Breast Disease 23 (2005,2006) 38 IOS Press

Epidemiology of Breast Cancer in Young Women

Bonnie C. Yankaskas
Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

Abstract. Breast cancer is a rare disease in young women, yet is the leading cause of cancer deaths in all ethnic groups in the United States and many parts of the world. The epidemiology for breast cancer in young women is reviewed, focusing on women under 40, prior to the recommended screening age. Specic age comparison groups used and results for young women vary in the literature, yet there are some common results. Young women have low incidence rates of breast cancer compared to older women. However, cancer incidence increases at a faster rate with increasing age in young women. Their cancers tend to be larger and higher grade with poorer prognostic characteristics, resulting in a higher risk of recurrence and death from breast cancer when compared to older women. Many of the usual risk factors for breast cancer in older women also increase risk in younger women including increasing age, Black race, family history, later age at rst birth and menarche, radiation exposure and lack of physical activity. Risk factors that have specic relevance to young women include reproductive factors, history of induced abortion or miscarriage, oral contraceptive use, smoking, and radiation exposure, most specically for treatment of Hodgkin Disease.

INTRODUCTION Breast cancer is a rare disease in young women yet is a leading cause of cancer deaths in all ethnic groups in the United States and many parts of the world. Writing about the epidemiology of breast cancer in young women is challenged by the lack of a standard denition of what ages are included in the denition of young women. Specic comparison groups used and results for young women vary for ages under 50. Most commonly, studies have presented results for studies in young women less than or equal to 45, 40 or 35. Many studies have described the very young as less than 35, or 2029. Cancer incidence patterns among adolescents and young women vary by age, and there appears to be a cross-over in racial differences as well as survival advantages after age 40 [1]. Consequently, it seemed that limiting the epidemiology to women under 40 would result in a more focused and perhaps accurate picture of breast cancer in young women, as it
author: Bonnie C. Yankaskas, M.P.H., Ph.D., Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7515, USA. Tel.: +1 919 966 6936; Fax: +1 919 966 0525; E-mail: bcy@med.unc.edu.
Corresponding

differs from older women. Many of the usual risk factors for breast cancer in older women also increase the risk in young women. In reviewing the risk literature, the emphasis has been on studies that included results for women less than 40, and highlighted differences for young women compared to older women. Women under 40 are outside the ages for screening recommendations and thus breast cancer diagnosis in this group of women is not affected by population screening. Most breast cancer detection in young women is a result of presentation with signs or symptoms or early screening because of a strong family history that is believed to put them at high risk for breast cancer at an early age [2]. Owing to the usual high breast parenchymal density and low prevalence of cancer in young women, mammography has low sensitivity, detecting 76% of 25 cancers in women < 35 and 69% of cancers in women 3640 in the only study specically designed to establish age-related accuracy of mammography and ultrasound [3]. Ultrasound in the presence of a palpable mass has better sensitivity, 84% for women < 40. The objective of this paper is to review the descriptive epidemiology of breast cancer in women under 40 (incidence, mortality and survival), as well as pathologic characteristics of the tumors and

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B.C. Yankaskas / Epidemiology of Breast Cancer in Young Women Table 1 Invasive breast cancer, SEER 19982002 Age 2024 2529 3034 3539 4044 All Races 1.3 7.6 26.8 61.7 120.3 Age Specic Rate White 1.2 7.2 25.6 62.3 122.4 Black 11.3 33.4 61.5 115.9

analytic data on risk factors specic to young women. For data by race and ethnic subgroups, the term Black is used for African American. At the time most data were published, this was the most frequently used terminology.

INCIDENCE OF BREAST CANCER IN YOUNG WOMEN There are some consistent ndings across the literature, regardless of population studied, method used, or denitions of young age. Breast cancer incidence rises with age in younger women, as in older women. The proportion of breast cancers in population-based data that occur in young women ranges from 1% when limited to node negative cancers to 11.5% in total cancers, varying depending on the age grouping and data source [2,410]. Data from the American Cancer Society Surveillance Research [11] estimates that there will be 11,110 new breast cancer cases in women under 40 the United States in 2005; 1,600 (14%) in situ cases and 9,510 (86%) invasive cases, 4.1% of cases across all ages. There will be an estimated 1,110 deaths in women under 40, 2.7% of deaths from breast cancer among all women. Age-specic incidence rates from the Surveillance Epidemiology and End Results (SEER) data for 19982002 (Table 1), increase with age for all women and are shown here for African American and White women. Age-specic incidence rates are per 100,000 women, age-adjusted for each age group to the 2000 US Standard Population [12]. There was no increase in the rate of breast cancer among women under 40 when comparing the 19982002 age specic rates to the 19801988 rates, even though there was a slow increase in incidence for women of screening age over 50, and a slight decrease in incidence rates for women 4049 [10]. United States national cancer incidence data are also available from the North American Association of Central Cancer Registries (NAACCR) [13]. These data are based on 22 population-based cancer registries that cover approximately 47% of the US population. In the data for ve-year age groups for incidence per 100,000 persons years for the years 19951999, rates rise by age from the early twenties to the late thirties. Incidence rates are higher in African American women compared to Whites, with the gap narrowing as women approach 40. In the age group 4549, the rates cross-over, and the incidence is higher in Whites (Table 2). Breast

Rate based on less than 25 cases.

cancer was the most commonly diagnosed female cancer among all racial groups, ranging in decreasing incidence from 36% among Filipino women to 24% among Vietnamese women (31% of cancers in White women, 30% of Black women) [13]. In SEER data, Incidence rates are higher in Black women compared to White women in the very young (less than 35) then crosses over to have lower incidence rates than White women. This pattern is seen mainly in local disease; for regional disease, Black women and White women have equal rates. Black women have higher rates than White women at all ages for distant disease [14,15]. Hispanic compared to non-Hispanic women have rates between Black and White women. As Hispanic ethnicity includes Black, White and Other women as well as women who only identify as Hispanic or Latino, the rates are not totally comparable. Incidence rates for other racial/ethnic groups are lower [16]. The rates may indeed be lower, but misclassication of race in cancer registry data should be considered. A study in Texas found that among a cohort of Mexican Hispanic women, the incidence rates were higher than those reported in SEER data [16]. Increase in incidence with age is not linear, but increases faster in the younger ages. Trends over time show incidence rates rise faster in young women; the rate of increase is lower in older women [17]. The rates of diagnosis of ductal carcinoma in situ (DCIS) have risen since 1980 in women 40 and over with the introduction of screening mammography. As women under 40 years of age are not recommended for routine screening, the increase in rates of DCIS have not been seen in this age group [11,18]. In situ rates increase with age in young women and the rates for White women are larger than for Black women. (Table 3) In the National Cancer Database of the American Cancer Society, 3.8% of breast cancer in women < 35 years was DCIS [19]. In one large series of breast cancer cases in Ohio, 6% of women < 40 presented with DCIS versus 16% of women > 40 years. DCIS in young women were larger in size; 40% of DCIS tumors were > 2 cm compared to 21% in women > 40 [20].

B.C. Yankaskas / Epidemiology of Breast Cancer in Young Women Table 2 Breast cancer incidence, NAACCR 19941998 Age 2024 2529 3034 3539 White 1.0 7.7 25.6 59.4 Black 2.1 11.9 35.3 69.0 Age Specic Rate American Indian Asian/Pacic Islanders 5.3 18.5 21.8 47.74

Rate based on less than 25 cases. Table 3 In situ breast cancer, SEER 19982002 [12] Age 2529 3034 3539 Age Specic Rate All Races 0.7 3.0 11.3 White 3.0 12.0 Black 8.3 Table 4 Invasive breast cancer mortality rates*, SEER 19982002 Age 2024 2529 3034 3539 All Races White 0.1 0.8 0.7 3.7 3.2 8.7 7.8 Age Specic Rate Black 1.7 7.2 15.5

Rate based on less than 25 cases.

Rates adjusted to 2000 US standard population age groups.

RECURRENCE OF BREAST CANCER IN YOUNG WOMEN The risk of ipsilateral breast cancer is higher in young women, and both age and presence of ipsilateral breast cancer recurrence are independent predictors of 15 year survival [21]. A study of risk for contralateral breast cancer following a diagnosis of invasive breast cancer was increased 5-fold in women less than 45. Compared to women 4045, women < 29 had a relative risk (RR) = 2.8; women 3034 had a RR = 2.1 and women 3540 had a RR = 1.9. Risk for contralateral breast cancer increased inversely with age among young women [22]. In a large European clinical trial, age and breast conserving therapy without chemotherapy were both independent predictors for 5-year loco-regional recurrence, the hazard ratios were highest among the subgroup of women < 35 years, for age (HR = 2.7 at 5-years, 2.3 at 1 year) and breast conserving therapy, (HR = 2.8) [23].

BREAST CANCER MORTALITY RATES AND SURVIVAL IN YOUNG WOMEN Similar to incidence rates, mortality rates from breast cancer rise with age (Table 4). Mortality rates in Black women are higher than in White women at all ages, continuing into older age groups. Mortality rates have declined since 1987 for Black and White women [24]. In a study in women < 35 years with stage I and stage II cancers from SEER data for 19881998, there was a higher proportion of young women among Black compared to White women. The hazard ratio (HR) for death for this time period comparing Black women to White

women, controlling for treatment, was 1.43 [25]. Direct comparisons of mortality rates differ depending on the method of analysis, and whether all cause or breastspecic mortality rates are used. The Danish Breast Cancer Control Group studied risk of dying from breast cancer in 10 years for women < 35 years of age compared to women 4549 years. The 10 year HR for all women < 45 compared to the older women was 2.2; it was 1.4 when comparing the 3539 year old women to the 4549. The HR for death at 10 years decreases with increasing age for younger women. Cheung, using SEER data, showed that the choice of the time scale in a Cox Regression Hazards model will give different results depending on whether the time variable is time since diagnosis or increasing age [26]. Models with age as the time variable have results similar to relative survival analyses, and show younger women have worse survival than older women [5]. Regardless of methods though, trends have similar results. Young women have poorer 5-year survival rates than older women; younger White women have a survival advantage over Black women [5,14,15,25,27]. These results are true at all stages of breast cancer. Survival studies have differed in their determination of the independent signicance of age after controlling for stage, tumor characteristics and treatment. A few studies found no independent effect of age [6,28, 29]; others have reported that age remained as an independent risk factor [21,30,31]. Studies have shown a bimodal distribution of survival, worse in young and very old women [5,8]. A hospital-based study of all young women treated for breast cancer found recurrence rates signicantly higher in women < 35 than

B.C. Yankaskas / Epidemiology of Breast Cancer in Young Women

women 36 and older. Cumulative 5-year local and distant disease-free survival were signicantly worse for patients younger than 36 years old. Most of the recurrence excess was accounted for in women receiving breast conserving surgery. After controlling for nodal involvement, tumor size, tamoxifen and chemotherapy, age was not an independent predictor of disease-free survival [28]. In SEER data, young women < 35 when compared to women 5055 had worse 5-year survival (74% versus 85%). The HR for death in 5 years for the young women was 1.1, and the regression models showed young age to be an independent factor for risk of death [30]. Age may be an independent risk factor for poor prognosis, or as all studies demonstrate, it is the poor prognostic characteristics of the tumors (presented below) in young women that put them at higher risk for recurrence and death. A study based on European cancer data of adolescents (ages 1519) versus young adults (ages 2024) found survival worse for the adolescents, 5-year survival for these very young women was 67.5% [32]. In population based data form Switzerland, 5-year breast cancer specic survival rates for women < 35 years were 91% compared to 90% for women 3645 years. Younger women in this cohort were more likely to receive chemotherapy, and this may improve their survival, even with poorer prognostic characteristics of their tumors [6]. The Danish study cited above, found that prognosis was worse mainly for young women with early stage disease who were not treated with chemotherapy [29], in line with the conclusions of the Swiss study. At all ages, survival is reduced with distant and node positive disease; the difference is magnied in young women [8]. As with incidence rates, survival rates have a bimodal curve highest in the youngest and oldest women [8].

TUMOR CHARACTERISTICS AND PROGNOSIS As young women are not routinely screened, a higher proportion will report symptoms when compared to older women, 70% compared to 43% in the Ohio study [11]. Young women are more likely to have total mastectomy than breast conserving surgery compared to older women, and more likely to have breast reconstruction. In addition, they are more likely to have chemotherapy and not have radiation therapy; young women with small cancers and negative nodes, in particular, will have chemotherapy in higher proportions

than older women [11,33]. Prognosis is worst in young women at low risk who are not treated with chemotherapy. At presentation younger women have larger tumors compared to older women, and Black women have larger tumors compared to White women. Black women compared to White women consistently present with worse tumor characteristics. For women of all ages, prognosis is worse in tumors with positive nodes; this is magnied in younger women [8]. There are consistent ndings related to tumor characteristics from the international literature [36,8,11, 21,2729,34,35]. Young women present with tumors with a higher proportion of late stage (Stage II, III and IV), high grade, positive nodes, and ER negativity (ER PR and ER PR ). Cancer histology is more frequently invasive than DCIS compared to older women. Incidence rates rise faster in young women. Inltrating ductal and tubular cancers have a steeper slope of increase in rates in younger women, compared to older women. Medullary and inammatory cancers rise with age in young women, level off around age 50 and have a constant rate in older women; rates of papillary and mucinous cancers rise steadily from young through older ages [17]. Tumors in young women have a higher proportion of p53 mutations, over-expression of c-erB-2 and tumor proliferation compared to older women [22,29,31]. A study of prognostic characteristics in 15-year survivors from the National Surgical Adjuvant Breast and Bowel Project (NSABP), multivariate analyses showed that treatment, patient age, nuclear grade, presence of intraductal carcinoma and a lymphocytic tumor inltrate were features that predicted ipsilateral recurrence. Presence of ipsilateral recurrence, Black race, age less than 40 (and > 60), positive axillary lymph nodes, tumor size 2.1, poor nuclear and histologic grades, and histology types that were lobular, medullary, mixed or atypical medullary or NOS affected survival. These poor prognostic factors described are more prevalent in women 40 [21].

RISK FACTORS FOR BREAST CANCER IN YOUNG WOMEN Many risk factors that are associated with higher risk of breast cancer are the same as for older women. The common risk factors include increasing age, Black race, positive family history, later age of rst birth, later age at menarche, radiation exposure and lack of phys-

B.C. Yankaskas / Epidemiology of Breast Cancer in Young Women

ical activity. These may be more marked in younger women [8,14,27,36,37]. Risk factors that have specic relevance to young women include reproductive factors [7,37,38], history of induced abortion or miscarriage [37,39], oral contraceptive use [37,40], smoking [41], and radiation exposure, most specically for treatment of Hodgkin Disease [4244]. Pregnancy has a transient association with increased risk and poorer survival immediately following birth [37,38]. Increased parity is associated with increased risk of non-localized breast cancer, and an increased HR for death compared to nulliparity. In a case-control study among women breast cancer cases 1534, comparing women with 3 or more children to nulliparous women: the odds ratio (OR) for non-localized tumors was 3.1 and the HR for death, adjusting for stage in women with 2 or more children, was 2.1. Women having their rst born when they were under 20 were also at an increased risk for non-localized tumors (OR = 3.0) and for higher grade of tumor, OR = 3.2 [38]. Studies of risk for breast cancer associated with oral contraceptive use have mixed results. The association with use decreases with increasing age, is dose related and is limited to ER+ tumors; the association is most signicant in women < 35 years [4,40]. Recent use (< 5 years) has been reported to have a RR of 2.2 compared to non-use. After 10 years, no association was found [40]. Two case-control studies, one a populationbased study in Iceland and a hospital-based study in Italy reported no increased risk associated with oral contraceptive use [7,37]. Other risk factors with limited literature specic to young women include studies related to physical activity, occupation, smoking and history of abortion. Several studies have found no increased risk associated with history of abortion [39]. Data from the Nurses Health Study found smoking to be associated with risk for ER+ tumors only [41]. Further work is necessary to draw any signicant conclusions from these few studies.

In addition to the usual risk factors for all women, risk factors of particular relevance to young women include family history, reproductive factors, history of induced abortion or miscarriage, oral contraceptive use, smoking, and radiation exposure, most specically for treatment of Hodgkin Disease. Further work using standard denitions for young age and more attention to methods of analysis would increase our understanding of breast cancer in young women.

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CONCLUSION Young women under 40 years of age have a low risk of breast cancer, but the breast cancer that occurs in this population, when compared to older women, has poorer prognostic characteristics which leads to higher recurrence rates and higher relative mortality rates. Risk increases with age at a faster rate than in older women.

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