“Women of Ashkenazi Jewish descent who tested positive for cancer-causing genetic mutations during random screenings have high rates of breast and ovarian cancer even when they have no family history of the disease, researchers reported Thursday.
“The finding calls into question the practice of screening women — particularly women of Ashkenazi descent, as are most Jews in the United States — for these mutations only if they report that many women in their family have had cancer. Some women are tested for mutations only after they develop cancer themselves.
“Many of the women identified by the researchers in Israel would never have known they were mutation carriers if not for the screening offered by the study, the researchers said. The study’s authors recommended routine screening of all women of Ashkenazi backgrounds for harmful mutations in the genes, called BRCA1 and BRCA2.”
Editor’s note: You may have heard about the BRCA2 mutation, which can increase a person’s risk for breast cancer. Studies have also shown that it can increase a man’s risk of prostate cancer. Studies have also shown that prostate cancer patients with BRCA2 mutations generally do not survive as long as prostate cancer patients without BRCA2 mutations. A new study explored this more in depth by looking at survival rates for BRCA2+ men who were diagnosed with prostate cancer after standard screening. These men did indeed have shorter survival times than prostate cancer patients without BRCA2 mutations. The researchers say these patients might “benefit from additional therapies, such as with cis-platinum or a PARP [poly ADP-ribose polymerase] inhibitor.”
“Among men with prostate cancer detected on screening, survival among those with a mutation in the BRCA2 gene is much poorer than in those without such a mutation, researchers report.
“The findings suggest that BRCA2 mutation carriers may warrant additional treatments to improve their prognosis, say Steven Narod (Women’s College Hospital, Toronto, Ontario) and fellow authors writing in the British Journal of Cancer.
“BRCA2 mutations are known to confer an increased risk for developing prostate cancer and also to be associated with more aggressive tumours. However, the effect of BRCA2 mutations status on mortality in the setting of screen-detected cancers is unclear.”
“Medical researchers have studied breast cancer risks for one of potentially the most important genes associated with breast cancer after the BRCA1/2 genes. Women with mutations in the PALB2 gene have on average a one in three chance of developing breast cancer by the age of 70.”
The gist: Researchers are conducting a clinical trial with volunteer patients to test a new breast cancer treatment called BMN673. BMN673 is a “PARP inhibitor” drug that may benefit patients who have hereditary mutations in the BRCA genes. Patients involved in the trial must have locally advanced and/or metastatic breast cancer, and must have undergone no more than two prior chemotherapy treatments for metastatic disease.
” ‘We are excited to collaborate with BioMarin on this landmark trial to increase the treatment opportunities for patients with BRCA related breast cancer,’ said Dr Alison Jones, Consultant Medical Oncologist and Principal Investigator for the EMBRACA Phase 3 trial at Sarah Cannon Research Institute UK.
” ‘This study is an important milestone for both organizations to foster future collaborations,’ highlighted Dr Hendrik-Tobias Arkenau, FRCP, PhD, Medical Oncologist and Medical Director at Sarah Cannon Research Institute UK.
” ‘Sarah Cannon Research UK has a long history of pioneering significant advances in medical therapy, and we are thrilled to commence enrollment outside of the United States to evaluate the safety and efficacy of BMN 673 in patients with hereditary breast cancer,’ said Hank Fuchs, M.D., Chief Medical Officer of BioMarin. ‘Breast cancer patients with germline BRCA-associated tumors have no targeted treatment options. There is an unmet need for therapies that target specific molecular defects in tumors, and PARP inhibitors offer that potential in BRCA-related breast cancer.’
“The EMBRACA Phse 3 study began in the United states in the fall of 2013 and has expanded internationally. BioMarin plans to enroll patients from sites around the world and to work with partners outside of the United States. The EMBRACA Phase 3 study is an open-label, randomized, parallel, two-arm, multi-center study of BMN 673 versus physician’s choice in approximately 430 germline BRCA mutation patients with locally advanced and/or metastatic breast cancer, who have received no more than two prior chemotherapy regimens for metastatic disease. The primary objective of the study is to measure progression free survival (PFS). Secondary objectives include evaluating the objective response rate (ORR) and the overall survival (OS).”
Editor’s note: After initial treatment, some cancer patients receive maintenance therapy to keep their cancer from returning. In a recent clinical trial with volunteer patients, scientists tested the effectiveness of maintenance therapy for platinum-sensitive recurrent serous ovarian cancer. Some of the women had BRCA1 or BRCA2 mutations, and some did not. Also, all of the women had previously been treated with platinum-based chemotherapy, and experienced tumor shrinkage or complete disappearance of their tumors. In the clinical trial, scientists randomly divided the women into two groups. One group received maintenance therapy with the drug olaparib, and for comparison, the other group was treated with a “fake” placebo drug. The scientists found that women with BRCA1 or BRCA2 mutations were more likely to benefit from the maintenance therapy treatment than women without BRCA mutations.
“Women with platinum-sensitive recurrent serous ovarian cancer who harbored BRCA mutations are more likely than BRCA wild-type patients to benefit from maintenance monotherapy with olaparib, results of a phase 2 study suggest.
“ ‘To our knowledge, our study is the first phase 2 trial in ovarian cancer to show that patients with BRCA1 or BRCA2 mutations respond preferentially to a PARP inhibitor,’ Jonathan Ledermann, MD, of UCL Cancer Institute at University College London, and colleagues wrote.
“Ledermann and colleagues conducted a randomized, double blind study that included 265 women with platinum-sensitive recurrent serous ovarian cancer. All patients received at least two platinum-based regimens and demonstrated a complete or partial response to their most recent platinum-based regimen.”
“When a woman is diagnosed with breast cancer, it’s important to know as much about her tumour as possible to determine the best treatment. Most cases of breast cancer are sporadic, but a minority are hereditary and caused by one or more mutations in genes such as BRCA1 or BRCA2. To find such genetic mutations in newly diagnosed patients, researchers must sequence the woman’s DNA, which is generally a relatively slow process that generates results weeks or months after patients have started treatment. Next generation sequencing (NGS) is a newer method of sequencing DNA that processes large amounts of data. It’s faster and more expensive than conventional sequencing, but in recent years it has become cheaper and more widely accessible by rapid advances in computing power. With the use of NGS, which will soon become the mainstay of clinical genetics, breast cancer units will likely be able to get the results of genetic testing before patients begin their breast cancer treatment.”
Sandhu SK, William R, Schelman WR, Wilding G, et al. The Lancet Oncology. Aug 2013.
“Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. Its safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles were investigated in a Phase I trial for advanced prostate, lung and ovarian cancer. Patient cohorts were enriched for mutations in BRCA1 or BRCA2. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer.”
Sandhu SK, William R Schelman WR, Wilding G, et al. The Lancet Oncology. Aug 2013.
“Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib.”
Killick E, Morgan R, Launchbury F, Bancroft E, et al. Sci Rep. Jun 24, 2013.
“Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals.”