Age

Age is the single most important risk factor for the development of breast cancer (Colditz and Rosner 2000). The incidence of breast cancer increases with age, doubling every 10 years to the menopause, and then the rate of increase slows, levelling to a plateau after 80 years (Anderson et al 2005). This creates a point of inflection in the age-specific incidence curve known as ‘Clemmensen’s hook’ (Clemmensen 1948). The incidence of oestrogen-receptor-alpha (ERα)-negative tumours rises rapidly to 50 years and then flattens out/decreases, whereas the incidence of ERα-positive tumours is similar up to the age of 50 years but then continues to increase, albeit at a slower pace. As a result, ERα-negative tumours tend to occur earlier in life and ERα-positive tumours are more common in older women. The peak age of onset for these two tumour phenotypes is 50 years and 70 years, respectively.

Ethnicity changes the effect of age on breast cancer risk. African-American women under 50 years of age have a higher age-specific incidence of breast cancer than their Caucasian counterparts (Vogel 1998). However, the incidence of breast cancer is higher in Caucasian women after 50 years of age. The difference in age-adjusted breast cancer mortality rates between African-American and Caucasian women in the 1980s was probably due to the greater incidence of ERα-negative tumours in African-American women, who will not have benefited from the introduction of adjuvant hormonal therapy (Jatoi et al 2005).

Geographical variation

Worldwide, more than 1 million women are diagnosed with breast cancer every year, accounting for 10% of all cancer cases and 23% of all female cancer cases (Ferlay et al 2004). Incidence rates for breast cancer are six times greater in the Western world than in underdeveloped countries. Approximately 430,000 new cases of breast cancer occur each year in Europe and an estimated 212,920 in the USA. The lowest rates in Europe are found in Romania and Latvia, and the highest rates are found in Northern and Western Europe. The incidence of breast cancer in American Hispanic women is 40–50% that of non-Hispanic White women.

Migrants from low-risk countries to high-risk countries have been shown to acquire the risk of the ‘host nation’ within two generations (Tominaga 1985, Ziegler et al 1993). Japanese migrants to the USA acquire an increased breast cancer risk compared with the population in Japan, and there is increasing evidence that the earlier in life a woman takes up residence in a ‘high-risk’ country, the higher the risk of breast cancer compared with the country of origin (Shimizu et al 1991, Ziegler et al 1993).

Ovulatory cycles

Events in a woman’s life that alter her lifetime ovulatory cycles appear to correlate with the risk of breast cancer. Women who start menstruating early or have a late menopause have a 30–50% increase in risk of developing breast cancer. Similarly, late menarche and an early menopause lead to an equivalent reduction in breast cancer risk. The risk of developing breast cancer is doubled in those women who have a natural menopause after 55 years of age compared with those who experience the menopause before 45 years of age. A menopause induced before 40 years of age reduces the risk of breast cancer by almost two-thirds (Hankinson et al 2004).

Age at first pregnancy

Late age at first birth and nulliparity increase the lifetime risk of breast cancer. Nulliparity has been a well-known risk factor for developing breast cancer since Ramizzini described horrendis mammarium canceris in Catholic nuns (Ramazzini 1713).The risk of breast cancer in women who have their first child after 30 years of age is double that of women who have their first child before 20 years of age. The group at highest risk are those women who have their first child after 35 years of age. These women have a greater risk than nulliparous women. An early age of birth of a second child confers a reduced risk. The protective effects of an early full-term pregnancy have been observed in a number of ethnic groups and geographic locations, suggesting that the parity-induced protection results from biological changes in the breast rather than environmental factors.

Benign breast disease

Prospective and retrospective studies have shown a relative risk of breast cancer of 1.5–1.6 for women with benign breast disease compared with the general population (Hartmann et al 2005). This increased risk has been shown to persist for 25 years after biopsy. The relative risk of proliferative changes with atypia was 4.24 compared with a relative risk of 1.88 for those without atypia and 1.27 for non-proliferative lesions. The age at diagnosis of the benign breast disease appears to modify the risks related to the histological appearance of benign breast disease. The presence of atypia in women under 45 years of age conveys twice the risk observed among women over 55 years of age. The Breast Cancer Detection and Demonstration Project showed that the risk of breast cancer among premenopausal women with atypia was elevated by a factor of 12.0, compared with 3.3 for postmenopausal women with aytpia (London et al 1992, Dupont et al 1993). An increase in breast cancers has been demonstrated in the same breast during the first 5 years of follow-up following a diagnosis of benign breast disease, particularly in women with atypia.

Ionizing radiation exposure

The understanding of radiation-related breast cancer in women derives from epidemiological studies of patients exposed to diagnostic or therapeutic medical radiation (mantle irradiation for lymphoma) and of the Japanese atomic bomb survivors (United Nations Scientific Committee on the Effects of Atomic Radiation 2000). The breast tissue of young women is highly sensitive to the carcinogenic action of ionizing radiation. Only the bone marrow and the infant thyroid gland are more sensitive to the cancer-causing effects of radiation. Ionizing radiation is an established breast cancer risk factor and this risk has been shown to increase linearly with dose. Age at exposure directly affects radiation-related breast cancer risk, with the greatest risk seen in women exposed before 20 years of age and a significantly reduced risk seen for postmenopausal women. Periods of enhanced cell proliferation, namely in utero, puberty and pregnancy, have been proposed to represent windows of increased susceptibility for mammary carcinogenesis (Ronckers et al 2005).

A two-view mammogram results in a breast tissue dose of approximately 0.3 cGy (annual exposure from all sources of natural ‘background’ radiation being approximately 0.1 cGy). Therefore, with a woman receiving 10 mammograms as a young woman, the total dose would be approximately 3 cGy to each breast. Bearing in mind that epidemiological studies have not detected statistically significant increases below a dose of approximately 20 cGy, and knowing that 100 cGy increases risk by approximately 40%, one can estimate that 3 cGy from periodic mammography screenings would increase the risk by approximately 1.2% or a relative risk of 1.012. Such low risks are not detectable in human studies. Nonetheless, all unnecessary radiation should be avoided and although the presumed risk is very small, it should be clear that the benefit from the medical exposure would far outweigh it.

Oral contraceptive pill

Use of the oral contraceptive pill slightly increases the risk of breast cancer in current and recent users (1–4 years following cessation) with relative risks of 1.24 and 1.16, respectively (Collaborative Group on Hormonal Factors in Breast Cancer 2002). This risk diminishes after discontinuing use and returns to normal after 10 years.

These estimates are based on the Collaborative Group on Hormonal Factors in Breast Cancer study; a collaborative meta-analysis of 54 studies in 25 countries with data on over 50,000 women with breast cancer (Anonymous 1996). Cancers diagnosed in women who have used the oral contraceptive pill tend to be less clinically advanced than those detected in women who have never used it. Users of the oral contraceptive pill are generally younger women whose breast cancer risk is comparatively low, so the small excess in current users will result in a relatively small number of additional cases. Other findings of the study were:

A large case–controlled study of 4575 women aged 35–64 years showed that current or former use of the oral contraceptive pill was not associated with a significantly increased risk of breast cancer (Marchbanks et al 2002).

Hormone replacement therapy

Hormone replacement therapy (HRT) use increases the risk of breast cancer and reduces the sensitivity of mammography. The risk of breast cancer for current or recent users of HRT increases by 2.3% per year of use. For women who have used HRT for at least 5 years (average 11 years), the increased risk was 35% (Anonymous 1997a). The effect is substantially greater for oestrogen–progesterone combinations than for oestrogen-only HRT. Risk increases with duration of use; the risk for current users of oestrogen–progesterone combinations for more than 10 years was 2.31 compared with 1.74 for 1–4 years of use. Risk decreases with cessation of use; past users (>5 years following cessation) have a similar risk to those who have never taken HRT. One recent study reported that current users of combined HRT had a 2.7-fold elevated risk of lobular cancer and a 3.3-fold risk of ductal cancer. The risk of lobular cancer was only raised in women who had used HRT for 3 years or more.

In the UK over the past 10 years, it is estimated that 20,000 extra breast cancer cases have occurred among women aged 50–64 years as a result of HRT use, and three-quarters (15,000) of these additional breast cancers are due to the use of oestrogen–progesterone HRT. HRT is used by over 20 million women in Western countries for the alleviation of perimenopausal and postmenopausal symptoms, and is an important source of exogenous oestrogen and, in some cases, progesterone exposure. A recent review concluded that the excess incidence of breast cancer, stroke and pulmonary embolism in postmenopausal women who use HRT for 5 years was greater than the reduction in incidence of colorectal cancer and hip fracture (Beral et al 2002). The risks and benefits for treating menopausal symptoms should be evaluated on an individual basis.

A decrease in the incidence of breast cancer among postmenopausal women in the UK may be linked to a decrease in the use of HRT. Researchers calculated that between 1999 and 2005, the risk of the disease fell by 14% in women in their 50s, representing 1400 fewer cases in 2005, and 3300 fewer over the period (Parkin 2009). They suggest that the decrease in breast cancer since 1999 in women aged 50–59 years and since 2003 in women aged 60–64 years is a consequence of the reduced use of HRT. The use of HRT began to fall after the Million Women Study in the UK and the Women’s Health Initiative Study in the USA showed that HRT could increase the risk of breast cancer. In women aged 45–69 years, the use of HRT increased from 1992 to reach a peak of 25% in 2000–2001, before falling to approximately half that by 2006.

Hormone therapy after breast cancer is becoming an increasingly relevant problem as more women survive breast cancer. The HABITS (Hormonal Replacement Therapy After Breast Cancer — Is It Safe?) trial was designed to confirm the efficacy of HRT given to women after treatment for breast cancer (Holmberg and Anderson 2004). The trial confirmed an unacceptably high risk in women allocated to receive HRT compared with those receiving best symptomatic treatment, and as a result was terminated. Analysis of women in the HABITS trial after a median follow-up of 4 years showed that 17.6% in the HRT treatment arm had developed breast cancer recurrence or a new breast cancer, compared with 7.7% in the control arm. The estimated 5-year cumulative rate for disease recurrence was 22.2% in the HRT arm and 9.5% in the control arm.

Endogenous hormones

Higher levels of endogenous hormones have been hypothesized to increase breast cancer risk. A pooled analysis of nine prospective cohort studies found a statistically significant increased risk of breast cancer in postmenopausal women with higher levels of sex hormones (Key et al 2002). The risk for women whose oestradiol levels were in the top quintile was approximately twice that compared with women whose oestradiol levels were in the bottom quintile. Evidence in premenopausal women was inconclusive.

Body weight

Increased weight and obesity, as measured by high body mass index (BMI), has been shown to moderately increase the risk of postmenopausal breast cancer and is one of the few modifiable risk factors. It is thought that between 7% and 15% of breast cancers in developed countries may be attributable to obesity. Two large studies — the EPIC study (European Prospective Investigation into Cancer and Nutrition) and the Million Women Study — have found that obese women have a 30% higher risk of postmenopausal breast cancer than women of a healthy weight. That means that if the average lifetime risk of breast cancer is one in nine, an obese woman’s lifetime risk is one in seven. An increase in weight over time can also increase the risk of breast cancer.

Diet

A high-fat diet has been positively associated with breast cancer in a number of animal and case–control studies. Pooled analysis of cohort studies found no significant association between fat intake and breast cancer risk, whilst a meta-analysis found an association between higher total and saturated fat intake and an increased risk of breast cancer. A recent prospective study confirmed a significant association between saturated fat and breast cancer risk (Bingham et al 2003).

Alcohol intake

A significant association between alcohol intake and breast cancer has been found, with an increased risk of 7% for each 10 g alcohol/day (Hamajima et al 2002, Baan et al 2007). Approximately 4% of breast cancers in women from developed countries may be attributable to alcohol. In a recent large cohort of middle-aged women in the UK, a population with low-to-moderate alcohol consumption [10 g alcohol (one drink)/day] has shown a statistically increased risk of breast cancer; they also showed an increase in cancers of the oral cavity, pharynx, oesophagus, larynx, rectum and liver (Allen et al 2009). They calculated that the increased risk accounted for an additional 11 breast cancers per 1000 women up to 75 years of age. Although alcohol and tobacco are closely related social habits, there is no direct association between tobacco and breast cancer.

Height

Taller women have an increased risk of breast cancer (Hunter and Willett 1993). A pooled analysis estimated that the relative risk for women over 1.75 m tall compared with women under 1.6 m tall was 1.22 for all women and 1.28 for postmenopausal women (van den Brandt et al 2000).

Physical activity

A report from the International Agency for Research on Cancer concluded that physical activity has a preventive effect on breast cancer. This may be an indirect effect as exercise lowers BMI, or a direct effect on hormonal and growth factor levels. This varies between studies, with one showing a 30–40% reduction in the risk of breast cancer with a few hours of vigorous activity per week versus none (Monninkhof et al 2007).

Socioeconomic status

Breast cancer has a higher incidence in higher social classes. The age-standardized incidence rate is 115.1 per 100,000 women in the least deprived quintile compared with 97.3 per 100,000 women in the most deprived quintile. This is likely to be a reflection of other factors including reproductive history and early nutritional intake.

Mammographic density

There is extensive evidence that mammographic density is a risk factor for breast cancer, independent of other risk factors, and is associated with large relative and attributable risks for the disease. Women with increasingly dense breasts have two to six times the risk of breast cancer compared with women with less dense breasts (Boyd et al 1995). Parity, menopause and other risk factors only explain 20–30% of the variance in mammographic density (Boyd et al 2002). Early studies of mother–daughter sets and small twin studies suggested that genetic factors might explain a proportion of the variation of breast tissue patterns within a given population (Boyd et al 2002, Stone et al 2006). The genetic factors that influence mammographic density may also explain variations in breast tissue involution.

Previous history of breast cancer

If a woman has had breast cancer previously, the risk of developing a second primary breast cancer is two to six times greater compared with the the risk of the general population of developing a primary breast cancer (Chen and Thompson 1999).

Family history

A family history of breast cancer, particularly in first-degree relatives, is a well-known risk factor for the development of breast cancer. The past few years have seen a significant increase in knowledge of inherited breast cancer. Approximately 80% of breast cancers are sporadic, and the other 20% are familial, occurring within the context of a positive family history. Twin studies have shown that inherited factors may account for up to 25–30% of all breast cancers (Lalloo et al 2003). These cancers are the result of a combination of genetic and environmental factors that cause acquired genetic mutations over time (Vogel and Bevers 2003). A woman with one first-degree relative has approximately double the risk of breast cancer of a woman with no family history of the disease. The risk is greater if two (or more) relatives are affected. Multiple primary cancers in one individual or related early-onset cancers in a family pedigree are highly suggestive of a predisposing gene.

The first two major susceptibility genes for breast cancer, BRCA1 and BRCA2, were identified in 1994 and 1995, respectively. Mutations and genomic rearrangements within the BRCA1 and BRCA2 genes have been clearly associated with breast cancer. The inherited mutation of these genes represents the first hit of Knudson’s two-hit model of tumorigenesis. BRCA gene mutations interfere with the DNA-repair function of the normal gene, resulting in the accumulation of chromosomal abnormalities and an increased susceptibility to develop malignancy.

BRCA1 and BRCA2 account for the largest proportion of familial breast cancer cases. It is thought that 20–25% of familial breast cancer cases are due to mutations or genomic rearrangements within these genes. The frequency of these mutations is rare, occurring in 0.1–0.5% of the general population, compared with 2% in Ashkenazi Jews (Rebbeck et al 2002). The breast cancer risk attributable to BRCA1 and BRCA2 mutations in Ashkenazi Jews is as high as 15–30% (FitzGerald et al 1996, Abeliovich et al 1997, Struewing et al 1997, Metcalfe et al 2004). A recent analysis of 22 studies showed that carrying a deleterious BRCA1 or BRCA2 mutation confers an estimated lifetime risk for developing breast cancer of 65% and 45%, respectively (Antoniou et al 2003). By the age of 40 years, carrying a deleterious BRCA1 mutation confers a 20% chance of developing breast cancer, and the risk increases with age (Kauff et al 2002). Mutations in BRCA1 are strongly associated with ovarian and fallopian tube cancers (Antoniou et al 2003). The risk of ovarian carcinoma for BRCA1 carriers is 17%, 39% and 54% at 40, 70 and 80 years, respectively (Antoniou et al 2003). Penetrance of BRCA1 with respect to ovarian, fallopian and breast cancer is greater than that for BRCA2.

Tumours associated with BRCA1 carriers are more frequently grade 3, and ERα-negative and ovarian carcinomas, which occur in BRCA1/2 families, are mostly non-mucinous epithelial cancers (Lakhani et al 2002). No single technique is able to detect all mutations, and even by sequencing the entire gene, the detection rate is only 85% (Evans et al 2003). Once a mutation has been identified in a family, definitive genetic testing can inform women more accurately of their risks and give them an informed choice of their options. Mutational analysis of an unaffected individual is problematic without checking an affected relative. Identification of a mutation will confirm an increased risk; however, the absence of a mutation does not exclude the possibility of a refractory mutation of another gene. Where there is not a dominant family history or a BRCA1/2 mutation is not identified, risk estimation gives a 1.5–3 fold relative risk with a family history of a single first-degree relative affected (Newman et al 1988, Claus et al 1994).

The Gail model

The Gail model quantifies a woman’s lifetime risk of developing breast cancer by incorporating patient age, age at menarche, age at first birth/nulliparity, number of breast biopsies, ethnic origin and history of breast cancer in first-degree relatives (Gail et al 1989, Costantino et al 1999). It does not, however, consider the ages of first-degree relatives with breast cancer, and overlooks a family history of bilateral breast disease, second-degree relatives with breast cancer and a family history of ovarian cancer. Also, the model does not account for a personal history of atypical hyperplasia and lobular carcinoma in situ, previous radiation therapy to the chest for the treatment of Hodgkin’s lymphoma, or recent migration from a region of low breast cancer risk (e.g. rural China) to a high-risk region. The Gail model remains the most frequently used in defining eligibility for risk reduction trials.

The Claus model

The Claus model provides breast cancer risk estimates based on which relatives were diagnosed with breast cancer and at what age their diagnosis was made. Initially, only data from mothers and sisters were included, but second-degree relatives were included subsequently (Claus et al 1994).

BRCAPRO

BRCAPRO was developed by statisticians at Duke University to calculate age-specific probabilities of developing breast and ovarian cancer, based on the probability that the individual carries a mutation on one of the BRCA genes (Berry et al 1997). The model uses the observed incidences of breast and ovarian cancer among BRCA gene mutation carriers and non-carriers to calculate the probability that a given individual is a mutation carrier based on his/her family history.

The Tyrer–Cuzick model

The Tyrer–Cuzick model identifies the risk of breast cancer in unaffected women by taking into account their probability of carrying genetic risk factors, namely a BRCA1/BRCA2 mutation; a notional common, low-penetrance dominant susceptibility allele that stands for all other genetic risk factors; and a number of other individual factors known to influence risk, such as age at menopause and menarche, weight, height, age, use of HRT, previous benign breast biopsies and parity (Tyrer et al 2004).

Future developments

The Breast Cancer Prevention Collaborative Group has advised that the following risk factors should be further examined by multivariate analysis in future studies: mammographic density, plasma hormone levels, bone density and fracture history, history of weight gain, BMI and hip–waist ratio (Santen et al 2007). It is thought that the addition of these risk factors will lead to a more accurate quantitative risk assessment model for use in future breast cancer prevention trials. Whilst breast cancer risk assessment using mathematical models based on epidemiological data is valid, no one model integrates benign breast disease, oestrogen exposure and family history in a comprehensive fashion. Therefore, it is important to use a variety of models in a specialized risk assessment clinic.

Surgical management

Prophylactic/risk-reducing mastectomy (RRM) is an option for breast cancer risk reduction in high-risk women. The significant psychological and physical burden associated with RRM is reserved for those women whose lifetime risk of developing breast cancer is high. High-risk women are classified as those with a lifetime risk above 25%. This risk is the equivalent of having one first-degree relative with breast cancer diagnosed below the age of 50 years, or three affected relatives (first-degree) diagnosed under the age of 60 years. The efficacy of RRM is controversial and depends on the amount of residual tissue following the procedure. A retrospective study of 639 women with a family history of breast cancer suggests that RRM is associated with a 90% reduction in risk (Hartmann et al 1999). One small prospective study investigating the efficacy of prophylactic mastectomy in BRCA1/2 carriers with a mean follow-up of 3 years showed that those women undergoing mastectomy had a significant reduction in the incidence of breast cancer (0 of 76 women) compared with the surveillance group (eight of 63 women) (Meijers-Heijboer et al 2001).

The use of RRM is increasing, with women often choosing to have breast reconstruction surgery either immediately or delayed. The timing of the reconstruction is controversial, with immediate reconstruction appropriate in the majority of women. It is now felt that the psychological benefit of emerging from a mastectomy with a breast mound far outweighs the need for a waiting period (Kronowitz 2007). The process from first consultation to surgery takes 6–12 months; this delay deliberately allows women enough time for the decision-making process.

Bilateral prophylactic oophorectomy

Studies have shown a significant reduction in the incidence of breast cancer in women with BRCA1/2 mutations that have undergone prophylactic bilateral oophorectomy (Rebbeck et al 2002). Before undergoing the procedure, the patient should take into account how long she wishes to maintain her fertility, and should receive counselling about the risks and benefits of prophylactic oophorectomy. Opinion is divided on the use of HRT following prophylactic oophorectomy, with some centres routinely recommending HRT for all patients up to 50 years of age; the decision to use oestrogens should be based on a consideration of symptoms affecting future health and quality of life.

Chemoprevention

Chemoprevention provides a non-invasive option for breast cancer risk reduction for many high-risk women. Tamoxifen, a selective oestrogen receptor modulator (SERM) well known for its antioestrogenic effects in breast tissue, was the first agent used in breast cancer risk reduction after it was found to reduce the incidence of all breast cancers by 38% and ER-positive tumours by 48% (Cuzick et al 2003).

In-situ carcinoma

These are preinvasive carcinomas. The proliferation of epithelial cells remains confined by an intact basement membrane, with no invasion into the surrounding stroma.

Ductal carcinoma in situ

Breast screening has resulted in a marked increase in the detection of ductal carcinoma in situ (DCIS), accounting for 25–30% of all screen-detected tumours (Schwartz et al 2000). Over 90% of DCIS is impalpable, asymptomatic and often detected by screening as microcalcifications (Figure 47.1). The remaining 10% are symptomatic, presenting with nipple discharge, a palpable mass or Paget’s disease of the breast. When diagnosed clinically, DCIS is often extensive or associated with a concurrent invasive tumour. Postmortem studies have shown prevalence of DCIS from 0.2% to 14% (Bartow et al 1987, Nielsen et al 1987). Risk factors for DCIS include older age at first childbirth, nulliparity and a family history of breast cancer (Raktovich 2000). Retrospective studies of cases of low-grade DCIS misdiagnosed as benign showed that 20 years after local excision, approximately 33% had developed invasive disease (Page et al 1995). DCIS is classified into two major subtypes according to the presence/absence of comedo necrosis (atypical cells with abundant luminal necrosis that fill at least one duct) (Silverstein et al 1996). A system of low, intermediate and high nuclear grade is used to classify DCIS.

• Low-grade DCIS: evenly spaced cells with centrally placed small nuclei, few mitoses and the nucleoli are not well seen.

• High-grade DCIS: pleomorphic irregularly spaced cells, with large irregular nuclei, frequent mitoses and prominent nucleoli. Often solid with comedo necrosis and calcification.

• Intermediate-grade DCIS: features between high- and low-grade DCIS.

Figure 47.1 Ductal carcinoma in situ. Intermediate-grade ductal carcinoma in situ (DCIS) exhibiting classical comedo-type casting calcification within the ducts. The linear branching pattern is very typical of DCIS. Small arrows demonstrate the casting branching pattern of DCIS. The more density clustered area of calcification is associated with a local area of invasive ductal carcinoma (arrow head).

Most cases of DCIS are unicentric, with only 1% showing multicentric disease (Holland et al 1990b).

Multicentric tumour is defined as separate foci of tumour found in more than one breast quadrant or more than 5 cm from the primary tumour. Multifocal tumour is defined as more than one tumour foci in the same quadrant (Anonymous 1998c).

The spread of DCIS locally is along the branching ducts that form the glandular breast, and explains why most DCIS recurrences occur at or near the site of the initial tumour (Holland et al 1998). Micro-invasion is uncommon in DCIS, but confers a 2% risk of lymph node metastasis (van Dongen et al 1989). Studies have shown that poorly differentiated, high-grade comedo DCIS has low ER expression, high rates of cell proliferation, and overexpression of c-erbB2 (HER-2/neu) and epidermal growth factor receptor (EGFR) (Millis et al 1996). Low-grade lesions have high ER expression, lower rates of cell proliferation and rarely express HER-2 (Millis et al 1996, Boland et al 2002). Small, localized areas of DCIS (<4 cm) should be treated with breast-conserving surgery (BCS) with or without radiotherapy, and larger lesions need to be treated with mastectomy (Schwartz et al 2000).

The incidence of macroscopic nodal involvement in DCIS is less than 1%; however, nodal micrometastases have been reported in 5–14% of patients (Schuh et al 1986, Kitchen et al 2000). Two small, single-institution studies have reported a 3.1% rate of sentinel lymph node involvement in 223 patients with pure DCIS. Sentinel lymph node biopsy (SNB) for DCIS is not currently indicated but is under investigation, and may have a role in mastectomy for DCIS (Intra et al 2003). SNB should only be considered in those patients with a higher likelihood of underlying, undetected invasive disease (i.e. younger patients, DCIS >4 cm, high-grade DCIS and patients undergoing mastectomy). Twenty-five percent of cases recur within 8 years of BCS alone, 50% of which will present with invasive disease (Fisher et al 1999, Julien et al 2000, Ottesen et al 2000, Chan et al 2001); the recurrence rate for DCIS following mastectomy is 1% (Silverstein et al 1995). The key factor for recurrence is a clear margin at the time of surgery, and poor prognostic indicators include younger age at diagnosis (<40 years), poorly differentiated/high-grade tumours, presence of comedo necrosis, ER negativity and HER-2 positivity (Yen et al 2005).

The NSABP-B17, EORTC 10853 and UK/ANZ DCIS trials evaluated the value of radiotherapy following BCS for DCIS (Fisher et al 1999, Julien et al 2000, Houghton et al 2003). All of the trials reported a significant reduction in ipsilateral recurrence following radiotherapy. The EORTC trial showed a reduction in recurrence of DCIS from 8% to 5%, and a reduction in invasive recurrence from 8% to 4% at 5 years.

Invasive carcinoma

Invasive lobular carcinoma

Invasive lobular carcinoma (ILC) is the second most common type of invasive breast cancer accounting for 8–14% of all invasive breast cancers (Arpino et al 2004). ILC clinically presents as a poorly defined thickening of the breast rather than a dominant mass. This makes the extent of the disease difficult to estimate on clinical examination, and difficult to visualize on mammography. Ultrasonography is more sensitive than mammography in detecting ILC, but may significantly underestimate the size of the lesions (Pritt et al 2004, Selinko et al 2004). Magnetic resonance imaging (MRI) is more accurate than either mammography or ultrasonography in defining the extent of the disease but is less widely available (Weinstein et al 2001). Due to the infiltrative growth pattern, there is a higher incidence of resection margin involvement than for IDC and a higher conversion rate to mastectomy (Yeatman et al 1995). ILC has a higher incidence of being bilateral, multifocal and multicentric than IDC (Figure 47.2) (Ashikari et al 1973). Axillary lymph nodes in ILC may remain impalpable even when extensively involved (Grube et al 2002). A large study from the National Cancer Database to examine treatment and outcomes in patients with ILC showed a similar 5-year survival rate between patients with ILC and IDC, and between those ILC patients receiving breast-conserving therapy and those receiving mastectomy (Winchester et al 1998).

Figure 47.2 Multifocal breast cancer. Most commonly seen in invasive lobular cancer. The left mammogram images [mediolateral oblique (MLO) and craniocaudal (CC)] have dense parenchyma and only show a single subtle mass with slight distortion (arrowhead) on the MLO view. Ultrasound shows two subtle lesions (arrowed) close to each other (LT BREAST 7.2 and 7.4). Contrast-enhanced subtraction magnetic resonance shows multiple enhancing lesions (arrow heads) in the left breast on different slices.

Breast screening

Breast screening aims to reduce mortality through early detection. A number of trials carried out between the 1960s and 1980s showed that population screening by mammography can be expected to reduce breast cancer mortality by 25% (Olsen and Gotzsche 2001, Tabar et al 2001, Anonymous 2002b, Duffy et al 2002, Nystrom et al 2002). The benefit of screening is greatest in women aged 55–70 years (Anonymous 2002b, Nystrom et al 2002). There is no mortality benefit of screening women under 40 years of age, and the mortality benefit of those aged between 40 and 55 years is 20% (Anonymous 2002b, Nystrom et al 2002). Breast screening has been introduced in many countries over the past 20 years. In some countries, screening is advised in all women over 40 years of age; however, in countries providing population-based screening, women over 50 years of age are targeted.

The UK National Breast Screening Programme (NHSBSP) was set up by the Department of Health in 1988 in response to the recommendations of a working group, chaired by Professor Sir Patrick Forrest, which had been set up to consider whether or not to implement a population screening programme in the UK. The report ‘Breast Cancer Screening’ was published in 1986, and became known as ‘The Forrest Report’ (Forrest 1986). The NHSBSP was the first of its kind in the world. It began inviting women for screening in 1988, and national coverage was achieved by the mid 1990s. It provides screening by invitation, free at the point of delivery to all women between 50 and 70 years of age (initially 50–64 years, age range increased in 2004). Women over 70 years of age can attend but are not invited, and more than 70% of the invited population are required to attend in order to obtain an overall mortality benefit. The screening method is two-view mammography (cranio-caudal and medio-lateral oblique views) every 3 years. Approximately 5% of women screened are recalled for further assessment of a problem identified at screening. Three-quarters of women recalled simply require further imaging (ultrasound and/or mammography) and clinical assessment before being reassured and discharged. The remaining 25% will undergo a needle biopsy procedure in order to diagnose six cancers per 1000 women screened. Despite advances in needle biopsy techniques, 0.25% of all women screened will require an open surgical biopsy. Mammography can be expected to detect breast cancer 2 years before it becomes clinically apparent, and the frequency of mammography is determined by the lead time of breast cancer. Mammographic screening intervals, based on average growth time of breast cancer to age, should be yearly for women between 40 and 50 years of age, every 2 years in women between 50 and 60 years of age, and every 3 years thereafter. However, the Breast Screening Frequency trial did not show a significant benefit for women aged 50–64 years screened yearly compared with those screened every 3 years (Anonymous 2002a). One-third of breast cancers will present in the interval between screens, called ‘interval cancers’, and half of these will present in the third year after screening.

Screening high-risk young women

A national study evaluating mammographic screening for young women with a family history of breast cancer is being conducted (FH01 study), comparing screening in women aged 40–44 years with a moderate risk with a control arm; this study is currently unreported. Mammography has a higher predictive value in young women at high risk compared with age-matched controls, but is not sensitive, particularly in women with BRCA1 mutations (Chang et al 1999, Brekelmans et al 2001, Goffin et al 2001, Tilanus-Linthorst et al 2002, Hamilton et al 2004, Robson 2004, Warner et al 2004). Women with BRCA1 rarely present with associated DCIS, and the mammographic features are therefore usually of a mass lesion with no microcalcifications and no architectural distortion. These often present as interval cancers. BRCA2 cancers present similarly to sporadic cancers, and are more likely to be detected by mammography. Ultrasonographic features in BRCA1 cancers are often indeterminate or benign.

MRI is the most sensitive imaging modality in young women (Kriege et al 2004, Robson 2004). Genetically predisposed women commonly develop breast cancer when young and when dense breast tissue reduces the sensitivity of mammography. The Magnetic Resonance Imaging for Breast Screening (MARIBS) study compared the performance of contrast-enhanced MRI with mammography in this group of women (Leach et al 2005). It confirmed that contrast-enhanced MRI was significantly more sensitive than mammography in cancer detection for the entire cohort, but especially in the subgroup of BRCA1 carriers. Specificity for both procedures was acceptable. In spite of a high proportion of grade 3 tumours, the tumours were small and few women were node positive. These findings confirm those from the Netherlands six-centre MRI Screening (MRISC) study and a single-centre study from Toronto (Warner et al 2004, Kriege et al 2007). These reports support a policy of annual screening combining contrast-enhanced MRI and mammography, which would detect most tumours. These studies show evidence of effective small cancer detection, but do not have sufficient power to show whether mortality is reduced, for which there is no current evidence. Age for starting screening must be based on age rather than age of affected relatives. For women at moderate risk, screening should be started at 40 years of age, and for those at high risk, screening may be started at 30–35 years of age. High risk can be described as more than 8% by 50 years or more than 25% for lifetime. It is important that these women be followed-up in a specialist centre.

Symptomatic disease

Approximately 60% of breast cancers present symptomatically with a discrete mass, skin changes (ulceration/dimpling), nipple changes or, rarely, pain (mastalgia). In the UK, guidelines have been issued by the Department of Health informing family practitioners of the suspicious symptoms which warrant urgent referral to a breast clinic. Referral must be within 24 h of seeing their general practitioner, and women should be seen by a specialist in a breast clinic within 2 weeks of referral. ‘One-stop’ clinics, where all the necessary tests required to make a diagnosis are performed, are recommended.

Triple assessment

Patients undergo a triple assessment, which is a combination of clinical examination, imaging (mammography for women >35 years and ultrasonography for women <35 years) and cytology (fine needle aspiration) with or without needle core biopsy (both guided by either X-ray or ultrasonography). Triple assessment has a high positive predictive value and a low false-positive rate. The aim of triple assessment is to make a diagnosis prior to counselling and definitive treatment.

Mammography

X-ray mammography has been the basis of breast imaging for more than 30 years. The sensitivity of mammography for breast cancer is dependent on age, as the denser the breast tissue, the less effective it is in detection (Figure 47.3). Breast tissue is more dense in younger women and whilst the sensitivity of mammography for breast cancer in women over 60 years of age approaches 95%, detection rates are less than 50% in women under 40 years of age (Kolb et al 2002). Mammography uses ionizing radiation and should only be used where a clinical benefit is likely. The benefits of mammography in women over 40 years of age is likely to outweigh the oncogenic effects of repeated exposure. There is rarely an indication for performing mammography in women under 35 years of age unless there is a strong clinical suspicion of malignancy. The false-negative rate for mammography has been reported to be between 10% and 30%. Although many cancers are mammographically occult, especially in dense breasts, a large number of these are visible retrospectively. These oversights can be reduced by double reading, improving sensitivity by up to 15% (Skaane et al 2007). Computer-aided design (CAD) programmes are available to assist radiologists to detect potentially suspicious abnormalities.

Figure 47.3 Invasive ductal carcinoma grade II mammogram. Irregular dense mass with a spiculated margin and fine spiculations extending out into the surrounding breast tissue. The spiculations are causing distortion and skin thickening (open arrows).

Ultrasound

High-frequency ultrasound (>10 MHz) is a highly effective diagnostic tool in the investigation of focal breast symptoms (Wilson and Teh 1998). Ultrasound does not use ionizing radiation and has a very high sensitivity for breast pathology (Lister et al 1998). High-resolution ultrasonography can easily distinguish between most solid and cystic lesions, and can differentiate between benign and malignant lesions with a high degree of accuracy (Figure 47.4). It is the technique of choice for further investigation of focal symptomatic breast abnormalities for women under 35 years of age, and is used in conjunction with mammography in those over 35 years of age. Ultrasound is being used increasingly to assess the axilla in women with breast cancer. Those nodes with an abnormal morphology can be accurately sampled by fine needle aspiration.

Figure 47.4 Invasive ductal carcinoma grade II ultrasound. This is the same tumour as shown in Figure 47.3. On the greyscale image, there is an irregular mass of reduced echogenicity which has posterior shadowing. The colour Doppler image shows surround vascularity which has a radial distribution feeding the cancer. Slight overlying skin thickening can be seen on the greyscale image.

Elastography ultrasound is a new adjunct to conventional B-mode ultrasound imaging, and uses the differences in tissue deformation to create an image of relative tissue stiffness (Wakeham et al 2006). Objects in the breast of different stiffness will displace different amounts, creating an image of relative stiffness (Svensson and Amiras 2006). Research into elasticity ultrasound has been ongoing for over 20 years, but it is only more recently with advances in computing power that commercial development of the potential clinical applications has become possible. A recent study has shown that benign lesions have a smaller size image on strain ultrasound than B-mode imaging, whilst malignant lesions usually have a larger strain image (Hall et al 2003). Malignant lesions mainly appear as stiff throughout, and strain imaging can reveal lesions that are occult on B-mode imaging, allowing accurate diagnostic biopsy. It may be that knowledge of the typical strain appearances may obviate the need to fine needle aspirate/biopsy certain benign lesions.

Magnetic resonance imaging

MRI of the breast is an important new investigation to evaluate breast cancer. Studies have shown almost 100% sensitivity in detecting invasive breast cancers, although most show poor specificity. Diagnostic breast MRI should be performed with a high field strength (>1.5 tesla) magnet with a dedicated breast radiofrequency coil. Contrast enhancement with gadopenate dimeglumine (Gd-DTPA) is essential in identifying breast cancers and distinguishing malignancies from benign masses. The role of MRI is evolving, and one of its most widely used indications is in preoperative evaluation of known tumours for size, extent of disease, multicentricity and multifocality (especially invasive lobular carcinoma). Few centres offer magnetic-resonance-guided breast biopsy, but most breast lesions over 10 mm seen on MRI can be visualized by ultrasound.

A Memorial Sloan-Kettering Cancer Center study of patients with invasive lobular cancer showed that MRI identified 27% more sites of cancer in the ipsilateral breast. Of these, 42% had DCIS and 58% had an infiltrating cancer (Quan et al 2003). Of the 62 women studied, multifocal cancer was present in 20%, multicentric cancer in 4%, and multifocal and multicentric cancer in 3%. Therefore, approximately one-quarter of additional ipsilateral cancers occur within the same quadrant. A recent multi-institutional study of women recently diagnosed with breast cancer showed that 3.1% had a cancer detected by MRI in an apparently uninvolved contralateral breast (Lehman et al 2007). MRI has been shown to accurately distinguish between scarring and tumour recurrence, provided that the scan is performed more than 18 months after surgery. The value of MRI screening in high-risk patients has been discussed previously. MRI is used to evaluate the integrity of saline and silicone implants (Figure 47.5), to discern extracapsular rupture from intracapsular rupture, and to identify silicone within the breast parenchyma (Holmich et al 2005). It is superior to ultrasonography (Figure 47.6) in detecting implant ruptures in patients with both double and single lumen implants (Di Benedetto et al 2008).

Figure 47.5 Magnetic resonance of ruptured prosthesis. Note the prosthesis lies behind the pectoral muscle (arrow heads). The right prosthesis has ruptured, and the curvilinear shape of the envelope of the prosthesis lying free within the silicone is clearly visible.

Figure 47.6 Leaking silicone breast prosthesis. Extended field of view image of a leaking prosthesis. The blue arrow shows free silicone outside the envelope of the prosthesis. There is increased echogenicity with a comet’s tail of reverberation echogenicity deep to it. In the axilla, free silicone is demonstrated by the white arrow; again, there is increased echogenicity with a comet’s tail of reverberation deep to it.

Positron emission tomography

Most breast malignancies have greater metabolism and concentrate 18F-fluorodeoxyglucose (FDG), the agent most frequently used in clinical PET. PET and PET/CT the latter of which combines anatomical and physiological imaging are increasingly used in oncology (Figure 47.7). However, it is widely agreed that FDG-PET does not have a role in the detection of primary breast cancer.

Figure 47.7 Positron emission tomography (PET)/computed tomography (CT) of breast carcinoma liver metastases. The whole-body PET image shows the extent of metastatic disease because of increased metabolic activity in the metastases demonstrated by the uptake of fluorodeoxyglucose, labelled with fluorine-18 (a positron emitter). The fused PET/CT images show the exact anatomical location of the metastases in mediastinal nodes, liver and left ilium adjacent to the anterior part of the sacroiliac joint. The colour denotes the increased metabolic activity which can be measured. The standard uptake value allows changes in metabolism to be detected, enabling assessment of whether or not metastases are responding to chemotherapy regimes before anatomical change occurs.

FDG-PET and FDG-PET/CT can improve staging by detecting otherwise occult disease, particularly in the locoregional and mediastinal nodal basins (Eubank et al 2004, Eubank and Mankoff 2005). Eubank et al showed that FDG-PET detected more widespread disease changes, affecting treatment in up to 44% of patients thought to have locoregional recurrence. Skeletal metastases account for 90% of all metastatic lesions, as well as being the most common site of initial metastatic involvement. A number of studies have shown that FDG-PET is superior to bone scintigraphy in detecting intramedullary and lytic lesions, but often fails to demonstrate blastic lesions, which are readily detected by bone scintigraphy (Cook et al 1998, Moon et al 1998, Kim et al 2001, Even-Sapir et al 2004, Isasi et al 2005, Nakai et al 2005, Tatsumi et al 2006).

Recently, a study of FDG-PET/CT evaluating asymptomatic breast cancer patients with rising tumour markers demonstrated 90% sensitivity for diagnosing recurrent tumour, affecting the clinical management in 51% of patients (Radan et al 2006). A number of studies have demonstrated the accuracy of FDG-PET in depicting response to treatment (Wahl et al 1993, Schelling et al 2000, Smith et al 2000, Chen et al 2004, Mankoff and Eubank 2006, Rousseau et al 2006). More recently, a decline in FDG uptake of more than 50% indicated a good response to treatment in the metastatic setting (Gennari et al 2000). One study demonstrated a change in FDG uptake after one cycle of chemotherapy, and an absence of FDG uptake following completion of treatment predicted a better survival than in those patients with residual FDG-positive disease (Cachin et al 2006).

Fine needle aspiration cytology

Fine needle aspiration cytology (FNAC) of breast lumps is an important part of the triple assessment of the palpable breast lump. FNAC of breast masses has been shown to be a simple and safe diagnostic procedure. However, diagnostic failure of aspiration cytology has been attributed to a high unsatisfactory aspirate rate. This may be due to either insufficient epithelial cells present, equivocal smears or unrepresentative aspirates resulting in false-negative diagnoses. However, some patients find FNAC painful; it can be associated with haematoma formation; and, if performed before mammography or ultrasound, it can make radiological assessment of the breast more difficult.

Needle core biopsy

Automated core biopsy (14 G, 22 mm) provides significantly better sensitivity, specificity and positive predictive value than FNAC (Teh et al 1998, Britton 1999, Britton and McCann 1999, Vargas et al 2000). Most units in the NHSBSP now perform automated core biopsy as the primary diagnostic tool. Ultrasound provides real-time visualization of the biopsy procedure, and confirmation of sampling. Between 80% and 90% of breast abnormalities can be visualized on ultrasound, with the rest being performed under stereotactic X-ray guidance. Needle core biopsy is highly accurate in determining the nature of most breast lesions, and women with benign lesions can avoid unnecessary surgery. For those with breast cancer, needle biopsy provides an accurate diagnosis enabling physicians to make informed management decisions. Needle biopsy provides histology and tumour grade. A non-operative diagnosis should be possible in more than 90% of invasive cancers and 85% of non-invasive cancers.

Some lesions only visible on MRI may require MRI guidance for biopsy. The likelihood that a clinically palpable lesion which cannot be visualized on mammography and ultrasonography is malignant is less than 1%. In these circumstances, it is important to carry out a freehand biopsy to exclude the possibility of a diffuse malignant mass such as lobular carcinoma. The number of core specimens obtained should reflect the nature of the abnormality being sampled. For a suspicion of a carcinoma, it is recommended that at least two core specimens should be taken. For a stereotactic biopsy, a minimum of five core biopsies should be taken. In the event of a sampling error, either a repeat biopsy or an open excision biopsy can be performed.

Vacuum-assisted mammotome

When there is diagnostic uncertainty, 8 G vacuum-assisted mammotome can be used to obtain larger tissue volumes (approximately 300 mg/core) (Heywang-Kobrunner et al 1998, Brem et al 2001, Parker et al 2001). This is very successful for improving the diagnostic accuracy of borderline breast lesions and at sites where it is difficult to biopsy using other techniques. Indications for use include: small mass lesions, architectural distortions, failed needle biopsy, small clusters of microcalcifications, excision of small benign lesions and diffuse non-specific lesions. Two other types of vacuum-assisted core biopsy systems include minimally invasive breast biopsy and automated tissue excision and collection (an MRI-guided vacuum-assisted breast biopsy system).

Advanced breast biopsy instrumentation

Advanced breast biopsy instrumentation (ABBI) is used for surgical stereotactic biopsy of non-palpable breast lesions under radiographic guidance. This biopsy was developed for both diagnosis and therapy. ABBI requires an incision of 5–20 mm, is restricted to use on a prone table and requires the insertion of a localizing T-wire. This vacuum-assisted biopsy obtains a large cylinder of tissue from the subcutaneous tissue down to and beyond the lesion with an electrocautery snare. ABBI removes a larger volume of tissue, theoretically increasing the diagnostic accuracy of the biopsy. Failure rates of up to 31.5% have been reported due to poor patient selection, technical problems with the T bar and failure to remove tissue. Complication rates of ABBI procedures requiring intervention are significantly higher than those of core biopsy (1.1% and 0.2%, respectively). Complete removal of small lesions does occur and positive margins of 19–100% have been reported (Leibman et al 1999, Matthews and Williams 1999). ABBI is more expensive than any other percutaneous needle biopsy technique.

Open surgical biopsy

Diagnostic excision biopsy is now uncommon but is still required for definitive histology of some breast lesions graded B3/4 or C3/4. To minimize patient anxiety, an operation for diagnostic purposes should be performed within 2 weeks of the decision to operate. For patients having surgical removal of a proven benign lesion in the National Health Service (UK), an 18-week waiting time applies. Any benign diagnostic resection specimen weighing more than 40 g should be discussed at the postoperative MDT meeting and any mitigating reasons should be recorded.

Surgery

The axilla

Management of the axilla is a subject of great debate. Surgical treatment of the axilla is two-fold, firstly in disease control and secondly in staging. Surgical staging of the axilla is by axillary lymph node dissection (ALND) for the majority of women, with data regarding nodal status being the most powerful variable in the prognosis for primary breast cancer. Disease-free interval and overall survival are directly related to the number of axillary nodes that contain metastases (Fisher et al 1984, Carter et al 1989). ALND provides the most accurate qualitative and quantitative assessment of the axilla, with the probability of lymph node involvement related to the size of the primary tumour. In small tumours with a size of approximately 10 mm, the risk of nodal metastases is 10% (Baxter et al 1996, Kollias et al 1999). Recurrence rates of 3–5% at 5 years have been reported following ALND, and it has been suggested that the axillary node recurrence rate should be less than 5% with a target of less than 3% (Fowble et al 1989, Siegel et al 1990, Halverson et al 1993, Forrest et al 1995).

Routine histological examination of dissected axillary lymph nodes may be inadequate in identifying the presence of small metastatic tumour deposits or ‘micrometastases’. This has been described as a small cluster of cells measuring 0.2–2 mm. Studies have shown that it is possible to identify micrometastases in 50% of ‘negative’ lymph node cases using serial axillary sections, immunohistochemistry and polymerase chain reaction to detect mRNA transcripts (Trojani et al 1987, Hainsworth et al 1993, Mann et al 2000). Recent studies have shown that cases initially deemed to be ‘node negative’ but subsequently shown to have micrometastases are associated with a worse outcome (Huvos et al 1971, Fisher et al 1978, Rosen et al 1981, Friedman et al 1988, Anonymous 1990, Clayton and Hopkins 1993, McGuckin et al 1996, Dowlatshahi et al 1997).

Significant morbidity is associated with axillary dissection, including seroma, wound infection, reduced shoulder mobility, motor nerve damage (median pectoral nerve, long thoracic nerve of Bell, thoracodorsal nerve), numbness and paraesthesia (80%), and lymphoedema (Siegel et al 1990, Shaw and Rumball 1990, Hladiuk et al 1992, Lin et al 1993). Lymphoedema incidence has been reported to be between 10% and 25%, with hypertension and BMI being risk factors. A 40% incidence of lymphoedema has been reported in those patients undergoing ALND and radiotherapy to the axilla.

Cabanas first proposed the concept of SNB for penile cancer in 1977, followed by Morton for melanoma in 1992 (Cabanas 1977, Cochran et al 1992, Morton 1997). Krag et al first published the use of SNB in breast cancer in 1993 (Krag et al 1993). SNB is based on the knowledge that for any given tumour-bearing site, there is orderly progression of lymph drainage to a draining lymph node (sentinel node). It relies on the premise that skip metastases do not occur, and that the absence of tumour of the sentinel lymph node implies that the entire lymphatic bed is clear of metastatic disease. The aim of SNB is to provide accurate axillary staging by use of a minimally invasive surgical procedure and significantly reduced morbidity. The sentinel lymph nodes are identified using a radioisotope (Figures 47.8 and 47.9), injected on the day of surgery, and a coloured patent blue dye injected peritumorally or interdermally in the peri- and subareolar region 5–10 min before surgery with the breast gently massaged; this leads to an identification rate of 97% (Albertini et al 1996, Veronesi et al 1997, Cody 1999). Intraoperative identification of the sentinel lymph node is confirmed by a hand-held gamma probe, and visually by blue staining of the node. Risk factors of the procedure include allergic and anaphylactic reactions to the blue dye (Mullan et al 2001). Exposure to clinical staff from the radioisotope is negligible.

Figure 47.8 Axillary sentinel lymph node dynamic study. Images taken at 1-min intervals showing initial drainage through the draining lymphatic and filling of the (A) sentinel node with uptake into the second-order nodes (B) on subsequent images.

Figure 47.9 Axillary sentinel lymph node. Anterior view of breast sentinel lymph node imaging. A, periareolar injection site where technetium-99m radiolabelled macroaggregated albumin has been injected; B, draining lymphatic; C, sentinel lymph node at level 1; D, two second-order lymph nodes which have filled after the sentinel lymph node and lie at level 2. There is a radioactive flood source behind the patient to outline the anatomy. The white arrows point to the left mediastinal and cardiac border.

One disadvantage of SNB is that women with a positive sentinel node will require a second operation to clear the axilla. Intraoperative frozen section and imprint cytology have been used to assess the status of the sentinel nodes; however, neither procedure has proved acceptable. A small trial evaluating intraoperative reverse-transcriptase polymerase chain reaction (assay time 20–30 min) for epithelial markers mammaglobin and cytokeratin 19 has shown sensitivity of 96%, specificity of 100% and a positive predictive value of 100% for sentinel node detection (Cutress et al 2008). In most studies, the number of sentinel lymph nodes identified ranged from 1.5 to 4.0, and recent studies have shown that, in a small number of cases, the sentinel lymph node was beyond the first two lymph nodes removed (McCarter et al 2001, Zervos et al 2001, Kennedy et al 2003). McCarter et al claimed that at least three nodes are required to identify 99% of node-positive patients, and the false-negative rate is significantly higher (16.5%) when only one lymph node is removed (McCarter et al 2001). Goyal has shown that 99.6% of metastases from node-positive tumours are found within the first four nodes, suggesting that between two and four nodes should be removed for optimum staging of the axilla (Goyal et al 2005).

Multifocality and multicentricity, once thought to be a relative contraindication to SNB, now appears to be feasible and accurate with an acceptably low false-negative rate, and can be used in patients presenting with a clinically negative axilla (Kumar et al 2003, Goyal et al 2004). Currently, there are no randomized controlled trials addressing the feasibility, accuracy or timing of SNB in neoadjuvant chemotherapy. A meta-analysis assessing the reliability of SNB in patients following neoadjuvant chemotherapy reported sensitivity of 88% (Xing et al 2006). Some centres advocate SNB at diagnosis, prior to initiation of neoadjuvant chemotherapy.

The increase in BCS for early breast cancer has resulted in a 10-year risk of ipsilateral recurrent breast cancer of 10–20% (Fisher et al 1989a, van Dongen et al 2000). This has resulted in an increasing population with ipsilateral tumour recurrence with prior axillary surgery, who were traditionally treated with salvage mastectomy and axillary node dissection. However, emerging data indicate that there may be a role for SNB in identifying aberrant lymphatic drainage patterns in recurrent breast cancer (Intra et al 2005, Roumen et al 2006, Taback et al 2006). The incidence of axillary disease in patients with DCIS (6–9%) is greater in a subset of patients with microinvasion, younger patients, DCIS (>4 cm) and those with high-grade disease (Silverstein et al 1991, Cox et al 2000, Pendas et al 2000, Leonard and Swain 2004, Yen et al 2005). Current guidelines from the American Society of Clinical Oncology (ASCO) only recommend SNB in those patients undergoing mastectomy for DCIS, as an incidental invasive component is seen in 20% of these patients (Meyer et al 1999, Lyman et al 2005).

Internal mammary nodes (IMN) have been shown to have prognostic significance (Lacour et al 1983). IMN have been successfully biopsied in 60–85% of cases, with a prevalence of metastases in 5–27% of cases, resulting in upstaging and/or a change in management in 2–8% of patients. Whilst not standard practice, sentinel biopsy of IMN requires further investigation to determine efficacy and safety.

SNB is a new procedure, so long-term follow-up for axillary recurrence will be the ultimate measurement of its success. To date, the rate of axillary recurrence is lower than anticipated given the average false-negative rate of 5–6%. Non-operative staging of the axilla remains elusive. Clinical examination is unreliable, with sensitivity varying from 30% to 75% and specificity approaching 50%. Ultrasound in combination with FNAC can identify 40–45% of patients with involved nodes. PET has shown some promising early results, with sensitivity of 75% and specificity of 90%. Some Italian centres are using PET to assess the need for SNB in low-risk, clinically node-negative patients with a low probability of nodal involvement (Greco et al 2001).

Radiotherapy/radiation therapy

Tamoxifen

Tamoxifen, a non-steroidal antioestrogen, is currently the most common form of endocrine therapy for women with ERα-positive breast cancer. Tamoxifen is a selective estrogen receptor modulator (SERM) which has partial agonist activity in some tissues, including bone, lipids and endometrium, but antagonist activity in breast tissue. The antitumour effect of tamoxifen is mediated via competitive inhibition of oestrogen binding to ERs. In women with ERα-positive breast cancer, 5 years of tamoxifen results in a 41% relative risk reduction of recurrence and a 34% relative risk reduction of death (Anonymous 2005). The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial and the Scottish Adjuvant Tamoxifen trial demonstrated no benefit in taking tamoxifen for more than 5 years; in contrast, the Eastern Cooperative Oncology Group (ECOG) trial studying indefinite tamoxifen therapy in node-positive patients showed a statistically significant improvement in disease-free survival with extended tamoxifen (Tormey et al 1996, Fisher et al 2001, Stewart et al 2001). The adjuvant Tamoxifen Treatment — Offer More? (ATTOM) and Adjuvant Tamoxifen — Longer against Shorter (ATLAS) trials examining the efficacy of long-term tamoxifen had consistent findings, reporting increased disease-free survival but no overall survival advantage for long-term tamoxifen.

Tamoxifen is generally well tolerated, with the most common side-effects being hot flushes (50% of women), vaginal discharge and irregular menses (Fisher et al 1989b, 1996, Love et al 1991). These side-effects occur more often in pre-/perimenopausal women. The most important side-effect of tamoxifen is an increased risk of endometrial cancer, which equates to 80 extra cases per 10,000 women treated with tamoxifen at 10 years. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) analysing data from 37,000 women demonstrated a two-fold increase in endometrial cancer in women taking tamoxifen for 1–2 years and a four-fold increase in those taking it for 5 years (Anonymous 1998b). Tamoxifen is also associated with an increase in endometrial polyps, ovarian cysts and endometrial hyperplasia (Kedar et al 1994). The overall reduction of risk in developing breast cancer outweighs the risk of developing endometrial cancer. In postmenopausal women, tamoxifen increases bone mineral density of the axial skeleton; however, in premenopausal women, there may be a decrease in bone density (Love et al 1992, Kristensen et al 1994, Powles et al 1996). Tamoxifen has been shown to reduce total cholesterol and low-density lipoproteins, which explains the reduction in cardiovascular deaths in those taking tamoxifen (Rutqvist and Mattsson 1993, Costantino et al 1997).

Aromatase inhibitors

Aromatase inhibitors (AIs) significantly reduce oestrogen production in postmenopausal women by inhibiting aromatase, a cytochrome P-450 enzyme found in adipose tissue, liver, muscle, the brain and breast cancer tissue (Miller 2003b). In premenopausal women, AIs are ineffective as they produce an increase in gonadotrophin secretion, which results in reduced feedback of oestrogen on the pituitary and hypothalamus. AIs present an alternative to tamoxifen for antagonizing oestrogenic effects on the breast in postmenopausal women. In the 1990s, third-generation AIs were developed which included two subgroups: a steroidal analogue exemethstane, which binds irreversibly to aromatase and is an enzyme inactivator (type 1 inhibitor); and non-steroidal inhibitors that bind reversibly to the haem group of the enzyme (type 2 inhibitor), of which the main agents are anastrozole and letrozole.

Two randomized trials compared initial adjuvant therapy with tamoxifen with an AI. The Arimidex, Tamoxifen Alone or Combination (ATAC) trial showed a significantly improved disease-free survival, time to recurrence and incidence of contralateral breast cancer for arimidex compared with tamoxifen (median follow-up 68 months) (Baum et al 2002, 2003, Howell et al 2005). There were significantly fewer disease recurrences in the arimidex group, but no difference was seen in overall survival. Similar results were seen in the Breast International Group (BIG) 1-98 study comparing letrozole with tamoxifen upfront (Thurlimann et al 2005). In both the ATAC and BIG 1-98 studies, more fractures, fewer thromboembolic events and fewer endometrial cancers were seen in those taking an AI compared with tamoxifen.

A number of trials have looked at sequential endocrine treatment (tamoxifen → AI) including Arimidex, Tamoxifem Alone or together (ATAC), Mayo Clinic-17 (MA-17), the Intergroup Exemethstane Study (IES), Arimidex-Nolvadex-95 (ARNO-95) and Austrian Breast and Colorectal Cancer Study Group (ABCSG) (Goss et al 2003, 2005, Coombes et al 2004, Boccardo et al 2005, Howell et al 2005, Jakesz et al 2005). The IES showed a 24% improvement in disease-free survival in women taking tamoxifen for 2–3 years followed by exemethstane compared with 5 years of tamoxifen (Coombes et al 2004). This trial demonstrated an improvement in overall survival in the sequential group, which was significant in the node-positive patients. These trials clearly demonstrate an improvement in disease-free survival, and ASCO advises that AIs should be part of the adjuvant treatment of early-stage breast cancer in postmenopausal women.

AIs have a different side-effect profile compared with tamoxifen; these include hot flushes, vaginal dryness, musculoskeletal pain and headache. AIs are not associated with an increase in thromboembolic disease or endometrial carcinoma, but are associated with an increase in bone fractures and osteoporosis (BIG 1-98 and ATAC trials). Bone monitoring, using dual energy X-ray absorptiometry scanning, should be available for patients taking AIs. All women that start an AI should be advised about calcium and vitamin D supplementation, smoking cessation and the importance of exercise (Hillner et al 2003). It is advised that bone mineral density should be obtained at baseline and monitored annually for all women taking an AI. The Zometa/Femara Adjuvant Synergy trial suggests that treatment with a bisphosphonate at initiation of an AI may prevent a decline in bone health (Brufsky et al 2005).

Faslodex (Fulvestrant or ICI 182,780)

Faslodex is a pure steroidal antioestrogen that binds with 100 times greater affinity to ERs than tamoxifen (Wakeling and Bowler 1992, Rajah et al 1996). It is licensed for use in postmenopausal women with hormone-receptor-positive advanced breast cancer failing on prior antioestrogen therapy. It has a distinct mechanism of action, differing from that of tamoxifen or the AIs, which may help to delay the development of resistance.

Ovarian ablation

There are many methods for suppressing ovarian function in premenopausal women, including surgical oophorectomy, radiation-induced ovarian ablation and gonadotrophin-releasing hormone (GnRH) agonists. GnRH agonists are increasingly being used to achieve ovarian suppression. They overstimulate and subsequently downregulate GnRH receptors. Their effect is to produce an initial rise in luteinizing hormone and follicle-stimulating hormone in the first 7–10 days of treatment, followed by a decrease after 14–21 days that leads to postmenopausal oestrogen and progesterone levels (Williams et al 1986, Cockshott 2000). After 7.3 years of follow-up, the Zoladex Early Breast Cancer Research Association (ZEBRA), randomizing 1640 lymph node-negative, premenopausal ER-positive women, demonstrated no difference in disease-free survival, overall survival or quality of life between the GnRH agonist goserelin (Zoladex) and cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy (Jonat et al 2002, Kaufmann et al 2003). A number of trials are investigating the role of GnRH agonists in adjuvant treatment of premenopausal, early-stage breast cancer — Suppression of Ovarian Function Trial (SOFT), Tamoxifen and Exemethstane Trial (TEXT), and the Premenopausal Endocrine Responsive Chemotherapy (PERCHE) trial.

Raloxifene

Raloxifene, initially studied as an osteoporotic drug, is a second-generation SERM that has oestrogen antagonist properties on the breast and endometrium, and oestrogenic effects on lipid metabolism, bone and blood clotting. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial confirmed a significant reduction in vertebral fractures in patients taking raloxifene, and as a secondary outcome reduced the incidence of breast cancer in ER-positive patients by 90% but had no effect on ERα-negative patients (Cummings et al 2002). The prospective, randomized controlled Study of Tamoxifen and Raloxifene (STAR) showed no significant difference in the incidence of invasive breast cancer in either group after 3.2 years; however, fewer uterine cancers were reported in the raloxifene group (not statistically significant) (Vogel 2009).

Targeting the epidermal growth factor receptor

The human EGFR-2 (HER-2)/neu (c-erbB-2) gene is localized to chromosome 17q and encodes a family of four transmembrane tyrosine kinase receptor proteins which are members of the EGFR or HER family (Ross et al 2003). These receptor tyrosine kinases provide a binding site for various ligands or proteins, which in turn activate downstream signalling pathways which are essential for cell proliferation and survival. Overexpression of the HER-2 protein occurs in 20–25% of breast cancers and is associated with a worse prognosis (disease-free survival and overall survival) (King et al 1985a, Slamon et al 1987, 1989). The most commonly used test for determining HER-2 protein overexpression is an immunohistochemical (IHC) assay scored from 0 to +3, with 0/+1 representing negative, +2 weakly positive and +3 positive. HER-2 can be measured quantitatively by fluorescence in-situ hybridization (FISH), which provides a direct measure of gene amplification (Perez et al 2002, Hicks and Tubbs 2005). FISH is currently the gold standard for evaluating HER-2 overexpression, and provides the best correlation with clinical response to trastuzumab. IHC3+ correlates well with FISH positivity, but only 20–24% of IHC2+ tumours are also FISH positive (Owens et al 2004).

A new method, chromogenic in-situ hybridization (CISH), has been approved by the US Food and Drug Administration for determining HER-2 status, as an alternative to FISH. CISH has several advantages over FISH in that it produces cheaper and permanent staining, allowing samples to be archived indefinitely (FISH signals are labile and fade over time). CISH is based on bright field microscopy and does not require an expensive fluorescence microscope with multiband pass filters. It allows concurrent analysis of morphological features of the tumours/cells and gene copy numbers, making the identification of components of interest easier. Tumour heterogeneity can be readily identified at low magnification (Tanner et al 2000, Zhao et al 2002, Arnould et al 2003).

Trastuzumab (Herceptin), a monoclonal antibody that targets HER-2, achieves tumour regression in some patients with HER-2-positive metastatic breast cancer (mBC). Patients with mBC taking trastuzumab in combination with chemotherapy have a longer time to progression (7.4 vs 4.6 months), a higher objective response rate (50% vs 32%), and a longer survival (25.2% vs 20.3%) than chemotherapy alone (Slamon et al 2001). A number of trials have been conducted investigating the role of trastuzumab in the adjuvant setting for HER-2-positive breast cancer. The Herceptin Adjuvant (HERA) trial compared 1–2 years of adjuvant trastuzumab with observation in HER-2-positive women who had completed adjuvant or neoadjuvant chemotherapy, surgery and/or radiotherapy (Piccart-Gebhart et al 2005). Analysis revealed a significant improvement in disease-free survival and overall survival in those taking trastuzumab, and this has become the standard of care for patients with HER-2-positive breast cancer.

Clinical benefit and response rates depend on the intensity of HER-2 overexpression (2+ or 3+), with response rates of 35% seen in grade 3+ but only minimal benefit seen in grade 2+ (Vogel et al 2002). Trastuzumab is well tolerated with side-effects including hypersensitivity and cardiotoxicity; the incidence of class III/IV congestive heart failure ranges from 0.4% to 3.8% (Adamo et al 2007, Anonymous 2008, Perez 2008).

Pertuzumab is a monoclonal antibody that prevents the formation of heterodimers between HER-2 and other members of the HER family (Nahta et al 2004). Pertuzumab localizes to a different domain of the HER-2 protein than trastuzumab. A synergistic interaction between pertuzumab and trastuzumab is being explored.

Dual tyrosine kinase inhibition

Lapatinib is an orally active dual erbB-1/2 tyrosine kinase inhibitor that blocks signalling of both epidermal growth factor (EGFR/erbB-1) and HER-2/neu (erbB-2). Lapatinib binds reversibly to the cytoplasmic ATP-binding site of the kinase and blocks receptor phosphorylation and activation, thereby preventing subsequent downstream signalling events, namely simultaneous activation of extracellular signal-related kinase-1/2 and phosphatidylinositol 3-kinase/Akt.

Lapatinib is active in refractory mBC patients and as a first-line metastatic treatment, with potential benefit in patients with brain metastases. Efficacy of lapatinib has been demonstrated in combination with capecitabine in patients with refractory erbB-2-overexpressing breast cancer (Geyer et al 2006). Lapatinib appears to have either very low or no incidence of cardiotoxicity. The most frequently reported adverse events include nausea, fatigue, itching, rash, diarrhoea, acne and dry skin. There are a number of ongoing phase III trials evaluating the role of lapatinib in the adjuvant setting, including the Tykerb Evaluation After Chemotherapy (TEACH) trial (Moy and Goss 2006).

Targeting the vascular endothelial growth factor pathway

Metastasis of all solid tumours requires angiogenesis (formation of new blood vessels). A number of agents have been developed that target the vascular endothelial growth factor (VEGF) pathway. Breast cancers that overexpress VEGF have a worse disease-free survival and overall survival. Bevacizumab (Avastin) is a human monoclonal antibody that recognizes all isoforms of VEGF-A. In the metastatic setting, bevacizumab has been shown to significantly increase response rates and progression-free survival when given in combination with paclitaxel (E2100 and Avastin and Docetaxel (AVADO) trials) (Miller 2003a, Miles et al 2008, Baar et al 2009). The Ribbon 1 and Ribbon 2 studies are currently investigating the combination of bevacizumab with a number of standard chemotherapy regimens for mBC.

Other targeted therapies

Other targeted therapies currently being evaluated include sunitinib (SU11248), an oral tyrosine kinase inhibitor which blocks a number of signalling pathways including VEGF receptor, platelet-derived growth factor receptor, kit and flt-3 (Miller and Burstein 2005). Rapamycin is an antibiotic that has demonstrated antitumour activity through cell cycle arrest resulting from inhibition of mammalian target of rapamycin (mTOR). Temsirolismus (CCI-779), an mTOR inhibitor, inhibited the proliferation of breast cancer cell lines in preclinical studies but has not entered routine clinical use (Yu et al 2001, Campbell et al 2004). Overexpression of insulin-like growth factor-1 receptor (IGF-1R) is associated with a poor prognosis and resistance to a number of therapies, including hormonal therapy and trastuzumab (Nahta et al 2005). A number of therapies are targeting IGF-1R, including the small molecule tyrosine kinase inhibitor (BMS-536924; Bristol-Myers Squibb) and monoclonal antibodies (CP-751,871; Pfizer).

Neoadjuvant endocrine therapy

The use of primary tamoxifen in older women as an alternative to surgery has demonstrated short-term tumour regression but unsatisfactory long-term local control (Cheung et al 2000). Higher response rates have been seen in older women treated with neoadjuvant anastrozole, letrozole and exemethstane compared with tamoxifen. Letrozole is currently the only AI licensed for use in the neoadjuvant setting.

Neoadjuvant chemotherapy

Neoadjuvant chemotherapy has significant activity in early breast cancer, with overall objective response rates of 70–90%, which is higher than response rates seen in patients with metastatic disease. Complete remission rates of approximately 20% are seen in patients receiving neoadjuvant chemotherapy (Smith and Lipton 2001).

Gene expression signatures as predictors of recurrence

In the top-down approach, a gene expression signature is derived by seeking profiles that are correlated with clinical outcome without a previous biological assumption (Loi et al 2005).

Gene expression signatures as predictors for drug sensitivity

Some gene signatures have been developed to identify patients who are sensitive to specific therapies; this is known as ‘pharmacogenomics’. Markers predicting treatment response could ultimately lead to individualization of adjuvant therapy.

Gene signatures clearly represent a major step forward in the molecular prediction of drug sensitivity and patient outcomes. Trials such as MINDACT and TAILORx are still required to prove that clinical benefit can be derived from this new technology. This shift in emphasis towards molecular profiling represents a significant revolution in the management of breast cancer patients. It is likely that gene expression profiles will become part of an integrated decision-making model, but for the time being, the treatment guidelines of theNational Comprehensive Cancer Network, National Institutes of Health and St Gallen will continue to be used.

Chemotherapy in metastatic breast cancer

Studies have shown that 24–30% of women with node-negative breast cancer and 50–60% of those with node-positive disease at diagnosis will relapse (Honig 1996). Approximately 6–10% of patients will present with de-novo metastatic disease at diagnosis (Honig 1996, Cardoso et al 2002). The median survival for women presenting with de-novo mBC is 2–4 years, although an increased survival is seen in a small percentage of patients (Falkson et al 1995, Greenberg et al 1996, Honig 1996). Despite the many new options for the treatment of mBC, mortality rates have only shown a small decline from 1930 to 1998 (1.6% annually from 1989 to 1995, and 3.4% more recently) (Jemal et al 2002).

The chemotherapy regimen selected will depend on previous adjuvant therapies received, and is chosen not just on the basis of efficacy, but also with the aim of minimizing toxicity. Anthracycline-based chemotherapy is well established as the first-line option for women with mBC, when this has not been used previously in the adjuvant setting. Both paclitaxel and docetaxel have been evaluated in mBC after anthracycline use. Recent meta-analysis has shown a significantly increased overall survival, time to progression and response rates in taxane-containing chemotherapy regimens compared with non-taxane-containing regimens. Combination of the orally bioavailable prodrug capecitabine with docetaxel has shown greater response rates, time to disease progression and overall survival compared with docetaxel alone. Other agents include the semisynthetic vinca alkaloid vinorelbine, gemcitabine and the platinum salts cisplatin and carboplatin. There has been some evidence to suggest that sequential single agents may be equally effective in terms of survival, with reduced toxicity compared with combination chemotherapy. There appears to be little survival benefit in giving chemotherapy for more than 6 months. There is an underlying assumption that improvements in overall response rates translate into long-term survival benefit (Greenberg et al 1996, Fossati et al 1998, Pierga et al 2001, Bruzzi et al 2005).

Trastuzumab in metastatic breast cancer

Trastuzumab is effective in those women with mBC overexpressing HER-2 (only IHC3+ or FISH-positive patients benefit). Slamon et al (2001) were the first to show that addition of trastuzumab to chemotherapy in patients with HER-2-positive mBC was associated with a longer time to progression (7.4 months vs 4.6 months), higher response rate (50% vs 32%) and longer survival (25.1 vs 20.3 months). Combining trastuzumab with docetaxel has shown significantly greater response rates (61% vs 36%) and overall survival (24.1% vs 13.2 months) compared with single-agent docetaxel (Marty et al 2005). The duration of treatment with trastuzumab is unknown; however, this is being addressed by a large randomized study.

Other agents used in metastatic breast cancer

Epithilones are macrolide antibiotics isolated from the myxobacterium Sorangium cellulosum, which promote microtubule stabilization via a similar mechanism to that of the taxanes (Bollag et al 1995, Wartmann and Altmann 2002). Epithilones are associated with a lower susceptibility to drug resistance and greater efficacy in taxane-resistant tumours. Recently, the epithilone ixabepilone (Ixempra, Bristol-Myers Squibb) has been approved for use by the US Food and Drug Administration after having shown activity in chemotherapy-sensitive and chemotherapy-resistant tumour models, and synergistic activity with other chemotherapeutic and targeted agents. Randomized trials in patients with bony metastatic disease have shown that bisphosphonates can significantly reduce skeletal-related events, including pathological fractures, spinal cord compression, hypercalcaemia and the need for intervention with radiotherapy by 30–50%. They have also been shown to reduce bony pain, but have not shown any improvement in survival (Paterson et al 1993, van Holten-Verzantvoort et al 1993, Lipton et al 2000, Rosen et al 2001). The dual tyrosine kinase inhibitor lapatinib has shown significant efficacy in refractory metastatic HER-2-positive breast cancer patients (previously treated with trastuzumab) and as a first-line metastatic treatment, with potential benefit in patients with brain metastases.

Risk of chemotherapy-related amenorrhoea and menopause

The risk of chemotherapy-related amenorrhoea depends on the patient’s age, the type of chemotherapeutic agents used and the total dose administered. Older women have a higher incidence of complete ovarian failure and permanent infertility compared with younger women (Minton and Munster 2002, Maltaris et al 2007). This higher incidence is explained by the greater primordial follicle reserve (ovarian reserve) in younger women, which decreases with age. The degree of damage will determine whether the amenorrhoea is permanent or temporary; should no oocytes remain viable, menses may cease altogether and menopause will follow. Menstrual function may resume months or occasionally years after treatment; however, the majority of women who remain amenorrhoeic 1 year after treatment will not regain ovarian function. Assessment of the ovarian reserve in patients treated with chemotherapy includes serum measurements of anti-Müllerian hormone, follicle-stimulating hormone, inhibin B and oestrogen levels (Lutchman Singh et al 2007, van Beek et al 2007). An ultrasound-guided antral follicle count can also be useful for assessing ovarian reserve (Lutchman Singh et al 2007).

Chemotherapy can cause ovarian damage by a number of mechanisms. Dividing cells are vulnerable to most cytotoxic agents; however, alkylating agents such as cyclophosphamide present the greatest potential for ovarian failure among all chemotherapeutic agents (Meirow 1999). Alkylating agents are not cell cycle specific and may affect cells not actively dividing, including the pregranulosa cells of the primordial follicles and oocytes. The higher the cumulative dose of cyclophosamide, the greater the observed incidence of menopause. It has been reported that with the classic CMF regimen, the incidence of amenorrhoea was 61% in women under 40 years of age and 95% in women over 40 years of age (Goldhirsch et al 1990). The regimen of six cycles of FEC induces menopause in 60% of patients (Venturini et al 2005). A prospective cohort study evaluating 595 women aged 25–40 years treated for early breast cancer with a number of different chemotherapy regimens showed that menstrual cycles were more likely to persist in women treated with regimens containing less cumulative cyclophosamide (Petrek et al 2006). Those patients on a CMF regimen were more likely than women on other regimens to bleed within the first month of chemotherapy, but were less likely to commence menses 1 year later. The study also showed that tamoxifen accounted for a 15% decrease in menstrual cycling at 1 and 2 years, regardless of chemotherapy regimen. Most premenopausal women will continue to menstruate whilst taking tamoxifen, although their menses may become irregular. One study has shown no effect of trastuzumab on fertility (Abusief et al 2006).

Strategies to preserve fertility in women with breast cancer

The ASCO and UK National Health Service guidelines recommend that the implications of oncological treatment for fertility should be discussed with patients. If sufficient time exists before a woman is about to start chemotherapy or radiotherapy, she may undergo IVF to cryopreserve embryos or an embryo (Falcone et al 2004, Roberts and Oktay 2005, Agarwal and Chang 2007, West et al 2007). This technique requires a delay in cancer treatment for up to 1 month, which may not be an option for some patients. Cryopreservation remains the most effective approach to preserve fertility; however, post-thaw survival rates of embryos are in the range of 35–90%, and implantation rates are between 8% and 30%. If multiple embryos are available, cumulative pregnancy rates can be more than 60% (Seli and Tangir 2005). Delivery rates per embryo transfer using cryopreserved embryos are in the range of 18–20%. This approach requires IVF and a male partner.

Oocyte banking is more difficult than embryo cryopreservation, as oocyte cooling and exposure to cryopreservation agents affects the cytoskeleton and causes hardening of the zona pellucida. The success is dependent upon the number of eggs harvested (<10 oocytes = very low chance of pregnancy). The overall livebirth rate per preserved oocyte is approximately 3%, which is much lower than that for IVF using fresh oocytes (Gosden 2005). Several studies are evaluating the use of GnRH analogues to preserve ovarian function during cytotoxic treatment. Research in a population of older women of reproductive age has suggested that addition of a GnRH analogue to treatment may increase a woman’s likelihood of remaining premenopausal after chemotherapy; however, the reproductive outcome was poor (Fox et al 2003).

It has been suggested that IVF could accelerate the disease process in women with ERα-positive breast cancer by increasing the oestrogen concentration. In one study of 100 patients, ovarian stimulation with concurrent administration of an AI or tamoxifen demonstrated no increase in recurrence and no effect on the IVF cycle (Oktay et al 2005, Azim et al 2008). Another technique whereby immature oocytes are collected and matured in vitro, avoiding ovarian stimulation, has been used in women with polycystic ovary syndrome (Lee 2007, Reinblatt and Buckett 2008). Oocyte donation is a well-established form of assisted reproduction, with 20% of replaced embryos resulting in a live birth. The harvesting of ovarian tissue is less established; this involves the removal of the ovarian cortex by laparoscopy, which is cryopreserved for later reimplantation. Only small numbers of women have had thawed ovarian tissue reimplanted, and only five live births have resulted to date (Donnez et al 2004, Meirow et al 2005, Demeestere et al 2007, Andersen et al 2008). The incidence of occult ovarian cancer in BRCA1/BRCA2 carriers is low, but the potential for development of ovarian cancer in the transplanted tissue makes it a poor option in this subgroup (Colgan et al 2001).

Oncoplastic techniques

A tumour may be excised within an area normally removed during a mastopexy (breast lift) or reduction, thereby achieving wide local excision of the mass and reconstruction of the breast. Symmetry can be achieved by contralateral breast reduction or mastopexy.

Nipple–areola reconstruction

Some patients are content with a prosthetic nipple, but all should have the opportunity to have a nipple–areola reconstruction. This is often performed 6 months after the reconstruction by a number of techniques including nipple sharing and use of local flaps. These procedures can be performed under local anaesthetic, and the areola is now reconstructed with a dermal tattoo using a three-dimensional colour chart to achieve a good colour match.