21 November 2024

Lung cancer: The new era of tumour understanding

Illustration ofanalysis stages in the treatment of personalised lung cancer treatment

 

Lung cancer is now the most prevalent cause of cancer-related deaths worldwide, posing a major challenge for the medical and scientific community. To support Lung Cancer Awareness Month, Porterhouse Medical shines a spotlight on  lung cancer and how personalised medicine approaches, such as molecular phenotyping, represent a new beacon of hope for those with this devastating disease.

What are the symptoms of lung cancer?

According to the World Health Organization, lung cancer is characterised by a series of symptoms: a persistent cough, chest pain, shortness of breath, coughing up blood, fatigue, unexplained weight loss and recurrent lung infections [1]. It is important to highlight that many of these symptoms overlap with those of common respiratory viral infections, such as colds, flu and more recently COVID-19, which may lead to delays in early diagnosis and possible life-saving treatment [2].

What are the risk factors for developing lung cancer?

A history of tobacco use is considered the principal risk factor for developing lung cancer; this risk also extends to those exposed to second-hand smoke. Cigarette smoke contains carcinogens that interact with key metabolic processes, resulting in mutations of important molecular barriers that prevent cancer development. These barriers include the gene TP53, which encodes for p53, and the oncogene KRAS. p53 is a tumour suppressor protein activated by cellular stress; it protects cells from tumour progression [3]. KRAS is part of the Ras/Raf pathway that controls key cellular activity such as anti-apoptosis, proliferation and cell survival. Mutations in either of these genes can lead to uncontrollable growth and tumour formation [4, 5]. A recent modelling study found that banning the sale of tobacco to the younger generation could prevent up to 1.2 million lung cancer–related deaths by 2095 [6]. Additional risk factors include air pollution and exposure to known workplace carcinogens such as asbestos [1].

What are the main types of lung cancer?

Primary lung cancers can be categorised into two histological subtypes: non–small cell carcinoma (NSCLC) and small cell carcinoma. NSCLC represents the most ubiquitous of these groups, occurring in 85% of lung cancer patients [7, 8]. Within NSCLC, further histological subtypes exist, including adenocarcinoma, squamous cell carcinoma and large cell carcinoma [9].

Drug resistance in lung cancer

A crucial challenge in the treatment of lung cancer is drug resistance. As tumours are dynamic, selection pressures imposed by treatment may cause a subpopulation of tumour cells to mutate and develop resistance against the biomarkers targeted by cancer therapeutics [10]. Other mechanisms of drug resistance include overexpression of efflux pumps, epigenetic modifications (i.e. changes in gene expression) and changes in the tumour microenvironment [11]. Multiple mutations and resistance strategies enable a tumour to become resistant against a variety of anticancer drugs, enhancing tumour survival [12].

A key example of a biomarker that is frequently mutated in NSCLC is the epidermal growth factor receptor (EFGR). This receptor has roles in cell proliferation, survival, invasion and the formation of new blood vessels – factors that supplement tumour formation and development when EFGR is mutated [7, 13]. Tumours with EFGR mutations are typically treated with tyrosine kinase inhibitors (TKIs); however, 20–30% of patients display intrinsic resistance to these agents [10]. Acquired resistance to TKIs can occur from therapeutic selection pressures and 50–63% of TKI-treated tumour samples were found to have the common T790M mutation within the EFGR gene [10].

Another major challenge in the treatment of cancer is the heterogeneity of tumours, with different sections of a tumour displaying a diverse genetic make-up of growth success, mutations and drug resistance capability. Typically, traditional tissue biopsy samples only represent a small snapshot of a potentially heterogeneous tumour. Additionally, it may not be possible to retrieve solid biopsies during an early diagnosis as the tumour could be too small or inaccessible.

Molecular phenotyping and a new era of personalised medicine

To treat tumours more successfully, a patient-targeted approach is needed. Next-generation sequencing (NGS) enables analysis of a patient’s tumour to determine what mutations are present and which potential cancer-causing genes are switched on or off (epigenetics). This approach informs decision-making on potential therapeutic drug choices.

Liquid biopsies that isolate tumour-derived entities from blood plasma could hold the key to understanding tumours at a level greater than traditional biopsies; moreover, this method has the advantage of being less invasive and more appropriate if the tumour is small and inaccessible [14]. Cells throughout the body release deoxyribonucleic acid (DNA) into the circulatory system known as cell-free DNA (cfDNA) [15]. These cells typically originate from the haematopoietic system (responsible for blood cell development), but primary tumours may release apoptotic or necrotic tumour cell DNA into the bloodstream where they can be detected as circulating tumour DNA (ctDNA) [15, 16]. This ctDNA can reflect the primary tumours’ genetic and mutational signature, facilitating a personalised medicine approach by highlighting potential targets susceptible to anticancer drugs. The accuracy of tumour analysis through ctDNA has been further improved by emerging advancements in artificial intelligence and machine-learning, which enable high-throughput analysis of hidden non-genetic features in cfDNA [17]. Following treatment, ctDNA detection assays can be used to determine tumour clearance success and to monitor cancer relapse [18].

Besides ctDNA, liquid biopsies reveal circulating tumour cells (CTCs) that can be sequenced following immunoaffinity-based isolation methods to obtain insights into the possible heterogeneity of the primary tumour [14]. Another novel biomarker that can be isolated from liquid biopsies and used to detect tumour presence are exosomes. These small vesicles contain important cellular messengers such as messenger ribonucleic acid (mRNA) and non-coding RNAs (microRNA), which can function to regulate oncogenes and tumour suppressor genes; aberrant levels of miRNAs may indicate cancer development [14].

These liquid biopsy biomarkers (cfDNA, CTCs and exosomes) can be utilised at all stages of treatment from disease indication and diagnosis to relapse surveillance. Importantly, these biomarkers enable near real-time monitoring of a tumour and how its drug susceptibility may evolve over the course of treatment, which could lead to improved patient outcomes [19].

What are the current challenges with ctDNA and liquid biopsies?

There are several notable challenges despite the potential of ctDNA assays to enhance tumour understanding. Firstly, as ctDNA is only a small fraction of cfDNA in the normal circulation, detection can be difficult and requires a high degree of sensitivity that needs to be further validated in future clinical studies [17]. Owing to the low abundance of ctDNA and the nature of genome assembly methods, some artefactual false positive mutations may be detected. False positives can be accounted for by introducing background error rates into mutation calling algorithms; however, this would come at the cost of reducing sensitivity [16]. Similarly, immature blood cells may accumulate mutations while aging and shed cfDNA without progression to cancer. This type of cfDNA makes up the majority of cfDNA in the plasma and may also affect the sensitivity of ctDNA detection through false positives, which will need to be accounted for [20]. Lastly, detection of CTCs is difficult because of their low frequency in blood plasma; additionally, CTCs present in liquid biopsies may be dead cells appearing as false positives.

Despite its current limitations, molecular phenotyping represents a powerful tool to better understand metastatic tumours during treatment and surveillance of possible relapse. This method could also permit cancer detection at an earlier stage of prognosis, with an ultimate goal of improving patient outcomes in the long term.

References

  1. World Health Organization. Lung cancer (2023). Available at: https://www.who.int/news-room/fact-sheets/detail/lung-cancer. Accessed November 2024.
  2. Maxwell SS and Weller D. Lung cancer and Covid-19: Lessons learnt from the pandemic and where do we go from here? NPJ Prim Care Respir Med 2022; 32 (1): 19.
  3. Mantovani F, Collavin L and Del Sal G. Mutant p53 as a guardian of the cancer cell. Death Differ 2019; 26 (2): 199–212.
  4. Jancík S, Drábek J, Radzioch D et al. Clinical relevance of KRAS in human cancers. J Biomed Biotechnol 2010; 2010: 150960.
  5. Hecht S. Lung carcinogenesis by tobacco smoke. Int J Cancer 2012; 131 (12): 2724–32.
  6. Brandariz J, Rumgay H, Ayo-Yusuf O et al. Estimated impact of a tobacco-elimination strategy on lung-cancer mortality in 185 countries: A population-based birth-cohort simulation study. Lancet Public Health 2024; 9 (10): E745–E754.
  7. Herbst R, Morgensztern D and Boshoff C. The biology and management of non-small cell lung cancer. Nature 2018; 553 (7689): 446–454.
  8. Tang M, Abbas HA and Negrao MV et al. The histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics. Nat Commun 2021; 12 (1): 7081.
  9. Xie X, Li X and Tang W et al. Primary tumour location in lung cancer: The evaluation and administration. Chin Med J (Engl) 2021; 135 (2): 127–136.
  10. Koulouris A, Tsagkaris C and Corriero AC et al. Resistance to TKIs in EGFR-mutated non-small cell lung cancer: From mechanisms to new therapeutic strategies. Cancers (Basel) 2022; 14 (14): 3337.
  11. Ashrafi A, Akter Z and Modareszadeh P et al. Current landscape of therapeutic resistance in lung cancer and promising strategies to overcome resistance. Cancers (Basel) 2022; 14 (19): 4562.
  12. Emran TB, Shahriar A and Mahmud AR et al. Multidrug resistance in cancer: Understanding molecular mechanisms, immunoprevention and therapeutic approaches. Front Oncol 2022; 12: 891652
  13. Cheng L, Alexander R and MacLennan G et al. Molecular pathology of lung cancer: Key to personalized medicine. Mod Pathol 2012; 25 (3): 347–369.
  14. Bertoli E, De Carlo E and Basile D et al. Liquid biopsy in NSCLC: An investigation with multiple clinical implications. Int J Mol Sci 2023; 24 (13): 10803.
  15. Yan YY, Guo QR and Wang FH et al. Cell-free DNA: Hope and potential application in cancer. Front Cell Dev Biol 2021; 9: 639233.
  16. Cabel L, Proudhon C and Romano E et al. Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy. Nat Rev Clin Oncol 2018; 15 (10): 639–650.
  17. Moser T, Kühberger S and Lazzeri I et al. Bridging biological cfDNA features and machine learning approaches. Trends Genet 2023; 39 (4): 285–307.
  18. Abbosh C, Hodgson D and Doherty GJ et al. Implementing circulating tumor DNA as a prognostic biomarker in resectable non-small cell lung cancer. Trends Cancer 2024; 10 (7): 643–654.
  19. Schroeder C, Gatidis S and Kelemen O et al. Tumour-informed liquid biopsies to monitor advanced melanoma patients under immune checkpoint inhibition. Nat Commun 2024; 15 (1): 8750.
  20. Bersani F, Morena D and Picca F et al. Future perspectives from lung cancer pre-clinical models: New treatments are coming? Transl Lung Cancer Res 2020; 9 (6): 2629–2644.

Author :

Joshua Yates

PhD Placement Intern