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Enzalutamide (Xtandi®) and abiraterone acetate (Zytiga®) are two approved hormone therapies commonly prescribed for men with hormone-resistant advanced prostate cancer. They block the androgen receptor signaling that is essential to the cancer’s growth. Although they represent breakthroughs in metastatic treatment, 20 to 40 percent of patients fail to respond to them. These men with advanced prostate cancer have an abnormal version of a prostate cancer protein that binds with testosterone. The protein is missing a key connector that binds to abiraterone and enzalutamide. The abnormal protein is caused by a genetic variant called AR-V7. Johns Hopkins researchers discovered that the variation, which lacks a portion of the full androgen receptor, was associated with resistance to abiraterone and enzalutamide. The drugs failed to block androgen receptor signaling, thus allowing prostate cancer cells to keep growing. Most patients who test positive for AR-V7 get limited or no benefit from abiraterone or enzalutamide. Conversely, Johns Hopkins researchers discovered that prostate cancer patients who lacked the AR-V7 androgen receptor variation survive longer than those with the variation. The initial study, “AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer” was published in the New England Journal of Medicine in 2014. A test for the genetic variant, AR-V7 was described further in this website’s October 13th, 2015 post.
An article in the April 24th, Prostate Cancer News Today, stated that Qiagen will begin marketing the test that Johns Hopkins University developed. If doctors know that a prostate cancer patient is resistant to the drugs, they can develop a more tailored treatment. The test, called AdnaTest Prostate Cancer Panel AR-V7, will detect that resistance. The test is called a liquid biopsy because it examines circulating tumor cells (CTC’s) in blood instead of tissue. It shows whether cancer cells in a blood sample have the AR-V7 variation.
In addition to the test being used in treatment, researchers can use it to help select patients for clinical trials. In a recent study, thirty-one men received Zytiga and 31 Xtandi. The results were clear. The PSA response rate was zero in patients with the AR-V7 variant. In other words, none of the patients with the variant responded to the drugs. In contrast, 54% of patients who lacked the variant responded to Zytiga, and 68% to Xtandi. Overall survival rates of patients with the variant were 5.5 months with Zytiga and 10.6 months with Xtandi. Patients without the variation survived beyond the duration of the study.
QIAGEN is working with several pharmaceutical companies on trying the test in prostate cancer clinical trials. They plan to make the AdnaTest kit commercially available this year.
When three different prostate cancer websites post the same subject article, it is significant. According to the April 11th MedLinePlus from the U.S. National Library of Medicine, in a significant shift, a key health advisory panel plans to soften its recommendation against prostate-specific antigen (PSA) screening for detecting prostate cancer. In 2012, the U.S. Preventive Services Task Force recommended that men no longer get their PSA tested. That recommendation was based on evidence that PSA screening resulted in overdiagnosis and unnecessary treatment that could leave men impotent and incontinent. Now, after reviewing follow-up evidence, the task force is recommending that men aged 55 to 69 have a discussion with their doctor about the pros and cons of PSA screening. For men aged 70 and older, the recommendation for no PSA screening remains in place.
The recommendation states PSA-based screening provides a small benefit for men ages 55 to 69, and that physicians should inform this group about the potential benefits and harms of PSA-based screening for prostate cancer. In addition, the statement pointed out that the decision of whether to screen or not should lie with the individual man, after an informed discussion with his physician.
The task force is an independent, volunteer panel of experts in prevention and evidence-based medicine that makes recommendations about preventive medical services, such as screenings, counseling services, and preventive medications.
“There is probably a small benefit overall to screening,” said task force chair Dr. Kirsten Bibbins-Domingo. She is a chair in medicine and a professor of medicine, epidemiology and biostatistics at the University of California, San Francisco. “But the right decision is not a one-size-fits-all decision. The right decision isn’t screening all men, it’s making all men aware of the benefits and harms, and then allowing each man to make the best decision for himself,” Bibbins-Domingo explained. The recommendation applies to men who have not been diagnosed with prostate cancer and have no signs or symptoms of the disease, Bibbins-Domingo said. In addition, the recommendation is for men at average risk and those at increased risk for prostate cancer, such as black men and men with a family history of prostate cancer. Men at increased risk for prostate cancer should take that into consideration when making the decision to be screened for PSA levels, she said.
One specialist, Dr. Anthony D’Amico a professor of radiation oncology at Harvard Medical School. views the new recommendation as a correction of an error the task force made in 2012. The more you follow the studies that look at the benefits of PSA screening, the more positive they are becoming, he said. Because prostate cancer takes many years to develop, the benefit only becomes apparent 10 to 20 years after the start of a study, he explained. Based on longer follow-up of studies, “the task force is backing off from, ‘Do not screen,’ to ‘Let’s talk about it,’ and then, I would say, in time, it will probably come to, ‘We think you should do it,'” he said.
When I come across a newsworthy article of interest, I usually summarize it on this post and link the reader to the entire article for more information. This is an exception as the original article from the Prostate Cancer Foundation (March 30th, 2017) contains specific visual and verbal information; hence I refer you to the following link.
The Decipher prostate cancer gene-expression classifier can predict patients’ risk of metastasis and prostate cancer-specific mortality (PCSM) using biopsy specimens prior to radical prostatectomy or radiotherapy plus androgen (hormonal) deprivation, according to a mixed-cohort study presented at the 2017 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, held February 16–18 in Orlando, Florida.
Decipher is a 22-gene metastasis risk-predicting RNA gene expression signature designed for use after radical prostatectomy, using surgical specimens, to provide adjuvant or salvage treatment decision making. Decipher is one of several commercially-available genomic tissue tests (including Prolaris and Oncotype DX) used to help determine prostate cancer aggressiveness.
The Decipher signature includes gene markers for cell cycle proliferation, adhesion and motility, immune modulation, and androgen signaling pathways. Previous studies have evaluated the use of Decipher after radical prostatectomy. The authors of the new study sought to assess the Decipher classifier’s prognostic utility when used earlier, with biopsy specimens, in order to inform initial treatment decisions.
The team studied mortality and metastasis among 175 patients treated with radical prostatectomy at the Cleveland Clinic or Johns Hopkins or radiation plus androgen deprivation therapy (ADT) at Dana-Farber in Boston. Just over half of the patients’ cancers were deemed to be intermediate-risk, 33.7% were high-risk. Only 13% of cohort patients had low-risk prostate cancer. At a follow-up of 6 years, 32 patients had developed metastatic disease and 11 had died of prostate cancer.
The classifier scores did correlate with the risk of metastasis. According to Dr. Paul Nguyen, the lead investigator from Dana-Farber, “the 5-year distant metastasis risk by Decipher score showed that the high-risk patients had a 23.4% risk of 5-year metastasis, the intermediate-risk patients had a 9.3% risk of metastasis, and the low-risk patients had a 5% risk of metastasis at 5 years.” There was no difference in outcomes between patients treated with radical prostatectomy and those treated with radiotherapy and androgen inhibition. For low and intermediate risk patients, the Decipher score also stratifies the risk of distant metastasis and “in fact, identifies a very high-risk group for distant metastasis that developed a 33.1% risk of metastasis at 5 years,” Nguyen said.
The Decipher test has prognostic value, but more work is needed to demonstrate its predictive value. That will require randomized clinical trials comparing different treatments. The full article appeared in the February 17th e mail issue of cancernetwork, home of the journal Oncology.
For further information on Decipher, see the following link.
This review is designed for physicians and patients who have access to multiparametric MRI technology available in several major health research institutions.
A recent article by Drs. Peter Choyke and Stacy Loeb (from the National Cancer Institute, NIH) in the journal Oncology and e mailed through the CancerNetwork provided a important summary of active surveillance, a safe, appealing approach that spares radical treatment and does not increase disease-specific mortality. However, the authors conclude that current methods of identifying low-risk patients are flawed and cannot always accurately predict candidates for active surveillance. In the article, the authors focus on the role of active surveillance for patients with low-risk disease and how multiparametric MRI (mpMRI) can impact decision making for entering and monitoring patients on active surveillance. The article is written mainly for physicians and should be discussed with them if you are considering active surveillance as an option.
The active surveillance decision-making process begins with a prostate biopsy, for which there are two main triggers: elevated PSA and/or a palpable lesion on digital rectal examination. The current standard of care is to obtain a 12-core biopsy under transrectal ultrasound (TRUS) guidance, in which two samples are obtained from the apex, the middle, and the base of the prostate on two sides (six samples per side). Each sample is interpreted by a pathologist using the Gleason scoring system ranging from 3+3 to 5+5. Patients who harbor low-volume 3+3 tumors or 3+4 tumors with only a small percentage of grade 4 are eligible for active surveillance. The use of active surveillance in the United States has increased in recent years, with over 40% of low-risk tumors managed in this manner, and even higher rates for men over 75 years of age. Active surveillance is different from watchful waiting, which is usually reserved for elderly men with reduced life expectancy. In watchful waiting, the physician will not perform serial tests such as biopsies because there is no curative intent, so treatment is only given for symptomatic progression. In contrast, active surveillance infers that the patient is followed with a schedule of serial PSA tests and biopsies, with the latter meant to detect patients who convert from a low-grade to an intermediate- or high-grade tumor over time.
Implementing active surveillance varies with the medical institution and presents its own problems. At this point, for this discussion, I would refer you the reader to the linked section entitled “Implementing Active Surveillance”.
The next section discussed the role of mpMRI in identifying active surveillance candidates. mpMRI can identify lesions missed by the standard TRUS biopsy or can more properly characterize cancers detected at TRUS biopsy. “Because a standard TRUS-guided biopsy predominantly samples the posterior peripheral zone, the rest of the gland is undersampled. Moreover, since TRUS-guided biopsies are really blind samples of the prostate, tumors in the posterior peripheral zone may be incompletely sampled or their size greatly underestimated. Therefore, before placing a patient on active surveillance, we perform an MRI to identify any lesions that were potentially missed or undersampled. In the case of active surveillance candidates, approximately 20% to 30% of patients who were initially considered good candidates for active surveillance are directed toward active treatments such as surgery or radiation as a consequence of finding additional lesions or resampling known lesions with MRI guidance. For patients in whom the MRI is negative or reveals nothing more than was discovered by TRUS biopsy, active surveillance is an excellent choice. Thus, an initial MRI followed by MRI-TRUS–guided biopsy has become routine in our institutions to identify patients who are ideal candidates for active surveillance. This provides greater assurance to the clinician and patient that the proper management has been selected.”
“It would seem logical that MRI could also be used in place of repeat biopsies to monitor patients who are on active surveillance. Although this is a very attractive possibility for patients due to the risk and burden associated with multiple biopsies over time, good long-term data are not yet available to support this policy. In our own institutions, MRI is commonly performed on a routine basis (annually in the case of the National Cancer Institute), and changes in the appearance of the MRI can trigger a repeat targeted biopsy.” …..” In our own experience, the vast majority of active surveillance patients who have an initial qualifying MRI and MRI-TRUS biopsy exhibit minimal or no change in their MRI over many years, making this approach quite promising.”
A variety of other commercially available serum, urine, and tissue biomarkers have been introduced to help clinicians decide whether to initiate and maintain a patient on active surveillance. Their value relative to MRI has not been tested adequately to draw conclusions as to whether these can be used in place of MRI or as an adjunct to MRI. One of these serum markers is the Prostate Health Index, which combines total, free, and proPSA using a mathematical formula. This test was previously shown to predict changes on biopsy in men on active surveillance, and in the future might be used to monitor patients in conjunction with mpMRI. Several genomic tissue tests including Prolaris, Oncotype DX, and Decipher are also commercially available to help determine aggressiveness beyond the information provided by Gleason score. These may be used to help assess eligibility for active surveillance in borderline cases such as high-volume Gleason 6 or low-volume Gleason 3+4; however, there are no published data on their utility for monitoring during surveillance, and they require tissue from a biopsy.”
The authors conclude that “active surveillance is an excellent alternative to surgery or radiation in patients with low-risk cancers. However, the current methods of ascertaining whether a patient harbors a low-risk cancer are flawed, and data obtained by PSA or traditional TRUS biopsy do not accurately predict good candidates for active surveillance. MRI- and MRI-TRUS–guided biopsies of the prostate appear to assist in the decision to place a patient on active surveillance by detecting lesions outside the normal biopsy template or by providing more information about a lesion within the potentially undersampled template. Less certain is the role of MRI in delaying or eliminating subsequent biopsies, although it is increasingly being used in this manner, since repeat prostate biopsies are a source of patient noncompliance. The role of other new biomarkers in the decision-making process and their utility compared with MRI remains to be determined. What is most encouraging is that more men can now safely and confidently delay or avoid unnecessary radical surgery for low-risk prostate cancers and retain a high quality of life even with a prostate cancer diagnosis.” The full article can be accessed in this link.
There has been a lot written recently about positron emission tomography (PET) scans. The following is a link to an overview published in Medical News Today on December 16th.
This website initially posted a review of positron emission tomography (PET) scanning on March 9th, 2015.
More recently, the Prostate Cancer Research Institute (PCRI) November Insights contained an updated and very informative review of the latest PET imaging techniques for managing recurrent and advanced prostate cancer. Their major utilities, advantages and their limitations are discussed clearly. The review was written by Dr. Fabio Almeida, Medical Director of Phoenix Molecular Imaging in Arizona. Rather than summarize the entire readable review, I will merely mention the various sections herein and provide the following link to the entire review.
In the November article, conventional types of imaging such as ultrasound, CT scans and prostate MRI and their uses are discussed initially. A section describing detection of bone metastases using Technetium-99 and sodium fluoride PET/CT scans follows. Carbon-11 acetate (available at Phoenix Molecular Imaging, Arizona) and C-11 choline (available at the Mayo Clinic, MN) are lipid metabolism PET agents both of which are useful for detecting recurrent disease and PSA relapse. In both cases, detection rates were dependent upon PSA values and doubling times.
Axumin (18F-FACBC) is a fluorine-18 radiolabeled synthetic leucine amino acid was has been recently approved by the FDA for detection of recurrent cancer in men with rising PSA after previous surgery or radiation. Amino acids are absorbed into cancer cells because of the increased metabolic demands of the growing cancer. In cited studies, optimal detection rates were seen when PSA levels were above 1.78. Direct comparison with C-11 choline scans indicated better performance for Axumin. For additional information on Axumin, see the website blog dated May 30, 2016.
The prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that occurs much more commonly in prostate cancer cells compared to benign prostate tissue. One of the PSMA agents under development is 68-gallium-PS-MA-11, which has demonstrated a higher diagnostic efficiency compared to C-11 choline. Detection rates were dependent on PSA values. For example, a 93% detection rate was observed when the PSA was over 2.0 but only 50% when the PSA was 0.2-0.5. There are limitations to PSMA-targeting agents. Not all prostate cancers exhibit PSMA overexpression. In one study, about 8% of prostate cancer patients did not show PSMA overexpression. Benign lesions and several other types of cancers may also exhibit increased PSMA expression. False positive celiac lymph nodes have frequently been noted in the upper abdomen and detection of small locally-recurrent lesions and lymph nodes in the lower pelvis is challenging.
There is still no perfect imaging methodology with 100% accuracy. However, PSMA-targeted agents are becoming the major focus of future attention and development. “Despite some limitations, PSMA-targeted imaging appears to provide high sensitivity and specificity and is likely to become part of the routine evaluation and management of men with prostate cancer in the near future.”
An excellent 3-minute video from Dr. H. Ballentine Carter, Professor of Urology and Oncology at Johns Hopkins, describes the use of MRI to view the prostate one day prior to performing a standard ultrasound-guided biopsy. The video speaks for itself and can be viewed at the following link.
This technique is also being used at the University of Texas Southwestern. See the following link for a complete description of how it is done and their positive results as compared with standard biopsy techniques.
In the light of recent discoveries (recently posted on this website) that some advanced prostate cancer patients harbor specific genetic mutations, a recent study summarized in the July 7th National Library of Medicine MedLine Plus suggested that testing for inherited abnormalities in DNA repair genes could provide patients and family members important information about their health and cancer risk. The research team led by Dr. Michael Walsh, a geneticist and pediatric oncologist at Memorial Sloan Kettering Cancer Center in New York states that “historically, the main benefit of identifying cancer-causing mutations has been prevention and early detection in families. Now we can use inherited genomic information to target treatment, with specific therapies shown to be effective in those with specific genomic subsets of prostate cancer.”
The research team found a link between advanced prostate cancer and mutations in DNA repair genes. The mutations occur far more often in men with advanced disease than in those with prostate cancer that hasn’t spread, the study authors said. In addition, men with the abnormal repair genes are more likely to have close relatives with cancers other than prostate cancer compared to men without the mutations. These findings could help identify families that are at high risk for cancer and help prevent it in future generations, the researchers said.
Mutations in DNA-repair genes, including the breast cancer genes BRCA1 and BRCA2, are involved in an inherited high risk of prostate cancer and, potentially, the risk of an aggressive cancer, according to researchers at Fred Hutchinson Cancer Research Center and the University of Washington.
The study entitled, “Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer”, published in The New England Journal of Medicine, found the mutations in about 12 percent of men with the cancer — and found that men with metastatic prostate cancer were five times more likely than most people to have these DNA-repair gene mutations. Results suggest that screening for such mutations could help tailor their treatment and encourage family members to consider their own cancer risk.
Because BRCA1 and BRCA2 mutations have long been associated only with breast and ovarian cancers, it was thought that the mutations only affected women.
“I think these data really suggest that we need to engage men in discussions about genetics, where it has not been central before,” Dr. Heather Cheng, a Fred Hutchinson and University of Washington prostate cancer researcher.
The team analyzed 20 DNA-repair genes in metastatic prostate tumors and healthy tissues of 692 men. They found that 16 of the genes were mutated in both malignant and healthy cells in 12 percent of the metastatic cancer patients — much higher than researchers ever suspected, said first author Dr. Colin Pritchard.
“The implications are big in terms of intercepting and preventing a cancer because [carriers of these mutations] are at high risk,” said Dr. Pete Nelson, a Fred Hutch prostate cancer researcher and senior author on the study.
The findings are also important because men with advanced prostate cancer who have the mutations in DNA-repair genes could be treated with PARP inhibitors or platinum chemotherapy, which is commonly used in breast cancer patients. Although not yet approved for prostate cancer treatment, the treatments are on fast-track review by the U.S. Food and Drug Administration.
“For men with metastatic disease who are found to have these mutations, there are very clear treatment implications that would not otherwise be considered for prostate cancer. It would essentially expand [the patients’] toolbox of treatments,” Cheng said.
The authors concluded that it may be of interest to routinely examine all men with metastatic prostate cancer for the presence of germline mutations in DNA-repair genes. Future work by investigators will focus on determining which mutations predispose patients to the most aggressive type of prostate cancer.
The researchers hope the findings will land the screening in National Comprehensive Cancer Network guidelines — with future coverage by insurance companies.
Some of this information above also appeared in the blog dated July 28th, 2016. Information on PARP inhibitors under development can be found in the post dated November 30th, 2015.