Spatial Heterogeneity and Evolutionary Dynamics Modulate Time to Recurrence in Continuous and Adaptive Cancer Therapies

Gallaher, Jill; Enríquez-Navas, Pedro M.; Luddy, Kimberly A.; Gatenby, Robert A.; Anderson, Alexander R.A.

doi:10.1158/0008-5472.can-17-2649

Cited by 226 publications

(284 citation statements)

References 48 publications

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“…However, intratumor heterogeneity (ITH) is common in human tumors and the ancestral information recorded by subclonal mutations can be used to reconstruct their growth [1][2][3] . The interpretation of the ancestral information encoded by ITH is critical because knowledge about tumor initiation and progression informs effective strategies to prevent, detect, and treat human cancers [4][5][6] .…”

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confidence: 99%

Minimal barriers to invasion during human colorectal tumor growth

et al. 2020

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Intra-tumoral heterogeneity (ITH) could represent clonal evolution where subclones with greater fitness confer more malignant phenotypes and invasion constitutes an evolutionary bottleneck. Alternatively, ITH could represent branching evolution with invasion of multiple subclones. The two models respectively predict a hierarchy of subclones arranged by phenotype, or multiple subclones with shared phenotypes. We delineate these modes of invasion by merging ancestral, topographic, and phenotypic information from 12 human colorectal tumors (11 carcinomas, 1 adenoma) obtained through saturation microdissection of 325 small tumor regions. The majority of subclones (29/46, 60%) share superficial and invasive phenotypes. Of 11 carcinomas, 9 show evidence of multiclonal invasion, and invasive and metastatic subclones arise early along the ancestral trees. Early multiclonal invasion in the majority of these tumors indicates the expansion of co-evolving subclones with similar malignant potential in absence of late bottlenecks and suggests that barriers to invasion are minimal during colorectal cancer growth.

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confidence: 99%

Minimal barriers to invasion during human colorectal tumor growth

et al. 2020

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“…As such, our data set further supports identification of genomic coalterations providing an additional facet in whether single agent FGFR2‐targeted strategies should continue to be prospectively tested. It is likely that dual targeting or sequential approaches will be needed for the patients with GEA with non‐pan‐WT tumors . We also observed FGFR2 rearrangements not previously reported in GEA in 14% of cases, and FGFR2 fusions are known to be responsive to FGFR2 agents in multiple other tumor types, although heterogeneity in those tumor types is not well described .…”

Section: Discussionmentioning

confidence: 47%

FGFR2-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape

Klempner

Madison²,

Pujara

et al. 2019

The Oncologist

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Background With the exception of trastuzumab, therapies directed at receptor tyrosine kinases (RTKs) in gastroesophageal adenocarcinomas (GEA) have had limited success. Recurrent fibroblast growth factor receptor 2 (FGFR2) alterations exist in GEA; however, little is known about the genomic landscape of FGFR2‐altered GEA. We examined FGFR2 alteration frequency and frequency of co‐occurring alterations in GEA. Subjects, Materials, and Methods A total of 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture‐based genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA, and microsatellite instability was determined on 95 or 114 loci. Descriptive statistics were used to compare subgroups. Results We identified a total of 269 (4.0%) FGFR2‐altered cases consisting of FGFR2‐amplified (amp; 193, 72% of FGFR2‐altered), FGFR2‐mutated (36, 13%), FGFR2‐rearranged (re; 23, 8.6%), and cases with multiple FGFR2 alterations (17, 6.3%). Co‐occurring alterations in other GEA RTK targets including ERBB2 (10%), EGFR (8%), and MET (3%) were observed across all classes of FGFR2‐altered GEA. Co‐occurring alterations in MYC (17%), KRAS (10%), and PIK3CA (5.6%) were also observed frequently. Cases with FGFR2amp and FGFR2re were exclusively microsatellite stable. The median TMB for FGFR2‐altered GEA was 3.6 mut/mb, not significantly different from a median of 4.3 mut/mb seen in FGFR2 wild‐type samples. Conclusion FGFR2‐altered GEA is a heterogenous subgroup with approximately 20% of FGFR2‐altered samples harboring concurrent RTK alterations. Putative co‐occurring modifiers of FGFR2‐directed therapy including oncogenic MYC, KRAS, and PIK3CA alterations were also frequent, suggesting that pretreatment molecular analyses may be needed to facilitate rational combination therapies and optimize patient selection for clinical trials. Implications for Practice Actionable receptor tyrosine kinase alterations assayed within a genomic context with therapeutic implications remain limited to HER2 amplification in gastroesophageal adenocarcinomas (GEA). Composite biomarkers and heterogeneity assessment are critical in optimizing patients selected for targeted therapies in GEA. Comprehensive genomic profiling in FGFR2‐altered GEA parallels the heterogeneity findings in HER2‐amplified GEA and adds support to the utility of genomic profiling in advanced gastroesophageal adenocarcinomas.

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“…Mathematical models have been useful to understand cancer biology and to help test what treatment strategies might improve patient outcomes over standard of care. Many model types have been used, including game theory models [42][43][44][45][46][47][48][49] , agent based models (ABMs) 33,[50][51][52][53][54][55] , and Lotka-Volterra type dynamical models that consider cancer clonal cells as interacting populations 56,57 . So far, very few of these models consider variation in the environment of cancer cells in time.…”

Section: A Simple Model Of the Storage Effect In Cancermentioning

confidence: 99%

What is the storage effect, why should it occur in cancers, and how can it inform cancer therapy?

Miller

Brown

Basanta

et al. 2020

Preprint

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Intratumor heterogeneity is a feature of cancer that is associated with progression, treatment resistance, and recurrence. However, the mechanisms that allow diverse cancer cell lineages to coexist remain poorly understood. The storage effect is a coexistence mechanism that has been proposed to explain the diversity of a variety of ecological communities, including coral reef fish, plankton and desert annual plants. Three ingredients are required for there to be a storage effect: 1) temporal variability in the environment, 2) buffered population growth, and 3) species-specific environmental responses. Here, we argue that these conditions are observed in cancers and that it is likely that the storage effect contributes to intratumor diversity. Data that show the temporal variation within the tumor microenvironment is needed to quantify how cancer cells respond to fluctuations in the tumor microenvironment and what impact this has on interactions among cancer cell types. The presence of a storage effect within a patient's tumors could have substantial impact on how we understand and treat cancer.

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Spatial Heterogeneity and Evolutionary Dynamics Modulate Time to Recurrence in Continuous and Adaptive Cancer Therapies

Cited by 226 publications

References 48 publications

Minimal barriers to invasion during human colorectal tumor growth

Minimal barriers to invasion during human colorectal tumor growth

FGFR2-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape

What is the storage effect, why should it occur in cancers, and how can it inform cancer therapy?

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