Patients with known BRCA 1 or 2 gene mutation
See below
Patients without personal history of breast cancer, but with a significant family history of breast cancer, with test not carried out (for rejection) or with negative test/no diagnostic/uncertain
In particular, the number of first-degree relatives affected by breast and/or ovarian cancer, in maternal or paternal line, and the age at which they got sick (regardless of the outcome of their illness) must be considered, paying attention to the presence of any males with breast cancer or bilateral cancer cases and/or breast and ovarian cancer in the same subject.
Patients with breast cancer
This group must be distinguished into:
• Patients with unilateral BC that is still present (recent diagnosis)
• Patients with a previous breast cancer history (and eventual adjuvant treatments) that months/years later decide for a contralateral prophylactic mastectomy or for a bilateral one (in case of previous quadrantectomy)
Patients with (surgical or percutaneous) breast biopsies that reveal histological situations with increased risk of developing breast cancer
Patients with (surgical or percutaneous) breast biopsies that reveal histological situations with increased risk of developing breast cancer. In particular intraductal lobular carcinoma (LCIS) or other borderline disease like atypical hyperplasia. LCIS has a risk of 1–1.5% per year and 20–30% in a lifetime of subsequent development of invasive cancer in either breast. The relative risk of invasive BC is 5.4× increasing age [1]. Atypical hyperplasia increases the the rate in general population, decreasing with relative risk to 4× that of the general population and to 8.9× in those with a family history [2].
Previous thoracic radiotherapy
For the treatment of lymphomas
Dense breast
Recent studies seem to demonstrate a risk not simply linked to the difficulty of diagnosis (which often means a delayed diagnosis), but also a real increase of developing cancer due to the breast structure [3].
13.3 BRCA1/2 Mutation Carriers
The literature suggests that 5–10% of all breast cancers have an inherited maternal or paternal basis [4, 5]; 50% of hereditary breast cancer is inherited from the father’s side. In the USA, more than 500,000 women are mutation carriers. Mary Claire King and colleagues localized the BRCA1 gene in 1990: studying families with early-onset breast cancer, they demonstrated that the disease had a marker on chromosome 17q. The newly discovered gene was considered to be a tumor suppressor gene (p53 related) since its loss was found in more than 90% of BRCA1 mutation carriers with BC. In 1994, the sequence of the BRCA1 gene was completely characterized and the research of BRCA2 gene started [6]. Thus a relation between BRCA1/2 mutations and BC or other carcinoma (pancreatic, prostatic), or some particular inherited syndromes like Li-Fraumeni, Peutz-Jeghuers and ataxia- telangiectasia, was demonstrated. Table 13.2 shows the peculiar characteristics of BRCA1 or 2 mutation carriers [7].
BRCA 1 and 2 | • They are autosomal dominant, tend to be highly penetrant. BC mutation inheritance can be maternal or paternal, following the Mendelian model • Their function is linked to DNA damage repair. In vitro and animal BRCA models have been shown to be radiosensitive: it is therefore important to combine the need of regular and frequent controls and the risk of RX damage • Frequently early-onset and bilateral tumors • The lifetime probability of a second breast cancer (after a previous one) is 60% in absence of risk-reducing maneuvers, if the patient survives the first BC |
BRCA1 | • BRCA1 carriers have a 50–80% lifetime risk of BC and a 30–40% of OC. BRCA1 mutated cancer account for 30–40% of inherited BC. • Mapped to a region on chromosome 17 • BRCA1 tumors (compared with sporadic ones) are often triple-negative, poorly differentiated, high proliferative rate tumors, and frequently medullary tumors; overexpression of p53 is common |
BRCA2 | • BRCA2 mutation carriers have a 40–70% lifetime risk of BC and 20% of OC. Its mutation is also linked to prostate cancer (4×), uterine, pancreatic and gastric cancer and melanoma • Mapped to a region on chromosome 13 • Men who are mutation carriers are more frequently BRCA2 carriers • BRCA2 tumors (compared with sporadic ones) are often well differentiated, with a medium-low mitotic rate and tend to be ER-positive with the same frequency as sporadic ones |
13.3.1 Genetic Testing
Genetic testing should be accompanied by a genetic counselling team [4], whose members must be prepared to deal with a spectrum of medical, psychological and social consequences of a positive, negative or ambiguous result of the test itself.
There are clear indications (see Table 13.3, according to The Italian FONCaM 2006 recommendations) for referring the patients (or healthy subject) to genetic counselling where, after careful history taking and calculation of the risk of being carriers of a mutation, genetic testing could be proposed (on peripheral blood, since genes BRCA1 and 2 are present in all cells).
Table 13.3
Indications for referring the patients (or healthy subject) to genetic counselling
BREAST CANCER PATIENT | |
|---|---|
Women with a personal history of BC/OC at any age IF | • Breast cancer diagnosed at age 36 or younger OR • Breast AND ovarian cancer in the same subject at any age OR • Bilateral breast carcinoma at age 50 or younger OR • Male breast carcinoma at any age OR • Ovarian or fallopian cancer at age 45 or younger |
Women with a personal history of BC at age 50 or younger AND | • One first-degree-relative with a history of BC at age 50 or younger OR One first-degree-relative with a history of bilateral BC at any age One first-degree-relative with a history of OC at any age |
Women with a personal history of BC at age 50 or older AND | • Two first-degree-relatives, both with a history of BC at any age |
Women with a personal history of OC at any age AND | • One first-degree-relative with a history of OC at any age |
HEALTHY SUBJECTS WITH A FAMILIAR HISTORY OF: | |
At least one first-degree relative with BC, IF | • Breast cancer diagnosed at age 36 or younger OR • Breast AND ovarian cancer in the same subject at any age OR • Bilateral breast carcinoma at age 50 or younger OR • Male breast carcinoma at any age OR • Ovarian or fallopian cancer at age 45 or younger |
Two first-degree relatives | • With a history of BC at age 50 or younger • With a history of OC at any age • One with a history of BC at age 50 or younger and one with a history of bilateral BC • One with a history of BC at age 50 or younger and one with a history of OC |
Three first-degree relatives | • With a history of BC at any age |
The DNA study normally takes quite a long time (months), however, in selected cases, it may be reduced to a few weeks: this is particularly important in patients eligible for conservative surgery, when the eventual mutation could be a reason for demolitive surgery. It is necessary that the patient who takes the test is adequately informed that:
A positive test should not be read as a condemnation but as an opportunity to learn of a risk and put in place the maneuvers that can reduce it (but not cancel). The patients’ reactions are heterogeneous in this sense; for their proper management, it is necessary to provide psychological support
A negative test (for mutations known up to now) does not exclude the possibility of being considered at high risk of hereditary BC
The presence of a negative genetic test in a patient with a mutation clearly established in other family members excludes this mutation and takes us back to a risk comparable to the general population.
The test should be performed, in families with multiple cases, on the youngest subject (referring to the age at the moment of the diagnosis) with a personal story of BC because she/he has, in that family, the highest probability of carrying the mutation.
Before performing the test, the patient must be properly informed (this must be documented in the informed consent) that there is no procedure that can reset the risk, in the case of a positive test. There are tools for primary (surgery and chemoprevention) or secondary prevention, essentially represented by clinical and instrumental monitoring. The important role of MRI in the surveillance of these subjects has been demonstrated. In fact, it is very sensitive and can pick up cancer at an earlier stage, but the impact on survival is unknown. The Dutch National Study [8] on more than 1,900 high-risk women (358 of which BRCA1/2 mutation carriers) concluded that MRI had a higher overall sensitivity, except for ductal carcinoma in situ (DCIS), a condition that was better detected by mammography.
13.3.2 Radiological Screening
In addition to risk-reducing surgery, which is the object of our present article and which will be discussed below, there are other strategies to reduce the risk, the main one of which is represented by the radiological monitoring in these patients, using traditional methods and breast MRI. The recommendations regarding radiological screening at different ages, according to Italian FONCaM 2006, are reported in Table 13.4.
Table 13.4
Recommendations about radiological screening at different ages, in high risk patients
Between 25–35 years old (or 10 years younger than the youngest affected relative) | Clinical examination twice a year, breast ultrasound twice a year, breast MRI every 12 months, one x-ray bilateral mammography projection every 12 months Semi-annual OC screening with pelvic examination, transvaginal ultrasound and CA-125 test |
Between 36–50 years old | Clinical examination twice a year, breast ultrasound every 12 months or twice a year in case of dense breast, breast MRI every 12 months, two x-ray bilateral mammography projections every 12 months. Semi-annual OC screening with pelvic examination, transvaginal ultrasound and CA-125 test |
50 years old or older | Clinical examination twice a year, breast MRI every 12 months, two x-ray bilateral mammography projections every 12 months, breast ultrasound if needed |
In male mutation carriers, the risk of BC at 70 years of age is 6%; for this reason a radiological screening is not indicated: the subject must be informed of the risk and warned that in presence of the slightest suspicion he should consult a specialist. He must also be informed of the increased risk of prostate cancer and colon cancer, and of the advisability of a regular check-up.
13.3.3 Chemoprevention
Chemoprevention uses hormonal drugs able to block the effects of estrogens, which are responsible for the development and growth of a significant proportion of tumors: among them, tamoxifen and raloxifene (active against osteoporosis and reduction of LDL-cholesterol) can be used, keeping in mind that their risk-reducing effect is about 50% and that they are accompanied by side effects. The randomized placedo-control Breast Cancer Prevention Trial [9] demonstrated a 50% reduction of invasive BC incidence among high-risk healthy women who took tamoxifen (in women with lobular carcinoma in situ (LCIS) the incidence of invasive BC decreased by 56%; and in cases with atypical hyperplasia, the decrease was 86%). There were no proven effects in terms of mortality, but an increased risk of developing an endometrial stage I carcinoma. Other more recent trials found a minor effect in particular in cases at low risk. Actual recommendations are:
Tamoxifen employment in chemoprevention must be individualized and used in cases with a risk of BC superior to 1.66 using the Gail model.
Patients with DCIS, LCIS and atypical hyperplasia, or BRCA1/2 mutation carriers could be considered for the treatment.
The treatment must be avoided if a history of stroke or cardiovascular disease is present.
Some studies have evaluated or are evaluating the protective role of the administration of raloxifene, aromatase inhibitors, non steroidal anti-inflammatory drugs, statins and more recently retinoids (fenretinide) without definitive and unequivocal results.
13.3.4 Bilateral Salpingo-oophorectomy
Finally, without going into details which are far from the goals of this chapter, it is important to mention the bilateral salpingo-oophorectomy (BSO); if performed between 35 and 40 years, it results in a 98% reduction in the risk of ovarian cancer (OC) and 50–70% of BC. Given that in mutation carriers OC occurs more frequently between 45 and 50 years old, performing the intervention after 35 years to allow a possible pregnancy is recommended. The BSO is a risk-reducing maneuver that is strongly recommended (much more than the mastectomy) because difficulties in diagnosis of OC, the absence of effective screening measures and poor prognosis are well known. However, there are also some adverse effects among which are decreased libido, the early-onset of osteoporosis and cardiac problems, all typical of postmenopausal women.
13.4 Looking at the Literature: Effectiveness of Bilateral Prophylactic Mastectomy
13.4.1 BRCA Carriers
In BRCA carriers, three milestone studies confirmed that bilateral prophylactic mastectomy (BPM) reduces the incidence of breast cancer. Meijers-Heijboer and colleagues [10] conducted a prospective study on 139 BRCA1 or BRCA2 mutation carriers. Seventy-six women underwent BPM, and 63 remained under close sureillance. No BC developed in the BPM group; however, the risk reduction effect of BPM in this study cannot be isolated from the risk-reducing effect of prophylactic BSO. In this study, a statistically greater proportion of women in the BPM group underwent premenopausal prophylactic salpingo-oophorectomy (PSO) (58%) compared with the surveillance group (38%).
Hartmann and colleagues [11] reported no case of BC at a median follow-up of 13.4 years in 26 BRCA mutated women who underwent BPM. Using various statistical models, the relative risk reduction due to BPM was estimated at 85–100%.
In the more recent Prevention and Observation of Surgical Endpoints (PROSE) study of Rebbeck and colleagues [12], 105 BRCA carriers were followed after BPM and compared with 378 matched BRCA controls, who did not undergo the procedure. With a mean follow-up of 6.4 years, BC was diagnosed in 2 (1.9%) of those who had BPM versus 184 (48.7%) of those who did not. Cases and controls in this study were matched based on PSO, with a relative breast cancer risk reduction of 95% in those who had PSO and 90% in the other group.
Taken together, these studies confirm a 90–95% reduction in breast cancer risk after BPM in BRCA carriers.
13.4.2 High-risk Women Regardless of BRCA Status
Several studies provide evidence on the efficacy of BPM for high-risk women regardless of BRCA status. Hartmann and colleagues [13] retrospectively studied BPM among high-risk women based on a positive family history of breast cancer. In their cohort of 639 women from 1960 to 1993, 90% underwent bilateral subcutaneous mastectomy with preservation of the nipple-areolar complex (NAC), whereas it was removed in the remaining 10%. The cohort was divided into high- and moderaterisk groups, and the incidence of breast cancer in these groups was compared with that of a control group consisting of their sisters, who did not undergo BPM. With a median follow-up of 14 years, the incidence of breast cancer was reduced by 90–94% in the high-risk group and 90% in the moderate-risk group.
The efficacy of BPM in community practice was evaluated in a population-based study by Geiger and colleagues [14]. In this retrospective case-cohort study, BPM reduced breast cancer risk by 95%, although the absolute risk of BC in the control population was low (4%).
13.5 Looking at the Literature: Effectiveness of Contralateral Prophylactic Mastectomy
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