Breast
Other carcinoma subtypes, not WHO classified
BRCA associated carcinoma
Editor-in-Chief: Debra L. Zynger, M.D.
Last author update: 23 January 2020
Last staff update: 30 December 2021
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PubMed search: BRCA1 associated [title] carcinoma breast
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Pathophysiology | Etiology | Clinical features | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style answer #2 | Board review style answer #2Cite this page: Vos S, van Diest PJ. BRCA associated carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/breastmalignantbrca1.html. Accessed March 30th, 2023.
Definition / general
- Breast cancer arising in patients with an underlying BRCA germline mutation
- BRCA1 is a tumor suppressor gene located on chromosome 17q21 (Science 1990;250:1684)
- BRCA2 is a tumor suppressor gene at 13q12-13 (OMIM 600185)
- This discussion is currently about BRCA1
Essential features
- About 3% of all breast carcinomas are due to an underlying BRCA1 germline mutation (Br J Cancer 2003;88:1263)
- Differs significantly from sporadic breast carcinomas with respect to histopathological and molecular characteristics
- Often high grade invasive ductal breast carcinomas of no special type, showing prominent lymphocytic infiltration and pushing tumor margins (J Natl Cancer Inst 1998;90:1138)
- Usually triple negative for ER, PR and HER2 (J Clin Oncol 2002;20:2310)
- Usually of basal-like intrinsic type (J Natl Cancer Inst 2003;95:1482)
Terminology
- Also known as BRCA1 related breast cancer or BRCA1 germline mutation related breast cancer
- BRCA1 associated breast cancer is not part of the WHO classification of breast tumors
ICD coding
- No specific ICD-10 code; classification based on factors other than BRCA1 status
- ICD-11: 2C65 - hereditary breast and ovarian cancer syndrome
Epidemiology
- Hereditary predisposition is one of the major risk factors for breast cancer development (Breast Cancer (Auckl) 2014;8:145)
- Comprises the largest group (approximately 25%) of hereditary breast cancer (Hum Genet 2013;132:845)
- Founder mutations have been found in Ashkenazi Jewish, Finnish, Icelandic, Swedish, Dutch and other populations (Am J Hum Genet 1997;60:505, Nat Genet 1996;13:117, Semin Oncol 2016;43:528)
- About 60% average cumulative risk to develop breast cancer by age 70 (J Natl Cancer Inst 2013;105:812)
- About 59% average cumulative risk to develop ovarian cancer by age 70 (J Natl Cancer Inst 2013;105:812)
- Genetic and environmental factors modify cancer risks for women with BRCA1 germline mutations (Endocr Relat Cancer 2016;23:T69)
- Most effective predictor is age of onset < 50 years, HER2 status (negative) and either ER or PR status (negative), as compared with sporadic or non-BRCA1 / BRCA2 cancers (Breast Cancer Res 2008;10:R17)
- The BRCAPRO and BOADICEA algorithms can be used to evaluate an individual's risk of having a BRCA1 or BRCA2 mutation (Breast 2013;22:1130)
- Up to 25% chance that BRCA1 and BRCA2 mutation carriers are being missed with current referral criteria for genetic analysis (Breast 2013;22:1130)
Pathophysiology
- BRCA1 gene is a large gene containing 5,592 nucleotides (Annu Rev Med 1998;49:425)
- Germline mutations have been found across the whole gene; no hot spot mutations (Annu Rev Med 1998;49:425)
- 80% of mutations cause generation of a premature stop codon (Annu Rev Med 1998;49:425, Mod Pathol 2005;18:1305)
- In > 80% of breast cancers that have developed in BRCA1 germline mutation carriers, the remaining wild type allele is lost (loss of heterozygosity) (Annu Rev Med 1998;49:425, Clin Cancer Res 1995;1:539)
- BRCA1 protein plays an important role in the DNA damage response, especially in DNA double strand break repair by homologous recombination (Nat Rev Cancer 2004;4:814)
- BRCA1 deficiency results in defective DNA double strand break repair, resulting in chromosomal instability and accelerating tumorigenesis (Front Biosci (Landmark Ed) 2014;19:605, Nat Rev Cancer 2004;4:814)
- Loss of p53 is thought to be essential for breast cancer development in BRCA1 germline mutation carriers: 40% of BRCA1 associated breast cancers have a p53 mutation compared with 20% of sporadic breast carcinomas (Cancer Res. 2001;61:4092)
Etiology
- Breast cancer arising in patients with an underlying BRCA1 germline mutation
Clinical features
- Early onset breast cancer (typically before age of 50) (Semin Oncol 2016;43:528)
- Triple negative breast cancer (Semin Oncol 2016;43:528)
- High frequency in Ashkenazi Jews (Semin Oncol 2016;43:528)
- Positive family history for breast and ovarian cancer and some other less frequently occurring cancers (Semin Oncol 2016;43:528)
Prognostic factors
- Contradictory reports on effect of BRCA1 status on prognosis (Oncotarget 2016;7:70113, PLoS One 2016;11:e0154789, N Engl J Med 2007;357:115)
Case reports
- 22 year old Pakistani woman with metaplastic breast carcinoma (Pathol Res Pract 2011;207:583)
- 29 year old woman with large BRCA1 deletion (Medicine (Baltimore) 2017;96:e8667)
- 33 year old woman with BRCA1 splice variant (Breast Cancer Res Treat 2018;168:543)
- 40 year old woman with BRCA1 germline mutation and HER2 positive breast cancer (Oncotarget 2015;6:35616)
- 46 year old French woman with metastatic breast cancer (Oncol Rep 2017;37:1573)
- 49 year old woman with invasive cancer 33 years after prophylactic bilateral subcutaneous mastectomies (World J Surg Oncol 2005;3:52)
- 63 year old woman with medullary-like features (Arch Pathol Lab Med 2009;133:1822)
Treatment
- Presymptomatic carriers: prophylactic mastectomy (reduces risk of cancer by > 90%) (Clin Cancer Res 2016;22:3971, Int J Clin Oncol 2018;23:45)
- Symptomatic breast cancer patients: mastectomy, relative contraindication for breast conserving therapy (Int J Clin Oncol 2018;23:45)
- Long term prognosis does not seem to significantly differ between the two surgical procedures
- High chemosensitivity
Microscopic (histologic) description
- Usually high grade invasive ductal carcinomas (Lancet 1997;349:1505, Pathobiology 2008;75:85)
- Abundant intra and peritumoral lymphocytes (J Natl Cancer Inst 1998;90:1138)
- Greater incidence of breast carcinoma with medullary features (Mod Pathol 2010;23:S46)
Microscopic (histologic) images
Contributed by Gary Tozbikian, M.D.
BRCA1 mutation associated breast carcinoma
Positive stains
- Basal / myoepithelial cell markers: CK5 / 6, CK14, EGFR (J Natl Cancer Inst 2003;95:1482, Clin Cancer Res 2005;11:5175)
- High Ki67 expression (Clin Cancer Res 2003;9:3606)
- Hypoxia related proteins: HIF1a, GLUT1, CAIX (J Natl Cancer Inst 2003;95:1482, Breast Cancer Res Treat 2008;111:475)
- Cell cycle related proteins: cyclin A, cyclin B1, cyclin E (Ann Oncol 2005;16:735, Breast Cancer Res Treat 2005;90:5)
Negative stains
- Triple negative for ER, PR and HER2 (69%) (Cancer Epidemiol Biomarkers Prev 2012;21:134, J Clin Oncol 2002;20:2310)
- ER associated genes: BCL2, p27, cyclin D1, p21, p16, CD4 (Cancer 1998;83:2335, Br J Cancer 2000;83:1318, Mod Pathol 2005;18:1305)
- Luminal cell marker CK8 / 18 (J Natl Cancer Inst 2003;95:1482, Clin Cancer Res 2005;11:5175)
- BRCA1 (variable) (Ann Oncol 2014;25:2372, Clin Cancer Res 1999;5:1249, Breast Cancer Res Treat 2015;150:81, Eur J Histochem 2007;51:219)
Molecular / cytogenetics description
- Tumor testing
- Specific pattern of chromosomal gains and losses in tumor is detectable by array CGH or MLPA analysis (Cancer Res 2002;62:7110, Breast Cancer Res 2011;13:R107)
- Germline testing
- High risk patients with breast cancer that meet criteria according to consensus guidelines (e.g. National Comprehensive Cancer Network [NCCN]) qualify for germline genetic testing; however, the American Society of Breast Surgeons recommends that genetic testing be available to all patients with newly diagnosed with breast cancer (Ann Surg Oncol 2019;26:3025)
- BRCA1 germline mutation can also be detected by DNA sequencing analysis of breast tumors (J Mol Diagn 2018;20:600)
Molecular / cytogenetics images
Images hosted on other servers:
Large deletion
Pedigree
Splice variant
Sample pathology report
- Right mastectomy:
- Poorly differentiated invasive ductal breast carcinoma (see comment)
- Sentinel nodes: no metastases / malignancy
- Comment: Considering the age of the patient and the histology, a hereditary breast carcinoma should be considered.
- Micro description: Sections show an atypical proliferation of irregular glands, solid groups and strands, composed of polymorphic cells with large, vesicular nuclei with prominent nucleoli and little cytoplasm. Mitotic count is 10 mitoses/10 HPF. Abundant peritumoral lymphocytes are seen. No signs of lymphovascular invasion. Microscopic diameter 2.0 cm. Bloom and Richardson grade 3 (tubule formation score: 3; nuclear size: score 3; mitotic count: score 2). ER negative (0%). PR negative (0%). HER2 negative (score 0). Foci of ductal carcinoma in situ were present around the tumor.
- Sentinel nodes: 2 reactive lymph nodes. No signs of malignancy.
Differential diagnosis
- Breast cancer with another mechanism of BRCA deficiency (BRCAness), including BRCA1 somatic mutations or BRCA1 hypermethylation (Nat Rev Cancer 2004;4:814, Ann Oncol 2016;27:1532, Gene 2016;584:26, Carcinogenesis 2000;21:1761, Breast Cancer Res Treat 2005;91:179, Oncogene 2007;26:2126)
- High grade triple negative ductal carcinoma of no special type without BRCA1 germline mutation
- Metastasis
Additional references
Board review style question #1
Which statement about BRCA1 associated breast cancer is true?
- Frequently negative for CK5 / 6 expression
- Histology is often high grade lobular
- IHC often shows a triple negative tumor
- Has a low Ki67 labeling index
Board review style answer #1
C. IHC often shows a triple negative tumor
Comment here
Reference: BRCA1 associated breast carcinoma
Comment here
Reference: BRCA1 associated breast carcinoma
Board review style answer #2
Which feature is associated with BRCA1 associated breast cancer?
- Ashkenazi Jewish heritage
- Diagnosis at age 50+ years
- Prominent neutrophilic infiltration
- BRCA1 somatic but not germline mutation
Board review style answer #2
