Tumour heterogeneity – a challenge to advances in precision treatment
Inter-tumour heterogeneity refers to the observation that a certain cancer type in distinct patient subgroups presents with vastly different genetic make-ups, histopathological features and clinical behaviours. Similarly, intra-tumour heterogeneity relates to the genetic heterogeneity between cancer cells within a single tumour, and might explain why some tumour cells remain present in the patient after cancer treatment has finished. Both can lead to different and unpredictable responses to therapy, including use of targeted therapy approaches. Starting with the reading list below, write an essay defining key challenges associated with intra-tumour heterogeneity in cancer management/treatment. Use specific examples from the literature of various cancer types to support or highlight each point you make. Begin your essay by briefly defining the difference between inter- and intra-tumour heterogeneity. Conclude your essay with a brief statement summarising the current state of our understanding with respect to intra-tumour heterogeneity, and your opinion whether today’s challenges might be insurmountable.
- Gerlinger et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012 Mar 8;366(10):883-92.
- McGranahan and Swanton. Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. Cell. 2017 Feb 9;168(4):613-628.
- Tabassum and Polyak. Tumorigenesis: it takes a village. Nat Rev Cancer. 2015 Aug;15(8):473-83.
- Welch (Commentary) Tumor Heterogeneity–A ‘Contemporary Concept’ Founded on Historical Insights and Predictions. Cancer Res. 2016 Jan 1;76(1):4-6.
Tumour development is caused by alterations in genes which modulate vital cellular processes such as replication, DNA repair, energy metabolism, and apoptosis . The original aberrations that occur are known as ‘driver mutations’, and allow the unrestricted and unregulated proliferation of cells to ensue, detrimentally affecting tissue function, and potentially resulting in metastasis. As this monoclonal cell line continues to replicate further alterations to the genomic profile arise. These partly occur due to a tumour environment which fosters genetic instability, and consequently results in the appearance of heterogenous subclones as a result of various selection pressures which promote Darwinian evolution .
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Throughout tumour advancement clonal evolution occurs whereby these subclones may be experience further mutagenesis, or alteration in the expression of genes. The clones which harbour an advantageous phenotype in the tumour microenvironment undergo further replication, and establish a sense of competition between the subpopulations.
There are two main levels of heterogeneity. Firstly there is inter-tumour heterogeneity, which describes when a tumour from the same cell origin presents differently between individual patients . This can be with respect to the gross and microscopic appearance, patient symptoms, treatment response, prognosis and survival [3, 4]. As a result, specific treatment approaches are required to be tailored for each case depending on how the disease presents and the mutation profile . Breast cancer for example consists of several subtypes. These are classified into categories based on the presence of aberrations in a select group of genes which have an associated treatment response and prognosis . These subtypes include luminal A, luminal B, and HER2 classifications .
Conversely, different subpopulations of cancer cells can also be present within a single individual, which is known as intratumor heterogeneity . Intratumor heterogeneity can further be classified as either spatial or temporal . Figure 1. below demonstrates the difference between these 3 distinct types of heterogeneity seen in, and between cancer patients.
Figure 1. Schematic drawing representing the differences between intertumour heterogeneity and intratumour heterogeneity; The different colours depict cell clones with distinct genomic profiles; a. intertumour heterogeneity; b. intratumour temporal heterogeneity; c. intratumour spatial heterogeneity.
Spatial heterogeneity explains the variation in genetic profiles of tumour subclones which are located in distinct tumour regions. This can be present between different areas of a tumor and/or between the individual metastatic populations . Furthermore, the idea of temporal heterogeneity illustrates the development of novel subclones that occurs over time, where cells progressively acquire new genomic alterations as a result of their instability and selection pressures by the tumour microenvironment .
Intra-tumour heterogeneity poses a significant challenge to the effectiveness of cancer treatment and management . Heterogeneity is particularly important in reference to the administration of targeted therapies, as eradicating one tumour subtype can allow a more aggressive and drug resistant cell line to proliferate. This review essay will address the key contributors of intratumor heterogeneity, the fundamental challenges presently faced by health professionals in overcoming intratumor heterogeneity in treatment, and the current research around solutions for these problems.
Intra-tumour heterogeneity & how it develops
The presence of heterogenous clones in an individual has been found to be evident across a wide range of cancers. For example, a study which involved an analysis of multiple distinct regions of a tumour in primary renal carcinomas and metastatic outgrowths revealed the presence of genetically unique clones with varying somatic mutations . Between 63-69% of mutations identified in the tumour and metastases were not present in every tumour region, indicating that spatial heterogeneity was present and well established . In a separate study, Glioblastomas were observed to display a large degree of heterogeneity, demonstrated by a variation in spatial genomic profiles such as gene amplifications, and up-regulation of receptors .
Intratumor heterogeneity is largely driven by environmental selection pressures such as those exerted by the tumour microenvironment . The microenvironment refers to the local habitat of the tumour, comprising of both cellular and extracellular material. The endothelium, fibroblasts and the extracellular matrix are examples of non-malignant components which modulate the delivery of oxygen, nutrients, growth factors and other metabolites, and therefore influence the growth and development of the clone [10, 11]. A combination of selection pressures exert an effect of natural selection, such as is seen in natural ecosystems, which will favour the proliferation of some clones and cause the decline of others, based on their phenotypic profile .
These environmental elements can also shield the tumour cells from therapeutic treatment such as chemotherapy drugs. Cell interaction, such as through junctional and adhesion complexes, as well as molecules secreted by the cells can enable survival of neoplastic cells even in the presence of damaging factors and negative selection pressures .
In addition to this, clonal cooperation also contributes to tumour heterogeneity . Synergy, mutualism, and commensalism are all types of interactions that occur between tumour subclones which lead to increased growth of either an individual clone, or multiple interacting subclones . These interactions can drive the survival of various genetically distinct subclones, thus ensuring the continuance of heterogeneity.
Genomic instability is another main contributor of heterogeneity in an individual . Genomic instability has been associated with the development of whole chromosomal aberrations, reduction in sensitivity to therapeutic treatments, as well as the recurrence of neoplasms following treatment termination . This instability refers to the abnormal and potentially harmful changes acquired by cells such as point mutations, chromosomal translocations, and aneuploidy . The consequence of the genetic instability in the tumour cells is that it will continually drive the occurrence of mutagenic events, promoting genetic diversity and thus consequently increasing heterogeneity.
Intratumor heterogeneity presents a significant challenge with respect to the detection and management of cancer. In some cases where cancer is suspected only one biopsy will be performed from a single area of the tumour, in order to characterise the tumour and investigate the genetic aberrations and histopathology that is present. However this poses a problem due to intratumor heterogeneity. As tumours display spatial heterogeneity, a biopsy taken from one area of the tumor may not accurately reflect the overall composition of the tumour . Due to spatial heterogeneity this type of sampling method may therefore provide misleading information about the tumour prognosis and best treatment options.
In addition to spatial heterogeneity there is also the threat of temporal heterogeneity. An original biopsy may not represent a tumours current state due to the constant evolution of the tumour subclones as a result of selection pressures, such as an evolving microenvironment or the administration of cytotoxic treatments [11, 16]. For example, a study involving sampling of Chronic Lymphocytic Leukaemia between two time points revealed clonal evolution whereby subclones acquired novel genetic mutations and regulation of gene expression . Therefore, the samples were genomically distinct between the original and follow-up biopsy, illustrating the requirement for continual cancer analysis .
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Biomarkers are important in the growth in our knowledge and understanding of cancer. Once a useful marker has been identified, a patients’ tumour presentation, symptoms, response to treatment, and outcome can be recorded, with this information then translating to other cases where the biomarker is found to be present. Biomarkers therefore contribute to a better understanding of cancer subtypes, including identification of an effective treatment and ultimately an improved outcome and survival for patients . Currently, there have been a few biomarkers identified in important breast cancer variants which are associated with different presentations, treatment sensitivity, and prognosis. This includes the presence of amplified HER2 and ER in breast cancers . HER2 positive breast cancers are typically treated with Herceptin, a monoclonal antibody which prevents HER2 binding and thus inhibits the signalling of growth to the tumour cells . ER positive breast cancers on the otherhand are commonly treated with a drug called Tamoxifen, which acts by inhibiting Estrogen binding to its receptor, this disrupting the Estrogen signalling pathway . These examples demonstrate that elucidating the unique tumour genomics through biomarkers can be implemented into clinical settings with beneficial outcomes.
Secondly, heterogeneity poses a significant threat to the effectiveness of targeted therapy and the capability of these personalised medications to successfully eliminate the tumour cells. Due to variation amongst the clones there may be cells which contain genetic aberrations which confer a survival advantage. At the beginning of treatment there may be a small number of tumour cells which harbour mutations that are resistant to the applied cancer treatment as a result of genomic variance. The administration of chemotherapy drugs, or other cytotoxic treatments, may target and effectively kill one tumour clone, however this would result in decreased inter-clone competition and potentially allow a more unstable and lethal clone to take over the tumour real estate . This has been evident in a study investigating the mutations present in a Mantle Cell Lymphoma, whereby the main identifiable clone in a patient was targeted through the administration of cytotoxic chemotherapy drugs. However this resulted in an once inferior subclone, that had a phenotypic profile divergent to the original clone, having a conferred survival advantage and was therefore able to proliferate and colonise the tumour landscape .
As the cells that are susceptible to the treatment die off it provides the opportunity for these resistant cells to multiply and proliferate. An intermittent decrease in tumour size can occur, but this would only be temporary. The resultant tumour, known as residual disease, could contain a more diverse range of clonal colonies, have increased malignancy potential and a decreased range of viable treatment options due to elevated clonal aggressiveness .
Intratumor heterogeneity also affects the selection and efficiency of targeted therapies. This is because many unique and genomically distinct subtypes will be present in a single individual. Although personalised medicine is a great development in cancer treatment as it is tailored to the specific presentation of an individual’s tumour type, this selectivity also comes at a price. A more individualised therapy targets a distinct tumour clone, but leaves the other clones present untouched. This application of more specific selection pressure could result in the clonal development and evolution of more belligerent cell lines when compared to the use of generalised treatments like chemotherapy .
Genomic instability may also contribute to the ability of cancers to become drug resistant, whereby the accumulation of new somatic mutations can confer a survival advantage in that the treatment cannot effectively kill or slow progression of this clone variant 
Current Technology & Treatment
Currently, there is a large drive and demand for research focusing on solutions to best minimise the development and effects of intratumor heterogeneity.
Patient-derived xenografts (PDX) is an emerging technology used to investigate heterogeneity and the progression of heterogenous clones in response to treatment. Patient-derived xenografts refers to the practice of introducing patient tumour samples into a foreign animal, such as a laboratory rat. The tumour cells become established in the host animal, whereby various treatments can then be administered to investigate their efficiency and specificity, as well as how these treatments contribute to tumour differentiation and induce further genetic diversity and drug resistant cell lines . As the tumour is a continually evolving ecosystem subject to various environmental selection pressures it is important to explore how these processes occur. The responsiveness of a tumour to various treatments can be investigated by administering these to the PDX animal. This is important as the results seen can translate to a clinical setting, by advising on the best course of treatment for this individual’s tumour. The clonal evolution over time can also be investigated by this technique to determine how to limit this development of heterogenous clones and thus minimise the risk of drug resistance from developing . This can also be applied clinically by predicting the evolution of tumour composition in response to treatment, and thus implementing solutions to mitigate this.
In order to gather a more in-depth and representational picture of a tumours genomic architecture multi-region sampling and analysis are required . Next generation sequencing is, and will continue to be a valuable tool in deciphering and identifying the subclones that are present in spatially or temporally distinct samples .
Continual sampling of the tumour architecture, including the phenotypic and genotypic variants present in an individual, will continue to become more important in cancer management. This would allow the modification of the personalised medications used throughout the clinical course of the disease as it evolves. Small quantities of cancer DNA can often work their way into the blood stream, with a relatively new technique described as a liquid biopsy catalysing off this . The technique involves examining the DNA of circulating tumour cells (ctDNA) in order to determine the presence of heterogenous clones and their genomic profiles. This procedure is relatively non-invasive compared to current solid tumour analysis techniques, involving only taking a single blood sample for processing. The use of this technique would be particularly valuable over the course of a patients treatment, in order to assess the developing mutation prolife of drug resistant clones [6, 20]
The use of a combination of therapeutic agents is another possible technique identified to overcome the challenge of the development of heterogenous drug resistant clones [4, 21].
Hypothesising or predicting the transformation of tumour cells in response to a treatment would be invaluable in treatment, as it would translate to a clinical advantage in that an additional drug regime can be initiated in order to combat a possible clone from becoming established. This technique has been validated in multiple studies, such as one involving the development of Cetuximab resistance in colorectal tumours. This resistance was found to be due to the presence of a novel mutation in the EGFR gene which conferred resistance to the treatment, with this protein being a main driver in tumour progression in colorectal cancer . This resistance however was combated by the use of an additional drug called Sym004 which acts as a monoclonal antibody against EGFR , which the clone was sensitive to, resulting in tumour size reduction.
Lastly, in some individuals the goal of treatment is now not to completely eradicate the tumour, but instead to establish a stable, steady tumour state. This therapeutic approach is aimed at minimising the further development of heterogenous clones which may be more aggressive and drug resistant . A precise selection of anti-cancer medications is required to achieve this, as well as the establishment of an optimal time between drug administrations.
In summary, heterogeneity, specifically intratumor heterogeneity, provides one of the greatest challenges in cancer management at present. The Darwinian evolution of the tumour architecture has proved to be difficult to both identify and treat, and contributes to increased drug resistance, tumour recurrence, and ultimately death. Future research is needed to determine how to best analyse patient samples to identify all of the subclones present, no matter how small the clonal population may be. Effective monitoring of the clonal evolution of a tumour is another fundamental area of cancer management and treatment that requires further investigation, in order to establish efficient techniques which can be translated into clinical action. Identifying combination therapies to limit the establishment and development of heterogeneity will also be vital. In review of the current research and level of understanding in these areas I believe that the battle against intratumor heterogeneity is not an insurmountable one, however a great deal of further research needs to be focused in this area to overcome it.
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