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The outcome from a Cancer Genetics referral depends on assessed risk and patient preference. The patient may be offered one or more of, lifestyle advice, early or more frequent screening, chemoprevention, genetic testing and prophylactic surgery.

Early screening for women with a family history is coordinated by Breast Test Wales as shown below.

Change in screening program (via Breast Test Wales)

Near population risk Normal screening program (i.e. women aged between 50 and 70 years will be offered screening by mammogram every 3 years)

Moderate Risk - 3-8% 10 year risk

Early breast screening - annual mammograms between the ages of 40 and 50 years then into screening program
High Risk - 8% or above 10 year risk Early breast screening - annual mammograms between the ages of 35 and 50 then 18 monthly screening to age 60, then into normal screening thereafter

In Wales, women with a proven BRCA gene are offered the same screening as women at high risk but their 18 monthly mammograms continue until age 70.

Prophylactic surgery

Risk reducing mastectomy in unaffected women at risk has received great publicity recently. Angelina Jolie has revealed that she underwent surgery in 2013, she also made public that she is a carrier of a BRCA gene.
Less well publicised is prophylactic oophorectomy, again Angelina Jolie revealed she underwent this procedure in 2015. Both procedures may be considered and pro-actively raisedwith women in the high-risk group and should be discussed, if raised, with women in the moderate-risk group.
The NICE guidance states that bilateral risk reducing mastectomy is appropriate for only a small proportion of women from high-risk families. NICE stresses the importance of the multi-disciplinary team and the involvement of clinical geneticists and specialist surgical teams in the process. NICE guidance is very similar for the consideration of oophorectomy. (see NICE guidance p34-36)

Chemoprevention

Interest in the chemoprevention of breast cancer arose from the (expected) observation that patients treated with tamoxifen for established breast cancer were at lower risk of developing a second breast cancer. In 1992 the Breast Cancer Prevention Trial was initiated. A double blind placebo controlled trial, it randomly assigned 13,388 women at increased risk of breast cancer, to tamoxifen 20mg daily or placebo for 5 years. It reported in 1998 with overall results showing a 49% decrease in the incidence of breast cancer. This effect is entirely on ER (Estrogen Receptor) positive tumours (69% reduction in the incidence) with no effect on the incidence of ER negative tumours. These findings have been confirmed by other studies.

In 2006 the STAR trial reported (Study of Tamoxifen And Raloxifene). A double blind randomized trial, it studied 19,747 postmenopausal women at increased risk of breast cancer. It concluded that:-

“Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs.”

As a result of these two major trials and additional evidence the FDA in the US has approved both tamoxifen and raloxifene to reduce the risk of breast cancer in post-menopausal women whose risk of developing the disease was at least 1.7% within the next 5 years based on the Gail score (calculated using the Gail Model risk tool). Furthermore it approved raloxifene to reduce the risk of breast cancer in postmenopausal women with average risk and osteoporosis.

A recent meta-analysis published in the Lancet demonstrated sustained benefit beyond the five years of treatment albeit at a lower (25%) level. (NNT to prevent 1 breast cancer over a 10 year period with 5 years of SERM treatment = 42)

The service configuration in Wales is such that the clinical geneticists do not prescribe and breast test Wales and breast surgeons have no direct clinical contact with asymptomatic patients. It is likely therefore that if a woman decides to opt for chemoprophylaxis that the initiation and prescription of these drugs will fall to general practice (albeit on the specific advice of clinical geneticists).

A discussion should have taken place in the genetics clinic, with each woman, who has made a decision on chemoprevention, having documented absolute risk/benefit information not only for chemoprevention but other alternatives. The prescriber should be aware of the benefits of prescribing (a 50% reduction in the incidence of breast cancer), menopausal status (raloxifene and Anastrozole for post menopausal women only), side effects and adverse effects.

Adverse effects of therapy

Both tamoxifen and raloxifene are Selective Estrogen Receptor Modulators (SERMs). Tamoxifen is first generation and raloxifene second. SERMs act on the estrogen receptor and have either agonist (oestrogenic) or antagonist (anti-oestrogenic) effects in different tissues in the body. Both compounds are antagonist in breast tissue and agonist in bone. Whereas tamoxifen is agonist in the uterus raloxifene is antagonist.

Anastrozole is an aromatase inhibitor. It has been known for sometime that they effectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women. It has been proven to be an effective preventative in postmenopausal women and is included in the updated (2017) Nice guidance as an option to offer postmenopausal women at high or moderate risk as an alternative to either tamoxifen or raloxifine.

NICE state: Chemoprevention of familial breast cancer with tamoxifen in premenopausal women, and with anastrozole, tamoxifen or raloxifene in postmenopausal women, is recommended as an option, Familial breast cancer: patient decision aids user guide March 2017 Page 5 of 13 in the NICE guideline (see the guideline for full details of recommendations). At the time of publication (March 2017), none of these medicines had UK marketing authorisations for this indication. The General Medical Council (GMC), in its Prescribing guidance: prescribing unlicensed medicines, states that although doctors should usually prescribe licensed medicines for their licensed indications, they may prescribe unlicensed medicines when it is necessary to do so to meet the specific needs of the patient.

TamoxifenRaloxifeneAnastrozole
Endometrial cancer

Increased risk

2.3 per 1000 in treatment arm v.

0.91 per1000 in placebo

(Breast Cancer Prevention Trial)

No increased risk

(US National Cancer Institute)

No increased risk

(IBIS 2)
Cancer other than breast or endometrial

No increased risk

(Breast Cancer Prevention Trial)

No increased risk

(STAR)

No increased risk
Fracture risk

Reduced by 19% in treatment group (did not reach statistical significance)

(Breast Cancer Prevention Trial)

Equivalence to tamoxifen

(STAR)

No increased risk in the IBIS 2 study however this excluded women with severe osteoporosis. Those at risk are recommended to undergo bone mineral density scanning
Ischaemic heart disease (n.b. both have positive effects on lipids)

No statistical difference

(Breast Cancer Prevention Trial)

Equivalence to tamoxifen No increased risk
Vascular events

Stroke increased risk 1.45 per 1000 in treatment group v. 0.95 per 1000 in placebo

Pulmonary embolus increased risk 0.69 per 1000 in treatment group v. 0.23 per 100 in placebo effect much stronger in post menopausal women

DVT increased risk 1.34 per 1000 in treatment group v. 0.84 per 1000 in placebo

(Breast Cancer Prevention Trial)

Stroke equivalence to tamoxifen

Thromboembolic events 30% lower in raloxifene arm

(STAR)

No increased risk

(IBIS 1)

Cataract

Slight increase in treatment group 24.82 per 1000 in treatment group v. 21.72 in placebo group

(Breast Cancer Prevention Trial)

Reduced risk v. tamoxifen

Raloxifene 56.3 per 1000

Tamoxifen 77.9 per 100 (these figures are over the 5 year study period as opposed to other figures in this table being annual incidence)

(STAR)

No data
All cause mortality

Similar to raloxifene

(STAR)

Similar to tamoxifen

(STAR)

No data

NICE have produced excellent patient decision aids:-

Genetic testing

In Wales genetic testing is currently offered to affected individuals with a greater than 20% risk of being a carrier of a BRCA1 or BRCA2 gene mutation. The risk is calculated using a computer algorithm called BOADICEA. This is a freely available program that can be used by members of the public, it uses family history to estimate the risk of BRCA1 and BRCA2 gene mutation in individuals.

It is 'preferable' to test affected family members (i.e. those with an established cancer diagnosis) as this gives more accurate information for the family as a whole.

Lifestyle advice (source NICE)

Hormonal contraceptives – up to the age of 35 no change in advice, over the age of 35 and a family history of breast cancer should be informed of an increased risk. BRCA1 mutation increased risk of breast cancer under 40 years but reduced lifetime risk of ovarian cancer

Breast-feeding reduces the risk of breast cancer

HRT – the use of HRT increases the risk of breast cancer

Alcohol consumption may increase the risk of breast cancer slightly and advice should be in line with limiting excessive intake

Smoking – advise to not smoke in line with general heath advice

Weight – increased risk of postmenopausal breast cancer from being overweight

Physical exercise – women should be informed about the potential benefits of physical activity on breast cancer risk