Which cancers are most survivable and why?

Cancer is not a death sentence; there is a great deal of difference between a prostate and a pancreatic cancer diagnosis, and even differences between subtypes of cancer within any particular organ. Recent statistics on cancer survival rates are instructive (Table 1).

Table 1. The most survivable cancers according to the US SEER database of cancers diagnosed between 2005 and 2011¹.

How can we understand the differences?

When, in the natural course of a cancer, do you feel sick?

If the symptoms of cancer appear early in the natural course of the disease, it is generally curable. There are two reasons for this. First, if you detect a cancer before it has escaped the reach of a surgeon’s knife, it can be removed. End of story.

Second, even if it can’t be cut out as is the case with most blood cancers, if the cancer has only had a few years to accumulate mutations, it is less likely to have acquired mutations that will make it resistant to a therapy. In contrast, if you don’t feel sick until very late in the process, as in pancreatic cancer, it is likely to have acquired resistance mutations and no matter what you try, you are unlikely to cure the disease. The result, in pancreatic cancer, is a 7% 5-year relative survival rate¹.

There is an evolutionary theory for why solid cancers are generally more lethal than blood cancers of the immune system; there appears to be more checks and tumour suppressor mechanisms in place to prevent solid cancers than there are to prevent immune cell cancers.

With immune cell cancers, typically only a few genes need to mutate in order for you to feel sick. Therefore, when a patient shows up with a leukemia or lymphoma, there are fewer mutations in their cells, and so there is less chance that a mutant cell has already acquired resistance to the coming therapy.

In contrast, everything but the kitchen sink has to break in order for cells in most organs to grow out of control. With so many different things broken, and such a diversity of mutant cells, it is no wonder that resistant cells often lurk somewhere in a solid cancer.

There is an important implication of this insight. We should be developing measurements of the diversity within cancers to help guide the management of those cancers. For tumours with low diversity, we have a better chance of achieving a cure through therapy². But for tumors with lots of diversity, we need to consider how to manage the therapeutic resistance that is most likely already present, perhaps through strategies like adaptive therapy^3,4. Of course, if a tumour has not yet metastasised, surgery can effectively avoid the whole issue of the evolution of therapeutic resistance.

Surgeons cure more cancer than oncologists

Or, to put it another way, oncologists have a more difficult problem than surgeons. Their drugs must find and kill every last cancer cell, no matter where it is hidden and what mutations it carries.

Skin cancers are extremely common but easy to surgically remove. Basal and squamous cell carcinomas of the skin are so common, they are often excluded from studies and cancer registries, like the SEER database that was used to produce most of Table 1. Approximately 5.4 million skin cancers (other than melanoma) are diagnosed in the US each year5, making up about 75% of all newly diagnosed cancers. However, only about 2,000 Americans die from them each year6 because the vast majority are detected before they metastasise and can be removed.

The surprise for me in Table 1 was melanoma. Melanoma is infamous for being one of the most mutated of all cancers (along with lung cancer)^7,8. Those mutations are the legacy of UV light and smoking. In addition, melanoma readily metastasises, and unlike most cancers, can spread anywhere in the body. Yet, it is listed as the fourth most survivable cancer. Because melanomas are exposed on the skin, we have the opportunity to see them every day in the mirror, and catch them early. The result is that 84% of melanomas are diagnosed before they metastasise and can be cured surgically, with a 98% 5-year relative survival rate.

The benefits of indolence and hormones

Some cancers are so slow growing that we can live with them without them killing us; they are indolent. This is famously true for both prostate cancer and thyroid cancer⁹. In the US, autopsy studies have revealed that 80% of men over the age of 70 have some cancer hanging out in their prostates, but few of them will die from this¹⁰. Small nodules of cancer in the thyroid are so common they are considered “normal”¹¹. Autopsy studies have found minute nodules of thyroid cancer in 8% of the general population¹², however, it rarely discovers a way to generate blood vessels to feed itself, and so it never grows large enough to harm us.

There are extensive screening programmes for both breast and prostate cancer. Unfortunately, there is an inherent bias in screening programs. They preferentially find the slowest growing tumours because those are the ones hanging around for years, available to be detected. In contrast, the fast-growing tumours can pop up and make us sick before we ever have a chance to detect them through a regular screen. This implies that many of the cancers we detect, many of the cancers in Table 1, would never kill us even if they were never treated. The survival statistics in Table 1 are inflated by indolence.

Hormones are also part of the story. The cells in most prostate and breast cancers need hormones (testosterone and estrogen) in order to reproduce. When we deny them those hormones, they stop growing, and in many cases they start behaving like they are starving, slowly consuming themselves.

It takes a long time, if ever, for some of those cells to discover ways to live without those hormones, and so survival times are much longer for breast and prostate cancers than for other solid cancers. This does suggest that if we are able to deny growth factors to other cancers, if we could stop their growth, rather than trying to kill them, we might be able to increase survival times in those cancers as well.

There is another piece to the puzzle of thyroid cancer. While it is generally detected when it is small enough to be removed surgically, it also has a particular Achilles heel. Because thyroid tissue is the only tissue that uses iodine, treatment with radioactive iodine efficiently targets any remaining thyroid tissue (and cancer) after surgery.

To be young and unmutated

In addition to being slow growing and dependent on iodine, thyroid cancer typically carries few mutations, probably because it is generally detected at relatively young ages. So, resistance mutations are less likely to be present at diagnosis, compared to highly mutated cancers.

Testicular cancer, Hodgkin lymphoma and the childhood cancers are all detected at young ages. In general, like thyroid cancer, this is associated with the accumulation of fewer mutations^8,13, and little genetic diversity. Since the success of systemic therapies, such as chemotherapy or targeted agents, depends on the absence of resistance mutations, these genetically homogeneous cancers are more likely to be curable than genetically diverse cancers^2,14.

The artefacts of technology

Don Pinkel, pioneer of childhood leukaemia treatment, has long argued that what makes for a good or bad cancer is mostly an artefact of treatment. Can we detect it when it has few mutations? Are we detecting things that aren’t really lethal cancers? Do we currently have good treatments for it? This all changes with advances in medicine and technology. A sizable minority of late stage melanomas and lung cancers can now be cured by immune blockade therapy, particularly the highly mutated tumors.

This goes against much of what I’ve said about the evolution of therapeutic resistance, but for a good reason. Highly mutated cancers produce more abnormal proteins that the immune system can recognize as non-self. Thus, the lineup of the most survivable cancers will change in the future. What won’t change, is the need to deal with their evolution.

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References

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