User login
Reversal of Ptosis in Metastatic Prostatic Adenocarcinoma Presenting as Cavernous Sinus Syndrome
INTRODUCTION
Prostate cancer rarely metastasizes to the pituitary gland and the close relationship of these sellar masses to cavernous sinuses and major vessels makes management challenging. We describe a unique case of complete reversal of ptosis in metastatic prostate cancer presenting as cavernous sinus syndrome
CASE REPORT
A 76-year-old male presented with left diplopia, ptosis, and facial numbness. Examination showed left oculomotor palsy and numbness in the V1 and V2 distribution of trigeminal nerve. MRI revealed an 11 × 26 × 17 mm posterior sellar mass extending into the left cavernous sinus. Prolactin was slightly elevated, but rest of the pituitary hormones were normal. Resection of the sellar mass showed metastatic prostatic adenocarcinoma positive for NKX-3.1 and prostate-specific antigen (PSA), and Gleason score 4. PSA was elevated at 32 ng/ mL. Positron emission tomography (PET) showed lesions in the left prostatic lobe, pelvic lymph nodes, L5 spine, and right femoral head. FoundationOne testing found no actionable mutations. He was started on leuprorelin-docetaxel and received radiation for the brain and bony lesions. He is currently being maintained on leuprorelin-abiraterone and prednisone, which he is tolerating well.
DISCUSSION
Pituitary metastases (PMs) from prostate cancer are rare and are usually confined to the posterior pituitary. The close relationship of pituitary masses to the cavernous sinuses and internal carotid artery can lead to catastrophic neurovascular consequences. Imaging has limited sensitivity for differentiating non-invasive metastases from adenomas. Older age, new-onset diabetes insipidus, invasive masses, and rapidly growing lesions should raise suspicion for PMs. Intracranial prostatic metastases indicate poor prognosis with a reported median survival of 6-10 months. Timely diagnosis and management can prevent permanent neurologic damage as illustrated by our case in which ptosis and extraocular symptoms were completely resolved by surgery and radiation. Such unique cases underline the significance of suspecting metastatic disease in appropriate demographic groups and the crucial role of multidisciplinary care for oncologic patients.
CONCLUSIONS
A high index of suspicion for PMs in elderly people with new-onset sellar symptoms and early involvement of multidisciplinary teams can lead to prevention and even reversal of serious neurologic symptoms.
INTRODUCTION
Prostate cancer rarely metastasizes to the pituitary gland and the close relationship of these sellar masses to cavernous sinuses and major vessels makes management challenging. We describe a unique case of complete reversal of ptosis in metastatic prostate cancer presenting as cavernous sinus syndrome
CASE REPORT
A 76-year-old male presented with left diplopia, ptosis, and facial numbness. Examination showed left oculomotor palsy and numbness in the V1 and V2 distribution of trigeminal nerve. MRI revealed an 11 × 26 × 17 mm posterior sellar mass extending into the left cavernous sinus. Prolactin was slightly elevated, but rest of the pituitary hormones were normal. Resection of the sellar mass showed metastatic prostatic adenocarcinoma positive for NKX-3.1 and prostate-specific antigen (PSA), and Gleason score 4. PSA was elevated at 32 ng/ mL. Positron emission tomography (PET) showed lesions in the left prostatic lobe, pelvic lymph nodes, L5 spine, and right femoral head. FoundationOne testing found no actionable mutations. He was started on leuprorelin-docetaxel and received radiation for the brain and bony lesions. He is currently being maintained on leuprorelin-abiraterone and prednisone, which he is tolerating well.
DISCUSSION
Pituitary metastases (PMs) from prostate cancer are rare and are usually confined to the posterior pituitary. The close relationship of pituitary masses to the cavernous sinuses and internal carotid artery can lead to catastrophic neurovascular consequences. Imaging has limited sensitivity for differentiating non-invasive metastases from adenomas. Older age, new-onset diabetes insipidus, invasive masses, and rapidly growing lesions should raise suspicion for PMs. Intracranial prostatic metastases indicate poor prognosis with a reported median survival of 6-10 months. Timely diagnosis and management can prevent permanent neurologic damage as illustrated by our case in which ptosis and extraocular symptoms were completely resolved by surgery and radiation. Such unique cases underline the significance of suspecting metastatic disease in appropriate demographic groups and the crucial role of multidisciplinary care for oncologic patients.
CONCLUSIONS
A high index of suspicion for PMs in elderly people with new-onset sellar symptoms and early involvement of multidisciplinary teams can lead to prevention and even reversal of serious neurologic symptoms.
INTRODUCTION
Prostate cancer rarely metastasizes to the pituitary gland and the close relationship of these sellar masses to cavernous sinuses and major vessels makes management challenging. We describe a unique case of complete reversal of ptosis in metastatic prostate cancer presenting as cavernous sinus syndrome
CASE REPORT
A 76-year-old male presented with left diplopia, ptosis, and facial numbness. Examination showed left oculomotor palsy and numbness in the V1 and V2 distribution of trigeminal nerve. MRI revealed an 11 × 26 × 17 mm posterior sellar mass extending into the left cavernous sinus. Prolactin was slightly elevated, but rest of the pituitary hormones were normal. Resection of the sellar mass showed metastatic prostatic adenocarcinoma positive for NKX-3.1 and prostate-specific antigen (PSA), and Gleason score 4. PSA was elevated at 32 ng/ mL. Positron emission tomography (PET) showed lesions in the left prostatic lobe, pelvic lymph nodes, L5 spine, and right femoral head. FoundationOne testing found no actionable mutations. He was started on leuprorelin-docetaxel and received radiation for the brain and bony lesions. He is currently being maintained on leuprorelin-abiraterone and prednisone, which he is tolerating well.
DISCUSSION
Pituitary metastases (PMs) from prostate cancer are rare and are usually confined to the posterior pituitary. The close relationship of pituitary masses to the cavernous sinuses and internal carotid artery can lead to catastrophic neurovascular consequences. Imaging has limited sensitivity for differentiating non-invasive metastases from adenomas. Older age, new-onset diabetes insipidus, invasive masses, and rapidly growing lesions should raise suspicion for PMs. Intracranial prostatic metastases indicate poor prognosis with a reported median survival of 6-10 months. Timely diagnosis and management can prevent permanent neurologic damage as illustrated by our case in which ptosis and extraocular symptoms were completely resolved by surgery and radiation. Such unique cases underline the significance of suspecting metastatic disease in appropriate demographic groups and the crucial role of multidisciplinary care for oncologic patients.
CONCLUSIONS
A high index of suspicion for PMs in elderly people with new-onset sellar symptoms and early involvement of multidisciplinary teams can lead to prevention and even reversal of serious neurologic symptoms.
BCR is unreliable surrogate for overall survival in prostate cancer
TOPLINE
METHODOLOGY
- In trials of localized prostate cancer, BCR remains a controversial surrogate endpoint for overall survival.
- The meta-analysis included 10,741 patients from 11 randomized clinical trials; the median follow-up was 9.2 years.
- Interventions included radiotherapy dose escalation, in which high-dose radiotherapy was compared with conventional radiotherapy (n = 3,639); short-term androgen deprivation therapy (ADT), in which radiotherapy plus short-term ADT was compared with radiotherapy alone (n = 3,930); and ADT prolongation, in which radiotherapy plus long-term ADT was compared with radiotherapy plus short-term ADT (n = 3,772).
- Prentice criteria and the two-stage meta-analytic approach were used to assess BCR as a surrogate endpoint for overall survival.
- The researchers assessed the treatment effect on BCR and on overall survival.
TAKEAWAY
- With regard to treatment effect on BCR, the three interventions significantly reduced BCR risk – dose escalation by 29%, short-term ADT by 47%, and ADT prolongation by 46%. With regard to survival, only short- and long-term ADT significantly improved overall survival, by 9% and 14%, respectively.
- At 48 months, BCR was associated with significantly increased mortality risk: 2.46-fold increased risk for dose escalation, 1.51-fold greater risk for short-term ADT, and 2.31-fold higher risk for ADT prolongation.
- However, after adjusting for BCR at 48 months, there was no significant treatment effect on overall survival (hazard ratio, 1.10; [95% confidence interval, 0.96-1.27]; HR, 0.96 [95% CI, 0.87-1.06]; HR, 1.00 [95% CI, 0.90-1.12], respectively).
- Patient-level correlation between time to BCR and overall survival was low after censoring for noncancer-related deaths. The correlation between BCR-free survival and overall survival ranged from low to moderate.
IN PRACTICE
Overall, “these results strongly suggest that BCR-based endpoints should not be the primary endpoint in randomized trials conducted for localized [prostate cancer],” the authors concluded. They added that metastasis-free survival represents a more appropriate measure.
SOURCE
The study was led by senior author Amar Kishan, MD, of the University of California, Los Angeles, and was published online in the Journal of Clinical Oncology.
LIMITATIONS
- The trials used different definitions of BCR – the older American Society of Therapeutic Radiation and Oncology definition, and the more current Phoenix criteria.
- Some trials were conducted more than 20 years ago, and a variety of factors, including patient selection, staging, diagnostic criteria, and therapeutic approaches, have evolved in that time.
- Quality of life was not captured.
DISCLOSURES
The study received support from Cancer Research UK, the UK National Health Service, the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, the UK Department of Defense, the Prostate Cancer Foundation, and the American Society for Radiation Oncology. Authors’ relevant financial relationships are detailed in the published study.
A version of this article appeared on Medscape.com.
TOPLINE
METHODOLOGY
- In trials of localized prostate cancer, BCR remains a controversial surrogate endpoint for overall survival.
- The meta-analysis included 10,741 patients from 11 randomized clinical trials; the median follow-up was 9.2 years.
- Interventions included radiotherapy dose escalation, in which high-dose radiotherapy was compared with conventional radiotherapy (n = 3,639); short-term androgen deprivation therapy (ADT), in which radiotherapy plus short-term ADT was compared with radiotherapy alone (n = 3,930); and ADT prolongation, in which radiotherapy plus long-term ADT was compared with radiotherapy plus short-term ADT (n = 3,772).
- Prentice criteria and the two-stage meta-analytic approach were used to assess BCR as a surrogate endpoint for overall survival.
- The researchers assessed the treatment effect on BCR and on overall survival.
TAKEAWAY
- With regard to treatment effect on BCR, the three interventions significantly reduced BCR risk – dose escalation by 29%, short-term ADT by 47%, and ADT prolongation by 46%. With regard to survival, only short- and long-term ADT significantly improved overall survival, by 9% and 14%, respectively.
- At 48 months, BCR was associated with significantly increased mortality risk: 2.46-fold increased risk for dose escalation, 1.51-fold greater risk for short-term ADT, and 2.31-fold higher risk for ADT prolongation.
- However, after adjusting for BCR at 48 months, there was no significant treatment effect on overall survival (hazard ratio, 1.10; [95% confidence interval, 0.96-1.27]; HR, 0.96 [95% CI, 0.87-1.06]; HR, 1.00 [95% CI, 0.90-1.12], respectively).
- Patient-level correlation between time to BCR and overall survival was low after censoring for noncancer-related deaths. The correlation between BCR-free survival and overall survival ranged from low to moderate.
IN PRACTICE
Overall, “these results strongly suggest that BCR-based endpoints should not be the primary endpoint in randomized trials conducted for localized [prostate cancer],” the authors concluded. They added that metastasis-free survival represents a more appropriate measure.
SOURCE
The study was led by senior author Amar Kishan, MD, of the University of California, Los Angeles, and was published online in the Journal of Clinical Oncology.
LIMITATIONS
- The trials used different definitions of BCR – the older American Society of Therapeutic Radiation and Oncology definition, and the more current Phoenix criteria.
- Some trials were conducted more than 20 years ago, and a variety of factors, including patient selection, staging, diagnostic criteria, and therapeutic approaches, have evolved in that time.
- Quality of life was not captured.
DISCLOSURES
The study received support from Cancer Research UK, the UK National Health Service, the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, the UK Department of Defense, the Prostate Cancer Foundation, and the American Society for Radiation Oncology. Authors’ relevant financial relationships are detailed in the published study.
A version of this article appeared on Medscape.com.
TOPLINE
METHODOLOGY
- In trials of localized prostate cancer, BCR remains a controversial surrogate endpoint for overall survival.
- The meta-analysis included 10,741 patients from 11 randomized clinical trials; the median follow-up was 9.2 years.
- Interventions included radiotherapy dose escalation, in which high-dose radiotherapy was compared with conventional radiotherapy (n = 3,639); short-term androgen deprivation therapy (ADT), in which radiotherapy plus short-term ADT was compared with radiotherapy alone (n = 3,930); and ADT prolongation, in which radiotherapy plus long-term ADT was compared with radiotherapy plus short-term ADT (n = 3,772).
- Prentice criteria and the two-stage meta-analytic approach were used to assess BCR as a surrogate endpoint for overall survival.
- The researchers assessed the treatment effect on BCR and on overall survival.
TAKEAWAY
- With regard to treatment effect on BCR, the three interventions significantly reduced BCR risk – dose escalation by 29%, short-term ADT by 47%, and ADT prolongation by 46%. With regard to survival, only short- and long-term ADT significantly improved overall survival, by 9% and 14%, respectively.
- At 48 months, BCR was associated with significantly increased mortality risk: 2.46-fold increased risk for dose escalation, 1.51-fold greater risk for short-term ADT, and 2.31-fold higher risk for ADT prolongation.
- However, after adjusting for BCR at 48 months, there was no significant treatment effect on overall survival (hazard ratio, 1.10; [95% confidence interval, 0.96-1.27]; HR, 0.96 [95% CI, 0.87-1.06]; HR, 1.00 [95% CI, 0.90-1.12], respectively).
- Patient-level correlation between time to BCR and overall survival was low after censoring for noncancer-related deaths. The correlation between BCR-free survival and overall survival ranged from low to moderate.
IN PRACTICE
Overall, “these results strongly suggest that BCR-based endpoints should not be the primary endpoint in randomized trials conducted for localized [prostate cancer],” the authors concluded. They added that metastasis-free survival represents a more appropriate measure.
SOURCE
The study was led by senior author Amar Kishan, MD, of the University of California, Los Angeles, and was published online in the Journal of Clinical Oncology.
LIMITATIONS
- The trials used different definitions of BCR – the older American Society of Therapeutic Radiation and Oncology definition, and the more current Phoenix criteria.
- Some trials were conducted more than 20 years ago, and a variety of factors, including patient selection, staging, diagnostic criteria, and therapeutic approaches, have evolved in that time.
- Quality of life was not captured.
DISCLOSURES
The study received support from Cancer Research UK, the UK National Health Service, the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, the UK Department of Defense, the Prostate Cancer Foundation, and the American Society for Radiation Oncology. Authors’ relevant financial relationships are detailed in the published study.
A version of this article appeared on Medscape.com.
Predicting prostate cancer risk: Are polygenic risk scores ready for prime time?
DNA testing for prostate cancer – of the patients’ inherited DNA and their tumors’ somatic DNA – is increasingly used in the U.S. to determine whether and how to treat low-grade, localized prostate cancers.
Another genetic approach, known as the polygenic risk score (PRS), is emerging as a third genetic approach for sorting out prostate cancer risks.
PRS aims to stratify a person’s disease risk by going beyond rare variants in genes, such as BRCA2, and compiling a weighted score that integrates thousands of common variants whose role in cancer may be unknown but are found more frequently in men with prostate cancer. Traditional germline testing, by contrast, looks for about 30 specific genes directly linked to prostate cancer.
Essentially, “a polygenic risk score estimates your risk by adding together the number of bad cards you were dealt by the impact of each card, such as an ace versus a deuce,” said William Catalona, MD, a urologist at Northwestern University Feinberg School of Medicine, Chicago, known as the father of prostate-specific antigen (PSA) screening.
In combination, these variants can have powerful predictive value.
Having a tool that can mine the depths of a person’s genetic makeup and help doctors devise a nuanced risk assessment for prostate cancer seems like a winning proposition.
Despite its promise, PRS testing is not yet used routinely in practice. The central uncertainty regarding its use lies in whether the risk score can accurately predict who will develop aggressive prostate cancer that needs to be treated and who won’t. The research to date has been mixed, and experts remain polarized.
“PRS absolutely, irrefutably can distinguish between the probability of somebody developing prostate cancer or not. Nobody could look at the data and argue with that,” said Todd Morgan, MD, a genomics researcher from the University of Michigan, Ann Arbor. “What [the data] so far haven’t really been able to do is distinguish whether somebody is likely to have clinically significant prostate cancer versus lower-risk prostate cancer.”
The promise of PRS in prostate cancer?
, according to Burcu Darst, PhD, a genetic epidemiologist at Fred Hutchinson Cancer Center, Seattle.
Research in the area has intensified in recent years as genome-wide association studies (GWAS) have become more affordable and the genetic information from these studies has been increasingly aggregated in biobanks.
“Because the sample sizes now are so much bigger than they used to be for GWAS studies, we’re able to develop much better polygenic risk scores than we were before,” said Dr. Darst.
Dr. Darst is lead author on the largest, most diverse prostate GWAS analysis, which led to the development of a PRS that is highly predictive of prostate cancer risk across diverse populations.
In the 2021 meta-analysis, which included 107,247 case patients and 127,006 control patients, Dr. Darst and colleagues identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants.
Compared with men at average genetic risk for prostate cancer – those in the 40%-60% genetic risk score category – men in the top 10% of the risk score (90%-100%) had between a 3.74-fold to fivefold higher risk for prostate cancer. However, the team did not find evidence that the genetic risk score could differentiate a person’s risk for aggressive versus nonaggressive disease.
As Dr. Darst’s team continues to improve the PRS, Dr. Darst says it will get better at predicting aggressive disease. One recent analysis from Dr. Darst and colleagues found that “although the PRS generally did not differentiate aggressive versus nonaggressive prostate cancer,” about 40% of men who will develop aggressive disease have a PRS in the top 20%, whereas only about 7% of men who will develop aggressive tumors have a PRS in the bottom 20%. Another recent study from Dr. Darst and colleagues found that PRS can distinguish between aggressive and nonaggressive disease in men of African ancestry.
These findings highlight “the potential clinical utility of the polygenic risk score,” Dr. Darst said.
Although the growing body of research makes Dr. Catalona, Dr. Darst, and others optimistic about PRS, the landscape is also littered with critics and studies showcasing its limitations.
An analysis, published in JAMA Internal Medicine, found that, compared with a contemporary clinical risk predictor, PRS did not improve prediction of aggressive prostate cancers. Another recent study, which used a 6.6 million–variant PRS to predict the risk of incident prostate cancer among 5,701 healthy men of European descent older than age 69, found that men in the top 20% of the PRS distribution “had an almost three times higher risk of prostate cancer,” compared with men in the lowest quintile; however, a higher PRS was not associated with a higher Gleason grade group, indicative of more aggressive disease.
“While a PRS for prostate cancer is strongly associated with incident risk” in the cohort, “the clinical utility of the PRS as a biomarker is currently limited by its inability to select for clinically significant disease,” the authors concluded.
Utility in practice?
Although PRS has been billed as a predictive test, Dr. Catalona believes PRS could have a range of uses both before and after diagnosis.
PRS may, for instance, guide treatment choices for men diagnosed with prostate cancer, Dr. Catalona noted. For men with a PRS that signals a higher risk for aggressive disease, a positive prostate biopsy result could help them decide whether to seek active treatment with surgery or radiation or go on active surveillance.
PRS could also help inform cancer screening. If a PRS test found a patient’s risk for prostate cancer was high, that person could decide to seek PSA screening before age 50 – the recommended age for average-risk men.
However, Aroon Hingorani, MD, a professor of genetic epidemiology at the University College London, expressed concern over using PRS to inform cancer screenings.
Part of the issue, Dr. Hingorani and colleagues explained in a recent article in the BMJ, is that “risk is notoriously difficult to communicate.”
PRS estimates a person’s relative risk for a disease but does not factor in the underlying population risk. Risk prediction should include both, Dr. Hingorani said.
People with high-risk scores may, for instance, discuss earlier screening with their clinician, even if their absolute risk for the disease – which accounts for both relative risk and underlying population disease risk – is still small, Dr. Hingorani and colleagues said. “Conversely, people who do not have ‘high risk’ polygenic scores might be less likely to seek medical attention for concerning symptoms, or their clinicians might be less inclined to investigate.”
Given this, Dr. Hingorani and colleagues believe polygenic scores “will always be limited in their ability to predict disease” and “will always remain one of many risk factors,” such as environmental influences.
Another caveat is that PRS generally is based on data collected from European populations, said Eric Klein, MD, chairman emeritus of urology at the Cleveland Clinic and now a scientist at the biotechnology company Grail, which developed the Galleri blood test that screens for 50 types of cancer. While a valid concern, “that’s easy to fix ultimately,” he said, as the diversity of inputs from various ethnicities increases over time.
Although several companies offer PRS products, moving PRS into the clinic would require an infrastructure for testing which does not yet exist in the U.S., said Dr. Catalona.
Giordano Botta, PhD, CEO of New York–based PRS software start-up Alleica, which bills itself as the Polygenic Risk Score Company, said “test demand is growing rapidly.” His company offers PRS scores that integrate up to 700,000 markers for prostate cancer depending on ancestry and charges patients $250 out of pocket for testing.
Dr. Botta noted that thousands of American patients have undergone PRS testing through his company. Several health systems, including Penn Medicine, Brigham and Women’s Hospital, and the University of Alabama at Birmingham, have been using the test to help “see beyond what traditional risk factors allow,” he said.
However, this and other PRS tests are not yet widely used in the primary care setting.
A major barrier to wider adoption is that experts remain divided on its clinical utility. “People either say it’s ready, and it should be implemented, or they say it’s never going to work,” said Sowmiya Moorthie, PhD, a senior policy analyst with the PHG Foundation, a Cambridge University–associated think tank.
Dr. Klein sits in the optimistic camp. He envisions a day soon when patients will undergo whole-genome testing to collect data on risk scores and incorporate the full genome into the electronic record. At a certain age, primary care physicians would then query the data to determine the patient’s germline risk for a variety of diseases.
“At age 45, if I were a primary care physician seeing a male, I would query the PRS for prostate cancer, and if the risks were low, I would say, ‘You don’t need your first PSA probably until you’re 50,’ ” Dr. Klein said. “If your risk is high, I’d say, ‘Let’s do a baseline PSA now.’ ”
We would then have the data to watch these patients a little more closely, he said.
Dr. Moorthie, however, remains more reserved about the future of PRS. “I take the middle ground and say, I think there is some value because it’s an additional data point,” Dr. Moorthie said. “And I can see it having value in certain scenarios, but we still don’t have a clear picture of what these are and how best to use and communicate this information.”
A version of this article first appeared on Medscape.com.
DNA testing for prostate cancer – of the patients’ inherited DNA and their tumors’ somatic DNA – is increasingly used in the U.S. to determine whether and how to treat low-grade, localized prostate cancers.
Another genetic approach, known as the polygenic risk score (PRS), is emerging as a third genetic approach for sorting out prostate cancer risks.
PRS aims to stratify a person’s disease risk by going beyond rare variants in genes, such as BRCA2, and compiling a weighted score that integrates thousands of common variants whose role in cancer may be unknown but are found more frequently in men with prostate cancer. Traditional germline testing, by contrast, looks for about 30 specific genes directly linked to prostate cancer.
Essentially, “a polygenic risk score estimates your risk by adding together the number of bad cards you were dealt by the impact of each card, such as an ace versus a deuce,” said William Catalona, MD, a urologist at Northwestern University Feinberg School of Medicine, Chicago, known as the father of prostate-specific antigen (PSA) screening.
In combination, these variants can have powerful predictive value.
Having a tool that can mine the depths of a person’s genetic makeup and help doctors devise a nuanced risk assessment for prostate cancer seems like a winning proposition.
Despite its promise, PRS testing is not yet used routinely in practice. The central uncertainty regarding its use lies in whether the risk score can accurately predict who will develop aggressive prostate cancer that needs to be treated and who won’t. The research to date has been mixed, and experts remain polarized.
“PRS absolutely, irrefutably can distinguish between the probability of somebody developing prostate cancer or not. Nobody could look at the data and argue with that,” said Todd Morgan, MD, a genomics researcher from the University of Michigan, Ann Arbor. “What [the data] so far haven’t really been able to do is distinguish whether somebody is likely to have clinically significant prostate cancer versus lower-risk prostate cancer.”
The promise of PRS in prostate cancer?
, according to Burcu Darst, PhD, a genetic epidemiologist at Fred Hutchinson Cancer Center, Seattle.
Research in the area has intensified in recent years as genome-wide association studies (GWAS) have become more affordable and the genetic information from these studies has been increasingly aggregated in biobanks.
“Because the sample sizes now are so much bigger than they used to be for GWAS studies, we’re able to develop much better polygenic risk scores than we were before,” said Dr. Darst.
Dr. Darst is lead author on the largest, most diverse prostate GWAS analysis, which led to the development of a PRS that is highly predictive of prostate cancer risk across diverse populations.
In the 2021 meta-analysis, which included 107,247 case patients and 127,006 control patients, Dr. Darst and colleagues identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants.
Compared with men at average genetic risk for prostate cancer – those in the 40%-60% genetic risk score category – men in the top 10% of the risk score (90%-100%) had between a 3.74-fold to fivefold higher risk for prostate cancer. However, the team did not find evidence that the genetic risk score could differentiate a person’s risk for aggressive versus nonaggressive disease.
As Dr. Darst’s team continues to improve the PRS, Dr. Darst says it will get better at predicting aggressive disease. One recent analysis from Dr. Darst and colleagues found that “although the PRS generally did not differentiate aggressive versus nonaggressive prostate cancer,” about 40% of men who will develop aggressive disease have a PRS in the top 20%, whereas only about 7% of men who will develop aggressive tumors have a PRS in the bottom 20%. Another recent study from Dr. Darst and colleagues found that PRS can distinguish between aggressive and nonaggressive disease in men of African ancestry.
These findings highlight “the potential clinical utility of the polygenic risk score,” Dr. Darst said.
Although the growing body of research makes Dr. Catalona, Dr. Darst, and others optimistic about PRS, the landscape is also littered with critics and studies showcasing its limitations.
An analysis, published in JAMA Internal Medicine, found that, compared with a contemporary clinical risk predictor, PRS did not improve prediction of aggressive prostate cancers. Another recent study, which used a 6.6 million–variant PRS to predict the risk of incident prostate cancer among 5,701 healthy men of European descent older than age 69, found that men in the top 20% of the PRS distribution “had an almost three times higher risk of prostate cancer,” compared with men in the lowest quintile; however, a higher PRS was not associated with a higher Gleason grade group, indicative of more aggressive disease.
“While a PRS for prostate cancer is strongly associated with incident risk” in the cohort, “the clinical utility of the PRS as a biomarker is currently limited by its inability to select for clinically significant disease,” the authors concluded.
Utility in practice?
Although PRS has been billed as a predictive test, Dr. Catalona believes PRS could have a range of uses both before and after diagnosis.
PRS may, for instance, guide treatment choices for men diagnosed with prostate cancer, Dr. Catalona noted. For men with a PRS that signals a higher risk for aggressive disease, a positive prostate biopsy result could help them decide whether to seek active treatment with surgery or radiation or go on active surveillance.
PRS could also help inform cancer screening. If a PRS test found a patient’s risk for prostate cancer was high, that person could decide to seek PSA screening before age 50 – the recommended age for average-risk men.
However, Aroon Hingorani, MD, a professor of genetic epidemiology at the University College London, expressed concern over using PRS to inform cancer screenings.
Part of the issue, Dr. Hingorani and colleagues explained in a recent article in the BMJ, is that “risk is notoriously difficult to communicate.”
PRS estimates a person’s relative risk for a disease but does not factor in the underlying population risk. Risk prediction should include both, Dr. Hingorani said.
People with high-risk scores may, for instance, discuss earlier screening with their clinician, even if their absolute risk for the disease – which accounts for both relative risk and underlying population disease risk – is still small, Dr. Hingorani and colleagues said. “Conversely, people who do not have ‘high risk’ polygenic scores might be less likely to seek medical attention for concerning symptoms, or their clinicians might be less inclined to investigate.”
Given this, Dr. Hingorani and colleagues believe polygenic scores “will always be limited in their ability to predict disease” and “will always remain one of many risk factors,” such as environmental influences.
Another caveat is that PRS generally is based on data collected from European populations, said Eric Klein, MD, chairman emeritus of urology at the Cleveland Clinic and now a scientist at the biotechnology company Grail, which developed the Galleri blood test that screens for 50 types of cancer. While a valid concern, “that’s easy to fix ultimately,” he said, as the diversity of inputs from various ethnicities increases over time.
Although several companies offer PRS products, moving PRS into the clinic would require an infrastructure for testing which does not yet exist in the U.S., said Dr. Catalona.
Giordano Botta, PhD, CEO of New York–based PRS software start-up Alleica, which bills itself as the Polygenic Risk Score Company, said “test demand is growing rapidly.” His company offers PRS scores that integrate up to 700,000 markers for prostate cancer depending on ancestry and charges patients $250 out of pocket for testing.
Dr. Botta noted that thousands of American patients have undergone PRS testing through his company. Several health systems, including Penn Medicine, Brigham and Women’s Hospital, and the University of Alabama at Birmingham, have been using the test to help “see beyond what traditional risk factors allow,” he said.
However, this and other PRS tests are not yet widely used in the primary care setting.
A major barrier to wider adoption is that experts remain divided on its clinical utility. “People either say it’s ready, and it should be implemented, or they say it’s never going to work,” said Sowmiya Moorthie, PhD, a senior policy analyst with the PHG Foundation, a Cambridge University–associated think tank.
Dr. Klein sits in the optimistic camp. He envisions a day soon when patients will undergo whole-genome testing to collect data on risk scores and incorporate the full genome into the electronic record. At a certain age, primary care physicians would then query the data to determine the patient’s germline risk for a variety of diseases.
“At age 45, if I were a primary care physician seeing a male, I would query the PRS for prostate cancer, and if the risks were low, I would say, ‘You don’t need your first PSA probably until you’re 50,’ ” Dr. Klein said. “If your risk is high, I’d say, ‘Let’s do a baseline PSA now.’ ”
We would then have the data to watch these patients a little more closely, he said.
Dr. Moorthie, however, remains more reserved about the future of PRS. “I take the middle ground and say, I think there is some value because it’s an additional data point,” Dr. Moorthie said. “And I can see it having value in certain scenarios, but we still don’t have a clear picture of what these are and how best to use and communicate this information.”
A version of this article first appeared on Medscape.com.
DNA testing for prostate cancer – of the patients’ inherited DNA and their tumors’ somatic DNA – is increasingly used in the U.S. to determine whether and how to treat low-grade, localized prostate cancers.
Another genetic approach, known as the polygenic risk score (PRS), is emerging as a third genetic approach for sorting out prostate cancer risks.
PRS aims to stratify a person’s disease risk by going beyond rare variants in genes, such as BRCA2, and compiling a weighted score that integrates thousands of common variants whose role in cancer may be unknown but are found more frequently in men with prostate cancer. Traditional germline testing, by contrast, looks for about 30 specific genes directly linked to prostate cancer.
Essentially, “a polygenic risk score estimates your risk by adding together the number of bad cards you were dealt by the impact of each card, such as an ace versus a deuce,” said William Catalona, MD, a urologist at Northwestern University Feinberg School of Medicine, Chicago, known as the father of prostate-specific antigen (PSA) screening.
In combination, these variants can have powerful predictive value.
Having a tool that can mine the depths of a person’s genetic makeup and help doctors devise a nuanced risk assessment for prostate cancer seems like a winning proposition.
Despite its promise, PRS testing is not yet used routinely in practice. The central uncertainty regarding its use lies in whether the risk score can accurately predict who will develop aggressive prostate cancer that needs to be treated and who won’t. The research to date has been mixed, and experts remain polarized.
“PRS absolutely, irrefutably can distinguish between the probability of somebody developing prostate cancer or not. Nobody could look at the data and argue with that,” said Todd Morgan, MD, a genomics researcher from the University of Michigan, Ann Arbor. “What [the data] so far haven’t really been able to do is distinguish whether somebody is likely to have clinically significant prostate cancer versus lower-risk prostate cancer.”
The promise of PRS in prostate cancer?
, according to Burcu Darst, PhD, a genetic epidemiologist at Fred Hutchinson Cancer Center, Seattle.
Research in the area has intensified in recent years as genome-wide association studies (GWAS) have become more affordable and the genetic information from these studies has been increasingly aggregated in biobanks.
“Because the sample sizes now are so much bigger than they used to be for GWAS studies, we’re able to develop much better polygenic risk scores than we were before,” said Dr. Darst.
Dr. Darst is lead author on the largest, most diverse prostate GWAS analysis, which led to the development of a PRS that is highly predictive of prostate cancer risk across diverse populations.
In the 2021 meta-analysis, which included 107,247 case patients and 127,006 control patients, Dr. Darst and colleagues identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants.
Compared with men at average genetic risk for prostate cancer – those in the 40%-60% genetic risk score category – men in the top 10% of the risk score (90%-100%) had between a 3.74-fold to fivefold higher risk for prostate cancer. However, the team did not find evidence that the genetic risk score could differentiate a person’s risk for aggressive versus nonaggressive disease.
As Dr. Darst’s team continues to improve the PRS, Dr. Darst says it will get better at predicting aggressive disease. One recent analysis from Dr. Darst and colleagues found that “although the PRS generally did not differentiate aggressive versus nonaggressive prostate cancer,” about 40% of men who will develop aggressive disease have a PRS in the top 20%, whereas only about 7% of men who will develop aggressive tumors have a PRS in the bottom 20%. Another recent study from Dr. Darst and colleagues found that PRS can distinguish between aggressive and nonaggressive disease in men of African ancestry.
These findings highlight “the potential clinical utility of the polygenic risk score,” Dr. Darst said.
Although the growing body of research makes Dr. Catalona, Dr. Darst, and others optimistic about PRS, the landscape is also littered with critics and studies showcasing its limitations.
An analysis, published in JAMA Internal Medicine, found that, compared with a contemporary clinical risk predictor, PRS did not improve prediction of aggressive prostate cancers. Another recent study, which used a 6.6 million–variant PRS to predict the risk of incident prostate cancer among 5,701 healthy men of European descent older than age 69, found that men in the top 20% of the PRS distribution “had an almost three times higher risk of prostate cancer,” compared with men in the lowest quintile; however, a higher PRS was not associated with a higher Gleason grade group, indicative of more aggressive disease.
“While a PRS for prostate cancer is strongly associated with incident risk” in the cohort, “the clinical utility of the PRS as a biomarker is currently limited by its inability to select for clinically significant disease,” the authors concluded.
Utility in practice?
Although PRS has been billed as a predictive test, Dr. Catalona believes PRS could have a range of uses both before and after diagnosis.
PRS may, for instance, guide treatment choices for men diagnosed with prostate cancer, Dr. Catalona noted. For men with a PRS that signals a higher risk for aggressive disease, a positive prostate biopsy result could help them decide whether to seek active treatment with surgery or radiation or go on active surveillance.
PRS could also help inform cancer screening. If a PRS test found a patient’s risk for prostate cancer was high, that person could decide to seek PSA screening before age 50 – the recommended age for average-risk men.
However, Aroon Hingorani, MD, a professor of genetic epidemiology at the University College London, expressed concern over using PRS to inform cancer screenings.
Part of the issue, Dr. Hingorani and colleagues explained in a recent article in the BMJ, is that “risk is notoriously difficult to communicate.”
PRS estimates a person’s relative risk for a disease but does not factor in the underlying population risk. Risk prediction should include both, Dr. Hingorani said.
People with high-risk scores may, for instance, discuss earlier screening with their clinician, even if their absolute risk for the disease – which accounts for both relative risk and underlying population disease risk – is still small, Dr. Hingorani and colleagues said. “Conversely, people who do not have ‘high risk’ polygenic scores might be less likely to seek medical attention for concerning symptoms, or their clinicians might be less inclined to investigate.”
Given this, Dr. Hingorani and colleagues believe polygenic scores “will always be limited in their ability to predict disease” and “will always remain one of many risk factors,” such as environmental influences.
Another caveat is that PRS generally is based on data collected from European populations, said Eric Klein, MD, chairman emeritus of urology at the Cleveland Clinic and now a scientist at the biotechnology company Grail, which developed the Galleri blood test that screens for 50 types of cancer. While a valid concern, “that’s easy to fix ultimately,” he said, as the diversity of inputs from various ethnicities increases over time.
Although several companies offer PRS products, moving PRS into the clinic would require an infrastructure for testing which does not yet exist in the U.S., said Dr. Catalona.
Giordano Botta, PhD, CEO of New York–based PRS software start-up Alleica, which bills itself as the Polygenic Risk Score Company, said “test demand is growing rapidly.” His company offers PRS scores that integrate up to 700,000 markers for prostate cancer depending on ancestry and charges patients $250 out of pocket for testing.
Dr. Botta noted that thousands of American patients have undergone PRS testing through his company. Several health systems, including Penn Medicine, Brigham and Women’s Hospital, and the University of Alabama at Birmingham, have been using the test to help “see beyond what traditional risk factors allow,” he said.
However, this and other PRS tests are not yet widely used in the primary care setting.
A major barrier to wider adoption is that experts remain divided on its clinical utility. “People either say it’s ready, and it should be implemented, or they say it’s never going to work,” said Sowmiya Moorthie, PhD, a senior policy analyst with the PHG Foundation, a Cambridge University–associated think tank.
Dr. Klein sits in the optimistic camp. He envisions a day soon when patients will undergo whole-genome testing to collect data on risk scores and incorporate the full genome into the electronic record. At a certain age, primary care physicians would then query the data to determine the patient’s germline risk for a variety of diseases.
“At age 45, if I were a primary care physician seeing a male, I would query the PRS for prostate cancer, and if the risks were low, I would say, ‘You don’t need your first PSA probably until you’re 50,’ ” Dr. Klein said. “If your risk is high, I’d say, ‘Let’s do a baseline PSA now.’ ”
We would then have the data to watch these patients a little more closely, he said.
Dr. Moorthie, however, remains more reserved about the future of PRS. “I take the middle ground and say, I think there is some value because it’s an additional data point,” Dr. Moorthie said. “And I can see it having value in certain scenarios, but we still don’t have a clear picture of what these are and how best to use and communicate this information.”
A version of this article first appeared on Medscape.com.
Improving Germline Genetic Testing Among Veterans With High Risk, Very High Risk and Metastatic Prostate Cancer
PURPOSE
To improve germline genetic testing among Veterans with high risk, very high risk and metastatic prostate cancer.
BACKGROUND
During our Commission on Cancer survey in 2021, it was noted that the Detroit VA’s referrals for germline genetic testing and counseling were extremely low. In 2020, only 1 Veteran was referred for prostate germline genetic testing and counseling and only 8 Veterans were referred in 2021. It was felt that the need to refer Veterans outside of the Detroit VA may have contributed to these low numbers. Our Cancer Committee chose prostate cancer as a disease to focus on. We chose a timeline of one year to implement our process.
METHODS
We made testing and counseling locally accessible to Veterans and encouraged medical oncology providers to make it part of the care of Veterans with high risk, very high risk and metastatic prostate cancer. We sought the assistance of the VA’s National Precision Oncology Program and were able to secure financial and logistical support to perform germline molecular prostate panel testing at the Detroit VA. We were also able to identify a cancer genetic specialist at the Ann Arbor VA that would perform genetic counseling among this group of patients based on their test results. Our medical oncology providers identified Veterans meeting the criteria for testing. Education regarding germline testing, its benefits and implications were conducted with Veterans, and performed after obtaining their informed consent in collaboration with our pathology department. The specimen is then sent to a VA central laboratory for processing. Detroit VA providers are alerted by the local laboratory once results are available. Veterans are then referred to the genetic counseling specialist based on the results. Some of these counseling visits are done virtually for the Veteran’s convenience.
DATA ANALYSIS
A retrospective chart analysis was used to collect the data.
RESULTS
After the implementation of our initiative, 97 Veterans with high risk, very high risk or metastatic prostate cancer were educated on the benefits of germline genetic testing, 87 of whom agreed to be tested. As of 4/2/23, 48 tests have already been performed. Pathogenic variants were recorded on 2 Veterans so far. One was for BRCA2 and KDM6A, and the other was for ATM. Data collection and recording is on-going.
IMPLICATIONS
Improving accessibility and incorporating genetic testing and counseling in cancer care can improve their utilization.
PURPOSE
To improve germline genetic testing among Veterans with high risk, very high risk and metastatic prostate cancer.
BACKGROUND
During our Commission on Cancer survey in 2021, it was noted that the Detroit VA’s referrals for germline genetic testing and counseling were extremely low. In 2020, only 1 Veteran was referred for prostate germline genetic testing and counseling and only 8 Veterans were referred in 2021. It was felt that the need to refer Veterans outside of the Detroit VA may have contributed to these low numbers. Our Cancer Committee chose prostate cancer as a disease to focus on. We chose a timeline of one year to implement our process.
METHODS
We made testing and counseling locally accessible to Veterans and encouraged medical oncology providers to make it part of the care of Veterans with high risk, very high risk and metastatic prostate cancer. We sought the assistance of the VA’s National Precision Oncology Program and were able to secure financial and logistical support to perform germline molecular prostate panel testing at the Detroit VA. We were also able to identify a cancer genetic specialist at the Ann Arbor VA that would perform genetic counseling among this group of patients based on their test results. Our medical oncology providers identified Veterans meeting the criteria for testing. Education regarding germline testing, its benefits and implications were conducted with Veterans, and performed after obtaining their informed consent in collaboration with our pathology department. The specimen is then sent to a VA central laboratory for processing. Detroit VA providers are alerted by the local laboratory once results are available. Veterans are then referred to the genetic counseling specialist based on the results. Some of these counseling visits are done virtually for the Veteran’s convenience.
DATA ANALYSIS
A retrospective chart analysis was used to collect the data.
RESULTS
After the implementation of our initiative, 97 Veterans with high risk, very high risk or metastatic prostate cancer were educated on the benefits of germline genetic testing, 87 of whom agreed to be tested. As of 4/2/23, 48 tests have already been performed. Pathogenic variants were recorded on 2 Veterans so far. One was for BRCA2 and KDM6A, and the other was for ATM. Data collection and recording is on-going.
IMPLICATIONS
Improving accessibility and incorporating genetic testing and counseling in cancer care can improve their utilization.
PURPOSE
To improve germline genetic testing among Veterans with high risk, very high risk and metastatic prostate cancer.
BACKGROUND
During our Commission on Cancer survey in 2021, it was noted that the Detroit VA’s referrals for germline genetic testing and counseling were extremely low. In 2020, only 1 Veteran was referred for prostate germline genetic testing and counseling and only 8 Veterans were referred in 2021. It was felt that the need to refer Veterans outside of the Detroit VA may have contributed to these low numbers. Our Cancer Committee chose prostate cancer as a disease to focus on. We chose a timeline of one year to implement our process.
METHODS
We made testing and counseling locally accessible to Veterans and encouraged medical oncology providers to make it part of the care of Veterans with high risk, very high risk and metastatic prostate cancer. We sought the assistance of the VA’s National Precision Oncology Program and were able to secure financial and logistical support to perform germline molecular prostate panel testing at the Detroit VA. We were also able to identify a cancer genetic specialist at the Ann Arbor VA that would perform genetic counseling among this group of patients based on their test results. Our medical oncology providers identified Veterans meeting the criteria for testing. Education regarding germline testing, its benefits and implications were conducted with Veterans, and performed after obtaining their informed consent in collaboration with our pathology department. The specimen is then sent to a VA central laboratory for processing. Detroit VA providers are alerted by the local laboratory once results are available. Veterans are then referred to the genetic counseling specialist based on the results. Some of these counseling visits are done virtually for the Veteran’s convenience.
DATA ANALYSIS
A retrospective chart analysis was used to collect the data.
RESULTS
After the implementation of our initiative, 97 Veterans with high risk, very high risk or metastatic prostate cancer were educated on the benefits of germline genetic testing, 87 of whom agreed to be tested. As of 4/2/23, 48 tests have already been performed. Pathogenic variants were recorded on 2 Veterans so far. One was for BRCA2 and KDM6A, and the other was for ATM. Data collection and recording is on-going.
IMPLICATIONS
Improving accessibility and incorporating genetic testing and counseling in cancer care can improve their utilization.
Do AI chatbots give reliable answers on cancer? Yes and no
two new studies suggest.
AI chatbots, such as ChatGPT (OpenAI), are becoming go-to sources for health information. However, no studies have rigorously evaluated the quality of their medical advice, especially for cancer.
Two new studies published in JAMA Oncology did just that.
One, which looked at common cancer-related Google searches, found that AI chatbots generally provide accurate information to consumers, but the information’s usefulness may be limited by its complexity.
The other, which assessed cancer treatment recommendations, found that AI chatbots overall missed the mark on providing recommendations for breast, prostate, and lung cancers in line with national treatment guidelines.
The medical world is becoming “enamored with our newest potential helper, large language models (LLMs) and in particular chatbots, such as ChatGPT,” Atul Butte, MD, PhD, who heads the Bakar Computational Health Sciences Institute, University of California, San Francisco, wrote in an editorial accompanying the studies. “But maybe our core belief in GPT technology as a clinical partner has not sufficiently been earned yet.”
The first study by Alexander Pan of the State University of New York, Brooklyn, and colleagues analyzed the quality of responses to the top five most searched questions on skin, lung, breast, colorectal, and prostate cancer provided by four AI chatbots: ChatGPT-3.5, Perplexity (Perplexity.AI), Chatsonic (Writesonic), and Bing AI (Microsoft).
Questions included what is skin cancer and what are symptoms of prostate, lung, or breast cancer? The team rated the responses for quality, clarity, actionability, misinformation, and readability.
The researchers found that the four chatbots generated “high-quality” responses about the five cancers and did not appear to spread misinformation. Three of the four chatbots cited reputable sources, such as the American Cancer Society, Mayo Clinic, and Centers for Disease Controls and Prevention, which is “reassuring,” the researchers said.
However, the team also found that the usefulness of the information was “limited” because responses were often written at a college reading level. Another limitation: AI chatbots provided concise answers with no visual aids, which may not be sufficient to explain more complex ideas to consumers.
“These limitations suggest that AI chatbots should be used [supplementally] and not as a primary source for medical information,” the authors said, adding that the chatbots “typically acknowledged their limitations in providing individualized advice and encouraged users to seek medical attention.”
A related study in the journal highlighted the ability of AI chatbots to generate appropriate cancer treatment recommendations.
In this analysis, Shan Chen, MS, with the AI in Medicine Program, Mass General Brigham, Harvard Medical School, Boston, and colleagues benchmarked cancer treatment recommendations made by ChatGPT-3.5 against 2021 National Comprehensive Cancer Network guidelines.
The team created 104 prompts designed to elicit basic treatment strategies for various types of cancer, including breast, prostate, and lung cancer. Questions included “What is the treatment for stage I breast cancer?” Several oncologists then assessed the level of concordance between the chatbot responses and NCCN guidelines.
In 62% of the prompts and answers, all the recommended treatments aligned with the oncologists’ views.
The chatbot provided at least one guideline-concordant treatment for 98% of prompts. However, for 34% of prompts, the chatbot also recommended at least one nonconcordant treatment.
And about 13% of recommended treatments were “hallucinated,” that is, not part of any recommended treatment. Hallucinations were primarily recommendations for localized treatment of advanced disease, targeted therapy, or immunotherapy.
Based on the findings, the team recommended that clinicians advise patients that AI chatbots are not a reliable source of cancer treatment information.
“The chatbot did not perform well at providing accurate cancer treatment recommendations,” the authors said. “The chatbot was most likely to mix in incorrect recommendations among correct ones, an error difficult even for experts to detect.”
In his editorial, Dr. Butte highlighted several caveats, including that the teams evaluated “off the shelf” chatbots, which likely had no specific medical training, and the prompts
designed in both studies were very basic, which may have limited their specificity or actionability. Newer LLMs with specific health care training are being released, he explained.
Despite the mixed study findings, Dr. Butte remains optimistic about the future of AI in medicine.
“Today, the reality is that the highest-quality care is concentrated within a few premier medical systems like the NCI Comprehensive Cancer Centers, accessible only to a small fraction of the global population,” Dr. Butte explained. “However, AI has the potential to change this.”
How can we make this happen?
AI algorithms would need to be trained with “data from the best medical systems globally” and “the latest guidelines from NCCN and elsewhere.” Digital health platforms powered by AI could then be designed to provide resources and advice to patients around the globe, Dr. Butte said.
Although “these algorithms will need to be carefully monitored as they are brought into health systems,” Dr. Butte said, it does not change their potential to “improve care for both the haves and have-nots of health care.”
The study by Mr. Pan and colleagues had no specific funding; one author, Stacy Loeb, MD, MSc, PhD, reported a disclosure; no other disclosures were reported. The study by Shan Chen and colleagues was supported by the Woods Foundation; several authors reported disclosures outside the submitted work. Dr. Butte disclosed relationships with several pharmaceutical companies.
A version of this article first appeared on Medscape.com.
two new studies suggest.
AI chatbots, such as ChatGPT (OpenAI), are becoming go-to sources for health information. However, no studies have rigorously evaluated the quality of their medical advice, especially for cancer.
Two new studies published in JAMA Oncology did just that.
One, which looked at common cancer-related Google searches, found that AI chatbots generally provide accurate information to consumers, but the information’s usefulness may be limited by its complexity.
The other, which assessed cancer treatment recommendations, found that AI chatbots overall missed the mark on providing recommendations for breast, prostate, and lung cancers in line with national treatment guidelines.
The medical world is becoming “enamored with our newest potential helper, large language models (LLMs) and in particular chatbots, such as ChatGPT,” Atul Butte, MD, PhD, who heads the Bakar Computational Health Sciences Institute, University of California, San Francisco, wrote in an editorial accompanying the studies. “But maybe our core belief in GPT technology as a clinical partner has not sufficiently been earned yet.”
The first study by Alexander Pan of the State University of New York, Brooklyn, and colleagues analyzed the quality of responses to the top five most searched questions on skin, lung, breast, colorectal, and prostate cancer provided by four AI chatbots: ChatGPT-3.5, Perplexity (Perplexity.AI), Chatsonic (Writesonic), and Bing AI (Microsoft).
Questions included what is skin cancer and what are symptoms of prostate, lung, or breast cancer? The team rated the responses for quality, clarity, actionability, misinformation, and readability.
The researchers found that the four chatbots generated “high-quality” responses about the five cancers and did not appear to spread misinformation. Three of the four chatbots cited reputable sources, such as the American Cancer Society, Mayo Clinic, and Centers for Disease Controls and Prevention, which is “reassuring,” the researchers said.
However, the team also found that the usefulness of the information was “limited” because responses were often written at a college reading level. Another limitation: AI chatbots provided concise answers with no visual aids, which may not be sufficient to explain more complex ideas to consumers.
“These limitations suggest that AI chatbots should be used [supplementally] and not as a primary source for medical information,” the authors said, adding that the chatbots “typically acknowledged their limitations in providing individualized advice and encouraged users to seek medical attention.”
A related study in the journal highlighted the ability of AI chatbots to generate appropriate cancer treatment recommendations.
In this analysis, Shan Chen, MS, with the AI in Medicine Program, Mass General Brigham, Harvard Medical School, Boston, and colleagues benchmarked cancer treatment recommendations made by ChatGPT-3.5 against 2021 National Comprehensive Cancer Network guidelines.
The team created 104 prompts designed to elicit basic treatment strategies for various types of cancer, including breast, prostate, and lung cancer. Questions included “What is the treatment for stage I breast cancer?” Several oncologists then assessed the level of concordance between the chatbot responses and NCCN guidelines.
In 62% of the prompts and answers, all the recommended treatments aligned with the oncologists’ views.
The chatbot provided at least one guideline-concordant treatment for 98% of prompts. However, for 34% of prompts, the chatbot also recommended at least one nonconcordant treatment.
And about 13% of recommended treatments were “hallucinated,” that is, not part of any recommended treatment. Hallucinations were primarily recommendations for localized treatment of advanced disease, targeted therapy, or immunotherapy.
Based on the findings, the team recommended that clinicians advise patients that AI chatbots are not a reliable source of cancer treatment information.
“The chatbot did not perform well at providing accurate cancer treatment recommendations,” the authors said. “The chatbot was most likely to mix in incorrect recommendations among correct ones, an error difficult even for experts to detect.”
In his editorial, Dr. Butte highlighted several caveats, including that the teams evaluated “off the shelf” chatbots, which likely had no specific medical training, and the prompts
designed in both studies were very basic, which may have limited their specificity or actionability. Newer LLMs with specific health care training are being released, he explained.
Despite the mixed study findings, Dr. Butte remains optimistic about the future of AI in medicine.
“Today, the reality is that the highest-quality care is concentrated within a few premier medical systems like the NCI Comprehensive Cancer Centers, accessible only to a small fraction of the global population,” Dr. Butte explained. “However, AI has the potential to change this.”
How can we make this happen?
AI algorithms would need to be trained with “data from the best medical systems globally” and “the latest guidelines from NCCN and elsewhere.” Digital health platforms powered by AI could then be designed to provide resources and advice to patients around the globe, Dr. Butte said.
Although “these algorithms will need to be carefully monitored as they are brought into health systems,” Dr. Butte said, it does not change their potential to “improve care for both the haves and have-nots of health care.”
The study by Mr. Pan and colleagues had no specific funding; one author, Stacy Loeb, MD, MSc, PhD, reported a disclosure; no other disclosures were reported. The study by Shan Chen and colleagues was supported by the Woods Foundation; several authors reported disclosures outside the submitted work. Dr. Butte disclosed relationships with several pharmaceutical companies.
A version of this article first appeared on Medscape.com.
two new studies suggest.
AI chatbots, such as ChatGPT (OpenAI), are becoming go-to sources for health information. However, no studies have rigorously evaluated the quality of their medical advice, especially for cancer.
Two new studies published in JAMA Oncology did just that.
One, which looked at common cancer-related Google searches, found that AI chatbots generally provide accurate information to consumers, but the information’s usefulness may be limited by its complexity.
The other, which assessed cancer treatment recommendations, found that AI chatbots overall missed the mark on providing recommendations for breast, prostate, and lung cancers in line with national treatment guidelines.
The medical world is becoming “enamored with our newest potential helper, large language models (LLMs) and in particular chatbots, such as ChatGPT,” Atul Butte, MD, PhD, who heads the Bakar Computational Health Sciences Institute, University of California, San Francisco, wrote in an editorial accompanying the studies. “But maybe our core belief in GPT technology as a clinical partner has not sufficiently been earned yet.”
The first study by Alexander Pan of the State University of New York, Brooklyn, and colleagues analyzed the quality of responses to the top five most searched questions on skin, lung, breast, colorectal, and prostate cancer provided by four AI chatbots: ChatGPT-3.5, Perplexity (Perplexity.AI), Chatsonic (Writesonic), and Bing AI (Microsoft).
Questions included what is skin cancer and what are symptoms of prostate, lung, or breast cancer? The team rated the responses for quality, clarity, actionability, misinformation, and readability.
The researchers found that the four chatbots generated “high-quality” responses about the five cancers and did not appear to spread misinformation. Three of the four chatbots cited reputable sources, such as the American Cancer Society, Mayo Clinic, and Centers for Disease Controls and Prevention, which is “reassuring,” the researchers said.
However, the team also found that the usefulness of the information was “limited” because responses were often written at a college reading level. Another limitation: AI chatbots provided concise answers with no visual aids, which may not be sufficient to explain more complex ideas to consumers.
“These limitations suggest that AI chatbots should be used [supplementally] and not as a primary source for medical information,” the authors said, adding that the chatbots “typically acknowledged their limitations in providing individualized advice and encouraged users to seek medical attention.”
A related study in the journal highlighted the ability of AI chatbots to generate appropriate cancer treatment recommendations.
In this analysis, Shan Chen, MS, with the AI in Medicine Program, Mass General Brigham, Harvard Medical School, Boston, and colleagues benchmarked cancer treatment recommendations made by ChatGPT-3.5 against 2021 National Comprehensive Cancer Network guidelines.
The team created 104 prompts designed to elicit basic treatment strategies for various types of cancer, including breast, prostate, and lung cancer. Questions included “What is the treatment for stage I breast cancer?” Several oncologists then assessed the level of concordance between the chatbot responses and NCCN guidelines.
In 62% of the prompts and answers, all the recommended treatments aligned with the oncologists’ views.
The chatbot provided at least one guideline-concordant treatment for 98% of prompts. However, for 34% of prompts, the chatbot also recommended at least one nonconcordant treatment.
And about 13% of recommended treatments were “hallucinated,” that is, not part of any recommended treatment. Hallucinations were primarily recommendations for localized treatment of advanced disease, targeted therapy, or immunotherapy.
Based on the findings, the team recommended that clinicians advise patients that AI chatbots are not a reliable source of cancer treatment information.
“The chatbot did not perform well at providing accurate cancer treatment recommendations,” the authors said. “The chatbot was most likely to mix in incorrect recommendations among correct ones, an error difficult even for experts to detect.”
In his editorial, Dr. Butte highlighted several caveats, including that the teams evaluated “off the shelf” chatbots, which likely had no specific medical training, and the prompts
designed in both studies were very basic, which may have limited their specificity or actionability. Newer LLMs with specific health care training are being released, he explained.
Despite the mixed study findings, Dr. Butte remains optimistic about the future of AI in medicine.
“Today, the reality is that the highest-quality care is concentrated within a few premier medical systems like the NCI Comprehensive Cancer Centers, accessible only to a small fraction of the global population,” Dr. Butte explained. “However, AI has the potential to change this.”
How can we make this happen?
AI algorithms would need to be trained with “data from the best medical systems globally” and “the latest guidelines from NCCN and elsewhere.” Digital health platforms powered by AI could then be designed to provide resources and advice to patients around the globe, Dr. Butte said.
Although “these algorithms will need to be carefully monitored as they are brought into health systems,” Dr. Butte said, it does not change their potential to “improve care for both the haves and have-nots of health care.”
The study by Mr. Pan and colleagues had no specific funding; one author, Stacy Loeb, MD, MSc, PhD, reported a disclosure; no other disclosures were reported. The study by Shan Chen and colleagues was supported by the Woods Foundation; several authors reported disclosures outside the submitted work. Dr. Butte disclosed relationships with several pharmaceutical companies.
A version of this article first appeared on Medscape.com.
FROM JAMA ONCOLOGY
Urine test shows promise for diagnosing urothelial carcinoma
, according to findings from a recent validation study.
The urinary comprehensive genomic profiling (uCGP) assay (UroAmp, Convergent Genomics) had a specificity of 95% and sensitivity of 90% for an initial diagnosis of urothelial carcinoma in patients with hematuria – identifying 95 of 100 people with urothelial carcinoma and 90 of 100 patients without the disease.
For patients under surveillance for urothelial cancer recurrence, the test was six times more accurate than traditional clinical risk factors for predicting recurrence.
“Considering its performance in multiple areas of urothelial carcinoma diagnosis and monitoring, uCGP shows great promise to enhance delivery of risk-stratified care,” Keyan Salari, MD, PhD, director of the prostate cancer genetics program at Massachusetts General Hospital in Boston, and colleagues wrote in a study published in Clinical Cancer Research.
“The idea is that this could be used as kind of a first-pass screening tool for patients with hematuria that could potentially obviate the need for undergoing imaging such as CT scans or cystoscopy,” Dr. Salari said in an interview.
The uCGP test is a next-generation sequencing assay that identifies mutations in 60 genes associated with bladder cancer. An earlier analysis evaluating the test as a potential screening tool focused on 10 key genes covered in the assay. The study found the test accurately predicted future bladder cancer in 66% of urine samples, including some that had been collected more than a decade prior to being tested.
In the current case-control study, Dr. Salari and colleagues used a total of 581 samples – 333 samples for classifying disease and developing algorithms for initial diagnosis, surveillance, and molecular-grade prediction, as well as 248 samples for blinded validation. The test’s performance was evaluated by calculating sensitivity, specificity, positive predictive value, and negative predictive value.
Overall, the test demonstrated a specificity of 95% and sensitivity of 90% for an initial urothelial carcinoma diagnosis, but performed even better for the most aggressive tumors, with 100% sensitivity for diagnosing high-grade urothelial carcinoma and muscle-invasive tumors.
On the diagnosis front, the test had a positive predictive value of 88% and a negative predictive value of 99%.
Among patients under surveillance, the test predicted the risk of recurrence significantly better than standard clinical risk factors (hazard ratio, 6.2). The test demonstrated a positive predictive value similar to that observed for cytology (45% vs. 42%) but a much higher sensitivity (79% vs. 25%). The test also demonstrated a negative predictive value of 91% for recurrence.
The molecular-grade algorithm performed well, with a positive predictive value for high-grade disease of 88% and a specificity of 95% in the validation cohort.
Overall, “uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients,” the authors concluded. The test is not currently reimbursed by Medicare, but negotiations with third-party payers are reportedly underway.
The study was supported by the National Cancer Institute. Dr. Salari reported grants from Convergent Genomics during the conduct of the study as well as grants from Urology Care Foundation and Prostate Cancer Foundation, and personal fees from OrigiMed outside the submitted work. Several coauthors are employees and stockholders of Convergent Genomics.
A version of this article first appeared on Medscape.com.
, according to findings from a recent validation study.
The urinary comprehensive genomic profiling (uCGP) assay (UroAmp, Convergent Genomics) had a specificity of 95% and sensitivity of 90% for an initial diagnosis of urothelial carcinoma in patients with hematuria – identifying 95 of 100 people with urothelial carcinoma and 90 of 100 patients without the disease.
For patients under surveillance for urothelial cancer recurrence, the test was six times more accurate than traditional clinical risk factors for predicting recurrence.
“Considering its performance in multiple areas of urothelial carcinoma diagnosis and monitoring, uCGP shows great promise to enhance delivery of risk-stratified care,” Keyan Salari, MD, PhD, director of the prostate cancer genetics program at Massachusetts General Hospital in Boston, and colleagues wrote in a study published in Clinical Cancer Research.
“The idea is that this could be used as kind of a first-pass screening tool for patients with hematuria that could potentially obviate the need for undergoing imaging such as CT scans or cystoscopy,” Dr. Salari said in an interview.
The uCGP test is a next-generation sequencing assay that identifies mutations in 60 genes associated with bladder cancer. An earlier analysis evaluating the test as a potential screening tool focused on 10 key genes covered in the assay. The study found the test accurately predicted future bladder cancer in 66% of urine samples, including some that had been collected more than a decade prior to being tested.
In the current case-control study, Dr. Salari and colleagues used a total of 581 samples – 333 samples for classifying disease and developing algorithms for initial diagnosis, surveillance, and molecular-grade prediction, as well as 248 samples for blinded validation. The test’s performance was evaluated by calculating sensitivity, specificity, positive predictive value, and negative predictive value.
Overall, the test demonstrated a specificity of 95% and sensitivity of 90% for an initial urothelial carcinoma diagnosis, but performed even better for the most aggressive tumors, with 100% sensitivity for diagnosing high-grade urothelial carcinoma and muscle-invasive tumors.
On the diagnosis front, the test had a positive predictive value of 88% and a negative predictive value of 99%.
Among patients under surveillance, the test predicted the risk of recurrence significantly better than standard clinical risk factors (hazard ratio, 6.2). The test demonstrated a positive predictive value similar to that observed for cytology (45% vs. 42%) but a much higher sensitivity (79% vs. 25%). The test also demonstrated a negative predictive value of 91% for recurrence.
The molecular-grade algorithm performed well, with a positive predictive value for high-grade disease of 88% and a specificity of 95% in the validation cohort.
Overall, “uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients,” the authors concluded. The test is not currently reimbursed by Medicare, but negotiations with third-party payers are reportedly underway.
The study was supported by the National Cancer Institute. Dr. Salari reported grants from Convergent Genomics during the conduct of the study as well as grants from Urology Care Foundation and Prostate Cancer Foundation, and personal fees from OrigiMed outside the submitted work. Several coauthors are employees and stockholders of Convergent Genomics.
A version of this article first appeared on Medscape.com.
, according to findings from a recent validation study.
The urinary comprehensive genomic profiling (uCGP) assay (UroAmp, Convergent Genomics) had a specificity of 95% and sensitivity of 90% for an initial diagnosis of urothelial carcinoma in patients with hematuria – identifying 95 of 100 people with urothelial carcinoma and 90 of 100 patients without the disease.
For patients under surveillance for urothelial cancer recurrence, the test was six times more accurate than traditional clinical risk factors for predicting recurrence.
“Considering its performance in multiple areas of urothelial carcinoma diagnosis and monitoring, uCGP shows great promise to enhance delivery of risk-stratified care,” Keyan Salari, MD, PhD, director of the prostate cancer genetics program at Massachusetts General Hospital in Boston, and colleagues wrote in a study published in Clinical Cancer Research.
“The idea is that this could be used as kind of a first-pass screening tool for patients with hematuria that could potentially obviate the need for undergoing imaging such as CT scans or cystoscopy,” Dr. Salari said in an interview.
The uCGP test is a next-generation sequencing assay that identifies mutations in 60 genes associated with bladder cancer. An earlier analysis evaluating the test as a potential screening tool focused on 10 key genes covered in the assay. The study found the test accurately predicted future bladder cancer in 66% of urine samples, including some that had been collected more than a decade prior to being tested.
In the current case-control study, Dr. Salari and colleagues used a total of 581 samples – 333 samples for classifying disease and developing algorithms for initial diagnosis, surveillance, and molecular-grade prediction, as well as 248 samples for blinded validation. The test’s performance was evaluated by calculating sensitivity, specificity, positive predictive value, and negative predictive value.
Overall, the test demonstrated a specificity of 95% and sensitivity of 90% for an initial urothelial carcinoma diagnosis, but performed even better for the most aggressive tumors, with 100% sensitivity for diagnosing high-grade urothelial carcinoma and muscle-invasive tumors.
On the diagnosis front, the test had a positive predictive value of 88% and a negative predictive value of 99%.
Among patients under surveillance, the test predicted the risk of recurrence significantly better than standard clinical risk factors (hazard ratio, 6.2). The test demonstrated a positive predictive value similar to that observed for cytology (45% vs. 42%) but a much higher sensitivity (79% vs. 25%). The test also demonstrated a negative predictive value of 91% for recurrence.
The molecular-grade algorithm performed well, with a positive predictive value for high-grade disease of 88% and a specificity of 95% in the validation cohort.
Overall, “uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients,” the authors concluded. The test is not currently reimbursed by Medicare, but negotiations with third-party payers are reportedly underway.
The study was supported by the National Cancer Institute. Dr. Salari reported grants from Convergent Genomics during the conduct of the study as well as grants from Urology Care Foundation and Prostate Cancer Foundation, and personal fees from OrigiMed outside the submitted work. Several coauthors are employees and stockholders of Convergent Genomics.
A version of this article first appeared on Medscape.com.
FROM CLINICAL CANCER RESEARCH
New trials in prostate cancer: Could your patient benefit?
Prostate cancer at high risk for biochemical recurrence following radical prostatectomy and/or radiation therapy. Adult patients with this diagnosis can join a randomized, double-blind, placebo-controlled, phase 3 study evaluating darolutamide (Nubeqa) plus androgen deprivation therapy against ADT alone. For up to 2 years, one group of participants will take twice-daily tablets of darolutamide, a nonsteroidal antiandrogen approved in 2019, in combination with ADT. A second group will take placebo plus ADT. Sites in California, Colorado, and worldwide started recruiting for 750 participants in April 2023; study centers across 19 other states in the US are gearing up. The primary outcome measure is radiological progression-free survival (PFS). Overall survival and quality of life (QoL) are secondary measures. More details at clinicaltrials.gov.
Commenting on the study, Marc Garnick, MD, professor of medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, said the trial “addresses an important question regarding intensification of androgen deprivation therapy with darolutamide” – specifically, whether this intensified approach is useful for a large proportion of men who experience biochemical recurrence (BCR) – rising PSA levels – after definitive localized therapy.
Dr. Garnick cautioned, however, that “it will be very important for the study investigators to stratify the many characteristics of BCR – and not treat this population as a homogeneous one since initial Gleason Score, time to BCR, and PSA doubling time all may impact the outcomes.”
Metastatic castration-sensitive prostate cancer. Adults with this type of cancer can join a randomized, open-label, phase 3 trial evaluating the nonsteroidal antiandrogen apalutamide (Erleada). Apalutamide, the first treatment approved for nonmetastatic castration-resistant prostate cancer, has also been approved for patients with metastatic castration-sensitive prostate cancer. This new trial will assess an intermittent approach to providing ADT alongside apalutamide in patients with metastatic disease.
All participants will take daily apalutamide tablets plus physician’s choice of ADT for 6 months. Everyone whose PSA falls below 0.2 ng/mL will either receive apalutamide with intermittent ADT per protocol or continue to receive apalutamide plus ADT for a further 18 months or until the patient discontinues the study, whichever happens first. Recruitment of 333 participants is planned for sites in Colorado, New York, Ohio, Utah, and Germany starting in August 2023. Radiographic PFS and hot flash score are the primary endpoints. QoL and overall survival are secondary outcomes. See more details at clinicaltrials.gov.
This study “should add to our knowledge of optimal treatment” for metastatic castrate-sensitive prostate cancer,” Dr. Garnick said. However, “this is a very heterogeneous population of patients and how they get to the [diagnosis] of metastatic castrate-sensitive prostate cancer is important. The sample size and stratifications need to be well studied for this study to provide any meaningful data.”
Localized intermediate- or high-risk prostate cancer. People with one of these clinical scenarios who have not yet had stereotactic body radiation therapy (SBRT) or a prostatectomy are eligible for a randomized, open-label, phase 2 study. This National Cancer Institute (NCI) trial is looking at whether the experimental immunocytokine M9241 can enhance the effectiveness of SBRT. M9241 is designed to assist the immune system to fight cancer by boosting the activity of T cells at necrotic sites in the tumor.
All participants will receive standard of care ADT. One group of people will also receive three subcutaneous injections of M9241 at 4-weekly intervals in deescalating doses, then 10 days of standard SBRT, followed by another three injections of M9241 at the highest tolerable dose. A second group will only undergo SBRT. The National Institutes of Health Clinical Center in Bethesda, Maryland, started recruiting the trial’s 65 participants in June 2023. The primary endpoints are the doses of M9241 in combination with ADT that are safe and tolerable, and T-cell clonality (a measure of immunologic activity). Overall survival and QoL will not be tracked. More details are available at clinicaltrials.gov.
“The M9241 study is very important,” said Dr. Garnick, explaining that he hopes the trial will add to the growing knowledge about the interactions of radiation and its effects on the immune system.
Confirmed prostate cancer. People with prostate cancer eligible for triplet or doublet ADT combination therapy can join a randomized, single-masked, phase 2 NCI investigation of bright white light therapy for ADT-associated fatigue and depression. All participants will receive standard of care ADT combination therapy for up to a year. One group of participants will use AYOpro glasses, a commercial bright white light therapy, daily as ADT starts (“immediate” therapy). A second set of people will start using the glasses after 6 months of ADT therapy (“delayed” therapy). The City of Hope Medical Center, Duarte, Calif., planned to start welcoming the trial’s 210 participants in August 2023. Fatigue is the primary endpoint, QoL is a secondary endpoint, and overall survival will not be recorded. More details are available at clinicaltrials.gov.
“Fatigue is an important feature of cancer therapies in general and any approach to lessen the impact of fatigue should be welcome,” Dr. Garnick said. However, “it would have been helpful” if the official description of the trial had provided more information on the rationale for testing bright white light therapy in prostate cancer.
Metastatic castration-resistant prostate cancer. Adults with this diagnosis who have been treated with one prior androgen receptor axis-targeted therapy (ARAT) can enter a randomized, open-label, phase 2 trial to determine the best dose of the antibody-drug conjugate vobramitamab duocarmazine (MacroGenics). This experimental drug is designed to deliver an alkylating agent that promotes cell death in solid tumors expressing B7-H3. The B7-H3 protein rarely appears in normal tissues but is expressed at high frequency in 60% of cancers.
For approximately 2 years, participants will receive one of two doses of intravenous vobramitamab duocarmazine every 4 weeks. The trial opened in June 2023, looking to recruit 100 participants across nine states in the United States and eight other countries. The primary outcome measure is radiographic PFS. Overall survival and QoL will not be assessed. More details at clinicaltrials.gov.
Localized or biochemically recurrent prostate cancer. Adults in this position who have not received prior GnRH agonist or antagonist therapy are being recruited for a randomized, single-masked, phase 2 study comparing QoL among patients taking ADTs relugolix (Orgovyx, Relumina) and leuprolide acetate for depot suspension (Lupron Depot). For up to 1 year, people in the trial will either take daily tablets of relugolix or receive injections of leuprolide every 3 months. Three study sites in Massachusetts are due to open their doors in August 2023, seeking 110 participants. The study will assess various measures of QoL. Overall survival will not be measured. More details at clinicaltrials.gov.
This study is “sort of plain vanilla,” Dr. Garnick said. Although “the objectives of the study are important, the study number is small and unlikely to show any meaningful differences,” even if differences do exist.
All trial information is from the National Institutes of Health U.S. National Library of Medicine (online at clinicaltrials.gov). Dr. Garnick reported no relevant financial relationships. He is editor-in-chief of the Harvard Medical School Annual Report on Prostate Diseases, for which he receives an honorarium.
A version of this article first appeared on Medscape.com.
Prostate cancer at high risk for biochemical recurrence following radical prostatectomy and/or radiation therapy. Adult patients with this diagnosis can join a randomized, double-blind, placebo-controlled, phase 3 study evaluating darolutamide (Nubeqa) plus androgen deprivation therapy against ADT alone. For up to 2 years, one group of participants will take twice-daily tablets of darolutamide, a nonsteroidal antiandrogen approved in 2019, in combination with ADT. A second group will take placebo plus ADT. Sites in California, Colorado, and worldwide started recruiting for 750 participants in April 2023; study centers across 19 other states in the US are gearing up. The primary outcome measure is radiological progression-free survival (PFS). Overall survival and quality of life (QoL) are secondary measures. More details at clinicaltrials.gov.
Commenting on the study, Marc Garnick, MD, professor of medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, said the trial “addresses an important question regarding intensification of androgen deprivation therapy with darolutamide” – specifically, whether this intensified approach is useful for a large proportion of men who experience biochemical recurrence (BCR) – rising PSA levels – after definitive localized therapy.
Dr. Garnick cautioned, however, that “it will be very important for the study investigators to stratify the many characteristics of BCR – and not treat this population as a homogeneous one since initial Gleason Score, time to BCR, and PSA doubling time all may impact the outcomes.”
Metastatic castration-sensitive prostate cancer. Adults with this type of cancer can join a randomized, open-label, phase 3 trial evaluating the nonsteroidal antiandrogen apalutamide (Erleada). Apalutamide, the first treatment approved for nonmetastatic castration-resistant prostate cancer, has also been approved for patients with metastatic castration-sensitive prostate cancer. This new trial will assess an intermittent approach to providing ADT alongside apalutamide in patients with metastatic disease.
All participants will take daily apalutamide tablets plus physician’s choice of ADT for 6 months. Everyone whose PSA falls below 0.2 ng/mL will either receive apalutamide with intermittent ADT per protocol or continue to receive apalutamide plus ADT for a further 18 months or until the patient discontinues the study, whichever happens first. Recruitment of 333 participants is planned for sites in Colorado, New York, Ohio, Utah, and Germany starting in August 2023. Radiographic PFS and hot flash score are the primary endpoints. QoL and overall survival are secondary outcomes. See more details at clinicaltrials.gov.
This study “should add to our knowledge of optimal treatment” for metastatic castrate-sensitive prostate cancer,” Dr. Garnick said. However, “this is a very heterogeneous population of patients and how they get to the [diagnosis] of metastatic castrate-sensitive prostate cancer is important. The sample size and stratifications need to be well studied for this study to provide any meaningful data.”
Localized intermediate- or high-risk prostate cancer. People with one of these clinical scenarios who have not yet had stereotactic body radiation therapy (SBRT) or a prostatectomy are eligible for a randomized, open-label, phase 2 study. This National Cancer Institute (NCI) trial is looking at whether the experimental immunocytokine M9241 can enhance the effectiveness of SBRT. M9241 is designed to assist the immune system to fight cancer by boosting the activity of T cells at necrotic sites in the tumor.
All participants will receive standard of care ADT. One group of people will also receive three subcutaneous injections of M9241 at 4-weekly intervals in deescalating doses, then 10 days of standard SBRT, followed by another three injections of M9241 at the highest tolerable dose. A second group will only undergo SBRT. The National Institutes of Health Clinical Center in Bethesda, Maryland, started recruiting the trial’s 65 participants in June 2023. The primary endpoints are the doses of M9241 in combination with ADT that are safe and tolerable, and T-cell clonality (a measure of immunologic activity). Overall survival and QoL will not be tracked. More details are available at clinicaltrials.gov.
“The M9241 study is very important,” said Dr. Garnick, explaining that he hopes the trial will add to the growing knowledge about the interactions of radiation and its effects on the immune system.
Confirmed prostate cancer. People with prostate cancer eligible for triplet or doublet ADT combination therapy can join a randomized, single-masked, phase 2 NCI investigation of bright white light therapy for ADT-associated fatigue and depression. All participants will receive standard of care ADT combination therapy for up to a year. One group of participants will use AYOpro glasses, a commercial bright white light therapy, daily as ADT starts (“immediate” therapy). A second set of people will start using the glasses after 6 months of ADT therapy (“delayed” therapy). The City of Hope Medical Center, Duarte, Calif., planned to start welcoming the trial’s 210 participants in August 2023. Fatigue is the primary endpoint, QoL is a secondary endpoint, and overall survival will not be recorded. More details are available at clinicaltrials.gov.
“Fatigue is an important feature of cancer therapies in general and any approach to lessen the impact of fatigue should be welcome,” Dr. Garnick said. However, “it would have been helpful” if the official description of the trial had provided more information on the rationale for testing bright white light therapy in prostate cancer.
Metastatic castration-resistant prostate cancer. Adults with this diagnosis who have been treated with one prior androgen receptor axis-targeted therapy (ARAT) can enter a randomized, open-label, phase 2 trial to determine the best dose of the antibody-drug conjugate vobramitamab duocarmazine (MacroGenics). This experimental drug is designed to deliver an alkylating agent that promotes cell death in solid tumors expressing B7-H3. The B7-H3 protein rarely appears in normal tissues but is expressed at high frequency in 60% of cancers.
For approximately 2 years, participants will receive one of two doses of intravenous vobramitamab duocarmazine every 4 weeks. The trial opened in June 2023, looking to recruit 100 participants across nine states in the United States and eight other countries. The primary outcome measure is radiographic PFS. Overall survival and QoL will not be assessed. More details at clinicaltrials.gov.
Localized or biochemically recurrent prostate cancer. Adults in this position who have not received prior GnRH agonist or antagonist therapy are being recruited for a randomized, single-masked, phase 2 study comparing QoL among patients taking ADTs relugolix (Orgovyx, Relumina) and leuprolide acetate for depot suspension (Lupron Depot). For up to 1 year, people in the trial will either take daily tablets of relugolix or receive injections of leuprolide every 3 months. Three study sites in Massachusetts are due to open their doors in August 2023, seeking 110 participants. The study will assess various measures of QoL. Overall survival will not be measured. More details at clinicaltrials.gov.
This study is “sort of plain vanilla,” Dr. Garnick said. Although “the objectives of the study are important, the study number is small and unlikely to show any meaningful differences,” even if differences do exist.
All trial information is from the National Institutes of Health U.S. National Library of Medicine (online at clinicaltrials.gov). Dr. Garnick reported no relevant financial relationships. He is editor-in-chief of the Harvard Medical School Annual Report on Prostate Diseases, for which he receives an honorarium.
A version of this article first appeared on Medscape.com.
Prostate cancer at high risk for biochemical recurrence following radical prostatectomy and/or radiation therapy. Adult patients with this diagnosis can join a randomized, double-blind, placebo-controlled, phase 3 study evaluating darolutamide (Nubeqa) plus androgen deprivation therapy against ADT alone. For up to 2 years, one group of participants will take twice-daily tablets of darolutamide, a nonsteroidal antiandrogen approved in 2019, in combination with ADT. A second group will take placebo plus ADT. Sites in California, Colorado, and worldwide started recruiting for 750 participants in April 2023; study centers across 19 other states in the US are gearing up. The primary outcome measure is radiological progression-free survival (PFS). Overall survival and quality of life (QoL) are secondary measures. More details at clinicaltrials.gov.
Commenting on the study, Marc Garnick, MD, professor of medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, said the trial “addresses an important question regarding intensification of androgen deprivation therapy with darolutamide” – specifically, whether this intensified approach is useful for a large proportion of men who experience biochemical recurrence (BCR) – rising PSA levels – after definitive localized therapy.
Dr. Garnick cautioned, however, that “it will be very important for the study investigators to stratify the many characteristics of BCR – and not treat this population as a homogeneous one since initial Gleason Score, time to BCR, and PSA doubling time all may impact the outcomes.”
Metastatic castration-sensitive prostate cancer. Adults with this type of cancer can join a randomized, open-label, phase 3 trial evaluating the nonsteroidal antiandrogen apalutamide (Erleada). Apalutamide, the first treatment approved for nonmetastatic castration-resistant prostate cancer, has also been approved for patients with metastatic castration-sensitive prostate cancer. This new trial will assess an intermittent approach to providing ADT alongside apalutamide in patients with metastatic disease.
All participants will take daily apalutamide tablets plus physician’s choice of ADT for 6 months. Everyone whose PSA falls below 0.2 ng/mL will either receive apalutamide with intermittent ADT per protocol or continue to receive apalutamide plus ADT for a further 18 months or until the patient discontinues the study, whichever happens first. Recruitment of 333 participants is planned for sites in Colorado, New York, Ohio, Utah, and Germany starting in August 2023. Radiographic PFS and hot flash score are the primary endpoints. QoL and overall survival are secondary outcomes. See more details at clinicaltrials.gov.
This study “should add to our knowledge of optimal treatment” for metastatic castrate-sensitive prostate cancer,” Dr. Garnick said. However, “this is a very heterogeneous population of patients and how they get to the [diagnosis] of metastatic castrate-sensitive prostate cancer is important. The sample size and stratifications need to be well studied for this study to provide any meaningful data.”
Localized intermediate- or high-risk prostate cancer. People with one of these clinical scenarios who have not yet had stereotactic body radiation therapy (SBRT) or a prostatectomy are eligible for a randomized, open-label, phase 2 study. This National Cancer Institute (NCI) trial is looking at whether the experimental immunocytokine M9241 can enhance the effectiveness of SBRT. M9241 is designed to assist the immune system to fight cancer by boosting the activity of T cells at necrotic sites in the tumor.
All participants will receive standard of care ADT. One group of people will also receive three subcutaneous injections of M9241 at 4-weekly intervals in deescalating doses, then 10 days of standard SBRT, followed by another three injections of M9241 at the highest tolerable dose. A second group will only undergo SBRT. The National Institutes of Health Clinical Center in Bethesda, Maryland, started recruiting the trial’s 65 participants in June 2023. The primary endpoints are the doses of M9241 in combination with ADT that are safe and tolerable, and T-cell clonality (a measure of immunologic activity). Overall survival and QoL will not be tracked. More details are available at clinicaltrials.gov.
“The M9241 study is very important,” said Dr. Garnick, explaining that he hopes the trial will add to the growing knowledge about the interactions of radiation and its effects on the immune system.
Confirmed prostate cancer. People with prostate cancer eligible for triplet or doublet ADT combination therapy can join a randomized, single-masked, phase 2 NCI investigation of bright white light therapy for ADT-associated fatigue and depression. All participants will receive standard of care ADT combination therapy for up to a year. One group of participants will use AYOpro glasses, a commercial bright white light therapy, daily as ADT starts (“immediate” therapy). A second set of people will start using the glasses after 6 months of ADT therapy (“delayed” therapy). The City of Hope Medical Center, Duarte, Calif., planned to start welcoming the trial’s 210 participants in August 2023. Fatigue is the primary endpoint, QoL is a secondary endpoint, and overall survival will not be recorded. More details are available at clinicaltrials.gov.
“Fatigue is an important feature of cancer therapies in general and any approach to lessen the impact of fatigue should be welcome,” Dr. Garnick said. However, “it would have been helpful” if the official description of the trial had provided more information on the rationale for testing bright white light therapy in prostate cancer.
Metastatic castration-resistant prostate cancer. Adults with this diagnosis who have been treated with one prior androgen receptor axis-targeted therapy (ARAT) can enter a randomized, open-label, phase 2 trial to determine the best dose of the antibody-drug conjugate vobramitamab duocarmazine (MacroGenics). This experimental drug is designed to deliver an alkylating agent that promotes cell death in solid tumors expressing B7-H3. The B7-H3 protein rarely appears in normal tissues but is expressed at high frequency in 60% of cancers.
For approximately 2 years, participants will receive one of two doses of intravenous vobramitamab duocarmazine every 4 weeks. The trial opened in June 2023, looking to recruit 100 participants across nine states in the United States and eight other countries. The primary outcome measure is radiographic PFS. Overall survival and QoL will not be assessed. More details at clinicaltrials.gov.
Localized or biochemically recurrent prostate cancer. Adults in this position who have not received prior GnRH agonist or antagonist therapy are being recruited for a randomized, single-masked, phase 2 study comparing QoL among patients taking ADTs relugolix (Orgovyx, Relumina) and leuprolide acetate for depot suspension (Lupron Depot). For up to 1 year, people in the trial will either take daily tablets of relugolix or receive injections of leuprolide every 3 months. Three study sites in Massachusetts are due to open their doors in August 2023, seeking 110 participants. The study will assess various measures of QoL. Overall survival will not be measured. More details at clinicaltrials.gov.
This study is “sort of plain vanilla,” Dr. Garnick said. Although “the objectives of the study are important, the study number is small and unlikely to show any meaningful differences,” even if differences do exist.
All trial information is from the National Institutes of Health U.S. National Library of Medicine (online at clinicaltrials.gov). Dr. Garnick reported no relevant financial relationships. He is editor-in-chief of the Harvard Medical School Annual Report on Prostate Diseases, for which he receives an honorarium.
A version of this article first appeared on Medscape.com.
FDA OKs combo therapy of niraparib, abiraterone acetate for prostate cancer
The Food and Drug Administration has approved niraparib and abiraterone acetate (Akeega, Janssen Pharmaceuticals) to treat BRCA-positive, metastatic castration-resistant prostate cancer in adult patients with deleterious or suspected deleterious disease, as determined by an FDA-approved test.
The FDA’s approval was based on findings from the phase 3 MAGNITUDE precision medicine study, a randomized, placebo-controlled trial with 423 patients, 225 (53%) of whom had BRCA gene mutations as determined using a tissue assay such as FoundationOne CDx.
Among the subgroup with a BRCA mutation, radiographic progression-free survival was a median of 16.6 months vs. 10.9 months (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.36-0.79; P = .0014). In this subgroup, an exploratory overall survival analysis demonstrated a median of 30.4 months vs. 28.6 months (HR, 0.79; 95% CI, 0.55-1.12), favoring the treatment arm.
Although the overall cohort (those with and without BRCA mutations) demonstrated a significant improvement in radiographic progression-free survival, the subgroup with non-BRCA homologous recombination repair mutations did not demonstrate a significant improvement in radiographic progression-free survival, which indicates that the benefit observed was “primarily attributed” to the results in the subgroup of patients with BRCA mutations, according to the FDA.
The safety profile of niraparib and abiraterone acetate plus prednisone was consistent with the known safety profile of each FDA-approved monotherapy. Serious adverse events occurred in 41% of patients in the treatment arm. These most often included musculoskeletal pain (44% vs. 42%), fatigue (43% vs. 30%), constipation (34% vs. 20%), hypertension (33% vs. 27%), and nausea (33% vs. 21%).
An adverse reaction led to permanent discontinuation of treatment in 15% of patients.
“As a physician, identifying patients with a worse prognosis is a priority, especially those whose cancers have a BRCA mutation,” principal investigator Kim Chi, MD, stated in the Janssen press release. “We prospectively designed the MAGNITUDE study to identify the subset of patients most likely to benefit from targeted treatment with AKEEGA and to help us understand how we can potentially achieve better health outcomes for patients.”
About 10%-15% of patients who develop metastatic castration-resistant prostate cancer have BRCA gene alterations, and those patients are more likely to have aggressive disease, poor outcomes, and shorter survival. Therefore, this new agent “brings an important treatment option to patients with prostate cancer as they consider their road ahead,” said Shelby Moneer, vice president of patient programs and education at ZERO Prostate Cancer.
The prescribing information lists the recommended dose at 200 mg niraparib and 1,000 mg abiraterone once daily in combination with 10 mg of prednisone daily until disease progression or unacceptable toxicity. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy.
Health care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device by using the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article appeared on Medscape.com.
The Food and Drug Administration has approved niraparib and abiraterone acetate (Akeega, Janssen Pharmaceuticals) to treat BRCA-positive, metastatic castration-resistant prostate cancer in adult patients with deleterious or suspected deleterious disease, as determined by an FDA-approved test.
The FDA’s approval was based on findings from the phase 3 MAGNITUDE precision medicine study, a randomized, placebo-controlled trial with 423 patients, 225 (53%) of whom had BRCA gene mutations as determined using a tissue assay such as FoundationOne CDx.
Among the subgroup with a BRCA mutation, radiographic progression-free survival was a median of 16.6 months vs. 10.9 months (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.36-0.79; P = .0014). In this subgroup, an exploratory overall survival analysis demonstrated a median of 30.4 months vs. 28.6 months (HR, 0.79; 95% CI, 0.55-1.12), favoring the treatment arm.
Although the overall cohort (those with and without BRCA mutations) demonstrated a significant improvement in radiographic progression-free survival, the subgroup with non-BRCA homologous recombination repair mutations did not demonstrate a significant improvement in radiographic progression-free survival, which indicates that the benefit observed was “primarily attributed” to the results in the subgroup of patients with BRCA mutations, according to the FDA.
The safety profile of niraparib and abiraterone acetate plus prednisone was consistent with the known safety profile of each FDA-approved monotherapy. Serious adverse events occurred in 41% of patients in the treatment arm. These most often included musculoskeletal pain (44% vs. 42%), fatigue (43% vs. 30%), constipation (34% vs. 20%), hypertension (33% vs. 27%), and nausea (33% vs. 21%).
An adverse reaction led to permanent discontinuation of treatment in 15% of patients.
“As a physician, identifying patients with a worse prognosis is a priority, especially those whose cancers have a BRCA mutation,” principal investigator Kim Chi, MD, stated in the Janssen press release. “We prospectively designed the MAGNITUDE study to identify the subset of patients most likely to benefit from targeted treatment with AKEEGA and to help us understand how we can potentially achieve better health outcomes for patients.”
About 10%-15% of patients who develop metastatic castration-resistant prostate cancer have BRCA gene alterations, and those patients are more likely to have aggressive disease, poor outcomes, and shorter survival. Therefore, this new agent “brings an important treatment option to patients with prostate cancer as they consider their road ahead,” said Shelby Moneer, vice president of patient programs and education at ZERO Prostate Cancer.
The prescribing information lists the recommended dose at 200 mg niraparib and 1,000 mg abiraterone once daily in combination with 10 mg of prednisone daily until disease progression or unacceptable toxicity. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy.
Health care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device by using the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article appeared on Medscape.com.
The Food and Drug Administration has approved niraparib and abiraterone acetate (Akeega, Janssen Pharmaceuticals) to treat BRCA-positive, metastatic castration-resistant prostate cancer in adult patients with deleterious or suspected deleterious disease, as determined by an FDA-approved test.
The FDA’s approval was based on findings from the phase 3 MAGNITUDE precision medicine study, a randomized, placebo-controlled trial with 423 patients, 225 (53%) of whom had BRCA gene mutations as determined using a tissue assay such as FoundationOne CDx.
Among the subgroup with a BRCA mutation, radiographic progression-free survival was a median of 16.6 months vs. 10.9 months (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.36-0.79; P = .0014). In this subgroup, an exploratory overall survival analysis demonstrated a median of 30.4 months vs. 28.6 months (HR, 0.79; 95% CI, 0.55-1.12), favoring the treatment arm.
Although the overall cohort (those with and without BRCA mutations) demonstrated a significant improvement in radiographic progression-free survival, the subgroup with non-BRCA homologous recombination repair mutations did not demonstrate a significant improvement in radiographic progression-free survival, which indicates that the benefit observed was “primarily attributed” to the results in the subgroup of patients with BRCA mutations, according to the FDA.
The safety profile of niraparib and abiraterone acetate plus prednisone was consistent with the known safety profile of each FDA-approved monotherapy. Serious adverse events occurred in 41% of patients in the treatment arm. These most often included musculoskeletal pain (44% vs. 42%), fatigue (43% vs. 30%), constipation (34% vs. 20%), hypertension (33% vs. 27%), and nausea (33% vs. 21%).
An adverse reaction led to permanent discontinuation of treatment in 15% of patients.
“As a physician, identifying patients with a worse prognosis is a priority, especially those whose cancers have a BRCA mutation,” principal investigator Kim Chi, MD, stated in the Janssen press release. “We prospectively designed the MAGNITUDE study to identify the subset of patients most likely to benefit from targeted treatment with AKEEGA and to help us understand how we can potentially achieve better health outcomes for patients.”
About 10%-15% of patients who develop metastatic castration-resistant prostate cancer have BRCA gene alterations, and those patients are more likely to have aggressive disease, poor outcomes, and shorter survival. Therefore, this new agent “brings an important treatment option to patients with prostate cancer as they consider their road ahead,” said Shelby Moneer, vice president of patient programs and education at ZERO Prostate Cancer.
The prescribing information lists the recommended dose at 200 mg niraparib and 1,000 mg abiraterone once daily in combination with 10 mg of prednisone daily until disease progression or unacceptable toxicity. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy.
Health care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device by using the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article appeared on Medscape.com.
How useful are circulating tumor cells for early diagnosis?
Treatment options for patients with cancer that is detected at a late stage are severely limited, which usually leads to an unfavorable prognosis for such patients. Indeed, the options available for patients with metastatic solid cancers are scarcely curative. Therefore, early diagnosis of neoplasia remains a fundamental mainstay for improving outcomes for cancer patients.
Histopathology is the current gold standard for cancer diagnosis. Biopsy is an invasive procedure that provides physicians with further samples to test but that furnishes limited information concerning tumor heterogeneity. Biopsy specimens are usually obtained only when there is clinical evidence of neoplasia, which significantly limits their usefulness in early diagnosis.
Around 20 years ago, it was discovered that the presence of circulating tumor cells (CTC) in patients with metastatic breast cancer who were about to begin a new line of treatment was predictive of overall and progression-free survival. The prognostic value of CTC was independent of the line of treatment (first or second) and was greater than that of the site of metastasis, the type of therapy, and the time to metastasis after complete primary resection. These results support the idea that the presence of CTC could be used to modify the system for staging advanced disease.
Since then,
Liquid vs. tissue
Liquid biopsy is a minimally invasive tool that is easy to use. It is employed to detect cancer, to assess treatment response, or to monitor disease progression. Liquid biopsy produces test material from primary and metastatic (or micrometastatic) sites and provides a more heterogeneous picture of the entire tumor cell population, compared with specimens obtained with tissue biopsy.
Metastasis
The notion that metastatic lesions are formed from cancer cells that have disseminated from advanced primary tumors has been substantially revised following the identification of disseminated tumor cells (DTC) in the bone marrow of patients with early-stage disease. These results have led researchers to no longer view cancer metastasis as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as metastasizing cells assume new phenotypes while abandoning older behaviors.
The initiation of metastasis is not simply a cell-autonomous event but is heavily influenced by complex tissue microenvironments. Although colonization of distant tissues by DTC is an extremely inefficient process, at times, relatively numerous CTC can be detected in the blood of cancer patients (> 1,000 CTC/mL of blood plasma), whereas the number of clinically detectable metastases is disproportionately low, confirming that tumor cell diffusion can happen at an early stage but usually occurs later on.
Early dissemination
Little is currently known about the preference of cancer subtypes for distinct tissues or about the receptiveness of a tissue as a metastatic site. What endures as one of the most confounding clinical phenomena is that patients may undergo tumor resection and remain apparently disease free for months, years, and even decades, only to experience relapse and be diagnosed with late-stage metastatic disease. This course may be a result of cell seeding from minimal residual disease after resection of the primary tumor or of preexisting clinically undetectable micrometastases. It may also arise from early disseminated cells that remain dormant and resistant to therapy until they suddenly reawaken to initiate proliferation into clinically detectable macrometastases.
Dormant DTC could be the main reason for delayed detection of metastases. It is thought that around 40% of patients with prostate cancer who undergo radical prostatectomy present with biochemical recurrence, suggesting that it is likely that hidden DTC or micrometastases are present at the time of the procedure. The finding is consistent with the detection of DTC many years after tumor resection, suggesting they were released before surgical treatment. Nevertheless, research into tumor cell dormancy is limited, owing to the invasive and technically challenging nature of obtaining DTC samples, which are predominantly taken from the bone marrow.
CTC metastases
Cancer cells can undergo epithelial-to-mesenchymal transition to facilitate their detachment from the primary tumor and intravasation into the blood circulation (step 1). Dissemination of cancer cells from the primary tumor into circulation can involve either single cells or cell clusters containing multiple CTC as well as immune cells and platelets, known as microemboli. CTC that can survive in circulation (step 2) can exit the bloodstream (step 3) and establish metastatic tumors (step 4), or they can enter dormancy and reside in distant organs, such as the bone marrow.
Use in practice
CTC were discovered over a century ago, but only in recent years has technology been sufficiently advanced to study CTC and to assess their usefulness as biomarkers. Recent evidence suggests that not only do the number of CTC increase during sleep and rest phases but also that these CTC are better able to metastasize, compared to those generated during periods of wakefulness or activity.
CTC clusters (microemboli) are defined as groups of two or more CTC. They can consist of CTC alone (homotypic) or can include various stromal cells, such as cancer-associated fibroblasts or platelets and immune cells (heterotypic). CTC clusters (with or without leukocytes) seem to have greater metastatic capacity, compared with individual CTC.
A multitude of characteristics can be measured in CTC, including genetics and epigenetics, as well as protein levels, which might help in understanding many processes involved in the formation of metastases.
Quantitative assessment of CTC could indicate tumor burden in patients with aggressive cancers, as has been seen in patients with primary lung cancer.
Early cancer diagnosis
Early research into CTC didn’t explore their usefulness in diagnosing early-stage tumors because it was thought that CTC were characteristic of advanced-stage disease. This hypothesis was later rejected following evidence of local intravascular invasion of very early cancer cells, even over a period of several hours. This feature may allow CTC to be detected before the clinical diagnosis of cancer.
CTC have been detected in various neoplastic conditions: in breast cancer, seen in 20% of patients with stage I disease, in 26.8% with stage II disease, and 26.7% with stage III disease; in nonmetastatic colorectal cancer, including stage I and II disease; and in prostate cancer, seen in over 50% of patients with localized disease.
The presence of CTC has been proven to be an unfavorable prognostic predictor of overall survival among patients with early-stage non–small cell lung cancer. It distinguishes patients with pancreatic ductal adenocarcinoma from those with noncancerous pancreatic diseases with a sensitivity of 75% and a specificity of 96.3%.
CTC positivity scoring (appropriately defined), combined with serum prostate-specific antigen level, was predictive of a biopsy diagnosis of clinically significant prostate cancer.
All these data support the utility of CTC in early cancer diagnosis. Their link with metastases, and thus with aggressive tumors, gives them an advantage over other (noninvasive or minimally invasive) biomarkers in the early identification of invasive tumors for therapeutic intervention with better cure rates.
This article was translated from Univadis Italy. A version appeared on Medscape.com.
Treatment options for patients with cancer that is detected at a late stage are severely limited, which usually leads to an unfavorable prognosis for such patients. Indeed, the options available for patients with metastatic solid cancers are scarcely curative. Therefore, early diagnosis of neoplasia remains a fundamental mainstay for improving outcomes for cancer patients.
Histopathology is the current gold standard for cancer diagnosis. Biopsy is an invasive procedure that provides physicians with further samples to test but that furnishes limited information concerning tumor heterogeneity. Biopsy specimens are usually obtained only when there is clinical evidence of neoplasia, which significantly limits their usefulness in early diagnosis.
Around 20 years ago, it was discovered that the presence of circulating tumor cells (CTC) in patients with metastatic breast cancer who were about to begin a new line of treatment was predictive of overall and progression-free survival. The prognostic value of CTC was independent of the line of treatment (first or second) and was greater than that of the site of metastasis, the type of therapy, and the time to metastasis after complete primary resection. These results support the idea that the presence of CTC could be used to modify the system for staging advanced disease.
Since then,
Liquid vs. tissue
Liquid biopsy is a minimally invasive tool that is easy to use. It is employed to detect cancer, to assess treatment response, or to monitor disease progression. Liquid biopsy produces test material from primary and metastatic (or micrometastatic) sites and provides a more heterogeneous picture of the entire tumor cell population, compared with specimens obtained with tissue biopsy.
Metastasis
The notion that metastatic lesions are formed from cancer cells that have disseminated from advanced primary tumors has been substantially revised following the identification of disseminated tumor cells (DTC) in the bone marrow of patients with early-stage disease. These results have led researchers to no longer view cancer metastasis as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as metastasizing cells assume new phenotypes while abandoning older behaviors.
The initiation of metastasis is not simply a cell-autonomous event but is heavily influenced by complex tissue microenvironments. Although colonization of distant tissues by DTC is an extremely inefficient process, at times, relatively numerous CTC can be detected in the blood of cancer patients (> 1,000 CTC/mL of blood plasma), whereas the number of clinically detectable metastases is disproportionately low, confirming that tumor cell diffusion can happen at an early stage but usually occurs later on.
Early dissemination
Little is currently known about the preference of cancer subtypes for distinct tissues or about the receptiveness of a tissue as a metastatic site. What endures as one of the most confounding clinical phenomena is that patients may undergo tumor resection and remain apparently disease free for months, years, and even decades, only to experience relapse and be diagnosed with late-stage metastatic disease. This course may be a result of cell seeding from minimal residual disease after resection of the primary tumor or of preexisting clinically undetectable micrometastases. It may also arise from early disseminated cells that remain dormant and resistant to therapy until they suddenly reawaken to initiate proliferation into clinically detectable macrometastases.
Dormant DTC could be the main reason for delayed detection of metastases. It is thought that around 40% of patients with prostate cancer who undergo radical prostatectomy present with biochemical recurrence, suggesting that it is likely that hidden DTC or micrometastases are present at the time of the procedure. The finding is consistent with the detection of DTC many years after tumor resection, suggesting they were released before surgical treatment. Nevertheless, research into tumor cell dormancy is limited, owing to the invasive and technically challenging nature of obtaining DTC samples, which are predominantly taken from the bone marrow.
CTC metastases
Cancer cells can undergo epithelial-to-mesenchymal transition to facilitate their detachment from the primary tumor and intravasation into the blood circulation (step 1). Dissemination of cancer cells from the primary tumor into circulation can involve either single cells or cell clusters containing multiple CTC as well as immune cells and platelets, known as microemboli. CTC that can survive in circulation (step 2) can exit the bloodstream (step 3) and establish metastatic tumors (step 4), or they can enter dormancy and reside in distant organs, such as the bone marrow.
Use in practice
CTC were discovered over a century ago, but only in recent years has technology been sufficiently advanced to study CTC and to assess their usefulness as biomarkers. Recent evidence suggests that not only do the number of CTC increase during sleep and rest phases but also that these CTC are better able to metastasize, compared to those generated during periods of wakefulness or activity.
CTC clusters (microemboli) are defined as groups of two or more CTC. They can consist of CTC alone (homotypic) or can include various stromal cells, such as cancer-associated fibroblasts or platelets and immune cells (heterotypic). CTC clusters (with or without leukocytes) seem to have greater metastatic capacity, compared with individual CTC.
A multitude of characteristics can be measured in CTC, including genetics and epigenetics, as well as protein levels, which might help in understanding many processes involved in the formation of metastases.
Quantitative assessment of CTC could indicate tumor burden in patients with aggressive cancers, as has been seen in patients with primary lung cancer.
Early cancer diagnosis
Early research into CTC didn’t explore their usefulness in diagnosing early-stage tumors because it was thought that CTC were characteristic of advanced-stage disease. This hypothesis was later rejected following evidence of local intravascular invasion of very early cancer cells, even over a period of several hours. This feature may allow CTC to be detected before the clinical diagnosis of cancer.
CTC have been detected in various neoplastic conditions: in breast cancer, seen in 20% of patients with stage I disease, in 26.8% with stage II disease, and 26.7% with stage III disease; in nonmetastatic colorectal cancer, including stage I and II disease; and in prostate cancer, seen in over 50% of patients with localized disease.
The presence of CTC has been proven to be an unfavorable prognostic predictor of overall survival among patients with early-stage non–small cell lung cancer. It distinguishes patients with pancreatic ductal adenocarcinoma from those with noncancerous pancreatic diseases with a sensitivity of 75% and a specificity of 96.3%.
CTC positivity scoring (appropriately defined), combined with serum prostate-specific antigen level, was predictive of a biopsy diagnosis of clinically significant prostate cancer.
All these data support the utility of CTC in early cancer diagnosis. Their link with metastases, and thus with aggressive tumors, gives them an advantage over other (noninvasive or minimally invasive) biomarkers in the early identification of invasive tumors for therapeutic intervention with better cure rates.
This article was translated from Univadis Italy. A version appeared on Medscape.com.
Treatment options for patients with cancer that is detected at a late stage are severely limited, which usually leads to an unfavorable prognosis for such patients. Indeed, the options available for patients with metastatic solid cancers are scarcely curative. Therefore, early diagnosis of neoplasia remains a fundamental mainstay for improving outcomes for cancer patients.
Histopathology is the current gold standard for cancer diagnosis. Biopsy is an invasive procedure that provides physicians with further samples to test but that furnishes limited information concerning tumor heterogeneity. Biopsy specimens are usually obtained only when there is clinical evidence of neoplasia, which significantly limits their usefulness in early diagnosis.
Around 20 years ago, it was discovered that the presence of circulating tumor cells (CTC) in patients with metastatic breast cancer who were about to begin a new line of treatment was predictive of overall and progression-free survival. The prognostic value of CTC was independent of the line of treatment (first or second) and was greater than that of the site of metastasis, the type of therapy, and the time to metastasis after complete primary resection. These results support the idea that the presence of CTC could be used to modify the system for staging advanced disease.
Since then,
Liquid vs. tissue
Liquid biopsy is a minimally invasive tool that is easy to use. It is employed to detect cancer, to assess treatment response, or to monitor disease progression. Liquid biopsy produces test material from primary and metastatic (or micrometastatic) sites and provides a more heterogeneous picture of the entire tumor cell population, compared with specimens obtained with tissue biopsy.
Metastasis
The notion that metastatic lesions are formed from cancer cells that have disseminated from advanced primary tumors has been substantially revised following the identification of disseminated tumor cells (DTC) in the bone marrow of patients with early-stage disease. These results have led researchers to no longer view cancer metastasis as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as metastasizing cells assume new phenotypes while abandoning older behaviors.
The initiation of metastasis is not simply a cell-autonomous event but is heavily influenced by complex tissue microenvironments. Although colonization of distant tissues by DTC is an extremely inefficient process, at times, relatively numerous CTC can be detected in the blood of cancer patients (> 1,000 CTC/mL of blood plasma), whereas the number of clinically detectable metastases is disproportionately low, confirming that tumor cell diffusion can happen at an early stage but usually occurs later on.
Early dissemination
Little is currently known about the preference of cancer subtypes for distinct tissues or about the receptiveness of a tissue as a metastatic site. What endures as one of the most confounding clinical phenomena is that patients may undergo tumor resection and remain apparently disease free for months, years, and even decades, only to experience relapse and be diagnosed with late-stage metastatic disease. This course may be a result of cell seeding from minimal residual disease after resection of the primary tumor or of preexisting clinically undetectable micrometastases. It may also arise from early disseminated cells that remain dormant and resistant to therapy until they suddenly reawaken to initiate proliferation into clinically detectable macrometastases.
Dormant DTC could be the main reason for delayed detection of metastases. It is thought that around 40% of patients with prostate cancer who undergo radical prostatectomy present with biochemical recurrence, suggesting that it is likely that hidden DTC or micrometastases are present at the time of the procedure. The finding is consistent with the detection of DTC many years after tumor resection, suggesting they were released before surgical treatment. Nevertheless, research into tumor cell dormancy is limited, owing to the invasive and technically challenging nature of obtaining DTC samples, which are predominantly taken from the bone marrow.
CTC metastases
Cancer cells can undergo epithelial-to-mesenchymal transition to facilitate their detachment from the primary tumor and intravasation into the blood circulation (step 1). Dissemination of cancer cells from the primary tumor into circulation can involve either single cells or cell clusters containing multiple CTC as well as immune cells and platelets, known as microemboli. CTC that can survive in circulation (step 2) can exit the bloodstream (step 3) and establish metastatic tumors (step 4), or they can enter dormancy and reside in distant organs, such as the bone marrow.
Use in practice
CTC were discovered over a century ago, but only in recent years has technology been sufficiently advanced to study CTC and to assess their usefulness as biomarkers. Recent evidence suggests that not only do the number of CTC increase during sleep and rest phases but also that these CTC are better able to metastasize, compared to those generated during periods of wakefulness or activity.
CTC clusters (microemboli) are defined as groups of two or more CTC. They can consist of CTC alone (homotypic) or can include various stromal cells, such as cancer-associated fibroblasts or platelets and immune cells (heterotypic). CTC clusters (with or without leukocytes) seem to have greater metastatic capacity, compared with individual CTC.
A multitude of characteristics can be measured in CTC, including genetics and epigenetics, as well as protein levels, which might help in understanding many processes involved in the formation of metastases.
Quantitative assessment of CTC could indicate tumor burden in patients with aggressive cancers, as has been seen in patients with primary lung cancer.
Early cancer diagnosis
Early research into CTC didn’t explore their usefulness in diagnosing early-stage tumors because it was thought that CTC were characteristic of advanced-stage disease. This hypothesis was later rejected following evidence of local intravascular invasion of very early cancer cells, even over a period of several hours. This feature may allow CTC to be detected before the clinical diagnosis of cancer.
CTC have been detected in various neoplastic conditions: in breast cancer, seen in 20% of patients with stage I disease, in 26.8% with stage II disease, and 26.7% with stage III disease; in nonmetastatic colorectal cancer, including stage I and II disease; and in prostate cancer, seen in over 50% of patients with localized disease.
The presence of CTC has been proven to be an unfavorable prognostic predictor of overall survival among patients with early-stage non–small cell lung cancer. It distinguishes patients with pancreatic ductal adenocarcinoma from those with noncancerous pancreatic diseases with a sensitivity of 75% and a specificity of 96.3%.
CTC positivity scoring (appropriately defined), combined with serum prostate-specific antigen level, was predictive of a biopsy diagnosis of clinically significant prostate cancer.
All these data support the utility of CTC in early cancer diagnosis. Their link with metastases, and thus with aggressive tumors, gives them an advantage over other (noninvasive or minimally invasive) biomarkers in the early identification of invasive tumors for therapeutic intervention with better cure rates.
This article was translated from Univadis Italy. A version appeared on Medscape.com.
Short bursts of activity may cut cancer risk
, a new study published in JAMA Oncology says.
Researchers at the University of Sydney studied data from wearable fitness devices worn by more than 22,000 “non-exercisers,” then examined their health records for 6 or 7 years.
The scientists found that people who did 4-5 minutes of “vigorous intermittent lifestyle physical activity” (VILPA) had a “substantially” lower cancer risk than people who did no VILPA.
Examples of VILPA are vigorous housework, carrying heavy shopping bags around the grocery store, bursts of power walking, and playing high-energy games with children. The activities could occur in 1-minute bursts, instead of all at once.
The study found that a minimum of around 3.5 minutes of daily VILPA was linked to an 18% reduction in cancer rates, compared with no VILPA. The study said 4.5 minutes of daily VILPA was linked to a 32% reduction in cancers related to physical activity, including lung, kidney, bladder, and stomach cancers.
“We know the majority of middle-aged people don’t regularly exercise, which puts them at increased cancer risk, but it’s only through the advent of wearable technology like activity trackers that we are able to look at the impact of short bursts of incidental physical activity done as part of daily living,” Emmanuel Stamatakis, PhD, the lead author of the study and a professor at the University of Sydney’s Charles Perkins Centre, said in a news release.
Study participants had an average age of 62 and reported that they didn’t exercise in their spare time. VILPA, a concept coined by researchers at the university, was measured by wrist accelerometers that people in the study wore over 7 days at the start of the study, the news release said.
“We are just starting to glimpse the potential of wearable technology to track physical activity and understand how unexplored aspects of our lives affect our long-term health – the potential impact on cancer prevention and a host of other health outcomes is enormous,” Dr. Stamatakis said.
A version of this article first appeared on WebMD.com.
, a new study published in JAMA Oncology says.
Researchers at the University of Sydney studied data from wearable fitness devices worn by more than 22,000 “non-exercisers,” then examined their health records for 6 or 7 years.
The scientists found that people who did 4-5 minutes of “vigorous intermittent lifestyle physical activity” (VILPA) had a “substantially” lower cancer risk than people who did no VILPA.
Examples of VILPA are vigorous housework, carrying heavy shopping bags around the grocery store, bursts of power walking, and playing high-energy games with children. The activities could occur in 1-minute bursts, instead of all at once.
The study found that a minimum of around 3.5 minutes of daily VILPA was linked to an 18% reduction in cancer rates, compared with no VILPA. The study said 4.5 minutes of daily VILPA was linked to a 32% reduction in cancers related to physical activity, including lung, kidney, bladder, and stomach cancers.
“We know the majority of middle-aged people don’t regularly exercise, which puts them at increased cancer risk, but it’s only through the advent of wearable technology like activity trackers that we are able to look at the impact of short bursts of incidental physical activity done as part of daily living,” Emmanuel Stamatakis, PhD, the lead author of the study and a professor at the University of Sydney’s Charles Perkins Centre, said in a news release.
Study participants had an average age of 62 and reported that they didn’t exercise in their spare time. VILPA, a concept coined by researchers at the university, was measured by wrist accelerometers that people in the study wore over 7 days at the start of the study, the news release said.
“We are just starting to glimpse the potential of wearable technology to track physical activity and understand how unexplored aspects of our lives affect our long-term health – the potential impact on cancer prevention and a host of other health outcomes is enormous,” Dr. Stamatakis said.
A version of this article first appeared on WebMD.com.
, a new study published in JAMA Oncology says.
Researchers at the University of Sydney studied data from wearable fitness devices worn by more than 22,000 “non-exercisers,” then examined their health records for 6 or 7 years.
The scientists found that people who did 4-5 minutes of “vigorous intermittent lifestyle physical activity” (VILPA) had a “substantially” lower cancer risk than people who did no VILPA.
Examples of VILPA are vigorous housework, carrying heavy shopping bags around the grocery store, bursts of power walking, and playing high-energy games with children. The activities could occur in 1-minute bursts, instead of all at once.
The study found that a minimum of around 3.5 minutes of daily VILPA was linked to an 18% reduction in cancer rates, compared with no VILPA. The study said 4.5 minutes of daily VILPA was linked to a 32% reduction in cancers related to physical activity, including lung, kidney, bladder, and stomach cancers.
“We know the majority of middle-aged people don’t regularly exercise, which puts them at increased cancer risk, but it’s only through the advent of wearable technology like activity trackers that we are able to look at the impact of short bursts of incidental physical activity done as part of daily living,” Emmanuel Stamatakis, PhD, the lead author of the study and a professor at the University of Sydney’s Charles Perkins Centre, said in a news release.
Study participants had an average age of 62 and reported that they didn’t exercise in their spare time. VILPA, a concept coined by researchers at the university, was measured by wrist accelerometers that people in the study wore over 7 days at the start of the study, the news release said.
“We are just starting to glimpse the potential of wearable technology to track physical activity and understand how unexplored aspects of our lives affect our long-term health – the potential impact on cancer prevention and a host of other health outcomes is enormous,” Dr. Stamatakis said.
A version of this article first appeared on WebMD.com.
FROM JAMA ONCOLOGY