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BRCA1-associated Hereditary Breast and Ovarian Cancer Syndrome

BRCA1-associated hereditary breast and ovarian cancer syndrome (BOCS) is one of the most common family cancer syndromes. Germline mutations in the BRCA1 gene are associated with a very high lifetime risk for breast cancer and malignancies of the ovaries. Accordingly, members of families known to be affected by BRCA1-associated BOCS should be tested for mutations in the respective gene and be referred for prophylactic surgery or clinical and radiological surveillance.


Presentation

The clinical presentation of BRCA1-associated malignancies doesn't differ from that of non-hereditary cancers. Symptoms are usually non-specific and may comprise palpable mass lesions, pain, and constitutional symptoms like fever, night sweats, chills, loss of appetite and weight. With regard to breast cancer, changes of the nipple or overlying skin may be presenting symptoms. Additionally, discharge may be described. Ovarian cancer may also be associated with discharge, or with rather common gastrointestinal and genitourinary complaints like early satiety, bloating and urinary urgency. Prostate cancer may not cause any symptoms but may also be related to frequent urination and dysuria. The presence of metastases usually broadens the spectrum of symptoms and may intensify the aforementioned constitutional symptoms.

Although clinical findings don't allow for the differentiation of BRCA1-associated malignancies and other types of cancer, anamnestic data may certainly provide valuable information to this end. Patients developing cancer due to hereditary cancer syndromes are rather young, often younger than 50 years. They may have a family and personal history of cancer, and tend to develop multiple tumors. Breast cancer in males is in itself suggestive of a predisposition to cancer [1].

Pain
  • Symptoms are usually non-specific and may comprise palpable mass lesions, pain, and constitutional symptoms like fever, night sweats, chills, loss of appetite and weight.[symptoma.com]
  • Because of pain, and concern for limitations in future cancer detection, she underwent bilateral NSM with immediate direct-to-implant reconstruction.[aetna.com]
Pain
  • Symptoms are usually non-specific and may comprise palpable mass lesions, pain, and constitutional symptoms like fever, night sweats, chills, loss of appetite and weight.[symptoma.com]
  • Because of pain, and concern for limitations in future cancer detection, she underwent bilateral NSM with immediate direct-to-implant reconstruction.[aetna.com]
Surgical Procedure
  • Nevertheless, these surgical procedures confer substantial benefits.[cancer.gov]
  • Prophylactic oophorectomy, as the sole surgical procedure, is not indicated under accepted guidelines for women without a BRCA mutation or a family history of ovarian cancer.[aetna.com]
Constitutional Symptom
  • The presence of metastases usually broadens the spectrum of symptoms and may intensify the aforementioned constitutional symptoms.[symptoma.com]
Chills
  • Symptoms are usually non-specific and may comprise palpable mass lesions, pain, and constitutional symptoms like fever, night sweats, chills, loss of appetite and weight.[symptoma.com]
Aspiration
  • Microscopic examination of tissue samples obtained by fine-needle aspiration, biopsy or surgery. Histological and immunohistochemical features should be considered. Carriers of pathogenic BRCA1 variants are most likely to develop ductal carcinoma.[symptoma.com]
Loss of Appetite
  • Symptoms are usually non-specific and may comprise palpable mass lesions, pain, and constitutional symptoms like fever, night sweats, chills, loss of appetite and weight.[symptoma.com]
Loss of Appetite
  • Symptoms are usually non-specific and may comprise palpable mass lesions, pain, and constitutional symptoms like fever, night sweats, chills, loss of appetite and weight.[symptoma.com]
Early Satiety
  • Ovarian cancer may also be associated with discharge, or with rather common gastrointestinal and genitourinary complaints like early satiety, bloating and urinary urgency.[symptoma.com]
Long Arm
  • This gene is located on the long arm of chromosome 17 and encodes for a nuclear phosphoprotein required for the maintenance of genomic stability. Accordingly, BRCA1 has been classified as a tumor suppressor gene.[symptoma.com]
Night Sweats
  • Symptoms are usually non-specific and may comprise palpable mass lesions, pain, and constitutional symptoms like fever, night sweats, chills, loss of appetite and weight.[symptoma.com]
Suggestibility
  • In that respect, Lord and Ashworth have recently suggested BRCA1-deficient tumor cells to be susceptible to PARP inhibitors like olaparib because these compounds mediate what is known as "synthetic lethality".[symptoma.com]
  • It would be reasonable to suggest that such individuals should be offered referral to screening programmes.[hccpjournal.biomedcentral.com]
  • If the tested person has a family history that suggests the possibility of having a harmful mutation in BRCA1 or BRCA2 but complete gene testing identifies no such mutation in the family, a negative result is less clear.[cancer.gov]
  • If pedigree analysis was suggestive of HBCS, genetic testing of the BRCA1, BRCA2, TP53, and CHEK2 genes was offered.[aetna.com]
  • However, the anticipated increased uptake of sequencing will require new approaches for communication to patients of findings from germline DNA that suggest increased risk for treatment toxicities or risk for disorders other than breast cancer (90, 93[es.slideshare.net]
Breast Mass
  • ., abnormal mammogram, breast mass) …. If AH is diagnosed on an excisional biopsy, no additional surgery is indicated.[aetna.com]
Urinary Urgency
  • Ovarian cancer may also be associated with discharge, or with rather common gastrointestinal and genitourinary complaints like early satiety, bloating and urinary urgency.[symptoma.com]
Dysuria
  • Prostate cancer may not cause any symptoms but may also be related to frequent urination and dysuria. The presence of metastases usually broadens the spectrum of symptoms and may intensify the aforementioned constitutional symptoms.[symptoma.com]

Workup

The diagnosis of breast and ovarian cancer is based on clinical, laboratory, imaging and histological data, regardless of a possible predisposition to cancer. The same applies to other malignancies that may arise in carriers of BRCA1 mutations. A positive family history of breast and/or ovarian cancer should, however, raise suspicion as to a genetic defect that may increase the individual risk of developing such malignancies and prompt molecular biological testing.

The detection of a heterozygous germline pathogenic variant in BRCA1 is diagnostic of BRCA1-associated BOCS [1]. In an ideal scenario, patients are tested for BRCA1 mutations before they develop any tumors. But genetic studies should also be carried out if an elder patient's personal or family history suggests a hereditary cancer syndrome: The results of these studies are relevant for their own prognosis and the identification of family members at risk. Targeted analyses may be carried out if a determined mutation has been found in a family member or if the patient at hand belongs to an ethnic group with a known founder mutation [2]. If BRCA1 mutations can't be identified, other genes have to be sequenced, e.g. BRCA2 (BRCA2-associated BOCS), TP53 (Li-Fraumeni syndrome), PTEN (PTEN hamartoma tumor syndrome), CDH1 (hereditary diffuse gastric cancer), and STK11 (Peutz-Jeghers syndrome) [1] [3] [4].

Briefly, the following measures may be taken to diagnose BOCS-associated malignancies. They may either be carried out in symptomatic patients or in the scope of surveillance programs:

  • Palpation of breast and axilla, abdomen, and prostate gland to detect mass lesions.
  • Measurements of concentrations of tumor markers like cancer antigen 125 and prostate-specific antigen in serum samples.
  • Sonography, radiography, computed tomography, and magnetic resonance imaging as well as other forms of diagnostic imaging to visualize anatomical and structural anomalies.
  • Microscopic examination of tissue samples obtained by fine-needle aspiration, biopsy or surgery. Histological and immunohistochemical features should be considered. Carriers of pathogenic BRCA1 variants are most likely to develop ductal carcinoma. Medullary carcinoma is the second most common form of BRCA1-associated breast cancer whereas this type of tumor is rarely seen in non-carriers [5]. BRCA1-associated mammary tumors are often triple-negative, i.e., tumor cells neither express estrogen receptors nor progesterone receptors and test negative for an overexpression of human epidermal growth factor receptor 2 [6]. Concerning BRCA1-related ovarian malignancies, serous adenocarcinoma is particularly common [7].

There is no universal grading system for malignancies due to BRCA1 mutations. Grading and staging systems specific to the tumor site are used, e.g., the TNM-based staging system for breast cancer and the FIGO staging system for ovarian cancer [8] [9]. These systems are not perfect but are certainly helpful to orient therapeutic decisions.

Treatment

Surgery is the mainstay of treatment. Because poor long-term survival is often attributed to second primary tumors in the breast or ovaries, women diagnosed with BRCA1-related breast or ovarian cancer are recommended ipsilateral mastectomy, contralateral risk-reducing mastectomy, and salpingo-oophorectomy [10]. Beyond that, there are no general guidelines on the management of BRCA1-related tumors. Treatment decisions generally rest on site-specific recommendations for cancer management and are thus made on a case-by-case basis. In this context, adjuvant chemotherapy is often administered, with platin-based treatment regimens being more effective in carriers of pathogenic BRCA1 variants than in non-carriers [11]. BRCA1-associated malignancies may also respond to radiotherapy, hormone therapy, and molecular targeted therapy. The latter is the focus of intense research. Scientists are currently analyzing potential relationships between BRCA1 genotypes and associated tumors' susceptibility to certain therapies. In that respect, Lord and Ashworth have recently suggested BRCA1-deficient tumor cells to be susceptible to PARP inhibitors like olaparib because these compounds mediate what is known as "synthetic lethality" [12]. It is hoped that further specific recommendations can be given in the near future.

Prognosis

BRCA1-associated BOCS patients have an estimated lifetime risk of 46-87% for breast cancer, and about 21% of those who have once been diagnosed with breast cancer will develop a second mammary tumor within ten years. Women carrying pathogenic BRCA1 variants have a lifetime risk of 39-63% for malignancies of the ovaries. In males, the lifetime risk for breast cancer amounts to >1%, which is about ten times as high as in the general population, and approximately 8% of male carriers are diagnosed with prostate cancer by the age of 65 years. Additionally, all patients have an increased risk for pancreatic cancer [1].

BRCA1-related tumors are usually high-grade malignancies associated with an unfavorable prognosis for long-term survival [5] [7] [13]. Beyond that, the presence of at least one distant metastasis, no surgery, large tumor size, and lymph node involvement have been identified as unfavorable prognostic factors and are listed here in decreasing order of hazard ratio [5]. In sum, breast-cancer-specific ten-year survival rates approximate 70% [5]. With regard to BRCA1-associated ovarian cancer, five-year survival rates may exceed 50%, but less than a third of affected women remain alive ten years after the initial diagnosis [7]. It remains a matter of discussion whether carriers of BRCA1 mutations have a worse prognosis than non-carriers who are diagnosed with the same type of tumor: So far, large-scale studies have not revealed significant differences between both groups of patients [5] [7].

Etiology

BRCA1-associated BOCS is caused by pathogenic mutations in the BRCA1 gene. This gene is located on the long arm of chromosome 17 and encodes for a nuclear phosphoprotein required for the maintenance of genomic stability. Accordingly, BRCA1 has been classified as a tumor suppressor gene. It has first been related to early-onset familial breast cancer in 1990 [13]. By now, more than 1,600 BRCA1 mutations have been described [2]. It has long since been assumed that there are breast cancer cluster regions and ovarian cancer cluster regions in the BRCA1 gene. This hypothesis has finally been confirmed by Rebbeck and colleagues, who have shown that mutations in the respective regions are associated with particularly high risks for one or the other type of cancer [14].

Epidemiology

The overall prevalence of BRCA1 mutations has been estimated to 0.1-0.3% of the population. However, there are considerable differences between geographical regions and ethnicities [2]. The prevalence of BRCA1-associated BOCS is highest among individuals of Ashkenazi Jewish ancestry. It has been estimated that 2.5% of Ashkenazi Jews are carriers of at least one of three deleterious founder mutations, including one mutation in the BRCA2 gene, which account for >90% of all cases in this ethnic group [15] [16]. BRCA1 founder mutations have also been detected in the French Canadian, Central-Eastern European and Mexican populations [2]. BRCA1-associated BOCS is inherited in an autosomal dominant manner, a fact that becomes clear when performing genealogical analyses: This pattern of inheritance is typically associated with a very high familial incidence of the disease in question. However, there may be carriers of pathogenic BRCA1 mutations who don't have a family history of breast, ovarian, or related cancer. Distinct circumstances may account for this situation. On the one hand, the penetrance of the mutated gene is incomplete, particularly in men. On the other hand, the patients' age at cancer development varies and family members may have died of non-related causes before malignancies were developed or detected [1].

Sex distribution
Age distribution

Pathophysiology

BRCA1 is a protein-coding gene. Its gene product is involved in homologous recombination repair and is thus required for the conservative repair of double-strand DNA breaks. BRCA1-deficient cells have to resort to non-conservative forms of DNA repair, e.g., to non-homologous end joining. Non-conservative mechanisms are more likely to be associated with deletions of genetic information and thus favor the accumulation of mutations that eventually trigger cancerogenesis [12]. BRCA1 may also be implicated in chromatin remodeling and transcriptional regulation, but experimental evidence regarding this hypothesis is scarce [17].

Prevention

First and second-degree relatives of known carriers of pathogenic BRCA1 mutations should be tested for the respective genetic defect. Beyond that, population screenings for BRCA1 mutations have been proposed for the Ashkenazi Jewish population [15]. Because comprehensive genetic studies provide little additional benefit, such population screenings could be limited to known founder mutations [16].

Due to the very high risks associated with BRCA1-associated BOCS, carriers are recommended prophylactic bilateral mastectomy and prophylactic salpingo-oophorectomy. Alternatively, they may opt for a surveillance program comprising regular clinical examination, assessment of the serum levels of tumor markers, and diagnostic imaging. Both females and males who (temporarily) opt against prophylactic surgery should be encouraged to partake in surveillance programs for the detection of breast cancer from the age of 35. The same starting age is recommended for ovarian cancer screenings; annual prostate cancer screenings should be offered to male carriers aged 45 years and older. It should be noted, though, that the sensitivity of the abovementioned techniques for the early detection of malignancies is limited [1].

A prenatal diagnosis of BRCA1-associated BOCS is feasible but rarely demanded.

Summary

BRCA1-associated BOCS is a hereditary cancer syndrome related to high risks for breast and ovarian cancer including fallopian tube and primary peritoneal malignancies. Furthermore, carriers of pathogenic mutations in the BRCA1 gene have moderately increased risks for prostate cancer and pancreatic cancer. BRCA1-associated BOCS is inherited in an autosomal dominant manner. The high penetrance of the mutated gene justifies regular examinations in the scope of surveillance programs and even prophylactic surgery, so it is highly recommended to perform a thorough familial workup, to identify affected kindreds and family members at risk. Molecular genetic studies are required to diagnose BRCA1-associated BOCS [1].

Patient Information

The causes of cancer remain unknown in the majority of cases, but some patients are genetically predisposed to the development of malignancies. They may have inherited mutated genes from either of their parents and thus become prone to certain types of tumors. If this is the case, they suffer from a hereditary cancer syndrome. BRCA1-associated hereditary breast and ovarian cancer syndrome (BOCS) is one of the most common ones. It is related to mutations in a gene named BRCA1 and renders affected individuals highly susceptible to breast cancer, ovarian cancer including fallopian tube and primary peritoneal malignancies, prostate cancer, and pancreatic cancer. BRCA1 mutations can be detected by molecular genetic studies at any age, so BRCA1-associated BOCS can be diagnosed before the development of any tumor.

Because BRCA1-associated BOCS is inherited, patients who carry pathogenic variants of the BRCA1 gene usually have a family history of cancer. They tend to develop cancer at rather young ages, often before turning 50 years old. With regard to female patients, their lifetime risk for malignancies of the breast and ovaries may be as high as 87%, so they are generally recommended prophylactic surgery. Risk-reducing bilateral mastectomy and salpingo-oophorectomy greatly improve their survival. Men's lifetime risk for breast and prostate cancer is lower, but males are still recommended to undergo regular examinations. In sum, every possible effort should be made to avoid the development of malignancies and to diagnose cancer during early stages of the disease to improve the patients' prognosis.

References

Article

  1. Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
  2. Rebbeck TR, Friebel TM, Friedman E, et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018.
  3. Fountzilas C, Kaklamani VG. Multi-gene Panel Testing in Breast Cancer Management. Cancer Treat Res. 2018; 173:121-140.
  4. Toss A, Tomasello C, Razzaboni E, et al. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int. 2015; 2015:341723.
  5. Schmidt MK, van den Broek AJ, Tollenaar RA, et al. Breast Cancer Survival of BRCA1/BRCA2 Mutation Carriers in a Hospital-Based Cohort of Young Women. J Natl Cancer Inst. 2017; 109(8).
  6. Lee E, McKean-Cowdin R, Ma H, et al. Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women. J Clin Oncol. 2011; 29(33):4373-4380.
  7. McLaughlin JR, Rosen B, Moody J, et al. Long-term ovarian cancer survival associated with mutation in BRCA1 or BRCA2. J Natl Cancer Inst. 2013; 105(2):141-148.
  8. Cserni G, Chmielik E, Cserni B, Tot T. The new TNM-based staging of breast cancer. Virchows Arch. 2018.
  9. Zeppernick F, Meinhold-Heerlein I. The new FIGO staging system for ovarian, fallopian tube, and primary peritoneal cancer. Arch Gynecol Obstet. 2014; 290(5):839-842.
  10. Metcalfe K, Lynch HT, Foulkes WD, et al. Effect of Oophorectomy on Survival After Breast Cancer in BRCA1 and BRCA2 Mutation Carriers. JAMA Oncol. 2015; 1(3):306-313.
  11. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012; 30(21):2654-2663.
  12. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017; 355(6330):1152-1158.
  13. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990; 250(4988):1684-1689.
  14. Rebbeck TR, Mitra N, Wan F, et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. Jama. 2015; 313(13):1347-1361.
  15. Lieberman S, Lahad A, Tomer A, Cohen C, Levy-Lahad E, Raz A. Population screening for BRCA1/BRCA2 mutations: lessons from qualitative analysis of the screening experience. Genet Med. 2017; 19(6):628-634.
  16. Petrucelli N, Mange S, Fulbright JL, Dohany L, Zakalik D, Duquette D. To reflex or not: additional BRCA1/2 testing in Ashkenazi Jewish individuals without founder mutations. J Genet Couns. 2015; 24(2):285-293.
  17. Starita LM, Parvin JD. The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair. Curr Opin Cell Biol. 2003; 15(3):345-350.

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Last updated: 2019-07-11 19:53