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New study shows breast tumors evolve in response to hormone therapy

Many breast tumors grow in response to female hormones, especially estrogen. Drugs that reduce estrogen levels in the body often are effective in reducing tumor size and preventing recurrence of the cancer. But some tumors become resistant to these therapies and continue to grow and spread.

A new analysis of breast tumors, before and after hormone-reduction therapy, reveals the extreme genetic complexity of these tumors and the variety of responses that are possible to estrogen-deprivation treatments. The findings also suggest that analyzing a single sample of the breast tumor is insufficient for understanding how a patient should best be treated.

The study, led by researchers at The McDonnell Genome Institute at Washington University School of Medicine in St. Louis and Baylor College of Medicine, appears Aug. 9 in the journal Nature Communications.

“Estrogen-receptor-positive breast cancers are not created equal,” said co-senior author Elaine R. Mardis, PhD, the Robert E. and Louise F. Dunn Distinguished Professor of Medicine and co-director of the McDonnell Genome Institute. “Each woman’s disease can have a range of responses to estrogen-lowering drugs. This study demonstrates that reducing estrogen levels in estrogen-receptor-positive breast cancer changes the genetics of the tumor, and these changes may be important for deciding how best to treat a patient after the surgical removal of the tumor.”

The researchers analyzed 22 breast tumors before and after four months of treatment with aromatase inhibitors, drugs commonly given to post-menopausal women with breast cancer. After menopause, the ovaries no longer produce estrogen, and aromatase inhibitors block the body’s remaining production of the hormone. Successful treatment reduces the size of a tumor before it is surgically removed, and the therapy has been shown to improve long-term outcomes for patients.

“In the post-treatment tumor samples, we found many new mutations or enrichment of mutations already seen in the pre-treatment samples,” said co-senior author Matthew J. Ellis, professor and director of the Lester and Sue Smith Breast Center at Baylor. “This means that under the environmental stress of the treatment, the tumors are spawning new sub-clones that subsequently can survive and grow despite therapy, and that is why we are having difficulty in the end treating estrogen-receptor-positive breast cancer. We found this result in the majority of tumors we studied.”

The majority of the tumors analyzed — 18 of 22 — had complex genetic landscapes and dynamic responses to hormone deprivation therapy, meaning that many of the gene mutations present in the tumors before and after treatment were different. For example, in one patient, certain mutations present in 92 percent of the initial tumor were totally absent in samples taken after four months of aromatase inhibitor therapy.

“The broad implication is that patients who undergo aromatase inhibitor therapy for several months prior to surgery should be re-evaluated immediately before their operation to determine how the tumor may have changed in response to the therapy,” Mardis said. “Such information can help indicate whether further estrogen suppression treatment is likely to contribute to a lower risk of relapse.”

The researchers analyzed only one tumor that had a complex but stable genetic landscape, meaning it was largely unchanged by aromatase inhibitor treatment. Another tumor had very simple and stable genetics before and after treatment. And two patient samples indicated evidence of two independent but intertwining tumors with separate genetic origins.

“It was surprising to find two ‘collision’ tumors in a group of only 22 patients,” said first author Christopher A. Miller, PhD, an instructor in medicine at Washington University. “This hints that collision tumors may be more common than we have previously realized. In these cases, estrogen suppression was the right approach for one of the tumors, but not the other, which limited the effectiveness of the treatment.”

“Our study also demonstrated that even single tumors can evolve in response to therapy very quickly,” Miller added. “This suggests that sequencing a tumor at diagnosis is not enough. Periodically scanning a tumor’s genome to understand how it is changing may ultimately help us evolve our treatment strategies to match.”

The study also reinforced past research suggesting that mutations in a gene called ESR1 are associated with resistance to aromatase inhibitor therapy, but the analysis did not identify any new genes that may also be responsible for conferring resistance to these drugs.

Study finds marker of aggressive prostate cancer

The level of a specific molecule present in prostate tumors is an indicator of whether the cancer is aggressive and likely to spread, according to new research from Washington University School of Medicine in St. Louis.

The study, available online in the journal European Urology, may inform future clinical tests that help doctors decide how best to treat prostate tumors. Many men with prostate cancer have slow-growing tumors that do not require surgery, radiation or other treatments that can leave patients impotent, incontinent or both. But doctors often have difficulty telling the difference between these indolent tumors and those that will prove to be more aggressive.

“Distinguishing patients who have indolent versus aggressive prostate cancer is probably one of the biggest challenges in the field,” said senior author Christopher A. Maher, PhD, an assistant professor of medicine. “Our study suggests that levels of a molecule called PCAT-14 may be a marker of whether the tumor is likely to be aggressive, helping doctors decide whether to intensify a patient’s treatment.”

The scientists measured levels of PCAT-14 from prostate tumors after their surgical removal. Maher said one of his group’s goals is to design a noninvasive method, such as a urine test, to make the same measurement.

The scientists found that levels of PCAT-14 — an RNA molecule — were elevated across 180 prostate cancer patients treated at three different institutions. Analyzing another 910 tumor samples from patients with known treatment outcomes, the researchers also showed that the patients with more aggressive tumors, perhaps surprisingly, had lower levels of PCAT-14. Patients with slow-growing tumors had higher levels of the molecule. That may seem counterintuitive, but according to Maher, the data suggest that high levels of this RNA molecule suppress tumor spreading. So when levels decrease, that suppression is lost and the cancer cells are free to metastasize.

Past work by Maher and his colleagues has identified PCAT-14 as one of 121 similar RNA molecules strongly associated with prostate cancer. Many of the other PCAT molecules they found associated with a variety of cancers, including prostate, but PCAT-14 was specifically found only in prostate cancer. RNA is similar in structure to DNA and serves various functions in cells, especially in turning genes on and off.

“We looked at all similar RNA molecules in these prostate tumors,” Maher said. “Only PCAT-14 was consistently altered in all prostate cancer patients and able to distinguish indolent and aggressive disease.”

Working with aggressive prostate cancer cells in the lab, the researchers showed that dialing up levels of PCAT-14 appeared to build up barriers to cancer spreading, slowing the growth and mobility of these normally aggressive cells. Likewise, dialing down levels of PCAT-14 appeared to remove barriers to spreading, making these cells even more aggressive, increasing the number of cells and their ability to move.

Maher and his colleagues also showed that low levels of PCAT-14 were associated with poor response to androgen deprivation therapy, a hormone-based treatment for prostate cancer that is less toxic than chemotherapy and radiation therapy. Prostate tumor growth often is driven by male hormones, such as testosterone. Depriving prostate tumors of hormonal fuel can slow or stop growth, but some tumors grow even in a state of hormone deprivation.

“We suspect that PCAT-14 may be a good predictor of whether patients will respond well to androgen deprivation therapy,” Maher said. “Low PCAT-14 means the cells are likely to grow and spread even when deprived of androgens.”

With improving diagnosis and treatment in mind, Maher said the development of a noninvasive test to measure levels of PCAT-14 could reduce the need for biopsy or removal of the prostate. This is an advantage of identifying a molecule that is only present in the prostate, according to Maher. In theory, if this molecule can be detected in a urine sample, for example, there would be no question it would indicate a problem with the prostate rather than some other organ, such as the kidney or bladder.

Potential drug target identified for deadly brain cancer

Glioblastoma is the most common and deadly form of brain cancer in adults, with an average survival time of only 15 months after diagnosis. New research at Washington University School of Medicine in St. Louis provides clues to why some patients with glioblastoma fare worse and identifies a drug target that potentially could improve survival.

The research shows that glioblastoma patients with a protein called oncostatin M receptor on their tumors face a particularly poor prognosis. Further, the findings suggest that treatments that target the receptor have the potential to halt progression of the especially aggressive tumor.

The research is available online in Nature Neuroscience.

“None of the treatments developed for glioblastoma over the past decades has been effective,” said senior co-corresponding author Azad Bonni, MD, PhD, the Edison Professor of Neuroscience and head of the Department of Neuroscience at Washington University. “We wanted to go back to the basic science and understand how these tumors arise so that we can identify new targets for potential therapy.”

Tumors arise when cells accumulate mutations that allow them to escape normal constraints and start multiplying uncontrollably. The typical tumor cell carries mutations in multiple genes, and the effect of mutating one gene can depend on which other genes also are mutated in the cell.

For example, earlier work by Bonni and colleagues at Harvard Medical School had shown that a protein called STAT3 protects against tumor formation, unless a mutated form of another protein, epidermal growth factor receptor (EGFR), is present. In such cases, STAT3 switches from protecting against tumor growth to actively promoting tumors.

More than half of glioblastoma tumors contain mutations in the gene for EGFR or the sections of DNA that control how much EGFR is produced. Researchers reasoned that since mutated EGFR promotes tumor formation, inhibiting it should shrink tumors. Drugs that target EGFR, however, have had little effect on the survival of glioblastoma patients.

“It looked like we were missing something in the EGFR-STAT3 pathway,” Bonni said. “If inhibiting EGFR didn’t work, maybe it was because we needed to hit something else, too.”

Using brain tumor stem cells derived from human tumors, Arezu Jahani-Asl, PhD – lead author of the study and an assistant professor at McGill University – and colleagues looked for other genes in the pathway. They found that the oncostatin M receptor, a protein associated with cell proliferation, was produced in cells that carried both STAT3 and the mutated form of EGFR. Furthermore, the receptor paired up with the mutated EGFR to trigger the production of even more of the receptor in a positive feedback loop.

“Oncostatin M receptor started looking like an important target because it amplifies the EGFR pathway, which we already know is important in glioblastoma,” Bonni said. “But before going further, we asked, ‘Is this really relevant to human patients?’”

Two publicly available databases collect information about the molecules expressed on tumors from individual patients and how long those patients survived. In both datasets, the researchers found that the more oncostatin M receptor on the tumor, the sooner the patient died.

The researchers then removed the receptor gene from human brain tumor stem cells and injected the modified cells into mice. The cells lacking the receptor formed tumors a fraction of the size of those formed by the same human brain tumor stem cell line with the receptor, indicating that the protein plays a key role in tumor formation, growth or both.

“Being able to stop tumor formation entirely was a dramatic and shocking result,” said senior co-corresponding author Michael Rudnicki, PhD, a professor at the University of Ottawa. “It means that this protein is a key piece of the puzzle and could be a possible target for future treatments.”

Scientists now are looking for drugs that can inhibit the receptor or block its interaction with EGFR. Such drugs potentially could lengthen survival times for glioblastoma patients.

“It really gets down to personalized medicine,” Bonni said. “People whose tumors don’t express the receptor wouldn’t see an effect. But for people who overexpress the receptor, blocking it might really help.”

Study aims to find clues to breast cancer outcomes in African-American women

Scientists’ understanding of the genetic roots of breast cancer is based largely on research conducted in women of European ancestry.

That knowledge does little to help explain why African-American women with the disease are more likely to be diagnosed at younger ages and with more aggressive tumors than their white counterparts. They also die of breast cancer at higher rates.

Now, researchers at Washington University School of Medicine in St. Louis are launching a major study in African-American women with breast cancer to learn whether their genetic risks are influenced by the same mutations that affect white women or are altogether different mutations. Such information may lead to new ways to prevent or treat breast cancer in African-American women.

“We’ve had a revolution in genetic testing over the past 10 years,” said the study’s senior investigator, Laura Jean Bierut, MD, the Alumni Endowed Professor of Psychiatry. “We’ve been able to identify many gene variants that contribute to a variety of cancers, including breast cancer. But as you examine the data, you realize most of these studies have been done in populations of European ancestry and that we don’t understand very much about the genetic causes of cancer in other populations, particularly in African-American women.”

According to the National Cancer Institute, African-American women with breast cancer often are diagnosed with the disease at younger ages, and they have a higher incidence of a particularly aggressive form of breast cancer, called the triple-negative subtype, than women from other racial and ethnic groups.

“Better understanding of the genetics of the disease in African-American women could be very helpful in earlier diagnosis, prevention and treatment,” said co-investigator Foluso Ademuyiwa, MD, an assistant professor of medicine in the Division of Medical Oncology.

In this new study, the researchers will enroll African-American women who have had breast cancer, regardless of when their diagnoses occurred. Bierut, who serves as the principal investigator of several national genetic studies, has teamed with Ademuyiwa and other researchers at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine to analyze the participants’ DNA.

At the same time, the National Institutes of Health (NIH) is launching a study to investigate how genetic and biological factors contribute to breast cancer risk in black women. As part of that study, researchers will compare the genomes of African-American women with breast cancer to the genomes of black women who don’t have the disease and to the genomes of white women who do. That study will share specimens, data and resources from 18 previous studies.

The Washington University study will gather and analyze new DNA samples from African-American women diagnosed with breast cancer. The researchers will conduct brief surveys with study volunteers to learn about their risk factors for breast cancer, such as family history, hormonal treatments the women may have undergone, and the number of children each may have had. After each interview, study volunteers will provide the researchers with two saliva samples to be sent to one of two commercial genomics companies for sequencing.

The companies — Color Genomics and 23andMe Inc. — will test each woman’s DNA, and the researchers will provide every study participant with an opportunity to find out what the genetic testing determines about the risk factors for breast cancer each woman carries.

The researchers also will offer participants genetic counseling, and they will contact study subjects about three months after the initial survey to determine whether they have shared the findings with family members who may have similar genetic risks for breast cancer, and with their physicians.

“Testing has become so easy that we don’t even need to do a blood draw,” Bierut said. “With saliva samples, we can analyze a woman’s DNA and take a look at known genetic variants that contribute to breast cancer. We also expect to find other, previously unidentified genetic variants specific to African-American populations. Our main goal is to improve diagnosis and treatment for these women.”

The study’s initial phase will involve only women in the St. Louis area. For more information, or to volunteer for the study, call 314-286-1393 or e-mail [email protected].

Sasa Mutic honored as innovator

Celebrating innovation in St. Louis, the St. Louis Business Journal on June 23 honored area individuals and companies with the publication’s third annual Innovation Awards. Among those honored were Sasa Mutic, PhD, director of the Medical Physics Division in the Department of Radiation Oncology at Washington University School of Medicine. He also is a Siteman Cancer Center research member.

The Business Journal selected individuals and companies demonstrating cutting-edge advancements that have propelled St. Louis to become one of the nation’s top tech hubs.

Mutic, who was honored in the award’s medical category, was recognized for his innovations in radiation therapy to treat cancer.

Among his achievements, Mutic co-founded Radialogica, a health-care information technology company that is helping the university perform audits of its radiation oncology facilities. The company’s aim is to empower health-care providers and payers with tools and data to manage the quality of treatment.

Mutic also has published more than 120 manuscripts in radiation therapy- and medical physics-related journals and has been named an inventor on four patents.

Tissue Procurement Core receives accreditation

The Washington University Tissue Procurement Core, which offers researchers a centralized laboratory to collect, store and use human biospecimens for translational cancer research, has received accreditation by the College of American Pathologists (CAP). The recognition is based on a recent onsite inspection, designed to ensure the highest standards for laboratory operations.

“We work hand in hand with researchers and strive to provide them the very best resources and services available,” said facility director Mark Watson, MD, PhD. “That takes a lot of dedication and hard work, and we appreciate being recognized as among the nation’s best lab facilities.”

Watson also is an associate professor of pathology and immunology at the School of Medicine and a Siteman Cancer Center research member.

During the CAP accreditation process, inspectors examine the laboratory’s operations and quality control procedures and review laboratory staff qualifications, equipment, facilities, the safety program and record, and overall management.

The Tissue Procurement Core is in the BJC Institute of Health. Brian Goetz is lab manager.

Ley to receive 2016 faculty achievement award

Timothy Ley, MD, an expert in cancer genomics and leukemia, will receive a 2016 Washington University in St. Louis faculty achievement award, Chancellor Mark S. Wrighton has announced.

A Siteman Cancer Center research member, Ley also is the Lewis T. and Rosalind B. Apple Professor of Medicine in the School of Medicine and chief of the Section of Stem Cell Biology in the Division of Oncology. He will receive the Carl and Gerty Cori Faculty Achievement Award.

Two other faculty member also will receive achievement awards: Deanna Barch, a leading researcher on the role of cognition, emotion and brain function in illnesses such as schizophrenia and depression, and Irving Boime, a professor of developmental biology and of obstetrics and gynecology in the School of Medicine.

“These faculty achievement awards are intended to build bridges between the Danforth Campus and our School of Medicine Campus,” Wrighton said. “As distinguished scholars and as members of the Washington University faculty, professors Barch and Ley embody the ideals of individual and collaborative excellence. Their work has done much to strengthen interdisciplinary scholarship among our campuses. I am extremely pleased to recognize their achievements with these awards. These awards are very significant because faculty peers select the honorees from a group of nominees from the faculty.”

Ley, Barch and Boime will be recognized at an awards ceremony Oct. 14. Ley and Barch also will make presentations on their scholarly work at the ceremony.

Ley’s pioneering research in cancer genomics has laid the groundwork for precision medicine in cancer, which targets treatment to a patient based on the genetic makeup of a tumor and how it responds to therapy.

In 2008, he led a team of researchers at The McDonnell Genome Institute that decoded the entire genome of a cancer patient’s tumor. It was the first time scientists compared the DNA in a patient’s healthy and malignant cells to find genetic mutations that likely caused the disease.

Last year, President Barack Obama named Ley to the National Cancer Advisory Board, which advises the U.S. Secretary of Health and Human Services, the director of the National Cancer Institute (NCI) and the president on the nation’s cancer program and reviews proposals awarded by the NCI. His term lasts until 2020.

Ley also is associate director for cancer genomics at The McDonnell Genome Institute and a research member at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

He currently holds $1.7 million in annual grants from the NCI and has authored nearly 200 publications. Ley has served on the boards of many medical and research organizations, including the National Human Genome Research Institute Board of Scientific Counselors, the Federation of American Societies for Experimental Biology Board of Directors, and the councils of the American Society for Clinical Investigation and the Association of American Physicians.

Ley is an elected member of the National Academy of Medicine and of the American Academy of Arts & Sciences. He also is a past president of the American Society for Clinical Investigation and was chair of the Board of Scientific Counselors for the National Human Genome Research Institute.

Ley earned his bachelor’s degree from Drake University in 1974 and his medical degree from Washington University in 1978. He is board-certified in internal medicine and hematology. He joined the School of Medicine faculty in 1986 as an assistant professor of medicine after being a senior investigator for two years at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH) in Bethesda, Md.

He has received numerous honors and awards, including the Erasmus Hematology Prize from Erasmus University in Rotterdam, Netherlands; NCI’s Alfred G. Knudson Award for Cancer Genetics, the American Society of Hematology’s E. Donnall Thomas Prize and its Mentor Award, and Washington University’s Second Century Award, which recognizes individuals whose long-term commitment and participation have enabled the School of Medicine to look to the future with strength and confidence.

Dacey receives Cushing Medal from neurosurgery society

Ralph G. Dacey Jr., MD, has been awarded the Harvey Cushing Medal by the American Association of Neurological Surgeons (AANS). He was honored with the medal, the association’s most prestigious award, for his many years of outstanding leadership, dedication and contributions to the field of neurosurgery.

The medal – named in honor of the father of modern neurosurgery – was awarded May 3 at the AANS annual meeting in Chicago.

“It means a lot to me to be recognized by my peers,” said Dacey, the Henry G. and Edith R. Schwartz Professor and head of the Department of Neurosurgery.

Dacey, who is also neurosurgeon-in-chief at Barnes-Jewish Hospital, is known for his work on the clinical management of cerebral aneurysms and brain tumors as well as how blood vessels in the brain control blood flow, which is important in a variety of neurosurgical diseases.

He counts among his achievements the recruitment of outstanding clinicians and researchers to his department.

“We’ve added great faculty and trained superb residents,” said Dacey. “We have some really innovative research being done here – for example, on the effective management of malignant brain tumors and spinal cord injuries, and on brain computer interfaces and complex cerebrovascular conditions.”

Dacey is a former chairman of the American Board of Neurological Surgery and has served as president of the Congress of Neurological Surgeons, the American Academy of Neurological Surgeons, and the Society of Neurological Surgeons. He was elected to the Institute of Medicine of the National Academy of Sciences in 2010 and is an honorary fellow of the Royal College of Surgeons in Ireland.

Founded in 1931 as the Harvey Cushing Society, the AANS is a scientific and educational association with more than 8,000 members worldwide. The AANS is dedicated to advancing the specialty of neurological surgery to provide the highest quality of neurosurgical care to patients.

Murphy, Virgin elected to National Academy of Sciences

Two scientists at Washington University School of Medicine in St. Louis and Siteman Cancer Center are among the 84 members and 21 foreign associates elected to the National Academy of Sciences this year. Election to the academy — which was announced May 3 — is considered one of the highest honors that can be awarded to a U.S. scientist or engineer.

The two are: Kenneth M. Murphy, MD, PhD, the Eugene Opie Centennial Professor of Pathology and Immunology and a Howard Hughes Medical Institute investigator; and Herbert W. “Skip” Virgin IV, MD, PhD, the Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology. Both also are Siteman Cancer Center research members.

Murphy

Murphy, who came to Washington University as a pathology resident in 1984, is known for his research into the development of immune cells known as T cells and the way they work with other factors to fight infections.

In recent years, Murphy has shifted his lab’s focus to transcriptional programs of dendritic cells. Such cells sense the presence of pathogens and direct the development of T cells and other immune cells. 

Previously, he was director of the Immunology Program of the Division of Biology and Biomedical Sciences. He also is the lead author of the widely respected and comprehensive textbook, “Janeway’s Immunobiology.”

Murphy earned his medical and doctoral degrees at Johns Hopkins University School of Medicine in 1984. He did postdoctoral work at Washington University and in 1989 was named an assistant professor of pathology and immunology. He became an associate professor in 1994, professor in 1999 and was named the Eugene L. Opie First Centennial Professor of Pathology and Immunology in 2011.

He is a member of the American Society for Clinical Investigation and the American Association of Physicians. 

He also is a past recipient of the Juvenile Diabetes Foundation’s Career Development Award and of the School of Medicine’s Distinguished Investigator Award.

Virgin

Virgin joined Washington University in 1990, as an instructor in the department of medicine and pathology and immunology. He became a professor of pathology and immunology in 2002 and was named the Edward Mallinckrodt Professor of Pathology and Immunology and head of the department in 2006. He was named a professor of medicine in 2008.

His research includes studies to understand how the immune system responds to chronic viral infections. Virgin and his colleagues have found that, in addition to causing disease, chronic viruses can have beneficial effects on host immunity. 

Among Virgin’s many contributions to scientific research, he and his colleagues became the first to successfully grow noroviruses in the laboratory. Norovirus disease is characterized by frequent vomiting and diarrhea over the course of 1-2 days. The accomplishment has helped scientists seek ways to weaken norovirus, for use as a vaccine.

Virgin also served as director and principal investigator of the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research.

He earned his medical and doctoral degrees at Harvard University Medical School in 1985. Before coming to Washington University, he completed a residency in internal medicine at Brigham and Women’s Hospital and a postdoctoral fellowship in microbiology and molecular genetics at Harvard.

He is a fellow of the American Association for the Advancement of Science and a member of the American Society for Clinical Investigation and the American Association of Physicians. He also is a recipient of the School of Medicine’s Outstanding Faculty Mentor Award and the Academic Mentorship Award of the Academic Women’s Network of Washington University.

Treating prostate cancer with precision

The treatment, called focal needle ablation, makes use of a needle that can freeze (cryoablation) or use heat (radiofrequency ablation) to destroy cancer cells.

In the past, when a biopsy—the standard diagnostic procedure for the past 20 years—detected a small amount of prostate cancer, it wasn’t known whether the cancer was small or whether the biopsy had grazed the side of a large tumor. Erring on the side of caution, urologic surgeons would make a large incision in the abdomen to remove the entire prostate. As treatment options advanced, the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine was among the first centers in the United States to perform laparoscopic, nerve-sparing radical prostatectomy for most patients with prostate cancer. During the past decade, treatment of small cancers has taken another step forward, with urologists using needle ablations to freeze and kill cancerous areas in the prostate.

“We’ve come to recognize that radical prostatectomy or radiation to treat the entire prostate can be overtreatment. And overtreatment results in too many side effects and unnecessary costs,” says Gerald Andriole Jr., MD, chief of the Division of Urologic Surgery. “If we can tailor the treatment to the man’s individual cancer, he will benefit, and the treatment will be more efficient.”

Cryoablation: The “male lumpectomy”

Washington University urologic surgeons at Barnes-Jewish Hospitalfirst used cryoablation as an investigational treatment and now use it in about 10 percent of prostate cancer cases. They also use cryoablation for focal treatment of kidney and liver cancer.

For prostate cancers, the treatment process begins with a biopsy and ultrasound to determine the size and location of the cancer. Optimally, magnetic resonance imaging (MRI) is used to confirm the cancer’s location and determine that it truly is localized.

During a cryoablation procedure, the urologic surgeon, using ultrasound guidance, inserts one or two cryoneedles below the scrotum and into the prostate. The needles freeze small pear-shaped areas that include the cancerous parts of the gland. The treatment is performed as an outpatient procedure, and most patients are well enough to return to work the next day.

“In the last few years, our targeting has improved as imaging technology has advanced,” says urologic surgeon Sam Bhayani, MD. “We work closely with radiologists at Washington University’s Mallinckrodt Institute of Radiology,  who use advanced 3 Tesla MRI and ultrasound technology.”

The procedure is known as male lumpectomy because it preserves a major part of the prostate, just as a lumpectomy to treat breast cancer preserves most of the breast tissue. Urologic surgeons take great care to avoid the rectum and the nerves needed for erections, which are located just outside the prostate. “You need very detailed, continuous monitoring when you are performing cryoablation,” says Andriole.

Vascular-targeted photodynamic therapy

Washington University urologists have completed a clinical trial to evaluate what may be the next advancement in focal ablation: vascular-targeted photodynamic therapy (VTP).

In VTP, an intravenously injected drug adheres to the capillaries that provide blood supply to tumors. These capillaries, which help the cancer grow, differ from blood vessels associated with healthy tissues. Laser energy released from a fiber placed next to the cancer-supplying capillaries blocks the blood vessels, which interrupts blood flow to the cancer and kills tumor tissue.

“Cancers have a growth pattern that’s a lot like a tree,” says Andriole. “There’s a good deal of normal prostate tissue in between the tentacles and branches of the cancer. When you perform cryoablation, you’re making a pear-shaped ice ball that kills everything inside the ball—cancerous and normal tissue. There are likely more side effects with cryoblation than with VPT, in which you’re more selectively killing the cancer.”

The Food and Drug Administration will review data from the VTP clinical trial at Washington University and elsewhere. If the therapy is approved, it will be offered at Siteman Cancer Center.

Identifying aggressive cancers

To determine the best treatment options, Washington University urologists are investigating new ways to determine which prostate cancers are slow-growing and which are more aggressive.

Pathologists have traditionally relied on Gleason scoring to measure cancer aggressiveness. Looking under a microscope at multiple biopsy specimens taken from different areas of a patient’s prostate, they categorize tumor patterns on a scale of 1 to 5, with 5 being the most aggressive. The two top scores are added, with a final range of 2 to 10.

But Gleason scores aren’t always accurate, so Andriole and a team of scientists at The Elizabeth H. and James S. McDonnell III Genome Institute at Washington University are looking at the genetic makeup of prostate cancers.

“When we remove a cancerous prostate, there are, on average, at least five separate cancers in it,” Andriole says. “Are the genes that these different cancers express the same or different? If they are different, how can we use those differences to more precisely characterize the aggressiveness of a man’s cancer?”