State of the Art Oncology in EuropeFont: aaa

Breast cancer (under review)


1.1 Epidemiological data

1.1.1 Incidence

Breast cancer is the most common cancer among women in Europe and the world. It is estimated the around 430 000 new case occur each year in Europe, representing 29% of all malignancies in European women, and 13,5% of all cancers diagnosed (Ferlay 2007). The lifetime probability of a woman to develop breast cancer varies both among and within the different western countries, ranging from 5% to more than 10% (= cumulative incidence of breast cancer from 0 to 74 years, conditional on not dying from other causes). Mean age at diagnosis is between 50 and 60 years. Annual incidence (age-standardised rate, with the world population as standard, per 100.000) varies considerably among European countries; recent data, comprising the countries that joined the European Union lately, report an average of 110 per 100.000 women. The incidence is higher in in western and northern countries (around 120) while lower incidence rates (around 80 per 100.000 women) are found in eastern and southern countries ( Ferlay 2007). The incidence of breast cancer increases dramatically with age, from around 10 cases per 100000 women between 20 and 30 years old, to more than 300 cases per 100000 over the age of 60 (Colditz 1993). The median age at diagnosis is 64 years in U.S.A, while in other regions of the world the median age at which breast cancer develops is 10-15 year younger. Incidence is increasing in all countries since 1960 at a mean rate of 1-2 per cent annually. In Western Europe and North America the observed increase in incidence rates since 1980 may be due, partly, to changes in screening patterns and partly to differences in the distribution of risk factors. The introduction of organized mammography screening has the short term effect to increase the incidence of breast cancer due to diagnosis of preclinical cases.

1.1.2 Mortality

Annual breast cancer-related mortality in Europe in 2006 was on average 25 per 100000 women. With an estimated 131 900 death in 2006, representing 17,6% of all cancer death in women, breast cancer kills more women than any other form of malignant disease. Both sexes combined, breast cancer mortality ranks third, after lung and colorectal cancer. There is variability in the reported mortality rates across Europe, form over 33 per 100000 in Denmark and Belgium to around 20 in Spain and Finland ( Ferlay 2007). Fortunately, a decrease in breast cancer mortality in Western Europe and the US was reported by several studies (Levi 2005; Tyczynski 2004; Peto 2000). This improvement have been linked to the combined effect od earlier detection and improving treatment, but it was only observed in women aged 35-69. Because of the ageing of the European population, the number of death from breast cancer is still rising. Moreover, this declined has not yet been observed in general in Eastern European Countries. A recent study showed that large disparities in changes in incidence and mortality rates probably reflect differences in detection and management of breast cancer (Hery 2008).

1.1.3 Male breast cancer

Breast cancer in males is rare, since it represents < 1% of all breast cancers. Annual incidence is below 1 per 100.000 men. It accounts for less than 1% of the male cancer-related mortality which has been decreasing since the late 1980’s. The mean age of male breast cancer is between 60 and 70 years, 10 years older than female breast cancer ( La Vecchia 1992.

1.1.4 Breast cancer in pregnancy

It represents less than 0.5% of all breast cancers, but 7-14% of breast cancers in childbearing-age women. Around 3 breast cancers per 10.000 pregnancies are observed. More cases are expected because of the trend for pregnancies in older ages (Petrek 1994).

1.1.5 Breast cancer in the very young women

Traditionally, very young women that developed breast cancer had been considered as having a poorer prognosis, due to a disease that is particularly aggressive. Several studies have shown the negative prognostic impact of young age (Aebi 2006a), more recently reassessed in a population-based analysis of patients with stage I breast cancer (Aebi 2006b). Age at diagnosis was a significant predictor for death, evens after adjusting for tumor size, histological grade, estrogen receptor expression, and year of diagnosis. The distinction between young and ‘very young’ premenopausal patients is fuzzy but most investigators who chose to dichotomize their analysis used an age limit of 35–40 years. In general, breast tumor occurring in younger patients are larger, involve regional nodes and tend to be more frequently poorly differentiated, rapidly proliferating, estrogen and progesterone receptor negative tumors.

1.2 Etiologic and risk factors

1.2.1 General data

The geographical variation in breast cancer incidence and mortality and the temporal variation within countries strongly suggest that breast cancer risk is determined to a large extent by environmental and lifestyle factors. In fact, migrant populations reach the incidence rates of lifelong residents after a couple of generations. Many risk factors have been identified for breast cancer. However, most of them are associated with moderate increases in risk ( < 2-fold) and do not explain the temporal and geographical incidence variation in breast cancer incidence. Furthermore, most of them, such as reproductive and menstrual history, are not suitable for prevention.

1.2.2 Minor risk factors
  • Hormone exposure
    Numerous studies suggest a strong link between the female hormone estrogen and the development of breast cancer, with increased and/or prolonged exposure to endogenous estrogens leading to increased risk of breast cancer. Ovarian ablation reduces dramatically the risk of mammary cancers in women and in experimental animals. Early onset of menarche, late onset of menopause, and greater number of years with ovulatory cycles have all been associated with an increased risk of breast cancer ( Henderson 1985). A late age at menarche appears to be associated with a slight protection, with an appproximately 20% RR reduction for each year of delay in menarche (Kelsey 1993). A direct relationship between age at menopause and risk has been consistently observed: for instance, women who had a natural menopause before the age of 45 have half the breast cancer risk than postmenopausal women of the same age, with a natural menopause after the age of 55 (Trichopoulos 1972). Women subjected to early oophorectomy have a reduced breast cancer incidence than menstruating controls. External influences that delay the onset of menses, such as poor nutrition or strenuous physical activity might, therefore, reduce the incidence of breast cancer (Bernstein 1994; Bernstein 1987). For every 5-year difference in age at menopause, the risk for breast cancer increases by about 17%. In postmenopause, exposure to increased levels of estrogens, such as obesity and HRT, determine a slight increase in the risk of breats cancer ( Huang 1997; CGHFBC 1997; Hankinson 1998; Cauley 1999). On the other side, lifetime breast cancer risk decreases with increasing number of livebirths of a woman, with earlier births (Kelsey 1993; Talamini 1996; Colditz 1996) and with lactation (CGHFBC 2002). Nulliparous women have a higher relative risk than parous women of 1.4 (McMahon 1970). However, a pregnancy at any age appears to be followed by a transient increase in risk followed by a prolonged protective effect (Bruzzi 1998; Rosner 1994). The effect of abortion, either spontaneous or induced, with a high initial exposure to estrogen unopposed by the protective effects of hormonal changes of later pregnancy, is uncertain (Melbye 1997; Newcomb 1996). Exogenous exposure to estrogens appears to confer an increased risk of developing breast cancer. HRT is associated with a slight increase in risk of breast cancer that is restricted to current and recent users, with risk proportional to duration of use. HRT for at least five yrears or more determines a RR of approximately 1.3 that of women not taking HRT ( CGHFBC 1997).This effect wears off within 5 years of HRT cessation. Among 1000 women who use HRT continuously for 10 years starting at age 50, it is estimated that there will be an additional six breast cancers raising the incidence from a background of 45 cases to 51 cases. Use of HRT for a few years should not lead to an appreciable risk of breast cancer. Addition of progestins to protect the endometrium can further increase the risk of breast cancer (Ross 2000). The risk appears to be reversible, decresing after cessation of treatment (Gapstur 1999). Tumours arising during HRT appear to have better biologic characteristics than average breast cancers (Panel 1999; Salmon 1999; Gapstur 1999). Contraceptive use of estrogen/progestin replacement before menopause has not consistently shown to alter the basis risk of breast cancer of a given woman (CGHFBC 1996; Hankinson 1997).
  • Diet
    International comparisons and time trends strongly suggest that dietary factors are responsible for the high incidence of breast cancer in western countries and for the increasing incidence in many other countries. However, the results of the many epidemiological studies focused on dietary fat have been, at best, disappointing: they indicate that dietary fat intake in middle life is not related to breast cancer development, although the hypothesis that very low fat intakes may be protective has not been fully tested. It is also possible that fat and energy intake early in life may affect breast cancer risk. However, at the moment, hypotheses relating diet early in life to breast cancer remain exceedingly difficult to test. On the other hand, breast cancer risk after menopause is reported to be slightly increased in obese women (Relative Risk = 1.2 for 1-point increase in Quetelet Index). High intakes of fruit and vegetables and, accordingly, of unsaturated fatty acids and various micronutrients were reported to be associated with a decreased risk of breast cancer, but the results of the various studies were inconsistent. A consistent, association between alcohol consumption and breast cancer has been observed, with RR of 1.3 to 1.4 according to the amount of alchool consumed ( Hamajima 2002).
  • Lifestyle
    Four hours of physical activity per week were associated with reduced risk in two recent case-control studies. Young athletes were reported to have a later age at menarche and hormonal modifications possibly related to a decreased breast cancer risk (Rockhill 1999).Smoking smoking has little or no independent effect on the risk of developing breast cancer (Hamajima 2002).
  • Environmental exposures
    The only firmly established environmental determinant of breast cancer risk is exposure to ionizing radiation. The increase in risk is directly related to the total dose, although the behaviour of the dose-response curve at very low doses is uncertain. The increase in risk is inversely related to age at exposure and lasts for life (i.e. highest for exposures very early in life), with little or no effect for exposures after the age of 40. The age at exposure to environmental risk factors seems to be a crucial factor, since mammary tissue is more susceptible to carcinogenesis at certain periods of breast development. Risk of breast cancer is high (estimated actuarial incidence around 35%) among women treated with radiation for childhood Hodgkin’s disease. Exposure to DDT may be linked to a fourfold increased risk of breast cancer. Studies are ongoing to clarify any cancer risk subsequent to pesticide exposure. Little evidence is available on the association between exposure to electromagnetic fields and breast cancer ( Bhatia 1996; Daudt 1996; Wolff 1996).
1.2.3 Major risk factors

Family history of breast cancer and genetic susceptibility
Genetic contribution to breast cancer risk can be suggested by the increased incidence of breast cancer in women with a family history and by the existance of families with a very high incidence of breast cancer cases. A family history of breast cancer in a 1st or 2nd degree relative is reported by approximately 10-20% of breast cancer cases, as compared to 5-10% of age-matched, general population controls, for a Relative Risk of approximately 2 (Pharoah 1997). If both the mother and a sister have had breast cancer and/or if the cancer in the relative was diagnosed at an early age, the risk is higher (up to relative risk of 5-10) (Pharoah 1997). In most instances of familiar aggregation, a pattern of Mendelian inheritance of a dominant, highly penetrant gene for breast cancer cannot be recognised, and it is conceivable that many of these aggregations are attributable to common exposures to environmental (dietary?) factors or to inheritance of susceptibility to frequent environmental factors. However, in a minority of cases, (about 10% of all cases, and up to 15% of cases diagnosed at a young age), breast cancer shows a pattern of familial transmission resembling that of dominant Mendelian factor with high penetrance ( Newman 1988; Anderson 1993). The presence of a predisposing breast cancer mutation is suspected in the event of several cases of breast cancer in a single family (at least three close relatives), early-onset breast or ovarian cancer, or both, and the presence of multiple epithelial cancers in family members (Kerber 1995). The majority (up to 90%) of these forms are due to mutations in BRCA1 or BRCA2 genes. Other genetic associations have been documented in Li-Fraumeni syndrome (p53 disfunctional mutations), in Cowden syndrome (PTEN mutations), in ataxia-teleangiectasia, in Peutz-jeghers syndrome, in Gorlin syndrome (basal cell nevus), in MEN1 and hereditary non-polyposis colon cancer syndromes. BRCA1 gene is a tumor-suppressor gene on chromosome 17q21 of whom more than 500 alterations have been identified. Estimated BRCA1 frequency in women is 1/800, with a higher frequency among women of Ashkenazi Jewish descent. The risk to develop a breast cancer among BRCA1 carriers is estimated to be around 50% by age 50 and 85% by age 70. Noteworthy, these estimates were obtained from BRCA1 carriers identified in high risk families, and cannot be extrapolated to ‘sporadic’ BRCA1 carriers. In the only study conducted outside high risk families, the cumulative breast cancer risk among carriers of a specific BCRA-1 mutation was estimated to be little more than 50% at 75 years ( Couch 1997; Healy 1997).

BRCA1 carriers may have an excess risk of ovarian, colon and prostate cancer. An increased risk of ovarian cancer is covered in BRCA1 carriers, but not BRCA2 carriers (Kunkler 1999). BRCA2 gene has been localised to chromosome 13q 12-13. BRCA2 abnormalities have been linked to familial male breast cancer (30% of men with breast cancer have a family history of breast cancer). The risk of developing a breast cancer among BRCA2 gene carrier women is estimated to be around 60% by age 60 up to 90% at age 80 (Daudt 1996; FitzGerald 1996; Langston 1996; Lindblom 1995; Peto 1996; Weber 1994). Increased risk of male breast cancer is reported in subjects affected by Klinefelter’s syndrome. Altered BRCA2 is associated with increased incidence of several other malignancies: prostate cancer (estimated relative risk, RR = 4.65), pancreatic cancer (RR = 3.51; 95% CI = 1.87-6.58), gallbladder and bile duct cancer (RR = 4.97; 95% CI = 1.50-16.52), stomach cancer (RR = 2.59; 95%CI = 1.46-4.61), and malignant melanoma (RR = 2.58; 95% CI = 1.28-5.17). The RR for prostate cancer for men below the age of 65 years was 7.33 (95% CI = 4.66-11.52) ( BCLC 1999). Benign breast disease. Benign breast disease is a generic label for a heterogeneous group of affections, including fibrocystic disease, with its innumerable variants, fibroadenoma, and other less common forms. Collectively, these affections are very common in Western women, (autoptic prevalence 60-80%), and most of them are associated with little or no increase in breast cancer risk, as compared to the general population. However, women reporting breast biopsies are at increased breast cancer risk, and the risk appears to be concentrated among women with hyperplasia without atypia (relative Risk=1.5-2) and with severely atypical hyperplasia (relative risk=4-5) (Page 1993). The increased risk involves the whole mammary tissue in both breasts, and it is not limited to the biopsied area. Cell atypia is found in about one quarter of intraductal papillomas. Usually, multiple intraductal papillomas carry a higher risk of breast cancer, while the risk is much lower for solitary central papillomas. Women with palpable cysts have a moderately increased risk (RR=1.5-3), but it has been suggested that, again, the increased risk is associated with dysplastic or atypical changes. Indirect evidence supporting the association between benign breast disease and breast cancer risk comes from the studies of mammographic density, that has been shown to be associated with histologic changes in the breast: women with radiologically dense breasts (or alternatively, with specific mammographic patterns) were consistently found to be at increased risk of subsequent breast cancer, as compared to women with radiologically lucent breasts (RR=2-3) ( Benichou 1996; Dupont 1993). Previous cancer of the breast. Untreated, about one third of patients with low-grade ductal carcinoma in situ appear to develop invasive breast cancer in the same breast during a follow up period of 10 to 18 years. About 15-20% of women with a diagnosis of lobular carcinoma in situ will develop breast cancer in the same breast and 10-15% will develop an invasive cancer in the contralateral breast if left untreated (Page 1995). The risk to develop a contralateral breast cancer after previous invasive breast cancer is 0.5-1 percent per year (relative risk 1.5 to 2). The risk remains constant over 20 years of follow-up (Rosen 1989).

1.3 Screening and case finding

1.3.1 Screening women aged between 50 and 70 years
1.3.2 Screening women aged 40 to 49

The efficacy of screening for women aged 40 to 49 remains controversial. Mortality reduction in women starting screening at age 40 to 49 is considerably smaller (13-23%), and partly may be attributable to the prevention of deaths caused by cancers diagnosed after the age of 49. Data from a recent meta-analysis do not give conclusive results on mortality reduction (Kerlikowske 1995; Smart 1995). Larger studies, longer follow-up time and more aggressive screening (yearly, double-view) are necessary to confirm the effectiveness in this age group, where a 23-30% reduction in death rate might be expected according to recent data (Feig 1995; Smart 1995). Therefore at the moment there is no evidence to support screening of women aged under 50 and screening programs for this age group should still be regarded as investigational.

1.3.3 Genetic testing

High-risk women can be identified by genetic testing for BRCA1 and BRCA2 mutations. Genetic testing for breast cancer susceptibility cannot be recommended for screening outside a research setting, since strategies for patient counselling, psychosocial and legislative support and prevention modalities are still developing. This procedure should still be regarded as investigational (ASCO 1996) and should not be publicised, nor offered to women unaware of their familiar risk.

1.3.4 Case finding

Evidence supporting efficacy of periodic screening mammography in asymptomatic women aged 50-70 years, outside organized screening programs, is less compelling. It is conceivable that, outside formal screening programs, the ratio between the benefits of periodic mammographic examinations and the associated risks and costs becomes less favourable, and strictly correlated with the experience of the radiologist and the associated surgeon, and their adherence to validated protocols of quality assurance and clinical guidelines. Reasons for the possible reduction may include inability to detect small cancer, unjustified reassurance of women, inappropriate diagnostic workup of suspect lesions, and inadequate treatment strategies. Reasons for the possible increase in risks and costs include a high rate of unnecessary biopsies, inappropriate diagnostic workup, overtreatment of benign or malignant lesions with aggressive or mutilating treatments and too short intervals between mammographic examinations. Although randomized trials have included too few women over age 70, a recent case-control study showed a reduction in breast cancer mortality for this age population ( Van Dijck 1996). As a consequence, in a woman aged 50-75 years living in an area where no screening program exists, a mammographic examination every 1 or 2 years, carried out by a radiologist with specific experience is considred suitable for individual clinical use on a type R basis. Double-view yearly mammography in women aged 40-50 years may be considered suitable for individual clinical use on a type R basis (Smart 1995). Periodic mammography, as well as ultrasonographic examinations or non-ionizing imaging examinations (MRI, PET), in asymptomatic women younger than 40 at high risk should only be performed as part of research programmes.

1.4 Prevention

1.4.1 General recommendations

Breast cancer is mainly an environmental disease (different incidence in geographical areas and results of studies on migrant populations) but the weight of the known environmental factors is weak and does not present a significant potential for control. Therefore, no preventive action besides avoidance of unnecessary exposure to radiation, especially at a young age, and weight control after menopause, can be recommended in order to reduce the risk of breast cancer.

1.4.2 Chemoprevention

The National Surgical Adjuvant Breast and Bowel Prevention (NSABP) Trial tested the value of tamoxifen as a preventive agent in women whose risk of breast cancer was equal to that of a 60 year old woman. The trial also enrolled patients with atypical hyperplasia. After a mean follow up of 47.7 months there was an 87% reduction in the risk of invasive cancer in women at risk due to a diagnosis of atypical hyperplasia. The benefits of tamoxifen were observed in all groups of women irrespective of breast cancer risk. No data are available on the group of patients who were gene carriers or those who were at high risk because of family history. Two other studies have failed to confirm the benefit of tamoxifen. These studies did show that toxicity was low for participants on tamoxifen or placebo and compliance was high. There was an excess of hot flushes, vaginal discharge and menstrual irregularities in women taking tamoxifen. At a median follow up of 4.5 years in the NSABP trial, tamoxifen was found to half the risk of breast cancer development ( Fisher 1998; Powles 1998; Veronesi 1998). Its use is at the moment investigational. A phase III trial of fenretinide (4-HPR) has recently been published on the prevention of contralateral breast tumours in patients with previous stage I breast cancer. Its use is at the moment investigational.

1.4.3 Prophylactic mastectomy

Bilateral prophylactic mastectomy with or without immediate breast reconstruction is suitable for individual clinical use on a type R basis (Hartmann 1999) for women at high risk of developing breast cancer, who require it to reduce excessive anxiety or are unable to attend close surveillance. Breast tissue may not be completely removed with subcutaneous or simple mastectomy and the potential of breast cancer following prophylactic mastectomy exists (Bilimoria 1995).

1.5 Referral

It is recommended that women with breast cancer be approached, treated and followed by a multidisciplinary team. This kind of team consists of a radiologist, a pathologist, a surgeon, a radiotherapist, and a medical oncologist. Community-based hospitals may be adequate if they can provide a comprehensive multidisciplinary approach including proper diagnostic and radiotherapeutic facilities (Dixon 1994).


6.1 Preoperative (neoadjuvant) systemic therapies

6.1.1 Preoperative chemotherapy

1. For patients candidated to mastectomy or expected to have unacceptable cosmetic results because of a large primary, pre-operative chemotherapy is suitable for individual clinical use on a type 1 level of evidence with the aim of tumour shrinkage ( Mauri 2005).
2. Although taxane-based regimens have not definitely shown to translate into disease-free or overall survival improvement over anthracycline alone, and toxicity is higher (with a slight excess of toxic deaths), the inclusion of taxanes in a pre-operative chemotherapy regimen is suitable for individual clinical use on a type 2 level of evidence with the purpose of increasing the likelyhood of tumour shrinkage and pathologic complete response.
3. Early response is an independent predictor of pathologic response and of long term survival. Pathologic complete response and nodal status after primary chemotherapy remain strong predictors of outcome, but it is not clear if a modest improvement in pCR necessarily can into significantly improved patient outcome.
4. Duration of preoperative chemotherapy can range from a minimun of 3-4 cycles, up to 6-8 cycles.Patients who achieve a complete clinical and instrumental complete response after at least 4 cycle pf therapy, may not benefit from any further chemotherapy on a type 2 level of evidence and can be treated with surgery at this point (studio B18).
5. For patients responding well to preoperative anthracicline, crossing over to a taxane regimen is suitable for individual clinical use on a type 2 level of evidence with the aim of achieving a higher rate of patlotolocal complete response, although the impact on survival in these responding patients is controversial (Bear 2006; Smith 2002). 6. Lack of response to anthracycline indicates generalized chemotherapy resistance and DFS and OS would not improve with additional cytotoxic chemotherapy on a type 2 level of evidence.
7. Benefit of a late response after switching of treatment is unclear.
8. Gene expression profiles to predict drug sensitivity are still investigational.
9. For postmenopausal patients with hormone receptor positive tumours who wish breast preservation and who are not considered candidates for cytoreductive chemotherapy, pre-operative hormonal treatment is suitable for individual clinical use on a type 2 level of evidence. In this case, aromatase inhibitors can be considered standard treatment on a type 2 level of evidence.
Preoperative systemic chemotherapy

Pre-operative (also called primary or neoadjuvant) systemic chemotherapy with anthracycline based chemotherapy can reduce tumour size, increasing chances of breast sparing surgery in patients with large tumours. No disease-free or overall survival benefit as compare to the same post-operative treatment have been demonstrated so far with anthracycline- and taxane-based preoperative chemotherapy from mature randomized trials. A recent meta-analysis (Mauri 2005) of nine randomized studies, including a total of 3946 patients with breast cancer, comparing neoadjuvant therapy with adjuvant therapy regardless of surgery and/or radiation treatment, found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms associated with overall survival (summary risk ratio [RR] = 1.00, 95% confidence interval [CI] = 0.90 to 1.12), disease progression (summary RR = 0.99, 95% CI = 0.91 to 1.07), or distant disease recurrence (summary RR = 0.94, 95% CI = 0.83 to 1.06). Furthermore, neoadjuvant therapy was statistically significantly associated with an increased risk of loco-regional recurrences (RR = 1.22, 95% CI = 1.04 to 1.43), compared with adjuvant therapy, especially in the case of radiation therapy without surgery after preoperative therapy (RR = 1.53, 95% CI = 1.11 to 2.10). Therefore, preoperative chemotherapy is suitable for individual clinical use with the aim of tumour shrinkage on a type 2 level of evidence for patients candidates for mastectomy or expected to have unacceptable cosmetic results because of a large primary ( Fisher 1998b; van der Hage 2001; Fisher 2002).
Pre-operative sequential use of an anthracycline-containing regimen followed by a taxane-regimen has been shown to significantly increase clinical (approx from 85 to 95%) and pathologic (approx. from 15 to 25-30%) tumour response. However, taxane use has not definitely shown to translate into disease-free or overall survival improvement over anthracycline alone, and toxicity is higher (with a slight excess of toxic deaths). Therefore, inclusion of taxanes in a pre-operative chemotherapy regimen is suitable for individual clinical use on a type 2 level of evidence with the purpose of increasing the likelyhood of tumour shrinkage and pathologic complete response (Bear 2006; Smith 2002).
Pathologic complete response is considered by many to be a surrogate marker for favorable long-term prognosis; infact, in both antracycline- and antracycline- plus taxane- based preoperative regimen patients who achieved pCR had prolonged DFS and OS ( Wolmark 2001; Bear 2006). In B 18 trial, at nine year follow up, patients who achieved pCR had superior DFS and OS (75% and 85%, respectively) compared with patients with residual disease (58% and 73%, respectively).

In B-27 trial pCR was a significant predictor of OS regardless of treatment (HR=0.33, p < 0.0001). Even pathologic complete response in nodes after primary chemotherapy is strongly associated with superior OS (p < 0.0001) compared with positive status (Bear 2006; Hennessy 2005). Therefore, the recommended definition of pCR is that of invasive tumor undetectable in breast and lymph nodes; residual ductal carcinoma in situ is allowed because has same prognosis as pCR without DCIS (Kaufmann 2006).

Predictive factors of chemotherapy sensitivity to neoadjuvant chemotherapy and of clinical and pathological response include: 1) receptor status: pCR is substantially more predictive in ER- than in ER+ disease ( Guarneri 2006; Gianni 2005a) pathology: invasive lobular carcinoma are less likely to achieve a pCR compared with patients with invasive ductal carcinoma (Cristofanilli 2005); 3) HER2 status: pCR is more predictive in HER2 positive disease (Buzdar 2005); 4) Molecular subtype: in basal like tumor and HER2 positive tumor, which results the most sensitive subtypes, can achieve pCR rate of 45% (Rouzier 2005). Failure to obtain pCR in basal like tumors predicts poor outcome. Novel treatment ideas are under investigation (Cleator 2007). Despite pCR is prognostic and predicts for better outcome, there are some limitations for its applications as a prognostic marker: a) not all patients with pCR remain free of recurrence; b) even if pCR is more predictive in ER- disease (CGuarneri 2006) and ER+ patients less likely get pCR, if they do, they have a better outcome than ER- patients. Therefore, some subgroups of ER+ patients may benefit from preoperative chemotherapy too; c) not all patients who do not achieve pCR do poorly ( Cristofanilli 2005). Therefore, pCR as a single surrogate is not adequate to predict outcome in all patients, and better markers are needed.

Duration of treatment and concomitant vs. sequential chemotherapy: duration of treatment can range from a minimun of 3-4 cycles, up to 6-8 cycles for patients who are expected to derive further benefit (i.e. further tumour shrinkage) from treatment continuation. Overall, longer administration of a concomitant regimen led to an improved rate of clinical and histological response: 6 cycles of antracycline/taxane chemotherapy led better pCR rate than 4 cycles (24% vs 17%) (Romieu 2002). Sequential strategies with non cross-resistent regimen are better than concomitant treatment for early responders; therefore early response is an independent predictor of pathologic response and can be used to select patients who may benefit from a sequential treatment (Smith 2002). In the Aberdeen Trial, patients responding after 4 cycles of neoadjuvant chemotherapy achieved higher pCR versus non responders (either with further 4 cycles of the same regimenwho or switching to docetaxel. In the Gepartrio Trial, patients responders after 2 cycles of neoadjuvant chemotherapy achieved 20% pCR versus 5% of non responders (p < 0.0001). Early response was also a predictor of long term outcome and of benefit from the addition of docetaxel: in fact, early responders were randomly assigned to receive 4 more cycles either of the same antracyclin regimen or of docetaxel. Adding docetaxel, significatively improved not only pCR rate (34% vs 14%, p=0.04) but also 5 years DFS (90% vs 71%, p=0.03) and OS (93% vs 78%, p=0.04). In non responders, pCR rate after switching therapy, was only 1.8%: this suggests that administering additional chemotherapy to anthracicline non responders does not substantially improve outcome ( Smith 2002).

In the larger Gepartrio Trial after 2 cycles of neoadjuvant anthracycline- and docetaxel-based chemotherapy, responders went on with the same chemotherapy (4-6 more cycles), while non responders where randomized to 4 more cycles of the same treatment versus crossover to a non cross-resistent treatment. Patients with an early clinical CR might not need further treatment intensification: pCR was not statistically higher after further 4 cycles of the same chemotherapy (21%, with additional pCR rate of only 7-9%). Patients with an early incomplete clinical PR, might benefit from treatment intensidfication: in the B-27 Trial (Bear 2006) and in the Aberdeen trial (Smith 2002), only patients who achieved initial PR, benefit from adding sequential docetaxel, while in the Gepartrio Trial, 8 cycles were better than 6. In early responders, PR may be due to incomplete chemoresistence (e.g due to ER+). A recent Overview, including seven neoadjuvant trials, ( Mazouni 2007) shows that pCR rates increase after switching to a longer therapy including taxane, both in ER positive and ER negative tumors, meaning that a subset of patients with ER positive tumor benefits from more aggressive chemotherapy, similarly to patients with ER negative tumors. Patients with an early clinical NC o PD are at high medical need for new treatment options (the non-cross-resistant chemotherapy, after switching, was comparable to the initial treatment in the Gepartrio Trial in terms of pCR achieved: 5-6%). At present, benefit of a late response after switching of treatment is unclear. Infact it seems that breast cancer that are resistent to one class of preoperative chemoterapeutic agents may also be resistent to a different class of agents (universal drug mechanisms?) Of interest is that homogeneous gene expression profile has been described in tumor less responsive or resistant to docetaxel primary chemotherapy (Chang 2005). These profiles provide therapeutic targets that could lead to improved treatment. On the other hand, gene expression profiles after pre-operative chemotherapy have been investigated to predict drug sensitivity ( Iwao-Koizumi 2005; Gianni 2005b; Thuerigen 2006), but none of these genes sets has enough predictive power to be implemented in a clinical setting. A randomized trial is ongoing with the aim of increase the chance of identifying predictive gene signature.
Dose dense regimen: dose dense regimens achieved the same pCR rate (20-25%) of antracycline-taxane containing regimen (Untch 2002; von Minckwitz 2005), and its use should still be considered investigational in early operalble breast cancer preoperative treatment.
Other non cross resistent drugs: other drugs (e.g gemcitabine, capecitabine et al) have not been studied extensively in the preoperative setting. However, in a concomitant setting (Lee 2008; Schneeweiss 2004), the achieved pCR rates (20%) are not superior to the anthracycline-taxane ones.Trials of sequential chemotherapy including different non cross-resistent drugs are ongoing.

6.1.2 Preoperative targeted therapy

1. Preoperative trastuzumab in conjunction with anthracycline- and taxane-base chemotherapy is suitable for individual clinical use on a type 2 level of evidence for patient with Her2 3+ neoplasms
2. Preoperative bevacizumab and other target therapies in conjunction with chemotherapy are still investigational.
Preoperative anti-HER2 therapy in HER2 positive tumors Use of trastuzumab as neoadjuvant therapy in addition to a sequential antracycline-taxane based therapy has shown to increase pCR up to 67% in HER-2 positive patients, without a significant increase of toxicity (Budzar 2005). These results need further confirmation: therefore, at the moment trastuzumab may not be considere a standard option but suitable for individual clinical use on a type 2 level of evidence. Ongoing trials of neoadjuvant trastuzumab are trying to identify the best treatment sequence, the optimal duration of trastuzumab administration before and after surgery, and the association with lapatinib (an oral dual multitargets tyrosine kinase inhibitor of EGFR/ErbB1 and HER2/ErbB2).
Antiangiogenetic therapy
Preoperative bevacizumab is still investigational and should not be used outside clinical trials. Caution warranted about wound healing, as surgery is performed after treatment. pCR may not be argumented, even if better, in long term outcome (which may be an issue with other biologic therapies).

6.1.3 Preoperative systemice endocrine-therapy

1. for postmenopausal patients with hormone receptor positive tumours who wish breast preservation and who are not considered candidates for cytoreductive chemotherapy, pre-operative hormonal treatment is suitable for individual clinical use on a type 2 level of evidence.
2. Aromatase inhibitors have shown higher activity than tamoxifen, with clinical responses of about 50%, and can be considered standard treatment in this setting on a type 2 level of evidence.
3. Optimal duration of preoperative hormonal therapy is uncertain
4. the use of hormone agents alone for patients with a life expectancy longer than 2 years and with operable disease is currently not recommended, while surgery or definitive breast radiation therapy in case of complete clinical response are recommended on a type C basis
Preoperative systemic endocrine treatment has not been studied extensively. The efficacy of neoadjuvant endocrine therapy do not seem to be inferior versus chemotherapy in postmenopausal women with ER positive breast cancer on a type 2 level of evidence (Semiglazov 2004), because the hormonal treatment arms results in higher rates of conversion to breast conserving surgery. This effect is probably due to the different shrinkage that occurs after endocrine therapy with central scarring, while chemotherapy results in more scattered response throughout the tumor ( Julian 2006). Therefore, for postmenopausal patients with hormone receptor positive tumours who wish breast preservation and who are not considered candidates for cytoreductive chemotherapy, pre-operative hormonal treatment is suitable for individual clinical use on a type 2 level of evidence (Kaufmann 2003). Aromatase inhibitors have shown higher activity than tamoxifen, with clinical responses of about 50%, and can be considered standard treatment in this setting on a type 2 level of evidence (Eiermann 2001; Dixon 2000; Semiglazov 2005; Smith 2005; Cataliotti 2006), but the significant increased rate of breast conservative surgery (> 40%) in patients initially candidate for mastectomy, has been evidenced in all trials. Clinical response rate at AI are superior than at tamoxifen, expecially in Her2/neu positive patients and at higher ER levels; nevertheless, responses to letrozole have been detected even at low ER levels ( Ellis 2001). Optimal duration of preoperative hormonal therapy is uncertain; longer treatment (at least 4 months) is probably better in terms of breast conserving rate than shorter (Ellis 2001 Smith 2005). Although some patients may respond for years, there is concern regarding disease resistance. Overall and breast cancer mortality appear worse if breast surgery is not finally performed after an adequate treatment period (Fennessy 2004). Therefore, the use of hormone agents alone for patients with a life expectancy longer than 2 years and with operable disease is currently not recommended, while surgery or definitive breast radiation therapy in case of complete clinical response are recoomended on a type C basis. Moreover, patients who have not responded by 3 months should be considered for alternative treatment if the are fit. Patients with shorter life expectancy, if controindications at aromatase inhibitors, can benefit from tamoxifen alone, but if they do not get a response within 3 months, they are unlikely to have long term benefit (Ellis 2001). Tamoxifene can be an effective treatment only in this selected group, because some studies reported a higher rate of local progression and shorter disease-free time (Mustacchi 2003). Clinical response is not a surrogate for long term survival. Neither pCR is, because of the low pCR rate achieved after preoperative endocrine therapy: 2% with letrozole after 3 months assumption (Eiermann 2001), 3% with anastrozole for 3 months (Semiglazov 2004) and 5-7% with examestane for 3-6 months (Semiglazov 2005). Molecular markers (proliferation and apoptosis markers, e.g Ki 67) could be easily more “useful” as predictors of short term outcome (Dowsett 2006).

6.6 Special presentations

6.6.1 Axillary lymph node involvement with an occult primary

1. For patients with biopsy proven adenocarcinoma involving axillary lymph nodes with an unknown primary, mammographic and ultrasound examination of the homolateral and contralateral breast and MRI scanning is recommended on a type R basis.
2. For patients with mobile nodes, an axillary node clearance (levels I and II dissection) is standard surgical procedure on a type C basis.
3. Therapeutic options for the treatment of the homolateral breast suitable for individual clinical use on a type 3 level of evidence (Patel 1981; Baron 1990; Whillis 1990; Merson 1992; Bundred 1994) include mastectomy or radical breast irradiation.
4. For patients with fixed nodes, pre-operative cytoreductive chemotherapy followed by surgical clearance of the axilla, or radical radiation therapy are suitable for individual clinical use on a type 3 level of evidence (Ellerbroek 1990; Fourquet 1995b).
5. Adjuvant radiation therapy of the supraclavicular and internal mammary nodal areas is suitable for non-standard clinical use on a type 3 level of evidence (Harris 1991; Fourquet 1995b). All patients should be considered for suitable systemic adjuvant therapy.

Less than one in 300 patients with breast cancer presents with nodal metastases and an occult primary breast cancer. Sometimes the axilarry lymph node represents a distant metastasis from a contralateral breast cancer.

The initial workup of a patient with axillary lymph node metastasis of an unknown primary should include a biopsy to establish the histologic diagnosis and to allow testing for estrogen, progesterone and other immunohistochemistry staining that my help guide the disgnosis. ER and PR expression is strongly suggesting a breast carcinoma. Several other tumors can have a similar presentation, including carcnomas of the lung, pancreas, gastrointestinal tract, thyroid, ovary or kidney, melanomas, lymphomas, germ cell tumors; benign inflammatory or tuberculosis should be ruled out.

Detecting the primary breast carcinoma is important, because in most cases leads to effective treatment planning, including breast conserving therapy. In about 70% of the women with histologically confirmed metastatic adenocarcinoma in the axilla, occult breast cancer, often visible on mammography, is observed (Blanchard 2004; Medina-Franco 2002; Matsuoka 2003; Shannon 2002). In such cases treatment for breast cancer with palpable lymph node metastases should be applied. In the remaining 30% a mammographic lesion is not shown. The false negative rate for mammography has been reported to be about 30% and the sensitivity of mammography is especially limited when the lesion is within dense breast parenchyma, and it is often as low as 45%. In studies on patients with axillary lymph node metastasis and negative clinical, mammographic and US findings, a lesion detection rate ranging from 40 to almost 90%were found with breast MRI. (Stomper 1999; Obdeijn 2000; Morris 1997; Schorn 1999; Ko 2007).
Therapeutic options for the treatment of patients with axillary lymph node presentation of an occult breast primary adenocarcinoma (Galimberti 2004; Patel 1981; Baron 1990; Whillis 1990; Merson 1992; Bundred 1994; Olson 2000; Chen 2002; Vlastos) include mastectomy or radical breast irradiation. Both methods have a type 3 level of evidence. The most common local treatment, for patients with movable lymph nodes is mastectomy, followed by appropriate systemic treatment and radiotherapy. For patients with adherent lymph nodes, preoperative systemic chemotherapy is warranted. When radiotherapy is administered as the oncly local treatment, doses of 45 to Gy Gy are recommended, with most authors favoring irradiation of the supraclavicular area in addition to the breast and axilla. Retrospective comparisons show that these procedures are roughly equivalent in terms of long-term survival, while radiation therapy allows breast conservation in the majority of patients who survive (Chen 2004).
6.6.2 Synchronous Bilateral Breast Cancer

1. Standard local treatment consists of a bilateral mastectomy with immediate or delayed breast reconstruction or bilateral breast conservation and radiation therapy on a type C basis, according to the patient’s preferences and to the final cosmetic outcome.
2. It is recommended on a type C basis that the overall therapeutic strategy follow recommendations based upon the worst cancer presentation.
3. Management of bilateral breast cancer of proven genetic predisposition should be manageg according to preventive/prophilactic stretgies of BRCA1-2 mutation positive patients (see chapter)

Synchronous bilateral breast cancer is seen in approximately 2% (0.3-3) of patients with breast cancer and is defined by the diagnosis of cancer in both breasts at the same time or shortly apart (3-6 months) (Hartman 2007). Some studies show that patients with synchronous bilateral breast cancer share a worse overall survival when compared with those with metachronous bilateral or unilateral breast cancer (Carmichael 2002; Kollias 2001) while other authors report similar survival rates for unilateral and bilateral breast cancer (Polednak 2003 ; Broet 1995; Hungness 2000). Women with metachronous and with early onset breast cancer are more likely to have positive family history and to be BRCA1 gene carriers (Lou 2007; Rogozinska-Szczepka J 2004; Verkooijen 2007).
Surgical approach, pre-operative neoadjuvant treatment as well as adjuvant radiation and systemic treatment should be planned following the same principles outlined for unilateral early breast cancer. When appropriate, bilateral breast conservation can be performed, followed by bilateral breast radiation treatment, carefully planning the matchline dosimetry (Fung 1997) The need for mastectomy for one breast does not preclude breast-conservation treatment for the contralateral breast (Yamauchi 2005; Intra 2004; Heron 2000; Heaton 1999.

6.6.3 Paget’s disease of the nipple without invasive cancer

In case of Paget’s disease without underlying malignancy or with minimal retroareolar non invasive component, modified radical mastectomy without axillary sampling is standard treatment on a type C basis. Wide resection of the nipple-areolar complex (with or without radiotherapy) may be considered suitable for individual clinical use on a type 3 level of evidence (Marshall 2003; Paone 1981; Lagios 1984; Fourquet 1987; Bulens 1990). Breast preservation without relapse is possible in the majority of patients (90%). Radiotherapy as exclusive treatment is investigational or suitable for non-standard individual use in patients who refuse surgery on a type 3 level of evidence (Stockdale 1989).
For patients with Paget’s disease and diffused areas of ductal carcinoma in situ, modified radical mastectomy without axillary sampling is standard treatment on a type C basis. Wide excision and radiation therapy may be suitable for individual clinical use on a type 3 level of evidence (Paone 1981; Lagios 1984; Bulens 1990) in patients where a wide central excision encompassing all visible breast cancer is feasible and desirable.

6.6.4 Paget’s disease of the nipple with associated invasive cancer

Surgical treatment, either conservative or radical, with axillary node dissection, is standard treatment on a type C basis. Choice between conservative approach or radical mastectomy should follow the same principles of other invasive breast cancers. Adjuvant radiation therapy and adjuvant systemic therapy should follow the same recommendations as for early breast cancer.

6.6.5 Male breast cancer

1. Surgery with radical or modified radical mastectomy, according to the involvement of the pectoral muscle, are recommended for primary male breast cancer on a type C basis (Vazquez 2007; Giordano 2002a). Partial surgery is suitable for individualized clinical use on a type 3 level of evidence (Golshan 2007).

2. Axillary sampling can follow guidelines as for women on a type R basis and sentinel lymph node biopsy is suitable for individualized clinical use on a type 3 basis (Gentilini 2007; Rusby 2006).

3. Adjuvant systemic therapy should be considered on the same basis as for a woman with breast cancer on a type R basis since there is no data supporting the fact that response to therapy is different for men or women. Currently, no controlled studies have compared adjuvant treatment options (Giordano 2005a).

4. Adjuvant hormonal therapy has been recommended in all receptor-positive patients on a type R basis. Tamoxifen is standard choice on a type R level of evidence.

5. Palliative systemic treatment should follow the same principles outlined for female metastatic breast cancer on a type R basis (Giordano 2005b).

Less than 1% of all breast carcinomas occur in men: mean age at diagnosis is between 60 and 70 years (Giordano 2004.) The pathology is similar to that of female breast cancer, and infiltrating ductal cancer is the most common tumor type. Risk factors appear to include radiation exposure, estrogen administration, and diseases associated with hyperestrogenism, such as cirrhosis or Klinefelter syndrome. Lymph node involvement and the hematogenous pattern of spread are similar to those found in female breast cancer. The TNM staging system for male breast cancer is identical to the staging system for female breast cancer (Fentiman 2006: Giordano 2002.) Familial clustering is evident with an increased incidence in families with a number of female relatives with breast cancer and an increased risk in families in which the BRCA2 mutation on chromosome 13q has been identified (Giordano 2005b; Fentiman 2006; Daly 2006).
Overall survival is similar to that of women with breast cancer. The impression that male breast cancer has a worse prognosis may stem from the tendency toward diagnosis at a later stage (Giordano 2005b).
In general, male breast cancer treatment follows the same indications as female breast cancer, with surgery, adjuvant systemic therapy and radiotherapy. Although mastectomy is the treatment of choice, breast conservation can be performed in selected cases(Golshan 2007). The benefit of adjuvant systemic chemotherapy is believed to be similar as in women, although due to the small number of cases no controlled trials have confirmed its value. Approximately 85% of all male breast cancers are estrogen receptor–positive, and 70% of them are progesterone receptor–positive. In men with hormone dependent tumors, both tamoxifen and other hormonal therapy have been used and can increase survival to the same extent as in women with breast cancer. Responses are generally similar to those seen in women with breast cancer. Hormonal therapy has been recommended in all receptor-positive patients. Tamoxifen use, however, is associated with a high rate of treatment-limiting symptoms, such as hot flashes and impotence in male breast cancer patients. (Dimitrov 2007; Nahleh 2006).

Tumour response for metastatic male breast cancer has shown a similar behaviour and similar predictive factors as for female breast cancer. Therefore, palliative systemic treatment are suitable for individual clinical use on a type R basis following the same principles outlined for female early and metastatic breast cancer (Giordano 2005b). Aromatase inhibitors are suitable for individualized clinical use on a type 3 leve of evidence (Giordano 2002b; Zabolotny 2005; Arriola 2007). Fulvestrant treatment as salvage therapy is suitable for individualized clinical use on a type 3 leve of evidence (Agrawal 2007).

6.6.6 Breast cancer during pregnancy

1. Surgery is standard treatment for pregnant patients with breast cancer on a type C basis..
2. Systemic chemotherapeutic agents during the first trimester of pregnancy is not recommended on a type C basis, due to the high risk of foetal malformations at birth (in excess of 10%). If pre-operative or adjuvant systemic chemotherapy is indicated, the use of adriamycin, cyclophosphamide and fluorouracil appears safe during the second and third trimester of pregnancy and is suitable for individual clinical use on a type 3 level of evidence.
3. To avoid any possible damage to the foetus, radiotherapy should be delayed until after delivery on a type C basis. Therefore, conservative surgery is suitable for individual clinical use on a type R basis for patients who can delay radiation therapy until after delivery, i.e. patients at low risk of local relapse.
4. Therapeutic abortion is suitable for individual clinical use on a type R basis in patients who desire it, in patients with locally advanced disease necessitating immediate pre-operative chemotherapy or radiotherapy, and in patients in their first trimester of pregnancy requiring adjuvant systemic treatment.
5. If the woman is in her third trimester, anticipation of delivery and of adjuvant or palliative systemic treatment is suitable for individual clinical use on a type R basis.

Diagnostic issues

Breast cancer is the most common cancer in pregnant and postpartum women at a median age between 32 to 38 years (Ring 2005a). Up to 3% of breast cancers may be diagnosed in pregnant women occurring in about 1 in 3,000 pregnancies. Between 80% and 100% of tumours are invasive ductal carcinomas and between 40% and 84% of patients present with poorly differentiated tumours. The incidence of inflammatory tumours probably ranges between 1.5% and 4%. Studies have shown that pregnant or lactating women may be more likely to present at a more advanced stage than matched non-pregnant controls, more pathological lymph node involvement (56–67%), larger tumours, more lymphovascular invasion, and a a high frequency of estrogenreceptor (ER)-negative tumours. Between 54% and 80% of pregnancy-associated breast cancers are ER-negative and in case–control studies ER-negative tumours have been found to be more common in pregnant patients than in age-matched controls. HER2 positivity is between 28% to 58% of pregnancy-associated breast cancers, apparently higher than in corresponding non-pregnant patients (Ring 2005a; Middleton 2003).

The diagnosis may be delayed and difficult owing to the physiological changes within the breast such as natural tenderness and engorgement of the breasts of pregnant and lactating women and limitations on investigations. Because of this delay, cancers are typically detected at a later stage than in a nonpregnant, age-matched population. Mammography with abdominal shielding can be performed during pregnancy with minimal risk: However at least 25% of mammograms in pregnant women with cancer may be negative (Nicklas 2000; Hogge) , therefore a biopsy such as fine-needle aspiration, core biopsy, or excisional biopsy under local anesthesia is essential for the differential diagnosis of any palpable mass. On the other hand, ultrasound represents a simple, sensitive alternative to mammography in pregnant and lactating women, and in two small series has been shown to be more sensitive than mammography (Ahn 2003). To avoid a false-positive diagnosis as a result of misinterpretation of pregnancy-related changes, the pathologist should be advised that the patient is pregnant. Moreover once a diagnosis has been confirmed and staging completed, options for treatment will be influenced by the need to give optimal treatment to the mother whilst minimising risks to the fetus. Irradiation in the peri-implantation and early post-implantation period (up to 8 days) may lead to embryonic death. During organogenesis (up to 8 weeks) the fetus is at its most sensitive to radiation-induced malformations, which may occur with exposure to more than 0.05 Gy. (Greskovich 2000). In general, chest X-rays are regarded as safe during pregnancy as the expected fetal doses are less than the thresholds described above. CT scans are usually avoided and metastases are sought using alternative imaging modalities
such as ultrasonography. There are theoretical risks to the fetus from exposure to the high magnetic fields used to generate a magnetic resonance image (MRI) and the contrast agent gadolinium should be avoided if possible, as it is has been shown to cross the placenta, and its effects on the developing fetus are not known (Shellock 1999).

Treatment issues
Surgery is standard treatment for pregnant patients with breast cancer. Although limited procedures under local anaesthesia can be considered, for the majority of patients a general anaesthetic is necessary. Small case series suggest that breast-conserving surgery, mastectomies and axillary surgery can all be performed safely with no unexpected complications (Berry 1999; Ring 2005b).The safety of sentinel lymph node biopsy in pregnant patients is not known.

Using careful fetal dose evaluation it may be possible to irradiate some parts of the mother without significantly irradiating the fetus. In terms of adjuvant breast radiotherapy, fetal dose exposure may be as low as 0.036–0.038 Gy when completed by the sixth week of gestation, but exposure may increase markedly after then when the fetus moves closer to the radiation field (Antypas 1998; Mayr 1998; Kal 2005). Therefore adjuvant breast radiotherapy is usually delayed until after delivery.

The effects rapid rate of cell division occurring in the fetus mean that it is likely to be particularly susceptible to the effects of chemotherapy. Methotrexate and 5- fluorouracil are distributed widely in tissues and fluid spaces, and certainly appear to have the potential to enter the amniotic fluid. In contrast, doxorubicin was not detected in amniotic fluid collected 4 and 16 h after drug administration in a woman who was 20 weeks pregnant (Roboz 1979). and very low levels of transplacental transfer of epirubicin (Gaillard 1995). There are minimal data concerning the transplacental transfer of taxanes.
Given the significant risks to the fetus of first trimester exposure to chemotherapy, treatment during this stage of pregnancy is usually avoided. In the first few weeks of pregnancy there is a significant risk of spontaneous abortion with chemotherapy and during the rest of the first trimester there is a risk of spontaneous abortion and an additional risk of fetal malformations as a result of exposure to chemotherapy. up to 17% (Espie 1998; Dool C 1989) with antimetabolites and alkylating agents more likely to be associated with miscarriage and malformations.
Chemotherapy has been more widely used in the second and third trimesters, as organogenesis is complete and fetal malformations are therefore unlikely to occur. A prospective series is from the M.D. Anderson Cancer Center (Berry 1999) and a retrospective series of 28 pregnant patients treated with chemotherapy for breast cancer at London teaching hospitals given after the first trimester showed no deaths or congenital malformations after chemotherapy was given (Ring 2005). Most retrospective series report patients who received anthracycline-based regimens.In terms of peri-partum complications and immediate fetal outcome it appears that these agents can be safely administered to women during the second and third trimesters.(Berry 1999, Ring 2005, Germann 2004) Case reports of other cytotoxic agents tested during the second and third trimesters include vinorelbine in combination with 5-fluorouracil, paclitaxel in combination with epirubicin, and docetaxel (Sood 2001; Gadducci 2003; De Santis 2000). Myelosuppression occurring around the time of delivery may put both mother and the newborn at risk of sepsis and haemorrhage, and it is therefore recommended that chemotherapy should be avoided for at least 3 weeks prior to delivery in order that maternal blood counts are optimal. Fetal exposure to chemotherapy may lead to gonadal damage and later problems with fertility, germ cell damage, and higher rates of malignancy and teratogenicity in subsequent generations, damage to organs such as the heart, kidneys or central nervous system may not manifest itself as physical or neurological impairment. In reality, there are very few reports documenting the long-term follow-up of children exposed to chemotherapy in utero and little is known about the long-term effects on the fetus of in utero chemotherapy exposure.
There is evidence from animal studies that the selective ER modulator tamoxifen may potentially be teratogenic including craniofacial, oculoauriculovertebral dysplasia and ambiguous genitalia. Therefore, the use of tamoxifen is usually delayed until the end of pregnancy
HER2 expression is also high in embryonic tissues, suggesting a role in embryonic development, and because placental transfer of the monoclonal antibody trastuzumab cannot be excluded, the use of the trastuzumab during pregnancy cannot currently be recommended.



Aebi S, Castiglione M. The enigma of young age. Ann Oncol 2006a; 17: 1475-1477 [Medline]

Aebi S, De Ridder M, Vlastos G, et al. Aebi S, De Ridder M, Vlastos G et al. Young age is a poor prognostic factor in women with stage I breast cancer. Eur J Cancer 2006b; Suppl 4: 121

Agrawal A, Cheung KL, Robertson JF. Fulvestrant in advanced male breast cancer. Breast Cancer Res Treat 2007; 101: 123 [Medline]

Ahn BY, Kim HH, Moon WK, Pisano ED, Kim HS, Cha ES, et al. Pregnancy- and lactation-associated breast cancer: mammographic and sonographic findings. J Ultrasound Med 2003; 22: 491-497 [Medline]

Anderson DE, Badzioch MD. Familial breast cancer risks. Effects of prostate and other cancers. Cancer 1993; 72: 114-119 [Medline]

Antypas C, Sandilos P, Kouvaris J, Balafouta E, Karinou E, Kollaros N, et al. Fetal dose evaluation during breast cancer radiotherapy. Int J Radiat Oncol Biol Phys 1998; 40: 995-999 [Medline]

Arriola E, Hui E, Dowsett M, Smith IE. Aromatase inhibitors and male breast cancer. Clin Transl Oncol 2007; 9: 192-194 [Medline]

ASCO. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility. J Clin Oncol 1996; 14: 1730-1736

Baron PL, Moore MP, Kinne DW, Candela FC, Osborne MP, Petrek JA. Occult breast cancer presenting with axillary metastases. Updated management. Arch Surg 1990; 125: 210-214 [Medline]

BCLC.The Breast Cancer Linkage Consolrtium. Cancer Risks in BRCA2 Mutation Carriers. J Natl Cancer Inst 1999; 91: 1310-1316 [Medline]

Bear HD, Anderson S, Smith RE, Geyer CE, Jr., Mamounas EP, Fisher B, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2006; 24: 2019-2027 [Medline]

Benichou J, Gail MH, Mulvihill JJ. Graphs to estimate an individualized risk of breast cancer. Journal of Clinical Oncology 1996; 14: 103-110 [Medline]

Bernstein L, Henderson BE, Hanisch R, Sullivan-Halley J, Ross RK. Physical exercise and reduced risk of breast cancer in young women. J Natl Cancer Inst 1994; 86: 1403-1408 [Medline]

Bernstein L, Ross RK, Lobo RA, Hanisch R, Krailo MD, Henderson BE. The effects of moderate physical activity on menstrual cycle patterns in adolescence: implications for breast cancer prevention. Br J Cancer 1987; 55: 681-685 [Medline]

Berry DL, Theriault RL, Holmes FA, Parisi VM, Booser DJ, Singletary SE, et al. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999; 17: 855-861 [Medline]

Bhatia S, Robison LL, Oberlin O, Greenberg M, Bunin G, Fossati-Bellani F, et al. Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N Engl J Med 1996; 334: 745-751 [Medline]

Bilimoria MM, Morrow M. The woman at increased risk for breast cancer: evaluation and management strategies. Ca Cancer J Clin 1995; 45: 263-278 [Medline]

Blanchard DK, Farley DR. Retrospective study of women presenting with axillary metastases from occult breast carcinoma. World J Surg 2004; 28: 535-539 [Medline]

Broet P, de la RA, Scholl SM, Fourquet A, Mosseri V, Durand JC, et al. Contralateral breast cancer: annual incidence and risk parameters. J Clin Oncol 1995; 13: 1578-1583 [Medline]

Bulens P, Vanuytsel L, Rijnders A, van der Schueren E. Breast conserving treatment of Paget’s disease. Radiother Oncol 1990; 17: 305-309 [Medline]

Bundred NJ, Morgan DA, Dixon JM. ABC of breast diseases. Management of regional nodes in breast cancer. BMJ 1994; 309: 1222-1225 [Medline]

Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005; 23: 3676-3685 [Medline]

Carmichael AR, Bendall S, Lockerbie L, Prescott R, Bates T. The long-term outcome of synchronous bilateral breast cancer is worse than metachronous or unilateral tumours. Eur J Surg Oncol 2002; 28: 388-391 [Medline]

Cataliotti L, Buzdar AU, Noguchi S, Bines J, Takatsuka Y, Petrakova K, et al. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative ‘quot;Arimidex’quot; Compared to Tamoxifen (PROACT) trial. Cancer 2006; 106: 2095-2103 [Medline]

Cauley JA, Lucas FL, Kuller LH, Stone K, Browner W, Cummings SR. Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer. Study of Osteoporotic Fractures Research Group. Ann Intern Med 1999; 130: 270-277 [Medline]

CGHFBC. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 2002; 360: 187-195 [Medline]

CGHFBC. The Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347: 1713-1727 [Medline]

CGHFBC. The Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1997; 350: 1047-1059 [Medline]

Chang JC, Wooten EC, Tsimelzon A, Hilsenbeck SG, Gutierrez MC, Tham YL, et al. Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients. J Clin Oncol 2005; 23: 1169-1177 [Medline]

Chen C, Orel SG, Harris E, Schnall MD, Czerniecki BJ, Solin LJ. Outcome after treatment of patients with mammographically occult, magnetic resonance imaging-detected breast cancer presenting with axillary lymphadenopathy. Clin Breast Cancer 2004; 5: 72-77 [Medline]

Chen C, Orel SG, Schnall MD, Harris E, Solin LJ. Breast conservation treatment for patients presenting with axillary lymphadenopathy from presumed primary breast cancer: the role of breast magnetic resonance imaging for staging. Clin Breast Cancer 2002; 3: 219-222 [Medline]

Chen CY, Sun LM, Anderson BO. Paget disease of the breast: changing patterns of incidence, clinical presentation, and treatment in the U.S. Cancer 2006; 107: 1448-1458 [Medline]

Cleator S, Heller W, Coombes RC. Triple-negative breast cancer: therapeutic options. Lancet Oncol 2007; 8: 235-244 [Medline]

Colditz GA, Rosner BA, Speizer FE. Risk factors for breast cancer according to family history of breast cancer.For the Nurses’ Health Study Research Group. J Natl Cancer Inst 1996; 88: 365-371 [Medline]

Colditz GA, Willett WC, Hunter DJ, Stampfer MJ, Manson JE, Hennekens CH, et al. Family history, age, and risk of breast cancer. Prospective data from the Nurses’ Health Study [published erratum appears in JAMA 1993 Oct 6;270(13):1548] [see comments]. JAMA 1993; 270: 338-343 [Medline]

Couch FJ, DeShano ML, Blackwood MA, Calzone K, Stopfer J, Campeau L, et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 1997; 336: 1409-1415 [Medline]

Cristofanilli M, Gonzalez-Angulo A, Sneige N, Kau SW, Broglio K, Theriault RL, et al. Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes. J Clin Oncol 2005; 23: 41-48 [Medline]

Daly MB, Axilbund JE, Bryant E, Buys S, Eng C, Friedman S, et al. Genetic/familial high-risk assessment: breast and ovarian. J Natl Compr Canc Netw 2006; 4: 156-176 [Medline]

Daudt A, Alberg AJ, Helzlsouer KJ. Epidemiology, prevention, and early detection of breast cancer. Curr Opin Oncol 1996; 8: 455-461 [Medline]

De Santis M, Lucchese A, De CS, Ferrazani S, Caruso A. Metastatic breast cancer in pregnancy: first case of chemotherapy with docetaxel. Eur J Cancer Care (Engl) 2000; 9: 235-237 [Medline]

Dimitrov NV, Colucci P, Nagpal S. Some aspects of the endocrine profile and management of hormone-dependent male breast cancer. Oncologist2007; 12: 798-807 [Medline]

Dixon JM, Mansel RE. ABC of breast diseases. Symptoms assessment and guidelines for referral. BMJ 1994; 309: 722-726 [Medline]

Dixon JM, Renshaw L, Bellamy C, Stuart M, Hoctin-Boes G, Miller WR. The effects of neoadjuvant anastrozole (Arimidex) on tumor volume in postmenopausal women with breast cancer: a randomized, double-blind, single-center study. Clin Cancer Res 2000; 6: 2229-2235 [Medline]

Doll DC, Ringenberg QS, Yarbro JW. Antineoplastic agents and pregnancy. Semin Oncol 1989; 16: 337-346 [Medline]

Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, Griffith C, et al. Proliferation and apoptosis as markers of benefit in neoadjuvant endocrine therapy of breast cancer. Clin Cancer Res 2006; 12: 1024s-1030s [Medline]

Dupont WD, Parl FF, Hartmann WH, Brinton LA, Winfield AC, Worrell JA, et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer 1993; 71: 1258-1265 [Medline]

Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 2001; 12: 1527-1532 [Medline]

Ellerbroek N, Holmes F, Singletary E, Evans H, Oswald M, McNeese M. Treatment of patients with isolated axillary nodal metastases from an occult primary carcinoma consistent with breast origin. Cancer 1990; 66: 1461-1467 [Medline]

Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001; 19: 3808-3816 [Medline]

Espie M, Cuvier C. Treating breast cancer during pregnancy. What can be taken safely? Drug Saf 1998; 18: 135-142 [Medline]

Feig SA. Estimation of currently attainable benefit from mammographic screening of women aged 40-49 years. Cancer 1995; 75: 2412-2419 [Medline]

Fennessy M, Bates T, MacRae K, Riley D, Houghton J, Baum M. Late follow-up of a randomized trial of surgery plus tamoxifen versus tamoxifen alone in women aged over 70 years with operable breast cancer. Br J Surg 2004; 91: 699-704 [Medline]

Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet 2006; 367: 595-604 [Medline]

Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18: 581-592 [Medline]

Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. Journal of Clinical Oncology 1998b; 16: 2672-2685 [Medline]

Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study [see comments]. J Natl Cancer Inst 1998a; 90: 1371-1388 [Medline]

Fisher ER, Wang J, Bryant J, Fisher B, Mamounas E, Wolmark N. Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 2002; 95: 681-695 [Medline]

FitzGerald MG, MacDonald DJ, Krainer M, Hoover I, O’Neil E, Unsal H, et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. N Engl J Med 1996; 334: 143-149 [Medline]

Fourquet A, Campana F, Vielh P, Schlienger P, Jullien D, Vilcoq JR. Paget’s disease of the nipple without detectable breast tumor: conservative management with radiation therapy. Int J Radiat Oncol Biol Phys 1987; 13: 1463-1465 [Medline]

Fourquet A, de la Rochefordiere A, Campana F. Occult primary cancer with axillary metastasis. In: Harris JR, Lippman ME, Morrow M, Hellman S, editors. Diseases of the Breast. 1995b. p. 892-896

Frei KA, Bonel HM, Pelte MF, Hylton NM, Kinkel K. Paget disease of the breast: findings at magnetic resonance imaging and histopathologic correlation. Invest Radiol 2005; 40: 363-367 [Medline]

Fung MC, Schultz DJ, Solin LJ. Early-stage bilateral breast cancer treated with breast-conserving surgery and definitive irradiation: the University of Pennsylvania experience. Int J Radiat Oncol Biol Phys 1997; 38: 959-967 [Medline]

Gadducci A, Cosio S, Fanucchi A, Nardini V, Roncella M, Conte PF, et al. Chemotherapy with epirubicin and paclitaxel for breast cancer during pregnancy: case report and review of the literature. Anticancer Res 2003; 23: 5225-5229 [Medline]

Gaillard B, Leng JJ, Grellet J, Ducint D, Saux MC. [Transplacental passage of epirubicin]. J Gynecol Obstet Biol Reprod (Paris) 1995; 24: 63-68 [Medline]

Galimberti V, Bassani G, Monti S, Simsek S, Villa G, Renne G, et al. Clinical experience with axillary presentation breast cancer. Breast Cancer Res Treat 2004; 88: 43-47 [Medline]

Gapstur SM, Morrow M, Sellers TA. Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women’s Health Study. [see comments]. JAMA 1999; 281: 2091-2097 [Medline]

Gentilini O, Chagas E, Zurrida S, Intra M, De CC, Gatti G, et al. Sentinel lymph node biopsy in male patients with early breast cancer. Oncologist 2007; 12: 512-515 [Medline]

Germann N, Goffinet F, Goldwasser F. Anthracyclines during pregnancy: embryo-fetal outcome in 160 patients. Ann Oncol 2004; 15: 146-150 [Medline]

Gianni L, Baselga J, Eiermann W, Guillem P, V, Semiglazov V, Lluch A, et al. Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clin Cancer Res 2005a; 11: 8715-8721 [Medline]

Gianni L, Zambetti M, Clark K, Baker J, Cronin M, Wu J, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol 2005b; 23: 7265-7277 [Medline]

Giordano SH, Buzdar AU, Hortobagyi GN. Breast cancer in men. Ann Intern Med 2002a; 137: 678-687 [Medline]

Giordano SH, Cohen DS, Buzdar AU, Perkins G, Hortobagyi GN. Breast carcinoma in men: a population-based study. Cancer 2004; 101: 51-57 [Medline]

Giordano SH, Perkins GH, Broglio K, Garcia SG, Middleton LP, Buzdar AU, et al. Adjuvant systemic therapy for male breast carcinoma. Cancer 2005a; 104: 2359-2364 [Medline]

Giordano SH, Valero V, Buzdar AU, Hortobagyi GN. Efficacy of anastrozole in male breast cancer. Am J Clin Oncol 2002b; 25: 235-237 [Medline]

Giordano SH. A review of the diagnosis and management of male breast cancer. Oncologist 2005b; 10: 471-479 [Medline]

Golshan M, Rusby J, Dominguez F, Smith BL. Breast conservation for male breast carcinoma. Breast 2007; 16: 653-656 [Medline]

Greskovich JF, Jr., Macklis RM. Radiation therapy in pregnancy: risk calculation and risk minimization. Semin Oncol 2000; 27: 633-645 [Medline]

Guarneri V, Broglio K, Kau SW, Cristofanilli M, Buzdar AU, Valero V, et al. Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol 2006; 24: 1037-1044 [Medline]

Hamajima N, Hirose K, Tajima K, Rohan T, Calle EE, Heath CW, Jr., et al. Alcohol, tobacco and breast cancer–collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 2002; 87: 1234-1245 [Medline]

Hankinson SE, Colditz GA, Manson JE, Willett WC, Hunter DJ, Stampfer MJ, et al. A prospective study of oral contraceptive use and risk of breast cancer (Nurses’ Health Study, United States). Cancer Causes Control 1997; 8: 65-72 [Medline]

Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. [see comments]. J Natl Cancer Inst 1998; 90: 1292-1299 [Medline]

Harris JR, Recht A. Primary treatment of breast cancer. Treatment of the axilla and other nodal areas. In: Harris JR, Hellman S, Henderson IC, et al, editors. Breast Disesases. 1991. p. 413-419

Hartman M, Czene K, Reilly M, Adolfsson J, Bergh J, Adami HO, et al. Incidence and prognosis of synchronous and metachronous bilateral breast cancer. J Clin Oncol 2007; 25: 4210-4216 [Medline]

Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer [see comments]. N Engl J Med 1999; 340: 77-84 [Medline]

Healy B. BRCA genes–bookmaking, fortunetelling, and medical care. N Engl J Medi 1997; 336: 1448-1449 [Medline]

Heaton KM, Peoples GE, Singletary SE, Feig BW, Ross MI, Ames FC, et al. Feasibility of breast conservation therapy in metachronous or synchronous bilateral breast cancer. Ann Surg Oncol 1999; 6: 102-108 [Medline]

Henderson BE, Ross RK, Judd HL, Krailo MD, Pike MC. Do regular ovulatory cycles increase breast cancer risk? Cancer 1985; 56: 1206-1208 [Medline]

Hennessy BT, Hortobagyi GN, Rouzier R, Kuerer H, Sneige N, Buzdar AU, et al. Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol 2005; 23: 9304-9311 [Medline]

Heron DE, Komarnicky LT, Hyslop T, Schwartz GF, Mansfield CM. Bilateral breast carcinoma: risk factors and outcomes for patients with synchronous and metachronous disease. Cancer 2000; 88: 2739-2750 [Medline]

Hery C, Ferlay J, Boniol M, Autier P. Quantification of changes in breast cancer incidence and mortality since 1990 in 35 countries with Caucasian-majority populations. Ann Oncol 2008; 19: 1187-1194 [Medline]

Hogge JP, De Paredes ES, Magnant CM, Lage J. Imaging and Management of Breast Masses During Pregnancy and Lactation. Breast J 1999; 5: 272-283 [Medline]

Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, et al. Dual effects of weight and weight gain on breast cancer risk. [see comments]. JAMA 1997; 278: 1407-1411 [Medline]

Hungness ES, Safa M, Shaughnessy EA, Aron BS, Gazder PA, Hawkins HH, et al. Bilateral synchronous breast cancer: mode of detection and comparison of histologic features between the 2 breasts. Surgery 2000; 128: 702-707 [Medline]

Intra M, Rotmensz N, Viale G, Mariani L, Bonanni B, Mastropasqua MG, et al. Clinicopathologic characteristics of 143 patients with synchronous bilateral invasive breast carcinomas treated in a single institution. Cancer 2004; 101: 905-912 [Medline]

Iwao-Koizumi K, Matoba R, Ueno N, Kim SJ, Ando A, Miyoshi Y, et al. Prediction of docetaxel response in human breast cancer by gene expression profiling. J Clin Oncol 2005; 23: 422-431 [Medline]

Julian H, Dixon JM, Thomas J. Central scarring is a common pattern of tumor response to neoadjuvant letrozole therapy for breast cancer but not neoadjuvent chemotherapy and correlates with tumor shrinkage and suitability for conservation surgery. Breast Cancer Res Treat 2006; 100 Suppl 1: S188

Kal HB, Struikmans H. Radiotherapy during pregnancy: fact and fiction. Lancet Oncol 2005; 6: 328-333 [Medline]

Kaufmann M, Hortobagyi GN, Goldhirsch A, Scholl S, Makris A, Valagussa P, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: an update. J Clin Oncol 2006; 24: 1940-1949 [Medline]

Kaufmann M, von MG, Smith R, Valero V, Gianni L, Eiermann W, et al. International expert panel on the use of primary (preoperative) systemic treatment of operable breast cancer: review and recommendations. J Clin Oncol 2003; 21: 2600-2608 [Medline]

Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev 1993; 15: 36-47 [Medline]

Kerber RA, Slattery ML. The impact of family history on ovarian cancer risk. The Utah Population Database. [see comments]. Arch Inter Med 1995; 155: 905-912 [Medline]

Kerlikowske K, Grady D, Rubin SM, Sandrock C, Ernster VL. Efficacy of screening mammography. A meta-analysis. JAMA 1995; 273: 149-154 [Medline]

Ko EY, Han BK, Shin JH, Kang SS. Breast MRI for evaluating patients with metastatic axillary lymph node and initially negative mammography and sonography. Korean J Radiol 2007; 8: 382-389 [Medline]

Kollias J, Ellis IO, Elston CW, Blamey RW. Prognostic significance of synchronous and metachronous bilateral breast cancer. World J Surg 2001; 25: 1117-1124 [Medline]

La Vecchia C, Levi F, Lucchini F. Descriptive epidemiology of male breast cancer in Europe. Int J Cancer 1992; 51: 62-66 [Medline]

Lagios MD, Westdahl PR, Rose MR, Concannon S. Paget’s disease of the nipple. Alternative management in cases without or with minimal extent of underlying breast carcinoma. Cancer 1984; 54: 545-551 [Medline]

Langston AA, Malone KE, Thompson JD, Daling JR, Ostrander EA. BRCA1 mutations in a population-based sample of young women with breast cancer. N Engl J Med 1996; 334: 137-142 [Medline]

Lee KS, Ro J, Nam BH, Lee ES, Kwon Y, Kwon HS, et al. A randomized phase-III trial of docetaxel/capecitabine versus doxorubicin/cyclophosphamide as primary chemotherapy for patients with stage II/III breast cancer. Breast Cancer Res Treat 2008; 109: 481-489 [Medline]

Levi F, Bosetti C, Lucchini F, Negri E, La VC. Monitoring the decrease in breast cancer mortality in Europe. Eur J Cancer Prev 2005; 14: 497-502 [Medline]

Lindblom A. Familial breast cancer and genes involved in breast carcinogenesis. Breast Cancer Res Treat 1995; 34: 171-183 [Medline]

Lou L, Cong XL, Yu GF, Li JC, Ma YX. US findings of bilateral primary breast cancer: retrospective study. Eur J Radiol 2007; 61: 154-157 [Medline]

MacMahon B, Cole P, Lin TM, Lowe CR, Mirra AP, Ravnihar B, et al. Age at first birth and breast cancer risk. Bull World Health Organ 1970; 43: 209-221 [Medline]

Marshall JK, Griffith KA, Haffty BG, Solin LJ, Vicini FA, McCormick B, et al. Conservative management of Paget disease of the breast with radiotherapy: 10- and 15-year results. Cancer 2003; 97: 2142-2149 [Medline]

Matsuoka K, Ohsumi S, Takashima S, Saeki T, Aogi K, Mandai K. Occult breast carcinoma presenting with axillary lymph node metastases: follow-up of eleven patients. Breast Cancer 2003; 10: 330-334 [Medline]

Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005; 97: 188-194 [Medline]

Mayr NA, Wen BC, Saw CB. Radiation therapy during pregnancy. Obstet Gynecol Clin North Am 1998; 25: 301-321 [Medline]

Mazouni C, Kau SW, Frye D, Andre F, Kuerer HM, Buchholz TA, et al. Inclusion of taxanes, particularly weekly paclitaxel, in preoperative chemotherapy improves pathologic complete response rate in estrogen receptor-positive breast cancers. Ann Oncol 2007; 18: 874-880 [Medline]

Medina-Franco H, Urist MM. Occult breast carcinoma presenting with axillary lymph node metastases. Rev Invest Clin 2002; 54: 204-208 [Medline]

Melbye M, Wohlfahrt J, Olsen JH, Frisch M, Westergaard T, Helweg-Larsen K, et al. Induced abortion and the risk of breast cancer. N Engl J Med 1997; 336: 81-85 [Medline]

Merson M, Andreola S, Galimberti V, Bufalino R, Marchini S, Veronesi. Breast carcinoma presenting as axillary metastases without evidence of a primary tumor. Cancer 1992; 70: 504-508 [Medline]

Middleton LP, Amin M, Gwyn K, Theriault R, Sahin A. Breast carcinoma in pregnant women: assessment of clinicopathologic and immunohistochemical features. Cancer 2003; 98: 1055-1060 [Medline]

Morris EA, Schwartz LH, Dershaw DD, van Zee KJ, Abramson AF, Liberman L. MR imaging of the breast in patients with occult primary breast carcinoma. Radiology 1997; 205: 437-440 [Medline]

Mustacchi G, Ceccherini R, Milani S, Pluchinotta A, de MA, Maiorino L, et al. Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: long-term results of the phase III randomized controlled multicenter GRETA trial. Ann Oncol 2003; 14: 414-420 [Medline]

Nahleh ZA. Hormonal therapy for male breast cancer: A different approach for a different disease. Cancer Treat Rev 2006; 32: 101-105 [Medline]

Newcomb PA, Storer BE, Longnecker MP, Mittendorf R, Greenberg ER, Willett WC. Pregnancy termination in relation to risk of breast cancer. JAMA 1996; 275: 283-287 [Medline]

Newman B, Austin MA, Lee M, King MC. Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci U S A 1988; 85: 3044-3048 [Medline]

Nicklas AH, Baker ME. Imaging strategies in the pregnant cancer patient. Semin Oncol 2000; 27: 623-632 [Medline]

Nystrom L, Rutqvist LE, Wall S, Lindgren A, Lindqvist M, Ryden S, et al. Breast cancer screening with mammography: overview of Swedish randomised trials. Lancet 1993; 341: 973-978 [Medline]

Obdeijn IM, Brouwers-Kuyper EM, Tilanus-Linthorst MM, Wiggers T, Oudkerk M. MR imaging-guided sonography followed by fine-needle aspiration cytology in occult carcinoma of the breast. AJR Am J Roentgenol 2000; 174: 1079-1084 [Medline]

Olson JA, Jr., Morris EA, van Zee KJ, Linehan DC, Borgen PI. Magnetic resonance imaging facilitates breast conservation for occult breast cancer. Ann Surg Oncol 2000; 7: 411-415 [Medline]

Page DL, Dupont WD. Anatomic indicators (histologic and cytologic) of increased breast cancer risk. Breast Cancer Res Treat 1993; 28: 157-166 [Medline]

Page DL, Steel CM, Dixon JM. ABC of breast diseases. Carcinoma in situ and patients at high risk of breast cancer. BMJ 1995; 310: 39-42 [Medline]

Panel. Hormone replacement therapy. Clinical Synthesis Panel on HRT. Lancet 1999; 354: 152-155 [Medline]

Paone JF, Baker RR. Pathogenesis and treatment of Paget’s disease of the breast. Cancer 1981; 48: 825-829 [Medline]

Patel J, Nemoto T, Rosner D, Dao TL, Pickren JW. Axillary lymph node metastasis from an occult breast cancer. Cancer 1981; 47: 2923-2927 [Medline]

Peto J, Easton DF, Matthews FE, Ford D, Swerdlow AJ. Cancer mortality in relatives of women with breast cancer: the OPCS Study. Office of Population Censuses and Surveys. Int J Cancer 1996; 65: 275-283 [Medline]

Peto R, Boreham J, Clarke M, Davies C, Beral V. UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet 2000; 355: 1822 [Medline]

Petrek JA. Breast cancer during pregnancy. Cancer 1994; 74: 518-527 [Medline]

Pezzi CM, Kukora JS, Audet IM, Herbert SH, Horvick D, Richter MP. Breast conservation surgery using nipple-areolar resection for central breast cancers. Arch Surg 2004; 139: 32-37 [Medline]

Pharoah PD, Day NE, Duffy S, Easton DF, Ponder BA. Family history and the risk of breast cancer: a systematic review and meta-analysis. Int J Cancer 1997; 71: 800-809 [Medline]

Polednak AP. Bilateral synchronous breast cancer: a population-based study of characteristics, method of detection, and survival. Surgery 2003; 133: 383-389 [Medline]

Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial [see comments]. Lancet 1998; 352: 98-101 [Medline]

Ring AE, Smith IE, Ellis PA. Breast cancer and pregnancy. Ann Oncol 2005a; 16: 1855-1860 [Medline]

Ring AE, Smith IE, Jones A, Shannon C, Galani E, Ellis PA. Chemotherapy for breast cancer during pregnancy: an 18-year experience from five London teaching hospitals. J Clin Oncol 2005b; 23: 4192-4197 [Medline]

Roboz J, Gleicher N, Wu K, Chanihian P, Kerenyi T, Holland J. Does doxorubicin cross the placenta? Lancet 1979; 2: 1382-1383 [Medline]

Rockhill B, Willett WC, Hunter DJ, Manson JE, Hankinson, SE, et al. A prospective study of recreational physical activity and breast cancer risk. Arch Intern Med 1999; 159: 2290-2296 [Medline]

Rogozinska-Szczepka J, Utracka-Hutka B, Grzybowska E, Maka B, Nowicka E, Smok-Ragankiewicz A, et al. BRCA1 and BRCA2 mutations as prognostic factors in bilateral breast cancer patients. Ann Oncol 2004; 15: 1373-1376 [Medline]

Romieu G, Tubiana-Hulin M, Fumoleau P, Namer M, Delva R, Guastalla JP, et al. A multicenter randomized phase II study of 4 or 6 cycles of adriamycin/Taxol® (paclitaxel) (AT) as neoadjuvant treatment of breast cancer (BC). Ann Oncol 2002; 13 Suppl 5: 33-34

Rosen PP, Groshen S, Kinne DW, Hellman S. Contralateral breast carcinoma: an assessment of risk and prognosis in stage I (T1N0M0) and stage II (T1N1M0) patients with 20-year follow-up. Surgery 1989; 106: 904-910 [Medline]

Rosner B, Colditz GA, Willett WC. Reproductive risk factors in a prospective study of breast cancer: the Nurses’ Health Study. Am J Epidemiol 1994; 139: 819-835 [Medline]

Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. [see comments]. Journal of the National Cancer Institute 2000; 92: 328-33 [Medline]

Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 2005; 11: 5678-5685 [Medline]

Rusby JE, Smith BL, Dominguez FJ, Golshan M. Sentinel lymph node biopsy in men with breast cancer: a report of 31 consecutive procedures and review of the literature. Clin Breast Cancer 2006; 7: 406-410 [Medline]

Salmon RJ, Ansquer Y, Asselain B, Languille O, Lesec G, Remvikos Y. Clinical and biological characteristics of breast cancers in post-menopausal women receiving hormone replacement therapy for menopause. Oncol Rep 1999; 6: 699-703 [Medline]

Schneeweiss A, Bastert G, Huober J, Wallwiener D, Hamerla R, Lichter P. Neoadjuvant therapy with gemcitabine in breast cancer. Oncology (Williston Park) 2004; 18: 27-31 [Medline]

Schorn C, Fischer U, Luftner-Nagel S, Westerhof JP, Grabbe E. MRI of the breast in patients with metastatic disease of unknown primary. Eur Radiol 1999; 9: 470-473 [Medline]

Semiglazov VF, Kletsel A, Semiglazov V, Zhiltzova E, Ivanov V, Dashyan G, et al. Exemestane (E) vs tamoxifen (T) as neoadjuvant endocrine therapy for postmenopausal women with ER+ breast cancer (T2N1-2, T3N0-1, T4N0M0). Proc Am Soc Clin Oncol 2005; 23: 11s

Semiglazov VF, Semiglazov V, Ivanov V, Bozhok A, Ziltsova E, Paltuev R, et al. The relative efficacy of neoadjuvant endocrine therapy vs chemotherapy in postmenopausal women with ER- positive breast cancer. Proc Am Soc Clin Oncol 2004; 22: 7s

Shannon C, Walsh G, Sapunar F, A’Hern R, Smith I. Occult primary breast carcinoma presenting as axillary lymphadenopathy. Breast 2002; 11: 414-418 [Medline]

Shellock FG, Kanal E. Safety of magnetic resonance imaging contrast agents. J Magn Reson Imaging 1999; 10: 477-484 [Medline]

Smart CR, Hendrick RE, Rutledge JH, Smith RA. Benefit of mammography screening in women ages 40 to 49 years. Current evidence from randomized controlled trials. Cancer 1995; 75: 1619-1626 [Medline]

Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, et al. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 2002; 20: 1456-1466 [Medline]

Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 2005; 23: 5108-5116 [Medline]

Sood AK, Shahin MS, Sorosky JI. Paclitaxel and platinum chemotherapy for ovarian carcinoma during pregnancy. Gynecol Oncol 2001; 83: 599-600 [Medline]

Stockdale AD, Brierley JD, White WF, Folkes A, Rostom AY. Radiotherapy for Paget’s disease of the nipple: a conservative alternative. Lancet 1989; 2: 664-666 [Medline]

Stomper PC, Waddell BE, Edge SB, Klippenstein DL. Breast MRI in the Evaluation of Patients with Occult Primary Breast Carcinoma. Breast J 1999; 5: 230-234 [Medline]

Tabar L, Faberberg G, Day NE, Holmberg L. What is the optimum interval between mammographic screening examinations? An analysis based on the latest results of the Swedish two-county breast cancer screening trial. Br J Cancer 1987; 55: 547-551 [Medline]

Talamini R, Franceschi S, La Vecchia C, Negri E, Borsa L, Montella M, et al. The role of reproductive and menstrual factors in cancer of the breast before and after menopause. Eur J Cancer 1996; 32A: 303-310 [Medline]

Thuerigen O, Schneeweiss A, Toedt G, Warnat P, Hahn M, Kramer H, et al. Gene expression signature predicting pathologic complete response with gemcitabine, epirubicin, and docetaxel in primary breast cancer. J Clin Oncol 2006; 24: 1839-1845 [Medline]

Trichopoulos D, MacMahon B, Cole P. Menopause and breast cancer risk. J Natl Cancer Inst 1972; 48: 605-613 [Medline]

Tyczynski JE, Plesko I, Aareleid T, Primic-Zakelj M, Dalmas M, Kurtinaitis J, et al. Breast cancer mortality patterns and time trends in 10 new EU member states: mortality declining in young women, but still increasing in the elderly. Int J Cancer 2004; 112: 1056-1064 [Medline]

UICC. UICC (International Union Against Cancer). TNM classification of malignant tumors. Sobin LH, Wittekind Ch, editors. 5th ed. New York, Chichester, Weinheim, Brisbane, Singapore, Toronto: Wiley-Liss. 1997

Untch M, Konecny G, Ditsch N, Sorokina Y, Moebus V, Muck B, et al. Dose-dense sequential epirubicin-paclitaxel as preoperative treatment of breast cancer: results of a randomised AGO study. Proc Am Soc Clin Oncol 2002; 21: 34a

van der Hage JA, van d, V, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 2001; 19: 4224-4237 [Medline]

Van Dijck JA, Verbeek AL, Beex LV, Hendriks JH, Holland R, Mravunac M, et al. Mammographic screening after the age of 65 years: evidence for a reduction in breast cancer mortality. Int J Cancer 1996; 66: 727-731 [Medline]

Vazquez B, Rousseau D, Hurd TC. Surgical management of breast cancer. Semin Oncol 2007; 34: 234-240 [Medline]

Verkooijen HM, Chatelain V, Fioretta G, Vlastos G, Rapiti E, Sappino AP, et al. Survival after bilateral breast cancer: results from a population-based study. Breast Cancer Res Treat 2007; 105: 347-357 [Medline]

Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson, et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study [see comments]. Lancet 1998; 352: 93-97 [Medline]

Vlastos G, Jean ME, Mirza AN, Mirza NQ, Kuerer HM, Ames FC, et al. Feasibility of breast preservation in the treatment of occult primary carcinoma presenting with axillary metastases. Ann Surg Oncol 2001; 8: 425-431 [Medline]

von Minckwitz G, Raab G, Caputo A, Schutte M, Hilfrich J, Blohmer JU, et al. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol 2005; 23: 2676-2685 [Medline]

Wald N, Chamberlain J, Hackshaw A. Report of the European Society of Mastology Breast Cancer Screening Evaluation Committee. Tumori 1993; 79: 371-379 [Medline]

Weber BL. Susceptibility genes for breast cancer. N Engl J Med 1994; 331: 1523-1524 [Medline]

Whillis D, Brown PW, Rodger A. Adenocarcinoma from an unknown primary presenting in women with an axillary mass. Clinical Oncology (Royal College of Radiologists) 1990; 2: 189-192 [Medline]

Wolff MS, Collman GW, Barrett JC, Huff J. Breast cancer and environmental risk factors: epidemiological and experimental findings. Annu Rev Pharmacol Toxicol 1996; 36: 573-596 [Medline]

Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 2001; 96-102 [Medline]

Yamauchi C, Mitsumori M, Nagata Y, Kokubo M, Inamoto T, Mise K, et al. Bilateral breast-conserving therapy for bilateral breast cancer: results and consideration of radiation technique. Breast Cancer 2005; 12: 135-139 [Medline]

Zabolotny BP, Zalai CV, Meterissian SH. Successful use of letrozole in male breast cancer: a case report and review of hormonal therapy for male breast cancer. J Surg Oncol 2005; 90: 26-30 [Medline]


Dr. Alexandru Eniu (Author)
Cancer Institute ?I. Chiricuta? – Cluj-Napoca, Romania

Dr. Carlo Tondini (Editor)
START Clinical Editor – Ospedali Riuniti – Bergamo, Italy