Anyone who has seen the video footage of snooker legend Joe Davis clear the first ever ‘century break’ on television, will appreciate how far technology has come. In the fuzzy greyscale broadcast of 1962, it is possible to make out that snooker is being played. After that, a large dose of imagination and guess-work is required.
We can hear the audience clapping, but see none of them. We can tell that there are snooker balls on the table, but most look identical in greyscale, and we rely on the commentator to figure out which colour is which. Recently, I watched in glorious High Definition as Mark Selby and Ronnie O’Sullivan slugged out the UK Championship final. Every colour crisp, every facial expression detailed, every pot captured, the outcome undisputed. I could rewind, replay, and analyse each moment on demand. This is the 21st Century after all.
Advances toward viewing lung cancer in HD are progressing in a similar fashion but we are not there yet. Non-small-cell lung cancer (NSCLC) accounts for the vast majority of lung cancer cases (~85 per cent, with small-cell lung cancer making up the other 15 per cent), and usually presents as locally advanced or metastatic, with very poor prognosis. The American Cancer Society estimates the five-year survival rate of metastatic NSCLC at about one per cent. This puts a huge responsibility on us to improve diagnosis and management of lung cancers. We have moved on from the fuzzy days of relying on terms like “small-cell” and “non-small-cell” (though still in use since the late 70s) to guide treatment of lung cancer. Today we use molecular profiling to more accurately portray the complexities of tumours.
Moving to HD diagnosis of NSCLC
Advanced tissue sampling techniques, such as endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound with fine-needle aspiration and biopsy (EUS-FNA), have made it easier to biopsy lung tissue. Immunohistochemical markers help delineate squamous cell carcinomas (markers: p63, p40, cytokeratin CK 5/6) from adenocarcinomas (markers: TTF1, Napsin A, CK7, Mucin), and to an extent, these classifications have helped guide treatment approaches. We know, for example, that pemetrexed (Alimta®) can improve survival in non-squamous NSCLC, but not squamous NSCLC.
For now, we at least see tumours in Technicolour. In future, we should expect analysis of tumours in HD, with almost real-time updates, to guide the best treatment option for patients.
As we learn more about what drives these cancers to grow, we are moving towards stratifying tumours at the genetic level. Many NSCLCs carry gene mutations that are thought to drive cancer growth. These include KRAS, EGFR and ALK gene mutations often seen in adenocarcinoma (for a comprehensive list, see Hiley et al. 2016). This gives us hope for developing new treatments (extensive review in Hirsch et al. 2016) that can target these mutations to kill cancer cells.
However, we have to contend with the reality that tumours found within the same patient may have different genetic mutations and that tumour cells within a single tumour can differ genetically from each other (inter- and intra-tumour heterogeneity, respectively). Add to this, that cancer treatments themselves can change the evolution of tumours, and it’s easy to appreciate the shifting sands that oncology teams grapple with on a daily basis.
Multi-gene next generation sequencing (NGS) aims to keep up with the complexity and evolution of tumours. The UK’s Stratified Medicine Programme 2 (SMP2) analyses NSCLC tumours using a 28-gene NGS platform. The data from that analysis allows patients to be enrolled in a clinical trial (The National Lung Matrix Trial) that better matches their tumour profile. Ideally, multi-gene NGS of tumours would happen throughout the patient’s treatment, to give the best chance for tailoring therapies based on how the cancer evolves.
Expanding treatment options
As we learn more about the complexities of NSCLC, clinical trials are looking at combining different therapeutic approaches. Cancertrials.ie provides links to the clinical trials currently ongoing in Ireland. Most of the trials listed investigate the combination of interventions targeting emerging molecular targets with the current standards of care (combinations of platinum-based chemotherapeutics along with gemcitabine or permetrexed) used in NSCLC (Table 1). This move mirrors global trends in clinical trials, judging by the 2016 ASCO Annual Meeting synopsis available online.
For now, we at least see tumours in Technicolour. In future, we should expect analysis of tumours in HD, with almost real-time updates, to guide the best treatment option for patients. Just as effective snookering requires that the player knows the colour of every ball, and can anticipate the opponent’s next move, snookering NSCLC requires that we know the molecular fingerprint of each tumour, are able to track the evolution of the disease, and design treatments that will deliver. To settle for anything less betrays our ambition to tackle the intricacies of tumour biology and tumour evolution in this lethal cancer.