By Douglas Arenberg, MD
In the lung cancer field, the last few years have seen numerous changes to the landscape. Even as we take stock of how far the field has advanced, it is important to define the substantial remaining challenges ahead. This editorial will take a look at some of the exciting advances in the lung cancer field, and highlight areas where there is opportunity to improve.
Advocacy and funding
From an advocacy standpoint, one of the most important victories is the recognition by Congress, spurred on by lung cancer advocacy groups, of the lack of lung cancer funding within the department of defense (DOD) research portfolio. In 1992 the DOD established a program in Breast Cancer research funding, fueled by an aggressive lobbying campaign by Breast Cancer advocates, and by Senator Tom Harkin, then chair of the Senate Armed Services Committee. Senator Harkin (whose two sisters had breast cancer) took advantage of a “surplus” in the Defense Department budget, the fruit of the break-up of the Soviet Union, and the resulting money available for pet projects. Nobody seriously questioned the use of DOD funding for Breast Cancer research—not even the veteran community—which (like my father) had been handed cartons of cigarettes while serving in World War II. This “greatest generation” had been largely introduced to tobacco through their service to their country, and many developed tobacco related diseases, like heart disease, emphysema, and lung cancer. Very few, ironically enough, were afflicted with breast cancer. The DOD has allocated over 2 billion dollars to its breast cancer research program since 1992, completely ignoring the relative impact of lung and breast cancer in the armed services and veterans communities. Advocates took notice, though, and in 2009 for the first time, were able to get the DOD to allocate 20 million to a lung cancer research program. This was a feather in the cap of the advocacy community, and a significant amount of money, but there still exists a large disparity in funding of biomedical research when the relative impact of disease is taken into consideration. The vast majority of biomedical research in the US is funded by the National Institutes of Health, a crown jewel of American pre-eminence in science. The disparity between lung cancer research funding and that for other disease largely rests there.
Advances in treating lung cancer
Popular press covers advances in cancer treatment if they are considered major advances. In reality, what most often occurs over the decades is the cumulative effect of many advances that either have a small amount of benefit to a large number of people, or a significant impact on the treatment of a small proportion of patients. In the lung cancer treatment arena, there have been many small victories of the latter type. The first of these that comes to mind was the completion in several trials showing that chemotherapy after successful lung cancer resection (adjuvant chemotherapy) improved long term survival of patients found to have lymph node involvement after surgery. As is the case with every well done study, each answer raises new questions. In this case the question is: Are there patients without nodal involvement that can benefit from adjuvant chemotherapy? Studies to definitively answer this question will be difficult to do.
The development of “targeted” therapy for lung cancer has also generated much attention in scientific literature and lay press. Drugs that target the epidermal growth factor receptor (EGFR) have proven to be very effective for a small—but well defined—group of patients with metastatic lung cancer who have activating EGFR mutations. Even more exciting was the report in 2007 of a “fusion protein” termed EML4-ALK, which was found to be an activating mutation capable of driving the proliferation of lung cancer cells. Think of this fusion-protein like Frankenstein, combining parts of two proteins, as a result of a “flipped” segment of DNA. In this case, one protein results in the inappropriate activation of another cancer-driving protein, much like a furnace being left on by a broken thermostat, resulting in the house over-heating. While this finding was relevant only to a small number of cancer patients (around 5% in most studies), the most amazing part of this discovery was that, within two years, drugs targeting this ALK protein were already in clinical trials, showing dramatic benefit for those with ALK activating mutations. This pace of progression from discovery to treatment is highly unusual, not just in cancer, but in any field of biomedical research. It is likely that additional driving mutations similar to the one that activates ALK will be discovered in the future.
Can we expect a similarly rapid translation to clinical trials from these yet-to-be-made discoveries? In part, luck plays a role. We have a long way to go until the entire population of lung cancer patients can benefit from this individualized approach to treatment. Nevertheless, this story is very encouraging to those interested in speeding the development of “personalized” cancer therapies.
Finally, the 800 pound gorilla in any discussion about lung cancer in 2011 is screening. Many are already, or soon will be, aware of the press release indicating that the National Lung Screening Trial concluded with the finding that among heavy smokers between the ages of 55 and 74, the risk of death from lung cancer was reduced by 20% by those screened with three annual low-dose helical CT scans (LDCT). This finding has generated great excitement and will continue to do so as more information comes out. This news was a breath of fresh air for those of us in the lung cancer field and will likely have an impact on how we approach this disease for years to come.
What does this mean for you? If you are a non-smoker, this means nothing. There is no indication that lung cancer screening would benefit persons outside of those who would have been eligible for this study. “Screening” is a tricky subject that appears simple on the surface. “Test me, tell me if I have a disease, and then cure it before it can progress.” In practice, screening is anything BUT simple. Every screening test currently in use can be falsely negative (that is, one can have the disease, and the test can be negative) and falsely positive (the test is positive, but the disease is not actually present). CT scans are no different, and in fact they have a tremendously high false positive rate. Nearly 98% of nodules found on screening CTs are not lung cancer, and proving the absence of lung cancer entails significant expense and anxiety, as well as risk to the screened individual. The future is uncertain, but with respect to screening for lung cancer this much is certain:
1. Screening the right population will save lives
2. Even among groups who are intensely screened, people will continue to develop and die from advanced cancer.
3. We still lack any effective means of early lung cancer detection among the 10-15% of never smokers who die from lung cancer.
The first item is welcome news, but there is nothing we can do at present about number two. Every cancer for which we currently screen has examples of very aggressive forms of disease for which screening is ineffective. As far as number three, the major advances in the future will be those which allow us to understand who is truly at risk for lung cancer. When we can focus our screening on those who are at the highest risk, we will have made real further progress in lessening the impact of lung cancer mortality.
Douglas Arenberg, MD is Associate Professor of Medicine, Pulmonary & Critical Care Medicine at the University of Michigan Medical School. As a physician scientist, his specialty is lung cancer.