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Research by UBC professor lays groundwork for life-saving breast cancer treatment

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A drug originally designed to prevent osteoporosis is now expected to save and improve the lives of millions of people with breast cancer, thanks in part to decades of foundational research by Dr. Josef Penninger, a professor in UBC’s Faculty of Medicine and director of the Life Sciences Institute.

The achievement highlights how UBC scientists are developing effective new treatments — and unlocking the full potential of existing drugs – through research into the fundamental biological principles behind disease. By advancing scientific discoveries from the lab to the clinic, UBC researchers are bringing life-changing treatments to patients everywhere.

The drug, called Denosumab, was recently shown in a long-term Phase 3 clinical trial to improve survival among postmenopausal women with hormone receptor-positive early breast cancer receiving aromatase inhibitor treatment. Moreover, the drug markedly improved patients’ quality of life by reducing broken bones by 50 per cent, a common side effect of breast cancer treatment. The results of the trial were recently reported in The New England Journal of Medicine.

Denosumab is a monoclonal antibody developed by American biopharmaceutical company Amgen to prevent bone loss. In the early 2000s, research by Dr. Penninger and his team revealed the therapeutic potential of Denosumab, as well as the drug’s surprising connections with breast cancer.

“More than two decades ago we started the experimental groundwork that revealed Donosumab’s potential as a treatment for breast cancer patients,” says Dr. Penninger. “These results are incredibly exciting and will help improve the lives of millions of patients. I am very proud of all the people in my lab over the years who did that work and helped pave the way for this achievement.”

Discovering the link between osteoporosis and breast cancer

Denosumab works by binding to and inhibiting the activity of a protein called RANKL, which plays a key role in bone-resorbing cells called osteoclasts. By blocking RANKL, denosumab reduces the activity of osteoclasts and slows down bone resorption, helping to increase bone density and preventing osteoporosis.

Dr. Josef Penninger

Dr. Penninger and his team began to draw the connection between osteoporosis and HR-positive breast cancer when they generated the first RANKL “knock-out” mice in the late 1990s.

A knockout mouse is a laboratory mouse that has been genetically engineered to have certain genes deactivated, or “knocked-out”. Dr. Penninger’s team engineered mice that lacked the genes necessary to produce the RANKL protein in an effort to study the protein’s essential function in bone metabolism.

However, to the researchers’ surprise, they discovered that the RANKL-deficient mice failed to develop a lactating mammary gland in pregnancy – a process that depends on sex hormones.

“This proved an evolutionary link: showing how bone loss is regulated by sex hormones, and how pregnant mammals activate RANKL to form breast tissue for lactation among other functions,” says Dr. Penninger.

Based on this initial finding, Dr. Penninger’s team went on to show that RANKL played a key role in progestin-driven breast cancer, as well as breast cancer driven by BRCA1 mutations.

“Further researcher revealed how RANKL controls the stem cells in the breast that respond to sex hormones and thereby drives growth of the breast tissue at every menstruation cycle and in particular in pregnancy and lactation,” adds Dr. Penninger.

In the case of breast cancer, RANKL spurs mammary epithelial cells to divide, and helps to maintain the stem cells that give rise to breast tumours.

A dual benefit drug

One in eight Canadian women will be diagnosed with breast cancer in their lifetime according to the Canadian Breast Cancer Network. An estimated 70 to 80 per cent of these breast cancers are hormone receptor-positive (HR-positive), making it the most prevalent breast cancer subtype.

The current standard treatment for HR-positive breast cancer involves surgery and radiation, followed by treatment with aromatase inhibitors for 5 to 7 years. While aromatase inhibitors diminish sex hormones that drive new cancer growth, they can have serious adverse effects on bone health, including increased risk of osteoporosis and fractures.

The now-published clinical trial, led by the Austrian Breast and Colorectal Cancer Study Group, was conducted to see if Denosumab could help in two ways: by reducing these negative effects on bone health, while also improving breast cancer survival outcomes.

“These results are incredibly exciting and will help improve the lives of millions of patients.”
Dr. Josef Penninger

The results reveal that 6 mg of Denosumab every six months — the recommended treatment level for osteoporosis — improved disease-free survival, bone metastasis-free survival, and overall survival among participants. It also effectively reduced bone fractures over the long term.

“Blocking RANKL in breast cancer patients reduces broken bones by 50 per cent, massively improving their quality of life, and even at a very low treatment dose,” says Dr. Penninger. “We now know that RANKL drives breast cancer cell growth, is the critical mechanism behind bone loss, and has also an effect on anti-cancer immunity and immunological rewiring in pregnancy. These clinical results in patients show how blocking RANKL could save the lives of 50,000 women among one million women with the diagnosis of breast cancer.”

Based on the data, the researchers behind the trials are recommending that Denosumab be considered for routine clinical use in postmenopausal breast cancer patients receiving aromatase inhibitor therapy.

These trials were largely based on the foundational research published by the Penninger laboratory, including Kong et al. Nature 1999, Fata et al. Cell 2000, Jones Nature 2006, Schramek et al. Nature 2010, Sigl et al. Cell Research 2016, and Paolino et al. Nature 2021.

Dr. Penninger is now part of a large international prevention trial evaluating Denosumab in young women who carry BRCA1 mutations.

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Pediatric group says doctors should regularly screen kids for reading difficulties

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The Canadian Paediatric Society says doctors should regularly screen children for reading difficulties and dyslexia, calling low literacy a “serious public health concern” that can increase the risk of other problems including anxiety, low self-esteem and behavioural issues, with lifelong consequences.

New guidance issued Wednesday says family doctors, nurses, pediatricians and other medical professionals who care for school-aged kids are in a unique position to help struggling readers access educational and specialty supports, noting that identifying problems early couldhelp kids sooner — when it’s more effective — as well as reveal other possible learning or developmental issues.

The 10 recommendations include regular screening for kids aged four to seven, especially if they belong to groups at higher risk of low literacy, including newcomers to Canada, racialized Canadians and Indigenous Peoples. The society says this can be done in a two-to-three-minute office-based assessment.

Other tips encourage doctors to look for conditions often seen among poor readers such as attention-deficit hyperactivity disorder; to advocate for early literacy training for pediatric and family medicine residents; to liaise with schools on behalf of families seeking help; and to push provincial and territorial education ministries to integrate evidence-based phonics instruction into curriculums, starting in kindergarten.

Dr. Scott McLeod, one of the authors and chair of the society’s mental health and developmental disabilities committee, said a key goal is to catch kids who may be falling through the cracks and to better connect families to resources, including quicker targeted help from schools.

“Collaboration in this area is so key because we need to move away from the silos of: everything educational must exist within the educational portfolio,” McLeod said in an interview from Calgary, where he is a developmental pediatrician at Alberta Children’s Hospital.

“Reading, yes, it’s education, but it’s also health because we know that literacy impacts health. So I think that a statement like this opens the window to say: Yes, parents can come to their health-care provider to get advice, get recommendations, hopefully start a collaboration with school teachers.”

McLeod noted that pediatricians already look for signs of low literacy in young children by way of a commonly used tool known as the Rourke Baby Record, which offers a checklist of key topics, such as nutrition and developmental benchmarks, to cover in a well-child appointment.

But he said questions about reading could be “a standing item” in checkups and he hoped the society’s statement to medical professionals who care for children “enhances their confidence in being a strong advocate for the child” while spurring partnerships with others involved in a child’s life such as teachers and psychologists.

The guidance said pediatricians also play a key role in detecting and monitoring conditions that often coexist with difficulty reading such as attention-deficit hyperactivity disorder, but McLeod noted that getting such specific diagnoses typically involves a referral to a specialist, during which time a child continues to struggle.

He also acknowledged that some schools can be slow to act without a specific diagnosis from a specialist, and even then a child may end up on a wait list for school interventions.

“Evidence-based reading instruction shouldn’t have to wait for some of that access to specialized assessments to occur,” he said.

“My hope is that (by) having an existing statement or document written by the Canadian Paediatric Society … we’re able to skip a few steps or have some of the early interventions present,” he said.

McLeod added that obtaining specific assessments from medical specialists is “definitely beneficial and advantageous” to know where a child is at, “but having that sort of clear, thorough assessment shouldn’t be a barrier to intervention starting.”

McLeod said the society was partly spurred to act by 2022’s “Right to Read Inquiry Report” from the Ontario Human Rights Commission, which made 157 recommendations to address inequities related to reading instruction in that province.

He called the new guidelines “a big reminder” to pediatric providers, family doctors, school teachers and psychologists of the importance of literacy.

“Early identification of reading difficulty can truly change the trajectory of a child’s life.”

This report by The Canadian Press was first published Oct. 23, 2024.

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UK regulator approves second Alzheimer’s drug in months but government won’t pay for it

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LONDON (AP) — Britain’s drug regulator approved the Alzheimer’s drug Kisunla on Wednesday, but the government won’t be paying for it after an independent watchdog agency said the treatment isn’t worth the cost to taxpayers.

It is the second Alzheimer’s drug to receive such a mixed reception within months. In August, the U.K. regulator authorized Leqembi while the same watchdog agency issued draft guidance recommending against its purchase for the National Health Service.

In a statement on Wednesday, Britain’s Medicines and Healthcare regulatory Agency said Kisunla “showed some evidence of efficacy in slowing (Alzheimer’s) progression” and approved its use to treat people in the early stages of the brain-robbing disease. Kisunla, also known as donanemab, works by removing a sticky protein from the brain believed to cause Alzheimer’s disease.

Meanwhile, the National Institute for Health and Care Excellence, or NICE, said more evidence was needed to prove Kisunla’s worth — the drug’s maker, Eli Lilly, says a year’s worth of treatment is $32,000. The U.S. Food and Drug Administration authorized Kisunla in July. The roll-out of its competitor drug Leqembi has been slowed in the U.S. by spotty insurance coverage, logistical hurdles and financial worries.

NICE said that the cost of administering Kisunla, which requires regular intravenous infusions and rigorous monitoring for potentially severe side effects including brain swelling or bleeding, “means it cannot currently be considered good value for the taxpayer.”

Experts at NICE said they “recognized the importance of new treatment options” for Alzheimer’s and asked Eli Lilly and the National Health Service “to provide additional information to address areas of uncertainty in the evidence.”

Under Britain’s health care system, most people receive free health care paid for by the government, but they could get Kisunla if they were to pay for it privately.

“People living with dementia and their loved ones will undoubtedly be disappointed by the decision not to fund this new treatment,” said Tara Spires-Jones, director of the Centre for Discovery Brain Sciences at the University of Edinburgh. “The good news that new treatments can slow disease even a small amount is helpful,” she said in a statement, adding that new research would ultimately bring safer and more effective treatments.

Fiona Carragher, chief policy and research officer at the Alzheimer’s Society, said the decision by NICE was “disheartening,” but noted there were about 20 Alzheimer’s drugs being tested in advanced studies, predicting that more drugs would be submitted for approval within years.

“In other diseases like cancer, treatments have become more effective, safer and cheaper over time,” she said. “ We hope to see similar progress in dementia.”

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The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

The Canadian Press. All rights reserved.

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Women in states with bans are getting abortions at similar rates as under Roe, report says

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Women living in states with abortion bans obtained the procedure in the second half of 2023 at about the same rate as before the U.S. Supreme Court overturned Roe v. Wade, according to a report released Tuesday.

Women did so by traveling out of state or by having prescription abortion pills mailed to them, according to the #WeCount report from the Society of Family Planning, which advocates for abortion access. They increasingly used telehealth, the report found, as medical providers in states with laws intended to protection them from prosecution in other states used online appointments to prescribe abortion pills.

“The abortion bans are not eliminating the need for abortion,” said Ushma Upadhyay, a University of California, San Francisco public health social scientist and a co-chair of the #WeCount survey. “People are jumping over these hurdles because they have to.”

Abortion patterns have shifted

The #WeCount report began surveying abortion providers across the country monthly just before Roe was overturned, creating a snapshot of abortion trends. In some states, a portion of the data is estimated. The effort makes data public with less than a six-month lag, giving a picture of trends far faster than the U.S. Centers for Disease Control and Prevention, whose most recent annual report covers abortion in 2021.

The report has chronicled quick shifts since the Supreme Court’s Dobbs v. Jackson Women’s Health Organization ruling that ended the national right to abortion and opened the door to enforcement of state bans.

The number of abortions in states with bans at all stages of pregnancy fell to near zero. It also plummeted in states where bans kick in around six weeks of pregnancy, which is before many women know they’re pregnant.

But the nationwide total has been about the same or above the level from before the ruling. The study estimates 99,000 abortions occurred each month in the first half of 2024, up from the 81,000 monthly from April through December 2022 and 88,000 in 2023.

One reason is telehealth, which got a boost when some Democratic-controlled states last year began implementing laws to protect prescribers. In April 2022, about 1 in 25 abortions were from pills prescribed via telehealth, the report found. In June 2024, it was 1 in 5.

The newest report is the first time #WeCount has broken down state-by-state numbers for abortion pill prescriptions. About half the telehealth abortion pill prescriptions now go to patients in states with abortion bans or restrictions on telehealth abortion prescriptions.

In the second half of last year, the pills were sent to about 2,800 women each month in Texas, more than 1,500 in Mississippi and nearly 800 in Missouri, for instance.

Travel is still the main means of access for women in states with bans

Data from another group, the Guttmacher Institute, shows that women in states with bans still rely mostly on travel to get abortions.

By combining results of the two surveys and comparing them with Guttmacher’s counts of in-person abortions from 2020, #WeCount found women in states with bans throughout pregnancy were getting abortions in similar numbers as they were in 2020. The numbers do not account for pills obtained from outside the medical system in the earlier period, when those prescriptions most often came from abroad. They also do not tally people who received pills but did not use them.

West Virginia women, for example, obtained nearly 220 abortions monthly in the second half of 2023, mostly by traveling — more than in 2020, when they received about 140 a month. For Louisiana residents, the monthly abortion numbers were about the same, with just under 700 from July through December 2023, mostly through shield laws, and 635 in 2020. However, Oklahoma residents obtained fewer abortions in 2023, with the monthly number falling to under 470 from about 690 in 2020.

Telehealth providers emerged quickly

One of the major providers of the telehealth pills is the Massachusetts Abortion Access Project. Cofounder Angel Foster said the group prescribed to about 500 patients a month, mostly in states with bans, from its September 2023 launch through last month.

The group charged $250 per person while allowing people to pay less if they couldn’t afford that. Starting this month, with the help of grant funding that pays operating costs, it’s trying a different approach: Setting the price at $5 but letting patients know they’d appreciate more for those who can pay it. Foster said the group is on track to provide 1,500 to 2,000 abortions monthly with the new model.

Foster called the Supreme Court’s 2020 decision “a human rights and social justice catastrophe” while also saying that “there’s an irony in what’s happened in the post-Dobbs landscape.”

“In some places abortion care is more accessible and affordable than it was,” she said.

There have no major legal challenges of shield laws so far, but abortion opponents have tried to get one of the main pills removed from the market. Earlier this year, the U.S. Supreme Court unanimously preserved access to the drug, mifepristone, while finding that a group of anti-abortion doctors and organizations did not have the legal right to challenge the 2000 federal approval of the drug.

This month, three states asked a judge for permission to file a lawsuit aimed at rolling back federal decisions that allowed easier access to the pill — including through telehealth.

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