‘Liquid’ Cancer Test Offers Hope for Alternative to Painful Biopsies

A blood test to detect cancer mutations produced results that generally agree with those of an invasive tumor biopsy, researchers reported, heralding a time when diagnosing cancer and monitoring its progression may become less painful and risky.

The blood tests, known as liquid biopsies, represent one of the hottest trends in oncology. They take advantage of the fact that DNA fragments from tumors can be found in tiny amounts in the blood of patients with cancer.

Researchers hope that such tests can become alternatives to conventional tumor biopsies, in which a piece of the tumor is extracted by needle or by surgery — procedures that can have complications.

The results of the study, the largest to date of a liquid biopsy test, give some reassurance that this might be possible.

“I think this study really demonstrates the veracity of the liquid biopsy approach,” said Philip C. Mack, director of molecular pharmacology at the University of California Davis Comprehensive Cancer Center, who is presenting the results here this weekend to the annual meeting of the American Society of Clinical Oncology.

The liquid biopsies are not currently used to diagnose cancer but rather to monitor disease progression or to detect genetic mutations in the tumor that could suggest which drug should be used to treat the disease.

Just this week the Food and Drug Administration gave its first approvalfor such a test, one developed by Roche to detect mutations in a particular gene. Lung cancers with mutations in that gene are vulnerable to treatment with certain drugs, including Roche’s own Tarceva. Many liquid biopsy tests are being sold by other companies under rules that do not require F.D.A. approval.

The study looked at the results of more than 15,000 liquid biopsies performed by Guardant Health, a Silicon Valley start-up that is one of the leaders in the field. While many liquid biopsy tests now look for only a few mutations, Guardant’s test, which has a list price of $5,800, looks at mutations in 70 cancer-related genes.

The 15,000 samples came from the blood of people with various types of cancer, including lung, breast and colorectal. The researchers on the study, most of whom worked for Guardant, said the frequency and types of mutations found were similar to what is known from scientific literature.

For nearly 400 patients, tumor biopsies were available, allowing for direct comparison to the blood test results from the same patient. For certain mutations that drive tumor growth, if a particular mutation was found in the blood it was also found in the tumor 94 to 100 percent of the time.

There was much less agreement for mutations that predict resistance to particular drugs. Those might have arisen only after treatment started, so might not have been seen in the tumor biopsy, which is usually taken at the time of diagnosis.

 

One shortcoming of the liquid biopsy was that for about 15 percent of the patients over all, no tumor DNA was detected in the blood.

“There are simply tumors that do not shed DNA into circulation at detectable levels, so we are bound to miss them,” said Dr. Mack, who has been a paid speaker for Guardant.

Dr. Edward Kim, an expert on lung cancer mutations who was not involved in the study, said the results showed the liquid biopsy accuracy was “very good.” He said, however, that use of an actual tumor sample allows for a more thorough analysis, including more mutations than is possible with a blood sample.

“I’m not personally ready to give up tissue,” said Dr. Kim, who is chairman of solid tumor oncology at the Carolinas HealthCare System’s Levine Cancer Institute in Charlotte, N.C. “It’s still the gold standard.”

Still, he said, there are times when a tissue biopsy cannot be obtained, and it is difficult to do second and third tissue biopsies on a patient. In those cases, he said, “I love the option of having the blood test available.”

Dozens of companies are now developing or offering liquid biopsies, and tissue biopsy companies are trying to defend their turf. Foundation Medicine, which analyzes tissue biopsies for mutations, sued Guardant last month, accusing it of patent infringement, which Guardant denies. Meanwhile, Foundation has introduced its own liquid biopsy test.

The next frontier could be to develop a blood test to detect many or virtually all types of cancer at an early stage, when they might be most easily treatable. That might be tricky because patients could be given needless treatments and needless anxiety in the case of false positives, or if the test detected cancers that were real but would not hurt the patient if left alone.

Illumina, a manufacturer of DNA sequencing machines, formed a company in January to develop such a test. It named the company Grail.

Not to be outdone in the hyperbolic naming department, Guardant last month began studies to validate its own early-detection test, using the name Project Lunar.

 

 

This article was originally published in The New York Times.  Read the original article.

Cross Talk between Cancer Cells and Neighboring Cells May Contribute to Tumor Growth

Pancreatic tumor cells and neighboring normal cells engage in a two-way molecular conversation that helps drive malignant behavior in the cancer cells, according to new study results.

Working in cell lines from mice, researchers showed that pancreatic cancer cells that have cancer-causing mutations in the KRAS gene can coerce nearby healthy cells to release growth signals. These signals then activate a chain of events in the tumor cells that enhance their ability to survive and multiply.

The new findings, published May 5 in Cell, suggest that effective treatments for pancreatic cancer, which is notoriously difficult to treat, may need to target signaling pathways activated by adjacent stromal cells as well as those independently activated by the tumor cells, the study authors wrote.

Detecting Reciprocal Signaling

Pancreatic cancers and other solid cancers contain both tumor cells and normal connective tissue cells called stromal cells. Interactions between the two types of cells are known to play an important role in cancer growth and progression, but the molecular signals underlying these interactions are poorly understood.

To gain insights into these signals, a team led by Claus Jørgensen, Ph.D., of the Cancer Research UK Manchester Institute analyzed communication networks in a mouse pancreatic ductal adenocarcinoma (PDA) cell line and in pancreatic stromal cells from mice. PDA is the most common type of pancreatic cancer and one of the most deadly and difficult-to-treat human cancers.

The PDA cells used in this study contained a normal KRAS gene and a mutated form of the gene that the researchers could switch on or off. KRAS, which is mutated in more than 90 percent of pancreatic tumors and in many other cancers, plays a key role in driving the rapid and uncontrolled cell growth that are hallmarks of cancer.

For their analysis, the team monitored thousands of growth factors, receptors, and other proteins in the PDA cells alone, with and without the mutated form of KRAS; in stromal cells grown in the presence of factors that were secreted by the KRAS-mutant PDA cells; and in the two cell types grown together in laboratory dishes.

For the final experiment, the researchers tagged the proteins produced in the tumor cells with one label, and the proteins produced in the stromal cells with another label, explained Douglas Lauffenburger, Ph.D., of the Massachusetts Institute of Technology, a computational biologist and study coauthor. This technique allowed the researchers to monitor what was happening in the two cell types at the same time.

These experiments, along with computational analyses by Dr. Lauffenburger’s lab, yielded the first evidence that this type of molecular cross-talk, or reciprocal signaling, can expand the effects of cancer-causing gene mutations beyond those that occur in tumor cells alone and provided details on some of the key signaling molecules involved in these conversations.

In particular, the researchers found that PDA cells with mutated KRAS produced a growth signal known as sonic hedgehog, which induces the stromal cells to release growth factors, including Gas6 and IGF-1, that the cancer cells don’t produce on their own. These growth factors activated signaling pathways in the tumor cells that increased cell proliferation and protected the tumor cells from a type of controlled cell death called apoptosis.

An Intricate Web of Interactions

“We now know that tumors are a complex mix of genetically diverse cancer cells and multiple types of healthy cells, all communicating with each other via an intricate web of interactions,” Dr. Jørgensen said in a news release. “Untangling this web, and decoding individual signals, is vital to identifying which of the multitude of communications are most important for controlling tumor growth and spread.”

Because some pancreatic tumors contain even more stromal cells than they do cancer cells, understanding how cancer cells turn their healthy neighbors into allies is critically important, added lead author Christopher Tape, Ph.D., a research fellow at the Institute of Cancer Research, London.

Indeed, Dr. Lauffenburger said, “We can already imagine a combination of existing drugs that would be predicted to work much better [for treating pancreatic cancer] than drugs currently being used based on looking at tumor cells in isolation.”

One such combination he said, is drugs that inhibit the activity of the proteins AXL and MEK. Blocking AXL could disrupt an important pathway activated via reciprocal signaling from stromal cells, whereas blocking MEK would disrupt signaling that the tumor cells control on their own.

The next step, he said, will be to test such drug combinations in mouse models of pancreatic cancer. “If we can show that targeting these two pathways together is effective in mice, now you’ve got a toehold to think about whether there’s an indication for this kind of drug combination in human trials.”

If these results can be generalized to provide evidence for reciprocal signaling across different tumor types, “they could call into question the way that almost all cancer drug screens are performed, as well as many other conclusions that researchers draw from studying tumor cells in isolation,” said Daniel Gallahan, Ph.D., deputy director of NCI’sDivision of Cancer Biology.

“These results highlight the need to study cancer systematically in its ‘native’ environment, where tumor cells are able to communicate and respond to a variety of outside signals to enhance their growth,” Dr. Gallahan continued. “Through better understanding of the entire tumor ecosystem, there is potential for developing new therapeutic regimens designed to disrupt multiple processes, not just at the level of the tumor cell but also at other critical and potentially more targetable points.”

 

This article was originally published on NIH.  Read the original article.

Precision Oncology: Nanoparticles Target Bone Cancers in Dogs

Many people share their homes with their pet dogs. Spending years under the same roof with the same environmental exposures, people and dogs have something else in common that sometimes gets overlooked. They can share some of the same diseases, such as diabetes and cancer. By studying these diseases in dogs, researchers can learn not only to improve care for people but for their canine friends as well.

As a case in point, an NIH-funded team of researchers recently tested a new method of delivering chemotherapy drugs for osteosarcoma, a bone cancer that affects dogs and people, typically teenagers and older adults. Their studies in dogs undergoing treatment for osteosarcoma suggest that specially engineered, bone-seeking nanoparticles might safely deliver anti-cancer drugs precisely to the places where they are most needed. These early findings come as encouraging news for the targeted treatment of inoperable bone cancers and other malignancies that spread to bone.

Nanoparticles are engineered in the lab by manipulating matter on an atomic and molecular scale into custom-made, three-dimensional materials that measure under 100 nanometers (a nanometer is 1 billionth of a meter). These materials can be programmed to seek out something unique about a tissue and bypass other parts of the body. Cancer researchers seek to utilize this homing ability to deliver a chemotherapy drug directly to a patient’s tumor, boosting its effectiveness and limiting its side effects.

But the development of nanoparticles to fight cancer has been slowed by some natural limitations of testing them in mice, the preferred mammalian research model. One is scale. For a nano-sized drug delivery system to work in people with advanced cancer, it must penetrate tumors much larger than those in any mouse. Another issue is the tumors in mice don’t often occur spontaneously as they do in people. Researchers typically induce them by injecting human cells into mice with compromised immune systems to avoid rejection.

As published recently in Proceedings of the National Academy of Sciences, veterinary researcher Timothy Fan and materials scientist Jianjun Cheng, both at the University of Illinois at Urbana-Champaign, teamed up to overcome these obstacles.  They did it by taking a nanoparticle developed in Cheng’s lab and testing it in pet dogs being treated for this cancer at Fan’s veterinary research clinic.

 

Here’s how the process worked. Cheng and his colleagues began in the lab constructing the virus-sized nanoparticles by fabricating polymers and attaching to them trace amounts of the chemotherapy drug doxorubicin (Doxo), which is used to treat many cancers including osteosarcoma. They then coated the polymers with a drug known as pamidronate (Pam). Pam is attracted to areas of active bone repair, which is the response in dogs and people when osteosarcoma invades and destroys bone tissue.

The researchers first confirmed that their Pam-coated nanoparticles bind to hydroxyapatite, a major inorganic component of bone. They then showed that the addition of Pam to their drug-laden nanoparticles also improved their ability to stick to lab dishes that mimic the surface of bone, resulting in improved killing of osteosarcoma cells. Their Pam-Doxo nanoparticles also concentrated in the cancer-ridden bones of mice with osteosarcoma, slowing tumor growth and minimizing bone loss.

To help Cheng bring his Pam-Doxo nanoparticle from lab to clinic, Fan and his colleagues enrolled—with the consent of their owners—nine dogs undergoing treatment for osteosarcoma at the University of Illinois Veterinary Teaching Hospital. The dogs in this Phase I safety trial weighed from 88 to 132 pounds, putting them within a comparable skeletal size range of a child or young adult with osteosarcoma.

The researchers showed in the dogs that Cheng’s nanoparticles accumulated in each bone tumor within two hours of intravenous infusion. Importantly, the dogs tolerated doses of the nanoparticle treatment equivalent to what might be given to a person with no signs of toxicity, as would be hoped with a targeted therapy.

Three weeks after the nanoparticle infusion, the dogs had their diseased limbs amputated, the standard of care for treating canine osteosarcoma. While this early clinical trial was designed primarily to test safety, studies of each dog’s amputated limb revealed dead or dying tumor tissue in the bone.

The next challenge will be to ramp up production of the Pam-Doxo nanoparticle and enable its continued clinical study. The nanoparticles used in this study were painstakingly produced in relatively small quantities by a couple of graduate students in the lab.

That aside, the findings offer proof-of-concept that nanoparticles could be used to target bone cancers in large mammals, including humans. The approach may one day be applied to treat metastatic bone cancers, which can be widely distributed throughout the body and impossible to remove with surgery. If so, this research would be good news for humans and, importantly, bring improved care to their four-legged “best friends” with cancer.

 

 

This article was originally published on NIH.  Read the original article.

A mechanical trigger for toxic tumor therapy

Cells in nearly any part of the body can become cancerous and transform into tumors. Some, like skin cancer, are relatively accessible to treatment via surgery or radiation, which minimizes damage to healthy cells; others, like pancreatic cancer, are deep in the body and can only be reached by flooding the bloodstream with cell-killing chemotherapies that, ideally, shrink tumors by accumulating in their ill-formed blood and lymph vessels in higher amounts than in vessels of healthy tissues. To improve the low efficacy and toxic side effects of chemotherapies that rely on this passive accumulation, a team of researchers at the Wyss Institute at Harvard University, Boston Children’s Hospital, and Harvard Medical School has developed a new drug delivery platform that uses safe, low-energy ultrasound waves to trigger the dispersal of chemotherapy-containing sustained-release nanoparticles precisely at tumor sites, resulting in a two-fold increase in targeting efficacy and a dramatic reduction in both tumor size and drug-related toxicity in mouse models of breast cancer. This research was recently published in Biomaterials.

“We essentially have an external activation method that can localize drug delivery anywhere you want it, which is much more effective than just injecting a bunch of nanoparticles,” says co-first author Netanel Korin, Ph.D., former Wyss Technology Development Fellow and current Assistant Professor at the Israel Institute of Technology.

The key to this new method is the creation of nanoparticle aggregates (NPAs), which are tiny structures consisting of drug-containing nanoparticles surrounded by a supportive matrix, akin to the berries suspended in a blueberry muffin. Like chefs trying to craft the perfect pastry, the researchers experimented with a variety of nanoparticle sizes and nanoparticle-to-matrix ratios to create NPAs that are stable enough to remain intact when injected, but also finely tuned to break apart when disrupted with low-energy ultrasound waves, freeing the nanoparticles that then release their drug payloads over time, like blueberries slowly leaking their juice.

To test whether the NPAs worked as designed, the team first exposed mouse breast cancer cells to either loose nanoparticles, intact NPAs, or NPAs that had been treated with ultrasound. The ultrasound-treated NPAs and loose nanoparticles both showed greater tumor internalization than the intact NPAs, showing that the ultrasound waves effectively broke up the NPAs to allow the nanoparticles to infiltrate cancer cells.

Next, the researchers repeated the experiments with nanoparticles containing doxorubicin (a common chemotherapy drug used to treat a variety of cancers) and found that the NPAs resulted in a comparable level of cancer cell death, demonstrating that NPA encapsulation did not negatively impact the efficacy of the drug.

Finally, to see whether the NPAs performed well compared with loose nanoparticles in vivo, both formulations were injected intravenously into mice with breast cancer tumors. Ultrasound-treated NPAs delivered nearly five times the amount of nanoparticles to the tumor site as intact NPAs, while loose nanoparticles delivered two to three times that amount. When the nanoparticles were loaded with doxorubicin, tumors in mice that received NPAs and ultrasound shrank by nearly half compared with those in mice that received loose nanoparticles. Crucially, by using NPAs, the researchers were able to cut tumor size in half using one-tenth of the dose of doxorubicin usually required, reducing the number of mouse deaths due to drug toxicity from 40% to 0%.

“Locking nanoparticles up in NPAs permits precise delivery of an army of nanoparticles from each single NPA directly to the tumor in response to ultrasound, and this greatly minimizes the dilution of these nanoparticles in the bloodstream,” says Anne-Laure Papa, Ph.D., co-first author and Postdoctoral Fellow at the Wyss Institute. “Additionally, our ultrasound-triggered NPAs displayed distribution patterns throughout the body similar to the FDA-approved PLGA polymer nanoparticles, so we expect the NPAs to be comparably safe.”

NPAs were also shown to limit the “burst release” commonly observed in nanoparticle drug delivery, in which a significant number of them break open and release their drug soon after injection, causing an adverse response around the site of injection and reducing the amount of the drug that gets to the tumor. When applied to cancer cells in vitro, loose nanoparticles released 25% of their drug payload within five minutes of being administered, while the nanoparticles contained within intact NPAs released just 1.8% of their drug. When ultrasound was applied, an additional 65% of the drug was released from the NPAs compared with loose nanoparticles, which only released an additional 11%.

The team says additional research could further improve the performance of ultrasound-sensitive NPAs, making the platform an attractive option for safer, more effective chemotherapy delivery. It could be made even more powerful through combination with other tumor-targeting strategies such as using peptides that home to the tumor microenvironment to further guide cancer drugs to their targets. “We hope that in the future our triggered accumulation technique can be combined with such targeting strategies to produce even more potent treatment effects,” says Papa.

“This approach offers a novel solution to the pervasive problem of delivering a high concentration of an intravenous drug to a very specific area while sparing the rest of the body,” says senior author and Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children’s Hospital, and Professor of Bioengineering at Harvard SEAS. “By using localized ultrasound to selectively deploy sustained-release nanoparticles loaded with high drug concentrations, we have created a non-invasive way to safely and effectively deliver chemotherapy only where and when it’s needed.”

 

 

This article was originally published in NIH. Read the original article.

 

Scouting for Metastasis: New Study Uncovers the Role of Exosomes in Cancer’s Spread

Cancer becomes especially lethal when it metastasizes from a primary tumor to other organs. But this spread does not occur randomly — within a population of cancer cells, certain subgroups preferentially seek out and colonize specific organs.

New research from scientists at Memorial Sloan Kettering and Weill Cornell Medical College has found that tumor cells send signals throughout the body to prepare specific organs for the arrival of metastatic cells. These signals are transmitted through small vesicles — microscopic bubble-like compartments — known as exosomes, which act as location scouts to set the stage at distant sites where cancer cells can take root and thrive.

After being secreted by cancer cells, the exosomes circulate throughout the body and are taken up by other cells. At particular metastatic sites, they prime what is called the microenvironment — noncancerous cells, molecules, and blood vessels that will eventually surround the tumor — to be nurturing to cancer cells after they arrive.

“If the cancer cells are seeds, then the soil of the microenvironment needs to be appropriately fertilized for the seeds to grow,” says MSK medical oncologist Jacqueline Bromberg, who has led pioneering research into exosomes in collaboration with David Lyden of Weill-Cornell Medical College.  

The researchers sought to learn whether certain molecules in the exosomes were “addressing” them to specific organs.

“We know that patients with metastatic disease to one organ can shed millions of cancer cells into the circulation and yet all the other organs in the body can remain cancer free for a long time,” she explains. “The question we asked was whether cancer exosomes could selectively prepare their favorite organs before the seeds arrive.” 

Directed by Surface Proteins

Earlier research had suggested that exosomes play a role in metastasis, but the details were unclear. While exosomes can be taken up by a wide variety of cells, in most cases they are not retained, nor do they transmit signals to change their surroundings.

In the new study, led by Drs. Bromberg and Lyden and published online by the journal Nature, the researchers sought to learn whether certain molecules in the exosomes were “addressing” them to specific organs, which might shed light on why tumor cells later preferentially go to those same organs.

Exosomes are shed by tumor cells and travel throughout the body to metastatic sites, such as the lung, to prepare them to be nurturing to cancer cells that spread there (top right). If exosomes do not prepare the metastatic site, any cancer cells that may spread there will not survive (bottom right).

They discovered that exosomes display a variety of receptor proteins called integrins on their surface, and that the integrin type determines which organ the exosome will target. For example, an integrin called αvΒ5 directs exosomes to the liver, while the integrin α6Β4 causes them to home in on the lung.

The specific integrin makes it easier for the exosome to be taken in and prime a particular organ because the integrin binds to other proteins, called adhesion molecules, amid the organ’s cells.

“These integrins are like cellular Velcro, and they’re looking for the right sticky ‘hook’ to adhere to,” Dr. Bromberg says. “When they connect with the right adhesion molecule, it allows the exosome to start doing its work preparing the organ to accept and nurture the cancer cells.”  

Powerful Effects on Organ Selection

The researchers also showed that when they blocked the expression of αvΒ5 or α6Β4 in cancer cells, the exosomes those cells shed were no longer able to educate their respective target organs — the liver and lung. In experiments with mice, cancer cells that usually take root and grow in these organs could not do so without the exosomes carrying out their advance work.

Another mouse study showed the exosomes can even redirect cancer cells to spread to organs they don’t usually target, further demonstrating their powerful effect.

“Remarkably, if we treated mice with lung-targeting exosomes, we could redirect breast cancer cells that would normally spread to the bone, causing them to spread to the lungs instead,” Dr. Bromberg says.

The researchers also found an important clue as to how the exosomes condition the target organs to be welcoming to cancer cells: They appear to stimulate the cells in the microenvironment to produce a protein group called S100, which are already known to precondition host cells for metastasis.   

“We think the exosome integrins not only help with adhesion to the microenvironment but also trigger key signaling pathways and inflammatory responses in target cells, resulting in the education of that organ to permit the growth of metastatic cells,” Dr. Bromberg explains.

Exosomes can even redirect cancer cells to spread to organs they don’t usually target, further demonstrating their powerful effect.

She says that the main short-term practical application of these findings might be to analyze exosomes, and the expression of integrins on their surface, to predict where a patient’s tumor is most likely to spread.

In the longer term, having earlier knowledge about the likely site of metastasis could someday help clinicians devise focused treatments that prevent the emergence of metastases at these sites.

“The next big challenge is to determine if this process is reversible — and if so, is there a step of no return?” Dr. Bromberg says. “Specifically, can we uneducate or reeducate these organs, rendering them inhospitable for metastasis?”

She explains that many have suggested using exosomes to deliver drugs or nucleic acids to cancers. “Identifying the integrin ‘zip codes’ that target specific cell types and tissues provides us with a unique opportunity to deliver such therapies to the organs that sustain the cancer,” she says.  “You could render future metastatic sites inhospitable so that cancer cells would not grow there.”

 

 

This article was originally published on AACR.  Read the original article.

In Developing World, Cancer Is a Very Different Disease

In the United States the median age at which colon cancer strikes is 69 for men and 73 for women. In Chad the average life expectancy at birth is about 50. Children who survive childbirth — and then malnutrition anddiarrhea — are likely to die of pneumonia, tuberculosis, influenza, malaria,AIDS or even traffic accidents long before their cells accumulate the mutations that cause colon cancer.

In fact, cancers of any kind don’t make the top 15 causes of death in Chad— or in Somalia, the Central African Republic and other places where the average life span peaks in the low to mid-50s. Many people do die fromcancer, and their numbers are multiplied by rapidly growing populations and a lack of medical care. But first come all those other threats.

How different this is from the United States, where oncologists are working to rid a 91-year-old former president of metastatic melanoma, one of the deadliest cancers. One of Jimmy Carter’s drugs, a new immunotherapy agent called Keytruda, has been priced at $12,500 a month, in addition to the cost of his surgery and treatment with computer-guided radiation beams.

Mr. Carter, a religious man, says he is prepared to meet his maker. But he is among the fortunate who first have the luxury of exhausting the most expensive remedies medicine has to offer.

So far the approach appears to be working, shrinking his brain tumors to invisibility. Should there be a setback, his doctors may have the option of combining Keytruda with other recently approved immune system therapies, the next line of defense. Last summer at the annual meeting of the American Society of Clinical Oncology, Dr. Leonard Saltz, chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center, estimated that medical bills for these cocktails could run $300,000 a year.

That is for just one person. For those with the will and the resources, the war on cancer has come to mean pushing incrementally toward some imagined immortality, the ultimate right to life. There appears to be no limit to what we — society in the abstract — will agree to pay for extending long and well-lived lives.

Vice President Joseph R. Biden Jr. was envisioning more of these death-defying acts when, borrowing a metaphor, he recently called for a “moon shot” to end cancer — infusions of additional dollars that, judging from the past, would go largely toward research that helps older people become older.

Children with leukemia, lymphoma or osteosarcoma might also benefit, along with some younger adults and those just reaching their prime, like the vice president’s son, Beau Biden, who died this year from a brain tumorat age 46. But the median age of diagnosis for cancers of all kinds in this country is 66. Seventy-eight percent of cases are diagnosed in people 55 or older. Childhood cancer, among the most curable, remains rare.

In the developing world, cancer has a very different look, as illustrated in maps drawn by the World Health Organization’s International Agency for Cancer Research.

The countries with the highest incidence, like the United States, Canada, Australia and those of Western Europe, are dark blue. With the exception of South Africa, almost all of the African continent is light blue or white. The map could serve double duty — as a pointer to places with the highest standards of living and hence the longest life spans.

But that is just part of the story. Cancers that arise in poorer countries are far less likely to be survived.

A disproportionately large number of these cases are caused by infectious agents. Look again at the international maps, and pick the ones showing the worldwide incidence of cervical cancer, which is brought on by infection with the human papilloma virus.

This map is almost a reverse image of the ones for colorectal cancer orbreast cancer — the leading cancers of the richer realms. For cervical cancer, the dark blues of trouble are concentrated in places like Mali, while the wealthier countries, with lower rates, are rendered in white.

This is a cancer that could practically be wiped out everywhere by the HPV vaccine, and those efforts are underway in poorer regions. Infection is also a major factor in stomach cancer and liver cancer. An Apollo-scale moon shot aimed at all of these killers would save millions of people who still have much of their lives to come.

As improvements in economic development and public health move forward, the disparities are evening out, as described in an update this week by epidemiologists at the American Cancer Society. Life expectancy will slowly increase, and rising alongside will be the overall cancer rate.

Cancers of the poor will gradually give way to cancers of the more affluent. They will move up the list of leading killers, replacing the old diseases.

This is already happening in countries like India, where more people are becoming overweight and living less active lives — risk factors for malignancies of the colon and breast. Women who forestall or forgo childbearing are also at higher risk for breast and other gynecological cancers.

More people are also able to afford a steady supply of cigarettes — and to live for the additional decades it takes for the cancerous mutations to pile up. China has joined North America and Europe as a hotbed of lung cancer, and other countries seem determined to catch up.

Dr. Vincent T. DeVita Jr., the renowned American oncologist, titled his new book “The Death of Cancer,” envisioning a time “when we’ll be able to cure almost all cancers” with an ever-improving stream of engineeredpharmaceuticals and other cutting-edge treatments yet to be discovered.

Maybe that will happen, if we can afford it. But there are so many lower-tech, lower-cost and ultimately more heroic cancer moon shots yet to be made — ones that would save younger lives in Africa and throughout the world.

 

This article was originally published on The New York Times.  Read the original article.

Fast thinking

A GENERAL besieging a city will often cut off its food supply and wait, rather than risking a direct assault. Many doctors dream of taking a similar approach to cancer. Tumours, being rapidly growing tissues, need more food than healthy cells do. Cutting this off thus sounds like a good way to kill the out-of-control cells. But, while logical in theory, this approach has proved challenging in practice—not least because starvation harms patients, too.

In particular, it damages cells called tumour-infiltrating lymphocytes (TILs) that, as their name suggests, are one of the immune system’s main anti-cancer weapons. Valter Longo of the University of Southern California, in Los Angeles, however, thinks he may have a way around this problem. As he and his colleagues write in a paper in this week’s Cancer Cell, they are trying to craft a diet that weakens tumours while simultaneously sneaking vital nutrients to healthy tissues, TILs included.

Dr Longo first used starvation as a weapon against cancer in 2012. In experiments on mice, he employed it in parallel with doxorubicin, a common anticancer drug. The combination resulted in the animals’ tumours shrinking by an average of four-fifths, as opposed to a half if they were dosed with the drug alone. No one, though, was willing to follow this experiment up by starving people in the same way. The consensus was that this would be too risky. That led Dr Longo to think about how he might mimic the benefits of starvation while minimising its problems. The result is a diet rich in vitamin D, zinc and fatty acids essential to TILs’ performance, while being low in the proteins and simple sugars that tumours make ready use of.

To test this diet’s efficacy, Dr Longo and his colleagues injected 30 mice with breast-cancer cells. For the first two days after the injections they fed these mice standard rodent chow, composed of 25% protein, 17% fat and 58% simple sugars and complex vegetable carbohydrates. This contained 3.75 kilocalories of energy per gram. They then put ten of the animals onto a transition diet of 1.88 kilocalories per gram for a day before switching them to the near-starvation diet. Besides its special ingredients this consisted of 0.5% protein, 0.5% fat and 99% complex carbohydrates that would be of little value to cancer cells.

The mice remained on their meagre commons for three days before being returned to standard rodent chow for ten days and then put through the cycle again. Another nine mice, chosen from the original 30 as controls, were starved for 60 hours (the maximum feasible without endangering lives) every ten days but otherwise kept on normal chow. And the remaining ten (one of the originals had died) were fed the chow continuously.

When the team terminated the experiment, they found that both the rodents which had been starved and those which had been fed the special diet developed tumours which were only two-fifths of the size of those found in the mice on the ordinary diet. Encouraged by these results, Dr Longo ran the experiment again, but with the addition of doxorubicin. The results were impressive. In combination with the special diet, doxorubicin drove tumours down to a quarter of the size of those found in control mice—close to the reduction he had reported in 2012.

To work out what was happening at the cellular level, the team collected samples of breast-cancer tissue from the mice in the re-run experiment and scanned these for TILs. They found that, while such cells were indeed present in the tumours of mice fed ordinary chow, there were 70% more of them in the tumours of mice given doxorubicin alone, 80% more in those of mice that were on the special diet alone and 240% more in mice that had been given both therapies.

A follow-up experiment revealed at least part of what was going on. An enzyme called haeme oxygenase-1, which helps regulate immune responses, turned out to be protecting tumours from the attention of TILs in mice on the normal diet. Dr Longo’s diet seems to suppress this enzyme’s production in a tumour—and that encourages TILs to accumulate. Add in the drug, and the tumour faces a two-pronged assault. Further work by the team suggests this approach also works on melanoma, a particularly aggressive form of skin cancer. A siege mentality can pay off.

 

This article was originally published on The Economist.  Read the original article.

What Is Immunotherapy? The Basics on These Cancer Treatments

Some of the most promising advances in cancer research in recent years involve treatments known as immunotherapy. These advances are spurring billions of dollars in investment by drug companies, and are leading to hundreds of clinical trials. Here are answers to some basic questions about this complex and rapidly evolving field.

What is immunotherapy?

Immunotherapy refers to any treatment that uses the immune system to fight diseases, including cancer. Unlike chemotherapy, which kills cancer cells, immunotherapy acts on the cells of the immune system, to help them attack the cancer.

What are the types of immunotherapy?

Drugs called checkpoint inhibitors are the most widely used form of immunotherapy for cancer. They block a mechanism that cancer cells use to shut down the immune system. This frees killer T-cells — a critically important part of the immune system — to attack the tumor. Four checkpoint inhibitors have been approved by the Food and Drug Administration and are on the market. They are given intravenously.

Another form of immunotherapy, called cell therapy, involves removing immune cells from the patient, altering them genetically to help them fight cancer, then multiplying them in the laboratory and dripping them, like a transfusion, back into the patient. This type of treatment is manufactured individually for each patient, and is still experimental.

Bispecific antibodies are an alternative to cell therapy, one that does not require individualizing treatment for each patient. These antibodies are proteins that can attach to both a cancer cell and a T-cell, that way bringing them close together so the T-cell can attack the cancer. One such drug, called Blincyto, has been approved to treat a rare type of leukemia.

Vaccines, another form of immunotherapy, have had considerably less success than the others. Unlike childhood vaccines, which are aimed at preventing diseases like measles andmumps, cancer vaccines are aimed at treating the disease once the person has it. The idea is to prompt the immune system to attack the cancer by presenting it with some piece of the cancer.

The only vaccine approved specifically to treat cancer in the United States is Provenge, for prostate cancer. Another vaccine, BCG, which was developed to prevent tuberculosis, has long been used to treat bladder cancer. As a weakened TBbacterium, BCG appears to provoke a general immune system reaction that then works against the cancer. Researchers hope that other vaccines may yet be made to work by combining them with checkpoint inhibitors.

Which types of cancer are treated with immunotherapy?

Checkpoint inhibitors have been approved to treat advanced melanoma, Hodgkin’s lymphoma and cancers of the lung, kidney and bladder. The drugs are being tested in many other types of cancer.

So far, cell therapy has been used mostly for blood cancers like leukemia and lymphoma.

Which cancer drugs are checkpoint inhibitors?

The four on the market are: Yervoy (ipilimumab) and Opdivo (nivolumab), made by Bristol-Myers Squibb; Keytruda (pembrolizumab), by Merck; and Tecentriq (atezolizumab), by Genentech.

How well does immunotherapy work?

Though immunotherapy has been stunningly successful in some cases, it still works in only a minority of patients. Generally, 20 percent to 40 percent of patients are helped by checkpoint inhibitors — although the rate can be higher among those with melanoma. Some patients with advanced disease have had remissions that have lasted for years. In some cases, combining two checkpoint inhibitors increases the effectiveness. But for some people the drugs do not work at all, or they help just temporarily.

Cell therapy can produce complete remissions in 25 percent to 90 percent of patients with lymphoma or leukemia, depending on the type of cancer. In some cases the remissions can last for years, but in others relapses occur within a year.

Have You Received Immunotherapy Treatment for Cancer?

The New York Times would like to hear from doctors and patients who have experience giving or receiving immunotherapy treatment for cancer.

What are the side effects?

Checkpoint inhibitors can cause severe problems that are, essentially, autoimmune illnesses, in which the immune system attacks healthy tissue as well as cancer. One result is inflammation. In the lungs it can cause breathing trouble; in the intestine it can cause diarrhea. Joint and muscle pain, and rheumatoid arthritis can also occur, and the immune system can also attack vital glands like the thyroid and pituitary. These reactions are dangerous, but can often be controlled with steroid medicines like prednisone.

Cell therapy can also lead to severe and potentially fatal reactions resulting from the overstimulation of the immune system. The reactions can usually be controlled, but patients may need to be treated in an intensive care unit.

What does immunotherapy cost? Does insurance cover it?

Checkpoint inhibitors can cost $150,000 a year. Many insurers will pay if the drug has been approved for the type of cancer the patient has. But sometimes there are high co-payments. Patients in clinical trials may get the drugs free.

Manufacturers have not said yet how much they will charge for cell therapies, assuming they win approval and reach the market. But experts expect the price to be as high as a few hundred thousand dollars.

Where can I get immunotherapy?

Any oncologist can prescribe the checkpoint inhibitors that are on the market. Patients with cancers for which the drugs have not been approved may find insurers reluctant to pay, but may be able to get the drugs for free by volunteering for clinical trials.

Cell therapies are available only through clinical trials now. Most of the study sites are major medical centers.

How can I find out about clinical trials in immunotherapy?

Information is available on the Cancer Research Institute website, or by calling 1-855-216-0127 (Monday through Friday, 8:30 a.m. to 6 p.m. E.T.). Another source is ClinicalTrials.gov.

 

This article was originally published on The New York Times.  Read the original article.

Lung Cancer in “Never Smokers”

Only about 15 percent of lung cancer patients diagnosed in the U.S. are individuals who have never smoked—known to cancer researchers as “never smokers.” Yet, says Charles Rudin, an oncologist at Johns Hopkins Hospital in Baltimore, lung cancer in never smokers is the sixth-leading cause of cancer mortality, with about 15,000 deaths each year.

Recent studies suggest that never smokers often get a different type of lung cancer than smokers. The EGFR genetic mutation, present in only 10 to 15 percent of all lung tumors, occurs in a considerable 25 to 30 percent of never smokers’ lung tumors. Likewise, genetic aberrations affecting an enzyme called anaplastic lymphoma kinase (ALK), seen in just 4 percent of all lung tumors, occur in 10 to 15 percent of tumors in never smokers. This means that never smokers are more likely to be candidates for the newer targeted therapies used to treat non–small cell lung cancer.

Kim Norris, the president of the Lung Cancer Foundation of America, says never smokers should be aware of the disease’s symptoms: a nagging cough, hoarseness, and pain in the chest, back, shoulder or ribs.

Just as important, doctors need to have lung cancer on their radars when they see these symptoms in never smokers. “We need to help physicians understand,” says Regina Vidaver, the executive director of the National Lung Cancer Partnership, “that the typical [patient] profile is not the whole story.” 

 

This article was originally published on AACR.  Read the original article.

THE IMPROVISATIONAL ONCOLOGIST

he bone-marrow biopsy took about 20 minutes. It was 10 o’clock on an unusually chilly morning in New York in April, and Donna M., a self-possessed 78-year-old woman, had flown in from Chicago to see me in my office at Columbia University Medical Center. She had treated herself to orchestra seats for “The Humans” the night before, and was now waiting in the room as no one should be asked to wait: pants down, spine curled, knees lifted to her chest — a grown woman curled like a fetus. I snapped on sterile gloves while the nurse pulled out a bar cart containing a steel needle the length of an index finger. The rim of Donna’s pelvic bone was numbed with a pulse of anesthetic, and I drove the needle, as gently as I could, into the outer furl of bone. A corkscrew of pain spiraled through her body as the marrow was pulled, and then a few milliliters of red, bone-flecked sludge filled the syringe. It was slightly viscous, halfway between liquid and gel, like the crushed pulp of an overripe strawberry.

I had been treating Donna in collaboration with my colleague Azra Raza for six years. Donna has a preleukemic syndrome called myelodysplastic syndrome, or MDS, which affects the bone marrow and blood. It is a mysterious disease with few known treatments. Human bone marrow is normally a site for the genesis of most of our blood cells — a white-walled nursery for young blood. In MDS, the bone-marrow cells acquire genetic mutations, which force them to grow uncontrollably — but the cells also fail to mature into blood, instead dying in droves. It is a dual curse. In most cancers, the main problem is cells that refuse to stop growing. In Donna’s marrow, this problem is compounded by cells that refuse to grow up.

Though there are commonalities among cancers, of course, every tumor behaves and moves — “thinks,” even — differently. Trying to find a drug that fits Donna’s cancer, Raza and I have administered a gamut of medicines. Throughout all this, Donna has been a formidable patient: perennially resourceful, optimistic and willing to try anything. (Every time I encounter her in the clinic, awaiting her biopsy with her characteristic fortitude, it is the doctor, not the patient, who feels curled and small.) She has moved nomadically from one trial to another, shuttling from city to city, and from one drug to the next, through a landscape more desolate and exhilarating than most of us can imagine; Donna calls it her “serial monogamy” with different medicines. Some of these drugs have worked for weeks, some for months — but the transient responses have given way to inevitable relapses. Donna is getting exhausted.

Her biopsy that morning was thus part routine and part experiment. Minutes after the marrow was drawn into the syringe, a technician rushed the specimen to the lab. There he extracted the cells from the mixture and pipetted them into tiny grain-size wells, 500 cells to a well. To each well — about 1,000 in total — he will add a tiny dab of an individual drug: prednisone, say, to one well, procarbazine to the next and so forth. The experiment will test about 300 medicines (many not even meant for cancer) at three different doses to assess the effects of the drugs on Donna’s cells.

Bathed in a nutrient-rich broth suffused with growth factors, the cells will double and redouble in an incubator over the course of the following two weeks, forming a lush outgrowth of malignant cells — cancer abstracted in a dish. A computer, taught to count and evaluate cells, will then determine whether any of the drugs killed the cancerous cells or forced them to mature into nearly normal blood. Far from relying on data from other trials, or patients, the experiment will test Donna’s own cancer for its reactivity against a panel of medicines. Cells, not bodies, entered this preclinical trial, and the results will guide her future treatment.

I explained all this to Donna. Still, she had a question: What would happen if the drug that appeared to be the most promising proved unsuccessful?

“Then we’ll try the next one,” I told her. “The experiment, hopefully, will yield more than one candidate, and we’ll go down the list.”

“Will the medicine be like chemotherapy?”

“It might, or it might not. The drug that we end up using might be borrowed from some other disease. It might be an anti-inflammatory pill, or an asthma drug. It might be aspirin, for all we know.”

My conversation with Donna reflected how much cancer treatment has changed in the last decade. I grew up as an oncologist in an era of standardized protocols. Cancers were lumped into categories based on their anatomical site of origin (breast cancer, lung cancer, lymphoma, leukemia), and chemotherapy treatment, often a combination of toxic drugs, was dictated by those anatomical classifications. The combinations — Adriamycin, bleomycin, vinblastine and dacarbazine, for instance, to treat Hodgkin’s disease — were rarely changed for individual patients. The prospect of personalizing therapy was frowned upon: The more you departed from the standard, the theory ran, the more likely the patient would end up being undertreated or improperly managed, risking recurrence. In hospitals and clinics, computerized systems were set up to monitor an oncologist’s compliance with standard therapy. If you chose to make an exception for a particular patient, you had to justify the choice with an adequate excuse. Big Chemo was watching you.

 

I memorized the abbreviated names of combination chemo — the first letter of each drug — for my board exams, and I spouted them back to my patients during my clinic hours. There was something magical and shamanic about the multiletter contractions. They were mantras imbued with promise and peril: A.B.V.D. for Hodgkin’s, C.M.F. for breast cancer, B.E.P. for testicular cancer. The lingo of chemotherapists was like a secret code or handshake; even the capacity to call such baleful poisons by name made me feel powerful. When my patients asked me for statistical data, I had numbers at my fingertips. I could summon the precise chance of survival, the probability of relapse, the chance that the chemo would make them infertile or cause them to lose their hair. I felt omniscient.

Yet as I spoke to Donna that morning, I realized how much that omniscience has begun to wane — unleashing a more experimental or even artisanal approach in oncology. Most cancer patients are still treated with those hoary standardized protocols, still governed by the anatomical lumping of cancer. But for patients like Donna, for whom the usual treatments fail to work, oncologists must use their knowledge, wit and imagination to devise individualized therapies. Increasingly, we are approaching each patient as a unique problem to solve. Toxic, indiscriminate, cell-killing drugs have given way to nimbler, finer-fingered molecules that can activate or deactivate complex pathways in cells, cut off growth factors, accelerate or decelerate the immune response or choke the supply of nutrients and oxygen. More and more, we must come up with ways to use drugs as precision tools to jam cogs and turn off selective switches in particular cancer cells. Trained to follow rules, oncologists are now being asked to reinvent them.

The thought that every individual cancer might require a specific individualized treatment can be profoundly unsettling. Michael Lerner, a writer who worked with cancer patients, once likened the experience of being diagnosed with cancer to being parachuted out of a plane without a map or compass; now it is the oncologist who feels parachuted onto a strange landscape, with no idea which way to go. There are often no previous probabilities, and even fewer certainties. The stakes feel higher, the successes more surprising and the failures more personal. Earlier, I could draw curtain upon curtain of blame around a patient. When she did not respond to chemotherapy, it was her fault: She failed. Now if I cannot find a tool in the growing kit of drugs to target a cancer’s vulnerabilities, the vector feels reversed: It is the doctor who has failed.

Yet the mapless moment that we are now in may also hold more promise for patients than any that has come before — even if we find the known world shifting under our feet. We no longer have to treat cancer only with the blunt response of standard protocols, in which the disease is imagined as a uniform, if faceless, opponent. Instead we are trying to assess the particular personality and temperament of an individual illness, so that we can tailor a response with extreme precision. It’s the idiosyncratic mind of each cancer that we are so desperately trying to capture.

THE THOUGHT THAT EVERY INDIVIDUAL CANCER MIGHT REQUIRE A SPECIFIC INDIVIDUALIZED TREATMENT CAN BE PROFOUNDLY UNSETTLING.

Cancer — and its treatment — once seemed simpler. In December 1969, a group of cancer advocates led by the philanthropist Mary Lasker splashed their demand for a national war on cancer in a full-page ad in The New York Times: “Mr. Nixon: You Can Cure Cancer.” This epitomized the fantasy of a single solution to a single monumental illness. For a while, the centerpiece of that solution was thought to be surgery, radiation and chemotherapy, a strategy colloquially known as “slash and burn.” Using combination chemotherapy, men and women were dragged to the very brink of physiological tolerability but then pulled back just in time to send the cancer, but not its host, careering off the edge.

Throughout the 1980s and 1990s, tens of thousands of people took part in clinical trials, which compared subjects on standard chemo combinations with others administered slightly different combinations of those drugs. Some responded well, but for many others, relapses and recurrences were routine — and gains were small and incremental for most cancers. Few efforts were made to distinguish the patients; instead, when the promised cures for most advanced malignancies failed to appear, the doses were intensified and doubled. In the Margaret Edson play “Wit,” an English professor who had ovarian cancer recalled the bewildering language of those trials by making up nonsensical names for chemotherapy drugs that had been pumped into her body: “I have survived eight treatments of hexamethophosphacil and vinplatin at the full dose, ladies and gentlemen. I have broken the record.”

To be fair, important lessons were garnered from the trials. Using combinations of chemotherapy, we learned to treat particular cancers: aggressive lymphomas and some variants of breast, testicular and colon cancers. But for most men and women with cancer, the clinical achievements were abysmal disappointments. Records were not broken — but patients were.

A breakthrough came in the 2000s, soon after the Human Genome Project, when scientists learned to sequence the genomes of cancer cells. Cancer is, of course, a genetic disease at its core. In cancer cells, mutated genes corrupt the normal physiology of growth and ultimately set loose malignant proliferation. This characteristic sits at the heart of all forms of cancer: Unlike normal cells, cancer cells have forgotten how to stop dividing (or occasionally, have forgotten how to die). But once we could sequence tens of thousands of genes in individual cancer specimens, it became clear that uniqueness dominates. Say two identical-looking breast cancers arise at the same moment in identical twins; are the mutations themselves in the two cancers identical? It’s unlikely: By sequencing the mutations in one twin’s breast cancer, we might find, say, 74 mutated genes (of the roughly 22,000 total genes in humans). In her sister’s, we might find 42 mutations, and if we looked at a third, unrelated woman with breast cancer, we might find 18. Among the three cases, there might be a mere five genes that overlap. The rest are mutations particular to each woman’s cancer.

No other human disease is known to possess this degree of genetic heterogeneity. Adult-onset diabetes, for example, is a complex genetic disease, but it appears to be dominated by variations in only about a dozen genes. Cancer, by contrast, has potentially unlimited variations. Like faces, like fingerprints — like selves — every cancer is characterized by its distinctive marks: a set of individual scars stamped on an individual genome. The iconic illness of the 20th century seems to reflect our culture’s obsession with individuality.

 

If each individual cancer has an individual combination of gene mutations, perhaps this variability explains the extraordinary divergences in responses to treatment. Gene sequencing allows us to identify the genetic changes that are particular to a given cancer. We can use that information to guide cancer treatment — in effect, matching the treatment to an individual patient’s cancer.

Many of the remarkable successes of cancer treatments of the last decades are instances of drugs that were matched to the singular vulnerabilities of individual cancers. The drug Gleevec, for instance, can kill leukemia cells — but only if the patient’s cancer cells happen to carry a gene mutation called BCR-ABL. Tarceva, a targeted therapy for lung cancer, works powerfully if the patient’s cancer cells happen to possess a particular mutant form of a gene; for lung-cancer patients lacking that mutation, it may be no different from taking a placebo. Because the medicines target mutations or behaviors that are specific to cancer cells (but not normal cells), many of these drugs have surprisingly minimal toxicities — a far cry from combination chemotherapies of the past.

A few days after Donna’s visit to the clinic, I went to my weekly meeting with Raza on the ninth floor of the hospital. The patient that morning was K.C., a 79-year-old woman with blood cancer. Raza has been following her disease — and keeping her alive — for a decade.

THE LINGO OF CHEMOTHERAPISTS WAS LIKE A SECRET CODE OR HANDSHAKE; EVEN THE CAPACITY TO CALL SUCH BALEFUL POISONS BY NAME MADE ME FEEL POWERFUL.

“Her tumor is evolving into acute leukemia,” Raza said. This, too, is a distinctive behavior of some cancers that we can now witness using biopsies, CT scans and powerful new techniques like gene sequencing: We can see the cancers morphing from smoldering variants into more aggressive types before our eyes.

“Was the tumor sequenced?” I asked.

“Yes, there’s a sequence,” Raza said, as we leaned toward a screen to examine it. “P53, DNMT3a and Tet2,” she read from the list of mutant genes. “And a deletion in Chromosome 5.” In K.C.’s cancer, an entire segment of the genome had been lopped off and gone missing — one of the crudest mutations that a tumor can acquire.

“How about ATRA?” I asked. We had treated a few patients carrying some of K.C.’s mutations with this drug and noted a few striking responses.

“No. I’d rather try Revlimid, but at a higher dose. She’s responded to it in the past, and the mutations remain the same. I have a hunch that it might work.”

 

CANCER BY GENES

Researchers have discovered that cancers they once assumed were quite different might be similar genetically, which means a treatment that used to work for only a small group of patients now might help a much larger group. Mutations in the gene E2F3, for example, are found in breast, lung, bladder and prostate cancers, among others. Knowing this, it’s possible to develop similar drugs that target the gene across different cancers.

As Raza and I returned to K.C.’s room to inform her of the plan, I couldn’t help thinking that this is what it had come down to: inklings, observations, instincts. Medicine based on premonitions. Chemo by hunch. The discussion might have sounded ad hoc to an outsider, but there was nothing cavalier about it. We parsed these possibilities with utmost seriousness. We studied sequences, considered past responses, a patient’s recent history — and then charged forward with our best guess. Our decisions were spurred by science, yes, but also a sense for the art of medicine.

Oncologists are also practicing this art in areas that rely less on genes and mutations. A week after Donna’s biopsy, I went to see Owen O’Connor, an oncologist who directs Columbia’s lymphoma center. O’Connor, in his 50s, reminds me of an amphibious all-terrain vehicle — capable of navigating across any ground. We sat in his office, with large, sunlit windows overlooking Rockefeller Plaza. For decades, he explained, oncologists had treated relapsed Hodgkin’s lymphoma in a standard manner. “There were limited options,” O’Connor said. “We gave some patients more chemotherapy, with higher doses and more toxic drugs, hoping for a response. For some, we tried to cure the disease using bone-marrow transplantation.” But the failure rate was high: About 30 percent of patients didn’t respond, and half of them died.

Then a year or two ago, he tried something new. He began to use immunological therapy to treat relapsed, refractory Hodgkin’s lymphoma. Immunological therapies come in various forms. There are antibodies: missile-like proteins, made by our own immune systems, that are designed to attack and destroy foreign microbes (antibodies can also be made artificially through genetic engineering, armed with toxins and used as “drugs” to kill cancer cells). And there are drugs that incite a patient’s own immune system to recognize and kill tumor cells, a mode of treatment that lay fallow for decades before being revived. O’Connor used both therapies and found that they worked in patients with Hodgkin’s disease. “We began to see spectacular responses,” he said.

Yet even though many men and women with relapsed Hodgkin’s lymphoma responded to immunological treatments, there were some who remained deeply resistant. “These patients were the hardest to treat,” O’Connor continued. “Their tumors seemed to be unique — a category of their own.”

Lorenzo Falchi, a fellow training with O’Connor and me, was intrigued by these resistant patients. Falchi came to our hospital from Italy, where he specialized in treating leukemias and lymphomas; his particular skill, gleaned from his experience with thousands of patients, is to look for patterns behind seemingly random bits of data. Rooting about in Columbia’s medical databases, Falchi made an astonishing discovery: The men and women who responded most powerfully to the immune-boosting therapies had invariably been pretreated with another drug called azacitidine, rarely used in lymphoma patients. A 35-year-old woman from New York with relapsed lymphoma saw her bulky nodes melt away. She had received azacitidine as part of another trial before moving on to the immunotherapy. A man, with a similar stage of cancer, had not been pretreated. He had only a partial response, and his disease grew back shortly thereafter.

Falchi and O’Connor will use this small “training set” to begin a miniature trial of patients with relapsed Hodgkin’s disease. “We will try it on just two or three patients,” Falchi told me. “We’ll first use azacitidine — intentionally, this time — and then chase it with the immune activators. I suspect that we’ll reproduce the responses that we’ve seen in our retrospective studies.” In lung cancer too, doctors have noted that pretreating patients with azacitidine can make them more responsive to immunological therapy. Falchi and O’Connor are trying to figure out why patients respond if they are pretreated with a drug that seems, at face value, to have nothing to do with the immune system. Perhaps azacitidine makes the cancer cells more recognizably foreign, or perhaps it forces immune cells to become more aggressive hunters.

Falchi and O’Connor are mixing and matching unexpected combinations of medicines based on previous responses — departing from the known world of chemotherapy. Even with the new combination, Falchi suspects, there will be resistant patients, and so he will divide these into subsets, and root through their previous responses, to determine what might make these patients resistant — grinding the data into finer and finer grains until he’s down to individualized therapy for every variant of lymphoma.

Suppose every cancer is, indeed, unique, with its own permutation of genes and vulnerabilities — a sole, idiosyncratic “mind.” It’s obviously absurd to imagine that we’ll find an individual medicine to treat each one: There are 14 million new cases of cancer in the world every year, and several million of those patients will present with advanced disease, requiring more than local or surgical treatment. Trying to individualize treatment for those cases would shatter every ceiling of cost.

Cancer works the same way all life works, through the process of cell division and mutation. All living things grow and heal through cell division, and all living things evolve and change through the occasional mutations that occur as the cells divide. But some mutations can be deadly, leading to the unchecked growth that defines cancer. More than 14 million Americans have a history of cancer; it is expected to kill 600,000 Americans this year.

But while the medical costs of personalized therapy are being debated in national forums in Washington, the patients in my modest waiting room in New York are focused on its personal costs. Insurance will not pay for “off-label” uses of medicines: It isn’t easy to convince an insurance company that you intend to use Lipitor to treat a woman with pre-leukemia — not because she has high cholesterol but because the cancer cells depend on cholesterol metabolism for their growth (in one study of a leukemia subtype, the increasing cells were highly dependent on cholesterol, suggesting that high doses of Lipitor-like drugs might be an effective treatment).

In exceptional cases, doctors can requisition pharmaceutical companies to provide the medicines free — for “compassionate use,” to use the language of the pharma world — but this process is unpredictable and time-consuming. I used to fill out such requests once every few months. Now it seems I ask for such exceptions on a weekly basis. Some are approved. A majority, unfortunately, are denied.

So doctors like Falchi and O’Connor do what they can — using their wiles not just against cancer but against a system that can resist innovation. They create minuscule, original clinical trials involving just 10 or 20 patients, a far cry from the hundred-thousand-patient trials of the ’80s and ’90s. They study these patients with monastic concentration, drawing out a cosmos of precious data from just that small group. Occasionally, a patient may choose to pay for the drugs out of his or her own pockets — but it’s a rare patient who can afford the tens of thousands of dollars that the drugs cost.

But could there be some minimal number of treatments that could be deployed to treat a majority of these cancers effectively and less expensively? More than any other scientist, perhaps, Bert Vogelstein, a cancer geneticist at Johns Hopkins University, has tackled that conundrum. The combination of genetic mutations in any individual cancer is singular, Vogelstein acknowledges. But these genetic mutations can still act through common pathways. Targeting pathways, rather than individual genes, might reorganize the way we perceive and treat cancer.

Imagine, again, the cell as a complex machine, with thousands of wheels, levers and pulleys organized into systems. The machine malfunctions in the cancer: Some set of levers and pulleys gets jammed or broken, resulting in a cell that continues to divide without control. If we focus on the individual parts that are jammed and snapped, the permutations are seemingly infinite: Every instance of a broken machine seems to have a distinct fingerprint of broken cogs. But if we focus, instead, on systems that malfunction, then the seeming diversity begins to collapse into patterns of unity. Ten components function, say, in an interconnected loop to keep the machine from tipping over on its side. Snap any part of this loop, and the end result is the same: a tipped-over machine. Another 20 components control the machine’s internal thermostat. Break any of these 20 components, and the system overheats. The number of components — 10 and 20 — are deceptive in their complexity, and can have endless permutations. But viewed from afar, only two systems in this machine are affected: stability and temperature.

Cancer, Vogelstein argues, is analogous. Most of the genes that are mutated in cancer also function in loops and circuits — pathways. Superficially, the permutations of genetic flaws might be boundless, but lumped into pathways, the complexity can be organized along the archetypal, core flaws. Perhaps these cancer pathways are like Hollywood movies; at first glance, there seems to be an infinite array of plot lines in an infinite array of settings — gold-rush California, the Upper West Side, a galaxy far, far away. But closer examination yields only a handful of archetypal narratives: boy meets girl, stranger comes to town, son searches for father.

How many such pathways, or systems, operate across a subtype of cancer? Looking at one cancer, pancreatic, and mapping the variations in mutated genes across hundreds of specimens, Vogelstein’s team proposed a staggeringly simple answer: 12. (One such “core pathway,” for instance, involves genes that enable cells to invade other tissues. These genes normally allow cells to migrate through parts of the body — but in cancer, migration becomes distorted into invasion.) If we could find medicines that could target these 12 core pathways, we might be able to attack most pancreatic cancers, despite their genetic diversity. But that means inventing 12 potential ways to block these core paths — an immense creative challenge for scientists, considering that they haven’t yet figured out how to target more than, at best, one or two.

Immunological therapies provide a second solution to the impasse of unlimited diversity. One advantage of deploying a patient’s own immune system against cancer is that immunological cells are generally agnostic to the mutations that cause a particular cancer’s growth. The immune system was designed to spot differences in the superficial features of a diseased or foreign cell, thereby identifying and killing it. It cares as little about genes as an intercontinental ballistic missile cares about the email addresses, or dietary preferences, of the population that it has been sent to destroy.

A few years ago, in writing a history of cancer, I interviewed Emil Freireich. Freireich, working with Emil Frei at the National Cancer Institute in the 1960s and ’70s, stumbled on the idea of deploying multiple toxic drugs simultaneously to treat cancer — combination chemotherapy. They devised one of the first standard protocols — vincristine, Adriamycin, methotrexate and prednisone, known as VAMP — to treat pediatric leukemias. Virtually nothing about the VAMP protocol was individualized (although doses could be reduced if needed). In fact, doctors were discouraged from trying alternatives to the formula.

Yet as Freireich recalled, long before they came up with the idea for a protocol, there were small, brave experiments; before trials, there was trial and error. VAMP was brought into existence through grit, instinct and inspired lunges into the unknown. Vincent T. DeVita Jr., who worked with Freireich in the 1960s, wrote a book, “The Death of Cancer,” with his daughter, Elizabeth DeVita-Raeburn. In it, he recalled a time when the leukemic children in Freireich’s trial were dying of bacterial meningitis during treatment. The deaths threatened the entire trial: If Freireich couldn’t keep the children alive during the therapy, there would be no possibility of remission. They had an antibiotic that could kill the microbe, but the medicine wouldn’t penetrate the blood-brain barrier. So Freireich decided to try something that pushed the bounds of standard practice. He ordered DeVita, his junior, to inject it directly into the spinal cords of his patients. It was an extreme example of off-label use of the drug: The medicine was not meant for use in the cord. DeVita writes:

“The first time Freireich told me to do it, I held up the vial and showed him the label, thinking that he’d possibly missed something. ‘It says right on there, “Do not use intrathecally,” ’ I said. Freireich glowered at me and pointed a long, bony finger in my face. ‘Do it!’ he barked. I did it, though I was terrified. But it worked every time.”

When I asked Freireich about that episode and about what he would change in the current landscape of cancer therapy, he pointed to its extreme cautiousness. “We would never have achieved anything in this atmosphere,” he said. The pioneer of protocols pined for a time before there were any protocols.

Medicine needs standards, of course, otherwise it can ramble into dangerous realms, compromising safety and reliability. But cancer medicine also needs a healthy dose of Freireich: the desire to read between the (guide)lines, to reimagine the outer boundaries, to perform the experiments that become the standards of the future. In January, President Obama introduced an enormous campaign for precision medicine. Cancer is its molten centerpiece: Using huge troves of data, including gene sequences of hundreds of thousands of specimens and experiments performed in laboratories nationwide, the project’s goal is to find individualized medicines for every patient’s cancer. But as we wait for that decades-long project to be completed, oncologists still have to treat patients now. To understand the minds of individual cancers, we are learning to mix and match these two kinds of learning — the standard and the idiosyncratic — in unusual and creative ways. It’s the kind of medicine that so many of us went to medical school to learn, the kind that we’d almost forgotten how to practice.

 

 

This article was originally published on The New York Times.  Read the original article.