MAKING PROGRESS AGAINST CANCER. Dr. Siddhartha Mukherjee is an Indian-American physician, biologist, oncologist, and author, known for his Pulitzer Prize winning 2010 book, The Emperor of all Maladies. A Biography of Cancer.  His next book, The Gene. An Intimate History, was among The New York Times 100 best books of 2016.  Dr. Mukherjee is currently an Associate Professor of Medicine in the Division of Hematology and Oncology at the Columbia University Medical Center in New York.

Why are you so interested in the Epstein-Barr virus?

I became interested in the idea of the Epstein-Barr virus causing cancer because it is one of the ancient viruses of humans that have evolved with humans for millennia.  I was an undergraduate at Stanford, a graduate at Oxford, and went to Harvard medical school for my MD, and I became more and more interested in human cancers.  By the time I was in medical school I was quite sure that I would be studying oncology.  I stayed on in Boston and did a long training to become an expert in cancer, and then I did more research in virology and cancer.  Now I have my own group at Columbia University, and am interested in blood cancers, leukaemia and lymphomas, among others.

How many years have you been working in the field?

I finished training in 2008, so ten years now.

Have you had any real results?

Yes, and a paper that just came out in Nature, the international journal of science, is a very important and intriguing result.  We showed that a particular kind of diet, a ketogenic diet, in combination with very particular kinds of molecular therapy, becomes synergistic.  We have begun to find out that diets can collaborate with molecular therapies in ways that we hadn’t expected.  Doctors usually give you very precise medical prescriptions but don’t tell you what to eat.

What is a ketogenic diet?

It strongly restricts any carbohydrates, so has protein and fats.

Is this a diet to cure cancer?

It can be applied to multiple forms of cancer.  These are preclinical tests that I did with Lewis Cantley, a professor at Cornell, and Nature is a preclinical journal.  Diet was neglected for a long time, but we point out that diets can collaborate or not collaborate with a therapy.  These are not preventative, and people should not randomly put themselves on these diets, which only work collaboratively with molecular therapy.

The established ways to cure cancer are by chemotherapy, radiation or surgery.  What is molecular therapy?

Molecular therapy is a kind of chemotherapy, but rather than acting as cellular poisons they try to be much more specific and exquisite in the therapy.  If chemotherapy is like a hammer, molecular therapy is like a screwdriver.  It takes out one particular cog in the machine, and is targeted.

What are the early results of this diet/molecular therapy collaboration?

We proved it works on human tumours growing in animals.  In a short while we will move onto the human studies on two or three cancers.  These are monitored clinical studies where we will give the molecular therapy in combination with the diet to see if it works.

“In the next 10 to 20 years we will learn to treat, detect, and prevent more cancers.”

Dr Siddhartha Mukherjee in his laboratory at Irving Center for Cancer Research, Columbia University Medical Center.

How many people die of cancer nowadays?

In the West, projections are that about 1 out of every 4 human beings will die of cancer.

How many people with cancer are cured and will survive, and how many will die?

There is no simple way to answer the question of how many people are cured or not, because when we remove a breast tumour we don’t know if that cancer would have killed the patient.  In the US and most of the West the historical curve of human cancer mortality has decreased steadily over time, by about half a percent a year.

Why?

There are many causes.  A majority of the decrease in cancer mortality was driven by changes in smoking behaviour.  There are other kinds of prevention that we are doing, our diet is changing, and some of it can be attributed to treatment.  The decrease in women of mortality from breast cancer is a mix of treatment, prevention and screening.  Screening has had a modest impact, as it has also in the prostate.

Is there less death from cancer?

Overall in the world the mortality from cancer is increasing, because our population is aging and we are living longer.  The longer you live the more cancer you have.  You have to do careful statistical comparisons over time and shrink the population so that you are not comparing apples and oranges.

Why are people living longer?

That’s a big mystery, but we are not infected by infectious diseases, our diets are better, and public health and hygiene is better.  Due to some combination of these and other factors, human lifespan in the West has gradually increased, and as that happens cancer increases.

Does cancer develop more slowly when you are old?

Some forms of cancer develop over many years, others arise suddenly in some and in others they have a long phase.  Some cancers are aggressive, some are not.  Some you can cure, some you cannot.  It depends on the genetic components of the cancer.  Cancer arises as a consequence of genetic changes in cells that make the cell unable to stop dividing or stop dying.  Other genetic changes collaborate with this, allowing the cells to escape the immune system.

How do these genetic changes come about?

There are 4 or 5 sources of genetic alteration in cells.  1) You can inherit the changes from your parents.  2) It can be caused by carcinogens, chemicals in the environment that can interact with your DNA and cause genetic mutations.  3) It can arise randomly because of chance.  Every time a cell divides it has to make a copy of its genes, and any copying process can have errors.  4) Viruses can enter cells and make changes in the genetic apparatus.  Not all viruses do this, some.  5) We now know that the genetic changes in a cell are crucial to making a cancer, but we also know that a cell can acquire genetic changes but still be unable to form a cancer tumour that will kill you.  We think that it’s because of the ecology in which the cell is staying, so a cell in the wrong environment will not be able to form a tumour and so is not dangerous.  This is my “seed and soil” hypothesis: cancer is the seed and it has to flourish in the right soil, and if the soil is not right it doesn’t grow.  By 2020 I will add three or four more chapters to The Emperor of all Maladies, and one will have to do with this mysterious fifth area.  The genetic changes in the cell have to collaborate with “the soil” around the cell in order for the tumour to grow.

“You have to be a crazy nihilist to say that we have not made any progress against cancer.”

Do cancer researchers collaborate successfully globally?

We work together and ideas come around.  There’s a big spectrum.  For example, our capacity to treat breast cancer has dramatically changed over the last 30-40 years, and you can live longer through a combination of therapy, but in cancer of the pancreas progress has been very limited.  In 2018 the mortality rate for pancreatic cancer is the same as in 1918.

Why do you work in America?

I am a clinical researcher, which is very tough to do in India.  Important studies come from Italy, and the Veronesi cancer centre in Milan has been a centre of excellence.  People move around and the talent is deepened.  Not all the discoveries are made in America, but the American discovery engine for new drugs is very powerful, so there are more tests being done here, but once they are discovered they are sold everywhere.

Why are some treatment centers better than others?

Medicine is a skilled profession, and American centers like the Mayo Clinic, Sloan Kettering, Mount Sinai, Columbia University, have built their reputation on the medical skills of correct diagnosis and giving the right medicine at the right time.  It is not just having access to the medicine, but to the crucial reasoning skillsets that doctors have.

Do you think that one day there will be a cure for cancer?

You have to be a crazy nihilist to say that we have not made any progress against cancer.  Some are now curable, like breast cancer.  Even breast cancer that has spread can be contained and the patient can live longer.  In prostate cancer progress has definitely been made.

‘The Emperor of All Maladies: A Biography of Cancer’ was published on 16 November 2010.  It won the 2011 Pulitzer Prize for General Non-Fiction: the jury called it “an elegant inquiry, at once clinical and personal”.

When Siddhartha Mukherjee was a young, exhausted, and isolated medical resident, he discovered a book that would forever change the way he understood the medical profession. The book, ‘The Youngest Science’, forced Dr. Mukherjee to ask himself an urgent, fundamental question: Is medicine a “science”? Sciences must have laws—statements of truth based on repeated experiments that describe some universal attribute of nature. But does medicine have laws like other sciences?

Siddhartha Mukherjee addresses graduates and guests, Sloan Kettering Commencement, 2013

‘The Gene: An Intimate History’ was published on 17 May 2016. The book chronicles the history of the gene and genetic research, from Aristotle to Crick, Watson and Franklin and then the 21st century scientists who mapped the human genome.

The ketogenic diet—also called the keto diet—consists of foods that are high in fat, moderate-to-low in protein, and very low in carbohydrates. It sends the body into a state of ketosis, resulting in the formation of molecules known as ketones. This process occurs when the body is forced to use fat for energy in the absence of carbohydrates.

Siddhartha Mukherjee photographed by Deborah Feingold.

“In the West, projections are that about 1 out of every 4 human beings will die of cancer.”

What about intestinal and lung cancers?

Early colon cancer is highly curable.  In contrast pancreatic cancer is highly incurable.  Lung cancer was a rare disease that only became a common disease after the increase in smoking men and women.

Can a transplant overcome liver cancer?

Once liver cancer has spread outside the liver a transplant does not help.  Alcoholism is a factor, as cirrhosis is a set up for liver cancer, but liver cancer has many causes.  One is the Hepatitis B virus which we now have a vaccine for.  Hepatitis C also causes liver cancer, and there is no vaccine, but we can test for it so that blood transfusions don’t convey it.  There are many factors which we are preventing in different ways, but, all of this said, if liver cancer spreads we don’t have a good treatment for it.

Do you believe in so-called ‘alternative medicines’?

Not at all.  All medicines start as alternative medicines.  My plea is that the medicine is subjected to the same tests, with randomised back-to-back study, and if the tests are not successful don’t then come and say it works.  Taking a not-properly-tested medicine is not a metric that works.

Is the advance in diagnostic tests increasingly useful?

To use blood to detect cancer in its earliest phases is very useful.  All cells spill their DNA into the blood, but in the past we couldn’t measure it.  Now we can.  If there is a breast cancer growing, because the genes are changed we now have techniques to pick that up from the blood.  What I cannot tell is whether the cancer is going to sit there and do nothing, or whether it’s going to kill.

Are vitamins helpful?

Vitamins have never been shown to have any effect on cancers.  If you have vitamin deficiencies they are of great use, but cancer is not a Vitamin C or Vitamin D deficiency.  Vitamins are useless for cancer, but your general health has an impact on your capacity to tolerate chemotherapy.

Is the psychological attitude of the patient important?

Cancer is a genetic disease.  A negative psychological state does not cause cancer, and the reaction to the news of cancer makes no difference unless you accept or reject treatment.  If you have a curable cancer of course it makes a difference.  But if the same person is sitting in treatment and one is positive and one is negative it makes no difference.

Is there progress in the handling of the patient?

The real progress in cancer treatment in the 1980s was not just chemotherapy but the palliative and supportive care, the confrontation of the fear of dying.  So called psycho-oncology, a whole discipline was created around this.

Are patients with cancer desperate when they come to see you?

Yes, there is a sense of desperation when you are facing mortality, and we don’t want to go through the pain of the process of suffering.  Pain and suffering is what most people are scared of, not death.  Some people who come to see me will be fine.  Their cancer has been removed, they need therapy to consolidate that removal, there’s a checking protocol, and they will be fine.  You can tell when a person will most likely be OK in five to ten years from now.

How many of your patients die?

30%.  So 70% are cured.

So cancer is not final.

It’s not final.  It depends on the treatment.  I am not demoralised.  I have lots of energy and hope.

What is your hope?

In the next 10 to 20 years we will learn to treat, detect, and prevent more cancers.  It is like a pyramid.  The bottom of the pyramid is prevention, the most important.  The next leveI is early detection, an arena where things are moving very rapidly, e.g. mammograms and colonoscopies.  The third is treatment, and there we are taking on the cancers that we cannot normally prevent.

New York, September 2018

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October is breast and liver cancer awareness month.