Last checked at 
* Disease evolves over many years along multiple pathways
* Diversity helps explain why disease so hard to treat
* Research highlights need for earlier detection
By Ben Hirschler
LONDON, Oct 9 (Reuters) - Lung cancer can lie dormant formore than 20 years before turning deadly, helping explain why adisease that kills more than 1.5 million a year worldwide is sopersistent and difficult to treat, scientists said on Thursday.
Two papers detailing the evolution of lung cancer reveal howafter an initial disease-causing genetic fault -- often due tosmoking -- tumour cells quietly develop numerous new mutations,making different parts of the same tumour genetically unique.
By the time patients are sick enough to be diagnosed withcancer, their tumours will have developed down multipleevolutionary pathways, making it extremely hard for any onetargeted medicine to have an effect.
The findings show the pressing need to detect lung cancerbefore it has shape-shifted into multiple malignant clones.
"What we've not been able to understand before is why thisis really the emperor of all cancers and one of the hardestdiseases to treat," said Charles Swanton, an author on one ofthe papers from Cancer Research UK's London Research Institute.
"Previously, we didn't know how heterogeneous theseearly-stage lung cancers were."
Lung cancer is the world's deadliest cancer, killing anestimated 4,300 people a day, according to the World HealthOrganisation. Around 85 percent of patients have non-small celllung cancer (NSCLC), the type analysed in the two studies.
To get a clearer understanding of the disease, the twogroups of British and American scientists looked at geneticvariability in different regions of lung tumours removed duringsurgery and worked out how genetic faults had developed overtime.
What they found was an extremely long latency period betweenearly mutations and clinical symptoms, which finally appearedafter new, additional faults triggered rapid disease growth.
In the case of some ex-smokers, the initial genetic faultsthat started their cancer dated back to the time they weresmoking cigarettes two decades earlier. But these faults becameless important over time and more recent mutations were causedby a new process controlled by a protein called APOBEC.
The research was published in the journal Science.
NEW DRUGS
Ramaswamy Govindan of Washington University School ofMedicine, who was not involved in the studies, said betterunderstanding of such genetic alterations was key to developingmore effective treatments.
There are also hopes for a new generation of immunotherapydrugs that boost the immune system's ability to detect and fighttumours, which could be particularly applicable to lung cancer.
"The large number of mutations may be the tumour's Achillesheel because every time a new mutation forms there is a chancefor the immune system to recognise it," Swanton told Reuters.
Immunotherapy drugs from companies such as Bristol-MyersSquibb, Merck & Co, Roche andAstraZeneca are already undergoing tests in lung cancer,with data on Bristol's medicine Opdivo due later this year.
Apart from better drugs, a critical challenge is to findimproved ways to detect lung cancer before it develops themultiple genetic faults that eventually trigger rapid tumourgrowth and spread.
Currently, doctors use computerised tomography (CT) todetect lung cancer -- but by the time a nodule is big enough tobe spotted it on a scan it may contain a billion geneticallydiverse cancer cells.
For the future, oncologists are pinning hopes on a newapproach, known as liquid biopsy, that may be able to detectsigns of cancer much earlier from DNA circulating in the blood.
The current prognosis for NSCLC is grim, with most patientsdiagnosed when the disease has already spread and only around 15percent surviving for at least five years after that. (Editing by Alison Williams)
