Unique Toronto-based clinical trial reveals new subtypes of advanced pancreatic cancer

Researchers identify five subtypes of pancreatic cancer, uncovering new opportunities for targeted treatment of the aggressive disease.

Researchers at the Ontario Institute for Cancer Research (OICR) and the University Health Network (UHN) have discovered detailed new information about the subtypes of pancreatic cancer. A better understanding of the disease groups may lead to new treatment options and improved clinical outcomes for this lethal disease.

The study, published today in Nature Genetics, represents the most comprehensive analysis of the molecular subtypes of pancreatic cancer to date. Through detailed genomic and transcriptomic analyses, the research group identified five distinct subtypes of the disease (Basal-like-A, Basal-like-B, Classical-A, Classical-B, and Hybrid) with unique molecular properties that could be targeted with novel chemotherapies, biologics and immunotherapies.

GENetic Education, Risk Assessment

Genetics play a role in up to 10 percent of pancreatic cancer cases. However, family members of pancreatic cancer patients often are not aware that certain genetic mutations can be passed down, which is why having information about genetic risk is so important. The GENERATE (GENetic Education, Risk Assessment, and TEsting) Study is designed for people who have a close relative with pancreatic cancer that was caused by an inherited mutation in a gene. The goal of this study, which will enroll up to 1,000 participants, is to improve genetic testing and cancer prevention in family members of pancreatic cancer
patients with identifi ed mutations.

Working in the lab.

Pancreatic Cancer and Genetics: Is There Genetic Testing for Pancreatic Cancer Patients?

According to the National Comprehensive Cancer Network (NCCN)’s 2019 Clinical Practice Guidelines, all pancreatic cancer patients should undergo genetic or germline testing for inherited genetic mutations, regardless of family history. Under these new recommendations, this testing should be done by a physician and the cost should be covered by insurance. The Lustgarten Foundation also encourages genetic testing, as there are options for screening programs if this testing demonstrates an inherited mutation.

Germline Testing for Inherited Risk

A gene mutation is a permanent alteration in the DNA sequence that makes up a gene.

A germline (genetic) mutation is an inherited mutation, passed down from your parents. These germline mutations are likely to be important for pancreatic cancer development. About 10% of pancreatic cancer patients carry an inherited, germline mutation, which can increase the risk of certain cancers, including not only pancreatic cancer, but also breast, ovarian, and prostate cancers. Six genes in particular contain mutations that may be passed down in families and increase a person’s pancreatic cancer genetic risk; BRCA1, BRCA2, CDKN2A, TP53, MLH1 and ATM.

If someone does have an inherited risk, there may be options for more frequent screening to identify cancer or pre-cancer at an earlier stage. The GENERATE (GENetic Education, Risk Assessment, and TEsting) Study (http://generatestudy.org/) is for people who have a close relative with pancreatic cancer that was caused by an inherited mutation in a gene.  Funded by The Pancreatic Cancer Collective, an initiative of the Lustgarten Foundation and Stand Up To Cancer, the study provides genetic education and testing in people’s homes. The study is recruiting up to 1,000 participants from families with a germline genetic mutation in one of the following: APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11 or TP53. Participants will mail in a saliva sample and receive genetic testing at no cost. They will also be required to complete a series of four short follow-up questionnaires. Local genetic counseling and support services will be provided to everyone in the study.

Anyone who would like genetic testing performed, but does not qualify for the GENERATE Study, can purchase this service through Color Genomics (https://www.color.com) or Myriad Genetics (https://myriad.com).

Molecular Profiling for an Informed Treatment Plan

Molecular profiling offers a blueprint of what’s happening in a tumor by identifying somatic mutations.

Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations may have the ability to cause cancer.

Molecular profiling tests analyze DNA, RNA, and protein in cancer cells to gain information that can be used to inform treatment decisions. Some molecular profiling tests may use one, two, or a combination of technologies to uncover information about the tumor. The findings are then used to identify new treatment programs for patients, which may include off-label use of medications that treat other cancers. The results can also be used to recommend enrollment in clinical trials testing new therapies.

For pancreatic cancer, there are two key examples of how molecular profiling can identify patients who are likely to respond to a given therapy: BRCA and MSI.

In human cells, both normal activities and environmental factors such as radiation can cause DNA damage. When normal DNA repair processes fail, irreparable DNA damage may occur.  This can eventually lead to cancer. BRCA1 and BRCA2 help repair damaged DNA.  Approximately 3 to 5 percent of pancreatic cancer patients carry mutations in either BRCA1 or BRCA2.  There is also a concept called BRCAness, which involves mutations in other key BRCA-related genes such as PALB2, ATM, or CHK2.  When you include these other BRCA-related genes, the target population in pancreatic cancer could be as high as 17 percent.

PARP (poly ADP-ribose polymerase) is an enzyme that plays a significant role in DNA repair. In patients who have defects in the ability of their cells to repair DNA, such as mutations in the BRCA genes, their cells are unable to repair these DNA breaks.  If a patient with a BRCA mutation receives a PARP inhibitor, tumor cells die, and normal cells are spared.

Microsatellite instability (MSI) is a change that occurs in the DNA of certain tumor cells because of defects in DNA mismatch repair. MSI is found in 1 in 50 advanced pancreatic cancer patients. Keytruda® (pembrolizumab) is effective for some patients with pancreatic cancer with high MSI. Keytruda targets PD-1, a checkpoint protein on immune system cells called T cells, that normally prevents T cells from attacking healthy cells in the body. By targeting PD-1, this drug boosts the immune response against pancreatic cancer cells and can often shrink tumors. Keytruda is the first cancer drug based on a genetic characteristic, rather than tumor site, to be approved by the FDA for use in pancreatic cancer patients. The Lustgarten Foundation played a critical role in bringing this new treatment to patients by funding the research, encouraging patients to get tested, and funding patients’ testing to determine if their tumors are mismatch repair deficient.

Knowing patients’ tumor (somatic) mutations and genetic (germline) mutations will help their oncologists to create the most effective, customized treatment plan and will enable patients to alert family members so they can undergo genetic testing for pancreatic cancer and early detection screening.  Both are critical to gain an advantage against pancreatic cancer.

U-M Team Sheds New Light on the Role of Regulatory T Cells in Pancreatic Cancer

In mouse models, the work uncovers a new potential target to improve immunotherapy approaches to the deadly disease.

A multidisciplinary Michigan Medicine team is shedding new light on the role of regulatory T cells in pancreatic cancer — and, in mouse models, have uncovered a new potential target to improve immunotherapy approaches to the deadly disease.

Regulatory T cells are a subpopulation of immune cells that help keep the immune system from going overboard and running amok, but if the system is tamped down too much it can end up protecting cancer cells from the body’s own defenders.

Pancreatic Cancer Cells Secrete Signal that Sabotages Immune Attack on Tumors

A key immune signal has a previously unknown role in turning off the immune system’s attack on pancreatic cancer cells, a new study finds.

Led by researchers at NYU Grossman School of Medicine, the study found that an immune signaling protein, interleukin-1β (IL-1β), is made and released by pancreatic tumor cells. This was shown to reduce anti-cancer immune responses, which promoted the growth of pancreatic ductal adenocarcinoma or PDA, a form of cancer that is usually deadly within two years.

Published online in Cancer Research, a journal of the American Association for Cancer Research, on January 8, the study found that blocking the action of IL-1β in mice with immune proteins called antibodies caused a 32 percent decrease in PDA tumor growth.

New Procedure Saves Lives Through Early Pancreatic Cancer Detection

Overall cancer survival has dramatically improved over the past two decades. However, the prognosis for pancreatic cancer remains bleak, with five-year survival at just 9 percent.

Patients usually don’t have symptoms until the cancer is advanced, making early diagnosis and treatment a challenge. Now, a study by researchers at The Ohio State University Wexner Medical Center finds a new diagnostic method that provides doctors with a “virtual biopsy” that allows them to definitively diagnose cysts in the pancreas and eliminate those that pose a risk of cancer.

“Pancreatic cysts are common, and it can be difficult to determine which are benign and which will be cancerous, but this procedure allows us to do that quickly and with confidence,” said Dr. Somashekar Krishna, a gastroenterologist at The Ohio State University Wexner Medical Center and lead author of the study.

John Lewis likely to stay in D.C. for treatment of pancreatic cancer

U.S. Rep. John Lewis is expected to remain in Washington to receive treatment for stage 4 pancreatic cancer, a diagnosis he announced Sunday. That treatment, according to medical experts, is likely to focus on preventing the disease from spreading further and inhibiting symptoms from growing worse. Dr. Bassel El-Rayes is an oncologist and clinical researcher with an emphasis on pancreatic cancer at the Winship Cancer Institute at Emory University. He has no direct knowledge of Lewis’ case but has worked with many other patients facing a similar diagnosis. One of the first things he explains to them is that successful treatment of stage 4 pancreatic cancer is not defined by curing the disease but managing it.

Lynparza approved in the US as a 1st-line maintenance treatment of germline BRCA-mutated metastatic pancreatic cancer

Lynparza reduced the risk of disease progression or death by 47% in patients
whose disease had not progressed on at least 16 weeks of a 1st-line platinum-based chemotherapy regimen

Only PARP inhibitor approved in germline BRCA-mutated
metastatic pancreatic cancer

AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) today announced that Lynparza (olaparib) has been approved in the US for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) metastatic pancreatic adenocarcinoma (pancreatic cancer) whose disease has not progressed on at least 16 weeks of a 1st-line platinum-based chemotherapy regimen. Patients will be selected for therapy based on an FDA-approved companion diagnostic for Lynparza.

AstraZeneca Says FDA Panel Backs Lynparza Use For Pancreatic Cancer

AstraZeneca and Merck & Co., said that the US Food and Drug Administration Oncologic Drugs Advisory Committee voted 7 to 5 to recommend Lynparza or olaparib as a 1st-line maintenance monotherapy for patients with germline BRCA-mutated metastatic adenocarcinoma of the pancreas (pancreatic cancer), whose disease has not progressed following 1st-line platinum-based chemotherapy. In August 2019, the FDA accepted the supplemental New Drug Application for Lynparza for this indication with Priority Review and set a Prescription Drug User Fee Act date for the fourth quarter of 2019.

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Clinical trials are critical to scientific breakthroughs and hold the promise of increasing patients’ quality of life, improving outcomes, and giving patients and their families more time together. Lustgarten-funded trials could one day lead to new treatment options and a potential cure for patients like Charlie, a patient who has undergone surgery and other treatments.

 

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