21 August 2019

Vicious cycle: why lung cancer is so unloved

Cancer Clinical Respiratory Smoking

Inside the TARDIS-like Woolcock Institute of Medical Research in Glebe in inner Sydney, a gleaming new laboratory is waiting to be populated with researchers dedicated to the study of the most lethal cancer and our No 4 cause of death.

The Lung Cancer Centre will investigate the role that the microbiome, both gut and lung, plays in whether someone responds or not to immunotherapy, a promising second-line treatment that at present works only on 20 to 30% of patients.

But it’s a lonely and impoverished road for researchers of this disease – let alone the patients.

Although lung cancer killed almost 8300 Australians in 2017, and regularly kills more women than breast and ovarian cancer combined, the cloud of cigarette smoke that hangs over the disease has ensured that it remains stigmatised, underfunded and understudied.

The powerful public health message that smoking causes lung cancer has driven away philanthropy as successfully as it has driven down tobacco usage, and has done little for the substantial proportions of lung cancer patients who have never smoked, or who once smoked but quit.

The clear association with smoking has been a double-edged sword in the fight against lung cancer, says Lung Foundation CEO Mark Brooke.

“We’ve been advocating for smoking cessation and reduction in tobacco usage for over 30 years,” he tells The Medical Republic. “But as a consequence of that we’ve aligned tobacco and lung cancer. And while we won’t retreat from our role on tobacco, it’s very clear to us that we’ve done the lung cancer community a disservice. Because everyone believes somehow that if you’ve got lung cancer it’s your own fault.

“At least one in five patients will never have been smokers, at least three in five will be non-smokers who’ve given up some time ago. So we’re talking about a substantial part of the population who made the difficult decision to give up a complex and addictive substance. It’s a tough bloody road.

“I’ve just been talking to a veteran who was conscripted into the Australian army at 19, had never smoked, was given cigarettes by the army, began smoking, gave up 15 years later when he left the army and now has lung cancer. This is someone who’s served his nation with great distinction, but he’s to be treated differently from someone with melanoma or breast or prostate cancer?”

The foundation’s campaign document, Making Lung Cancer a Fair Fight: A Blueprint for Reform, sets out the psychosocial burden of the disease as well as the financial ($284 million a year in direct treatment costs), and projects that 2.9 million years of life will be lost over the next 10 years.

To improve that prognosis, Mr Brooke says the funding imbalance must be addressed.

He cites Cancer Australia’s 2015 Cancer Research in Australia report, which shows the huge mismatch between disease burden and funding.

“There’s a significant disparity between the burden of disease and the investment,” Mr Brooke says. “Lung cancer counts for about 20% of the cancer burden but only receives about 4.8% of the funding. Breast cancer receives about 30% of total cancer funding but its burden of disease is only about 5%.

“We’re not at war with other cancers, we don’t want their funding redistributed, but we are calling for the government to substantially increase funding proportionate with the disease.”

The other problem with attracting philanthropic investment is a lack of advocates, thanks not only to the stigma, but also simply to the disease’s poor survival rates. While breast cancer, with 90% five-year survival, has an army of advocates to appeal for research funding, lung cancer’s five-year survival rate is 17%.

So it’s a vicious cycle: the prognosis needs to improve in order to attract funding for research to improve the prognosis.

“There is no Pink Test for lung cancer, as there is thanks to the wonderful work by the McGrath Foundation,” Mr Brooke says. “So it’s hamstrung, by not just lack of government investment, but by lack of community empathy for people with lung cancer.  We are seeing with new immunotherapy, among other things, that survivability can improve.”

That’s exactly what the Lung Cancer Centre is targeting, in collaboration with UNSW’s Microbiome Research Centre, by testing whether the bacteria in our guts and lungs might account for why some patients respond to immunotherapy and others don’t.

Recruiting patients from Chris O’Brien Lifehouse, Royal Prince Alfred Hospital and St George, and later other centres, the plan is to sequence the DNA of flora in patients’ lungs and guts using bronchoalveolar lavage and stool samples. After the patients are treated with immunotherapy, the microbiome profiles will be analysed for patterns in who responds and who does not, and will also be compared with a second sample.

“It was thought for a long time that lungs were sterile and that only with an infection would there be bacteria,” the centre’s director, Professor Maija Kohonen-Corish, tells The Medical Republic. “But in fact there are commensal bacteria that are meant to be there, they’re part of the defence mechanism of the lungs.

“It’s now known that the gut microbiome profile correlates with immunotherapy response: some profiles will respond well and others won’t. Which is easy – and also not easy because it’s unpleasant, patients may really not want to give us that sample – but the microbiome from the guts is easy to analyse because it’s so well characterised now. So we’d like to get both specimens at the same time and compare the two, then do the same with the immunotherapy response.”

The implications for treatment are that by manipulating the gut microbiome with probiotics it may be possible to boost the response to immunotherapy – something that is already in clinical trials in the US.

“The big hope is to raise that 30% figure,” Professor Kohonen-Corish says.

“It’s not well understood, but there is some interaction – some ‘cross-talk’ – between the gut microbiome and lung microbiome through metabolic effects. Nothing works in isolation.

“There’s a lot of commercial interest in making the perfect probiotic cocktail that works everywhere, because the microbiome can vary from country to country. That’s why we need to do the research in Australia as well, because the microbiome may vary.

“Even in the US it’s mostly the gut microbiome that has been studied. What we’re proposing here for the lung microbiome is very new – and difficult.”

A partner on the project is Dr Steven Kao, a medical oncologist at Chris O’Brien Lifehouse with a special interest in mesothelioma, senior lecturer at Sydney University and board member of the Lung Cancer Research Network based at the Woolcock.

“Lung cancer is the biggest cancer killer worldwide because the prognosis is so poor, so we should be doing a lot more in terms of research and improving patient outcomes,” he tells The Medical Republic, echoing Mr Brooke’s remarks.

“Funding favours cancers with a lot of advocates. Breast cancer patients live longer, so they can advocate. Lung cancer always falls really low [in funding], and I think that’s partly because it’s hard to find advocates, because they all die. So for the worst-prognosis cancer, it’s hard to find someone passionate about trying to improve things.

“And with breast and, say, prostate cancer, there’s no precipitant for them, whereas with lung cancer there’s the stigma of smoking, the idea that the patient brought it upon themselves.

“When my patients tell people they have lung cancer, they tell me the first thing they’re asked is ‘do you smoke?’, which makes them feel terrible. And there’s an increasing population of young women who’ve never smoked and who get lung cancer for some other reason, and there’s a huge stigma for them. And that plays out in the research arena.”

Dr Kao says while the evidence for a genetic predisposition to lung cancer is lacking, it would make sense that it plays some role.

“You have someone who’s smoked 100 cigarettes a day his whole life who dies at 80 from heart disease with no trace of cancer, and someone who smoked five a day for 10 years and gets lung cancer. Clearly, while there’s a strong association with cigarette smoking and the development of lung cancer, there’s other things at play, which could be environmental or genetic.

“In Australia the important thing to recognise is asbestos, which we know predisposes people to lung cancer, too.”

It is not yet known how exactly the microbiome might interact with the immune system so as to influence the development of cancer and the response to immunotherapy. Broadly speaking, Dr Kao says, “It’s possible those bugs have trained your immune system to think a certain way and that may have led to a more or less favourable interaction with the cancer cells.”

He says while there is increasing evidence in the literature to suggest that the microbiome influences the immune system when faced with a cancer, there are still “believers and non-believers out there”.

“I don’t want to sound like it’s definite – there’s some conflicting evidence in the literature as well. Some groups have sequenced the genes in the colon and suggested how certain bugs would help or hinder immunotherapy, and others have not shown that.”

The present study, which has been through ethics committees and is now at the stage of hospital governance approval, is still quite preliminary.

“Initially we want to show feasibility – that we can recruit patients, that we can sequence the bugs in the lavage – because no one has done that here in Australia,” Dr Kao says.

“If we are wanting to correlate patients who respond versus those that don’t, it’s going to be a much bigger project longitudinally. So, potentially, we’d like to have more than 100 patients who’ve had immunotherapy, but the first step is all-comers who’ll consent to the project.”

Although the current study will only look at immunotherapy response, Professor Kohonen-Corish – who previously worked at the Garvan Institute for 15 years and whose primary research field was on the inheritance of colon cancer – would ultimately like to know whether the microbiomes play a role in carcinogenesis.

She cites a study published this year in Cell by Jin et al. looking at mice genetically predisposed to develop lung cancer, and found that germ-free mice were significantly protected from cancer compared with those with normal microbiota.

Mr Brooke, meanwhile, met with Health Minister Greg Hunt last month ahead of World Lung Cancer Day to discuss the potential for national lung cancer screening for those at high risk, and came away encouraged.

“I’m optimistic that government is coming to understand that lung cancer has been overlooked,” he says.  “We want to see at least a national pilot program of low-dose CT screening for patients, and case finding of those at high risk is going to be an important piece of policy discussion over the next 12 to 18 months.”

Finally, he says, there’s an important way to address the inequity experienced by lung cancer patients that doesn’t require any research at all, but only staffing and empathy.

“I can only quote a patient: when they go to receive their treatment there is just a complete absence of dedicated lung cancer nurses to support them,” Mr Brooke says.

“They’re sitting in chemo and radiotherapy and seeing lots of pink-shirted nurses running around for breast cancer patients and blue-shirted nurses for prostate and bowel cancer patients. But there are fewer than 30 full-time dedicated lung cancer nurses in Australia, where there are 450 breast care nurses, 350 prostate care nurses.

“There’s a lack of psychosocial support, case management, and people to helping patients get through the system.”