, which can alter the copy number of a multitude of genes simultaneously. Indeed, therapeutic efforts that can attenuate this process may limit the ensuing heterogeneity and tumor evolution that drive poor rates of RFS.” – by Chuck Gormley
Disclosure: Cancer Research UK funded this study. Swanton reports grant support from Cancer Research UK, Rosetrees Trust and UCLH Biomedical Research Council during the conduct of the study; personal fees from Boehringer Ingelheim, Celgene, Eli Lilly, Novartis, GlaxoSmithKline, Pfizer, Roche and Servier; personal fees and other support from Achilles Therapeutics and Grail, and other support from APOGEN Biotechnologies and EPIC Biosciences outside the submitted work. In addition, Swanton reports a patent related to a method of detecting tumor recurrence (1618485.5), a patent related to a method for treating cancer (PCT/EP2016/059401), and a patent related to immune checkpoint intervention in cancer (PCT/EP2016/071471). Please see the full study for a list of all other researchers’ relevant financial disclosures.
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