Our inspiration for the BRCA Project.
Breast Cancer is the most common malignancy in women in Europe and the United States, and it is the second leading cause of cancer-related deaths. The major genes associated with hereditary breast cancer are BRCA1 and BRCA2. A mutation in either BRCA1 or BRCA2 confers a significantly increased risk of breast and other cancers in both women and men. (1) The clinical syndrome seen in BRCA carriers is referred to as Hereditary Breast/Ovarian Cancer (HBOC) syndrome. Tumors due to mutations in BRCA1 tend to be of the basal-like phenotype, have a high histologic grade, and do not typically express estrogen or progesterone receptors or Her2/neu, and has been nicknamed “the triple negative tumor”.(1, 2,) BRCA2 related tumors more closely resemble sporadic tumors (3) For both Male and Female patient BRCA1 and BRCA2 mutations pose significant lifetime risks. Female carriers of mutations in BRCA1 or BRCA2 have a lifetime risk of breast cancer of 50-85% (4,5) In women there is a greater lifetime risk with the BRCA1 gene while BRCA2 is more significant in men. Studies report the overall cancer risk to male BRCA2 carriers exceeds the risk for female carriers. Specifically, the relative risk to male BRCA2 mutation carriers is high before age 65 years and is attributable to breast, prostate and pancreatic cancers. BRCA2 carriers are also at risk of developing stomach cancer and melanoma (of the skin and eye)(6). The risk is so significant that population based screening for BRCA1 and BRCA2 is advocated by leading scientists such as Mary-Claire King et al in the 2014 Lasker award winning paper in JAMA (7) We believe patients with BRCA1/2 mutations provide an excellent population to study the role of ISET CRCs in cancer screening because BRCA1/2 carriers have a high incidence of malignancy and limited options for cancer screening. The National Cancer Institute recommends that patients identified as carriers of BRCA1 and BRCA2, undergo “enhanced screening, prophylactic surgery and chemo-prevention”(8). Enhanced screening includes earlier breast examinations, mammograms and MRI for breast cancers starting at age 25(8,11). The NCI states that no effective ovarian cancer screening methods currently exist. Some groups recommend trans-vaginal ultrasound, blood tests for the antigen CA-125, and clinical examinations. These methods do not appear to detect ovarian tumors at an early enough stage to reduce the risk of dying from ovarian cancer and are not officially recommended by the NCI though they are mentioned on the NCI website (8,10) The recommendations for and benefits of screening for men with BRCA1/2 mutations are not known thoughApproval Number: IRCM-2015-093 Renewal Date: December 5,
Protocol Number: BP-ISET-101 Approval Date: December 6, 2015
annual mammography and workup for prostate cancer have been suggested (PSA, DRE) (8,9). The ISET CTC blood test may provide a more sensitive test for cancer screening in BRCA1/2 patients. Previous reports have found CTC identified by cell surface markers, are associated with metastatic disease and a poor prognosis (12) Recently a new technology for isolation of CTC from blood has used cell size rather than markers to isolate circulating tumor cells. The analysis of these circulating cells by size rather than 2016expression of cell surface markers significantly changes the way in which ISET CTC’s may be used in patient care. The presence of ISET isolated circulating tumor cells (CTCs) is currently thought to be an early finding and is correlated with the growth of the primary tumor rather than metastasis. These cells are sloughed early during carcinogenesis. In animal models, ISET isolated CTC’s can be isolated from tumors as small as 1mm. Until recently, ISET CTC research has primarily focused on existing tumors, but a recent publication by Marius IIie et al has identified “Sentinel” Circulating Tumor Cells in COPD patients, allowing increased surveillance with annual CT scans and earlier diagnosis of Lung Cancer in this “at risk” population. Most remarkable is the finding that ISET CTCs were identified 1-4 years before detection of cancer by CT scans. They also reported significantly improving survival rates (13). Their study demonstrates the value of CTC detection and enhanced imaging surveillance to aid in an earlier diagnosis of lung cancer. These findings clearly suggest that blood testing for ISET CTCs may provide a very valuable tool in screening high-risk patients such as those with BRCA1/2 mutations. In BRCA1/2 patients found to have ISET CTC, continued blood testing may be helpful in identifying preferred therapeutic options as well as the efficacy of treatment protocols. If CTCs can be identified years before the current screening modalities, these BRCA1/2 patients may be motivated to proceeding with earlier prophylactic procedures and may, therefore, have improved survival rates. In contrast, if ISET CRC testing proves to be very sensitive, patients and physicians may be more comfortable delaying prophylactic procedures that are perceived as disfiguring or sterilizing Furthermore, once ISET CTC’s are identified, continued testing for ISET CTCs may allow better analysis of the role of chemoprevention, to reduce the risk of, or delay the recurrence of cancer. Although two chemo-preventive drugs (tamoxifen and raloxifene) have been approved by the USFDA, to reduce the risk of breast cancer in women at increased risk, the role of these drugs in women with BRCA1/2 is unclear and might be further elucidated. In addition, there is some data that suggests the fallopian tubes place a dominant rule in the associated ovarian cancer. ISET CTC testing may provide a tool for following patients undergoing limited prophylactic procedures such as excision of fallopian tubes while preserving ovaries.
ISET study began November 1, 2016
The ISET filter will isolate CSC and CRC from the patient's blood.
CSC – Circulating Sentinel Cells
CRC – Circulating Rare Cells
Phase I: Addition of annual blood testing using ISET CSC assay to current protocols for monitoring patients with BRCA1/2 mutations
Phase II: Addition of blood testing using ISET CSC assay to current protocols for monitoring CSCs during of treatment of patients with BRCA1/2 mutations with ISET identified circulating Sentinel cells, during and for two years following treatment.
Barbara B. Hayden, MD
Patrizia Paterlini-Brechot MD/PhD
1) ISET CSC is earlier indicators of carcinogenesis in BRCA1/2 patients when compared to current conventional surveillance strategies including breast examination, mammography, MRI, CA-125, PSA and DRE (diagnostic rectal examination)
2) ISET CSC will facilitate earlier diagnosis of cancer and improve survival rates in patients with BRCA1/2 related Sentinels particularly in those cancers that do not have reliable methods for early detection
3) ISET CSC can be used to continue to monitor efficacy of treatments provided to BRCA1/2 study patients who are identified as having CSCs
Our objective is to:
1) Add ISET CSC blood testing to current surveillance screening recommended to 100 male and 100 female BRCA1/2 patients. (regular screening process may include mammography, ultrasound, and MRI for breast/ PSA and DRE for prostate/ CA-125 and vaginal ultrasound for ovaries).
2) Continue annual ISET CSC blood testing for BRCA1/2 patients noted to be ISET CRC-positive who have been diagnosed with cancers and are being followed with or without treatment.
1) Shiovitz, S, Korde, LA Genetics of breast cancer: a topic in evolution; Annals of Oncology 201510.1093
2) Rakha, EA, Reis-Filho, JS, Ellis, IO. Basal-like breast cancer: a critical review. J. Clin Oncol. 2008; 26:2568-2581
3) Lakhani, SR, Van De Vijer, MJ, Jacquemier, J., et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 2002; 20:2310-2318
4) King, MD, Marks, JH, Mandel,l JB; New York Breast Cancer Study Group. Breast and Ovarian cancer risks due to inherited mutation in BRCA1 and BRCA 2. Science 2003; 302:643646
5) Lindor, NM, McMaster, ML, Lindor, CJ, et al J Natl Cancer Inst Mongr. 2008 Concise handbook of familial cancer susceptibility syndromes-second edition; p1-93
6) Liede, A, Karlan, BY, Narod, SA, Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature; J Clin Oncol. 2004 Feb15; 22(4): 735-42
7) King, MC; Levy-Lahad, E, MD; Lahad, A
Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award;
8) National Cancer Institute BRCA1 and BRCA2: Cancer Risk and Genetic Testing
9) American Cancer Society Recommendations for Prostate Cancer Early Detection
Last revised 01/06/2015
10) Evans DG, Gaarenstroom, KN, Stirling, D, et al., Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers. Journal of Medical Genetics 2009; 46(9)593-597.
11) Warner, E, Plewes, DB, Shuma,l RS, et al. (2001) Comparison of Breast Magnetic Resonance Imaging, Mammography, and Ultrasound for Surveillance of Women at High Risk for Hereditary Breast Cancer
12) Sanne de Wit et al; Scientifica Volume 2014(2014), Article ID 819362,11pages
13) “Sentinel” Circulating Tumor Cells Allow Early Diagnosis of Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease,” Marius Ilie, et al.; PLOS October 2014/ Vol9/Issue 10/e111597; 1-7