Can we predict cancer a decade in advance?

The Daily Mail, The Telegraph and The Independent are among the many media outlets that reported this week that we could predict cancer a full decade before it appears. Some outlets even went as far as to claim that we could predict it with 100% accuracy 13 years in advance. Unfortunately however, this is media hype of a study that makes claims its data cannot support, helped by a poor press release. There is some interesting science behind this headline, but the simple fact is that we cannot detect cancer that far in advance. If a news story appears too good to be true, then it probably is.The cancer test that these articles are referring to is telomere measurement. Telomeres are protective caps on our DNA. They are found at the end of every chromosome and protect the DNA from degradation. They are often compared to the plastic tips at the end of shoelaces, which protect them from unravelling. They are needed because cells in your body divide at an incredible rate, and every time a cell divides new errors can be introduced to the DNA.To try to get around this problem, every very time a cell divides the telomeres get a little shorter, and when the telomeres get too short, the cell stops dividing. This ensures that no more damage is accumulated, and makes sure that older, damaged cells stop dividing. As a result, telomeres play an important role in ageing (older cells have shorter telomeres than young cells), but also in cancer. Cancer cells, which divide indefinitely, are able to overcome this natural stopping mechanism by building their telomeres back up. Because of this, telomeres have been studied in cancer for decades.This week, a study was published in EBioMedicine which tried to relate changes in telomere size with the odds of developing cancer. To do this, the authors tracked the changes in telomeres in our blood cells over the course of 14 years. They then looked at these changes in patients who developed cancer during the course of the study, as opposed to those who were cancer free. What they report is that patients who are going to develop cancer lose their telomeres at a quicker rate until 3 – 4 years pre-diagnosis, when the trend reverses and the telomeres loss slows down. They suggest that this could be used to predict cancer years before standard diagnosis is possible.The paper has several problems, particularly with the interpretation of the findings. I have included a more technical explanation of some of these problems in “Further Explanations” below, but the authors themselves acknowledge some of these in their discussion.

“Thus, caution should be exercised in interpreting our results as different cancer subtypes have different biological mechanisms, and our low sample size increases the possibility of our findings being due to random chance and/or our measures of association being artificially high.”Hou et al. EBioMedicine 2015

They correctly point out that various cancers act very differently, and crucially that their conclusions may be down to pure chance. This type of correlational study (where measurements are taken and then compared with other things to see if they correlate) is useful as initial data to inform what needs to be studied further, but it is very prone to false positives. It is inevitable that pure chance will cause some correlations in the data. For example, in this study they also reported that less educated people have longer telomeres than their more educated counterparts. Whether this, or the correlation they found with cancer, is true or not can’t be determined without further study.The scientific method is based on the reproducibility of experiments, with the more implausible the finding, the greater the need for repetition. In this case we have an implausible finding using questionable interpretations of the data. While it can’t be ruled out that there is some truth in this finding, it would need to be extensively studied further before any concrete conclusions can be drawn about telomere length in the blood and cancer. But for the time being, we can say that we won't be predicting cancer with this method any time soon.Further ExplanationThe biggest problems I have with this paper are in Figure 2 (above). Firstly, the authors base their conclusion on the fact that there is a statistically significant difference between the groups 3 – 5 years pre-diagnosis (demonstrated in the Figure with “*”). This seems like “cherry picking”, whereby people pick their data to suit their hypothesis. As you can see, any difference between the groups disappears in the 1 – 2 years before diagnosis, a fact that is ignored by the authors. Should their hypothesis be correct (and the cancer is causing decreased telomere degradation), the difference in telomere length should persist.Secondly, the comparison they make in this figure is between the years before people got diagnosed with cancer, versus years before the end of the experiment. As the people who get cancer are inevitably younger than the people who get to the end of the experiment without it, the cancer-free people in this analysis are likely to be significantly older than those diagnosed with the disease. The authors have already shown that telomere length declines with age, so this could be playing a major role in the observed results.

Can dogs smell cancer?

This week the Guardian reported on the ability of dogs to detect prostate cancer.

Dogs trained to detect prostate cancer with more than 90% accuracy The Guardian - 11/04/2015

Italian scientists published a study this week that showed that two dogs they tested were able to detect prostate cancer with remarkable accuracy. One of the dogs correctly detected all cases of prostate cancer and the other detected 98.6% of cancers. On the other hand, the dogs falsely detected cancer in 1.3% and 2.4% of the negative samples too. Both dogs are German Shepherds that had previously been trained for bomb detection, and while their success as bomb sniffers was not addressed, the paper shows that as prostate cancer sniffers they are pretty amazing.How does this compare?In real terms, what do these numbers mean?Consider the UK male population of roughly 30 million, with 0.15% of them being diagnosed with prostate cancer every year. That is 45,000 men.If we test all 30 million men every year, the more accurate dog will detect almost all of the 45,000 cancers each year. However, as it also detects 1.3% false positives, it will also falsely identify the disease in 390,000 perfectly healthy men (1.3% of 30,000,000).This number of false positives may not sound very impressive, but let’s put it in perspective: the standard lab-test for prostate cancer (PSA test) would detect around 27,000 of the 45,000 cancers, but crucially would detect a whopping 3,900,000 false positives! (The exact numbers for this depends on various variables, but I have used the estimates from here, using 3.0 ng/ml testing). So not only does it falsely detect many more prostate cancers than there really are, but importantly almost half of men that do have the disease walk away undiagnosed.This is still a hypothetical situation as PSA is not used routinely to screen for prostate cancer in the general population, but it does emphasise just how effective these dogs are at detecting this disease. I have included a little explanation of cancer screening below for anyone who is interested.Practicalities of using dogs in the clinicThis isn’t the first time dogs have been suggested as good cancer detectors. There have previously been reports of them detecting lung cancer, breast cancer and bladder cancer (albeit with far less impressive results than this). However, at the moment it is just not viable to introduce dogs to the clinic. A test used for cancer detection has to be reliable, and other studies haven’t proven as successful as this one. Add to that the practicalities of using live animals in the clinic (training, housing, feeding and handlers), and you can begin to see why this is not currently planned.However, if scientists can figure out what it is the dogs are actually detecting (at the moment they have no idea), it may be possible to design a much better lab-test for it which will be far easier to get into the clinic. These “electronic noses” are already in clinical trials for lung cancer, and are showing promising results. Whether these will prove to be cheaper and more effective than dogs remains to be seen, but for the time being it is a very active and interesting area of research. And, let’s be honest, most people are likely to prefer having their urine sniffed by a dog than have a rectal examination, the current standard test for prostate problems… Screening for cancerScreening for a disease means testing an entire group of people for the disease, regardless of whether they show symptoms or not. The NHS in the UK provides a screening service for breast, cervical and bowel cancer. These are tests that people undergo as part of a normal health check-up, once they reach a certain age. These screens aim to flag up any potential problems, so the patients can go for further tests.While we have tests for many other cancers, these are the only three that it is deemed cost effective to screen for. Take the PSA test for prostate cancer, mentioned above. The cost to the NHS to further test the high number of false positives would be immense. On top of that there is the worry and stress experienced by people who test positive wrongly. There has been debate in the medical field as to whether breast cancer screen is worth doing, for the same reason.Obviously it would be very desirable to screen the population for every cancer. The earlier a tumour is caught, the better. However, the tests we have for the large majority of cancers are either not reliable enough, or are too expensive, for screening purposes.

Vaccinating ourselves against cancer

Several news outlets carried a story this week regarding very promising results of cancer vaccines trials. This was a very small trial (on just three patients) who had an aggressive and late-stage skin cancer known as melanoma. In all three patients the cancers stopped growing, and they were alive and well at the time of publication. In spite of the low number of patients, this study provides a tantalising glimpse of a brand new form of cancer therapy.So how would these vaccines work? The aim is to teach the patient’s own immune system that cancer cells are bad. That way, our own bodies could potentially mount a natural and effective response, free of the side-effects of conventional chemotherapy. Myriam has previously posted a great blog on how the immune system works (which can be found here), so I’ll stick to the basics.Our immune system recognises invaders or abnormal growths by reading what molecules are sticking out from the surface of cells. These molecules are known as antigens. If the immune system recognizes a cell's antigens as being foreign or abnormal, it will mount an immune-response to clear it from our system. The key is to correctly differentiate foreign antigens from normal, and this is the responsibility of a group of “teacher” immune cells which differentiate friend from foe and teach the other immune cells to do the same. These teacher cells include cells known as “dendritic cells”, which were used in this study.However, cancer cells are problematic for these “teacher” cells. Because cancers arise from a cell that was once healthy, they are sometimes not recognised as being abnormal, and as a result the immune system isn’t alerted to the problem.What these scientists did was to analyse the cells in a biopsy of the patient’s tumour to understand what molecules (antigens) are sticking out from the surface of only the cancer cells. The next step was to train the teaching cells (dendritic cells) to see these specific antigens as foreign. These newly-educated dendritic cells were then put back into the patient’s blood, where they could teach other immune cells to attack the tumour. Encouragingly, after the dendritic cells were infused back into the patients, they mounted a massive immune response to the tumour. It remains to be seen whether this presents a long term solution to these people’s cancers, but it is an exciting “proof of principle” study.This is a very promising new therapy for cancer. It has the potential to be very specific to the tumour and hence have very few side effects. Large scale use of such technology is still quite a few years away, but his is a very exciting step along that path.