Q: What Motivates You To Study Prostate Cancer In Particular
I started my career as a nurse at a major academic hospital and have taken care of many patients who are battling a cancer diagnosis. Oncology nurses focus not just on administering treatments and managing side effects but holistically, on the entire patient experience. Most patientsexperience fear and anxiety about what comes next.
Guckert and her dad
I also have a personal perspective: My father was diagnosed with prostate cancer many years ago, when I was in college. We spent many years holding our breath waiting to receive his PSA blood test results, since a significant rise could mean his cancer had recurred. Fortunately, he is doing well.
Testing for the BRCA gene, in addition to other mutations potentially associated with familial cancers, is something I have undergone personally. In addition to my father, all three of my sisters have had cancer, and two of them have died. While none of us were found to have a genetic mutation of significance, like BRCA, it was important information to gather.
However, there are people out there with certain oncological mutations that we may be able to target with treatment in the future. Thats what motivates me to get up each morning and go to work: the belief that our work will allow thousands of people to continue to lead full, productive lives.
Efficacy Of Parp Inhibitors For Mcrpc
PARP inhibitors have been approved for the treatment of breast, ovarian, and pancreatic cancers harboring BRCA mutations. PARP inhibitors have also shown promising efficacy in patients with mCRPC .
The PROfound trial was a landmark phase III HRR alteration-driven study in mCRPC that evaluated for the first time the efficacy of the PARP inhibitor olaparib for mCRPC harboring HRR gene mutations . This study enrolled mCRPC patients with progression while on ARATs and/or taxanes, such as docetaxel and cabazitaxel. All men had alterations in one or more HRR genes. Cohort A patients had at least one mutation in BRCA1, BRCA2, or ATM, whereas cohort B patients had mutations in 12 other HRR genes. Patients were randomized to olaparib or the physicianâs choice of abiraterone or enzalutamide . In cohort A, this study met the primary endpoint of radiological progression-free survival . The objective response rate and time to pain progression were also better in the olaparib arm compared with the control arm. In cohort A, the median OS for patients treated with olaparib was significantly longer than that for those who received a control therapy . In patients without BRCA mutations, olaparib was not effective in terms of rPFS, radiological response, or OS .
Cinical trials for mCRPC after ARAT and/or taxanes.
Parp + Zytiga Improves Outcomes
Adding the PARP inhibitor Zejula to the anti-androgen drug Zytiga may be a new first-line treatment for patients with metastatic castration-resistant prostate cancer with homologous recombination deficiency. The phase 3 MAGNITUDE clinical trial compared the Zejula-Zytiga combination to Zytiga alone in 423 men with mCRPC and biomarkers of HRR. The combination significantly reduced the risk of radiographic progression or death by 27% and the median time to cancer progression was 16.5 months for Zejula treated patients compared to 13.7 months for Zytiga alone. The combination was most effective in patients with BRCA1/2 alterations. Among these high-risk patients, the treatment combination reduced the risk of progression or death by 47% .14
Results are similar the PROpel clinical trial that combined the PARP inhibitor Lynparza with Zytiga as 1st-line treatment for men with mCRPC with or without HRR gene mutations.12 In the PROpel study, researchers randomly assigned 796 to treatment with Xytiga with our without Lynparza. The interim analysis showed that the combination therapy significantly delayed cancer progression regardless of patients HRR mutational status, to a median of 24.8 months with the addition of Lynparza compared to 16.6 months for Zytiga alone. It is not yet clear if survival is improved.13
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Surgical procedures to remove the diseased prostate are usually necessary. Surgical procedures are not always necessary. If the disease is caused by bacterial infections, a doctor can treat the symptoms using alpha-blockers or surgery. Physical therapy, relaxation exercises, and warm baths are all recommended. A physician may also prescribe antibiotics to cure the infection. A bacterial infection can also cause a recurrence of the condition.
An enlarged prostate can be uncomfortable for both men and women. Some of the symptoms of an enlarged male reproductive organ include a weakened urine stream, urgent need to urinate, and urinary tract infections. BPH can also cause damage to the kidneys. A sudden inability to urinate can be life-threatening, as it can lead to bladder and kidney damage. Unfortunately, most men with enlarged prostrates put up with the symptoms for years before they seek treatment. However, many of the men with symptoms finally decide to go to a doctor for proper gynecological evaluation and to begin enlarged prostatic therapy.
What Does This Mean For Prostate Cancer
Men who have a BRCA mutation are at a higher risk for developing prostate cancer than men without a BRCA mutation. A BRCA mutation may also increase a mans risk of being diagnosed with an aggressive form of prostate cancer.
Genetic testing is a personal decision. Speaking with your doctor and a genetic counselor is always recommended.
Additional BRCA Resources for Prostate Cancer
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I Tested Positive On The Brca Test What Now
Euhus says that for patients diagnosed with a BRCA1 or BRCA2 gene mutation, careful, frequent and regular surveillance with their doctors can safeguard their health.
He and his team start screening such patients when they reach age 25. We do yearly MRIs to look for any signs of cancer, and add mammograms when the patient reaches age 30, he says.
For BRCA-positive patients who have completed childbearing and breastfeeding, prophylactic mastectomy is discussed. Depending on the patients specific mutation and other factors, this isnt always necessary.
When the patient reaches age 40, we consider surgery to remove the fallopian tubes and ovaries , since the risk of ovarian cancer is so much higher in these individuals, Euhus says. Surgery can prevent disease and significantly extend longevity.
Prostate Cancer With Faulty Brca2 Gene Spreads More Quickly
A new study finds that prostate cancer spreads more quickly and is more likely to be fatal in men who have inherited a faulty BRCA2 gene. The researchers say such patients should be treated straight away with surgery or radiotherapy rather than just be monitored.
Research has already established that men who inherit a faulty BRCA2 gene have a higher risk of developing prostate cancer, but this, the largest study of its kind, is the first to show that the faulty gene also means carriers are more likely to experience more rapid spread of the disease and poorer survival.
The study, reported this week in the Journal of Clinical Oncology, poses a potential challenge to health systems like the UKs NHS where carriers of the faulty gene are offered the same prostate cancer treatment options as non-carriers.
Senior author Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research in the UK, says in a statement that the study clearly shows prostate cancers linked to inheritance of the faulty BRCA2 cancer gene are more deadly than other types.
It must make sense to start offering affected men immediate surgery or radiotherapy, even for early-stage cases that would otherwise be classified as low-risk, says Eeles, who is also Honorary Consultant in Clinical Oncology at The Royal Marsden in London.
However, she also cautions that:
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Thank You For Helping To Make Breakthroughs In Treating Prostate Cancer Possible
These results represent a giant leap forward for men with prostate cancer. A leap weve been building towards since 2014, with your support, through research funding and behind-the-scenes work.
With your help were moving from a one-size-fits-all approach to treating advanced prostate cancer to a much more effective approach where drugs target the genetic drivers of an individuals cancer. Thanks to you Olaparib is ready to blaze a trail for future precision medicines of this kind.
This is by no means the end of the story. Theres still plenty of work to do to ensure that all the men who can benefit from drugs like Olaparib can get access. We will continue to champion the use of Olaparib, through working with the relevant pharmaceutical company, healthcare regulators, researchers and men to make sure this happens.
Help develop our precision treatment programme by donating today.
Researchers Urge Prostate Cancer Screening For Men With Brca Gene Defects
- By Charlie Schmidt, Editor, Harvard Medical School Annual Report on Prostate Diseases
Prostate cancer screening with the prostate-specific antigen test has been criticized for flagging too many slow-growing tumors that might never be life-threatening.
But some men have inherited gene defects that boost their risk of developing prostate cancers that can be quite aggressive. Is PSA screening particularly well-suited for these genetically defined groups? New research suggests the answer is yes.
In November, a team of British scientists released highly anticipated findings from a study of PSA screening in men with defects in a pair of important genes called BRCA1 and BRCA2. Better known for increasing the odds of breast and ovarian cancer in women, BRCA gene defects are also risk factors for aggressive prostate cancer in men. Cells with defective BRCA genes have a compromised ability to repair the DNA damage they sustain routinely every day. As that damage accumulates, those cells become prone to forming tumors.
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What Do Brca1 And Brca2 Genetic Test Results Mean
BRCA1 and BRCA2 mutation testing can give several possible results: a positive result, a negative result, or a variant of uncertain significance result.
Positive result. A positive test result indicates that a person has inherited a known harmful variant in BRCA1 or BRCA2 and has an increased risk of developing certain cancers. However, a positive test result cannot tell whether or when the tested individual will develop cancer. Some people who inherit a harmful BRCA1 or BRCA2 variant never develop cancer.
A positive test result may also have important implications for family members, including future generations.
- Both men and women who inherit a harmful BRCA1 or BRCA2 variant, whether or not they develop cancer themselves, may pass the variant to their children. Each child has a 50% chance of inheriting a parents variant.
- All blood relatives of a person who has inherited a harmful BRCA1 or BRCA2 variant are at some increased risk of having the variant themselves. For example, each of that persons full siblings has a 50% chance of having inherited the variant as well.
- Very rarely, an individual may test positive for a harmful variant not inherited from either parent. This is called a de novo variant. Such a variant is one that arose in a germ cell of one of the parents and is present in all the cells of the person who grew from that cell. The children of someone with a de novo variant are at risk of inheriting the variant.
New Drugs Approved For Advanced Brca
- By Charlie Schmidt, Editor, Harvard Medical School Annual Report on Prostate Diseases
Defective BRCA genes are well known for their ability to cause breast and ovarian cancers in women. But these same gene defects are also strong risk factors for aggressive prostate cancer in men. About 10% of men with metastatic prostate cancer meaning cancer that is spreading away from the prostate test positive for genetic mutations in BRCA genes. Fortunately, these cancers can be treated with new types of personalized therapies.
In May, the FDA approved two new drugs specifically for men with BRCA-positive metastatic prostate cancer that has stopped responding to other treatments. One of the drugs, called rucaparib, was approved on May 15. The other one, olaparib, was approved on May 19.
Both drugs work by shutting down the cancer cells ability to fix its DNA. Like all cells in the body, cancer cells are bombarded every day by free radicals, low-level radiation, and other stressors that cause DNA damage. BRCA genes ordinarily fix that damage so that cells can function normally and survive. But if the genes are defective, then the damage piles up. BRCA-positive tumors get around that problem by deploying an alternate DNA repair gene called PARP. Rucaparib and olaparib both inhibit PARP, leaving cancer cells without any way to fix their increasingly mangled DNA eventually the cells die.
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Who Should Consider Genetic Counseling And Testing For Brca1 And Brca2 Variants
Tests are available to see if someone has inherited a harmful variant in BRCA1 and BRCA2. However, testing is not currently recommended for the general public. Instead, expert groups recommend that testing be focused on those who have a higher likelihood of carrying a harmful BRCA1 or BRCA2 variant, such as those who have a family history of certain cancers. Testing can be appropriate for both people without cancer as well as people who have been diagnosed with cancer. If someone knows they have a mutation in one of these genes, they can take steps to reduce their risk or detect cancer early. And if they have cancer, the information about their mutation may be important for selecting treatment.
Before testing is done, a person will usually have a risk assessment, in which they meet with a genetic counselor or other health care provider to review factors such as which of their relatives had cancer, what cancers they had, and at what ages they were diagnosed. If this assessment suggests that someone has an increased risk of carrying a harmful BRCA1 or BRCA2 gene variant, their genetic counselor can discuss the benefits and harms of testing with them and order the appropriate genetic test, if the individual decides to have genetic testing .
Olaparib A New Option For Men With Metastatic Prostate Cancer And Brca Mutation
PARP inhibition is moving on from breast and ovarian cancer to the treatment of patients with prostate cancer and BRCA1/2 mutation. Olaparib reduced the risk for death by 31% versus enzalutamide or abiraterone in men with metastatic castration-resistant prostate cancer and BRCA1 or BRCA2, and to a lesser extent ATM mutations, according to the final analysis of the phase 3 PROfound trial.
These results were presented by Joaquin Mateo, MD, PhD, Leader, Prostate Cancer Translational Research Group, Vall dHebron Institute of Oncology, Barcelona, Spain, during the 2020 virtual meeting of the European Society for Medical Oncology and were published online to coincide with this presentation .
In men with metastatic CRPC progression on newer hormonal agents, olaparib improved overall survival in cohort A versus enzalutamide or abiraterone despite crossover. Metastatic CRPC with BRCA1 and BRCA2 achieve the most benefit from olaparib. This is the first randomized trial to prospectively demonstrate improved overall survival in a molecularly defined population in mCRPC. The study results support genetic analysis of men with advanced prostate cancer, stated Dr Mateo.
Olaparib is currently approved by the FDA for the treatment of men with metastatic CRPC after disease progression during treatment with another agent. All men enrolled in the PROfound study had disease progression during treatment with enzalutamide or abiraterone.
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How Can A Person Who Has Inherited A Harmful Brca1 Or Brca2 Gene Variant Reduce Their Risk Of Cancer
Several options are available for reducing cancer risk in individuals who have inherited a harmful BRCA1 or BRCA2 variant. These include enhanced screening, risk-reducing surgery , and chemoprevention.
Enhanced screening. Some women who test positive for harmful BRCA1 and BRCA2 variants may choose to start breast cancer screening at younger ages, have more frequent screening than is recommended for women with an average risk of breast cancer, or have screening with magnetic resonance imaging in addition to mammography.
No effective ovarian cancer screening methods are known. Some groups recommend transvaginal ultrasound, blood tests for the CA-125 antigen , and clinical examinations for ovarian cancer screening in women with harmful BRCA1 or BRCA2 variants. However, none of these methods appear to detect ovarian tumors at an early enough stage to improve long-term survival .
The benefits of screening men who carry harmful variants in BRCA1 or BRCA2 for breast and other cancers are not known. Some expert groups recommend that such men undergo regular annual clinical breast exams starting at age 35 . The National Comprehensive Cancer Network guidelines recommend that men with harmful germline variants in BRCA1 or BRCA2 consider having a discussion with their doctor about prostate-specific antigen testing for prostate cancer screening starting at age 40 .
A Rational Approach To Gene Mutations And Cancer Risk
Euhus stresses that not all genetic cancer risks are the same. Some genetic mutations increase the likelihood of cancer dramatically others, only by a few percentage points. These variations are important for doctors to understand, so they can work with the patient on a rational strategy for staying well.
Recommending any preventive treatment should be based on carefully calculating the actual risk to the patient. Practitioners can use tools to quantitatively calculate the probability of cancer, based on patient data. This extra attention can go a long way to avoid unnecessary, stressful and potentially harmful screenings, biopsies and surgeries.
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What The Studies Showed
Clinical trial results showed the drugs were well-tolerated, with side effects similar to mild chemotherapy. Rucaparib was tested in a single-arm clinical trial , enrolling nearly 400 men with BRCA-positive metastatic prostate cancer who were no longer responding to other treatments. Results showed that tumors shrank in 44% of the enrolled subjects, in some cases for up to two years. Olaparib was tested in a similar population and delayed disease progression by an average of 7.4 months, which was just over two times longer than a type of hormonal therapy used in the control arm of that study.
Both drugs have their shortcomings. As personalized therapies, they work only for men with BRCA-positive prostate cancer, and just half the treated men will benefit. Furthermore, the experience with PARP-inhibitors so far is that tumors become resistant to therapy within six to 12 months. Whether PARP-inhibitors actually lengthen survival for men with metastatic prostate cancer is still being investigated. And many other questions remain about how to use the drugs most effectively to maximize their benefits.
About the Author
Charlie Schmidt, Editor, Harvard Medical School Annual Report on Prostate Diseases