Cancer and the “Bad Luck” Problem

There is a war being waged inside your body, at this very moment. Cells, mutated beyond recognition, have become cancerous, only to be targeted by your immune system for destruction. Unfortunately, some of these cells go unnoticed, for some reason or another, and proliferate into the disease we know today as cancer.

At the same time, researchers have taken it upon themselves to design strategies to battle cancer and save human lives. However, even now, researchers are still arguing over the basic strategies combatting cancer – and it’s not a trivial discussion.

Currently, we stand at a possible paradigm change in how we think of cancer. Vogelstein and Tomasetti are researchers that believe that a large part of the risk of cancer is due to intrinsic factors, i.e. the number of stem cell replications. This is a problem out of most patients’ control, what both have dubbed “bad luck”. Unexpectedly, their findings may decide how the future of cancer research plays out.

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Figure 1: The contribution that each of these factors makes on cancer of their respective regions. Notice how large of a role Vogelstein and Tomasetti claim stem cell replications contribute to the risk of cancer. Figure taken from their most recent paper in 2017. [1]

Imagine this. You’re a patient at a hospital, waiting for results from your mammography to come back in. You’ve lived a relatively healthy lifestyle, have never smoked, exercised daily, and made sure to periodically get mammographs to check for breast cancer. However, for some reason today, the doctor has strayed off his normal routine, where he gives you the report and lets you off to continue with your own day. He comes in with furrowed brows and a look of worry – it’s bad news – it’s stage four breast cancer.

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Figure 2: What you would expect to see when you get home.

Of course, not knowing what lies ahead, you go on to google “stage four breast cancer” to try to understand it better. What’s my prognosis? What should I be looking ahead to planning for? Unfortunately, you find that some websites claim that breast cancer is mainly preventable due to environmental factors, even though you’ve done everything you could in that capacity!

In fact, this is one of the problems that Vogelstein and Tomasetti are trying to address, the misguided guilt that survivors may feel for their cancer, when in actuality, the proliferation of cancer was due to factors out of their own hand. In 2015, Vogelstein and Tomaseetti made an incredible claim that 65% of the risk of cancer is attributable to this “replicative component”, backed by epidemiological data (the study of how the disease is spread). As you would imagine, there was a lot of backlash in response to their claims, with hundreds of papers written both in support of and fervently against their assumptions.

“We don’t need to add guilt to an already tragic situation.”[2]

Song Wu and Yusuf Hannun, researchers at Stony Brook University, go so far as to claim the exact opposite, that “cancer risk is heavily influenced by extrinsic factors. These results are important for strategizing cancer prevention, research and public health.”[] Wu and Hannun also recognize the monumental precedent that Vogelstein and Tomasetti have set with their paper and the far-reaching economic implications the paper could have. Their research points out flaws in Vogelstein and Tomasetti’s papers, and carefully pieces together their own argument.

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Figure 3: A timeline of the papers as they were released to clarify the chronological order of events.

Strangely enough, the “winner” of this battle will probably influence where money on cancer research will go in the future years. Like the giant battle over ownership of CRISPR-Cas9 this year, a gene editing tool that has changed the landscape of science, there is a gigantic stake in the direction research will pursue, depending on the response to this paper. Like a high school popularity contest, the proponents of both sides are fighting to clarify their viewpoints and make cogent arguments to achieve recognition and bragging rights, although in this case, it’s funding towards the future.

A Harvard researcher (Nowak) has bridged the gap between the two, addressing possible shortcomings from both Song Wu’s and Vogelstein and Tomasetti’s perspective. While I won’t go into the mathematical modeling he did to break down their arguments, after reexamining the data from Vogelstein and Tomasetti’s paper, he did find unexplained variance with their data. Currently, the perspective is meant to be read alongside the paper, as Vogelstein and Tomasetti’s previous paper had received a lot of backlash. [3]

However, Vogelstein and Tomasetti have undoubtedly shaken the roots of cancer prevention. One of the criticisms that they have tried to clarify involves prevention. They argue that even if the majority of mutations causing cancer is due to replicative errors in stem cells, a single environmental “driver gene mutation” may still be responsible for the advent of disease. This clarification has addressed one of the main problems with the previous paper, as the previous paper had made prevention sound almost entirely useless, although that was never their intention.

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Figure 4: A couple of scenarios that Vogelstein and Tomasetti illustrate with different cancers. [4]

In conclusion, the rules of engagement with cancer still haven’t been clearly defined. We’re still changing our ways of thinking to better address the problem at hand. While a battle is being fought over the strategic subtleties, at the heart of the matter are people that care deeply about the outcome of the patients, and the pursuit of the truth.

Your friend,

Joseph Maa

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