GENETICS OF BREAST CANCER FOR THE PRACTISING SURGEON
PRASAD P AGASHE, SHAILESH V SHRIKHANDE
Department of Surgery, Shrikhande Clinic Dadar, Mumbai.
Breast cancer is the commonest malignancy among women. There is now definite evidence that breast cancer is a genetic disease (Autosomal dominant) arising from an accumulation of mutations that promote clonal selection of cells with increased aggressive behaviour. [2,3] About 5-10% of breast cancers are hereditary. 
While surgery, chemotherapy and radiotherapy all continue to play invaluable roles in the management of breast cancer, the treatment approach for BRCA-1 and BRCA-2 related breast cancers has undergone significant change in recent times owing to a better understanding of the genetic basis of breast cancer.
Important genes in relation to breast cancer [4-9]
TABLE 1 No. Gene Chromosome Inheritance 1. BRCA 1 Chromosome17 (17q21) Autosomal dominant 2. BRCA 2 Chromosome13 (13q12) Autosomal dominant 3. TP 53 (tumor suppressor gene) Chromosome17 (17q13) Autosomal dominant(Li Fraumeni Syndrome) 4. PTEN Chromosome10 (10q22) Autosomal dominant(Cowden’s Disease) 5. ATM (Ataxia Telangiectasia mutation gene) Chromosome11 (11q23) Autosomal recessive(Ataxia Telangiectasia Syndrome) 6. HRAS-1 (Harvey rat sarcoma-1 viral oncogene) Chromosome11 (11p15) Autosomal dominant
Clinicopathological criteria which will help the surgeon to suspect occurrence of BRCA 1 and 2 related breast cancer and differentiate it from sporadic breast cancer are given below in Table 2. [10,11]
From Table 2 it is clear that the striking feature in BRCA-1 and BRCA-2 related breast cancer is the young age of disease onset.
The Table also shows the differing tumour biology, and receptor expression in BRCA-1 and BRCA-2 related cancers that can help us to differentiate between the two.
TABLE 2 Characteristics BRCA-1 related BRCA-2 related 1. Age of Onset < 36 years < 40 years 2. Bilaterality/ Risk of developing contralateral tumour 60-70% 60-70% 3. Occurrence of male breast cancer Less chance More chance 4. Predisposition to ovarian cancer Increased incidence Increased incidence 5. Tumour size No significance No significance 6. Axillary node status Trend towards lymphnode negative Not known 7. Histological type Ductal invasive carcinoma, Medullary carcinoma Invasive lobular carcinoma 8. Mitotic count More Less 9. Lymphocyte infiltration More Less 10. Defective micro tubule formation Less More 11. Oestrogen/Progesterone Receptor expression (ER/PR) Trend towards absence of ER/PR ER/PR present 12. Proliferation (S-phase) More Not known 13. DNA ploidy Aneuploid Not known 14. Chromosomal aberrations Losses of 2q, 4p, 4q, 5q, 12q Losses of 17q, 22q, 24, 20q 13 15. TP53 mutations Occurs in 53% of BRCA-1 related breast cancer Occurs in 29% of BRCA-2 related breast cancer 16. c-erb-2/neu/Her-2 over expression Lower over- expression rates compared to sporadic cases Not known
Criteria for referral for genetic counseling [12-15]
A.Women or men with a maternal or paternal blood relative who has been proven to have a clinically significant alteration in a BRCA gene.
B.Women or men with a personal and family history of breast and/or ovarian cancer in maternal or paternal blood relative(s) as defined by at least one of the following:
1. Women with breast cancer < 49 years plus one or more first or second-degree relatives with breast cancer diagnosed <49 years.
2. Women with breast cancer at any age plus:
3. Women with ovarian cancer plus:
- Breast cancer in two or more first or second-degree relatives where any of the affected relatives are diagnosed â age 49 years or
- Ovarian cancer in one or more first or second-degree relatives
4. Men with breast cancer plus breast and/or ovarian cancer in one or more first or second-degree relatives.
- Breast cancer in one or more first or second-degree relatives or
- Ovarian cancer with one or more first or second-degree relatives.
C.Women with a personal history (but no family history) of breast and/or ovarian cancer as defined by at least one of the following:
1. Breast cancer < age 29, or
2. Breast cancer < age 40, and is of Ashkenazi Jewish descent, or
3. Ovarian cancer and is of Ashkenazi Jewish descent, or
4. Breast and ovarian cancer or
5. Multiple primary breast cancers.
D.Women or men with family history (but no personal history) of breast and/or ovarian cancer in maternal or paternal blood relatives as defined by at least one of the following:
1. Breast cancer in at least
2. Ovarian cancer in at least two first or second-degree relatives.
- Two first or second-degree relatives both diagnosed â age 49 and at least one of the relatives is first degree or
- Three first or second-degree relatives with at least one relative diagnosed â age 49.
3. Breast cancer in at least one first or second-degree relative and ovarian cancer in at leastone first or second-degree relative.
Method of Genetic testing
After an informed consent, mutation analysis begin with acquisition of a blood sample from an affected individual and then subsequently from his/her family members belonging to a high-risk family.
Tests used to detect mutation are:
1. Protein Truncation Test (PTT). [16,17]
2.Polymerase chain reaction (PCR) based DNA sequencing technique.
Test results (What do they mean?)
After genetic testing the results are interpreted as given in Table 3.
TABLE 3 Test result Significance for the patient already affected with Breast Cancer Significance for her family members who are mutation carriers Negative (BRCA 1 and 2 mutation absent) Better prognosis and better 5- year survival • Risk of developing breast cancer is same as that in general population or• Presence of unidentifiable mutation Positive (BRCA 1 and 2 mutation present) Poor prognosis18,19 • 56% more chance of developing breast cancer as compared to the general population.20
• 16% chance of developing ovarian cancer.20
Management of breast cancer patient with BRCA-1 and/or BRCA-2 mutant gene
1.Breast conserving surgery is not recommended. [21,22]
2.Adjuvant chemotherapy/radiotherapy should be given. [23,24]
3.The option of prophylactic mastectomy of the other breast and oophorectomy should be considered. 
Management of mutation carriers (i.e. Family members who have BRCA-1 or BRCA-2 mutant genes)
A. Advice lifestyle modification by [26-28]
1. Reduce obesity
2. Avoid oral contraceptive pills
3. Parity of 3 or more births reduces risk of breast cancer significantly
B. Monthly breast self-examination beginning in early adulthood i.e. from 18 years. 
C. Clinical breast examination (by a doctor) every six monthly starting 25 years. 
D. Mammography every six monthly beginning from 25-35 years. [31,32]
Prevention (Options available for carriers with BRCA-1 and/or BRCA-2 mutation)
TABLE 4 Treatment option Percentage risk reduction of developing breast cancer 1. Tamoxifen treatment for 5 years  49% 2. Prophylactic bilateral oophorectomy  77% 3. Prophylactic bilateral mastectomy (different from subcutaneous mastectomy that was practised before)  90% 4. Bilateral oophorectomy with bilateral mastectomy  98%
With the advent of modern molecular biology techniques, genetic alterations in breast cancer have become increasingly evident in recent years. More importantly, these molecular alterations already have a clinical relevance to the practicing clinician and the transition from the bench to thebedside has already taken place.
It is obvious that breast conserving surgery should not be considered in BRCA-1 and BRCA-2 related cancers [21,22] as these patients have a higher risk of ipsilateral local recurrence.
It has been suggested that, optimal surgical treatment of these cancer patients should also involve contralateral prophylactic mastectomy, as the risk of a contralateral breast cancer in BRCA-1 and BRCA-2 cancer is high as 60%. [25 , 37,38] The philosophy that there is no point in performing prophylactic surgery after the diagnosis of breast cancer may be inappropriate since the first cancer might be curable and the patient could succumb from a second primary breast cancer or an ovarian malignancy. 
For BRCA-1 and BRCA-2 mutation carriers, early surveillance protocols will definitely help in earlier diagnosis of these cancers. Biannual surveillance is more beneficial as these cancers tend to grow rapidly. Furthermore, BRCA-1 and BRCA-2 mutation carriers are also prone to develop ovarian cancers so surveillance to detect it is also desirable. [39,40]
An interesting finding which needs to be stressed that the risk of transmission of a mutant gene is equally high from the paternal (father’s) side as that from the maternal side. So a history of breast cancer in father’s ancestors is also an important part of family history and should be specifically asked. 
Prophylactic Tamoxifen/Bilateral oophorectomy (Table 4) are valid options that may reduce the risk of breast cancer for women harbouring BRCA-1 and BRCA-2 mutations.
Previously prophylactic subcutaneous mastectomy with preservation of nipple and areola was performed. Subcutaneous mastectomy has been supplanted by total, or simple, mastectomy (Table 4). [35 , 41-43] This is because only 90-95% of the breast parenchyma is excised in the subcutaneous mastectomy and the development of breast cancer despite this form of surgery has been well documented.  A complete mastectomy should be performed  to the clavicle superiorly, the superior border of the rectus inferiorly, to the sternum medially, and to the anterior border of the latissimus dorsi laterally. Care should be taken to raise thin flaps, and to remove the fascia of the pectoralis major and the entire tail of Spence. There is no need to perform an axillary dissection, and the intercostobrachial cutaneous nerve should be preserved. Most women undergo immediate breast reconstruction with either a transverse rectus abdominus myocutaneous flap or with an implant. A close evaluation and collaboration with a plastic surgeon is essential.
Although the evidence outlined herein suggest that these surgical or hormonal interventions may produce significant cancer risk reduction and prolongation of survival, it must be understood that most women decline these interventions. After genetic counseling, interest in proceeding with testing declines to less than 50%.  Studies of women who have tested positive for a BRCA-1 mutation demonstrate that only 17% to 35% were considering prophylactic mastectomy, and 33% to 76% were considering prophylactic oophorectomy. [45,46] A French survey of 179 women attending cancer genetic clinics revealed that 97% were in favour of mammography. 57% supported chemoprevention, 22% favoured prophylactic oophorectomy, and only 10% favoured prophylactic mastectomy.  Other studies have shown that of women who underwent prophylactic mastectomy, 69% were satisfied with the procedure, and 74% reported diminished levels of emotion concern about developing breast cancer. Only 5% expressed regret for having had the surgery. [48,49]
Based on genetic information it is now evident that breast cancers involving BRCA-1 and BRCA-2 mutation are distinct entities and behave different than sporadically occurring breast cancers.
Management strategies of BRCA mutation breast cancers are different and also involve genetic counseling of family members for identification of the mutant genes and advising them about the risk of developing breast cancer and offering them chemoprevention and in selected cases even prophylactic surgery.
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