Prevalence and Clinical Outcomes of Advanced Prostate Cancer Patients with Inherited DNA-Repair Mutations

DNA Helix_NCICollaborative work has shown that approximately 12% of men with advanced prostate cancer have inherited, or germline, DNA-repair mutations that disrupt the normal function of the genes involved in repairing damaged DNA. Somatic alterations in DNA-repair pathways are also common in prostate cancer, particularly in late-stage disease. Somatic alterations affect only tumor cells, but are not inherited or passed on. Inherited mutations in DNA-repair genes – such as BRCA2, ATM, and CHEK2 – are associated with an increased risk of several other cancers as well as prostate cancer, including breast, ovarian, and pancreatic cancer. In particular, mutations in BRCA2, associated with 1.8% of overall prostate cancer cases, have been associated with more aggressive prostate cancer characteristics and worse outcomes, including increased risk of recurrence and poorer overall survival rates.

As a result of the increasing number of men with these types of mutations, the National Comprehensive Cancer Network (NCCN) guidelines have recently changed, now recommending genetic testing for all men with metastatic prostate cancer.

Weill Cornell Medicine

“Genetic testing for inherited mutations may provide some men with prognostic information about their prostate cancer risk,” says Dr. Scott Tagawa, Director of the Weill Cornell Medicine and NewYork-Presbyterian Genitourinary (GU) Oncology Program. “Even more importantly, genetic testing can also be used to inform screening of family members and may increasingly inform precision-medicine based approaches to manage the disease using specific molecular features such as DNA-repair genes,” says Dr. Tagawa.

How do Inherited Mutations Impact Treatment?

Clinical research studies are continually being conducted to investigate new ways to treat advanced prostate cancer patients with germline DNA-repair mutations since these patients comprise a unique subset of patients. Currently, little has been known about whether DNA-repair mutation status impacts benefit from standard therapies for the disease and this is just one area that needs to be researched in order to specifically tailor treatment options for this subset of patients.

Weill Cornell Medicine and NewYork-Presbyterian’s Drs. Himisha Beltran, Scott Tagawa and David Nanus, along with collaborators from around the globe, address this in research published today in the high impact factor journal European Urology and simultaneously presented at the American Society of Oncology (ASCO) 2018 Genitourinary (GU) Cancers Symposium by Dr. Misha Beltran. The researchers reviewed 390 medical records of patients who previously participated in a New England Journal of Medicine (NEJM) study examining men with advanced prostate cancer with known germline DNA-repair mutations and those without these mutations. The goal of the research was to determine whether germline mutations in DNA-repair genes impact the benefit of standard therapies for metastatic prostate cancer, such as docetaxel chemotherapy and androgen receptor signaling inhibitors abiraterone acetate and enzalutamide. Results showed that all patients appeared to benefit from standard therapies similarly to other metastatic prostate cancer patients, regardless of germline mutation status.

“The data suggest that metastatic prostate cancer patients with inherited mutations in DNA damage repair genes, including those with BRCA2 mutation, derive similar benefit from standard of care therapies in terms of both response rate and progression-free survival,” says Dr. Scott Tagawa. “While we continue to investigate additional agents thought to preferentially benefit those with DNA repair alterations, current evidence indicates that detection of any of these mutations should not prevent metastatic prostate cancer patients from receiving standard therapies including taxanes, abiraterone and enzalutamide, as standard of care treatment.”

Additionally, sophisticated genetic analysis and testing may be performed by genetic counselors and widely-available commercial testing is also available to physicians and patients. Dr. Panagiotis Vlachostergios, fellow and medical oncologist at Weill Cornell Medicine and NewYork-Presbyterian, presented research at ASCO Genitourinary (GU) Cancers Symposium focused on using a commercial 30-gene panel to test men with localized prostate cancer and advanced prostate cancer for the presence of inherited gene mutations. Out of the 17 men with localized disease and 35 men with metastatic prostate cancer, eight of 52 (15%) were found to have a germline alteration. A higher percentage of men with an inherited mutation had localized (23.5%) versus advanced disease (11.4%), though testing might have been biased towards those with family history of cancer or those diagnosed with high-grade cancer at earlier age.

Both the results published in European Urology and research presented at the 2018 ASCO GU Cancer Symposium underscore the importance of genetic testing to determine what, if any, mutations may be present in prostate cancer in order to determine the best possible treatment options. While the published data supports the use of standard therapies in those with metastatic prostate cancer who have germline DNA-repair mutations, not all patients respond to these types of treatment, demonstrating the need for alternate treatment options for this patient population. Weill Cornell Medicine and NewYork-Presbyterian are in the process of opening several clinical trials to include men with prostate cancer in need of different lines of therapy. Clinical trials testing PARP inhibitors, a drug target for cancer therapy that appears to be more effective in prostate cancer patients with DNA-repair mutations, are ongoing and may offer additional therapy options for this group of patients in the near future.

Movember 2017 is Here!

For nearly 10 years, we have been proud to participate in a month-long campaign to raise awareness and funds for men’s health each November, also known as Movember.

The campaign dates back to 2003 when two friends in Australia tried to bring back the moustache trend by growing out moustaches (or “mo’s” as they are commonly called in Australia) during the month of November. The following year, after realizing that this facial hair served as a conversation-starter, they decided to channel that energy to raise money for prostate cancer research.

Awareness (and mustaches) have grown over the years, and in 2007, Movember officially launched a global campaign to change the face of men’s health – literally and figuratively through increased awareness and funds. Another way people can get involved is by “moving” and setting a walking, running, biking or swimming goal and working to achieve it every day throughout Movember. Today, over 5 million people from more than 20 countries have collectively raised over $700 million dollars. The Movember Foundation uses this money to fund research around the world to reduce the number of men dying from prostate and testicular cancer, as well as mental health issues. Movember is committed to funding research that will reduce the number of deaths from prostate and testicular cancer by 50% by 2030.

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From L to R: Dr. Scott Tagawa, last year’s Movember Captain, Dr. Daniel Margolis, this year’s Movember captain

We’ve been proud Movember partners for nearly 10 years now and have benefitted from many Movember research grants to further our cancer research, most recently being named one of six teams to receive a 2017 Challenge Award from the Prostate Cancer Foundation (PCF) and the Movember Foundation to investigate new, cutting-edge treatments for metastatic prostate cancer.

This 2017 Movember-PCF Challenge Grant has funded our latest research developing new treatments for treatment-resistant advanced prostate cancer. More details on the grant and research it supports can be found here.
In past years, Movember-funded grants have supported our research in the following areas:

  • Blood tests that assess the tumor’s circulating DNA to predict reasons for treatment resistance.
  • Circulating tumor cell (CTC) tests to predict which patients are more or less likely to respond to hormonal therapy or chemotherapy.
  • Assessing the genome of initial tumors in the prostate compared to advanced, treatment resistant tumors.
  • Evaluating inflammation in adipose (fat) tissue around the prostate, which is associated with tumor growth.

Throughout the month of November, staff and physicians at Weill Cornell Medicine and NewYork-Presbyterian will be growing mustaches, exercising and raising funds for the Movember Foundation in support of our shared mission to cure cancer.

Get Involved!

  • Join our team by visiting
  • Grow a moustache and commit to going razor-free. It’s a great conversation starter to encourage friends and family members to donate to Movember.
  • Spin for a cure! Kill two birds with one stone. Get your workout in and support the Wild Weill Cornell Mos. Attend our cycling events on November 16th and 18th, with proceeds benefiting our team’s Movember fundraising goal.
  • Shave the date and celebrate the end of Movember by attending a happy hour. Stay tuned for final details including date and location.

Last year, we raised $13,000. We want to top that this year by raising $20K or more. Help us get there and remember that every dollar counts in the quest to cure cancer!



First-Ever Clinical Trial Testing PSMA-Targeted Antibody and Radioactive Alpha Particles for Treatment of Advanced Prostate Cancer

Radiation is one of the most common treatments for prostate cancer. Using radiation, physicians are able to cure some men with cancer confined to the prostate, as well as improve symptoms for men with metastatic disease. There are many different types of radiation treatments.

One type of treatment includes injecting radioactive isotopes into the blood in order to directly reach the prostate cancer cells regardless of where they are located in the body, including the cells that have spread to the bone and other organs. For example, Radium-223 (Xofigo) is FDA-approved to treat prostate cancer that has metastasized to the bone and has been shown to improve both the quality and duration of the lives of men with advanced prostate cancer.

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Red marker = PSMA, Green = radiation, demonstrating that the drug targets the cancer cell directly.

Radioimmunotherapy or radioligand therapy involves the practice of attaching a radioactive isotope to a cancer-targeting antibody or small molecule that binds only to a specific cancer-related molecule on a tumor cell. This is similar to a “lock and key” scenario, where the antibody or molecule resembles the key that will only recognize a very specific lock (the cancer-related molecule).

Essentially all prostate cancers have a specific “lock” called prostate-specific membrane antigen (PSMA). This “lock” is a protein that sits on the surface of most prostate cancer cells but is absent from most other normal places in the body.

Physicians and scientists have engineered very specific “keys” in the form of monoclonal antibodies and molecules that will bind only to PSMA. When we attach radioactive particles to these keys, we are able to deliver what we call “molecularly targeted” radiotherapy.

For example, J591 is a monoclonal antibody (an engineered protein) that recognizes PSMA. Actinium-225 (225Ac) is a small radioactive particle that emits alpha-particles, a powerful form of radiation requiring fewer particles to cause damage to the cancer cells. When these are attached to one another, we call the compound 225Ac-J591 (a radioactive particle linked with a monoclonal antibody). It is designed so that J591 will recognize the PSMA on the prostate cancer cells and bring the radioactive particle 225Ac with it into prostate cancer cells wherever it goes in the body.

Our physicians and scientists are building on prior laboratory-based research presented at the 2017 Meeting for the Annual Association for Cancer Research (AACR) and are now studying the role this experimental therapy may have for men with advanced prostate cancer that has spread throughout the body. Thanks to generous support from the Prostate Cancer Foundation and the NIH SPORE award, Dr. Scott Tagawa, medical oncologist and Director of the Weill Cornell Medicine Genitourinary (GU) Oncology Program, and his team are conducting the first-ever clinical trial testing the PSMA-targeted antibody and radioactive alpha particles (225Ac-J591) for treatment of advanced prostate cancer. This promising new and unique approach has the potential to lead to another treatment option for those patients who are not experiencing the best clinical outcomes possible from standard of care therapies. Some men in Germany have received 225Ac linked to PSMA-617 with a handful of cases published with impressive responses. However, no formal studies have been performed and there are reports of bothersome dry mouth (xerostomia) and the potential for delayed kidney damage (seen in mice).

“We look forward to advancing science and also making this treatment available to men with advanced prostate cancer in the near future, says Dr. Scott Tagawa. “Our goal is to translate the existing knowledge base into true clinical gains for prostate cancer patients and it’s great that in October, 2017, we are able to treat our first patient.”