Siddhartha Mukherjee
Related people
Episodes
Notes
The Peter Attia Drive · #412 ‒ The evolving science of cancer: emerging approaches to…
-
Will There Be a Drug That Prevents Cancer?
Siddhartha Mukherjee says yes, there will be chemoprevention. Asked where the gains that save lives will come from, he says the answer is always prevention.
Peter Attia asked whether that could be a drug in the way Lipitor is given before a heart attack, or an ACE inhibitor when blood pressure is high. Mukherjee says it is not clear that cancer chemoprevention will be that simple. Lipitor lowers LDL. Losartan, or another ACE inhibitor or ARB, acts on the kidney's hormonal system to lower high blood pressure. He does not see a relationship that simple for preventing cancer.
-
Do Most Pancreatic Cancers Have a KRAS Mutation?
Siddhartha Mukherjee says most pancreatic cancers have KRAS mutations. Peter Attia asked whether that was so, and whether the mutation makes an antigen a CAR T cell could attack.
Mukherjee says not really. KRAS produces an antigen in some patients, but most of KRAS is hidden inside, so most of KRAS is not a CAR T target. He says KRAS is a target for small molecules that shut off its function, a lock and a key, and that this is not immunotherapy. A second path he describes is a CAR T cell against a unique pancreatic antigen, even if that removed the pancreas. He says that antigen has not been found. He says people can live without an endocrine pancreas, as in type 1 diabetes, and that patien
-
Can a Person Live Without B Cells?
Siddhartha Mukherjee says human beings can live with their B cells killed. The CAR T cells aimed at B-cell leukemias and B-cell lymphomas do not kill only the cancer. They kill all B cells.
He says that fact is why the treatment can work, and that the reasons, which he calls evolutionary among others, are not known. He says CAR T cells should be thought of as lineage specific and tissue specific, not cancer specific. A woman can live without mammary tissue, without ovaries, or without an endometrium, so the same approach would kill that tissue, not only the tumor.
-
How Does CAR T Cell Therapy Work?
Siddhartha Mukherjee says a CAR T cell is made by taking cells from the body, using a virus to insert a gene, growing those T cells, and putting them back so the weaponized T cells kill the cancer.
He sets that beside standard immunotherapy. Keytruda, he says, is one example of letting T cells recognize a cancer cell that does not carry enough surface flags. A CAR T cell overrides those signals. He says the result in B-cell leukemias and B-cell lymphomas has been durable cures, not only small responses.
-
What Does the Thymus Have to Do With Cancer?
Siddhartha Mukherjee says a talk from someone at Harvard used AI to read CAT scans and found one correlate of disease: whether the thymus was still there. People with an intact thymus tended to have less autoimmune disease and less cancer. People who lost the thymus with age tended to have more.
He says the study is correlative, not causal, and that someone could propose 10,000 ways to probe it. The thymus is why T cells are called T cells. He describes it as the nursery, or the kindergarten, where T cells grow up, and he says it naturally involutes and dies. He compares the possible marker to Lipitor or to hypertension in heart disease: the size of the thymus, or whether it is still presen
-
What Are Cancer Sleeper Cells?
Siddhartha Mukherjee calls dormant cells that already carry cancer mutations sleeper cells. A person can have them and still not have cancer.
In the illustration he gives, a lung of several million or maybe a billion cells might hold 2,000 cells carrying cancer mutations, and another lung might hold 750. He says those cells most likely arose by bad luck, as cells grew and made mistakes, and he says he does not know that for certain. The split he draws is an inflammatory response. One person gets that stimulation and then develops cancer. The other person's 750 cells stay dormant, quiescent, and asleep, and that person does not have cancer.
-
How Much Does BRCA1 Raise Breast Cancer Risk?
Siddhartha Mukherjee says a BRCA1 mutation is a shove mutation: it puts a person at a ninefold or tenfold risk, above the normal population, of hereditary breast cancer at an early age. He calls BRCA2 a shove mutation as well.
He says the single genes already known still cover only about a third, maybe a fourth, of hereditary breast cancer. The rest, he says, is probably hundreds of genes, each pushing risk by a small percentage. He calls those nudge mutations. He also says the old figure, 5 percent of mutations being hereditary, is no longer 5 percent.
-
Should Everyone Get a Blood Test for Cancer?
Siddhartha Mukherjee says blood tests that can find some cancers early are probably not going to work if they are used on everyone, with no selection for people at high risk or for people who have already had cancer.
He says those tests lead to false positives, extra biopsies, and more follow-up tests, and that they are unlikely to lower deaths from cancer. Used in people who carry genetic mutations that raise risk, or in people who have had cancer before, he says the same tests may yield very important results. That "may" is his, not a promise that the tests work.
-
Why Is There No Cholesterol Test for Cancer?
Siddhartha Mukherjee says medicine has no simple screening biomarker for cancer the way blood pressure and cholesterol work for heart disease: hypertension and high cholesterol levels mark cardiovascular disease, and he has no high cholesterol for cancer.
He says cancer can arise from more than the traditional carcinogens he names, x-rays, benzene, and tobacco. Inflammatory states almost certainly cause cancer, and he says the picture is not a gun and a trigger, with inflammation as the gun and mutations as the trigger. He still cannot look at his own patient and say that person is in an inflammatory state that will cause cancer. He expects that biomarker to be found, and he says people at
-
What Is Dream Time Before Writing a Book?
Siddhartha Mukherjee calls the first part of writing a book dream time. Before the first word goes on the page, he spends a long time thinking about what the book will sound like. People can use different words for that stretch of thinking. He tells anyone who asks about the process that the answer will sound generic, and he says it is real.
He asks who is driving the narrative, because there has to be a who. He asks where the story is placed, where it goes, and where it sits geographically. He asks what time the story is in and what mood it conveys. He asks who the reader is and why he or she is being moved by the book. He works out the structure and the anatomy, including whether the book
-
Do People Over 110 Die of Cancer?
Siddhartha Mukherjee says people more than 110 years old do not die of cancer. They die of regenerative failure. Skin stops regenerating and falls off. Bones break. Immune cells break down, infections follow, and the blood system fails.
They still die of atherosclerosis and of infections. He says they are not taking every drug used against atherosclerosis, because they live in Greece or some island. Cancer is still absent from what kills them. The deaths he emphasizes are bone breaks, skin failure, immune failure, and blood failure.
He describes two worlds of dying. In one, humans die at 70, 80, or 90 from the usual causes: neurological disease, cancer, and heart disease. In the other, peo
-
Why Is Colorectal Cancer Going Up?
Siddhartha Mukherjee says he does not know why colorectal cancer is going up. Peter Attia frames it as the third leading cause of cancer death and asks whether antibiotics, gut health, or obesity are to blame.
Mukherjee's speculation is that the colorectal milieu has changed rapidly in the last few decades. People ingest more forever chemicals, and animal models show that some of them, including chemicals eaten in food, are very pro-inflammatory. He connects the rise to the inflammation theory of cancer, multiplied by a gut microbiome disrupted by antibiotics and other foods. Dennis Burkitt, who discovered Burkitt's lymphoma, went from Oxford to Africa in the 1950s and 60s and virtually fou
-
Why Does a Lower Tumor Burden Improve Cancer Treatment?
Siddhartha Mukherjee says a lower tumor burden raises the chance treatment works because fewer cancer cells are left that can resist the therapy. For the most part, fewer tumor cells mean a better outcome. He names a few exceptions. Papillary thyroid cancer does not seem to matter, and a handful of remarkable checkpoint inhibitors often do not matter either.
Bert Vogelstein gives the arithmetic. Three zeros separate one million from one billion. Start with one billion cancer cells and leave one million, and the count has fallen by one thousand. Mukherjee says that fall reduces, by one thousand, the chance of a cancer cell resistant to the therapy. He calls the change huge.
The same idea si
-
Can Surgery Cure Cancer in the Tail of the Pancreas?
Siddhartha Mukherjee says surgery can cure some pancreatic cancers that start in the tail. He has patients who have lived 10 years after a Whipple when the tumor sat far from the crowded head of the pancreas and was found incidentally.
The pancreas is a long organ shaped like a leaf in the gut. Cancers in the head sit closer to the intestines and tend to show up with pain and jaundice. Cancers in the tail sit farther away and tend to be found incidentally. Mukherjee says tail tumors are less involved with other organs, so they are an anatomically distinct cancer and some patients can live longer after surgery. The head is where intestines run downward and blood vessels cross. He compares it
-
Why Do Immune Cells Leave Cancer Alone?
Siddhartha Mukherjee says immune cells leave cancer alone because the cancer cells that survive display dozens of surface flags telling T cells and B cells they are normal. Siddhartha Mukherjee says a checkpoint is a gene or a flag that a normal cell floats on its surface, saying it is normal and should be left alone.
The flags are why people do not live with desperate, terrifying autoimmunity. The body has enough T cells to eat itself alive. People who have mutations in some checkpoints are consumed by T cells. Diabetes type 1 is a T cell autoimmune disease that eats the pancreas alive. Lupus, another immune-cell disease, eats the body alive. In scleroderma, a patient is eaten alive by the
-
Why Can't T Cells Finish Off Cancer?
Peter Attia says T cells rarely mount a response strong enough to finish the job on their own, even when they already know a lethal tumor is not self. A couple of years earlier on his podcast, Steve Rosenberg shared data that 80% of solid organ tumors had novel neoantigens the immune system is able to recognize. Attia says the figure covers the cancers people think of as the really bad ones, breast, colon, lung, and pancreas. In his reading, T cells know the tumor is bad and it is not self.
Checkpoint inhibitors remove the brakes on the immune system and unleash the immune system on the cancer. Attia says the success of the class suggests immune cells at least have the potential to recogniz
-
Is Osteoarthritis an Obesity Disease?
Siddhartha Mukherjee says he has never believed osteoarthritis is an obesity disease. People who are not obese get osteoarthritis, and the disease can appear in joints that do not carry body weight.
His laboratory discovered the first osteoarthritic stem cells and published the finding in Cell, then in Nature and Nature Medicine. Knees and hips, the weight-bearing limbs, do get osteoarthritis, and people have hips and knees replaced. The pattern is usually women who are obese. Mukherjee says the explanation seems backwards, in the way much of medicine has treated women: obesity, therefore a weight-bearing problem, therefore a weight disease. A woman with no obesity can still have massive in
-
Does High Insulin Make Cancer Resist Treatment?
Siddhartha Mukherjee says chronic insulinemic tone has the capacity to make cancers grow and to leave them resistant to some forms of therapy. Removing chronic insulinemic tone is what lets the cancers become vulnerable. He presents the treatment results as facts.
Peter Attia cites a paper Mitch Lazar wrote at Penn about 15 years ago on cardiometabolic disease. Lazar built a two-by-two of obesity and metabolic health. Lean people can be metabolically unhealthy, and obese people can be metabolically healthy. The paper looked at cardiovascular disease. Disease prevalence tracked with hyperinsulinemia and the changes that accompany it. Disease prevalence did not track with adiposity. Attia say
-
What Percent of Cancer Mutations Are Random?
Peter Attia says about two-thirds of cancer mutations, 66-ish percent, are purely random. Recalling the math from a 2015 paper in Science, he puts about 5 percent of mutations down as hereditary and on the order of 30 percent down to environmental triggers or carcinogens.
The paper looked at cancers by tissue type. Hereditary mutations include BRCA1 and many others talked about less often. Smoking raises the risk of a mutation, and lots of UV light can cause one too. In 2017 the authors published another paper that revisited the result. The idea that stuck was that cancer is a bad luck disease: the healthiest person can do everything right and still get a random mutation, and Peter Attia sa
-
Does Immune Therapy Help Smokers With Lung Cancer?
Siddhartha Mukherjee says immune therapy is now known to extend the lifespan of smokers with lung cancer if it is given to the right population of people. Fifteen years ago he wrote a personal note to himself saying he would not live to a time when a medicine would potentially extend the lifetime of a smoker with lung cancer. He says the note is no longer true.
He places the result in the last 15 years, when immunotherapy, which he describes as activating the immune system, has been extremely productive against some cancers. The lung cancer example is the one he gives. The drugs unveil or unleash the immune system to recognize cancers as foreign cells and enable treatment of cancers.
The c