MD Antonio Piñero Madrona
email: antonio.pinero@carm.es

Surgical treatment of breast cancer in young women

Introduction

Surgical treatment is a fundamental aspect in the proper management of breast cancer. It is not only the mainstay of loco-regional treatment, but it also allows disease staging and optimization of adjuvant chemotherapy through histopathological and immunohistochemical analysis of the biopsied tissue.

From a strict oncologic point of view, surgical treatment of breast cancer in young women does not differ greatly from that in older women, but the physical consequences of large breast resections can have a major impact on self image, and can result in significant emotional and psychosocial distress in younger women [START_REF] Dow | Quality of life, survivorship, and psychosocial adjustment of young women with breast cancer after breast-conserving surgery and radiation therapy[END_REF]. Moreover, the fact that the majority of women in this age group are of childbearing age calls for the need to consider distinct aspects of surgical treatment [START_REF] Anders | Breast cancer before age 40 years[END_REF][START_REF] Shannon | Breast cancer in adolescents and young women[END_REF].

When choosing between a conservative or a more radical surgical approach, it is also important to bear in mind that breast tumors in younger patients tend to be strongly associated with a family history of breast cancer, and therefore patients have an increased risk for carrying BRCA1 or BRCA2 (BRCA1/2) mutations [START_REF] Lalloo | BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives[END_REF]. In confirmed cases of BRCA1/2 mutations, risk-reducing salpingo-oophorectomy has been demonstrated to be the best strategy [START_REF] Rebbeck | Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers[END_REF]. In patients with established disease, radical mastectomy (RM), instead of breast-conserving surgery (BCS), is the most sensible approach [START_REF] Axelrod | Breast cancer in young women[END_REF].

Surgical treatment in localized disease

As in other malignant solid tumors, local surgery consists of the excision of the primary tumor with acceptable resection margins. In the case of breast cancer, and particularly in young women, tumor excision should be accomplished while preserving as much breast tissue as possible in order to achieve a satisfactory cosmetic result.

BCS (lumpectomy or partial mastectomy)

Several issues must be evaluated when deciding between BCS or RM; some of them are inherent to this particular age group, and others are common to all breast cancer patients.

De Bock et al [START_REF] De Bock | The impact of loco-regional recurrences on metastatic progression in early-stage breast cancer: a multistate model[END_REF] showed that younger age (defined as < 40 years of age versus > 50 years of age) and breast-conserving therapy were risk factors for isolated loco-regional recurrence. More recently, van der Leest et al [START_REF] Van Der Leest | The safety of breast-conserving therapy in patients with breast cancer aged < or = 40 years[END_REF] found that the risk of local recurrence and contralateral breast cancer in women younger than 40 years who underwent BCS decreased by more than 50% in those who had received adjuvant systemic treatment. This finding argues in favor of advising the use of adjuvant chemotherapy in all patients aged 40 years or less who undergo BCS.

The use of early screening programs for breast cancer has allowed the identification of increasingly smaller tumors, and consequently the possibility of performing more conservative surgery. However, because breast tissue in young women is morphologically and structurally different from that in older women [START_REF] Devolli-Disha | Comparative accuracy of mammography and ultrasound in women with breast symptoms according to age and breast density[END_REF], and sensitivity and specificity of mammography is substantially less, in consequence diagnosis of breast cancer is sometimes delayed, and at diagnosis, tumors tend to be larger [START_REF] Bharat | Patient and tumor characteristics associated with increased mortality in young women (< or =40 years) with breast cancer[END_REF].

Pregnancy, which is frequently associated with breast cancer in this group of women, remains a therapeutic challenge. Nevertheless, studies indicate that overall, surgery and chemotherapy can be performed during pregnancy, whereas radiotherapy and endocrine or antibody treatment should be postponed until after delivery [START_REF] Lenhard | Breast cancer and pregnancy: challenges of chemotherapy[END_REF].

The possibility of carrying out conservative surgery in candidate patients largely depends on tumor size, multicentricity and breast volume. Multicentricity, understood as multiple tumor foci involving different quadrants of the breast, should be considered a contraindication for BCS [START_REF] Arriagada | Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group[END_REF]. If the tumor size is too large, or the breast volume too small to allow surgical resection with acceptable volume and shape-wise esthetic results, then a RM should also be considered.

Before surgery, two important aspects must be discussed with the patient. The first is the possibility of neoadjuvant chemotherapy. Studies have shown that neoadjuvant chemotherapy may lead to complete clinical response in 10-30% and partial responses in 50-60% [START_REF] Rustogi | Management of locally advanced breast cancer: evolution and current practice[END_REF]. Prior to neoadjuvant chemotherapy, tumor marking is essential to identify reduced lesions in good responders [START_REF] Newman | Surgical issues and preoperative systemic therapy[END_REF], as well as breast magnetic resonance imaging before and after neoadjuvant therapy to assess local extent [START_REF] Mameri | Impact of breast MRI on surgical treatment, axillary approach, and systemic therapy for breast cancer[END_REF]. Secondly, if a conservative approach is feasible, but the almost inevitable asymmetry it will produce is a concern for the patient, symmetrizing surgery of the other breast may be warranted, which can be carried out either during the primary surgery or at a later date.

Plastic surgical techniques in breast cancer surgery (i.e. oncoplastic breast surgery) allow cosmetic preservation of the breast after neoadjuvant chemotherapy and adjuvant radiotherapy. They combine oncologic extirpation of the tumor with immediate reconstruction of breast shape and symmetry through the use of diverse surgical techniques chosen according to the tumor, and size and form of the breast [START_REF] Franceschini | Conservative and radical oncoplastic approches in the surgical treatment of breast cancer[END_REF].

RM and breast reconstruction

RM refers to a variety of surgical procedures involving complete removal of the breast and some of the axillary lymph nodes [START_REF] Rustogi | Management of locally advanced breast cancer: evolution and current practice[END_REF]. When BCS is not feasible because of the need for multiple breast tissue resections, or for performing a prophylactic contralateral mastectomy due to genetic predisposition to the disease, breast reconstruction should be considered. A number of studies support the benefits of breast reconstruction from a psychological point of view, particularly in younger women [START_REF] Eldor | Breast reconstruction after bilateral prophylactic mastectomy in women at high risk for breast cancer[END_REF]. However, some aspects regarding the ideal technique and optimal timing of breast reconstruction are still controversial.

Breast reconstruction can be carried out using the patient's own tissue (autologous breast reconstruction) or with the aid of breast prostheses and expanders (heterologous breast reconstruction). Nonetheless, the need to administer adjuvant radiotherapy is a major limiting factor for a successful outcome in the case of heterologous reconstructions. Current data indicate that complications develop in more than 40% of patients undergoing post-mastectomy radiotherapy [START_REF] Kronowitz | Radiation therapy and breast reconstruction: a critical review of the literature[END_REF]. Although radiotherapy by itself is not an absolute contraindication for breast reconstruction, some authors recommend delaying the breast reconstruction procedure until radiotherapy has been administered, because it improves the chances of obtaining favorable cosmetic results, and avoids difficulties related to the optimal radiation delivery after an immediate reconstruction [START_REF] Kronowitz | Radiation therapy and breast reconstruction: a critical review of the literature[END_REF][START_REF] Fernández-Frías | Immediate reconstruction after mastectomy for breast cancer: which factors affect its course and final outcome?[END_REF].

Traditionally, RM involved the excision of the nipple-areola complex (NAC). Some authors have declared that nipple-sparing mastectomy should not be advocated in cases of large tumors, positive lymph node disease, small tumor-nipple distance, and clinical suspicion of nipple or areola involvement [START_REF] Cense | Nipplesparing mastectomy in breast cancer: a viable option?[END_REF][START_REF] Cunnick | Skin-sparing mastectomy[END_REF]. More recent studies show broader indications for NAC conservation, the absolute contraindications being extensive tumor involvement of the skin, inflammatory breast cancer and a clinically suspicious nipple [START_REF] Paepke | Subcutaneous mastectomy with conservation of the nipple-areola skin: broadening the indications[END_REF].

Sentinel node biopsy (SNB)

Axillary surgery is an important part of loco-regional treatment of breast cancer, not only as a therapeutic procedure, but also to evaluate the extent of the disease, since the degree of axillary lymph node involvement is the most significant prognostic factor for patients with early-breast cancer. SNB is increasingly being used as an axillary staging method for patients with early-stage cancer, although its impact on tumor recurrence and patient survival is as yet unknown. Compared to axillary lymph node dissection, SNB produces significantly fewer complications, which include lymphedema, nerve injury, and shoulder dysfunctions [START_REF] Lyman | American Society of Clinical Oncology Guideline Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer[END_REF].

Besides physician experience, another factor affecting the identification rate of sentinel nodes is the patient's age. Studies have shown that an age of 60 years or older results in significantly lower rate of identification than in women below that age, and that for every increase of 1 year of age, the odds of successful SNB identification decreases by 0.05 [START_REF] Lyman | American Society of Clinical Oncology Guideline Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer[END_REF].

SNB is perfectly feasible in women younger than 40 years. However, issues of safety in pregnant women are still a matter of debate, among other reasons, because of the need to use radioactive markers. Currently the most sensible approach is to openly discuss the benefits and risks with the patient before making any decision [START_REF] Mondi | Sentinel lymph node biopsy during pregnancy: initial clinical experience[END_REF].

Surgical treatment in systemic disease

Standard treatment of stage IV breast cancer does not usually involve surgical resection of the primary tumor unless it is causing symptoms, such as tumor ulceration or infection. However, during the last decade several retrospective trials have shown that surgical resection of the primary tumor is associated with a reduction in mortality risk of around 40% when performed early after the diagnosis [START_REF] Ruiterkamp | Surgical resection of the primary tumour is associated with improved survival in patients with distant metastatic breast cancer at diagnosis[END_REF].

The presence of systemic metastases immediately confers a worse prognosis.

Nevertheless, surgical treatment may be feasible in selected candidates, i.e. young patients with metastasis confined to a single organ (involving one or more resectable, metastatic lesions), good performance status and in whom immunohistochemical markers reveal tumors likely to be sensitive to specific chemotherapeutic agents or targeted therapies [START_REF] Durán | Papel de la cirugía en las metástasis del cáncer de mama[END_REF].

Conclusions

Surgical treatment underpins the management of breast cancer. Although technically similar, in contrast to older women the physical consequences of breast resections can have a major psychosocial and emotional impact on younger women. Also, pregnancy and fertility are a special concern in younger women when deciding the best surgical approach. Surgical treatment can be divided into BCS (lumpectomy) or RM. Factors affecting the decision between using the two approaches include tumor size, multicentricity, breast volume and genetic predisposition to the disease (i.e. BRCA1/2 mutation carriers). Fortunately, due to major advances in the field of oncoplastic surgery, better and more esthetic results are being increasingly obtained. In the case of advanced breast cancer, recent data indicate that surgical resection of the primary tumor is associated with a significant increase in survival rate when carried out soon after diagnosis, which may bring hope to many women with stage IV disease.

Acknowledgements

The authors acknowledge the support of Pfizer Spain, which has facilitated the necessary meetings to evaluate and discuss all the data presented in this review, and Dr. Ximena Alvira from HealthCo SL (Madrid, Spain) for assistance in the preparation of this manuscript.


MD Álvaro Rodríguez-Lescure

Adjuvant chemotherapy in young women with breast cancer

Introduction

Adjuvant chemotherapy in operable breast cancer is a field that has not stopped evolving since 1976 when Bonadonna et al [START_REF] Bonadonna | Combination chemotherapy as an adjuvant treatment in operable breast cancer[END_REF] observed a reduction in the risk of recurrence of breast cancer in women with positive axillary lymph nodes after having received a combination of cyclophosphamide, methotrexate and 5-fluorouracil. Later, anthracyclines and taxanes were incorporated into polychemotherapy regimens, and further improvements in terms of disease free-survival (DFS), overall survival (OS) and loco-regional control were obtained [START_REF] Levine | Adjuvant chemotherapy for breast cancer--30 years later[END_REF][START_REF] López-Tarruella | Recent advances in systemic therapy: advances in adjuvant systemic chemotherapy of early breast cancer[END_REF]. Today, many different combinations of cytotoxic agents exist, but because of the lack of specific markers for response to individual chemotherapeutic agents, there are no clear indications to prefer one particular regimen over another in the setting of adjuvant chemotherapy [START_REF] Goldhirsch | Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009[END_REF].

Benefits of adjuvant chemotherapy in breast cancer

The last quinquennial meta-analysis of the Early Breast Cancer Trialists' Collaborative Group on adjuvant chemotherapy, which included overviews from 1985 to 2000, showed that being treated for approximately 6 months with an anthracycline-based polychemotherapy reduces the annual breast cancer death rate by approximately 38% in women younger than 50 years old, an effect that is largely independent of the use of tamoxifen, and estrogen receptor (ER) status, lymph node involvement, or other tumor characteristics. They also demonstrated that these benefits were significantly better than those obtained with a regimen of cyclophosphamide, methotrexate and 5fluorouracil [START_REF]Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials[END_REF].

In the largest meta-analysis of randomized trials to date on the efficacy of incorporating taxanes into anthracycline-based regimens for early breast cancer, De Laurentiis et al [START_REF] De Laurentiis | Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials[END_REF] reported that taxane administration resulted in an absolute 5-year risk reduction of 5% for DFS, and 3% for OS in patients with high-risk early breast cancer, regardless of ER status, lymph node involvement, type of taxane, age, menopausal status and administration schedule. Nevertheless, despite the advantages of adjuvant chemotherapy, the magnitude of the benefit is modest, and approximately 100 patients have to be treated to benefit only 3-5 of them [START_REF] López-Tarruella | Recent advances in systemic therapy: advances in adjuvant systemic chemotherapy of early breast cancer[END_REF]. In addition, adjuvant chemotherapy is associated with considerable adverse effects, such as cardiac, bone and hematologic toxicities. In younger women, gynecological adverse effects such as infertility and premature ovarian failure are of particular importance.

Benefits of adjuvant chemotherapy in young women with breast cancer

Young women are considered a unique group of breast cancer patients in terms of tumor biology and genetics. According to several studies, breast tumors in young women are often larger, have a higher tumor grade, mitotic rate, and lymphatic vascular invasion, increased expression of human epidermal growth factor receptor-2 (HER-2), and lower estrogen and progesterone receptor expression than those of their older counterparts [START_REF] Anders | Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression[END_REF][START_REF] Bharat | Patient and tumor characteristics associated with increased mortality in young women (< or =40 years) with breast cancer[END_REF]. Altogether, these features contribute to the higher rates of loco-regional recurrences and worse prognosis observed in young patients [START_REF] Zhou | Factors affecting outcome for young women with early stage invasive breast cancer treated with breast-conserving therapy[END_REF][START_REF] Xiong | Female patients with breast carcinoma age 30 years and younger have a poor prognosis: the M.D. Anderson Cancer Center experience[END_REF].

However, the amount of information on breast cancer in young women is limited. The fact that the incidence of breast cancer in women younger than 35 years is relatively low, representing approximately 11% of all breast cancer patients according to the latest (2002-2006) National Cancer Institute Surveillance, Epidemiology and End Results data (http://seer.cancer.gov/statfacts/html/breast.html), may be partly responsible for the underrepresentation of this age group in clinical trials.

Consequently, guidelines and recommendations on treatment approaches are generally derived from larger trials including women of different age groups, or retrospective studies involving small samples. Moreover, differences in the cut-off age for considering a woman as young further affects the interpretation of results. Because of this, at present it is not very clear whether young women should be treated differently from older women [START_REF] Peppercorn | Breast cancer in women under 40[END_REF], but what is certain is that young women seem to obtain especial benefit from adjuvant chemotherapy. Kroman et al [START_REF] Kroman | Factors influencing the effect of age on prognosis in breast cancer: population based study[END_REF] conducted a study in 10356 women to evaluate if age at diagnosis was a negative prognostic factor in primary breast cancer, and how disease stage and the use of adjuvant chemotherapy influenced this association. Interestingly, they found that, compared with the other age groups included in the study (45-49, 40-44 and 35-39), women with low-risk breast cancer younger than 35 years who did not receive adjuvant chemotherapy were more than twice as likely to die as similarly treated older women. This increased risk remained when women were grouped according to the presence of node negative disease and by tumor size, and was not observed among women who did receive adjuvant chemotherapy. Their results indicate that in breast cancer, being younger can be considered itself a risk factor for increased mortality.

Therefore, young age alone may also be regarded as an indication for adjuvant chemotherapy [START_REF] Kroman | Factors influencing the effect of age on prognosis in breast cancer: population based study[END_REF].

More recently, Beadle et al [START_REF] Beadle | Ten-year recurrence rates in young women with breast cancer by locoregional treatment approach[END_REF] sought to determine the impact of several loco-regional treatment strategies on loco-regional recurrence (LRR) in patients under 35 years of age. Patients were treated with one of three treatment strategies: breast -conserving surgery, mastectomy or mastectomy followed by adjuvant radiotherapy. Adjuvant chemotherapy, generally doxorubicin-based, and taxane-based in patients with positive lymph nodes, was administered according to clinical staging, physician discretion and patient preference. Univariate analysis showed that the use of adjuvant chemotherapy had a statistically significant impact on the rate of distant metastases in the entire population. Multivariate analysis showed that lack of adjuvant chemotherapy had a statistically significant impact on LRR rates, regardless of whether patients were treated with breast-conserving surgery or mastectomy. This effect was not noted in patients with stage II disease. In patients with stage III disease, lack of adjuvant chemotherapy was associated with a worse OS [START_REF] Beadle | Ten-year recurrence rates in young women with breast cancer by locoregional treatment approach[END_REF].

Besides confirming that young women with breast cancer have high rates of LRR, the data presented in this study supports considering the use of adjuvant chemotherapy in young patients with stage I disease at diagnosis until more definite data on appropriate selection criteria are collected [START_REF] Beadle | Ten-year recurrence rates in young women with breast cancer by locoregional treatment approach[END_REF].

Current recommendations for adjuvant chemotherapy in young women

Adjuvant chemotherapy is currently the standard of care for women with operable breast cancer. Nevertheless, important changes related to patient selection have been introduced in the latest St. Gallen Consensus [START_REF] Goldhirsch | Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009[END_REF]. Given the current state of knowledge of this disease, the classification of patients according to single independent risk factors, such as hormone receptor status, axillary node status, risk of recurrence, HER-2, and BRCA1/2 status, is no longer applicable. Tumors with low expression of ER, HER-2 overexpression and increased proliferation predict response to chemotherapy in general, not to specific agents. Only the categorization of patients as highly endocrine or incompletely endocrine responsive remains important for the selection of patients with ER positive tumors to receive chemotherapy [START_REF] Goldhirsch | Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009[END_REF].

According to the St. Gallen Consensus, adjuvant chemotherapy is definitely indicated in women with triple-negative disease who are at sufficient risk of relapse to justify its use, and in patients with HER-2 positive invasive breast cancer along with or before administration of trastuzumab [START_REF] Goldhirsch | Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009[END_REF].

It is generally accepted that patients with high expression of ER obtain less benefit from the addition of adjuvant chemotherapy than from endocrine therapy. Nevertheless, data presented by the International Breast Cancer Study Group on DFS and OS indicate that younger women (<35 years) with ER positive tumors have a significantly worse DFS than those with ER negative tumors (25% vs 47%, respectively; p=0.014). In contrast, results for younger and older premenopausal patients are similar if their tumors are classified as endocrine nonresponsive [START_REF] Goldhirsch | Adjuvant therapy for very young women with breast cancer: need for tailored treatments[END_REF].

Therefore, the use of adjuvant chemotherapy, even in young women with endocrineresponsive tumors, seems to be justifiable.

Adverse effects of adjuvant chemotherapy in young women

Young women with breast cancer face special issues when discussing systemic therapeutic options for their disease, which include concerns about quality of life, fertility preservation and pregnancy [START_REF] Hickey | Breast cancer in young women and its impact on reproductive function[END_REF]. Chemotherapy-induced amenorrhea (CIA) due to ovarian failure is a common adverse effect seen in cancer patients. The incidence of CIA ranges from 20% to 68%, although it is largely dependent on patient age at diagnosis, ovarian function at the time of treatment and cytotoxic regimen used [START_REF] Hickey | Breast cancer in young women and its impact on reproductive function[END_REF][START_REF] Lee | Chemotherapy-related amenorrhea in premenopausal women with breast cancer[END_REF][START_REF] Chabbert-Buffet | Pregnancy after breast cancer: A need for global patient care, starting before adjuvant therapy[END_REF]. Fortunately, in a large proportion of young patients, menses return after the treatment is stopped [START_REF] Hickey | Breast cancer in young women and its impact on reproductive function[END_REF].

If ovarian failure and permanent CIA are a concern, several fertility preservation strategies can be offered to the patient. Unfortunately, reliable data are scarce, and the majority comes from non-randomized trials and observational studies. Some of the methods frequently used on young patients reported in these studies are ovarian protection with gonadotropin-releasing hormone agonists, embryo cryopreservation following in vitro fertilization, ovarian stimulation followed by oocyte cryopreservation, and ovarian tissue cryopreservation [START_REF] Cruz | Fertility preservation in women with breast cancer undergoing adjuvant chemotherapy: a systematic review[END_REF]. It should be kept in mind that each technique carries potential disadvantages that must be weighed against the advantages [START_REF] Hickey | Breast cancer in young women and its impact on reproductive function[END_REF].

Conclusions

The issue of whether young women with breast cancer should be treated differently from older women is a matter of debate, partly because of the lack of randomized trials comparing different strategies in this age group. Nevertheless, because existing data indicate that overall young women have a worse prognosis and clinical outcome, they seem to obtain especial benefit from adjuvant chemotherapy. Currently, no single independent risk factor should be used to guide patient selection, although determination of hormone receptor status remains important. In this particular group of patients, the effects of adjuvant chemotherapy on fertility and ovarian function, as well as the available fertility-preserving strategies, must be openly discussed with the patient to minimize the impact on quality of life.

Acknowledgements

The authors acknowledge the support of Pfizer Spain, which facilitated the necessary meetings to evaluate and discuss all the data presented in this review, and Dr. Ximena Alvira from HealthCo SL (Madrid, Spain) for assistance in the preparation of this manuscript.


Manuel Las

MD Heras González

Manuel De Las

Radiation therapy in young women with breast cancer

Introduction

Breast cancer is the most common cause of cancer death in women aged 20 to 59 years [START_REF] Jemal | Cancer Statistics[END_REF]. Younger women with breast cancer are considered a unique group of patients, among other reasons because data from epidemiological, retrospective studies indicate that young women have worse clinical outcomes, increased rates of loco-regional recurrences (LRR), and a lower overall 5-year survival [START_REF] Bharat | Patient and tumor characteristics associated with increased mortality in young women (< or =40 years) with breast cancer[END_REF][START_REF] Xiong | Female patients with breast carcinoma age 30 years and younger have a poor prognosis: the M.D. Anderson Cancer Center experience[END_REF].

The fact that young women are more likely to present higher grade tumors at diagnosis than their older counterparts is partly responsible for the poorer prognosis. Young women are not screened as rigorously as older women, and the anatomical characteristics of the breast tissue for that age group makes it difficult to differentiate between normal and tumor tissue in a mammogram [START_REF] Axelrod | Breast cancer in young women[END_REF].

Intrinsic tumor characteristics also contribute to the worse prognosis in young patients.

Breast cancer in young women is considered a unique biologic and oncologic entity.

Tumors in younger patients (less than 40-45 years old) are frequently estrogen receptor-and progesterone receptor-negative, have an increased expression of Ki-67, human epidermal growth factor receptor-2 (HER-2/EGFR) and p53, and have greater lymphovascular invasion [START_REF] Axelrod | Breast cancer in young women[END_REF][START_REF] Hartley | Differential expression of prognostic factors and effect on survival in young (< or =40) breast cancer patients: a case-control study[END_REF][START_REF] Anders | Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression[END_REF].

Young women are also considered to have a higher risk of developing LRR after breast-conserving surgery (BCS) than their older counterparts. Voogd et al [START_REF] Voogd | Differences in risk factors for local and distant recurrence after breastconserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials[END_REF] reported that women younger than age 35 had a more than nine-fold (hazard ratio: 9.24) greater risk of local recurrence after breast-conserving therapy than older women, but young women treated with mastectomy had a similar rate of chest wall recurrence compared with older patients.

On the other hand, recent evidence suggests that, although still higher than would be expected for older women, the incidence of local breast tumor recurrences and failures may be substantially lower than previously [START_REF] Zhou | Factors affecting outcome for young women with early stage invasive breast cancer treated with breast-conserving therapy[END_REF]. This apparent risk reduction seems to stem from several factors, including the widespread use of systemic adjuvant therapy (endocrine and/or cytotoxic) and loco-regional treatments (surgery and/or radiotherapy) [START_REF] Axelrod | Breast cancer in young women[END_REF][START_REF] Fredriksson | Risk factors for local recurrence after breast-conserving surgery[END_REF].

Factors that significantly influence local control in young women treated with BCS include the presence of positive surgical margins, a negative lymph node status and positive family history [START_REF] Jobsen | The value of a positive margin for invasive carcinoma in breast-conservative treatment in relation to local recurrence is limited to young women only[END_REF][START_REF] Jobsen | The impact of age on local control in women with pT1 breast cancer treated with conservative surgery and radiation therapy[END_REF]. Jobsen et al [START_REF] Jobsen | The value of a positive margin for invasive carcinoma in breast-conservative treatment in relation to local recurrence is limited to young women only[END_REF] demonstrated that in women aged 40 years or less, the 5-year local recurrence rate was 8% in patients with negative margins and 37% in patients with positive margins. Also, the 5-year disease-free survival was 27% in patients with positive margins and 75% in those with negative margins [START_REF] Jobsen | The value of a positive margin for invasive carcinoma in breast-conservative treatment in relation to local recurrence is limited to young women only[END_REF].

Impact of adjuvant radiotherapy in women with breast cancer

Radiotherapy has been used for over sixty years in the treatment of breast cancer.

During this time, it has been the subject of a vast number of randomized studies alone or in combination with other cancer treatments, showing that it not only improves locoregional control of the breast tumor, but may also increase overall survival [START_REF] Freedman | Radiation therapy for operable breast cancer: sixty years of progress as seen through the articles published in the journal Cancer[END_REF].

In the early years, the type of radiation therapy used for breast cancer consisted of lowvoltage beams (orthovoltage) that had limited penetration and were highly absorbed by the bone compared to soft tissue. Acute skin reactions were the major dose-limiting factor, and late effects of radiation included skin necrosis, fibrosis, atrophy, ulceration, fractures, lymphedema or even the need for palliative mastectomy. In addition, local control rates were dismal [START_REF] Freedman | Radiation therapy for operable breast cancer: sixty years of progress as seen through the articles published in the journal Cancer[END_REF].

Nowadays, the efficacy of radiotherapy in combination with surgery (pre-or postsurgery) for the control of subclinical disease, local control and survival, is unquestionable, and currently it is considered critical in the management of operable and locally advanced breast cancer [START_REF] Rustogi | Management of locally advanced breast cancer: evolution and current practice[END_REF]. In a trial from the Danish Breast Cancer Group including 3083 patients, adjuvant radiotherapy significantly decreased the 18year probability of any breast cancer event from 73% in high-risk patients who did not receive adjuvant radiotherapy to 59% in patients who received adjuvant radiotherapy. Also, in the same order, LRR rates decreased significantly from 49% to 14%, the probability of distant metastases after a LRR dropped from 35% to 6%, and the probability of distant metastases reduced from 64% to 53% [START_REF] Nielsen | Study of failure pattern among high-risk breast cancer patients with or without postmastectomy radiotherapy in addition to adjuvant systemic therapy: long-term results from the Danish Breast Cancer Cooperative Group DBCG 82 b and c randomized studies[END_REF].

Veronesi et al [START_REF] Veronesi | Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer[END_REF] carried out a randomized trial to compare the efficacy of radical mastectomy with that of BCS followed by adjuvant radiotherapy. Seven hundred and one women with breast cancers smaller than 2 cm in diameter were enrolled. After a median of 20 years of follow-up, they found that long-term survival rate among women who underwent BCS followed by adjuvant radiotherapy was comparable to that of women who underwent a radical mastectomy.

In early breast cancer, where variations in local treatment can considerably affect the risk of LRR and, hence, long-term survival, adjuvant radiotherapy has also been demonstrated to significantly reduce the rate of LRR from 26% to 7% in patients without and with radiotherapy, respectively [START_REF] Clarke | Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials[END_REF].

Impact of adjuvant radiotherapy in young women with breast cancer

To date, there are few studies on adjuvant radiotherapy conducted exclusively in young women with breast cancer. However, this situation seems to be changing, and studies providing meaningful data are being published with increased frequency. Garg et al [START_REF] Garg | Effect of postmastectomy radiotherapy in patients <35 years old with stage II-III breast cancer treated with doxorubicin-based neoadjuvant chemotherapy and mastectomy[END_REF] analyzed retrospectively 107 consecutive cancer patients aged 35 years or less with stage IIA to IIIC breast cancer treated with doxorubicin-based chemotherapy and mastectomy, with or without adjuvant radiotherapy. They found that, compared with patients who did not receive adjuvant radiotherapy, patients who did had a significantly better 5-year loco-regional control rate (63% vs 88%, respectively) and 5-year overall survival rate (48% vs 67%, respectively).

More recently, Beadle et al [START_REF] Beadle | Ten-year recurrence rates in young women with breast cancer by locoregional treatment approach[END_REF], conducted a retrospective study to evaluate the impact of BCS, mastectomy alone, or mastectomy plus adjuvant radiotherapy on LRR rates in 652 patients aged 35 years or younger. After a median follow-up period of 114 months, the 10-year actuarial LRR rates in the entire cohort were 20% for BCS, 24% for mastectomy and 15% for mastectomy plus adjuvant radiotherapy. When divided according to disease stage, patients with stage I disease showed no differences in LRR rates according to the treatment strategy. However, in patients with stage II disease, the best loco-regional control rates were achieved with mastectomy plus adjuvant radiotherapy.

On the other hand, the issue of whether mastectomy followed by radiotherapy is superior to BCS followed by radiotherapy is also a matter of debate in young patients, because of the desire to achieve the best cosmetic outcome possible without risking clinical efficacy. In one of the largest meta-analyses to date, Clarke et al [START_REF] Clarke | Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials[END_REF] evaluated the relationship between different local treatments (radiotherapy vs no radiotherapy; more extensive vs less extensive surgeries; and more extensive surgeries vs radiotherapy) and overall mortality in data obtained from 42000 women involved in 78 randomized treatment comparisons. Among other results, they found that BCS followed by radiotherapy yielded similar absolute gains in terms of 5-year LRR rates, 15-year breast cancer mortality risk and overall mortality as mastectomy followed by radiotherapy. Moreover, regardless of age and tumor characteristics, radiotherapy produced similar reductions in LRR rates in all major trials [START_REF] Clarke | Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials[END_REF].

Impact of boost radiotherapy in young women with breast cancer

Although studies evaluating the use of boost radiotherapy have not demonstrated a significant correlation between its relative effect on loco-regional control and the patient's age, nevertheless because younger patients have an increased risk of LRR they may obtain more benefit than their older counterparts from this additional procedure [START_REF] Antonini | Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882[END_REF][START_REF] Bartelink | Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial[END_REF][START_REF] Jones | Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the EORTC boost versus no boost trial[END_REF]. However, to date no studies have demonstrated benefits from boost radiotherapy regarding overall survival in patients with breast cancer, and adverse events, such as severe fibrosis, may increase significantly [START_REF] Bartelink | Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial[END_REF].

Complications from adjuvant radiotherapy

The last decade has brought about important improvements in the simulation, planning and delivery of radiotherapy. Acute and long-term skin, cardiac and lung toxicities have been reduced with the use of intensity-modulated radiation therapy [START_REF] Freedman | Radiation therapy for operable breast cancer: sixty years of progress as seen through the articles published in the journal Cancer[END_REF]. Although more than 90% of women develop mild to moderate grade acute radiation dermatitis, and moist desquamation occurs in approximately 30% of women, the incidence of arm and breast edema has reduced to approximately 20% [START_REF] Freedman | Radiation therapy for operable breast cancer: sixty years of progress as seen through the articles published in the journal Cancer[END_REF][START_REF] Back | Impact of radiation therapy on acute toxicity in breast conservation therapy for early breast cancer[END_REF]. In the long-term, fewer than 5% of women develop infection, and the cumulative incidence of myocardial infarction and coronary artery disease has decreased to 1% and less than 3%, respectively [START_REF] Freedman | Radiation therapy for operable breast cancer: sixty years of progress as seen through the articles published in the journal Cancer[END_REF].

Another potential complication that may arise from the use of radiotherapy is the development of contralateral breast cancer and secondary tumors. Recent retrospective trials have shown that in women less than 40 years of age who receive more than 1.0 Grey of absorbed dose, or are irradiated with breast tangential fields, the risk of developing contralateral breast cancer may be 1.5 to 2.5-fold [START_REF] Stovall | Dose to the contralateral breast from radiotherapy and risk of second primary breast cancer in the WECARE study[END_REF][START_REF] Hooning | Roles of radiotherapy and chemotherapy in the development of contralateral breast cancer[END_REF] greater than unexposed women. No excess risk was observed in women older than 40 years of age. This risk increases with decreasing age, specially when there is a positive family history for breast cancer [START_REF] Hooning | Roles of radiotherapy and chemotherapy in the development of contralateral breast cancer[END_REF].

Conclusions

Evidence indicates that breast tumors in young women are a distinct biological and genetic entity. Young women have worse clinical outcomes, increased rates of LRR, and a lower overall 5-year survival than their older counterparts, characteristics that warrant the use of better preventive and therapeutic options. Currently, adjuvant radiotherapy is recommended for all women following BCT or mastectomy, because it significantly reduces the rate of LRR and overall mortality. In addition, younger patients with breast cancer may obtain greater benefit from the use of boost radiotherapy than older patients. Nowadays, complications and adverse events resulting from the use of radiotherapy have been notably reduced, although the greater risk of developing contralateral or secondary breast cancers in younger women is still a matter of concern. Hopefully, future randomized studies will shed light on unresolved issues regarding the benefits of radiotherapy in young women with breast cancer.

Acknowledgements

The authors acknowledge the support of Pfizer Spain, which has facilitated the necessary meetings to evaluate and discuss all the data presented in this review, and Dr. Ximena Alvira from HealthCo SL (Madrid, Spain) for assistance in the preparation of this manuscript.


MD Antonio González Martín

Susana Cruz

Raúl Márquez

Susana De La Cruz

Adjuvant endocrine therapy in premenopausal women with breast cancer

Introduction

Adjuvant endocrine therapy is indicated in almost all women whose tumors show evidence of endocrine responsiveness, defined as the presence of any detectable level of estrogen receptors (ER). Patients with tumors <1 cm in size, without axillary node involvement or other signs of metastatic potential might be spared from adjuvant endocrine therapy [START_REF] Goldhirsch | Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009[END_REF]. Nevertheless, young women with breast cancer represent a particular therapeutic challenge, among other reasons because breast tumors in young women tend to have higher tumor grade at diagnosis, higher mitotic rate and lymph node involvement, and less hormone receptor expression [START_REF] Bharat | Patient and tumor characteristics associated with increased mortality in young women (< or =40 years) with breast cancer[END_REF]. Furthermore, in some studies the role of adjuvant therapy is not clear due to the inclusion of patients with ERnegative disease [START_REF] Carlson | NCCN Task Force Report: Adjuvant Therapy for Breast Cancer[END_REF]. This review will focus on endocrine therapy for patients younger than 40 years old. Patients between 40 and 50 years old are also a challenge because they may become amenorrheic with chemotherapy. In this specific subgroup of patients several consensus have been proposed. Figure 1 summarizes a consensus statement launched by a panel of experts in Spain [START_REF] Albanell | Consenso en el tratamiento hormonal adyuvante del cáncer de mama de pacientes premenopáusicas[END_REF].

Endocrine therapeutic options in young women

Around 60% of women younger than 50 years have ER-positive disease compared with 80% of women in postmenopausal status [START_REF] Anderson | Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database[END_REF], which means that more than half of all premenopausal women with early breast cancer could benefit from adjuvant endocrine therapy. Also, there is evidence suggesting that young women with ERpositive disease treated with adjuvant cytotoxic therapy alone have a significantly worse prognosis than women of the same age with ER-negative disease [START_REF] Aebi | Is chemotherapy alone adequate for young women with oestrogenreceptor-positive breast cancer?[END_REF][START_REF] Fisher | Findings from recent National Surgical Adjuvant Breast and Bowel Project adjuvant studies in stage I breast cancer[END_REF].

Consequently, additional endocrine therapy should be strongly considered in this age group.

Tamoxifen therapy in young women

Tamoxifen is a first-generation selective ER modulator that has a predominantly antagonistic effect in the breast and breast cancer cells. Traditionally, tamoxifen has been the standard of care for premenopausal women with early-stage ER-positive breast cancer. Results from the latest meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) [8] confirmed that allocation to approximately 5 years of adjuvant tamoxifen in women with ER-positive or ER-unknown disease resulted in a reduction in the annual recurrence rate of 41% (risk ratio 0.59; p=0.03) and the mortality rate of approximately 30% (risk ratio 0.66; p=0.04), largely irrespective of the use of chemotherapy, age, progesterone receptor status, or other tumor characteristics. This benefit was observed in women under 40 years of age (risk ratio 0.56; p=0.10) and in patients aged 41-49 years (risk ratio 0.71; p=0.07). In absolute terms, tamoxifen reduced by almost 10% the risk of relapse at 5 years.

Other interesting findings of this meta-analysis were that (i) the proportional risk reductions produced by tamoxifen were little affected by nodal status; (ii) 5 years of tamoxifen were significantly more effective than 1-2 years of tamoxifen, resulting in a reduction in the risk of recurrence of 18% (risk ratio 0.82; p=0.03) and risk of death of 9% (risk ratio 0.91; p=0.04 ) in women allocated to 5 years instead of 1-2; and (iv) the combination of tamoxifen with cytotoxic therapy is superior to tamoxifen therapy alone in patients younger than 50 years with ER-positive disease, regardless of the timing of tamoxifen administration in relation to cytotoxic therapy [8].

Further increases in the duration of tamoxifen therapy have not demonstrated additional clinical benefit, and have been associated with increased toxicity. The adjuvant Tamoxifen-To offer more? (aTTom) [START_REF] Gray | aTTom (adjuvant Tamoxifen--To offer more?): Randomized trial of 10 versus 5 years of adjuvant tamoxifen among 6,934 women with estrogen receptorpositive (ER+) or ER untested breast cancer--Preliminary results[END_REF] and 'Adjuvant Tamoxifen-Longer Against Shorter' (ATLAS) [10] trials are assessing the benefits and risks of prolonging adjuvant tamoxifen by at least 5 years. Preliminary results indicate that continuing tamoxifen beyond the first 5 years produces discrete reductions in the rate of recurrences, but does not seem to improve overall survival. Regarding timing, based on results from the Southwest Oncology Group Intergroup Trial S8814 (INT-100) [START_REF] Albain | ER) and/or progesterone (PgR) receptor-positive breast cancer: Mature outcomes and new biologic correlates on phase III intergroup trial 0100[END_REF], the current practice is to administer tamoxifen sequentially after adjuvant cytotoxic therapy.

Serious adverse events of tamoxifen therapy include an increased incidence of thromboembolic disease and uterine cancers, although mortality is not significantly increased [8].

Ovarian function suppression

Ovaries are the main site of estrogen production in premenopausal women. Therefore ovarian ablation/suppression is an effective endocrine therapeutic option to consider in young women with ER-positive disease. However, the timing and optimal duration of treatment are still a matter of debate and research.

In the EBCTCG overview [8], which included 7601 women aged 50 years or less with ER-positive or ER-unknown disease randomized into ovarian ablation/suppression trials, these treatments were associated with a decrease in the rate of recurrence and breast cancer mortality of 30%, and a 15-year absolute decrease in risk of 4%. No significant differences were detected in the effects of ovarian ablation from those of ovarian suppression, nor in the risk reduction for women <40 years from that of women who were 40-49 years of age. Interestingly, in any age range, outcome did not improve in women who had received concurrent adjuvant cytotoxic therapy. A possible explanation for this finding could be the ability of cytotoxic therapy to permanently reduce ovarian activity, thereby limiting the benefits provided by other ovarian treatments.

In order to determine the true benefits of ovarian suppression with luteinizing hormonereleasing hormone (LHRH) agonists, the LHRH-agonists in Early Breast Cancer Overview group [START_REF] Cuzick | Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials[END_REF] analyzed data from 16 randomized trials that included 9022 premenopausal women with hormone receptor-positive disease. The main results of the various comparisons are as follows:

 LHRH agonist vs no systemic therapy (n=338, 4 trials)

The use of a LHRH agonist alone did not have a significant effect on death after recurrence or death from any cause. However, a trend towards a reduction in the risk of recurrence was observed (HR 0.72; CI 95% 0.49-1.04; p= 0.08). This result is in line with the results of the EBCTCG overview [8], although the small sample size and the relatively short duration of treatment (for a median of 2 years) could have affected the statistical power of the analysis.

 LHRH agonist plus tamoxifen vs tamoxifen (n=1013, 5 trials)

The addition of LHRH agonist to tamoxifen did not improve the outcome of tamoxifen alone. However, there was a trend towards a lower recurrence rate when used together (HR 0.85; CI95%:0.67-1.09; p=0.20) and in the absence of other systemic therapy, significant reductions in recurrence and death from any cause were obtained. Again, the small sample size may have affected the statistical power of the analysis.

 LHRH agonist vs cytotoxic therapy (n=3184, 4 trials) No differences were observed in the risk of recurrence (HR 1.04) or death (HR 0.93) from breast cancer. In addition, no differences were observed in patients younger than 40 years. However, the extent of the results must be analyzed taking into account that the majority of cytotoxic regimens did not involve taxanes, and none of the treatment arms included tamoxifen.

 LHRH agonist plus tamoxifen vs cytotoxic therapy (n=1577, 3 trials)

Compared with cytotoxic therapy, the combination of LHRH plus tamoxifen did not significantly decrease the rate of recurrence or death from any cause, although a trend in favor of endocrine therapy was observed (HR 0.9; CI 95%: 0.75-1.08; p=25). Again, major criticisms of this analysis are the lack of tamoxifen in all the treatment arms, and the use of non-taxane-based cytotoxic regimens in the three studies that were analyzed (cyclophosphamide, methotrexate, and 5-fluorouracil [CMF] was used in two studies and 5-fluorouracil, epirubicin and cyclophosphamide in the other one).

 LHRH agonist plus cytotoxic therapy plus tamoxifen (n=1577, 11 trials) An analysis of a very heterogeneous group from 11 trials in women aged 40 years or younger seemed to show that the addition of a LHRH agonist to cytotoxic therapy with or without tamoxifen significantly reduced the rates of recurrence by 12% and death by 15% from any cause. However, a sub-analysis of patients according to age showed that the benefit was restricted to women aged 40 years or younger, suggesting that the benefits of LHRH agonists are restricted to young patients who do not develop chemotherapy-induced amenorrhea. This observation is in accordance with the results from the INT 0101 study. In this trial, the addition of a LHRH agonist and tamoxifen for 5 years to chemotherapy with 5fluorouracil, adriamycin, and cyclophosphamide (FAC) increased disease-free survival compared to FAC alone or FAC plus a LHRH analogue in node positive premenopausal women. However, the addition of a LHRH agonist to FAC without tamoxifen was associated to a significant increase in disease-free survival only in patients younger than 40 years, reinforcing the concept of the benefit of LHRH agonists in patients not becoming amenorrheic after chemotherapy [START_REF] Davidson | Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188)[END_REF].

Another important study not included in the above-mentioned meta-analysis, was the 'International Adjuvant Breast Cancer Ovarian Ablation or Suppression Trial'. In this trial, 2144 pre-or peri-menopausal women were randomized to tamoxifen with or without ovarian ablation or suppression. The majority of patients (80%) had received CMF-based chemotherapy. Although no significant differences were observed in disease-free survival or overall survival, the results are largely limited by the high rate of unknown hormonal receptor status (40%) and the rate of ER negative patients (20%) [14].

The abrupt interruption of ovarian function is a significant problem in young premenopausal patients. Adverse events may include severe menopause-related signs and symptoms, psychological distress, impaired quality of life, sexual dysfunction, changes in personal and family relationships and bone loss [START_REF] Goldhirsch | Adjuvant therapy for very young women with breast cancer: need for tailored treatments[END_REF][START_REF] Ganz | Breast cancer in younger women: reproductive and late health effects of treatment[END_REF][START_REF] Schover | Premature ovarian failure and its consequences: vasomotor symptoms, sexuality, and fertility[END_REF]. The ongoing Suppression of Ovarian Function Trial (SOFT) is addressing the question of whether younger premenopausal patients experience worse side effects from ovarian suppression/ablation than older premenopausal patients [START_REF] Parton | Controversies in the Management of Patients With Breast Cancer: Adjuvant Endocrine Therapy in Premenopausal Women[END_REF].

Aromatase inhibitors (AIs)

AIs are part of the standard adjuvant endocrine therapy in postmenopausal women. However, their role in younger women remains unclear. AIs alone are contraindicated in premenopausal patients because of a reduced feedback to the hypothalamus, which increases the secretion of LHRH and consequently stimulates ovarian function [START_REF] Goldhirsch | Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009[END_REF]. Furthermore, in women who have experienced chemotherapy-induced menopause, the use of AIs maybe associated with a return of ovarian function, and even pregnancy [START_REF] Smith | Adjuvant aromatase inhibitors for early breast cancer after chemotherapyinduced amenorrhoea: caution and suggested guidelines[END_REF].

In young women with ER-positive disease who are unable to tolerate tamoxifen, or in whom this therapy is contraindicated, AIs may be administered together with ovarian suppression [START_REF] Goldhirsch | Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009[END_REF]. The question of whether premenopausal patients obtain more benefit from tamoxifen alone, from tamoxifen plus ovarian suppression or from exemestane plus ovarian suppression is being further explored in the SOFT and the Tamoxifen and Exemestane Trial (TEXT) trials [START_REF] Parton | Controversies in the Management of Patients With Breast Cancer: Adjuvant Endocrine Therapy in Premenopausal Women[END_REF].

Conclusions

At this time, tamoxifen is the standard of care for young premenopausal women with ER-positive disease, and until further data from the aTTom and ATLAS trials are available, the standard duration of tamoxifen therapy remains 5 years. Currently, there is no evidence that ovarian suppression/ablation is superior to tamoxifen, except perhaps in women who have not developed chemotherapy-induced menopause. Some women are being offered treatment with ovarian suppression in association with AI therapy, mostly because of intolerance or contraindications for tamoxifen.

Nevertheless, confirmation of the benefits and risks of this association awaits results from the SOFT and TEXT trials. (2) This is the recommended option for women older than 45 years, as well as those aged 40-45 years with postmenopausal hormone levels at initial assessment. In all cases, FSH, LH and E2 levels, and the possible recurrence of menses, should be monitorized.

Abbreviations: AI: Aromatase inhibitors. CT: Chemotherapy. E2: Estradiol. FSH: Follicule stimulating hormone. LH: Luteinizing hormone. LMP: Last menstrual period. TAM: Tamoxifen.

Figure 1 .( 1 )

 11 Figure 1. Adjuvant endocrine treatment for estrogen receptor positive (ER+) women

Acknowledgements

The authors acknowledge the support of Pfizer Spain, which facilitated the necessary meetings to evaluate and discuss all the data presented in this review, and Dr. Ximena Alvira from HealthCo SL (Madrid, Spain) for assistance in the preparation of this manuscript.


MD Melchor Sentís
email: msentis@tauli.cat

Imaging diagnosis of young women with breast cancer

Introduction

Breast cancer in young women deserves special consideration as there are complex issues raised by a cancer diagnosis at a young age. Breast cancer in these women may present differently to breast cancer in older women and may be more difficult to diagnose. For women under the age of 40, there are also particular concerns regarding pregnancy, fertility and contraception, sexuality and body image, as well as familial and genetic issues.

Breast tumors in young women tend to be larger (median tumor size 2 cm in young women compared to 1.5 cm in older women), more advanced at diagnosis (more likely to be lymph node positive) and more aggressive (less well differentiated) than breast cancer in older women [START_REF] Foxcroft | The diagnosis of breast cancer in women younger than 40[END_REF]. Also, breast cancer in young women has a higher mortality and shorter disease free survival than in older women, and is more likely to recur locally or at distant sites after treatment [START_REF] Nixon | Relationship of patient age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer[END_REF].

The diagnosis of breast cancer in young women has limitations in terms of recruitment of patients and how the imaging diagnostic technologies come to them. Basically, there are two large groups of patients: symptomatic patients, in whom the physical examination reveals positive findings, and patients included in high-risk groups who are following protocols for early diagnosis. Recommendations for both groups differ and often overlap one another or are complicated with the recommendations from patients enrolled in clinical studies. The low suspicion of malignancy in young women due to the lower prevalence of cancer and lack of patient stratification according to risk profiles often leads to delays in diagnosis or in the delivery of the most appropriate treatment strategies based on their individual characteristics. Overall, this fact contributes to the worse long-term outcomes observed in this patient group [START_REF] Barber | Diagnostic delay in breast cancer[END_REF].

There are few studies evaluating this situation in depth. Recently, a prospective, multicenter cohort study including 220 young women with breast cancer reported that 80% of patients presented with a self-detected breast abnormality, and most of them were diagnosed soon after they developed a sign/symptom. However, nearly 25% delayed seeking medical attention and experienced a delay in diagnosis after seeking medical attention [START_REF] Ruddy | Presentation of breast cancer in young women[END_REF].

Digital mammography

Young women have a higher breast parenchymal density than older women, making it more difficult to differentiate between tumors and normal breast tissue [START_REF] Nubila | Radiological features and pathological-biological correlations in 348 women with breast cancer under 35 years old[END_REF]. According to the results of a study by Harris et al. [START_REF] Harris | Indications for breast imaging in women under age 35 years[END_REF] to determine the appropriate indications for breast imaging in 625 women aged 13-34 years young women, those with indications different from a palpable mass or a suspected abscess, i.e. associated with a very low likelihood of any imaging abnormality, should be followed up clinically rather than be referred for imaging studies.

In recent years, digital mammography has established itself as the most appropriate technique for diagnosing breast cancer, and is gradually replacing analog mammography. In the context of population screening, digital mammography has demonstrated its superior performance by both the easier reading and the improvement in the quality and consistency of images, and is far superior in some situations such as in dense breasts. The Digital Mammographic Image Screening Trial demonstrated that digital mammography had a considerable advantage among women under 50 years of age, perimenopausal, or women with dense breasts [START_REF] Pisano | Diagnostic performance of digital versus film mammography for breastcancer screening[END_REF].

In digital mammography, the process of image acquisition, display (both locally and remotely), and storage are separated, allowing optimization of each step and therefore providing substantial advantages. Transmitted radiation through the breast is absorbed by an electronic detector, a response which is faithful over a wide range of intensities.

Once this information is recorded, it can be displayed by using computer imageprocessing techniques to allow modification of image brightness and contrast settings without the need for further exposure to radiation. The standardization of medical image formats under the Digital Imaging and Communication in Medicine (DICOM) standard has universalized image quality criteria [START_REF] Lynes | Learning the fundamentals of[END_REF].

Digital mammography has a higher technological development than traditional mammography such as computer-aided diagnosis and detection (CAD) systems, tomosynthesis, telemammography, and an emerging field of future systems based upon administration of contrast and digital subtraction. These techniques are already available in the market and help assess objectively individual risk factors for breast cancer such as breast density [START_REF] Pisano | Digital mammography[END_REF].

The use of digital mammography in population programs improves detection rates, primarily because of improved contrast resolution and a higher sensitivity for detection of microcalcifications, without the need of increased exposure.

Breast ultrasound

Although mammography is the gold-standard for breast imaging, it is not an optimal screening tool, especially in cases of dense breast parenchyma. Breast ultrasound has not proven its value as a primary screening method for breast cancer, but it represents an additional diagnostic tool for the detection of benign and malignant breast lesions.

Thus, this technique is the method of choice for differentiating solid from cystic lesions, for further characterizing mammographic findings and for better identification of palpable breast lesions. Houssami et al. [START_REF] Houssami | Sydney Breast Imaging Accuracy Study: Comparative sensitivity and specificity of mammography and sonography in young women with symptoms[END_REF] showed that ultrasound was more sensitive than mammography in evaluating breast masses in women younger than 45.

Also, ultrasound has been demonstrated to be more sensitive than mammography for screening women with dense breasts, and hence, ultrasound may be particularly useful for surveillance of young women at high risk [START_REF] Kolb | Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations[END_REF]. Morrow et al. [START_REF] Morrow | The evaluation of breast masses in women younger than forty years of age[END_REF] showed that when mammography and ultrasound were performed concomitantly, 37% of imaging studies performed for a palpable breast mass in young women had abnormal findings. Any suspicious dominant breast mass should be biopsied, even if the imaging studies are negative.

Ultrasound has also a key role in guiding biopsy procedures and in studies to reevaluate incidental findings on magnetic resonance imaging (MRI). Additionally, it is the method of choice for the initial evaluation of the axilla in patients with a diagnosis of carcinoma [START_REF] Swinson | Ultrasound and fine needle aspiration cytology of the axilla in the pre-operative identification of axillary nodal involvement in breast cancer[END_REF], and allows the initial characterization of symptomatic lesions in young women.

Current ultrasound-associated developments include the use of contrast media to enhance lesion detectability, Doppler examination and elastography. Additionally, there is a recently developed prototype scanner that allows evaluation of the whole breast and then treating the images obtained in an evaluation console [START_REF] Athanasiou | How to optimize breast ultrasound[END_REF].

Breast MRI

For women at increased risk of breast cancer, screening technologies other than mammography may also contribute to the earlier detection of breast cancer, particularly in women under the age of 40 in whom mammography is less sensitive. The American Cancer Society (ACS) guidelines for the early detection of breast cancer state that women at increased risk of breast cancer might benefit from additional screening strategies beyond those offered to women at average risk (i.e. mammography and physical examination), such as earlier initiation of screening, shorter screening intervals, or the addition of screening modalities, including ultrasound and MRI [START_REF] Smith | American Cancer Society guidelines for breast cancer screening: update 2003[END_REF]. MRI is the most sensitive technique for the detection and characterization of malignant breast lesions. MRI has demonstrated its high sensitivity and moderate specificity in detecting both invasive carcinoma and carcinoma in situ not visible by other modalities, and has become the technique of choice for screening high-risk patients [START_REF] Saslow | American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography[END_REF]. MRI detects more cancers in high-risk women than mammography, with a sensitivity of 80% compared with 33% for mammography [START_REF] Kriege | Factors affecting sensitivity and specificity of screening mammography and MRI in women with an inherited risk for breast cancer[END_REF].

MRI is now being used for surgical planning in the setting of a known breast cancer, both to evaluate the extent of the disease, and to detect multifocal, multicentric, and contralateral malignancies. Tumor diameter measured by MRI correlates more closely with histologic measurements compared with mammography and ultrasound [START_REF] Lehman | MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer[END_REF]. MRI could be the preferred technique for the study and pre-treatment of detected lesions and the monitoring of patients in neoadjuvant chemotherapy. In all scenarios, due to its moderate specificity, MRI-guided biopsy methods are essential for proper characterization of lesions detected and only visible on MRI [START_REF] Kuhl | MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study[END_REF].

There are studies demonstrating the usefulness and impact of MRI in the management of local recurrence, the predictive value of MRI in differentiating between recurrence or secondary changes to treatment, and its ability to decrease recurrence rates when used as a method of radiation therapy planning [START_REF] Whipp | True Local Recurrence Rate in the Conserved Breast after Magnetic Resonance Imaging-Targeted Radiotherapy[END_REF].

Conclusions

Many high-risk women develop breast cancer before the age of 40. For these women, cancer risk is managed through vigilant surveillance, in hopes of identifying the disease at an early stage. Traditional surveillance methods for breast cancer include mammography, ultrasound and clinical breast examinations. While mammography is indicated for screening before and after diagnosis and for localization prior to guided biopsy, ultrasound is indicated for diagnosis and characterization of suspected lesions, especially in breasts with dense parenchyma, and for localization of lesions and guided biopsies. There is a need for other promising breast cancer screening techniques in women at high risk of breast cancer such as MRI. This need arises due to follow up after breast surgery when mammograms may be difficult to interpret. MRI may enable the distinction of tumour recurrence from the usual post-operative scarring.

The use of MRI in young women with breast cancer has a considerable performance despite the lack of evidence of improved survival or reduction in the staging of the lesions detected.

Acknowledgements

The authors acknowledge the support of Pfizer Spain, which facilitated the necessary meetings to evaluate and discuss all the data presented in this review, and Dr.

Fernando Sánchez-Barbero from HealthCo SL (Madrid, Spain) for assistance in the preparation of this manuscript.


MD Joan Brunet
email: jbrunet@ico.scs.es

Hereditary breast cancer and genetic counseling in young women

Introduction

It is well established that a family history of breast cancer is associated with an increased risk of developing breast cancer. In fact, among those variables that have been shown to bear a relationship with breast cancer, the highest risk, after age, is the presence of a positive family history of breast cancer [START_REF] Colditz | Family history, age, and risk of breast cancer. Prospective data from the Nurses' Health Study[END_REF].

Among breast cancer patients, up to 5%-10% are considered directly related to the inheritance of mutations in BRCA1 or BRCA2 genes [START_REF] Claus | The genetic attributable risk of breast and ovarian cancer[END_REF], which accounts for most hereditary breast cancers. Claus et al. [START_REF] Claus | The genetic attributable risk of breast and ovarian cancer[END_REF] estimated the proportion of breast cancer attributable to inherited autosomal dominant genes to be approximately 33% in subjects aged 20-29 years. This estimated risk decreased with age at onset to approximately 1.5% of case subjects aged 70 years or more. Women carrying these mutations have a lifetime risk of breast cancer of 60%-80% [START_REF] Easton | Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium[END_REF]; therefore, detection of mutations in these two genes can be used as a molecular predictor for breast cancer.

At present, data suggest that a mutation in BRCA1 accounts for the majority (80%-90%) of families containing multiple case subjects with breast and/or ovarian cancer, and approximately 45% of inherited breast cancers [START_REF] Easton | Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium[END_REF], whereas a mutation in BRCA2 is thought to account for approximately 35% of inherited breast cancers [START_REF] Easton | Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium[END_REF].

Genetic screening

As a consequence of current trends in multidisciplinary therapy for breast cancer, BRCA1 and BRCA2 genes are not only useful as molecular markers for hereditary breast cancer risk screening, but have also become important indicators for prevention, treatment and prognosis of breast cancer.

Screening for BRCA1 or BRCA2 mutations is difficult. In a large proportion of patients with breast cancer who have a family history strongly pointing to hereditary disease, a BRCA1 or BRCA2 mutation cannot be demonstrated. This may be partly explained by germline mutations in less common genes other than BRCA1 or BRCA2, such as in the TP53 gene, which is associated with Li-Fraumeni syndrome; in the PTEN gene, which is associated with Cowden syndrome; in the CHEK2 gene; or in the ataxia telangiectasia mutated gene [START_REF] Nusbaum | Susceptibility to breast cancer: hereditary syndromes and low penetrance genes[END_REF]. Mutations in BRCA1 or BRCA2 may be missed in current screening procedures, even with complete sequencing [START_REF] Andrulis | Comparison of DNA-and RNA-based methods for detection of truncating BRCA1 mutations[END_REF]. It is currently possible to detect about 90% of all BRCA1 or BRCA2 mutations by using standard diagnostic procedures, and a mutation is detected in almost 25% of cases presenting with familial cancer. Not all women are candidates for genetic testing. In order to maximize both the efficiency of testing and the public health impact of a genetic screening program, many centers offer screening to women when the prior probability of finding a mutation is 10% or greater [START_REF] Young | The prevalence of BRCA1 mutations among young women with triplenegative breast cancer[END_REF]. Several mathematical models such as BRCAPRO (http://astor.som.jhmi.edu/BayesMendel/brcapro.html) and the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) can be used to estimate the prior probability of carrying a mutation [START_REF] Euhus | Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO[END_REF][START_REF] Antoniou | The BOADICEA model of genetic susceptibility to breast and ovarian cancer[END_REF]. These models consider age of onset and family history of cancer.

Although the decision to offer genetic testing to a breast cancer patient is usually based on family history, if the family history is not available, some women may qualify for testing based on age of onset or the breast tumor's pathologic features.

Certain tumor characteristics can also be used to predict the presence of a mutation.

BRCA1-associated cancers are typically of high grade and 'triple negative' (i.e. negative for estrogen receptors [ER], progesterone receptors [PR] and human epidermal growth factor receptor-2 [HER2] expression) [START_REF] Foulkes | Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer[END_REF]. The majority of triple negative cancers (80% to 90%) also exhibit a basal phenotype (expression of cytokeratins and HER2). The proportion of basal phenotype BRCA1-associated cancers has been estimated at 88% [START_REF] Foulkes | Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer[END_REF].

The proportion of BRCA1-associated cancers that are ER-negative diminishes with increasing age of onset. Foulkes et al. [START_REF] Foulkes | Estrogen receptor status in BRCA1-and BRCA2-related breast cancer: the influence of age, grade, and histological type[END_REF] found that 81% of BRCA1-associated breast cancers diagnosed before age 45 were ER-negative, compared to 62% of breast cancers diagnosed after age 65.

Genetic syndromes that carry a significant risk of breast cancer are responsible for a small but significant percentage of these cancers. However, the vast majority of breast tumors occur in women with no family history of the disease. Non-genetic risk factors include age, previous breast disease, breast tissue density, radiation exposure, and lifestyle factors such as weight, exercise, and alcohol consumption [START_REF] Korde | Assessing breast cancer risk: genetic factors are not the whole story[END_REF].

When a woman under the age of 40 years develops breast cancer, a hereditary predisposition may be suspected whether there is a family history or not. If there is a family history of two or more family members under 50 years of age with breast cancer, male breast cancer, or ovarian cancer, or a Li-Fraumeni or Cowden syndrome is suspected, the likelihood of a genetic predisposition is high. If there is no family history, the suspicion that the breast cancer is due to a heritable genetic mutation is based in tumor bilaterality, tumor phenotype (triple negative and basal phenotypes), and a simultaneous diagnosis of ovarian cancer. It is also important to discard a possible paternal transmission due to little information regarding inheritance patterns.

Studies comparing survival between BRCA1 and BRCA2-associated and sporadic breast cancers have inconsistent results. The prognosis of the disease depends on whether the mutation has occurred in the BRCA1 or BRCA2 gene. If a mutation has occurred in BRCA1, some studies have attributed a similar prognosis when compared with sporadic breast cancer patients [START_REF] Gaffney | Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations[END_REF], while other studies have attributed a worse prognosis [START_REF] Brekelmans | Survival and prognostic factors in BRCA1-associated breast cancer[END_REF]. In BRCA2 mutation carriers, the prognosis may also be better [START_REF] Sigurdsson | Survival among breast cancer patients in families carrying the BRCA2 susceptibility gene[END_REF] or similar when compared with age-matched sporadic breast cancer patients [START_REF] Verhoog | Survival in hereditary breast cancer associated with germline mutations of BRCA2[END_REF].

Genetic counseling and management of women with hereditary breast cancer

A young woman with breast cancer will probably express her concern about whether her tumor is inherited because of the possibility of transmitting it to her offspring. The patient will also be concerned about whether there will be additional risks throughout her life to develop other mutations or, if by virtue of being inherited, she has a worse prognosis. Furthermore, knowing if breast cancer is inherited is important in deciding the treatment of advanced disease.

The discovery of BRCA1 and BRCA2 mutations has raised a number of questions regarding the optimal management of women with hereditary breast carcinoma. The appropriateness of breast-conserving therapy for women with hereditary breast carcinoma is an area of ongoing discussion. Women with BRCA-associated breast carcinoma who undergo breast-conserving surgery appear to have a risk of metachronous ipsilateral breast carcinoma similar to that reported for young women without known mutations [START_REF] Robson | Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: a clinic-based series[END_REF]. The indications for unilateral mastectomy in this group of women should therefore be the same as for women with nonhereditary carcinoma. However, a significant risk of contralateral breast carcinoma and possibly late metachronous ipsilateral breast carcinoma may prompt consideration of bilateral mastectomy as a preventive measure [START_REF] Robson | Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: a clinic-based series[END_REF]. A study by Garcia-Etienne et al. [START_REF] Garcia-Etienne | Breast-Conserving Surgery in BRCA1/2 Mutation Carriers: Are We Approaching an Answer?[END_REF] showed that the risk of ipsilateral breast tumor recurrence after breast-conserving surgery in BRCA1/2 mutation carriers was increased compared with patients who had sporadic breast cancer. Likewise, the risk of contralateral breast cancer seemed to be increased in this group.

Neoadjuvant chemotherapy for breast cancer is often given prior to surgery to decrease the size of the tumor so that breast-conserving surgery can be performed, and to reduce the probability of lymph node involvement. Patients with BRCA1/2 mutations show a better clinical response rate to neoadjuvant chemotherapy than patients without mutations in the BRCA gene.

The use of platinum-based neoadjuvant chemotherapy has been effective in a high proportion of patients with BRCA1-associated breast cancers [START_REF] Byrski | Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients[END_REF]. Another study reported that BCRA1/2 carriers showed a better clinical response rate to neoadjuvant treatment than non-carriers [START_REF] Chappuis | A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer[END_REF]. There is also a study that has demonstrated the therapeutic efficacy of treatment in advanced breast cancer. In a phase II trial, the efficacy of the oral poly (ADP-ribose) polymerase inhibitor olaparib in BRCA-deficient advanced breast cancer was evidenced [START_REF] Tutt | Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer[END_REF].

BRCA1/2 genes are transmitted in an autosomal dominant pattern. Because this can influence an individual's decision regarding reproduction, health care professionals should ensure patient education regarding the potential impact of BRCA inheritance on family planning. Preimplantation genetic diagnosis in women carrying BRCA mutations has been approved in some countries. Women at increased risk for hereditary cancer may consider this procedure as part of their reproductive decision making. Therefore, it is important to understand existing levels of awareness and attitudes toward this technology to provide optimal counseling and support [22].

Conclusions

The identification of a possible hereditary predisposition to breast cancer is important because the prevalence of familial breast cancer is sufficiently high to have a clinical impact. Importantly, genetic screening must be done at the time of diagnosis, not when adjuvant chemotherapy is being administered as has been done so far. This is because information regarding BRCA1/2 mutation status is important for the young patient with breast cancer in order to undertake opportune prophylactic measures, such as bilateral mastectomy, evaluate consequences on reproduction, make timely treatment decisions in case a breast tumor develops, and provide adequate genetic counseling to the patient and family members. Hospitals that do not have access to Genetic Counseling Units should have contact with a referral center.

Acknowledgements

The authors acknowledge the support of Pfizer Spain, which facilitated the necessary meeti ngs to evaluate and discuss all the data presented in this review, and Dr. Fernando Sánchez Barbero from HealthCo SL (Madrid, Spain) for assistance in the preparation of this manuscript.