A recent study in The Lancet Oncology showed that AI found 20 percent more cancers on mammogram screens than radiologists alone.
Published in The Lancet Oncology, the study analyzed the scans of 80,000 Swedish women with a moderate hereditary risk of breast cancer who had undergone a mammogram between April 2021 and July 2022. Half of these scans were read by AI and then a radiologist to double-check the findings. The second group of scans was read by two researchers without the help of AI. (Currently, the standard of care across Europe is to have two radiologists analyze a scan before diagnosing a patient with breast cancer.)
The study showed that the AI group detected cancer in 6 out of every 1,000 scans, while the radiologists detected cancer in 5 per 1,000 scans. In other words, AI found 20 percent more cancers than the highly-trained radiologists.
Scientists have been using MRI images (like the ones pictured here) to train artificial intelligence to detect cancers earlier and with more accuracy. Here, MIT's AI system, MIRAI, looks for patterns in a patient's mammograms to detect breast cancer earlier than ever before. news.mit.edu
But even though the AI was better able to pinpoint cancer on an image, it doesnât mean radiologists will soon be out of a job. Dr. Laura Heacock, a breast radiologist at NYU, said in an interview with CNN that radiologists do much more than simply screening mammograms, and that even well-trained technology can make errors. âThese tools work best when paired with highly-trained radiologists who make the final call on your mammogram. Think of it as a tool like a stethoscope for a cardiologist.â
AI is still an emerging technology, but more and more doctors are using them to detect different cancers. For example, researchers at MIT have developed a program called MIRAI, which looks at patterns in patient mammograms across a series of scans and uses an algorithm to model a patient's risk of developing breast cancer over time. The program was "trained" with more than 200,000 breast imaging scans from Massachusetts General Hospital and has been tested on over 100,000 women in different hospitals across the world. According to MIT, MIRAI "has been shown to be more accurate in predicting the risk for developing breast cancer in the short term (over a 3-year period) compared to traditional tools." It has also been able to detect breast cancer up to five years before a patient receives a diagnosis.
The challenges for cancer-detecting AI tools now is not just accuracy. AI tools are also being challenged to perform consistently well across different ages, races, and breast density profiles, particularly given the increased risks that different women face. For example, Black women are 42 percent more likely than white women to die from breast cancer, despite having nearly the same rates of breast cancer as white women. Recently, an FDA-approved AI device for screening breast cancer has come under fire for wrongly detecting cancer in Black patients significantly more often than white patients.
As AI technology improves, radiologists will be able to accurately scan a more diverse set of patients at a larger volume than ever before, potentially saving more lives than ever.
A scientist works on a blood test in the Ajay Goel Lab, one of many labs that are developing blood tests to screen for different types of cancer.
In recent years, this type of cancer has been on the upswing in adults under age 50 and in those without a family history. In 2021, the American Cancer Society's revised guidelines began recommending that colorectal cancer screenings with colonoscopy begin at age 45. But that still wouldnât catch many early-onset cases among people in their 20s and 30s, says Ajay Goel, professor and chair of molecular diagnostics and experimental therapeutics at City of Hope, a Los Angeles-based nonprofit cancer research and treatment center that developed the new blood test.
âThese people will mostly be missed because they will never be screened for it,â Goel says. Overall, colorectal cancer is the fourth most common malignancy, according to the U.S. Centers for Disease Control and Prevention.
Goel is far from the only one working on this. Dozens of companies are in the process of developing blood tests to screen for different types of malignancies.
Some estimates indicate that between one-fourth and one-third of all newly diagnosed colorectal cancers are early-onset. These patients generally present with more aggressive and advanced disease at diagnosis compared to late-onset colorectal cancer detected in people 50 years or older.
To develop his test, Goel examined publicly available datasets and figured out that changes in novel microRNAs, or miRNAs, which regulate the expression of genes, occurred in people with early-onset colorectal cancer. He confirmed these biomarkers by looking for them in the blood of 149 patients who had the early-onset form of the disease. In particular, Goel and his team of researchers were able to pick out four miRNAs that serve as a telltale sign of this cancer when theyâre found in combination with each other.
The blood test is being validated by following another group of patients with early-onset colorectal cancer. âWe have filed for intellectual property on this invention and are currently seeking biotech/pharma partners to license and commercialize this invention,â Goel says.
Heâs far from the only one working on this. Dozens of companies are in the process of developing blood tests to screen for different types of malignancies, says Timothy Rebbeck, a professor of cancer prevention at the Harvard T.H. Chan School of Public Health and the Dana-Farber Cancer Institute. But, he adds, âItâs still very early, and the technology still needs a lot of work before it will revolutionize early detection.â
The accuracy of the early detection blood tests for cancer isnât yet where researchers would like it to be. To use these tests widely in people without cancer, a very high degree of precision is needed, says David VanderWeele, interim director of the OncoSET Molecular Tumor Board at Northwestern Universityâs Lurie Cancer Center in Chicago.
Otherwise, âyouâre going to cause a lot of anxiety unnecessarily if people have false-positive tests,â VanderWeele says. So far, âthese tests are better at finding cancer when thereâs a higher burden of cancer present,â although the goal is to detect cancer at the earliest stages. Even so, âwe are making progress,â he adds.
While early detection is known to improve outcomes, most cancers are detected too late, often after they metastasize and people develop symptoms. Only five cancer types have recommended standard screenings, none of which involve blood testsâbreast, cervical, colorectal, lung (smokers considered at risk) and prostate cancers, says Trish Rowland, vice president of corporate communications at GRAIL, a biotechnology company in Menlo Park, Calif., which developed a multi-cancer early detection blood test.
These recommended screenings check for individual cancers rather than looking for any form of cancer someone may have. The devil lies in the fact that cancers without widespread screening recommendations represent the vast majority of cancer diagnoses and most cancer deaths.
GRAILâs Galleri multi-cancer early detection test is designed to find more cancers at earlier stages by analyzing DNA shed into the bloodstream by cellsâwith as few false positives as possible, she says. The test is currently available by prescription only for those with an elevated risk of cancer. Consumers can request it from their healthcare or telemedicine provider. âGalleri can detect a shared cancer signal across more than 50 types of cancers through a simple blood draw,â Rowland says, adding that it can be integrated into annual health checks and routine blood work.
Cancer patientsâeven those with early and curable diseaseâoften have tumor cells circulating in their blood. âThese tumor cells act as a biomarker and can be used for cancer detection and diagnosis,â says Andrew Wang, a radiation oncologist and professor at the University of Texas Southwestern Medical Center in Dallas. âOur research goal is to be able to detect these tumor cells to help with cancer management.â Collaborating with Seungpyo Hong, the Milton J. Henrichs Chair and Professor at the University of Wisconsin-Madison School of Pharmacy, âwe have developed a highly sensitive assay to capture these circulating tumor cells.â
Even if the quality of a blood test is superior, finding cancer early doesnât always mean itâs absolutely best to treat it. For example, prostate cancer treatmentâs potential side effectsâthe inability to control urine or have sexâmay be worse than living with a slow-growing tumor that is unlikely to be fatal. â[The test] needs to tell me, am I going to die of that cancer? And, if I intervene, will I live longer?â says John Marshall, chief of hematology and oncology at Medstar Georgetown University Hospital in Washington, D.C.
Ajay Goel Lab
A blood test developed at the University of Texas MD Anderson Cancer Center in Houston helps predict who may benefit from lung cancer screening when it is combined with a risk model based on an individualâs smoking history, according to a study published in January in the Journal of Clinical Oncology. The personalized lung cancer risk assessment was more sensitive and specific than the 2021 and 2013 U.S. Preventive Services Task Force criteria.
The study involved participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial with a minimum of a 10 pack-year smoking history, meaning they smoked 20 cigarettes per day for ten years. If implemented, the blood test plus model would have found 9.2 percent more lung cancer cases for screening and decreased referral to screening among non-cases by 13.7 percent compared to the 2021 task force criteria, according to Oncology Times.
The conventional type of screening for lung cancer is an annual low-dose CT scan, but only a small percentage of people who are eligible will actually get these scans, says Sam Hanash, professor of clinical cancer prevention and director of MD Andersonâs Center for Global Cancer Early Detection. Such screening is not readily available in most countries.
In methodically searching for blood-based biomarkers for lung cancer screening, MD Anderson researchers developed a simple test consisting of four proteins. These proteins circulating in the blood were at high levels in individuals who had lung cancer or later developed it, Hanash says.
âThe interest in blood tests for cancer early detection has skyrocketed in the past few years,â he notes, âdue in part to advances in technology and a better understanding of cancer causation, cancer drivers and molecular changes that occur with cancer development.â
However, at the present time, none of the blood tests being considered eliminate the need for screening of eligible subjects using established methods, such as colonoscopy for colorectal cancer. Yet, Hanash says, âthey have the potential to complement these modalities.â
A recent study by researchers at the University of Pennsylvania examined how CAR-T therapy helped Doug Olson beat a cancer death sentence for over a decade - and how it could work for more people.
Soon afterward, however, his doctor revealed a possible escape route. He and some colleagues at the University of Pennsylvaniaâs Abramson Cancer Center were starting a clinical trial, he said, and Olsonâstill mostly symptom-freeâmight be a good candidate. The experimental treatment, known as CAR-T therapy, would use genetic engineering to turn his T lymphocytes (immune cells that guard against viruses and other pathogens) into a weapon against cancer.
In September 2010, technicians took some of Olsonâs T cells to a laboratory, where they were programmed with new molecular marching orders and coaxed to multiply into an army of millions. When they were ready, a nurse inserted a catheter into his neck. At the turn of a valve, his soldiers returned home, ready to do battle.
âI felt like Iâd won the lottery,â Olson says. But he was only the second person in the world to receive this âliving drug,â as the University of Pennsylvania investigators called it. No one knew how long his remission would last.
Three weeks later, Olson was slammed with a 102-degree fever, nausea, and chills. The treatment had triggered two dangerous complications: cytokine release syndrome, in which immune chemicals inflame the patientâs tissues, and tumor lysis syndrome, in which toxins from dying cancer cells overwhelm the kidneys. But the crisis passed quickly, and the CAR-T cells fought on. A month after the infusion, the doctor delivered astounding news: âWe canât find any cancer in your body.â
âI felt like Iâd won the lottery,â Olson says. But he was only the second person in the world to receive this âliving drug,â as the University of Pennsylvania investigators called it. No one knew how long his remission would last.
An Unexpected Cure
In February 2022, the same cancer researchers reported a remarkable milestone: the trialâs first two patients had survived for more than a decade. Although Olsonâs predecessorâa retired corrections officer named Bill Ludwigâdied of COVID-19 complications in early 2021, both men had remained cancer-free. And the modified immune cells continued to patrol their territory, ready to kill suspected tumor cells the moment they arose.
âWe can now conclude that CAR-T cells can actually cure patients with leukemia,â University of Pennsylvania immunologist Carl June, who spearheaded the development of the technique, told reporters. âWe thought the cells would be gone in a month or two. The fact that theyâve survived 10 years is a major surprise.â
Even before the announcement, it was clear that CAR-T therapy could win a lasting reprieve for many patients with cancers that were once a death sentence. Since the Food and Drug Administration approved Juneâs version (marketed as Kymriah) in 2017, the agency has greenlighted five more such treatments for various types of leukemia, lymphoma, and myeloma. âEvery single day, I take care of patients who would previously have been told they had no options,â says Rayne Rouce, a pediatric hematologist/oncologist at Texas Childrenâs Cancer Center. âNow we not only have a treatment option for those patients, but one that could potentially be the last therapy for their cancer that theyâll ever have to receive.â
Immunologist Carl June, middle, spearheaded development of the CAR-T therapy that gave patients Bill Ludwig, left, and Doug Olson, right, a lengthy reprieve on their terminal cancer diagnoses.
Penn Medicine
Yet the CAR-T approach doesnât help everyone. So far, it has only shown success for blood cancersâand for those, the overall remission rate is 30 to 40 percent. âWhen it works, it works extraordinarily well,â says Olsonâs former doctor, David Porter, director of Pennâs blood and bone marrow transplant program. âItâs important to know why it works, but itâs equally important to know why it doesnâtâand how we can fix that.â
The teamâs study, published in the journal Nature, offers a wealth of data on what worked for these two patients. It may also hold clues for how to make the therapy effective for more people.
Building a Better T Cell
Carl June didnât set out to cure cancer, but his serendipitous career pathâand a personal tragedyâhelped him achieve insights that had eluded other researchers. In 1971, hoping to avoid combat in Vietnam, he applied to the U.S. Naval Academy in Annapolis, Maryland. June showed a knack for biology, so the Navy sent him on to Baylor College of Medicine. He fell in love with immunology during a fellowship researching malaria vaccines in Switzerland. Later, the Navy deployed him to the Fred Hutchinson Cancer Research Center in Seattle to study bone marrow transplantation.
There, June became part of the first research team to learn how to culture T cells efficiently in a lab. After moving on to the National Naval Medical Center in the â80s, he used that knowledge to combat the newly emerging AIDS epidemic. HIV, the virus that causes the disease, invades T cells and eventually destroys them. June and his post-doc Bruce Levine developed a method to restore patientsâ depleted cell populations, using tiny magnetic beads to deliver growth-stimulating proteins. Infused into the body, the new T cells effectively boosted immune function.
In 1999, after leaving the Navy, June joined the University of Pennsylvania. His wife, whoâd been diagnosed with ovarian cancer, died two years later, leaving three young children. âI had not known what it was like to be on the other side of the bed,â he recalls. Watching her suffer through grueling but futile chemotherapy, followed by an unsuccessful bone-marrow transplant, he resolved to focus on finding better cancer treatments. He started with leukemiaâa family of diseases in which mutant white blood cells proliferate in the marrow.
Cancer is highly skilled at slipping through the immune systemâs defenses. T cells, for example, detect pathogens by latching onto them with receptors designed to recognize foreign proteins. Leukemia cells evade detection, in part, by masquerading as normal white blood cellsâthat is, as part of the immune system itself.
June planned to use a viral vector no one had tried before: HIV.
To June, chimeric antigen receptor (CAR) T cells looked like a promising tool for unmasking and destroying the impostors. Developed in the early â90s, these cells could be programmed to identify a target protein, and to kill any pathogen that displayed it. To do the programming, you spliced together snippets of DNA and inserted them into a disabled virus. Next, you removed some of the patientâs T cells and infected them with the virus, which genetically hijacked its new hostsâinstructing them to find and slay the patientâs particular type of cancer cells. When the T cells multiplied, their descendants carried the new genetic code. You then infused those modified cells into the patient, where they went to war against their designated enemy.
Or thatâs what happened in theory. Many scientists had tried to develop therapies using CAR-T cells, but none had succeeded. Although the technique worked in lab animals, the cells either died out or lost their potency in humans.
But June had the advantage of his years nurturing T cells for AIDS patients, as well as the technology heâd developed with Levine (whoâd followed him to Penn with other team members). He also planned to use a viral vector no one had tried before: HIV, which had evolved to thrive in human T cells and could be altered to avoid causing disease. By the summer of 2010, he was ready to test CAR-T therapy against chronic lymphocytic leukemia (CLL), the most common form of the disease in adults.
Three patients signed up for the trial, including Doug Olson and Bill Ludwig. A portion of each manâs T cells were reprogrammed to detect a protein found only on B lymphocytes, the type of white blood cells affected by CLL. Their genetic instructions ordered them to destroy any cell carrying the protein, known as CD19, and to multiply whenever they encountered one. This meant the patients would forfeit all their B cells, not just cancerous onesâbut regular injections of gamma globulins (a cocktail of antibodies) would make up for the loss.
After being infused with the CAR-T cells, all three men suffered high fevers and potentially life-threatening inflammation, but all pulled through without lasting damage. The third patient experienced a partial remission and survived for eight months. Olson and Ludwig were cured.
Learning What Works
Since those first infusions, researchers have developed reliable ways to prevent or treat the side effects of CAR-T therapy, greatly reducing its risks. Theyâve also been experimenting with combination therapiesâpairing CAR-T with chemo, cancer vaccines, and immunotherapy drugs called checkpoint inhibitorsâto improve its success rate. But CAR-T cells are still ineffective for at least 60 percent of blood cancer patients. And they remain in the experimental stage for solid tumors (including pancreatic cancer, mesothelioma, and glioblastoma), whose greater complexity make them harder to attack.
The new Nature study offers clues that could fuel further advances. The Penn team âprofiled these cells at a level where we can almost say, âThese are the characteristics that a T cell would need to survive 10 years,ââ says Rouce, the physician at Texas Childrenâs Cancer Center.
One surprising finding involves how CAR-T cells change in the body over time. At first, those that Olson and Ludwig received showed the hallmarks of âkillerâ T-cells (also known as CD8 cells)âhighly active lymphocytes bent on exterminating every tumor cell in sight. After several months, however, the population shifted toward âhelperâ T-cells (or CD4s), which aid in forming long-term immune memory but are normally incapable of direct aggression. Over the years, the numbers swung back and forth, until only helper cells remained. Those cells showed markers suggesting they were too exhausted to functionâbut in the lab, they were able not only to recognize but to destroy cancer cells.
June and his team suspect that those tired-looking helper cells had enough oomph to kill off any B cells Olson and Ludwig made, keeping the pairâs cancers permanently at bay. If so, that could prompt new approaches to selecting cells for CAR-T therapy. Maybe starting with a mix of cell typesânot only CD8s, but CD4s and other varietiesâwould work better than using CD8s alone. Or perhaps inducing changes in cell populations at different times would help.
Another potential avenue for improvement is starting with healthier cells. Evidence from this and other trials hints that patients whose T cells are more robust to begin with respond better when their cells are used in CAR-T therapy. The Penn team recently completed a clinical trial in which CLL patients were treated with ibrutinibâa drug that enhances T-cell functionâbefore their CAR-T cells were manufactured. The response rate, says David Porter, was âvery high,â with most patients remaining cancer-free a year after being infused with the souped-up cells.
Such approaches, he adds, are essential to achieving the next phase in CAR-T therapy: âGetting it to work not just in more people, but in everybody.â
Doug Olson enjoys nature - and having a future.
Penn Medicine
To grasp what that could mean, it helps to talk with Doug Olson, whoâs now 75. In the years since his infusion, he has watched his four children forge careers, and his grandkids reach their teens. He has built a business and enjoyed the rewards of semi-retirement. Heâs done volunteer and advocacy work for cancer patients, run half-marathons, sailed the Caribbean, and ridden his bike along the sun-dappled roads of Silicon Valley, his current home.
And in his spare moments, he has just sat there feeling grateful. âYou donât really appreciate the effect of having a lethal disease until itâs not there anymore,â he says. âThe world looks different when you have a future.â
This article was first published on Leaps.org on March 24, 2022.