A positive family history of cancer is a very strong risk factor for women under 35 (RR, 3.22) and suggests the presence of a familial cancer syndrome [9]. Early-onset breast cancer in AYAs is more likely to be associated with a positive family history of breast cancer, especially in women harboring a germline BRCA1 mutation [16]. Patients with BRCA1 mutations develop aggressive triple-negative tumors in about 80 % of cases. Conversely, constitutional BRCA mutations are found in 11–16 % of women diagnosed with triple-negative breast cancer [17]. In a study of women with breast cancer diagnosed before age 30, BRCA1, BRCA2, and TP53 mutations were found in about half of patients with strong family histories of breast cancer but less than 10 % of women with negative family history of breast cancer [18]. Compared to the general population, women with constitutional PALB2 mutations have at least an eightfold increased risk of developing breast cancer under 40 years of age [19]. Women with constitutional PTEN mutations (Cowden’s syndrome) also have an increased risk for early breast cancer [20].

Some hormonal risk factors are similar between AYA and older women. Breast cancer risk is increased by later age (>30 years) at first birth (RR, 1.10; 95 % CI, 0.80–1.50 for women under age 40), early menarche (age <40: RR, 0.93; 95 % CI, 0.87–0.99 for each additional year after age 12 for onset of at menarche), and breastfeeding (age <40: RR, 0.84; 95 % CI, 0.57–1.22) [21].

Other hormonal risk factors are somewhat different for AYA in comparison to older women. For women aged less than 35, recent oral contraceptive use is a risk factor for early-onset breast cancer (RR, 2.26), particularly for ER-negative tumors [22]. For AYAs under 40, current oral contraceptive use for ≥5 years prior to diagnosis is associated with and increased risk of ER(−) tumors (OR, 3.5; 95 % CI, 1.3–9.0) and triple-negative tumors (OR, 3.7; 95 % CI, 1.2–11.8) [23]. BRCA1 carriers who use oral contraceptives prior to age 20 have an increased risk for early-onset breast cancer before age 40 (OR, 1.45; 95 % CI 1.20–1.75; p = 0.0001). Risk increases by 11 % for each additional year of contraceptive use prior to age 20 [24].

Childbearing and multiparity are risk factors, due to a short-term elevation in breast cancer risk for several months immediately following a birth [22]. There is a positive association between high estradiol levels in the first trimester of pregnancy and risk of hormone receptor-negative cancer diagnosed under age 40 . Women with anovulatory infertility are at high risk for early-onset breast cancer [26].

The combination of obesity, high-energy (caloric) intake, and sedentary lifestyle imparts a higher risk of breast cancer for premenopausal women [27]. Large hip circumference (whether or not abdominal obesity is present) is also a risk factor for premenopausal breast cancer [hazard ratio (HR), 2.85; 95 % CI, 1.33–6.13] for ER−/PR− tumors before and also after adjustment for BMI and for ER + PR+ tumors after adjustment for BMI [HR, 1.65; 95 % CI, 1.04–2.62].

Other risk factors for breast cancer in premenopausal women include a history of prior mantle irradiation for Hodgkin lymphoma, heavy alcohol consumption, and a high intake of red meat [9, 20, 28]. Intense physical activity and a high intake of certain fruits and vegetables (e.g., citrus fruits, cruciferous vegetables [29], tomatoes) are associated with a decreased breast cancer risk in premenopausal women [30–32]. Substituting legumes for one serving of meat per day was associated with a 19 % lower risk of breast cancer in premenopausal women (0.81; 95 % CI, 0.66–0.99) [33].

Increased mammographic density is a risk factor for breast cancer at all ages [34]. Breast density in premenopausal women is mediated by intake of vitamin D, calcium, dietary fat, and alcohol in premenopausal women [35]. Mammographic density is genetically mediated, but no causative genes have been conclusively identified. Genetic variations in IL6 correlate with mammographic density [36]. Also, high levels of endogenous sex hormones such as dehydroepiandrosterone sulfate (DHEAS) in early adolescence have been positively associated with breast density during young adulthood [37].

Several studies suggest that high vitamin D intake, with or without calcium, may protect against premenopausal breast cancer. Low calcium/vitamin D intake has been associated with larger and higher-grade breast tumors [38–40]. Premenopausal women who consumed at least 400 IU vitamin D and 1,000 mg calcium daily were noted to have an 8.5 % (95 % CI, 1.8–15.1) lower mean breast density than those who consumed less [41]. One study noted an inverse association between plasma 25-hydroxyvitamin D level and breast cancer risk in premenopausal women with high mammographic density. No significant association was noted for premenopausal women with lower mammographic density [42].

In a series of women with breast cancer aged 20–44, significant weight gain (BMI increase of >10 kg/m2) after age 18 conferred a 2.0-fold increased risk of ER-negative breast cancer (95 % CI, 1.2-fold to 3.3-fold increased risk). Height, current weight, and weight at 18 years of age had no effect on risk. Smoking history of >10 pack-years increased risk of ER-positive breast cancer by 1.6-fold (95 % CI, 1.1-fold to 2.4-fold increased risk), but did not increase risk of triple-negative breast cancer [43].

For many reasons, including lactation, sexual function, body image, and quality of life, breast-conserving surgery, whenever possible, is desirable for most young women. However, one of the most important risk factors for local recurrence after breast-conserving surgery is age <35 years at presentation [59]; these patients were found to have a nine times higher risk of local recurrence after conservative surgery than patients over 60 years [60]. Nevertheless, no studies have demonstrated conservative surgery in young women to have a negative impact on survival, so breast conservation remains appropriate for many. Breast conservation surgery should always be followed by radiation in young women, and adjuvant radiation is more often considered after mastectomy for young patients [61]. Patients who carry deleterious BRCA mutations (which are more common in those diagnosed with breast cancer at a young age) have been hypothesized to harbor a greater risk of radiation-induced malignancies, but data are limited [62].

In addition, young women are at heightened risk for distant recurrence, so adjuvant systemic therapies (e.g., chemotherapy and endocrine therapy) are usually warranted [63]. Young women are more likely than older women to have ER-negative tumors, which benefit more from chemotherapy. Adjuvant chemotherapy for early breast cancer in patients under 50 years old reduces the relative risk of recurrence by 35 % and of death by 27 % [64]. The choice of whether or not to give chemotherapy, and what regimen to give, is based more on stage and receptor status (i.e., clinical subtype) of disease than on age. However, it is important to recognize that the use of adjuvant therapies in young women can cause unique long-term side effects, including the induction of an early menopause, and associated fertility impairment, bone loss, and menopausal symptoms. Reductions in risk of recurrence with more aggressive therapies must be weighed against associated quality of life impairments and fully discussed with patients.

For young women with ER-positive early-stage breast cancers, adjuvant endocrine therapy reduces the risk of recurrence by approximately half [65]. Until recently, 5 years of tamoxifen was standard endocrine therapy for premenopausal early-stage breast cancer patients, but data from the ATLAS trial, aTTom trial, SOFT trial, and TEXT trial have revealed additional treatment options. ATLAS and aTTom found that 10 years of tamoxifen were superior to five [66, 67]. SOFT revealed that the addition of ovarian suppression to tamoxifen reduces risk of recurrence in patients under 35 and premenopausal patients who receive chemotherapy, and both SOFT and TEXT showed that treating these same patients with ovarian suppression and an aromatase inhibitor reduces risk of recurrence to an even greater degree [68, 69]. These findings are consistent with older studies showing that both relapse-free and overall survival are worse in patients who do not become amenorrheic following chemotherapy [70–73]. However, the SOFT trial data did not convincingly show that patients over age 35 who did not receive chemotherapy benefit from ovarian suppression. There may be a real, but small, risk reduction from ovarian suppression (with either tamoxifen or aromatase inhibitor) in some higher-risk patients aged 35–40 even if the disease was not biologically aggressive enough to warrant chemotherapy. On the contrary, it is important to consider the impact of ovarian suppression on physical and emotional health for very young women, including menopausal symptoms, insomnia, depression, and bone loss. Additional research is warranted to identify strategies to minimize the toxicities of endocrine therapy in young women diagnosed with breast cancer.

Metastatic breast cancer in young patients is treated palliatively, with sequential systemic therapy regimens given until time of progression, just as in older patients. One caveat is that premenopausal patients with advanced ER-positive disease should additionally be treated with either bilateral salpingo-oophorectomy at the time of diagnosis with metastatic disease or receive an ovarian-suppressing medication (i.e., gonadotropin-releasing hormone (GnRH) agonist) throughout their subsequent endocrine therapies (including tamoxifen, aromatase inhibitor, fulvestrant, etc.) [74–76].

AYA women diagnosed with breast cancer experience worse cancer-specific survival and relative survival compared to all other age groups below age 75 (Fig. 8.7). Young women had a worse survival from breast cancer compared to other cancers; in older age groups, breast cancer survival was superior to survival from other cancers. Breast cancer survival rates are lower for AYA women compared to older women, both cumulatively and stage by stage (Fig. 8.8) [1, 77]. The lowest overall rate of breast cancer survival for females diagnosed during 2000–2012 was in those aged 15–39 years, with 5-year rates of 81–88 %. In contrast, breast cancer survival for women between age 45 and 75 was 90–93 % (Fig. 8.7).

The age-related disparities in breast cancer survival vary by stage at diagnosis, although survival is inferior for AYAs compared to 40–50-year-old women at all stages of breast cancer (Fig. 8.8). Above the age of 40, stage 0 in situ breast cancer has a 100 % 5-year relative survival, even in elderly women. For all age groups with stage 0 disease, only AYAs have less than 100 % 5-year survival. For stage I breast cancer, women greater than 50 years of age have the highest survival rates and 25–35-year-olds have the lowest survival rates. Women with stage II–IV cancer who are 40–50 years of age have the best prognosis, with comparatively inferior prognosis for AYA women. Stage IV breast cancer has a far worse prognosis than any other stage. Within the AYA age group, survival is inversely proportional to age for all stages of breast cancer, with the most inferior survival rates occurring in the youngest AYA women (Fig. 8.8).

Most histologic subtypes have a worse prognosis in AYA women than in older women. The 5-year relative survival for AYA was also inferior for women with each histologic subtype of breast cancer, including infiltrating ductal, medullary, lobular, and inflammatory breast cancer, as well as Paget’s disease of the breast (SEER 18 data, not shown) [78]. The outcome disparity between age groups by histologic subtype is most apparent for invasive ductal carcinoma (p < 0.001, SEER 18 data, not shown).

Since 1985, the rate of survival improvement has been greater in AYA women than in older women for all stages at diagnosis (Fig. 8.9). The rate of survival improvement in AYA women has been directly proportional to the extent of disease at diagnosis, with the greatest relative gains for women with distant disease at diagnosis (Fig. 8.9). Thus, the discrepancy in survival between younger and older women is narrowing over the last three decades, possibly due to increasing clinical focus on the distinctive health-care needs of young women with breast cancer and to more effective palliative and supportive care strategies for previously healthy women diagnosed with advanced disease.

The recent Prospective Outcomes in Sporadic versus Hereditary breast cancer (POSH) study examined breast cancer outcomes for British women diagnosed at age 18–40 years of age at diagnosis. Young patients had similar and inferior outcomes regardless of hormone receptor expression, with the incidence of relapse peaking at 2 years post-therapy for patients with ER-negative tumors and continuously declining over an 8-year period for patients with ER-positive tumors [79]. Patients with a positive family history of breast cancer were more likely to have high-grade tumors, but were not more likely to have an adverse outcome by multivariable analysis [80]. Obesity was associated with adverse biological features and was an independent risk factor for death from breast cancer [81].

In women <40 years of age (as in all age groups), African Americans and Native North Americans have the worst survival, and Asians have the highest survival rates. Young African American women have disproportionately high breast cancer mortality in comparison to other racial groups (Fig. 8.10). One study found that black women <40 had larger tumor size, higher rates of local and distant metastasis, a higher proportion of ER negativity, and a higher rate of medullary tumors. Relative risk for death was 1.94 for localized disease, 1.58 for regional disease, and 2.32 for metastatic disease compared to white women [82]. Another study showed that young black women with stages III and IV disease had worse prognosis despite standard therapy [82]. In the POSH study, black race was associated with adverse biological features and with adverse outcome despite equal access to health care, with 71.1 % 5-year OS in black compared to compared to 82.4 % in white patients (P = 0.0160) [83]. Because 10 % of black women (vs. 5 % of white women) with breast cancer are diagnosed prior to age 40 and because young black women have worse outcomes, they are considered a particularly high-risk group [84].