blood cancer treatment research paper

Blood Cancers and Research Progress

LLS has invested over $1.5 billion in cancer research since our founding in 1949, leading to nearly every advancement in blood cancer treatment and breakthroughs in immunotherapy, genomics and personalized medicine.

Our support of pioneering research at nearly 100 medical institutions worldwide is breaking new ground in the fight against cancer.

Image source: the LLS Annual Report

See our impact across all the disease areas we fund:

Leukemia Research Funded by LLS

Nearly every breakthrough in cancer treatment has emerged from our support of leukemia research, from chemotherapy to groundbreaking CAR T-cell immunotherapy. With more than $65 million committed to leukemia research, we are leading the way to cures.

Lymphoma Research Funded by LLS

Our investment in lymphoma research has led to significant advances, such as rituximab (Rituxan®) and innovative immunotherapy, such as the first first chimeric antigen receptor (CAR) T-cell-therapy approved by the FDA for lymphoma patients: axicabtagene ciloleucel (Yescarta®). Our current lymphoma research commitment exceeds $73 million, so we can continue to bring promising new treatments to patients.

Multiple Myeloma Research Funded by LLS

LLS is a leading funder of visionary myeloma research, and this investment has led to many approved therapies for patients in recent years. While progress has been made, our work continues. We have committed more than $31 million to myeloma research to find cures.

Myelodysplastic Syndrome (MDS) Research Funded by LLS

We are supporting advanced genomics and molecular research to understand the causes of MDS and improve diagnosis and treatment. LLS is funding nearly 30 active grants in MDS research worldwide.

Myeloproliferative Neoplasms (MPN) Research Funded by LLS

LLS is collaborating with the MPN Research Foundation to develop therapies for polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) – the group of blood cancers collectively known as myeloproliferative neoplasms.

Automated Diagnosis and Detection of Blood Cancer Using Deep Learning-Based Approaches: A Recent Study and Challenges

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Treatment Research

In a new study in mice, researchers showed they could enhance radiation therapy by boosting levels of the BAMBI protein in MDSC immune cells in the tumor microenvironment. After radiation, T cells flooded into the tumor and killed tumors elsewhere in the body.

In a clinical trial, people being treated for cancer who participated in virtual mind–body fitness classes were less likely to be hospitalized, and had shorter stays when they were hospitalized, than people who did not take the classes.

NCI’s James H. Doroshow, M.D., reflects on the accomplishments of NCI-MATCH, a first-of-its-kind precision medicine cancer trial, and gives an overview of three new successor trials: ComboMATCH, MyeloMATCH, and iMATCH.

A new study, conducted largely in mice, may help explain why a currently used molecular marker—called mismatch repair deficiency—doesn’t always work to predict which patients will respond to immunotherapies called immune checkpoint inhibitors.

New approach may increase the effectiveness of T-cell-based immunotherapy treatments against solid tumors.

A cancer-infecting virus engineered to tamp down a tumor’s ability to suppress the immune system shrank tumors in mice, a new study shows. The modified oncolytic virus worked even better when used along with an immune checkpoint inhibitor.

Despite recommendations, a new analysis shows few people with cancer undergo germline testing to learn if their cancer may have been caused by gene changes inherited from a parent. Germline testing can help doctors determine the best treatments for a patient and help identify people whose family members may be at higher risk of cancer.

ComboMATCH will consist of numerous phase 2 cancer treatment trials that aim to identify promising drug combinations that can advance to larger, more definitive clinical trials.

A new study has compared three formulations of an mRNA vaccine designed to treat cancers caused by human papillomavirus (HPV) infections. All three vaccines showed promise in mice.

Researchers have identified a mechanism by which cancer cells develop specific genetic changes needed to become resistant to targeted therapies. They also showed that this process, called non-homologous end-joining (NHEJ), can potentially be disrupted.

For some people with cancer, is 6 months of immunotherapy the only treatment they might ever need? Or 4 weeks of immunotherapy followed by minor surgery? Results from several small clinical trials suggest these scenarios may be bona fide possibilities.

Two research teams have developed ways of overcoming barriers that have limited the effectiveness of CAR T-cell therapies, including engineering ways to potentially make them effective against solid tumors like pancreatic cancer and melanoma.

In people with cancer treated with immune checkpoint inhibitors, a rare, but often fatal, side effect is inflammation in the heart, called myocarditis. Researchers have now identified a potential chief cause of this problem: T cells attacking a protein in heart cells called α-myosin.

Researchers have modified a chemo drug, once abandoned because it caused serious gut side effects, so that it is only triggered in tumors but not normal tissues. After promising results in mice, the drug, DRP-104, is now being tested in a clinical trial.

Two research teams have developed a treatment approach that could potentially enable KRAS-targeted drugs—and perhaps other targeted cancer drugs—flag cancer cells for the immune system. In lab studies, the teams paired these targeted drugs with experimental antibody drugs that helped the immune system mount an attack.

Inflammation is considered a hallmark of cancer. Researchers hope to learn more about whether people with cancer might benefit from treatments that target inflammation around tumors. Some early studies have yielded promising results and more are on the horizon.

NCI researchers are developing an immunotherapy that involves injecting protein bits from cytomegalovirus (CMV) into tumors. The proteins coat the tumor, causing immune cells to attack. In mice, the treatment shrank tumors and kept them from returning.

FDA has approved the combination of the targeted drugs dabrafenib (Tafinlar) and trametinib (Mekinist) for nearly any type of advanced solid tumor with a specific mutation in the BRAF gene. Data from the NCI-MATCH trial informed the approval.

People with cancer who take immunotherapy drugs often develop skin side effects, including itching and painful rashes. New research in mice suggests these side effects may be caused by the immune system attacking new bacterial colonies on the skin.

Researchers have developed tiny “drug factories” that produce an immune-boosting molecule and can be implanted near tumors. The pinhead-sized beads eliminated tumors in mice with ovarian and colorectal cancer and will soon be tested in human studies.

Women are more likely than men to experience severe side effects from cancer treatments such as chemotherapy, targeted therapy, and immunotherapy, a new study finds. Researchers hope the findings will increase awareness of the problem and help guide patient care.

Research to improve CAR T-cell therapy is progressing rapidly. Researchers are working to expand its use to treat more types of cancer and better understand and manage its side effects. Learn how CAR T-cell therapy works, which cancers it’s used to treat, and current research efforts.

Experts say studies are needed on how to best transition telehealth from a temporary solution during the pandemic to a permanent part of cancer care that’s accessible to all who need it.

Removing immune cells called naive T cells from donated stem cells before they are transplanted may prevent chronic graft-versus-host disease (GVHD) in people with leukemia, a new study reports. The procedure did not appear to increase the likelihood of patients’ cancer returning.

A specific form of the HLA gene, HLA-A*03, may make immune checkpoint inhibitors less effective for some people with cancer, according to an NCI-led study. If additional studies confirm the finding, it could help guide the use of these commonly used drugs.

The success of mRNA vaccines for COVID-19 could help accelerate research on using mRNA vaccine technology to treat cancer, including the development of personalized cancer vaccines.

Aneuploidy—when cells have too many or too few chromosomes—is common in cancer cells, but scientists didn’t know why. Two new studies suggest that aneuploidy helps the cells survive treatments like chemotherapy and targeted therapies.

New research suggests that fungi in the gut may affect how tumors respond to cancer treatments. In mice, when bacteria were eliminated with antibiotics, fungi filled the void and impaired the immune response after radiation therapy, the study found.

FDA has approved belumosudil (Rezurock) for the treatment of chronic graft-versus-host disease (GVHD). The approval covers the use of belumosudil for people 12 years and older who have already tried at least two other therapies.

In lab studies, the antibiotic novobiocin showed promise as a treatment for cancers that have become resistant to PARP inhibitors. The drug, which inhibits a protein called DNA polymerase theta, will be tested in NCI-supported clinical trials.

A drug called avasopasem manganese, which has been found to protect normal tissues from radiation therapy, can also make cancer cells more vulnerable to radiation treatment, a new study in mice suggests.

While doctors are familiar with the short-term side effects of immune checkpoint inhibitors, less is known about potential long-term side effects. A new study details the chronic side effects of these drugs in people who received them as part of treatment for melanoma.

Cholesterol-lowering drugs known as PCSK9 inhibitors may improve the effectiveness of cancer immune checkpoint inhibitors, according to studies in mice. The drugs appear to improve the immunotherapy drugs’ ability to find tumors and slow their growth.

Researchers have developed a nanoparticle that trains immune cells to attack cancer. According to the NCI-funded study, the nanoparticle slowed the growth of melanoma in mice and was more effective when combined with an immune checkpoint inhibitor.

A comprehensive analysis of patients with cancer who had exceptional responses to therapy has revealed molecular changes in the patients’ tumors that may explain some of the exceptional responses.

Researchers are developing a new class of cancer drugs called radiopharmaceuticals, which deliver radiation therapy directly and specifically to cancer cells. This Cancer Currents story explores the research on these emerging therapies.

FDA has recently approved two blood tests, known as liquid biopsies, that gather genetic information to help inform treatment decisions for people with cancer. This Cancer Currents story explores how the tests are used and who can get the tests.

Cancer cells with a genetic feature called microsatellite instability-high (MSI-high) depend on the enzyme WRN to survive. A new NCI study explains why and reinforces the idea of targeting WRN as a treatment approach for MSI-high cancer.

Efforts to contain the opioid epidemic may be preventing people with cancer from receiving appropriate prescriptions for opioids to manage their cancer pain, according to a new study of oncologists’ opioid prescribing patterns.

The gene-editing tool CRISPR is changing the way scientists study cancer, and may change how cancer is treated. This in-depth blog post describes how this revolutionary technology is being used to better understand cancer and create new treatments.

FDA’s approval of pembrolizumab (Keytruda) to treat people whose cancer is tumor mutational burden-high highlights the importance of genomic testing to guide treatment, including for children with cancer, according to NCI Director Dr. Ned Sharpless.

Patients with acute graft-versus-host disease (GVHD) that does not respond to steroid therapy are more likely to respond to the drug ruxolitinib (Jakafi) than other available treatments, results from a large clinical trial show.

NCI is developing the capability to produce cellular therapies, like CAR T cells, to be tested in cancer clinical trials at multiple hospital sites. Few laboratories and centers have the capability to make CAR T cells, which has limited the ability to test them more broadly.

An experimental drug may help prevent the chemotherapy drug doxorubicin from harming the heart and does so without interfering with doxorubicin’s ability to kill cancer cells, according to a study in mice.

In people with blood cancers, the health of their gut microbiome appears to affect the risk of dying after receiving an allogeneic hematopoietic stem cell transplant, according to an NCI-funded study conducted at four hospitals across the globe.

A novel approach to analyzing tumors may bring precision cancer medicine to more patients. A study showed the approach, which analyzes gene expression using tumor RNA, could accurately predict whether patients had responded to treatment with targeted therapy or immunotherapy.

Bone loss associated with chemotherapy appears to be induced by cells that stop dividing but do not die, a recent study in mice suggests. The researchers tested drugs that could block signals from these senescent cells and reverse bone loss in mice.

Some experts believe that proton therapy is safer than traditional radiation, but research has been limited. A new observational study compared the safety and effectiveness of proton therapy and traditional radiation in adults with advanced cancer.

In people with cancer, the abscopal effect occurs when radiation—or another type of localized therapy—shrinks a targeted tumor but also causes untreated tumors in the body to shrink. Researchers are trying to better understand this phenomenon and take advantage of it to improve cancer therapy.

An experimental drug, AMG 510, that targets mutated forms of the KRAS protein completely shrank tumors in cancer mouse models and data from a small clinical trial show that it appears to be active against different cancer types with a KRAS mutation.

Researchers have engineered an oncolytic virus to kill cancer cells and boost the immune response against tumors. In a new study, the virus provided T cells around tumors with a hormone they need for their own cell-killing functions.

FDA has approved entrectinib (Rozlytrek) for the treatment of children and adults with tumors bearing an NTRK gene fusion. The approval also covers adults with non-small cell lung cancer harboring a ROS1 gene fusion.

A new NCI-supported study showed that altering cancer cell metabolism by feeding mice a diet very low in the nutrient methionine improved the ability of chemotherapy and radiation therapy to shrink tumors.

An NCI-funded clinical trial is testing the immunotherapy drug nivolumab (Opdivo) in people who have advanced cancer and an autoimmune disease, such as rheumatoid arthritis, lupus, or multiple sclerosis, who are often excluded from such trials.

Researchers have identified a protein called CD24 that may be a new target for cancer immunotherapy. The protein is a ‘don’t eat me’ signal that prevents immune cells called macrophages from engulfing and eating cells.

Injecting cells undergoing necroptosis, a form of cell death, into tumors in mice kickstarted an immune response against the tumors, researchers have found. When combined with immunotherapy, the treatment was effective at eliminating tumors in mice.

Researchers have identified proteins that may play a central role in transforming T cells from powerful destroyers to depleted bystanders that can no longer harm cancer cells. The findings could lead to strategies for boosting cancer immunotherapies.

Did you know that NCI supports clinical trials of new treatments for pet dogs with cancer? Learn more about NCI’s comparative oncology studies and how they may also help people with cancer.

Researchers have discovered a potential way to turn on one of the most commonly silenced tumor-suppressor proteins in cancer, called PTEN. They also found a natural compound, I3C, that in lab studies could flip the on switch.

New findings from a clinical trial suggest that a single dose of radiation therapy may control painful bone metastases as effectively as multiple lower doses of radiation therapy.

The expanding use of cancer immunotherapy has revealed a variety of side effects associated with this treatment approach. Researchers are now trying to better understand how and why these side effects occur and develop strategies for better managing them.

The investigational immunotherapy drug bintrafusp alfa (also called M7824), a bifunctional fusion protein, shrank the tumors of some patients with advanced HPV-related cancers, according to results from a phase 1 clinical trial.

A new study provides insight into how cancer immunotherapy works and suggests ways to enhance the treatment’s effectiveness. The NCI-led study, published in Science, examined the effect of high potassium levels on T cells.

Pain is a common and much-feared symptom among people with cancer and long-term survivors. As more people survive cancer for longer periods, there is a renewed interest in developing new, nonaddictive approaches for managing their chronic pain.

• Medical Xpress
• Tech Xplore

Using open research tools to uncover a new therapeutic target for an aggressive blood cancer

Dr. Maria Teresa Esposito, Senior Lecturer in Biochemistry, and her team of researchers have been embracing the principles of open research and using open methods, data, and tools to support the discovery of a new therapeutic target for an aggressive form of leukemia.

Despite the establishment of national biobanks, for academics, having access to a big collection of well- annotated human biological samples can be very challenging, especially when studying rare diseases.

These samples are very important as they provide a tremendous resource to unravel the origin of a disease as well as to identify and validate new diagnostic biomarkers and therapeutic targets.

We used publicly available datasets and bioinformatic tools to validate the clinical relevance of an oncogene, called SET, in the prognosis of a blood cancer known as KMT2A-rearranged (KMT2A-r) leukemia, that represents a particularly aggressive subtype of acute myeloid leukemia (AML).

The analysis of some of these datasets was done using various pieces of software. Some of them are freely available and user-friendly, whereas others required a dedicated bioinformatician and computer power that we did not have in our team. We established a collaboration with a group of bioinformaticians to overcome this issue.

The clinical data we accessed were fundamental to validate the role of SET in AML and to make important new discoveries regarding its role in KMT2A-r leukemia. We confirmed that SET is over-expressed in AML patients and that its expression correlates with poor prognosis.

In addition, we discovered, that the expression of SET correlates with the expression of genes that characterize the "molecular signature" of KMT2A-r leukemia, prompting us to further investigate SET in our laboratory models of KMt2A-r leukemia.

Overall, the results of this research indicate that SET is required for the survival of KMT2A-r leukemia cells and that SET could be a novel therapeutic target for this disease.

We made our own datasets, generated as part of this project, freely available through the platform NCBI (National Center for Biotechnological Information) and PRIDE (Proteomics Identification Database EMBL-EBI), with the aim to increase transparency in research process and methodology and enable other researchers to benefit from our data.

We made the preprint manuscript publicly available on Research Square and then we published the final version of the paper open access in the journal Oncogene to disseminate our results widely and to increase collaboration opportunities.

Since then, we have established new collaborations with researchers in China and U.S. and engaged in conversations with pharma industries with the aim to pursue SET as a new therapeutic target for KMT2A-r leukemia. We hope that this research will eventually lead to new treatment options for patients affected by this disease.

To conclude, we have learnt that:

• Open research allows to address research challenges, such as access to gene expression profiles and prognostic data of patients, that might not be manageable otherwise.
• Analyzing and validating publicly available datasets contributes to making research more reproducible.
• Open research practices create opportunities for new interdisciplinary collaborations, both with academics and with industry, that could increase the societal impact of research.

More information: Antonella Di Mambro et al, SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML, Oncogene (2023). DOI: 10.1038/s41388-023-02840-1

Provided by University of Surrey

Patients Over 80 Still Benefit From Treatment for AML Blood Cancer

By Dennis Thompson HealthDay Reporter

TUESDAY, May 14, 2024 (HealthDay News) -- Seniors over 80 with acute myeloid leukemia can safely and effectively take the standard targeted therapy for the blood cancer, a new study finds.

The oral drug venetoclax is typically given to older AML patients whose bodies can’t handle the rigors of chemotherapy. The drug targets a protein in cancer cells that helps them live longer than they should.

It’s often combined with a hypomethylating agent that boosts the body’s cancer-fighting abilities, to form a combo therapy called VEN-HMA.

“Our study reveals that a significant portion of these patients at the extremes of older age still derive benefit from the VEN-HMA regimen -- which is the standard of care for older AML patients and those who are ineligible to receive intensive chemotherapy,” said researcher Dr. Justin Watts , a hematologist with the University of Miami's Sylvester Comprehensive Cancer Center.

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“While acknowledging it certainly isn’t for everyone, we hope our findings encourage health care providers to thoughtfully explore all treatment avenues for elderly patients with AML, rather than prematurely resorting to HMA alone, best supportive care or hospice care,” Watts added in a university news release.

Acute myeloid leukemia starts in the bone marrow, and most often quickly moves into the blood, the American Cancer Society says. From there, it spreads aggressively to other parts of the body.

For the study, researchers analyzed electronic medical records from 154 patients with AML treated with VEN-HMA between March 2015 and April 2022 at six hospitals in the United States and Italy.

The average age of the patients was 82. About 77% had been newly diagnosed with AML while 10% had relapsed or hard-to-treat AML.

About 20% to 25% of all treated patients experienced prolonged survival, which encompassed roughly 40% of those who responded to the treatment.

Average overall survival for patients who responded to the treatment was 13.2 months, compared to an average 8.1 months across the entire group, researchers found.

At about eight months follow-up, 23% of patients remained in remission, while 20% were still receiving treatment, researchers said.

Death rates within 30 and 60 days of treatment were 8.5% and 17%, comparable to earlier clinical trials with the combination therapy, researchers said.

This treatment can reduce the bone marrow’s ability to produce healthy blood cells and weaken the immune system, researchers noted.

Because of this, they suggest reducing the dosage and duration of treatment for some.

"Unlike typical adult AML cases, these patients exhibit lower tolerance to venetoclax, suggesting that they may benefit from a reduced dosage,” Watts said.

The new study was published May 9 in the journal Blood Neoplasia .

More information

The American Cancer Society has more on acute myeloid leukemia .

SOURCE: American Society of Hematology, news release, May 9, 2024

Copyright © 2024 HealthDay . All rights reserved.

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Clinical trials: A significant part of cancer care

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By Mayo Clinic staff

A cancer diagnosis is an emotional experience. Learning that you have cancer can create feelings of hopelessness, fear and sadness. This is especially true if your cancer is advanced or available treatments are unable to stop or slow its growth.

"Often, when patients are diagnosed with cancer , they feel hopeless and scared. Clinical trials are one way patients can be proactive. They can make a choice in how their care is going to be," says Matthew Block, M.D., Ph.D. , a Mayo Clinic medical oncologist.

Cancer clinical trials help physician-scientists test new and better ways to control and treat cancer. During a clinical trial, participants receive specific interventions, and researchers determine if those interventions are safe and effective. Interventions studied in clinical trials might be new cancer drugs or new combinations of drugs, new medical procedures, new surgical techniques or devices, new ways to use existing treatments, and lifestyle or behavior changes.

Clinical trials provide access to potential treatments under investigation, giving options to people who otherwise may face limited choices. "Clinical trials open the door to a new hope that maybe we can fight their cancer back and give them a better quality of life," says Geoffrey Johnson, M.D., Ph.D. , a Mayo Clinic radiologist, nuclear medicine specialist and co-chair of the Mayo Clinic Comprehensive Cancer Center Experimental and Novel Therapeutics Disease Group.

You will receive cancer treatment if you participate in a clinical trial. "I think one common misperception about clinical trials is that if you enter a clinical trial, you may not get treatment (receive a placebo). And that's actually very much not true. Most clinical trials are looking at one treatment compared to another treatment," says Judy C. Boughey, M.D. , a Mayo Clinic surgical oncologist, chair of Breast and Melanoma Surgical Oncology at Mayo Clinic in Rochester, Minnesota, and chair of the Mayo Clinic Comprehensive Cancer Center Breast Cancer Disease Group.

"I think one common misperception about clinical trials is that if you enter a clinical trial, you may not get treatment (receive a placebo). And that's actually very much not true. Most clinical trials are looking at one treatment compared to another treatment." Judy C. Boughey, M.D.

Watch this video to hear the experiences of people who have participated in cancer clinical trials and to hear Drs. Block, Johnson and Boughey discuss the importance of clinical trials in cancer care:

Clinical trials are a significant part of cancer care at Mayo Clinic Comprehensive Cancer Center. Cancer care teams work together across specialties to make sure the right clinical trials are available to serve the needs of people with cancer who come to Mayo Clinic.

"We are very particular in how we select the clinical trials that we have available for patients," says Dr. Boughey. "We want to have the best trials available for our patients. Some of the clinical trials are evaluating drugs — we are so excited about those drugs, but we can't prescribe those drugs for patients without having that trial. And so we will actually fight to try to get that trial open here to have it available as an opportunity for our patients."

If you choose to participate in a clinical trial, you will continue to receive cancer care. "For most patients that we evaluate, there's always the standard of care treatment option for those patients. And then, in many situations, there's also a clinical trial that the patient can participate in," says Dr. Boughey.

People who participate in clinical trials help make new and better cancer care available for future patients. The treatments available for cancer patients today exist because of the clinical trial participants of yesterday. "We couldn't advance medicine if it wasn't for people volunteering for trials. And the promise from our side is to say we're not going to put patients on trials or offer trials for them to consider unless we think there's a good chance that they'll get a benefit or that society at large will get a benefit," says Dr. Johnson.

"We couldn't advance medicine if it wasn't for people volunteering for trials. And the promise from our side is to say we're not going to put patients on trials or offer trials for them to consider unless we think there's a good chance that they'll get a benefit or that society at large will get a benefit." Geoffrey Johnson, M.D., Ph.D.

Participating in a clinical trial may give you access to cutting-edge treatment, improve your quality of life and extend your time with loved ones.

"It's definitely worth reaching out to your healthcare provider and asking, 'What clinical trials could I be a potential candidate for?'" says Dr. Boughey. "And remember, you can ask this of your surgical oncologist, your medical oncologist, your radiation oncologist, or any of the physicians you're seeing because there are trials in all disciplines. There are also ongoing trials that require the collection of tissue or the donation of blood. They can also be important in trying to help future generations as we continue to work to end cancer."

Participating in a clinical trial is an important decision with potential risks and benefits. Explore these FAQ about cancer clinical trials, and ask your care team if a clinical trial might be right for you.

Learn more about cancer clinical trials and find a clinical trial at Mayo Clinic.

Join the Cancer Support Group on Mayo Clinic Connect , an online community moderated by Mayo Clinic for patients and caregivers.

Read these articles about people who have participated in clinical trials at Mayo Clinic:

• A silent tumor, precancerous polyps and the power of genetic screening
• Mayo Clinic’s DNA study reveals BRCA1 mutations in 3 sisters, prompts life-changing decisions

Read more articles about Mayo Clinic cancer research made possible by people participating in clinical trials.

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Drs. Terry Burns and Alfredo Quiñones-Hinojosa discuss brain tumors called gliomas and the hope being offered by new technology and clinical trials.

Dr. Sujay Vora is studying a new approach to glioblastoma treatment that is improving health outcomes and quality of life for elderly people like Richard Casper.

Dr. S. John Weroha discusses new treatments and research that are helping more people survive ovarian cancer.

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Warning signs in blood could be used to predict cancer seven years earlier, scientists find

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Warning signs in the blood could predict cancer up to seven years before diagnosis and give hope for new preventative drugs , studies have found.

Scientists have discovered proteins in the blood which are linked to the development of dozens of different types of cancer, including the biggest killers such as breast and lung cancer .

Two studies by the University of Oxford, funded by Cancer Research UK, analysed proteins in the blood samples of tens of thousands of people and looked at genetic data for hundreds of thousands of cancer cases. These included blood samples taken from people seven years before they received a cancer diagnosis.

Dr Karl Smith-Byrne, senior molecular epidemiologist at Oxford Population Health and an author in both studies, said: “This research brings us closer to being able to prevent cancer with targeted drugs – once thought impossible but now much more attainable.”

Researchers indicated the results provide insight into how cancer starts and grows, but said further research would be needed to find out the exact role the proteins play and what tests could be developed to detect them.

In the first study blood samples from more than 44,000 people were analysed, including 4,900 who subsequently had a cancer diagnosis. In the second study scientists looked at data from 300,000 people with cancer to look at which proteins were linked to the development of the disease, and could be targeted by specific treatments .

Researchers believe some of the proteins found could be used to detect cancer much earlier than is currently possible and could be used to develop earlier-stage treatments or even prevent the disease altogether.

Cancers linked to the proteins found included breast, lung, ovary, bladder and skin cancer.

Dr Joshua Atkins, senior genomic epidemiologist at Oxford Population Health and joint first author of the first study, said: “The genes we are born with, and the proteins made from them, are hugely influential in how cancer starts and grows. Thanks to the thousands of people who gave blood samples to UK BioBank, we are building a much more comprehensive picture of how genes influence cancer development over many years.”

In the first study, the team of researchers compared the proteins of those who did go on to have cancer and those who didn’t to find any differences between them to identify which ones might be linked to cancer.

The second study, which looked at genetic data for more than 300,000 cases of cancer, found 40 proteins in the blood that were linked to nine different cancers.

Professor Ruth Travis, senior molecular epidemiologist at Oxford Population Health and a senior author of both studies, said : "To be able to prevent cancer, we need to understand the factors driving the earliest stages of its development. These studies are important because they provide many new clues about the causes and biology of multiple cancers, including insights into what’s happening years before a cancer is diagnosed.

​“We now have technology that can look at thousands of proteins across thousands of cancer cases, identifying which proteins have a role in the development of specific cancers, and which might have effects that are common to multiple cancer types."

Executive director of research and innovation at Cancer Research UK, Dr Iain Foulkes, said : ​ “Preventing cancer means looking out for the earliest warning signs of the disease. That means intensive, painstaking research to find the molecular signals we should pay closest attention to.

​“Discoveries from this research are the crucial first step towards offering preventative therapies which is the ultimate route for giving people longer, better lives, free from the fear of cancer.”

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• Introduction
• Conclusions
• Article Information

OS indicates overall survival; PFS, progression-free survival.

Incidence of adverse events (A), incidence of severe (grade 3-5) adverse events (B), median time to onset of adverse events (C), and median time to resolution of adverse events (D) for each age group with statistically significant differences.

HR indicates hazard ratio.

OS indicates overall survival.

a P  < .01.

b P  < .05.

eTable 1. Demographic and Clinical Characteristics of Patients With Metastatic Colorectal Cancer From Study 1 and Study 2 Stratified by Age Groups

eTable 2. The Prognostic Values of Age Groups and Other Common Demographic and Clinical Factors in Patients With Metastatic Colorectal Cancer From Study 1 and Study 2

eTable 3. Incidence (%) of Adverse Events for Each Age Group From Study 1 and Study 2

eTable 4. Median (IQR) Time to Onset (Weeks) of Adverse Events for Each Age Group From Study 1 and Study 2

eTable 5. Median (IQR) Time to Resolution (Weeks) of Adverse Events for Each Age Group From Study 1 and Study 2

eTable 6. The Prognostic Value of Adverse Events (None vs Grade 1-2 vs Grade 3-5) in Patients With Early-Onset Metastatic Colorectal Cancer From Study 1 and Study 2

eTable 7. Demographic and Clinical Characteristics of Patients With Metastatic Colorectal Cancer in the Moffitt Cancer Center Cohort Stratified by Age Groups

eTable 8. Prevalence of Common Gene Mutations in Patients With Metastatic Colorectal Cancer From the Moffitt Cancer Center Cohort Stratified by Age Groups

eMethods. Study Design and Methods of Three Clinical Trials Evaluating First-Line Treatment for Metastatic Colorectal Cancer: NCT00272051, NCT00305188, and NCT0036401

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Meng L , Thapa R , Delgado MG, et al. Association of Age With Treatment-Related Adverse Events and Survival in Patients With Metastatic Colorectal Cancer. JAMA Netw Open. 2023;6(6):e2320035. doi:10.1001/jamanetworkopen.2023.20035

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Association of Age With Treatment-Related Adverse Events and Survival in Patients With Metastatic Colorectal Cancer

• 1 Department of Hematology and Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa
• 2 Division of Medical Oncology, The Ohio State University College of Medicine, Columbus
• 3 Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
• 4 Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
• 5 Department of Personalized Cancer Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
• 6 Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota
• 7 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida

Question   Is there any difference in treatment-related adverse events and outcomes between patients with early-onset (age <50 years) and older patients with metastatic colorectal cancer (mCRC)?

Findings   In this cohort study of 1223 patients with mCRC from 3 clinical trials, early-onset mCRC had significantly worse survival and displayed unique patterns of treatment-related adverse events. Analysis in a separate Moffitt Cancer Center cohort of 736 patients noted worse overall survival in early-onset mCRC and showed distinct genomic profiles in this population, which may partially explain the disparity.

Meaning   These findings might have utility for an individualized approach to chemotherapy, counseling, and management of treatment-related adverse events in patients with early-onset mCRC.

Importance   While the incidence of early-onset metastatic colorectal cancer (mCRC) has been increasing, studies on the age-related disparity in this group of patients are limited.

Objective   To evaluate the association of age with treatment-related adverse events and survival in patients with mCRC and explore the potential underlying factors.

Design, Setting, and Participants   This cohort study included 1959 individuals. Individual data on 1223 patients with mCRC who received first-line fluorouracil and oxaliplatin therapy in 3 clinical trials, and clinical and genomic data of 736 patients with mCRC from Moffitt Cancer Center were used to assess genomic alterations and serve as an external validation cohort. All statistical analyses were conducted from October 1, 2021, through November 12, 2022.

Exposures   Metastatic colorectal cancer.

Main Outcomes and Measures   Survival outcomes and treatment-related adverse events were compared among patients in 3 age groups: younger than 50 (early onset), 50 to 65, and older than 65 years.

Results   In the total population of 1959 individuals, 1145 (58.4%) were men. Among 1223 patients from previous clinical trials, 179 (14.6%) in the younger than 50 years group, 582 (47.6%) in the 50 to 65 years group, and 462 (37.8%) in the older than 65 years group had similar baseline characteristics except for sex and race. The younger than 50 years group had significantly shorter progression-free survival (PFS) (hazard ratio [HR], 1.46; 95% CI, 1.22-1.76; P  < .001) and overall survival (OS) (HR, 1.48; 95% CI, 1.19-1.84; P  < .001) compared with the 50 to 65 years group after adjustment for sex, race, and performance status. Significantly shorter OS in the younger than 50 years group was confirmed in the Moffitt cohort. The younger than 50 years group had a significantly higher incidence of nausea and vomiting (69.3% vs 57.6% [50-65 years] vs 60.4% [>65 years]; P  = .02), severe abdominal pain (8.4% vs 3.4% vs 3.5%; P  = .02), severe anemia (6.1% vs 1.0% vs 1.5%; P  < .001), and severe rash (2.8% vs 1.2% vs 0.4% P  = .047). The younger than 50 years group also had earlier onset of nausea and vomiting (1.0 vs 2.1 vs 2.6 weeks; P  = .01), mucositis (3.6 vs 5.1 vs 5.7 weeks; P  = .05), and neutropenia (8.0 vs 9.4 vs 8.4 weeks; P  = .04), and shorter duration of mucositis (0.6 vs 0.9 vs 1.0 weeks; P  = .006). In the younger than 50 years group, severe abdominal pain and severe liver toxic effects were associated with shorter survival. The Moffitt genomic data showed that the younger than 50 years group had a higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%; P  = .047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%; P  = .005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%; P  = .05), but lower prevalence of BRAF mutation (7.7% vs 8.5% vs 16.7%; P  = .002).

Conclusions and Relevance   In this cohort study of 1959 patients, those with early-onset mCRC showed worse survival outcomes and unique adverse event patterns, which could be partially attributed to distinct genomic profiles. These findings may inform individualized management approaches in patients with early-onset mCRC.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. 1 Despite the decrease of overall incidence and mortality of CRC as a result of nationwide-adopted screening programs, 2 - 4 the incidence of the early-onset CRC (EO-CRC) in patients diagnosed with CRC before age 50 years has been increasing by 2% annually since the 1990s. 5 , 6 It is projected that by 2030 10.9% of all colon cancers and 22.9% of all rectal cancers will be diagnosed as EO-CRC. 7 , 8

Neither the etiology of increased incidence nor the distinct biology of EO-CRC compared with its older counterparts is clearly revealed. For example, inherited cancer syndromes, such as Lynch syndrome, may be more prevalent in patients with EO-CRC. However, only 5% to 7% of those with EO-CRC carry deleterious germline mutations of mismatch repair genes. 9 , 10 Previous studies examining the genomic profile of EO-CRC showed few molecular differences between EO-CRC and its older counterparts. 11 Even the few molecular differences reported were often not confirmed in other studies likely due to selection bias in different patient cohorts. 8 , 12 , 13 Some studies investigated nongenetic risk factors for CRC, such as low physical activity, excess alcohol consumption, smoking, and obesity, but the results were neither conclusive nor adequate explanations of the increased incidence of EO-CRC. 14 - 16

The increased incidence of EO-CRC poses unique challenges to the management of treatment in younger patients, especially with regard to the prognosis and treatment-related adverse events. 17 In current clinical practice, patients with EO-CRC receive similar, if not more aggressive, therapies in the advanced disease setting compared with their older counterparts. Fluoropyrimidine-based combination chemotherapy plus biologic agents remains the most common first-line therapy for patients with metastatic colorectal cancer (mCRC). 18 Triplet chemotherapy combination is an alternative for patients who are younger and have more aggressive disease and good performance status, offering a better outcome at the expense of worse toxic effects. 19 Although chemotherapy in combination with biologic agents 20 , 21 showed comparable benefit in patients with advanced CRC of all ages, 22 , 23 it is unclear whether there is disparity in treatment-related adverse events and outcome from advanced CRC between EO and its older counterparts. Previous studies suggested an increased incidence of some specific toxic effects, such as nausea and vomiting in EO-mCRC, but the data were largely limited in the adjuvant setting and findings across studies were not always in agreement. 24 - 28 Similarly, some studies reported a poorer survival in patients with advanced EO-CRC, 24 , 25 , 29 whereas others observed a similar survival outcome between patients with EO-mCRC and those with average onset. 26 - 28 , 30 , 31 These discrepancies might be due to selection bias and/or the inclusion of older patients (age >65 years) in the average-onset group for comparison.

To address this literature gap, we used individual patient data from 3 clinical trials in which patients with mCRC received first-line fluorouracil and oxaliplatin (FOLFOX) therapy and a contemporary patient cohort to compare the differences of treatment outcome and adverse events among 3 different age groups of patients with mCRC.

We used individual patient data from 3 multicenter randomized phase 3 clinical trials in the Project Data Sphere, which were divided into study 1 ( NCT00272051 , NCT 00305188 ) and study 2 ( NCT00364013 ). Study 1 assessed the efficacy of xaliproden in reducing (NCT00272051) or preventing (NCT 00305188) the neurotoxic effects of FOLFOX as first-line treatment for patients with mCRC. Study 2 evaluated the efficacy of panitumumab combined with FOLFOX as first-line therapy for patients with mCRC. Only patient data from the control (FOLFOX only) arms of the 3 clinical trials were combined and used in our study. Study design, inclusion and exclusion criteria, interventions, end points, adverse events, and outcomes of the 3 clinical trials have been previously reported 23 , 32 - 35 and are briefly described in the eMethods in Supplement 1 . Given these patients were treated in a clinical trial setting before 2010, we included a contemporary patient population as an external validation cohort for overall survival (OS). Patients of this cohort were identified from the prospectively maintained Moffitt Clinical Genomic Action Committee Database and CARIS clinical database. These include patients diagnosed with mCRC and treated at Moffitt Cancer Center (MCC) from 2006 to 2022 and have available clinical and next-generation sequencing (NGS) data. Clinical NGS data were provided by common commercially available platforms, including FoundationOne, FoundationOne ACT, FoundationOne CDx, CARIS, and Guardant360, along with an in-house NGS assay called Moffitt STAR. These platforms have been described in depth elsewhere. 36 - 38 The patient data from the 3 clinical trials were deidentified and sourced from a central, password-protected database managed by Project Data Sphere. Access to these data for research purposes was granted by the Project Data Sphere scientific committee. The MCC Scientific Review Committee and the Institutional Review Board granted approval for the collection and analysis of data from the Moffitt Clinical Genomic Database and waived the requirement for informed consent from study participants because of the use of deidentified data. Racial information used in our research was obtained from these databases, with data including Asian, Black, White, unknown, and other. Data on races other than White were combined because of very small sample sizes. This study adhered to the reporting requirements established by the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

Overall survival was defined as the time from randomization to death. Participants who were alive at the analysis data cutoff were censored at their last contact date. Progression-free survival (PFS) was defined as the time from randomization to date of disease progression assessed radiographically per the Response Evaluation Criteria in Solid Tumors 1.0. Safety end points included incidence of any grade and grade 3 to 5 (severe) treatment-related adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, the time of their onset, and their duration. Analyses of the differences of genetic alterations among 3 age groups were exploratory.

Our statistical analysis was performed using R Statistical Software, version 4.1.2 (R Foundation for Statistical Computing) along with the survival package 3.2-13. The χ 2 test and Fisher exact test were used to test the distribution of baseline characteristics, adverse events, and NGS genomic features in the 3 groups. Continuous variables were compared with the Kruskal-Wallis test and χ 2 or Fisher exact test were performed for categorical variables. Overall survival and PFS were evaluated according to the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards regression model was used to determine the association of adverse events with OS and PFS. P values in this study were 2-sided, and P  < .05 was considered statistically significant. Pairwise comparisons adjusting for multiple testing were performed using the Benjamini and Hochberg method.

Among all 1959 patients (1145 [58.4%] men; 814 [41.6%] women) included, 1223 were from study 1 and study 2 for analyses of survival outcomes and treatment-related adverse events. A total of 736 patients were from the Moffitt cohort for assessment of OS and tumor genetic alterations. As presented in the Table , the Moffitt cohort included a significantly higher rate of patients with EO-mCRC (26.6%) compared with study 1 (15.2%) and study 2 (13.7%) ( P  < .001), but a lower prevalence of White patients (83.3%) vs those of other races and ethnicities (16.7%) ( P  < .001). Of the patients from study 1 and study 2, 179 (14.6%) were younger than 50 years, 582 (47.6%) were aged 50 to 65 years, and 462 (37.8%) were older than 65 years at the time of stage IV CRC diagnosis (eTable 1 in Supplement 1 ). There were significantly more women younger than 50 years in contrast to more men older than 65 years. Fewer White patients and more individuals of other races and ethnicities were represented in the age less than 50 years group. No significant difference of Eastern Cooperative Oncology Group (ECOG) performance status was observed among the 3 age groups (eTable 1 in Supplement 1 ).

In study 1, patients younger than 50 years had shorter median OS compared with those aged 50 to 65 and older than 65 years (15.5 vs 20.5 vs 20.8 months; P  = .003) ( Figure 1 A). Patients younger than 50 years also had shorter median PFS than that of the other 2 age groups (8.1 vs 9.4 vs 8.6 months; P  = .004) ( Figure 1 B). Similar findings were observed in study 2, as shown in Figure 1 C (median OS, 18.4 vs 22.7 vs 18.0 months; P  = .008) and in Figure 1 D (median PFS, 7.3 vs 9.3 vs 8.7 months; P  = .005). In univariate survival analysis, age younger than 50 years (<50 vs 50-65 years: hazard ratio [HR], 1.50; 95% CI, 1.21-1.85; P  < .001) and poor ECOG performance status (2 vs 0/1: HR, 2.49; 95% CI, 1.75-3.54; P  < .001) were identified as poor prognostic factors for OS in both study 1 and study 2 combined. Age younger than 50 years was noted in multivariable analysis to be an independent factor for worse OS (age <50 vs 50-65 years: HR, 1.48; 95% CI, 1.19-1.84; P  < .001) after adjustment for sex, race, and ECOG performance status. Age younger than 50 years was similarly found to be an independent factor for poor PFS (age <50 vs 50-65 years: HR, 1.46; 95% CI, 1.22-1.76; P  < .001), as reported in eTable 2 in Supplement 1 .

Examination of treatment-related adverse events of all patients from study 1 and study 2 combined revealed a unique pattern for patients younger than 50 years ( Figure 2 ). As shown in Figure 2 A, B and eTable 3 in Supplement 1 , compared with the study 1 and study 2 age groups, patients younger than 50 years had a higher incidence of nausea and vomiting (69.3% vs 57.6% 60.4%; P  = .02), severe abdominal pain (8.4% vs 3.4% vs 3.5%; P  = .02), severe anemia (6.1% vs 1.0% vs 1.5%; P  < .001), and severe rash (2.8% vs 1.2% vs 0.4%; P  = .047), but a lower incidence of fatigue (44.1% vs 46.9% vs 55.6%; P  = .005), neutropenia (38.5% vs 39.7% vs 49.8%; P  = .002), severe diarrhea (6.1% vs 9.1% vs 13.0%; P  = .02), severe fatigue (4.5% vs 5.5% vs 9.5%; P  = .02), and severe neutropenia (25.7% vs 26.5% vs 38.1%; P  < .001). Patients younger than 50 years had an earlier onset of nausea and vomiting (1.0 vs 2.1 vs 2.6 weeks; P  = .01), mucositis (3.6 vs 5.1 vs 5.7 weeks; P  = .05), and neutropenia (8.0 vs 9.4 vs 8.4 weeks; P  = .04), as shown in Figure 2 C and eTable 4 in Supplement 1 . In addition, patients younger than 50 years had a shorter duration of mucositis (0.6 vs 0.9 vs 1.0 weeks; P  = .006) as shown in Figure 2 D and eTable 5 in Supplement 1 .

As summarized in Figure 3 A and eTable 6 in Supplement 1 , severe abdominal pain (HR, 2.24; 95% CI, 1.23-4.09; P  = .008) and severe liver toxic effects (HR, 3.99; 95% CI, 0.95-16.76; P  = .06) were associated with worse OS. In contrast, moderate (grade 1/2) fatigue (HR, 0.66; 95% CI, 0.44-0.97; P  = .008), moderate mucositis (HR, 0.64; 95% CI, 0.43-0.97; P  = .04), and moderate rash (HR, 0.63; 95% CI, 0.40-1.00; P  = .049) were associated with better OS. Similarly, severe abdominal pain (HR, 2.51; 95% CI, 1.43-4.41; P  = .001) and severe liver toxic effects (HR, 2.82; 95% CI, 0.89-8.97; P  = .08) were associated with poor PFS. In contrast, severe peripheral neuropathy (HR, 0.43; 95% CI, 0.26-0.71; P  = .001) was associated with better PFS ( Figure 3 B; eTable 6 in Supplement 1 ).

As reported in eTable 7 in Supplement 1 , of the 736 patients in the MCC cohort, 196 (26.6%) were younger than 50 years, 319 (43.3%) were 50 to 65 years, and 221 (30.0%) were older than 65 years. Patients younger than 50 years were more likely to receive triplet therapy and carry a left-sided tumor, while those older than 65 years had a higher rate of patients who were White. Despite the difference of baseline characteristics between the MCC cohort and study 1 and 2 ( Table ), patients younger than 50 years consistently showed worse median OS compared with those aged 50 to 65 years and comparable median OS to those older than 65 years (39.2 vs 51.3 vs 38.0 months; P  = .02) ( Figure 4 A). Further examination of genetic alterations was performed to explore the potential underlying factors in this age-related disparity of survival outcome in patients with mCRC. As presented in Figure 4 B and eTable 8 in Supplement 1 , we found that all 3 age groups had very similar genetic alterations except that, compared with the other 2 age groups, the tumors of patients younger than 50 years had a higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%; P  = .047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%; P  = .005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%; P  = .05). Both patients younger than 50 years and those aged 50 to 65 years exhibited a lower incidence of BRAF mutation than those older than 65 years (7.7% vs 8.5% vs 16.7%; P  = .002).

A hypothesis for an increased incidence of EO-CRC despite a decrease in the overall incidence 5 , 6 was that EO-CRC may be a different disease as reflected by distinct clinicopathologic and molecular features. 5 , 39 Previous studies that attempted to investigate such age-related disparity of survival outcomes had discordant findings. Several studies found an association between younger age and worse survival, 25 , 29 , 40 , 41 whereas other studies revealed opposite findings. 24 , 26 , 27 , 30 , 42 , 43 Lieu and colleagues 29 observed younger and older ages were associated with worse survival in patients with mCRC. However, other studies showed at least comparable 26 - 28 , 30 , 31 if not better prognosis 44 in patients with EO-mCRC. To our knowledge, the present study is the first analysis of individual patient data from clinical trials and a more contemporary cohort that observed worse survival outcomes in patients with EO-mCRC. The inclusion of an external validation cohort from a different time period and with diverse baseline characteristics may have helped to enhance the reliability of our findings.

Inconsistent findings from some of the previous studies could be partially attributed to the dichotomization of patient populations with a single cutoff at age 50 years. The assumption of homogeneity of patients older than 50 years was not valid, as an abundance of literature in geriatric oncology has reported unique treatment response and outcome in patients who are very old. 45 , 46 For example, in the study of Lieu and colleagues, 29 when age was treated as a continuous variable, older age (age >65 years) was associated with worse survival, presumably due to reduced life expectancy, increased comorbidities, or inability to tolerate aggressive chemotherapy. 47 Therefore, in our study, we divided patients into 3 age groups (<50, 50-65, and >65 years). As expected, we found that patients both younger than 50 and those older than 65 years had worse OS compared with those aged 50 to 65 years. Another distinct feature of our study is that patients received the same treatment, first-line FOLFOX, to minimize possible risk modification from different treatment regimens on survival. Similar observations have been found in our contemporary patient cohort who received different treatment regimens, including triplet chemotherapy with biologic agents.

Differences in baseline characteristics could also prevent us from observing the age-related disparity of survival outcomes in previous studies. In our study, we found a higher proportion of women in patients with EO-mCRC in line with previous studies, 24 , 27 , 28 , 42 , 48 likely due to selection bias or differential genetic susceptibility. Meanwhile, consistent with previous studies, 26 , 48 a lower proportion of White patients was observed in the EO-mCRC group. Given prior studies that suggested sex and race disparity on survival, 49 we performed multivariable analysis to adjust for sex, race, and ECOG performance status, which was better at baseline in younger patients. 26

To use excellent recording of treatment-related adverse events in clinical trial data, we also compared these data among the 3 age groups and observed age-related disparity in patients with mCRC. Consistent with previous findings in the adjuvant setting, 24 - 28 our data showed an increased incidence of nausea and vomiting but a decreased incidence of diarrhea, fatigue, and neutropenia in younger patients. The previously reported potential improvement of the toxic effect profile in younger patients 27 , 50 was not entirely supported by our study, as we observed a higher incidence of severe abdominal pain, severe anemia, and severe rash in patients with EO-mCRC. These are in line with the findings from the IDEA trials, which revealed an increased incidence of severe nausea and vomiting in younger patients. 25 In addition, EO-mCRC had an earlier onset of nausea and vomiting, mucositis, and neutropenia. Hence, it is more appropriate to say that patients with EO-mCRC exhibited a unique pattern of adverse events after receiving first-line FOLFOX therapy. Moreover, the association between severe abdominal pain and severe liver toxic effects with worse survival in younger patients suggested an individualized approach to the monitoring and management of these unique treatment-related adverse events.

The age-related disparity of survival and adverse events may suggest unique underlying disease biologic factors in different age groups. Comprehensive genomic profiling in some studies noted a higher prevalence of TP53 and CTNNB1 mutations, but a lower prevalence of BRAF and APC mutations in EO-mCRC, 11 , 28 , 43 , 51 , 52 which is consistent with some findings in our study.

The CTNNB1 and CREBBP genes are involved in the Wnt/β-catenin pathway, 53 and ERBB2 amplification is involved in the MAPK/ERK pathway. 54 Thus, our study suggests that these pathways might be implicated in worse survival outcomes in EO-mCRC. However, it is still unclear whether these differential genetic alterations might partially explain the observed disparity in survival outcome given the inconsistent findings across studies and the numerically small differences in few of many genes. Therefore, further efforts should likely focus on multiomic studies to inform disease biologic factors and therapy.

This study has limitations. The 3 clinical trials took place in an era during which biologic agents had not become standard first-line therapy for patients with mCRC and clinical NGS was not used to guide treatment. These clinical trials were conducted with FOLFOX treatment before more intensive therapy, such as folinic acid, fluorouracil, oxaliplatin and irinotecan, became available. Furthermore, they did not collect information on treatment intensity, adherence, and location and number of metastases, which prevented us from adjusting for these factors in our analysis. To compensate and address these limitations intrinsic to the data used in our study, we incorporated institutional patient and clinical NGS data from the modern era, encompassing a more diverse range of patients and treatments, as an external validation cohort. Distributions of some important baseline characteristics, such as race and ethnicity, tumor sidedness, and first-line treatments in this MCC patient cohort were consistent with those previously reported. 26 , 28 , 31 , 48 However, we acknowledge a limitation in not evaluating adverse events, PFS, or conducting multivariable survival analysis in this cohort due to the following concerns: retrospective data collection, even when sourced from prospectively maintained databases, is susceptible to selection bias and inaccuracy; and the highly heterogeneous nature of this patient population concerning multiple genes, treatments, and histopathologic characteristics may lead to overfitting and nonconvergence of the multivariable model, given the relatively small sample size of this patient cohort. Consequently, we used Moffitt data solely for external validation of OS, rather than for the primary analysis. In addition, these findings may not generalize to other racial and ethnic categories given that the majority of trial participants were identified as White individuals.

In this cohort study, patients with EO-mCRC who received first-line treatment appeared to have worse survival compared with their older counterparts and experienced unique treatment-related adverse events. Distinct genomic profiles could possibly explain the disparities in EO-mCRC. These findings might improve an individualized approach to chemotherapy, counseling, and management of treatment-related adverse events in this patient population.

Accepted for Publication: May 10, 2023.

Published: June 26, 2023. doi:10.1001/jamanetworkopen.2023.20035

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 Meng L et al. JAMA Network Open .

Corresponding Author: Hao Xie, MD, PhD, Division of Medical Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905 ( [email protected] ).

Author Contributions: Drs Meng and Xie had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Meng, Ji, Hubbard, Wang, Kim, Xie.

Acquisition, analysis, or interpretation of data: Meng, Thapa, Delgado, Gomez, Knepper, Hubbard, Wang, Permuth, Laber, Xie.

Drafting of the manuscript: Meng, Thapa, Hubbard, Laber, Xie.

Critical revision of the manuscript for important intellectual content: Meng, Delgado, Gomez, Ji, Knepper, Hubbard, Wang, Permuth, Kim, Laber, Xie.

Statistical analysis: Thapa, Wang, Xie.

Obtained funding: Xie.

Administrative, technical, or material support: Knepper, Laber.

Supervision: Hubbard, Wang, Kim, Laber, Xie.

Conflict of Interest Disclosures: Dr Knepper reported receiving personal fees from AstraZeneca for serving on the advisory board outside the submitted work. Dr Kim reported receiving personal fees from Pfizer, AstraZeneca, Incyte, Roche, Eisai, GSK, and Taiho outside the submitted work. No other disclosures were reported.

Funding/Support: A Moffitt Support Grant was awarded to Dr Xie and the University of South Florida Continuing Medical Education Funding.

Role of the Funder/Sponsor: H. Lee Moffitt Cancer Center & Research Institute had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2 .

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Blood proteins could indicate cancer seven years before diagnosis

Scientists have discovered proteins in the blood that could indicate that cancer is developing up to seven years before diagnosis.

Researchers in two studies funded by Cancer Research UK identified 618 proteins linked to 19 types of cancer — including 107 proteins in blood collected seven years before the disease was found.

The scientists, from Oxford Population Health, suggest that these proteins may be involved in the earlier stages of cancer and could be used to detect it much earlier.

Dr Keren Papier, senior nutritional epidemiologist at Oxford Population Health and joint lead author of the first study, said: “To save more lives from cancer, we need to better understand what happens at the earliest stages of the disease. Data from thousands of people with

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• Published: 24 March 2021

Advancing Cancer Therapy

Nature Cancer volume  2 ,  pages 245–246 ( 2021 ) Cite this article

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Cancer therapies have evolved considerably in recent decades, substantially improving the quality of life and survival of patients with cancer. In this issue, we launch our Series on Cancer Therapy, exploring current paradigms and recent advances and challenges in this field, through specially commissioned articles.

The earliest evidence of cancer treatment can be traced back to an ancient Egyptian medical text, written around 3000 BC and known widely as the ‘Edwin Smith Papyrus’, that described the cauterization of breast tumors for which, according to the text, there was no cure . The situation is very different now, as, depending on breast cancer subtype, stage and demographic factors, the 5-year survival rates for this disease can surpass 90% in developed countries. For cancer types that are responsive to therapy, including certain subtypes of breast, blood and prostate malignancies, patients now face the management of a chronic disease, rather than a fatal one, owing to the rapid advances in clinical oncology over recent decades. Similarly, the prognosis for several other cancer types has also been improving. For example, patients with melanoma, which used to be considered a deadly disease, have much better prospects thanks to the breakthroughs in targeted and immune-based therapies.

These advances reflect the focus placed on cancer research and oncology by governments, funders and research institutes across the globe over the past several decades. In the USA, 2021 marks the 50-year anniversary of the signing of the National Cancer Act into law, which marked the beginning of a concerted effort to address cancer as a leading cause of death in the USA at the federal level. The National Cancer Program that arose from this initiative resulted in a profound institutional reorganization within the National Institutes of Health, with the overarching goal of developing the infrastructures required ‘for the treatment, cure, and elimination of cancer’. Other countries and international agencies also adopted cancer-focused initiatives over the years, including, for example, the PRIME scheme of the European Medicines Agency, which supports the development of medicines that target an unmet medical need, including cancer, through accelerated planning, evaluation and approval processes.

Thus, substantial progress has been made across first-line cancer therapy modalities. Surgery continues to be a first-line treatment for many cancer types, but it now includes precision and minimally invasive surgery, molecular imaging support and, more recently, robot- or artificial intelligence–assisted surgical procedures. The clinical use of one of the most widely used treatment modalities, chemotherapy, has been improved through better dosing regimens, neoadjuvant or adjuvant administration, and combination therapies. Similarly, radiation oncology has been advanced through precision radiotherapy. First-line recommendations depend on the cancer type and stage at diagnosis, and have continued to be modified as new therapeutic modalities have become available. The advent of targeted therapy and immunotherapy has revolutionized the treatment of cancer, especially with the development and availability of sophisticated diagnostic and molecular characterization technologies. Among these, ‘-omics’ techniques stand out for increasingly enabling a more precise and granular molecular characterization of cancer types and subtypes and the identification of biological correlates of response to specific therapies, thereby enriching the roster of biomarkers at the disposal of clinicians.

Targeted therapies have swiftly taken a prominent position in cancer research and clinical oncology in recent decades, thanks to the molecular insights into oncogenic processes and mechanisms gained from fundamental research and technological development. A key example of how basic research on oncogenic alterations translated into substantial clinical benefits for a large number of patients is BCR-ABL1 tyrosine-kinase inhibitors for chronic myeloid leukemia. The first BCR-ABL1 tyrosine-kinase inhibitor was discovered through drug screens in 1992, and in 2001 it became the first-line therapy with long-term remission rates for BCR-ABL–driven chronic myeloid leukemia 1 ; second-generation tyrosine-kinase inhibitors, rationally designed to circumvent acquired resistance, earned approval from the US Food and Drug Administration as frontline therapies only a decade later. More recently, the announcement of the two first-in-class inhibitors of the mutant kinase KRAS G12C was a milestone in the decades-long efforts to study and treat tumors bearing these, up-to-now considered undruggable, KRAS mutations 2 . However, not every effort in precision oncology and targeted therapy is yielding similarly positive results, especially given the issue of adaptive and acquired resistance, a complication of therapy that a large part of the cancer-research community is striving to address. It should also be noted that advances in sophisticated cancer therapeutics are sometimes associated with a high financial burden for patients, a pressing societal issue tied to the complexities of addressing the challenge of cancer 3 .

In light of the progress made so far and the goals and challenges ahead, we are pleased to launch in this issue of Nature Cancer a Series on Cancer Therapy comprising specially commissioned Review, Perspective, News and Comment articles and a collection of relevant primary research articles published in Nature Cancer . The series is housed in a dedicated page on the Nature Cancer website and will be continually updated with additional content from key opinion leaders discussing novel therapeutic opportunities, the path to drug discovery, and how these advances are transforming clinical practice.

Our series launches with two Review articles that focus on different but important aspects of cancer treatment. Whereas substantial achievements have been witnessed in the treatment of primary tumors, progress has been more modest for metastatic disease. Yibin Kang and colleagues discuss the clinical challenge of treating metastatic disease, and how preclinical and mechanistic knowledge accumulated over the years is being translated into tangible clinical benefits for disseminated disease 4 . The authors also discuss the challenges of running clinical trials for metastatic disease, and the different degrees of success of clinical trials in the metastatic setting. In a separate Review, Frank McCormick and colleagues discuss the multiple and complex links between oncogenic KRAS—one of the most frequently mutated and, as noted above, hard-to-target cancer drivers—and metabolism, highlighting the potentially targetable vulnerabilities that arise at the interface of the two 5 . Although various aspects of targeting KRAS-dependent cancer metabolism have been explored extensively in preclinical settings, ongoing and future clinical trials will hopefully shed light on the translatability of these approaches to the clinic.

Despite the many milestones achieved in cancer treatment, much remains to be addressed. In future issues we will present additional pieces focusing on a breadth of topics under this theme, including key pathways deregulated in cancer, such as EGFR or PI3K, and ongoing clinical approaches for preventing and bypassing therapy resistance. Future issues will also discuss progress in radiotherapy, immunotherapy and therapy combinations, as well as new therapeutic modalities, such as bispecific antibodies, and innovative drug-development approaches through the implementation of artificial intelligence.

Through this selection of commissioned and primary research publications, we aim to underscore how much cancer therapy has advanced over the past several decades, which goals need to be prioritized, and the challenges that should be overcome to continue improving quality of life and outcomes for patients with cancer. We thank our authors and referees for their valuable contributions and hope that our readers will find this Series on Cancer Therapy informative and inspiring.

Druker, B. J. et al. N. Engl. J. Med. 344 , 1038–1042 (2001).

Article   CAS   Google Scholar  

Bar-Sagi, D., Knelson, E. H. & Sequist, L. V. Nat. Cancer 1 , 25–27 (2020).

Article   Google Scholar  

Gruber, K. Nat. Cancer 1 , 1136–1139 (2020).

Esposito, M. et al. Nat. Cancer https://doi.org/10.1038/s43018-021-00181-0 (2021).

Mukhopadhyay, S. et al. Nat. Cancer https://doi.org/10.1038/s43018-021-00184-x (2021).

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• v.12(7); 2021 Jul 15

Current cancer therapies and their influence on glucose control

Department of Medicine, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada

Kerry Mansell

College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada

Nassrein Hussein

Department of Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada

Terra Arnason

Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada. [email protected]

Corresponding author: Terra Arnason, FRCPC, MD, Academic Research, Doctor, Professor, Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Room 3654 Royal University Hospital 103 Hospital Drive, Saskatoon S7N 0W8, Saskatchewan, Canada. [email protected]

This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs. Both of these classes have been in use in cancer therapy since the 1950s. Also considered are the phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth, proliferation and survival signaling pathways, and have been in clinical use as early as 2007. The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors (ICIs). These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors. For each drug class, the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use. The incidence of new glucose elevations in euglycemic individuals, as well as glycemic changes in those with established diabetes has been considered, as has the expected onset of hyperglycemia from their first use. This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels, whereas other classes can have lengthy delays of up to 1 year. A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs. There are distinct differences in the reversibility of glucose elevations after treatment is stopped, as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term. These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia, with clinical presentations ranging from potent yet transient insulin resistant states [type 2 diabetes mellitus (T2DM) -like] to rare permanent insulin-deficient causes of hyperglycemia. Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.

Core Tip: Immune checkpoint inhibitors (ICI) rarely cause hyperglycemia, but glucose monitoring from their initiation is critical as rapid diabetic ketoacidosis can develop from underlying immune-mediated pancreatic beta-cell destruction. Therapy with mammalian target of rapamycin (mTOR) inhibitors, 5-fluorouracil (5-FU)-analogs and glucocorticoids have higher rates of hyperglycemia early in therapy that is not generally severe, but needs to be recognized and treated to optimize patient outcomes. The hyperglycemia occurring from the 5-FU and ICI classes is not reversible. The diabetes from ICIs arises from an absolute insulin deficiency vs the partial deficiency from the 5-FU class. Glucocorticoids and mTOR inhibitors predominantly cause insulin resistance.

INTRODUCTION

Cancer therapies have had profound impacts on increased life expectancy over the past few decades, however, it is widely known to have a multitude of unintended effects. Quality of life concerns such as hair loss, intractable nausea or visible surgical scars are widespread in individuals initiating their treatment cycles. Physicians initiating chemotherapy are also concerned about treatment side effects and routinely monitor for signs or symptoms of serious complications that may require urgent hospitalization, a change in treatment management or a pause in therapy to avoid a life-threatening event. Hyperglycemia is a common and potentially significant adverse effect arising from the use of several widely applied cancer therapeutic classes including immune checkpoint inhibitors (ICIs), phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors, 5-fluorouracil (5-FU) analogs, and glucocorticoids[ 1 - 4 ]. The latest understanding of the characteristics of the hyperglycemia that is associated with the use of these drug classes is presented in order to raise awareness of the adverse effects these agents have on glucose control to enable its early recognition, trigger regular monitoring plus timely intervention, and to ultimately improve patient outcomes. Emphasized below is the current knowledge pertaining to these drug classes regarding the incidence, onset, reversibility and severity of hyperglycemia associated with their use in cancer therapy.

The significance of hyperglycemia on cancer therapy outcomes

Untreated hyperglycemia has been associated with a multitude of negative outcomes for cancer patients including longer hospital stays[ 5 ], worsened prognosis and decreased survival[ 6 , 7 ]. Glucose is a key substrate metabolized by cells to produce ATP and is a preferred energy supply; cancer cells are known to increase their glucose uptake, with the subsequent increase in energy reserves able to support further cellular proliferation[ 8 ]. Hyperglycemia has also been associated with a reduction in cancer therapy effectiveness[ 9 ], an increased rate of infections and sepsis in those who may already have immunosuppression from their cancer treatments[ 10 ], and an increased length in hospital[ 11 , 12 ]. Hyperglycemia fosters a proinflammatory environment that enhances the production of cancer stimulating signals that promote cell proliferation, increase resistance to cell death and may also induce drug resistance to chemotherapy[ 11 - 16 ]. Clinically, hyperglycemia has been found to be an independent risk factor for earlier cancer recurrences, and higher mortality rates[ 17 ].

Glucose levels and clinical presentation define the severity of hyperglycemia

The research referenced below has graded both the severity of hyperglycemia and the degree of clinical symptoms as a means of comparing patient adverse events (AE) with drug use. Four grades of severity are defined that consider glucose levels, but also includes the severity of the clinical consequence such a diabetic ketoacidosis (DKA) or permanent diabetes. Grade 1 AE (G1) relates to asymptomatic or mild symptoms, no ketosis or evidence of type 1 diabetes (T1DM), fasting glucose (FG) above normal. Grade 2 AE (G2) involves moderate symptoms, FG > 8.9-14 mmol/L, or the presence of ketosis or T1DM at any glucose level. Grade 3-4 AE are severe symptoms, that are medically significant or life-threatening, differentiated from G2 and each other by the degree of glucose elevations with Grade 3 AE (G3) encompassing glucose levels between 13.9-27.8 mmol/L, and Grade 4 AE (G4) including glucose levels > 27.8 mmol/L[ 18 ].

IMMUNE CHECKPOINT INHIBITORS

Immune checkpoint inhibitors target one of three t-cell ligands to promote antitumor activity.

A relatively new class of chemotherapy agents that are recognized for their potential side effects on glucose control are the immunomodulators that target and inhibit immune checkpoints, resulting in an increase in T-cell mediated immune responses that benefit patient treatment responses[ 19 ]. These ICIs are monoclonal antibodies that bind and block (inhibit) immune cell-cell interactions that would normally suppress the immune response. The result is that there is an effective and durable increase in antitumour activity[ 20 ]. This class is very successful in the treatment of advanced melanoma including those with BRAF mutations[ 21 ], and have since been used successfully for treatment of additional advanced stage cancers including hepatocellular carcinoma[ 22 , 23 ], non-small-cell lung cancer[ 24 ], renal cell carcinoma[ 25 ] and metastatic clear cell renal cancer[ 26 ]. The ICIs in current use specifically block three T-cell checkpoints; the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptor, the programmed cell death-1 (PD-1) receptor, and the third and most recent class of antibodies targeting the programmed cell death-Ligand 1 (PD-L1)[ 19 , 20 ].

ICIs trigger immune-related endocrinopathies, and the incidence of diabetes with ICI differs with the checkpoint being targeted

There is an association between the use of these ICIs and the frequent appearance of immune-related AE, including a wide-spectrum of endocrine dysfunctions. The onset of hyperglycemia in individuals taking ICIs is infrequent, and the incidence differs depending on the receptor being targeted, as well as whether receptor targeting combinations are used[ 27 ]. Not all ICIs appear to have the same potential. The highest probability appears to reside in those targeting either the PD-1 receptor (nivolumab, pembrolizumab) or PD-L1 (atezolizumab, durvalumab, avelumab), whereas the CTLA-4 targeting agent (ipililmumab) does not seem to have a significant risk when used alone, as only a handful of case reports were noted[ 28 ]. A recent 2020 meta-analysis estimated the incidence of serious (G3 and G4) and all-grade hyperglycemia (G1-G4) in every reported case of ICI-associated diabetes, noting that the PD-1/PD-L1 targeted therapies were associated with hyperglycemia in 0.2%-4.9%, with a 0.49% incidence of serious hyperglycemia in patients using these drugs[ 1 ]. A 2018 study reported an overall incidence of 0.9%[ 28 ]. The combination of PD-1/PD-L1 and CTLA-4 immune-targeted therapy showed the highest overall rates of diabetes, spanning 2.0%-3.4% in different cohorts studies, and a notably higher rate of serious hyperglycemia events at almost 2%[ 28 ]. This same study confirmed that the CTLA-4 inhibitors do not seem to have a risk of hyperglycemia when used without PD-1 therapies[ 28 ].

ICI therapy stimulates immune-mediated antitumor activities, but also stimulates autoimmune disorders

The inhibitory monoclonal antibodies used to interrupt immune response checkpoints results in a reinvigoration of the immune response. The ICI antibodies bind and block the specific inhibitory ligand on the T-cell surface, interrupting those activity-dampening signaling pathways[ 29 , 30 ]. The result is T-cell activation and stimulation of their immune surveillance and antitumor activity, to the benefit of the patient[ 31 ]. However, immune checkpoints are also central to maintaining immunological self-tolerance and preventing autoimmune disorders[ 32 , 33 ]. Immune-mediated self-damage causing endocrine dysfunctions are one of the most common side effects of the ICI class, including loss of thyroid, adrenal and pituitary activity, plus rare cases of pancreatic insulin deficiency[ 34 ]. Autoimmune recognition and destruction of pancreatic beta (β)-cells is the well-established mechanism resulting in classic T1DM[ 35 , 36 ], and the ICI drugs likely trigger this same destructive loss of function in cancer patients who developed hyperglycemia[ 37 ]. Human pancreatic islets lack CTLA-4 receptors, but do present PD-L1 to protect them against immune cells[ 38 ]. The ICI monoclonal antibodies that bind PD-1/PD-L1 should be capable of inhibiting this pathway in pancreatic β-cells, leaving them susceptible to (auto)immune destruction and diabetes, providing a rationale why PD-1/PD-L1 but not CTLA-4 inhibitors are associated with new onset diabetes.

The hyperglycemia associated with ICI use is due to autoimmune destruction of the pancreatic ß-cells and loss of endogenous insulin release

With ICI use, the new onset of hyperglycemia found in those without diabetes, and the worsening glucose control in those with known diabetes, does appear to be directly due to immune-mediated pancreatic damage. Pancreatitis was found in 42% of individuals developing diabetes, and auto-antibodies classically associated with T1DM can be found elevated in these individuals, with 47% having glutamate decarboxylase autoantibodies[ 28 ]. The appearance of new hyperglycemia in those exposed to ICI therapy is not caused by an associated insulin resistance, as three large case series evaluating patients that developed diabetes after ICI exposure found low C-peptide (62%-93%), positive ketosis (59%-77%) and detectable autoantibodies (39%-56%)[ 28 , 37 , 39 ], with the antibodies in at least some cases not present prior to ICI treatment[ 28 ].

Loss of glucose regulation in type 2 patients taking ICIs may indicate a transformation into an insulin-deficient state

It is less well known how ICI use has impacted glucose levels in those with underlying T2DM as the stress of illness, pain, or other medical therapies may also contribute to loss of tight glucose control. It is well documented, however, that when blood glucose levels become acutely and significantly more difficult to control in known T2DM, that it is important to consider that the ICI therapy may have caused pancreatic β-cell dysfunction and insulin deficient diabetes[ 40 ].

The onset of Insulin-deficient diabetes after ICI therapy is unpredictable and is permanent

Of the cases of insulin-deficient diabetes (IDD) reported with ICI therapy, the onset is unpredictable and can appear as early as a few weeks after starting treatment, up to greater than one-year following therapy; over half occurred within 4 mo of treatment initiation, typically in their fourth cycle of therapy[ 28 ]. The presence of hyperglycemia with ICI therapy does not require cessation of the ICIs or provision of high dose steroid pulse therapy, as this does not appear to restore pancreatic function[ 41 , 42 ]. In fact, reversal of IDD after ICI use has rarely been reported. A single case of ICI-induced diabetes successfully used infliximab, an immunosuppressant, to reverse the hyperglycemia[ 43 ], yet in general, once present the hyperglycemia is persistent and does not appear to be mitigated by decreasing or stopping the ICI treatment[ 34 , 44 ].

ICI associated hyperglycemia has a high risk of serious and severe consequences, notably DKA and permanent diabetes

ICI therapy can lead to severe complications of hyperglycemia that can occur very rapidly. The severity is due to the damage to the pancreatic β-cells, leading to irreversible insulin deficiency. Because of this T1DM-like defect, there is a distinct risk of DKA, and this can be an acute and potentially life-threatening presentation. The association between ICI-dependent onset of hyperglycemia and ketosis/DKA was remarkably high, at 77.8 % in newly diagnosed cases of diabetes[ 37 ]. There are many case reports of rapid DKA as the first presentation of hyperglycemia with ICI use, raising the possibility that this overlaps with Fulminant T1DM, a clinical presentation that is characterized by rapid development of markedly elevated glucose, near-normal glycated hemoglobin A1c (A1C), ketoacidosis, negative autoantibodies, severe insulin deficiency and elevated levels of pancreatic enzymes[ 45 ]. A careful review, however, revealed that there does appear to be distinct differences, including the presence of autoantibodies in ICI IDD, that are typically not found in Fulminant T1DM[ 37 ]. Due to the risk of DKA with this drug class, the practice guidelines developed to monitor for adverse effects of ICIs commonly recommend routine monitoring of glucose levels both at baseline, with each treatment cycle throughout induction and then every 3-6 wk thereafter for up to one year[ 18 ]. For safety, the use of insulin for diabetes developing from ICI therapy is recommended unless insulin deficiency can be ruled out[ 18 ].

PI3K/AKT/MTOR PATHWAY INHIBITORS

Inhibition of the pi3k/akt/mtor pathway interrupts multiple cancer promoting cell signals.

The PI3K-AKT-mTOR signaling pathway plays a vital role in responding to nutrient abundance[ 46 ], making it an attractive target for blockade[ 47 ]. The proteins being inhibited are kinases that target downstream proteins for phosphorylation to change cellular responses including promoting normal cell growth and proliferation when nutrients are abundant[ 48 ]. They ultimately work within the same pathway as growth factors and insulin signaling, and can therefore also influence glucose and lipid metabolism[ 49 ].

mTOR, PI3K inhibitors and their derivatives are effective in many cancer types

mTOR inhibitors are derived from the original drug of this family, rapamycin, that was initially isolated as an antifungal agent[ 50 ], but was later determined to inhibit a kinase important in cancer growth[ 51 ]. This target was subsequently named “mechanistic target of rapamycin” or mTOR. mTOR inhibitors and their related analogs are used in many advanced stage solid tumors including renal cell, neuroendocrine tumors of the pancreas, and breast cancer[ 52 ]. There are presently three mTOR inhibitors approved by the United States Food and Drug Administration (FDA) that are derivatives of rapamycin; sirolimus, temsirolimus, and everolimus. Closely related medications are the PI3K inhibitors, of which there are four currently approved by the FDA; copanlisib, idelalisib, duvelisib, and alpelisib. These latter agents are approved for use in the treatment of breast cancer and hematological malignancies. AKT inhibitors and combination PI3K/mTOR inhibitors are still under development and some have entered Phase II clinical trials[ 53 ].

The hyperglycemia arising from the inhibition of mTOR is primarily due to insulin resistance

The usual activity of mTOR not only influences cell growth and development, but also affects glucose regulation[ 54 ]. mTOR inhibitors primarily promote hyperglycemia through increased insulin resistance via mTOR complex 1 (mTORC1) inhibition, as they impair the efficiency of the insulin signaling pathway at multiple points in its phosphorylation cascade[ 55 , 56 ]. In a diabetic rodent model, exposure to rapamycin resulted in a reduction in insulin signaling via proteins IRS1/2, a reduction in phosphorylation by AKT, and inhibition of PI3K activity[ 55 ]. Moreover, rapamycin increased the activation of Jun N-terminal kinase pathway, which is a pathway implicated in insulin resistance[ 55 ]. Together, the effect observed with these chemotherapy drugs is consistent with a predominant T2DM-like insulin resistant state, due to impaired insulin signaling[ 55 ]. Lastly, a component of insulin deficiency is also thought to play a role in the development of hyperglycemia as mTORC1 is a known positive regulator of pancreatic β-cell function, and molecular studies using pancreatic β-cells exposed to rapamycin detected a 33% reduction in glucose-induced insulin secretion[ 55 ].

There are two mTOR complexes that differ in their influence on glucose levels and sensitivity to inhibition

The mTOR complex is a serine/threonine protein kinase that exists in two different multi-protein complexes. The mTORC1 is sensitive to rapamycin, whereas complex 2 (mTORC2) is less responsive to rapamycin, although chronic exposure to rapamycin does ultimately result in reduced mTORC2 signaling[ 56 ]. The mTORC2 pathway is much less well characterized than the mTORC1 pathway. It was initially thought that the mTORC2 pathway was resistant to rapamycin treatment, but it was later discovered that long term exposure reduces mTORC2 signaling in some cell types by suppressing the assembly of the mTORC2 complex[ 57 ]. mTORC2 activates AKT, and the mTORC2-AKT pathway has been shown to promote pancreatic beta cell proliferation and survival, and to inhibit gluconeogenesis by blocking Fox01 activity[ 57 ]. Normal mTORC2-AKT activity also induces glucose uptake in insulin-sensitive tissues and blocks protein catabolism. The loss of mTORC2 activity through inhibition, therefore, increases insulin resistance as well as promoting protein catabolism and reducing muscle mass. Inhibition of mTORC2 also leads to the loss of the mTORC2-AKT-dependent inhibition of gluconeogenesis as well as decreased insulin production, contributing further to hyperglycemia[ 56 ]. The effect of mTORC1 and mTORC2 inhibition on glycemia is complex, and related to the degree and chronicity of inhibition, but ultimately treatment with all mTOR inhibitors leads to hyperglycemia[ 56 ]. The three mTOR inhibitors approved by the FDA are derivatives of rapamycin; sirolimus, temsirolimus, and everolimus, and are primarily mTORC1 inhibitors, although dual mTORC1/C2 inhibitors are in development[ 57 ].

The PI3K/AKT/mTOR pathway inhibitors are potent drivers of hyperglycemia

The incidence of hyperglycemia associated with the use of PI3K/AKT/mTOR inhibitors is significant and ranges between 12%-50%[ 2 ]. A 2015 meta-analysis considered twenty-four trials of mTOR inhibitor use in solid organ cancer treatment and noted a 5.25-fold increased risk of significant hyperglycemia (blood sugars > 14 mmol/L)[ 58 ]. Pre-existing diabetes was an independent risk factor for glucose levels > 14 mmol/L[ 59 ]. It is worth noting that the PI3K inhibitors can also induce hyperglycemia[ 60 ], and AKT inhibitors have revealed significant hyperglycemia in preclinical studies[ 61 ].

Most cases of hyperglycemia occur during initial exposure, are mild and transient

A retrospective study of 341 patients treated with PI3K and mTOR inhibitors revealed that the mean FG increased from 5.3 mmol/L at baseline to 7.1 mmol/L during the first chemotherapy cycle, but returned to 5.4 mmol/L prior to the next cycle[ 59 ]. This supports the conclusion that the rise in blood glucose is transient. The majority of these patients experienced their highest glucose levels early on in therapy, during the first (87.9%) or second (14.4%) cycle of mTOR inhibitor treatment, and most cases of hyperglycemia in this study were mild (G1)[ 59 ]. However, more significant glucose elevations can occur, as 6.7% of patients receiving this therapy had glucose elevations > 14 mmol/L compared to controls not taking mTOR inhibitors[ 62 ]. Additionally, it was observed that the median time of elevated glucose levels (> 8.3 mmol/L) was 56 d in patients showing clinical benefit, and 113 d for those patients who progressed[ 62 ]. It remains to be determined if the timing of new hyperglycemia development after therapy initiation is predictive of treatment responses.

mTOR-induced hyperglycemia is typically managed with oral therapies

Insulin deficiency or DKA are not significant risks with using this class of drugs, as only a very small percentage of patients require insulin[ 59 ]. and to our knowledge there have been no cases of hyperglycemic emergency or DKA in any clinical trials to date. A single case report was found that describes DKA and pancreatitis in a patient treated with everolimus for breast cancer, supporting that this is a very rare association with mTOR inhibitor drugs[ 63 ]. When uncontrolled hyperglycemia develops (defined as glucose > 14 mmol/L, A1C ≥ 9%), expert committee guidelines recommend stopping the chemotherapy medication and reintroducing it a lower dose in the rare cases of uncontrolled hyperglycemia despite optimal diabetes management[ 2 ]. Both American and French guidelines for PI3K/AKT/mTOR use are available to direct surveillance and treatment best practices[ 2 , 64 ], and an A1C target of ≤ 8% is suggested for pre-existing patients with diabetes prior to mTOR inhibition[ 2 ].

5-FU AND DERIVATIVES

5-FU is an antimetabolite agent that has been used in the initial treatment of breast, gastric, colon and pancreatic cancers and has been in active use for over sixty years[ 65 , 66 ]. It is a pyrimidine analogue that is structurally related to thymine, uracil and cytosine bases in DNA, RNA or both, respectively[ 67 ]. 5-FU acts as an antimetabolite to inhibit cell growth through its interference with DNA and RNA function upon its incorporation into newly synthesized DNA or RNA.

Derivatives of 5-FU have been created to increase their stability and to overcome their drug toxicities

Over the years, additional 5-FU oral prodrugs have been developed that reduce their toxicity and improve tumour selectivity, as well as increase their stability[ 68 - 70 ]. In the last 20 years, capecitabine has been developed and used predominantly for metastatic breast and gastrointestinal cancers[ 66 , 70 ]. It is activated into 5-FU through three sequential enzymes, with the final enzyme being found in high concentrations in tumour tissues[ 66 ]. As such, capecitabine activation is very targeted and is generally better tolerated[ 66 , 70 ]. There have been numerous reports of glucose disorders with 5-FU and its derivatives including case reports of hyperglycemia following the administration of the newest 5-FU prodrug, capecitabine[ 71 ].

5-FU prodrugs can contribute to new onset diabetes, and the majority have persistent hyperglycemia after therapy is stopped

There is a paucity of data on 5-FU therapies and their specific effects on glucose control. The majority of information comes from a 2013 study involving 362 patients with normal fasting plasma glucose prior to 5-FU-based therapies in which overt diabetes developed in 11.6% of individuals and impaired fasting glucose (IFG) in another 11.3%[ 3 ]. Of the 42 patients that developed diabetes, 32 occurred during therapy, with the remaining 10 being detected during follow-up after treatment was completed. Only 16% (7/42) of these patients had glucose levels spontaneously return to normal[ 3 ], indicating that the hyperglycemia related to 5-FU therapy is persistent in most cases. Those remaining were managed with a variety of interventions including diet (30%), insulin (10.8%) or oral medications[ 3 ]. Given that these patients did not have pre-existing risk factors for diabetes, it was thought that the development of diabetes was secondary to 5-FU chemotherapy[ 3 ].

Hyperglycemia typically develops early during 5-FU analog therapy, and is generally mild

The timing of new-onset hyperglycemia with 5-FU treatments varies, but most (77%) patients developed diabetes during their early chemotherapy cycles (median third cycle), and the remaining individuals present up to 1 year after completion of treatment[ 3 ]. It is unclear how 5-FU chemotherapy affects glucose control in those with established diabetes. In this study, the timing of the onset of IFG after 5-FU treatment was not reported[ 3 ]. While 5-FU-associated hyperglycemia was typically mild during active treatment (95% had glucose < 14 mmol/L), after therapy was complete it was noted that seven out of 42 patients developed significant hyperglycemia (>14 mmol/L), and one patient in the study died of ketoacidosis[ 3 ]. Aside from this study, there are two additional case reports of DKA associated with 5-FU based treatments[ 72 , 73 ].

5-FU therapies decrease pancreatic β-cell insulin storage and release

The underlying mechanism causing the hyperglycemia upon 5-FU exposure appears to be due to a decrease in insulin being released from the pancreatic β-cells[ 3 , 74 ]. Those patients who developed diabetes had a progressive decrease and delay in C-peptide secretion, seemingly due to a pancreatic deficiency in endogenous insulin processing and production[ 3 ]. A case control study also demonstrated that insulin levels failed to increase appropriately with the development of hyperglycemia[ 74 ]. Preclinical animal studies also suggest that hyperglycemia may result from impaired insulin production as there was a relative insulin deficiency in rats following 5-FU administration, as well as a decrease in the abundance of secretory granules in pancreatic islet cells[ 75 ]. Cellular studies designed to reveal how these drugs cause hyperglycemia have shown that 5-FU related therapy stimulates immune mediators in pancreatic β-cells, resulting in their destruction via cell-mediated T-cell infiltration[ 76 ]. Consistent with this, capecitabine has been linked to acute pancreatitis[ 77 , 78 ].

The rare cases of DKA reported with 5-FU therapies suggests that there is sufficient endogenous insulin production to offset severe hyperglycemia consequences in the majority of cases. Nonetheless, there is a real risk of significant glucose elevations, as 16.7% (7 of 42) of newly diabetic individuals had glucose levels > 14 mmol/L despite therapy[ 3 ]. Management of hyperglycemia following capecitabine therapy included successful treatment with dietary control and lifestyle changes[ 79 , 80 ], although some individuals did require insulin[ 3 ].

GLUCOCORTICOIDS

Glucocorticoids are a class of medications that have been used to treat a plethora of medical conditions since the 1950’s. Glucocorticoids are prescribed widely for a variety of medical conditions, with estimates of use approaching 1% of the general population[ 81 ]. Although their efficacy and adverse effect profile have been described extensively in the literature, their effect on the human body varies due to the heterogeneous nature of the underlying disease states they are treating and the individuals who are using them; hence there is variability in their use and dosage recommendations[ 82 ].

Steroids are useful as adjunct therapy to offset adverse side effect of cancer treatments

Glucocorticoids are often included as a part of cancer therapy to mitigate the adverse effects of the chemotherapies being used at the same time. They can be very useful in controlling nausea and improving appetite, and are frequently given as an antiemetic before and after chemotherapy[ 83 ]. The dosing and duration often depends on the emetogenic potential of the chemotherapy. Glucocorticoids are also given to prevent some of the other adverse effects of chemotherapy like generalized rash or thrombophlebitis when drugs are given through peripheral vein, or to offset hypersensitivity reactions[ 11 , 84 , 85 ]. Glucocorticoids may also be included as an inherent part of the cancer therapy, such as their use within the CHOP protocol in lymphoma. There are several other regimens used in multiple myeloma and prostate cancer that include glucocorticoids as a part of the treatment, and the dosing and formulation varies.

Glucocorticoid-induced hyperglycemia is a very common adverse effect of steroid use

Along with their known benefits, there are many recognized adverse effects of glucocorticoids, both acute and chronic. Supraphysiologic glucocorticoid use is known to raise glucose levels, particularly at the high doses that are required for therapeutic advantages. Glucocorticoid-induced hyperglycemia (GIH) is a well-known complication of their use in individuals with known diabetes (T1DM and T2DM) as well as those who were previously euglycemic[ 4 , 86 ]. Hyperglycemia is commonly reported in patients undergoing cancer therapy that includes glucocorticoids, however its true incidence is hard to define due to the variability in chemotherapy combinations, durations, and cycles. One study of hospitalized patients taking high dose glucocorticoids reported hyperglycemia in 52% of patients[ 87 ], with another two studies reporting 34%[ 88 ] and 37%[ 89 ] in patients during induction therapy for acute lymphocytic leukemia[ 88 , 89 ]. A more recent study found that 94% of women with gynecological cancer whose chemotherapy regimen included high dose dexamethasone experienced hyperglycemia[ 85 ]. These patients were undergoing continuous glucose monitoring (CGM) which the authors felt led to the remarkably high incidence rate, and postulated that glucose elevations may be significantly under-recognized in many previous clinical trials that did not utilize CGM[ 85 ].

GIH occurs acutely and is generally mild

GIH is a phenomenon that typically occurs acutely with initiation[ 85 , 87 , 90 , 91 ], and hyperglycemia was found to be significant by day 2 in those being treated systemically for hematologic malignancies[ 11 ]. The degree of glucose elevations range widely and are most frequently modest (< 14 mmol/L)[ 92 ], nonetheless severe hyperglycemia (> 28 mmol/L) and DKA have also been reported[ 11 , 93 ], with rare reports of hyperglycemic hyperosmolar syndrome as well[ 94 ]. Other AE associated with GIH range from mild to serious, such as increased infections and lengthened of hospital stays[ 11 , 16 , 86 , 95 - 98 ]. The acute hyperglycemia associated with glucocorticoids will typically resolve upon discontinuation[ 4 , 99 , 100 ].

The formulation and duration of steroid use influences the incidence of hyperglycemia

The most commonly used glucocorticoids in chemotherapeutic regimens are prednisone (oral) and dexamethasone (oral or intravenous). The dose and duration at which they are used varies with the chemotherapy and clinical situation, making general conclusions difficult[ 16 ]. To give an example of the variance that confounds these clinical assessments, a study by Ochola et al [ 95 ] considered patient outcomes with prednisone use; there was a range in total daily doses of 40-150mg; once to four times daily; and between 5-14 d duration.

It is commonly considered that higher glucocorticoid doses and longer durations of use confers a greater risk of developing GIH[ 11 , 16 , 101 , 102 ], yet there have been exceptions to this association[ 82 , 94 , 98 ]. Most hospitalized patients developed hyperglycemia after taking ≥ 40 mg/d of prednisone for two days[ 103 ]. There is some evidence that splitting the dose of prednisone, rather than administering it all at once in the morning, may help reduce GIH[ 104 ]. The type of glucocorticoid used may also correlate with the risk of hyperglycemia[ 92 ]. Healy et al [ 11 ] found that hyperglycemia was associated with higher doses and the longer-acting steroids in those without diabetes, yet it was not in those with previous diabetes.

Due to the differences in the pharmacokinetic profiles of shorter acting glucocorticoids (such as prednisone, prednisolone, and hydrocortisone) vs longer-acting glucocorticoids such as dexamethasone, one could anticipate a delayed effect with the latter[ 90 ]. Prednisone levels peak 4-8 h after ingestion and its duration of action is between 12 h to 16 h; these pharmacokinetics correlated with increases in postprandial glucose in the afternoon and evening when administered in the morning[ 11 , 87 , 92 ]. During induction therapy for acute lymphoblastic leukemia the use of long-lasting dexamethasone was linked with a significant increase in risk of GIH when compared to those prescribed the intermediate-acting prednisone[ 93 ]. In contrast, a comparison between dexamethasone 8-12mg IV and prednisone 40mg orally found extensive hyperglycemia in the majority of all patients, without differences between the two therapies[ 94 ].

Steroids induce a potent insulin resistance resulting in hyperglycemia

The effects of glucocorticoids on glucose levels are complex[ 4 ]; although GIH occurs most commonly in patients with pre-existing diabetes, it also presents in those without any prior history of hyperglycemia[ 82 , 105 ]. Glucocorticoids can cause an increase in both fasting and postprandial glucose levels, but it is generally recognized that the largest impact is on postprandial levels[ 16 , 87 , 92 , 95 , 96 , 105 , 106 ]. High dose glucocorticoid use impairs insulin signaling, leading to key increases in insulin resistance at the liver (promoting hepatic gluconeogenesis) and skeletal muscle (impairing glucose uptake)[ 4 , 92 , 106 ]. Glucocorticoids can also diminish normal insulin secretion by pancreatic β-cells[ 4 , 99 ]. Some of the predictors of risk for increased blood glucose with glucocorticoid use in the context of cancer therapy include older age and higher BMI[ 88 , 98 , 102 ] and while an elevated A1C was found to be a predictor, a discrete HbA1c cut-off was not determined[ 85 ].

SUMMARY AND DISCUSSION

For all of these classes of drugs, it would be prudent to initiate glucose monitoring upon the initiation of chemotherapy and to continue to do so throughout treatment. As summarized in Table ​ Table1, 1 , glucocorticoids and AKT/mTOR inhibitors can be expected to cause the majority of patients (up to 94%[ 85 ] and 50%[ 2 ] respectively) to develop hyperglycemia very early after drug initiation. In contrast, the diabetes that develops upon the initiation of ICIs and 5-FU therapies will affect fewer individuals (up to 5%[ 1 ] and 11%[ 3 ], respectively) and could be anticipated to present at slightly later timelines on average, with the 5-FU analogs typically in their third chemotherapy cycle[ 3 ] and ICIs in their fourth chemotherapy cycle (about 4 mo[ 28 ]). Despite searching the literature, it was not found that there are dosing ‘cut-offs’ for any drug class below which the risk of hyperglycemia is nil, nor are there specified doses above which there are significantly increased rates of hyperglycemia.

Summary of reported characteristics of hyperglycemia incidence, onset and severity with the use of current chemotherapy agents

5-FU: 5-fluorouracil; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; PI3K: Phosphatidyl inositol-3-kinase; mTOR: Mammalian target of rapamycin; DKA: Diabetic ketoacidosis; HHS: Hyperglycemic hyperosmolar syndrome; IFG: Impaired fasting glucose.

The insulin resistance arising from either glucocorticoids or AKT/mTOR inhibitors nearly always resolved once the treatments have stopped[ 4 , 59 , 99 , 100 ] and there have not been any reports of delayed reappearance, implying that ongoing daily glucose monitoring will not be necessary upon completion (Table ​ (Table2). 2 ). When mild hyperglycemia is present, standard management approaches used for T2DM have been effective including diet adjustments, oral metformin or sulfonylureas[ 2 , 64 ] (Table ​ (Table3). 3 ). While there is little information specifically related to all of these drug classes, it would be anticipated that DPP-4 inhibitors, SGLT-2 inhibitors, or GLP-1 analog medications would also be effective at normalizing blood glucose levels. Increases to therapy intensiveness to manage more severe glucose elevations would follow usual best practices for T2DM management, and patients may ultimately require insulin for optimal control in the short term.

Hyperglycemia can be a class or drug-specific effect and may not be reversible with discontinuation

5-FU: 5-fluorouracil; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; PI3K: Phosphatidyl inositol-3-kinase; mTOR: Mammalian target of rapamycin; PD-1: Programmed cell death-1; PD-L1: Programmed cell death-Ligand 1.

The underlying mechanisms and treatment considerations of hyperglycemia differ between chemotherapy classes

5-FU: 5-fluorouracil; PI3K: Phosphatidyl inositol-3-kinase; mTOR: Mammalian target of rapamycin; T2DM: Type 2 diabetes mellitus.

The ICIs and 5-FU analog classes cause hyperglycemia due to varying degrees of insulin deficiency at the level of the pancreatic β-cell, and once present the diabetes is generally permanent[ 3 , 34 , 44 ] (Table ​ (Table2). 2 ). As discussed above, it is very important to continue glucose monitoring even after therapy has been completed with these two classes, as diabetes can develop for up to at least one year. To date, there is little direction surrounding the specific monitoring and management of hyperglycemia in patients treated with 5-FU, in contrast to multiple current guidelines available for the numerous autoimmune adverse effects of ICI, including IDD[ 18 ] (Table ​ (Table3 3 ).

The diabetes developing as a result of 5-FU analog therapies has rarely led to DKA, suggesting that the insulin deficiency is not absolute in the great majority of cases (Table ​ (Table1). 1 ). This raises the possibility that sulfonylureas may have a beneficial role in mild glucose elevations due to their ability to enhance pancreatic β-cell insulin secretion; this increased release of insulin may compensate for the underlying low insulin levels and thereby normalize blood glucose levels. This has neither been specifically investigated nor reported, but their use could be rationalized based on the underlying defect driving hyperglycemia with 5-FU therapy.

Independent of ICI therapy, the majority of T1DM occurs in children or young adults, and there is a global all-age incidence of 15 per 100000 persons[ 107 ]. The 0.2%-4.9% incidence of insulin-deficient hyperglycemia in adults after ICI therapy (median age > 60 years years[ 1 ]) is higher than global rates and presents in older than expected age groups, suggesting that its development may be more complex than merely unmasking those at inherent risk for developing T1DM. Without doubt there are complexities not yet appreciated, yet it is not known how to identify those at highest risk for the development of T1DM with ICI use. As these therapies become more widespread and cases rise, it may become more clear. At this time, it has been considered that the HLA-DR4 genotype and presence of other autoimmune diseases may correlate with increased risk[ 28 ].

For the ICI class, insulin therapy is essential in new onset diabetes given the extreme risk of IDD causing severe hyperglycemia and ketosis, reported to be as high as 77.8%[ 37 ]. Furthermore, insulin should be strongly considered in those with previous T2DM who fail to control their diabetes with ICI treatments, given the risk of a new underlying insulin deficiency. In patients with T2DM already taking non-insulin therapies, the initiation of a long acting basal insulin and rapid acting prandial insulin should be strongly considered, as simply adjusting their current medical therapy for T2DM may be ineffective as insulin-resistance may no longer be the main driving force for their hyperglycemia (Table ​ (Table3). 3 ). Insulin therapy would be necessary to reduce their risk of acute DKA in these cases[ 1 ].

Patient education regarding symptoms of hyperglycemia is an important safety component when initiating any of these medications, as are the more critical symptoms of hyperventilation and nausea or vomiting that may be associated with imminent DKA upon ICI therapy, in particular. The appearance of these symptoms should trigger an immediate evaluation for hyperglycemia, endogenous insulin levels (post-meal C-peptide and insulin), and acidosis/ketones to rule out developing DKA.

Given the consequences of uncontrolled blood sugars for these patients, it is important to recognize and manage hyperglycemia during cancer therapy, whether because of a worsening control of pre-existing diabetes or new onset hyperglycemia arising as a side effect of the chemotherapy itself. Current recommendations suggest tailoring glycemic control according to the underlying etiology of the hyperglycemia (insulin-resistance vs insulin-deficiency)[ 16 ] (Table ​ (Table3) 3 ) and to also consider that many cancer therapies are prescribed in cycles, which will require monitoring and perhaps intermittent treatment of the hyperglycemia[ 106 ].

Conflict-of-interest statement: Authors declare no conflict of interests for this article.

Manuscript source: Invited manuscript

Peer-review started: February 7, 2021

First decision: March 16, 2021

Article in press: June 25, 2021

Specialty type: Endocrinology and metabolism

Country/Territory of origin: Canada

Peer-review report’s scientific quality classification

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P-Reviewer: Park JH, Vela D S-Editor: Liu M L-Editor: A P-Editor: Wang LL

Contributor Information

Carly Yim, Department of Medicine, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada.

Kerry Mansell, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada.

Nassrein Hussein, Department of Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada.

Terra Arnason, Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada. [email protected] .

Research explains new method to engineer immune cells that could treat multiple cancer patients

I mmunotherapies have revolutionized cancer treatment by harnessing the body's own immune system to attack cancer cells and halt tumor growth. However, these therapies often need to be tailored to each individual patient, slowing down the treatment process and resulting in a hefty price tag that could soar well into the hundreds of thousands of dollars per patient.

To tackle these limitations, UCLA researchers have developed a new, clinically guided method to engineer more powerful immune cells called invariant natural killer T cells, or iNKT cells, that can be used for an "off-the-shelf" cancer immunotherapy in which immune cells from a single cord-blood donor can be used to treat multiple patients.

This novel technology, described in a study published in Nature Biotechnology , marks a major step toward enabling the mass production of cell therapies like CAR-T cell therapy, making these life-saving treatments more affordable and accessible to a broader range of patients.

The study's senior author, Lili Yang, a professor of microbiology, immunology and molecular genetics and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and of the UCLA Health Jonsson Comprehensive Cancer Center, breaks down why this new system is poised to finally help a universal cell product advance to a clinical trial.

What are the key developments of this paper?

In 2021, our team reported a method for producing large numbers of iNKT cells using blood stem cells. That system required the use of three-dimensional thymic organoids and supportive cells, which posed both a manufacturing and regulatory challenge that prevented that method from ever reaching clinical application.

Now, we've developed a technology that can produce large quantities of iNKT cells from blood stem cells in a feeder-free and serum-free manner. This update to the method eliminates the previous hurdles, bringing us closer than ever to delivering an "off-the-shelf" cancer immunotherapy to patients.

How did you reach these findings?

Our team isolated the blood stem cells, which can self-replicate and produce all kinds of blood and immune cells, from 15 donor cord-blood samples representing diverse genetic backgrounds. We then genetically engineered each of those cells to develop into useful iNKT cells and estimate that one cord-blood donation can produce between 1,000 to 10,000 doses of a therapy—making the system really well suited to create an "off-the-shelf" immunotherapy.

Next, our team equipped the iNKT cells with chimeric antigen receptors, or CARs, molecules that enable immune cells to recognize and kill a specific type of cancer, to target seven cancers that included both blood cancers and solid tumors.

The CAR-iNKT cells showed a robust anti-tumor efficacy against all seven cancers, indicating their promising potential for treating a wide spectrum of cancers. Then in a multiple myeloma model, we demonstrated the CAR-iNKT cells' ability to halt tumor growth without causing complications that can sometimes occur when donor cells are transplanted into a patient.

Why are iNKT cells so special?

We consider invariant natural killer T cells to be the special forces of the immune cells because they're stronger and faster than conventional T cells and can attack tumors using multiple weapons. It's ideal to use iNKT cells as an "off-the-shelf" cancer immunotherapy because they don't carry the risk of graft-versus-host disease, a condition in which transplanted cells attack the recipient's body and the reason most cell-based immunotherapies have to be created on a patient-specific basis.

What excites you about these developments?

No "off-the-shelf" cell therapy has ever been approved by the U.S. Food and Drug Administration. With this new technology, not only have we shown a high output of iNKT cells, but we've also proven that the CAR-equipped iNKT cells don't lose their tumor-fighting efficacy after being frozen and thawed, which is a key requirement for the widespread distribution of a universal cell product.

While CAR-T cell therapies have been a transformative treatment for certain blood cancers like leukemia and lymphoma, it has been challenging to develop a cancer immunotherapy for solid tumors. This is in part because solid tumors have an immunosuppressive tumor microenvironment, meaning the immune cell function is impaired in the environment.

iNKT cells can change the tumor microenvironment by selectively and effectively depleting the most immunosuppressive cells in its surroundings—giving them the unique opportunity to attack solid tumors. We're extremely excited that this technology has a potential broad application to target a range of blood cancers, solid tumors and other conditions such as autoimmune diseases.

What's the biggest bottleneck in cancer immunotherapy?

The biggest bottleneck right now for immunotherapies, particularly cell therapies, is manufacturing. As of 2023, the FDA has approved six autologous CAR-T cell therapies with an average cost of around $300,000 per patient, per treatment. Using this novel technology to scale up iNKT cell production, there's a real possibility that the price per dose of immunotherapy can drop significantly to $5,000.

By definition, an "off-the-shelf" product would be readily on hand in clinical settings, so my hope is that this new system will result in a reality where all patients who need the treatment will be able to receive it immediately.

What are the next steps in the study?

Our team is advancing this multiple myeloma model project into an IND-enabling study this year, which would result in a Phase 1, first-in-human clinical trial of this technology.

Since this flexible platform allows us to switch the CARs to target different cancers, our team has since adapted this same system to target ovarian cancer, one of the deadliest gynecologic cancers. This represents a big leap from targeting blood cancers to solid tumors, but we're hopeful to bring this project to a clinical trial over the next couple of years.

More information: Yan-Ruide Li et al, Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method, Nature Biotechnology (2024). DOI: 10.1038/s41587-024-02226-y

Provided by University of California, Los Angeles