Women who carry a BRCA variant have an estimated 45-72 percent risk of developing breast cancer in their lifetime and an estimated 11-44 percent risk of developing ovarian cancer. That's compared with a 13 percent and 1 percent risk that women in the general population have of developing breast cancer or ovarian cancer, respectively. Many women choose to undergo invasive, risk-reducing surgery, including removal of the breast, ovaries, and/or fallopian tubes, to avoid a potential future cancer.
But, what if once a woman found out she carried a BRCA mutation, her care team could predict if she was likely to go on to get one of these types of cancer and when such a tumor was likely to start?
That's what a team of researchers at Cedars-Sinai are working on. They're utilizing induced pluripotent stem cell technology to use patients' cells to grow models of these women's tissues and observe whether cancer develops in the models before it develops in the patients.
They have a lot more work to do before such a test might be used outside of a clinical trial to predict a woman's cancer trajectory. However, the team has published a proof-of-concept study that suggests their tissue models of women who had been diagnosed with ovarian cancer do (and in a much shorter time frame) develop tumors in a lab, and tissue models of women who served as healthy controls (with no ovarian cancer diagnosis) did not develop tumors. The research was published online in Cell Reports (2021; https://doi.org/10.1016/j.celrep.2021.110146).
“With this technology, we can go back to the beginning of the cancer and follow the steps that led to that tumor forming,” noted study co-author Clive Svendsen, PhD, Executive Director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and Professor of Biomedical Sciences and Medicine at Cedars-Sinai, during an interview with Oncology Times.
For the work reported in this paper, the researchers took blood cells from three women who previously had ovarian cancer and blood cells from a group of women who served as healthy controls (with no history of cancer). The researchers then reprogrammed the cells to be pluripotent, meaning they could be turned into any type of cell in the body.
It has all the DNA from the person the cell came from, but researchers essentially take it back in time to a primitive state called an induced pluripotent stem cell, and in the lab you're able to grow it into any type of tissue in the body by making a small clump of cells called an organoid, Svendsen explained. It's one of many human stem cell models now being developed to learn more about the causes of disease.
For this work, the researchers turned the pluripotent cells into fallopian tube organoids, leaving them with models of the women's fallopian tubes, each in their own petri dish. Then they monitored what happened to those fallopian tube models.
“We watched them make a fallopian tube. And then we watched the cancer emerge,” Svendsen said.
For the ones that came from the women who previously had ovarian cancer, the models showed the development of ovarian cancer. The model from the woman with the most severe case of ovarian cancer developed ovarian cancer in the petri dish the quickest, and the model from the woman with the least severe cancer grew cancer cells in the petri dish the slowest. None of the models from the healthy controls developed cancer cells in the petri dishes.
Svendsen cautions that this paper only included models from three women, which is a very small number. The correlation between the rate of cancer growth in the organoid models and the severity of the women's cancers was too small to be considered statistically significant. But the data suggests this type of modeling might work and could be predictive of cancer growth for women with BRCA mutations.
“I honestly believed that it would take years to maybe see this in the dish. But it turns out that the stressors—an organoid is a stressful environment—were bringing this out within 3-6 months,” Svendsen said.
The models also help confirm the long-held conception that ovarian cancer does in fact first develop in the fallopian tubes.
Much More Data Needed
Until now, it has been really difficult to model fallopian tube cell lines to study where and how ovarian cancer develops, explained Ronny Drapkin, MD, PhD, Director of both the Ovarian Cancer Research Center and Gynecologic Cancer Research in the Basser Center for BRCA at the University of Pennsylvania Perelman School of Medicine.
“In the absence of fallopian tube cell lines from BRCA mutation carriers, many labs generated immortalized fallopian tube cell lines from cases that were not associated with cancer and did not come from high-risk individuals. The ability to circumvent this barrier by using induced pluripotent stem cells from BRCA1 mutation carriers is a significant breakthrough.”
But Drapkin believes more data is needed before it will be possible to say with certainty whether the models can truly be predictive of cancer growth in the person from which the cells came.
“While the authors carefully characterize the morphologic features of these organoids, probed for the expression of cancer-related genes, and clearly show the malignant features of the organoids, they did not perform DNA sequencing of these cells to see whether other alterations were acquired during culture (or as a result of chemotherapy since these samples came from cancer patients) that could explain the phenotype. This remains an open question,” he stated.
It is interesting that the models from patients with more severe disease had more aggressive cancerous activity than those from patients with less severe disease, he added. “This is an exciting possibility,” Drapkin noted. “A larger cohort of samples needs to be studied.”
Svendsen said the next step is indeed to replicate these findings in many more women to show that you can in fact use induced pluripotent stem cells from women with BRCA mutations to model if they will develop tumors, when those cancers will start, and how severe they will be. This involves creating organoids and repeating this process for other women with BRCA mutations who go on to develop ovarian cancer and those who don't, as well as for healthy controls.
“The next goal is testing how predictive the model is,” Svendsen said. By looking at many more women with BRCA mutations who have already developed cancer, the question is: “How predictive would this have been if we would have been able to do this from the start?”
But that will take time. To get the type of diagnostic test that the team is hoping to develop approved for use in patients requires really strong evidence.
Svendsen's group also plans to model tissue from younger women with BRCA mutations who have not yet developed cancer to see if the models can in fact correctly predict who will develop tumors and when. And the group is working on similar projects modeling breast cancer using induced pluripotent stem cells, too.
The cost of doing this type of tissue modeling is high, Svendsen noted. But hopefully if further results are equally encouraging, such a process could be scaled to make it more affordable.
Predicting Treatment Effectiveness
Another finding from this experiment was that, for the organoids from the three women with ovarian cancer, the researchers treated those cells with three different anti-cancer drugs currently used to treat ovarian cancer (olaparib, niraparib, and rucaparib). And they found that the drugs had differing efficiency in reducing cell proliferation, suggesting the model may allow screening of different drugs, prior to using in patients, to see whether they might work for that patient.
Again, Svendsen said that the data reported here is very limited given that it comes from such a small number of patients (and in this case just one). But the potential is really exciting.
If you could model patients' tumors before cancer even develops in the body or spreads and starts to cause damage, and the models could predict what types of treatments might be effective against the tumor, you might be able to treat a cancer in its very early stages or prophylactically, Svendsen said. “Maybe you could actually stop the cancer from developing with taking this drug.”
Sarah DiGiulio is a contributing writer.