Chemotalk Newsletter

Chemotalk Newsletter, Vol. 83: March 1, 2015

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Much to think about this month, some of it pretty amazing.


By Gina Kolata

CHEMOTHERAPY and radiation failed to thwart Erika Hurwitz's rare CANCER of white blood cells.  So her doctors offered her another option, a drug for MELANOMA.  The result was astonishing.

Within four weeks, a red rash covering her body, so painful she had required a narcotic patch and the painkiller OxyContin, had vanished.  Her cancer was undetectable.

"It has been a miracle drug," said Mrs. Hurwitz, 78, of Westchester County.

She is part of a new national effort to try to treat cancer based not on what organ it started in, but on what mutations drive its growth.

Cancers often tend to be fueled by changes in genes, or mutations, that make cells grow and spread to other parts of the body.  There are now an increasing umber of drugs that block mutations in cancer genes and can halt a tumor's growth

While such an approach has worked in a few isolated cases, those cases cannot reveal whether other patients with the same mutation would have a similar experience.

Now, medical facilities like Memorial Sloan Kettering Cancer Center in New York, where Mrs. Hurwitz is a patient, are starting coordinated efforts to find answers.  And this spring, a federally funded national program will start to screen tumors in thousands of patients to see which might be attacked by any of at least a dozen new drugs.  Those whose tumors have mutations that can be attacked will be given the drugs.

The studies of this new method, called basket studies because they lump together different kinds of cancer, are revolutionary, much smaller than the usual studies, and without control groups of patients who for comparison's sake receive standard treatment.

Researchers and drug companies asked the Food and Drug Administration for its opinion, realizing that if the F.D.A. did not accept the studies, no drugs would ever be approved on the basis of them.  But the F.D.A. said it sanctioned them and could approve drugs with basket study data alone.

Instead of insisting on traditional studies, said Dr. Richard Pazdur, who directs the F.D.A. office that approves new cancer drugs, the agency will look at the data and ask, "Is the American population going to be better off with this drug than without it?"

These are the sorts of studies many seriously ill patients have been craving -- a guarantee that if they enter a study they will get a promising new drug.  And the studies move fast; it does not take years to see a big effect of there is one at all.

In Mrs. Hurwitz's case, the mutation in her rare cancer is in a gene, BRAF, found in about 50% of melanomas but rare in other cancers.  She is among dozens of patients with the same mutation, but different cancers, in the new study that gives everyone the melanoma drug that attacks the mutation.

Basket studies became possible only recently, when gene sequencing became so good and its price so low that doctors could routinely look for 50, 60 or more known cancer-causing mutations in tumors.  At the same time, more and more drugs were being developed to attack those mutations.  So even if, as often happens only a small percentage of patients with a particular tumor type have a particular mutation, it was possible to find a few dozen patients or more for a clinical trial by grouping everyone with that mutation together.

In a way, this is a leading edge of precision medicine that aims to target the drug to the patient.  Unlike previous efforts that looked for small differences between a new treatment and an older one, with basket studies, researchers are gambling on finding huge effects.

"This is realty a new breed of study," said Dr. David Hyman, a cancer specialist at Memorial Sloan-Kettering who directs the study Mrs. Hurwitz is in and two similar ones.

And they are seeing some unprecedented responses, along with some failures.  The responses, though, can be so striking that control groups might be unwarranted or infeasible, Dr. Pazdur said.

"Conventional therapy might give a response rate of 10 or 20 percent," Dr. Pazdur said.  "The newer drug has a response rate of 50 or 60 percent. Does it make sense to do a randomized trial?"  And even if a trial were planned, he said, "Who would go on that trial?  Would you go on that trial?

"When you are having a big effect it is kind of jaw dropping Dr. Pazdur added.  "These are response rates we haven't seen before in diseases."

But these are still the early days, researchers caution.  "It is a different world we are walking into," said Dr. Daniel Costa, a LUNG CANCER researcher at Beth Israel Deaconess Medical Center in Boston.  "And we are learning as we go along."

The new studies pose new problems.  With no control groups, the effect has to be enormous and unmistakable to show it is not occurring by chance. When everyone gets a drug, it can be hard to know if a side effect is from the drug, a cancer or another disease.  And gene mutations can be so rare that patients for a basket study are difficult to find.

The rarity of the mutations, in fact, is one reason for the new national effort, supported by the National Caner Institute.  Its study, called Match, is essentially a basket of basket studies.  Doctors around the country will be sending tumor samples from at least 3,000 patients to central labs that will examine them for mutations.  Those with any of a dozen or so mutations in their tumors can enroll in studies of drugs that target that tumor's mutation.

Dr. Keith Flaherty of Massachusetts General Hospital, principal investigator for the Match trial, said the number of baskets was uncertain -- it would depend on the number of drugs.  But he expects 12 to 15 baskets to start, expanding to perhaps 40 or more.  There will be 31 patients per drug.

He anticipates mixed results.  "We are exploring an unknown space here," Dr. Flaherty said.  "But it is essentially impossible for this whole set of baskets to fail."

To show what is possible, Dr. Jose Baselga of Memorial Sloan-Kettering, points to preliminary results he presented in December (2014) for the basket study that includes Mrs. Hurwitz.

Among 70 patients, there are eight types of cancer.  Eighteen patients had one of two very rare cancers.  Erdheim-Chester disease or Langerhans disease, the cancer that struck Mrs. Hurwitz.  Of them, 14 responded to the melanoma drug -- their tumors vanished, shrank or stopped growing -- and the remaining four have not been taking the drug long enough to say.

"Unbelievable," Dr. Baselga said.

"This is working in a way that is clear, that is unprecedented," he said.  "I don't have enough patients to do a Phase 3 study," he added referring to the large, randomized study traditionally used to test new drugs, "and I even question the morality of it."

But others in basket studies have not fared so well.

Eleni Vavas entered a basket study at Memorial Sloan-Kettering hoping to stop the stomach cancer that was killing her.  The study, said her husband, John Vavas, "was our last-ditch, Hail Mary effort."  His wife, who was 36, entered it last spring, the only patient with stomach cancer.  But, Mr. Vavas said, "she just didn't respond.

She died on July 1.

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And on the same F.D.A. - related track:


The Food and Drug Administration has proposed a greatly simplified process for doctors to obtain experimental drugs for patients who are suffering from serious or life-threatening illnesses and have no other alternative.  In a breathtaking reduction of red tape, the simplification should reduce the time it takes a doctor to apply for experimental drugs from 100 hours to less than one hour.  Their desperately ill patients can only benefit.

Instead of making doctors provide 26 separate types of information and seven attachments, the new form asks for only eight elements of information, one of which requires the patient's clinical history and the doctor's rationale for wanting to use the experimental drug, and a single attachment.

Although the proposed simplified form won't become final until after a 60-day comment period, the F.D.A. says it won't turn away doctors who want to use it before then.

The proposal was announced by Dr. Peter Lurie, associate F.D.A. commissioner for public health strategy and analysis.  Dr. Lurie described the new form as a continuation of a policy that started in the early years of the AIDS epidemic to allow "compassionate use" of experimental drugs even though their safety and efficacy had yet to be demonstrated.  The policy has since been broadened, but, in the process, it has become too complex.

Not every patient who wants an experimental drug can get it.  Patients are eligible only when there is no other product that can diagnose, monitor or treat the patient's disease or condition and the patient cannot be enrolled in a clinical study testing it.  The doctor must determine that the probable risk from the experimental drug is not greater than the probably risk from the disease.  And the doctor must ensure that the manufacturer is willing to provide it.  The F.D.A. can't compel the manufacturer to provide the drug to an individual; it simply offers guidance on how to do it.  Once an application has been filed, the F.D.A. authorizes a vast majority of requests within days or even hours.

The new policy comes on the heels of a campaign by the Libertarian Goldwater Institution to persuade states to pass "right to try" laws to make it easier for terminally ill patients to obtain unapproved drugs.  So far, "right to try" is now law in five states -- Colorado, Louisiana, Michigan, Missouri and, most recently, Arizona.  Some 26 other states have had legislation introduced.

The laws give terminally ill patients the right to try experimental drugs that have passed at least the first of three phases of F.D.A. testing (to determine safety) but are still years away from reaching pharmacy shelves.  The laws don't require manufacturers to provide the treatment or insurers to pay for it.

Instead of relying on the F.D.A. to move quickly, the "right to try" laws seek to speed up access by eliminating the F.D.A. from the process entirely.  Once a doctor and patient decide that an experimental drug is the right choice, the laws let them apply to the drug company directly.

There are downsides to that approach.  Many manufacturers prefer to keep the F.D.A. in the loop.    And there could be safety issues in some cases. The F.D.A. has more information about potential risks and benefits of drugs under development than a doctor or patient is apt to know.  Thus far, the laws have not helped anyone obtain a drug, but backers are hopeful that some patients will gain access in coming months. The F.D.A. has no position on the state "right to try" laws but encourages patients to use its new simplified process for obtaining experimental drugs.

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By Denise Grady

It may sound flippant to say that many cases of CANCER are caused by bad luck, but that is what two scientists suggested in an article published in the journal Science.  The bad luck comes in the form of random genetic mistakes, or mutations, that happen when healthy cells divide.

Random mutations may account for two-thirds of the risk of getting may types of cancer, leaving the usual suspects -- heredity and environmental factors -- to account for only one-third, say the authors, Cristian Tomasetti and Dr. Bert Vogelstein, of Johns Hopkins University School of Medicine.  "We do think this is a fundamental mechanism, and this is the first time there's been a measure of it," said Dr. Tomasetti, an applied mathematician.

Though the researchers suspected that chance had a role, they were surprised at how big it turned out to be.

"This was definitely beyond my expectations," Dr. Tomasetti said.  "It's about double what I would have thought."

The finding may be good news to some people, bad news to others, he added.

Smoking greatly increases the risk of LUNG CANCER, but for other cancers, the causes are not clear.  And yet many patients wonder if they did something to bring the disease on themselves, or if they could have done something to prevent it.

"For the average cancer patient, I think this is good news," Dr. Tomasetti said.  "Knowing that over all a lot of it is just bad luck, I thin in a sense it's comforting."

Among people who do not have cancer, Dr. Tomasetti said he expected there to be two camps. "There are those who would like to control every single thing happening I their lives, and for those, this may be very scary," he said.  "There is a big component of cancer I can just do nothing about.

"For the other part of the population, it's actually good news.  'I'm happy.  I can of course do all I know that's important to not increase my risk of cancer, like a good diet, exercise, avoiding smoking, but on the other side, I don't want to stress out about every single thing or every action I take in my life, or everything I touch or eat."  Dr. Vogelstein said the question of causation had haunted him for decades, since he was an intern and his first patient was a 4-year-old girl with LEUKEMIA.  Her parents were distraught and wanted to know what had caused the disease.  He had no answer, but time and time again heard the same question from patients and their families, particularly parents of children with cancer."

"They think they passed on a bad gene or gave them the wrong foods or exposed them to point in the garage," he said.  "And it's just wrong.  It gave them a lot of guilt."

Dr. Tomasetti and Dr. Vogelstein said the finding that so many cases of cancer occur from random genetic accidents means that it may not be possible to prevent them, and that there should be more of an emphasis on developing better tests to find cancers early enough to cure them.

"Cancer leaves signals of its presence, so we just have to basically get smarter about how to find them," Dr. Tomasetti said.

Their conclusions comes from a statistical model they developed using data in the medical literature on rates of cell division in 31 types of tissue.  They looked specifically at stem cells, which are a small, specialized populations in each organ or tissue that divide to provide replacement for cells that wear out.

Dividing cells must make copies of their DNA, and errors in the process can set off the uncontrolled growth that leads to cancer.

The researchers wondered if higher rates of stem-cell division might increase the risk of cancer simply by providing more chances for mistakes.

Dr. Vogelstein said research of this type became possible only in recent years, because of advances in the understanding of stem-cell biology.

The analysis did not include BREAST or PROSTATE CANCERS, because there was not enough data on rates of stem-cell division in those tissues.

A starting point for their research was an observation made more than 100 years ago but never really explained: Some tissues are far more cancer-prone than others.  In the large intestine, for instance, the lifetime cancer risk is 4.8% -- 24 times higher than in the small intestine, where it is 0.2%.

The scientists found that the large intestine has many more stem cells than the small intestine, and that they divide more often: 73 times a year, compared with 24 times.  In many other tissues, rates of stem cell division also correlated strongly with cancer risk.

Some cancers, including certain lung and SKIN CANCERS, are more common than would be expected just from their rates of stem-cell division -- which matches up with the known importance of environmental factors like smoking and sun exposure in those diseases.  Others more common than expected were linked to cancer-causing genes.  To help explain the findings, Dr. Tomasetti cited the risks of a car accident.  In general, the longer the trip, the higher the odds of a crash.  Environmental factors like bad weather can add to the basic risk, ad so can defects in the car.

"This is a good picture of how I see cancer," he said.  "It's really the combination of inherited factors, environment and chance.  At the base, there is the chance of mutations, to which we add, either because of thing we inherited or the environment, our lifestyle."

Dr. Kenneth Offit, chief of the clinical genetics service at Memorial Sloan-Kettering Cancer Center in Manhattan, called the article "an elegant biological explanation of the complex pattern of caners observed in different human tissues."

He said the hypothesis "appears to be correct," but added that it is "just a first approximation," and he noted that certain types of cancer did not fit the model.  One form of THYROID CANCER, for instance, has a much bigger hereditary component than the model would suggest," he said.

Although the article focused on factors in cancer beyond people's control, Dr. Offit said that about half of cancer deaths could be avoided.

"So one would not want to dilute the important public health message that although most cancer is likely due to random events (affecting FNA replication) at the cellular level, at the population level, the most powerful interventions to decrease the burden of cancer are to stop smoking, know your family history and aim for ideal weight," he said.

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Until next month...

This is a short newsletter.  I promise to make up for it next month. There's definitely enough to talk about...

And if you have any thoughts of how this newsletter could be improved, please email me directly, at

Elaine Jesmer

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