Learning about advanced cancer from the people who donate their bodies after death

by Daimona Kounde, Cancer Research UK

A breast cancer cell. Credit: LRI EM unit

"Cancer has a way of evolving and adapting," says Dr. Mariam Jamal-Hanjani, a cancer doctor and researcher at the Cancer Research UK Lung Cancer Centre of Excellence. "When tumours are under selection pressures, for example as a result of cancer treatment, they can develop new features that allow them to become resistant and, therefore, more aggressive."

02 jun 2019--Advanced cancers have often spread to other parts of the body. And it's these secondary tumours that reach and compromise vital organs like the brain or lungs that can ultimately lead to death.

To tackle aggressive cancers, scientists need to understand how they evolve, spread and become resistant to treatment. But as cancer progresses and patients become more unwell, it becomes increasingly difficult to study.

Doctors might ask a patient for permission to use tissue removed during surgery for research. But when cancer has spread to multiple locations, or to somewhere that might not be possible to operate on or obtain a biopsy from, it isn't possible to collect these gifts of precious tissue.

But now, thanks to an even greater gift to research, patients with advanced cancers are leaving a different type of legacy.

In new research, 10 patients with advanced breast cancer chose to donate their bodies after their death. Their gift allowed Cancer Research UK scientists in Cambridge to collect multiple samples of advanced cancer in all the places it had spread to—up to 37 tumours in a single patient. They analysed these samples to unravel how the cancers spread and developed treatment resistance, publishing their in-depth picture in the journal Cell Reports.

"It's really an unprecedented view of lethal cancers," says study lead Professor Carlos Caldas, from the Cancer Research UK Cambridge Institute.

Talking about death

Studies like this, and a larger national study called PEACE, involve collecting samples from patients after death and can sometimes require delicate conversations. For some patients the subject of death is a difficult one for many reasons, and patients are aware of the fact that their participation in studies like PEACE will not benefit themselves.

Despite how sensitive the topic is, patients often want to contribute to the research supported by PEACE, which is funded by Cancer Research UK. And they remain its biggest advocates.

"The truth is, even before PEACE existed I would often have patients ask me: "Is there anything I can do for science? Can I donate my body to research?"" recalls Jamal-Hanjani, who is the Principal Investigator for PEACE at the lead centre, UCL Cancer Institute.

"Our patients still want to give something of themselves to help cancer research, knowing that they won't benefit, but that future patients might. It's incredibly humbling."

In these circumstances, a strong doctor-patient relationship is key to an open and honest conversation. Understanding how the patient feels is the main steer for doctors in whether to discuss participating in PEACE.

Although it can be intimidating, Jamal-Hanjani believes this is something doctors need to become more comfortable with. "In treating patients with cancer especially, we as doctors have to overcome that stigma, because patients do think about death and we need to allow them to speak freely with us."

And these patients' contribution can be invaluable in helping those who come after them.

Decoding cancer spread

Cancer evolution has become one of the big topics in research. Studies are analysing tumours from when they are first discovered and throughout treatment.

Now, samples collected after death are helping to understand the hardest to treat stages of some cancers. Caldas and his team compared multiple tumours collected from patients who had died from breast cancer that had become resistant to treatment.

The results paint a more comprehensive picture of how closely related tumours can be, retracing the steps that led to these cancers growing and spreading. Caldas says the results are unexpected.

"Our work suggests something rather extraordinary: that cancer spread is not a continuous process. It seems to happen in waves," he says. Rather than new tumours appearing one after the other, each wave involves a group of cancer cells creating new tumours in several organs at the same time.

These could be cells breaking away from the primary tumour, or from elsewhere in the body where cancer cells can remain hidden and dormant for sometimes years.

"Even in patients who have a lot of secondary tumours," adds Caldas, "cancer appears to have spread in as few as two or three of these waves."

What triggers these waves? Could there be 'pauses' between them when cancer is unlikely to spread? Answers to these questions could change the way patients are monitored.

"This is just starting to open the book," Caldas says. "There is a lot more to be learned from studies like this."

The PEACE study is on a much larger scale: 150 patients have already volunteered in the first 2 years of the study. The research will focus on themes that scientists struggle to study without access to advanced cancer samples, like why certain cancers readily spread to specific organs but not others.

Coming together

Narrowing down the research questions to ensure these precious samples are used for the best possible research is an important aspect of PEACE.

A project of this scale also involves an element of unpredictability that represents a huge challenge for Jamal-Hanjani. Often, it's a patient's family who notifies the PEACE team that their loved one has died. An entire team must then come together very quickly, including researchers, laboratory staff, pathologists, mortuary technicians and clinical nurses.

"I would say that is far more challenging than talking to patients about death and about the PEACE study," Jamal-Hanjani says.

Yet she feels a sense of responsibility. "Ultimately, we make a promise to the patient when they are alive, and we want to fulfil the living wish of our patients," she says.

"We want our patients to know that even after they die, we will treat them with dignity and respect. We are very privileged to receive their samples and to be able to do the research we do."

Paying it forward

As we start to better understand the behaviour of advanced cancers, PEACE and other post-mortem studies continue to centre on the people affected. For those who take part, this is their legacy.

"The vast majority of patients want to help other patients," says Jamal-Hanjani. "I think that's just the nature of human beings."

That legacy will support many ongoing research projects focusing on several types of cancers, including lung, kidney, skin and breast, to name a few. Not only that, but samples will also be stored so that PEACE can contribute to future research projects. "It's about the research we can do now, but also the research we can offer future doctors and scientists," says Jamal-Hanjani.

More information: Leticia De Mattos-Arruda et al. The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer, Cell Reports (2019). DOI: 10.1016/j.celrep.2019.04.098

Journal information: Cell Reports 

Provided by Cancer Research UK 

Accidental fungus leads to promising cancer drug

By Maggie Fox
30 june 2008--A drug developed using nanotechnology and a fungus that contaminated a lab experiment may be broadly effective against a range of cancers, U.S. researchers reported on Sunday.
The drug, called lodamin, was improved in one of the last experiments overseen by Dr. Judah Folkman, a cancer researcher who died in January. Folkman pioneered the idea of angiogenesis therapy -- starving tumors by preventing them from growing blood supplies.
Lodamin is an angiogenesis inhibitor that Folkman's team has been working to perfect for 20 years. Writing in the journal Nature Biotechnology, his colleagues say they developed a formulation that works as a pill, without side-effects.
They have licensed it to SynDevRx, Inc, a privately held Cambridge, Massachusetts biotechnology company that has recruited several prominent cancer experts to its board.
Tests in mice showed it worked against a range of tumors, including breast cancer, neuroblastoma, ovarian cancer, prostate cancer, brain tumors known as glioblastomas and uterine tumors.
It helped stop so-called primary tumors and also prevented their spread, Ofra Benny of Children's Hospital Boston and Harvard Medical School and colleagues reported.
"Using the oral route of administration, it first reaches the liver, making it especially efficient in preventing the development of liver metastasis in mice," they wrote in their report. "Liver metastasis is very common in many tumor types and is often associated with a poor prognosis and survival rate," they added.
'ALMOST CLEAN' LIVERS
"When I looked at the livers of the mice, the treated group was almost clean," Benny said in a statement. "In the control group you couldn't recognize the livers -- they were a mass of tumors."
The drug was known experimentally as TNP-470, and was originally isolated from a fungus called Aspergillus fumigatus fresenius.
Harvards's Donald Ingber discovered the fungus by accident while trying to grow endothelial cells -- the cells that line blood vessels. The mold affected the cells in a way known to prevent the growth of tiny blood vessels known as capillaries.
Ingber and Folkman developed TNP-470 with the help of Takeda Chemical Industries in Japan in 1990.
But the drug affected the brain, causing depression, dizziness and other side-effects. It also did not stay in the body long and required constant infusions. The lab dropped it.
Efforts to improve it did not work well. Then Benny and colleagues tried nanotechnology, attaching two "pom-pom"-shaped polymers to TNP-470, protecting it from stomach acid.
In mice, the altered drug, now named lodamin, went straight to tumor cells and helped suppress melanoma and lung cancer, with no apparent side effects, Benny said.
All untreated mice had fluid in the abdominal cavity, and enlarged livers covered with tumors. Mice treated with lodamin had normal-looking livers and spleens, the researchers said.
Twenty days after being injected with cancer cells, four out of seven untreated mice had died, while all treated mice were still alive, Benny's team reported.
"I had never expected such a strong effect on these aggressive tumor models," she said. The researchers believe lodamin may also be useful in other diseases marked by abnormal blood vessel growth, such as age-related macular degeneration.

Excess Body Fat Associated with Increased Risk for Six Cancers

WASHINGTON, Oct. 31 -- Obesity is on course to overtake tobacco as the leading risk factor for cancer in America, according to a report issued today.
Moreover, the risk for cancer increases even with modest weight gain, said Walter C. Willett, M.D., Ph.D., of the Harvard School of Public Health. He said excess body fat increased the risk for cancers of the colon, kidney, and pancreas, adenocarcinoma of the esophagus and endometrium, and breast cancer in postmenopausal women.
That was the major finding from a mega-analysis of more than 7,000 published studies conducted by a 21-member board assembled by the American Institute for Cancer Research and the World Cancer Research Fund International.
The results of the analysis, Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective, were released at a press conference here.
Dr. Willett pointed out that obesity is now the second leading cause of cancer, just behind tobacco, because "obesity increases the risk of so many cancers and because two-thirds of Americans are overweight."
He and his colleagues predicted that over the next decade "obesity will become the number one risk factor for cancer" as obesity increases and the number of smokers decreases.
Dr. Willett said the finding was a call to action for clinicians, who he said should begin counseling patients about the danger of excess weight with "the first few pounds gained or first few extra inches of abdominal girth."
He faulted clinicians for failing to mention weight until patients need to lose 30 pounds or more, which he said was the wrong approach.
In addition to excess weight, Dr. Willett and colleagues said that 18 ounces of red meat per week was a safe amount but for every 1.7 additional ounces consumed per week the risk of cancer increased by 15%.
For processed meats, the panelists said it was not able to identify a safe level. "Every 1.7 ounces of processed meats consumed per day increased the risk of colorectal cancer by 21%," they said.
Dr. Willett said that alcohol was also linked to a variety of cancers and in some cases -- older women for example -- the risk of breast cancer begins to increase at levels as low as a single glass of wine per day.
How clinicians should balance the risk of breast cancer against the reported cardiovascular benefit of a daily glass of red wine is problematic, Dr. Willett admitted. But he said that folic acid consumption appeared to counterbalance the increased risk associated with alcohol.
His advice to patients who want the heart protective benefit of red wine is to take a multivitamin daily. "I believe that will offset the increased risk."
On the basis of the analysis, the panelists issued these 10 recommendations for cancer prevention:
Be lean as possible within the normal range of body weight.
Be physically active as part of everyday life.
Limit consumption of energy-dense foods. Avoid sugary drinks.
Eat mostly foods of plant origin.
Limit alcoholic drinks.
Limit consumption of salt. Avoid moldy cereals (grains) or pulses (legumes).
Aim to meet nutritional needs through diet alone.
Women of childbearing age should plan to breastfeed and children should be breastfed.
Cancer survivors should follow the recommendations for cancer prevention.
AICR supports research and educational programs focused on diet and cancer. It is a member of the World Cancer Research Fund International, which along with AICR funded the analysis. Additional source: American Institute for Cancer Research and World Cancer Research Fund InternationalSource reference: World Cancer Research Fund, American Institute for Cancer Research, "Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective" 2007.

Prognosis: Cancers Not Affected by Emotional Health

By NICHOLAS BAKALAR
The idea that emotional well-being can affect the course of disease finds no support in a new report on head and neck cancer.
The study involved more than 1,000 men and women older than 18 with cancers of the mouth, tongue and throat that had not spread. A questionnaire assessed quality of life, including physical health, family and social connections and emotional status. The patients were followed for an average of nine years, until death or until they stopped participating.
Although age, tumor classification, cigarette smoking and other variables were predictors of survival, scores on emotional well-being tests had no predictive value.
“A fighting spirit has its advantages, but one of them is not, apparently, cancer survival,” said James C. Coyne, lead author of the study, which appeared online Oct. 22 in the journal Cancer. “We looked at whether exceptionally high emotional well-being or exceptionally low emotional well-being had an effect. We found absolutely no evidence for either.”
Dr. Coyne is a professor of psychology at the University of Pennsylvania.
The authors acknowledge that participants had to be judged mentally fit to consent, follow instructions and keep appointments, which may make the sample somewhat unrepresentative.
But its large size — there were 646 deaths in the group, which is larger than the entire sample in most previous studies — gives the work considerable strength.