Breast cancer in young women

Although uncommon, breast cancer in young women is worthy of special attention due to the unique and complex issues that are raised. This article reviews specific challenges associated with the care of younger breast cancer patients, which include fertility preservation, management of inherited breast cancer syndromes, maintenance of bone health, secondary prevention, and attention to psychosocial issues.


Introduction
Breast cancer incidence increases with age, with the vast majority of women diagnosed after the age of 40 years [1]. Nevertheless, approximately 7% of women diagnosed with breast cancer between 2000 and 2005 were below the age of 40 [2]. Interestingly, breast cancer risk factors, clinical outcomes, and tumor biology are somewhat diff erent in the subgroup of women below 40, suggesting that breast cancer in young women represents a distinct entity [3][4][5][6][7]. Th e defi nition of a 'young woman' in the fi eld of breast oncology varies, with most articles referring to women under either age 35 or 40 years as 'young' .

Epidemiology
Th e incidence of breast cancer in younger women diff ers according to race. Overall, breast cancer is more common in Caucasian women than in African Americans; however, in women under the age of 35, breast cancer is more than twice as common in African American women. Premenopausal African American women are more likely to have hormone receptor negative tumors (and even more specifi cally tumors of the basal phenotype) compared to Caucasian women [3,8]. Young African American women are more likely to be diagnosed at a more advanced stage than young Caucasians; however, after adjusting for stage, survival appears equivalent between races [4].
Delayed childbirth (fi rst child after age 30 years) is known to be a risk factor for breast cancer in women older than 35. Conversely, early childbearing seems to be a risk factor for developing breast cancer before the age of 35. Th is discrepancy could possibly be explained by the transient increase in breast cancer risk that occurs around 2 to 7 years following a pregnancy, but more infor mation is needed about this association [3].
Th e characteristics of tumors that arise in women under the age of 35 diff er from those that arise in premenopausal women who are older than 35. Women younger than 35 have a lower rate of ductal carcinoma in situ, likely due to detection bias (women in this age range do not typically have screening mammograms) [4]. Tumors in women younger than 35 are more likely to be of a higher histological grade [4] and to be classifi ed as estrogen receptor (ER) and progesterone receptor negative [5,6]. In addition, young women are more likely to have local recurrences, to be diagnosed at a more advanced stage, and to have an inferior 5 year survival compared to their older premenopausal counterparts [4,6,7].
Th ese diff erences in breast cancer risk factors, tumor characteristics, and clinical outcomes suggest that breast cancer arising in young women may be a distinct clinical entity. A study by Anders and colleagues [5] looked at tumor gene expression between two age specifi c cohorts (young, ≤45 years; and older, ≥65 years), and identifi ed 367 gene sets that could diff erentiate tumors in young women from tumors in older women. Th is suggests that breast cancer in young women may be distinct with a unique underlying biology. added benefi t of distinguishing solid masses from simple and complex cysts [9,13].
Currently, the American Cancer Society recommends a screening breast MRI for women with a 20 to 25% lifetime risk of breast cancer, which includes women with familial breast cancer syndromes (discussed below) and those who have received chest radiation for Hodgkin's lymphoma [14]. Breast MRI has high sensitivity for malignant lesions; however, specifi city is low, which can lead to unnecessary biopsies. In women in high risk groups, the benefi ts of MRI are considered to outweigh the risks of unnecessary biopsies. MRIs have also been shown to be more sensitive than mammograms, particu larly in women with dense breasts [15]; however, accord ing to American Cancer Society guidelines, breast density alone is not justifi cation for MRI screening at the current time.
In addition to considerations of MRI for primary screening, at the current time there is insuffi cient evidence to recommend for or against a breast MRI for women with personal histories of breast cancer [14] who do not have a BRCA1 or BRCA2 mutation.

Genetics
Breast cancer in a woman under age 35 years should prompt one to consider familial breast cancer syndromes and genetic testing for BRCA1/2 mutations and, less commonly, TP53 mutations. In a population-based case control study, the likelihood that a woman with breast cancer under the age of 35 had a detectable BRCA1/2 mutation was 9.4% (compared to a population prevalence of 0.2%) [16]; these fi ndings have been demonstrated by other studies as well. A family history of breast and/or ovarian cancer or Ashkenazi Jewish ancestry makes the probability of having a mutation even higher.
Tumor characteristics can help identify women who are likely to carry a BRCA1 mutation. High grade triple negative breast cancers (ER negative, progesterone receptor negative, and Her2 negative) are more common in women with BRCA1 mutations, whereas pathologic and immunohistochemical features of tumors associated with BRCA2 mutations are similar to those of sporadic cases [17]. A French study found the prevalence of BRCA1 mutations in women under age 35 years with triple negative and poorly diff erentiated tumors to be 28.6% (4 out of 14) regardless of family history [18]. Similarly, Lakhani and colleagues [17] derived BRCA1 mutation carrier probabilities on the basis of ER status and tumor grade, and determined that a woman between the ages of 30 and 34 with an ER-negative, grade 3 tumor has a 26.5% chance of harboring a BRCA1 mutation compared with a 5% chance in women of the same age range with any tumor type (Table 1).
Women who test positive for a BRCA1/2 mutation have a 40 to 50% chance of developing a second primary breast cancer [19][20][21]. BRCA 1/2 carriers are also at increased risk for ovarian cancer, with a lifetime risk of 40 to 50% in BRCA1 carriers and 10 to 20% in BRCA2 carriers [22][23][24]. Studies have shown that a prophylactic bilateral salpingooophorectomy (BSO) can reduce the risk of ovarian cancer by as much as 80 to 96% [25,26], decrease the risk of developing a second primary breast cancer [21], and also reduce short-term mortality [27]. For these reasons, a prophylactic BSO is recommended when childbearing is complete. Yearly breast MRIs, in addition to yearly mammograms, are recommended for screening in BRCA1/2 mutation carriers [14]. Due to the high risk of a second primary, many BRCA1/2 mutation carriers choose to undergo a prophylactic bilateral mastectomy (PBM) in the setting of unilateral disease. Th e risks, benefi ts, and controversies surrounding PBM are discussed below in the section 'Secondary prevention' .
Although very rare, Li-Fraumeni syndrome (LFS) should also be considered when a very young woman is diagnosed with breast cancer. LFS is a highly penetrant, autosomal dominant condition characterized by early onset breast cancer and a variety of other rare tumors, including sarcoma, brain tumors, and adrenocortical carcinoma [28][29][30]. Many families meeting strict criteria for LFS have identifi able germline mutations in the TP53 gene [31,32]. Nearly one-third of breast cancers in TP53 mutation positive families occur prior to age 30 years [33]. Knowledge of the presence of a TP53 mutation may help make decisions about breast cancer therapy, especially since radiation may substantially increase an LFS patient's risk for a second primary malignancy [34].
In a recent study, Gonzalez and colleagues [35] examined the characteristics of 525 patients whose samples were submitted for clinical TP53 genetic testing, of whom 91 (17%) had detectable mutations. Several working defi nitions for LFS exist for identifying families with TP53 mutations; these consider age of onset of cancer diagnosis, type of cancer, and cancer in fi rst and second degree relatives. In this study, two of these defi nitions, the classic LFS criteria and the Chompret's criteria, identifi ed 95% of patients with TP53 mutations [35] [36].
Although de novo TP53 mutations have been reported in individuals without a family history [37,38] such de novo mutations are uncommon and, therefore, there is currently insuffi cient evidence to routinely recommend TP53 mutation testing in breast cancer patients under the age of 30 in the absence of a personal or family history suggestive of LFS. Since the use of the classic LFS and Chompret's criteria in combination have a high sensitivity in identifying individuals with TP53 mutations, individuals meeting their criteria should be referred for testing [35] (Table 2).

Treatment
Young women are generally treated similarly to their older counterparts. Options for local therapy include a mastectomy or breast conserving surgery followed by radiation. As in older women, factors guiding surgical decisions include tumor size, location, ability to achieve a good cosmetic outcome, prior radiation or any contraindication to radiation, and patient preference. However, younger women have higher local recurrence rates than older women when treated with breast conservation [39][40][41]. In an analysis of two large randomized trials comparing mastectomy versus breast conservation plus radiation, Voogd and colleagues [39] found that women under age 35 years treated with breast conservation had a nine times greater risk of recurrence than women over the age of 60 (hazard ratio, 9.24; 95% confi dence interval (CI), 3.74 to 22.81); however, younger patients treated with a mastectomy did not have an increased recurrence rate compared to older patients. Freedman and colleagues [41] retrospectively analyzed risk factors for local recurrence after breast conservation plus radiation and found that in women under the age of 35 whose excised tumors had both negative margins and a nonextensive intraductal component, the rate of local recurrence was similar to that of older women. Th is fi nding suggests that the increased risk of local recurrence in this age group may be due to the extensive intraductal components of the tumors and diffi culty in achieving negative margins in young patients.
In addition to appropriate radiotherapy, adjuvant therapy with chemotherapy and/or hormonal therapy should be strongly considered in young women. A Danish study showed that young women with early stage disease who were not treated with cytotoxic therapy had an increased risk of dying compared to older age groups. Th is risk increased with decreasing age of diagnosis, with those under the age of 35 having the poorest prognosis. In contrast, young women who did receive cytotoxic therapy had a comparable prognosis to their older counterparts [42]. In another study, women under the age of 30 with stage I disease had a particularly poor relapse-free survival compared to older controls, presumably because very few of these women received adjuvant chemotherapy [43].
Women who achieve chemotherapy-induced amenorrhea have a better prognosis than women who retain their menses [44,45]. Th e NASBP B-30 trial (National Surgical Adjuvant Breast and Bowel Project Protocol B-30) looked at the effi cacy of three diff erent adjuvant chemotherapy regimens containing doxorubicin, cyclophos phamide, and docetaxel (one regimen did not contain cyclophosphamide). Th e study's secondary aim was to correlate chemotherapy-induced amenorrhea with survival in premenopausal women. Overall survival was signifi cantly improved in women who achieved at least 6 months of chemotherapy-induced amenorrhea, regardless of chemotherapy, and, surpris ingly, regardless of hormone receptor status [44]. Th ese data suggest that the therapeutic eff ects of chemotherapy are, at least in part, due to ovarian suppression. Th e eff ect of chemotherapy on the menstrual cycle is dependent upon the age of the patient, with young premenopausal women (<35 years) less likely to achieve amenorrhea with chemotherapy compared with older premenopausal women [46,47]. It is unknown whether chemotherapy can be replaced by ovarian suppression alone (such as with a luteinizing releasing hormone (LHRH) agonist). In patients with hormone responsive tumors, four studies suggest that the use of a LHRH agonist in the adjuvant setting is as effi cacious as chemotherapy with fewer side eff ects [48][49][50][51][52][53]. However, these studies all used older chemotherapy regimens (that is, cyclophosphamide, methotrexate, fl uor ouracil (CMF)) with out subsequent hormonal therapy; thus, it is currently unclear how LHRH agonists would compare against third generation regimens plus tamoxifen [54].
Although the therapeutic eff ects of chemotherapy appear to be at least partially due to eff ects on the endocrine system, chemotherapy alone is insuffi cient for the treatment of hormone receptor positive tumors in young women [55]. Endocrine therapy should be off ered to young women with hormone responsive tumors. Th e usual treatment is tamoxifen, but ovarian suppression/ ablation (with LHRH analogs, oophorectomy, or ovarian radiation) can be used as alternative therapy or added in combination with tamoxifen [51,[56][57][58][59][60]. In women who remain premenopausal after chemotherapy, it is currently unclear whether adding ovarian suppression to tamoxifen is superior to tamoxifen alone. Th is is the subject of several randomized clinical trials, including the Suppression of Ovarian Function Trial (SOFT; NCT00917969).
Aromatase inhibitors are avoided in women who are premenopausal at diagnosis even if they develop chemotherapy-associated amenorrhea as there are concerns that reduced estrogen feedback to the hypothalamus and pituitary will stimulate gonadotropin release and thus ovarian stimulation. Chemotherapy-induced amenorrhea may not be permanent (and is less likely to be permanent the younger the woman is), and aromatase inhibitors can promote the recovery of ovarian function in these women. Th us, aromatase inhibitors should be used with caution in women with chemotherapy-induced amenorrhea, and serum estradiol and gonadotropin levels should be serially monitored to ensure that ovarian function is not recovering [61]. Th ere is some evidence that treatment with an aromatase inhibitor plus ovarian suppression with an LHRH analog is effi cacious in pre menopausal women, and is at least as effi cacious as tamoxifen plus an LHRH agonist, as shown in the ABCSG 12 trial (by the Austrian Breast and Colorectal Cancer Study Group) [62]. How this combination com pares to tamoxifen alone is currently being investigated by the SOFT trial (NCT00917969).
Breast cancer diagnosed during pregnancy is rare, with an incidence of 1 in 3,000 pregnancies [63]. Diagnosis and treatment of breast cancer during pregnancy requires special consideration and is beyond the scope of this review. A recent article published by Litton and colleagues [64] reviews the challenges in diagnosis and treatment of breast cancer during pregnancy.

Fertility
Preserving fertility is a concern that aff ects treatment decisions for many young women faced with a new diagnosis of breast cancer [65]. Chemotherapy can cause amenorrhea and, in some cases, permanent menopause. A recent prospective study examined diff erences in chemo therapy-induced amenorrhea among chemotherapy regimens (CMF; doxorubicin and cyclophosphamide (AC); doxorubicin, cyclophosphamide, and paclitaxel (ACT)). Th e rate of chemotherapy-induced amenorrhea among the three regimens was similar; however, patients treated with CMF were less likely to resume their menses [46]. Th e risk of chemo therapy-induced menopause is also dependent on the patient's age at diagnosis. Women under the age of 35 who undergo chemotherapy have a lower risk of meno pause (approximately 15%) compared to, for example, a 40-year-old woman who has a greater than 40% risk of menopause. Tamoxifen may marginally increase a woman's risk of early menopause [47]. More importantly, because of teratogenicity, women must wait until they complete treatment with tamoxifen before getting pregnant. Th e optimal treatment duration is 5 years, and fertility declines with age.
Fortunately, pregnancy after a diagnosis of early stage breast cancer does not appear to increase the risk of relapse [66]. In fact, a recent meta-analysis presented at the 2010 European Breast Cancer Conference suggested that pregnancy after a diagnosis of breast cancer is associated with improved survival when compared to breast cancer patients that do not have a pregnancy after their diagnosis [67]. One possible explanation for this supposed survival advantage is the 'healthy mother eff ect, ' as women who feel healthy may be more likely to conceive, leading to selection bias [68]. However, there are also biologic theories as to why pregnancy may protect against relapse, such as alloimmunization against breast cancer cells [69], or the cytotoxic eff ects of high dose estrogen during pregnancy [70,71]. Nonetheless, pregnancy after a diagnosis of early stage breast cancer does not appear to decrease survival.
If a woman desires to bear children after her breast cancer treatment, she should be counseled on fertility preservation options. Fertility preservation should be discussed as early as possible, as these fertility procedures must be initiated prior to starting systemic therapy. Options to preserve fertility include ovarian preservation with LHRH analogs, embryo cryopreservation via in vitro fertilization, and oocyte or ovarian tissue cryopreservation [72].
Ovarian preservation with LHRH analogs is the only fertility option that does not involve assisted reproductive techniques. LHRH analogs stop ovarian follicular development by suppressing gonadotropins, which, theoreti cally, can protect a woman's ovaries from damage from cytotoxic therapy. However, the effi cacy of LHRH analogs for fertility preservation has not yet been established. Several small studies have looked at the use of LHRH agonists given concurrently with chemotherapy to preserve ovarian function with mixed results. Randomized controlled trials are currently underway to evaluate this strategy in women with cancer [73].
To date, the most eff ective approach to preserve fertility in cancer patients is embryo cryopreservation. However, this procedure requires in vitro fertilization and, thus, a participating male partner (or sperm donor). Oocyte and ovarian tissue cryopreservation are emerging options for women who do not have a male partner at diagnosis. However, these methods are currently investigational, and have resulted in lower pregnancy rates when compared to embryo cryopreservation [74][75][76][77][78].
Both embryo and oocyte cryopreservation require controlled ovarian stimulation, which is associated with a marked increase in estradiol levels. To avoid the potential risks of rising estradiol levels during ovarian stimulation, Oktay and colleagues [79] have developed an ovarian stimulation protocol using the aromatase inhibitor letrozole, which results in estradiol levels that are similar to unstimulated cycles. Oocyte and embryo yields using this protocol have been comparable to those using standard ovarian stimulation protocols, and after 23.4 months of follow-up, recurrence and survival rates were comparable to unstimulated controls. Th e lag time between surgery and chemotherapy was greater in the group undergoing stimulation, likely due to the extra time needed for ovarian stimulation. However, time to the start of chemotherapy for the group undergoing stimulation was well within 12 weeks, which has been established as an acceptable time frame between surgery and chemotherapy for breast cancer [80,81].
In summary, fertility preservation is possible in young women undergoing treatment for breast cancer. Oncologists should discuss options to preserve fertility prior to initiating systemic treatment, and refer to fertility specialists when appropriate.

Bone health
Women who experience chemotherapy-induced amenorrhea have been shown to experience a rapid decline in bone density compared to women who retain their menstrual function [82]. In one prospective study, the incidence of vertebral fractures was markedly increased in women followed from diagnosis of breast cancer (mean follow-up 2.1 years) compared to age-matched controls [83]. For this reason, there has been recent interest in preventing bone loss in premenopausal women undergoing treatment for breast cancer.
Two randomized trials have shown that zoledronic acid, an intravenous bisphosphonate, prevents bone loss in premenopausal women undergoing treatment for breast cancer. Th e zoledronic acid was well tolerated, and there were no reports of renal insuffi ciency or osteonecrosis of the jaw in either trial [84,85]. Additionally, preclinical and clinical studies suggest that bisphosphonates may have antitumor and antimetastatic properties [86][87][88][89]. In the ABCSG 12 trial, 1,803 premenopausal women receiving adjuvant hormonal therapy for early breast cancer were randomly assigned to receive goserelin plus tamoxifen or anastrazole with or without zolendronic acid. Th ere was no diff erence in disease free survival between the two hormonal therapy groups; however, the addition of zolendronic acid led to a signifi cant improvement in disease-free survival (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P = 0.01), and insignifi cant trend towards overall survival (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P = 0.11). Th is study only included women with endocrine responsive tumors who did not receive chemotherapy, so it is unknown if these results are generalizable to all women with breast cancer [62]. Conversely, a meta-analysis evaluating the eff ect of clodronate, another bisphosphate, on breast cancer outcomes showed no diff erence in overall survival, bone metastasis free survival, and non-skeletal metastasis free survival in those receiving adjuvant clodronate compared to those who did not receive adjuvant bisphosphonate treatment [90]. Currently, there are no formal guidelines regarding the use of bisphosphonates in the adjuvant treatment of breast cancer. Results from ongoing studies (AZURE, NSABP-B-34, S0307 -all of which are closed to accrual) are expected to clarify the role of bisphosphonates in maintaining bone health and improving breast cancer outcomes.

Secondary prevention
Women treated for breast cancer are at increased risk of developing a contralateral breast cancer (CBC), with young age being an important risk factor [91][92][93][94][95]. In addition, the local recurrence rate is higher in young women treated with breast conservation compared to their older counterparts [39,40]. Guidelines recommend that women with a history of breast cancer have yearly mammograms to screen for CBCs and local recurrences. However, mammograms are less sensitive in younger women due to increased breast density [10][11][12]. Although MRIs are more sensitive than mammograms in young women [15], there is no consensus regarding breast MRI for young women with a personal history of breast cancer [14]. To decrease their risk of local recurrence and CBC, some women choose to have PBM for unilateral disease. Multiple studies have shown that a PBM reduces the risk of a CBC by as much as 95% [96][97][98]. A recent populationbased study has shown that the proportion of women who choose to have a PBM is increasing, and has more than doubled between the years 1998 and 2003 [99]. Age has been shown to be an important predictor in the selection of bilateral mastectomy, with women younger than 40 years more likely to have this procedure [100]. Although a PBM can dramatically decrease the risk of a CBC, evidence that the procedure improves diseasespecifi c or overall survival is lacking [101]. One recent study, based on data from the Surveillance, Epidemiology and End Results (SEER) program, has suggested that bilateral mastectomy at the time of a unilateral breast cancer diagnosis may improve survival in women under the age of 50 with triple negative tumors [102], but more data are needed.
BRCA 1/2 mutation carriers have an even higher risk for developing a second primary breast cancer [19][20][21]. Both prophylactic BSO and tamoxifen use have been shown to decrease the risk of a second primary [21]. A retrospective cohort study that com pared BRCA1/2 mutation carriers with breast cancer who underwent a PBM with those who did not showed that a PBM reduced the risk of developing a CBC by 91%. After adjustment for BSO uptake, there was no diff erence in overall survival among the two groups [103]. PBMs are not without complications, which occur more frequently in women undergoing immediate reconstruction [104]. For these reasons, in women with BRCA1/2 mutations and in sporadic cases, PBMs are considered an option rather than a mandate and remain a personal decision. Patients should be aware of the risks, benefi ts, and uncertainties of this procedure.
Observational studies suggest that some lifestyle and dietary factors are associated with breast cancer prognosis. Physical activity and maintaining a healthy weight are associated with a decreased risk of recurrence [105]. Vitamin D defi ciency has been associated with an increase in distant recurrence and death in women treated for early stage breast cancer [106]. Although there are no randomized trials that tell us whether exercise programs, maintaining a healthy weight, or vitamin D supplementation improve prognosis, in otherwise healthy women, there appear to be few downsides to these interventions.

Psychosocial issues
A diagnosis of breast cancer is distressing at any age but younger patients seem to experience a greater degree of psychological distress than their older counterparts [107]. A retrospective study looking at quality of life in 577 breast cancer survivors who were under age 50 years at diagnosis found that women younger than 35 reported more emotional distress and less energy than older survivors even years after initial treatment. Women who experienced treatment-induced menopause reported lower health perceptions than their peers. African American women and women who were either married or had a stable partner were less likely to experience emotional distress [108]. It is not known why younger breast cancer patients suff er more emotionally than older patients. It has been theorized that breast cancer is viewed as a disease of older women and a diagnosis in this age group is an emotional shock. In addition, younger women often have more physical demandssuch as taking care of young children and/or working full time -which may make it especially diffi cult to endure treatment [107,108].
Concern over loss of fertility may also contribute to the emotional distress experienced by younger breast cancer survivors [65]. Sexual dysfunction, most notably vaginal dryness, is also a common complaint among breast cancer survivors [109]. Breast cancer survivors who have had a mastectomy as opposed to breast conservation surgery report poor body image, which may contribute further to sexual dysfunction [110]. In conclusion, younger women are at high risk for emotional distress when faced with a diagnosis of breast cancer. Clinicians should consider early referral to support and counseling services in this high risk group.
Th e Young Survival Coalition [111] is an international organization dedicated to increasing awareness and providing resources for young women diagnosed with breast cancer under the age of 40. Th rough this organization, young women can fi nd local support groups and community events geared towards young women with breast cancer, which can hopefully reduce the sense of isolation felt when diagnosed with this disease at such a young age.

Conclusion
Management of young women with breast cancer diff ers from that of their older counterparts. Breast cancers in women under ages 35 to 40 years have more aggressive features, tend to be diagnosed at a later stage, and have inferior outcomes. Diff erences in risk factors and gene expression suggest that breast cancer in young women may be a distinct entity. Radiographic diagnosis in this population is challenging due to increased breast density. Genetic testing for the BRCA1 and BRCA2, and in certain cases, TP53 mutations, should be considered. Treatment is generally the same as for older women; however, the optimal type of hormonal therapy is currently unknown (but is actively being investigated). Fertility preservation is often a top concern for many women. Th ey should be referred to a fertility specialist as early as possibledefi nitely prior to initiating systemic therapy. Treatment related menopause can lead to a rapid decline in bone density, and there may be a future role for the use of bisphosphonates in the adjuvant setting to both maintain bone health and prevent breast cancer recurrence. Prophylactic contralateral mastectomies are increasingly pursued, but it is unclear if they improve survival. Lastly, young women with breast cancer are at greater risk for psychological distress. Clinicians should consider early referral to support services in this high risk group.