Cancer
New insights into the origins of ovarian cancer
Researchers have identified a novel trigger of a deadly form of ovarian cancer: a subset of progenitor cells that reside in fallopian tube supportive tissue, or stroma.
The discovery of these high-risk cells could pave the way for better approaches to prevent and detect high-grade serous ovarian cancer (HGSOC), the most common form of ovarian cancer, which kills more than 12,000 women in the U.S. each year.
“Ovarian cancer is the leading cause of death from gynaecologic cancer in the Western world, but we currently have no way to detect it early and no prevention strategies apart from surgical castration, which is only indicated in high-risk women,” said co-senior author Lan Coffman, associate professor at the Pitt School of Medicine and member of Magee-Womens Research Institute and UPMC Hillman Cancer Center.
“Understanding the underlying biology of how ovarian cancer forms is critical to improving outcomes for our patients.”
HGSOC begins in the fallopian tubes when healthy epithelial cells transform into precursor lesions known as serous tubal intraepithelial carcinoma (STIC). Similar to how precancerous colon polyps can become colorectal cancer, STIC lesions often develop into HGSOC tumours.
But why do healthy cells become STIC? To find out, Coffman and her team turned to the stroma, the non-cancerous connective tissue that helps cancer grow.
“Most researchers have been focused on the epithelial cells that turn into these STIC lesions and eventually into cancer,” said Coffman. “Until now, no one has really looked at the surrounding stromal microenvironment of these lesions.”
In the stroma of ovarian cancer, a type of progenitor cell normally involved in growth and repair of healthy tissue, mesenchymal stem cells (MSCs), become reprogrammed by tumour cells to support cancer growth. Coffman started by asking when these cancer-associated MSCs form and how early they play a role in cancer formation.
When she and her team profiled MSCs in the fallopian tubes of patients who did not have cancer, they were surprised to find cells that looked like cancer-associated MSCs in these healthy women.
These cells, which the researchers named high-risk MSCs, were more common in women with higher risk of ovarian cancer, those of older age or with mutations in the BRCA gene, suggesting that they play a role in cancer initiation.
When the researchers introduced these high-risk MSCs into organoids, or mini organs, derived from patient fallopian tube tissue, healthy epithelial cells transformed into cancerous cells.
“High-risk MSCs promote DNA damage in epithelial cells and then help those mutated cells survive,” explained Coffman.
“It’s the perfect storm for cancer initiation.”
High-risk MSCs also promoted tumour cell growth and increased resistance to a chemotherapy drug.
In search of a mechanism for why high-risk MSCs drive ovarian cancer, the researchers found that these cells have loss of an antioxidant called AMP kinase. Lower levels of AMP kinase led to higher levels of a protein called WT1, which in turn drove formation of compounds that cause DNA damage.
“This is the first report that stromal changes in the fallopian tube actually have a causative role in ovarian cancer initiation,” said Coffman.
“It also points to a path where we might be able to intervene.”
For example, already existing drugs that upregulate AMP kinase could potentially prevent or reverse early changes in the stroma that lead to ovarian cancer.
The findings could also inform approaches for early detection, which are sorely lacking for ovarian cancer. According to Coffman, compounds secreted by high-risk MSCs that are detectable in the bloodstream could act as biomarkers for early-stage ovarian cancer.
A new ovarian cancer drug has been approved for NHS use in England, offering hundreds of women with hard-to-treat disease a life-prolonging treatment.
Elahere is the first new drug for chemotherapy-resistant ovarian cancer to be approved by the NHS for more than 20 years.
Ovarian cancer is the 18th most common type of cancer globally, affecting more than 300,000 women a year.
More than three-quarters of patients are diagnosed at an advanced stage, making the disease harder to treat.
Prof Ruth Plummer, national clinical lead for cancer drugs at NHS England, said: “This represents the most significant breakthrough in NHS treatment for these hard-to-treat ovarian cancers in over two decades – and we’re delighted it will now offer hundreds of women much-needed hope of precious extra time with their loved ones.”
Standard treatment for ovarian cancer usually involves surgery and chemotherapy, but about 80 per cent of patients with advanced disease relapse and most eventually develop resistance to chemotherapy.
According to the National Institute for Health and Care Excellence, patients with folate receptor-alpha-positive platinum-resistant epithelial cancers have until now had limited options when their tumours stop responding to standard chemotherapy.
Now NICE has approved mirvetuximab soravtansine, also known as Elahere, for patients with epithelial ovarian, peritoneal or fallopian tube cancer that has become resistant to platinum-based chemotherapy and whose tumours contain the FRα protein that the drug targets.
FRα is a protein found on the surface of some cancer cells.
NHS England said up to 400 women a year in England could benefit, in what it described as a major milestone for treatment.
Mirvetuximab soravtansine is given through a drip once every three weeks.
A global clinical trial involving eight NHS hospitals found that the treatment delayed cancer progression and prolonged survival by an average of four months, compared with chemotherapy alone, with more manageable side-effects.
Cancer progression means the disease is growing, spreading or worsening.
In 37 per cent of patients, tumours shrank by at least 30 per cent, compared with 16 per cent of those given chemotherapy.
The drug, made by AbbVie, combines a “homing” antibody, which seeks out the FRα protein on the surface of cancer cells, with a cancer-killing molecule that destroys the cell from within.
Experts said the decision was a seminal moment and could significantly improve the quality of life of affected patients.
Rachel Downing, head of policy and external affairs at Target Ovarian Cancer, said: “This is a hugely important moment for women with platinum-resistant ovarian cancer and their families, who have faced limited effective treatment options for far too long. Today’s announcement offers real hope of improved quality of life.”
Victoria Clare, chief executive of the charity Ovacome, said: “Today marks a landmark moment. Being told that platinum-based chemotherapy is no longer working can bring anxiety and uncertainty, particularly when the disease is at an advanced stage, where time and options are limited.
“This recommendation is the first in over 20 years to offer the ovarian cancer community an additional choice at a critical stage, with the potential to make a real difference to patients and their families.”
Helen Knight, director of medicines evaluation at NICE, said: “We heard clearly from patients and clinicians about the very limited options available at this stage of the disease and the substantial burden that chemotherapy places on women’s lives.
“We are pleased that, following a robust process and a new commercial arrangement with AbbVie, we are now able to recommend this treatment for NHS use.”
AI may help speed breast cancer diagnosis for high-risk women after abnormal mammograms, a study suggests.
Women with abnormal mammograms often wait weeks to learn whether they have breast cancer.
Researchers at UC San Francisco and UC Berkeley said an AI-guided workflow could help reduce that wait by quickly identifying those most likely to have the disease. Some women could move from imaging to evaluation, and sometimes biopsy, in a single day.
Dr Maggie Chung, first author of the study, said: “This is a really an exciting time.
“This moves us closer to personalised care, where we can tailor a plan so that each patient gets the right intervention at the right time.”
The study used an open-source AI model called Mirai.
The model was trained on hundreds of thousands of mammograms linked to patients’ cancer outcomes.
A mammogram is an X-ray scan of the breast used to look for signs of cancer. A biopsy involves taking a small tissue sample to test for disease.
The AI tool is designed to detect subtle patterns in screening mammograms and predict a woman’s cancer risk.
Researchers at UC San Francisco and UC Berkeley applied the model to more than 4,100 screening mammograms at Zuckerberg San Francisco General Hospital and Trauma Center.
Mirai identified 525 women, about 12.7 per cent of screened patients, as high risk.
Those patients could receive an interpretation of their mammograms immediately after the scan and have additional diagnostic imaging for suspicious areas on the same day.
Some women who needed biopsies were also able to have them on the same day.
The researchers said Mirai reduced the wait time for diagnostic evaluation from several weeks to about an hour.
For women who were ultimately diagnosed with breast cancer, it reduced the average wait for biopsy from more than two months to fewer than 10 days.
The researchers stressed that Mirai does not replace radiologists or make diagnoses on its own.
Instead, it acts as a triage tool to help physicians identify the patients who can benefit most from accelerated care.
The team analysed more than 114,000 archival mammograms before launching the programme, to ensure the model would capture enough high-risk patients without overloading the clinic with too many expedited evaluations.
The researchers said they hope AI will support a more personalised approach to breast cancer screening tailored to each patient’s breast cancer risk.
Chung said: “Right now, many women follow the same screening schedule but their individual risk can be very different.
“AI risk assessment gives us the chance to identify the women most likely to benefit from expedited care and get them what they need.”
Adam Yala, senior author of the study and a data scientist at UC Berkeley, said: “This is a powerful example of how AI can be a collaborative partner for physicians.
“It shows how we can improve care when we bring clinicians and data scientists together to design these systems.”
A genomic test may help some women with breast cancer avoid chemotherapy, with near-identical outcomes in an international trial.
The findings suggest patients with a low test score could be treated with hormone therapy alone without increasing the risk of their cancer returning.
Researchers said the results could support more personalised treatment decisions and spare some women the side-effects of chemotherapy.
Prof Rob Stein, the trial’s chief investigator and a professor of breast oncology at UCL, said: “Optima addresses a longstanding challenge in breast cancer care: identifying who truly benefits from chemotherapy and who does not.
“Our findings show that many patients can safely avoid chemotherapy without compromising their outcomes.
“These results mark an important and significant step toward more personalised treatment.
“The trial has successfully used tumour biology to guide decisions rather than relying solely on traditional clinical features.”
Breast cancer treatment usually involves surgery to remove tumours. Chemotherapy is then often recommended if doctors believe there is a risk the disease will return.
Chemotherapy can cause side-effects including hair loss, rashes, nausea, insomnia and fatigue. Some women may also face longer-term consequences such as infertility, cognitive impairment or early menopause.
The Optima trial followed more than 4,000 patients with newly diagnosed breast cancer in the UK, Norway, Sweden, Australia, New Zealand and Thailand.
The trial was led by University College London.
One woman who took part in the trial told the Guardian that being able to skip chemotherapy felt “like Christmas”. Nine years after being diagnosed, taking the test and skipping chemotherapy, she is healthy and enjoying a full and active life.
The trial tested whether a genomic test could identify which patients need chemotherapy and which could safely avoid it.
The Prosigna test, made by diagnostics company Veracyte, analyses the activity of 50 genes in tumour tissue. It identifies the molecular subtype of the cancer and gives a score estimating the risk of breast cancer returning in the next 10 years.
The randomised trial involved 4,429 patients aged 40 or over with hormone-positive breast cancer. Hormone-positive breast cancer grows in response to hormones such as oestrogen or progesterone. It is the most common form of breast cancer, accounting for up to 80 per cent of cases globally.
Participants were assigned to one of two groups. In the standard treatment group, patients received chemotherapy followed by hormone therapy.
In the second group, patients had their tumours analysed using the genomic test. Those with a high score received chemotherapy and hormone therapy. Those with a low score received hormone therapy alone.
Radiotherapy and other treatments were given as usual in both groups.
In the second group, outcomes were very similar whether chemotherapy was given or not. Five years after treatment, 95 per cent of patients who had chemotherapy and hormone therapy were alive and free from breast cancer recurrence, while 94 per cent of those who skipped chemotherapy were also alive and recurrence-free.
The findings suggest chemotherapy offered little or no additional benefit for patients with low test scores.
Some men also took part in the study, but researchers said there were too few to draw firm conclusions for this group.
The trial received funding from the National Institute for Health and Care Research, Veracyte and cancer charities.
Prof Iain MacPherson, a co-chief investigator and professor of breast oncology at the University of Glasgow, said: “Optima provides robust, practice-changing evidence that we can safely reduce the use of chemotherapy for many patients with hormone-sensitive breast cancer.
“These findings represent a major step forward in delivering more personalised, precise care, ensuring that treatment decisions are driven by what will genuinely improve outcomes for patients, while avoiding unnecessary toxicity.
“The potential impact for both patients and health services is substantial.”
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