Fig. 2.1
Trends in ductal carcinoma in situ incidence rates (per 100,000 females, 2-year moving averages, age adjusted to the 2000 US standard population and adjusted for reporting delay) by age (US, 1992–2011). Source: Surveillance, Epidemiology, and End Results (SEER) Program, 13 SEER registries, National Cancer Institute, 2014 (With permission from American Cancer Society, Inc., Surveillance Research, 2015)
Data on more than five million women from 84 local screening units in Great Britain from the National Health Service Breast Screening Program (NHSBSP) reported that the average incidence of DCIS detected at screening is 0.8–1.6 per 1000 women screened [3]. A significant negative association of screen-detected DCIS cases with the rate of invasive interval cancers is also reported [3].
DCIS is a very curable disease, with a 10-year survival of 98%, according to reports from the Surveillance, Epidemiology, and End Results (SEER) database [4].
For this reason, DCIS is becoming one of the most important diseases in preventive medicine screening, although the full impact of this diagnosis on breast cancer survival needs to be better clarified in the future.
2.2 Epidemiology
In the USA and in the Netherlands, the rate of DCIS has increased fivefold in the last 25 years, likely due to a widespread adoption of mammography and screening programs [5, 6].
In women less than 50 years of age, the incidence increased less dramatically, followed by a continuous decline, probably due to a drastic reduction in the use of hormone replacement therapy (HRT) in more recent years [7].
The incidence of DCIS is approximately 32 cases per 100,000 women [8].
DCIS is rarely diagnosed in women less than 40 years of age, its incidence steadily increases between the age of 40 and 70, and it plateaus after the age of 70, according to data from the North American Association of Central Cancer Registries (NAACCR) (Table 2.1) [2].
Table 2.1
Ductal carcinoma in situ incidence ratesa by race, ethnicity, and age group (US, 2007–2011)
Age | All races | Non-Hispanic White | Non-Hispanic Black | Asian and Pacific Islander | American Indian and Alaska Nativeb | Hispanic/Latina |
|---|---|---|---|---|---|---|
All ages | 25.8 | 26.6 | 26.5 | 23.9 | 14.4 | 17.9 |
20–39 years | 3.4 | 3.7 | 3.5 | 3.4 | 1.9 | 2.1 |
40–49 years | 37.9 | 40.7 | 32.8 | 42.1 | 20.5 | 25.9 |
50–59 years | 57.9 | 59.8 | 56.9 | 57.0 | 33.4 | 41.7 |
60–69 years | 81.8 | 82.9 | 91.3 | 70.1 | 49.6 | 58.2 |
70–79 years | 84.3 | 85.8 | 94.6 | 66.8 | 46.3 | 57.2 |
≥80 years | 47.4 | 47.6 | 55.8 | 33.2 | 19.4 | 32.2 |
It is estimated that if incidence and survival rates for DCIS will remain constant, in 2020, more than one million women worldwide will have received a diagnosis and treatment for this disease [9].
Prior to the introduction of mammography, DCIS was detected only after excision of palpable lumps and histological examination of the tissue, while nowadays 90% of DCIS are diagnosed by mammography [5, 8, 10–14]. At the present time, only 10% of DCIS cases are detected due to symptoms, such as nipple discharge, Paget’s disease of the nipple, or a palpable mass [5].
It is estimated that for DCIS detection rates up to 1.5 per 1000 women screened, there may be one fewer invasive interval cancer for every three cases of DCIS over the subsequent 3 years [3].
This finding supports a great benefit of detecting DCIS through screening programs, even if screening recommendations do vary around the world, as mammography is offered triennially in the UK, biennially in most European countries [15], and every 1–2 years in the USA [16, 17].
Currently, DCIS accounts for 17–34% of mammographically detected breast neoplasms [18, 19]. Data from eight population-based trials of mammography screening demonstrate an association between screening programs and the increased incidence of DCIS [18].
In the USA, the incidence rate of DCIS also varies by state, as this is associated with the state-level prevalence of mammography screening (Fig. 2.2) [2].
Fig. 2.2
Association between state-level prevalence of mammography screening (percent of women ≥40 years who reported having a mammogram within the past year) (2008) and incidence rates (rates are per 100,000 females and age adjusted to the 2000 US standard population) of ductal carcinoma in situ (2007–2011) among women ≥40 years. DCIS ductal carcinoma in situ. ‡Pearson correlation coefficient. Source: Mammography screening prevalence—Behavior Risk Factor Surveillance System 2008, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 2010. Incidence—NAACCR, 2014. Not all states met high-quality standards for all years according to NAACCR. DCIS incidence rate for Arkansas is based on incidence data for the years 2007–2009; for Nevada, the rate is based on incidence data for the years 2007–2010. Minnesota did not submit 2007–2011 incidence data to NAACCR and is not included (With permission from American Cancer Society, Inc., Surveillance Research, 2015)
Detection of DCIS is greatest at baseline screening. The Breast Cancer Surveillance Consortium reported DCIS incidence at the first screening of 1.5 per 1000 women, and this figure decreased to 0.83 per 1000 for subsequent screening mammograms [18].
Higher DCIS detection rates may be associated with diminished returns for invasive cancer by increasing the proportion of low-grade DCIS cases [20].
In a study of 3167 DCIS obtained from the Cancer Registry of Norway , the distribution of the tumor grade was 24% for grade 1, 23% for grade 2, and 53% for grade 3 [23]. However, it is well known that the accuracy of DCIS grading has major limitations, as interobserver variability does exist.
It is commonly believed that DCIS progresses to invasive cancer in the absence of treatment, but there is limited data on this issue, because almost all women are currently undergoing some sort of treatment [18, 24, 25]. Long-term follow-up studies of women whose DCIS was erroneously diagnosed as a benign lesion found that 20–53% of these patients were diagnosed with an invasive disease over the course of the next 10 years [26–30].
Since high-grade DCIS is associated with a greater risk of 5-year recurrence after treatment [31] and an increased mortality if it progresses to invasive breast cancer [32], this is often considered as stronger evidence that it is a true precursor lesion.
Instead, early detection and treatment of low-grade DCIS remains of unclear demonstrated benefit [33], and it has been suggested that a percentage of women with screen-detected DCIS might not benefit indeed from treatment [34, 35]. It is also reported that the incidence of non-comedo form of DCIS has increased more rapidly compared to the most aggressive (comedo) subtype of DCIS [5].
It has been hypothesized that other than a predisposing type of DCIS which may progress to invasive disease, an indolent form does exist and will remain idle throughout the lifespan of a patient [36].
Therefore, overdiagnosis and overtreatment are current concerns for clinicians, as receiving diagnosis of DCIS, treatment, and follow-up may impact on long-term health and quality of life of women.
For this reason, several randomized trials are undergoing in Europe, in the UK, and in the USA to address the hypothesis that “observation only” may be safe for women diagnosed with “pure” low-grade DCIS [37, 38].
In recent years, diagnosed DCIS cases are usually of small size (less than 2 cm, 51%) and are frequently ER positive (72%) [2]. The distribution of ER status does not seem to vary with race and is different from the invasive counterpart, for which non-Hispanic Black women are known to have a prevalence of triple negative disease [2].
Low- and intermediate-grade DCIS are significantly more commonly ER positive than high-grade disease (p < 0.001) (ER+ low grade 99%, intermediate grade 94%, high grade 69%) [39].
A review of 15 screening programs from 12 countries found that 67–90% of DCIS received breast conservation surgery (BCS) , and in 41–100% of the cases, this was followed by radiotherapy [40]. Similar findings have been reported by a study in Western Australia [41].
Invasive cancer is not infrequently found in the specimen obtained after resection of DCIS and is reported in 8–43% of such cases [6]. This major variability can be in part explained by the size and the number of biopsies obtained at the diagnostic level. Most studies, however, agree that the larger the lesions, the more frequent an upgrade is reported [6]. Different studies carry conflicting results, as grade is a predictor for diagnosing an invasive component at final pathology.
2.3 Risk Factors
In literature, multiple risk factors are reported for the development of DCIS. In general, they are shared with those—even better studied—of the invasive counterpart.
2.3.1 Family History
There is evidence, from epidemiological studies, to suggest an inherited predisposition to DCIS. One study reported that women affected by DCIS are 2.4 times (95% CI 0.8, 7.2) more likely to have an affected mother—or sister—with breast cancer compared to controls [42]. An older study of almost 40,000 women reported that a family history of DCIS carries a greater risk of the disease among relatives compared to a family history of invasive breast cancer. In women aged 30–49 years, the odds ratio (OR) for developing DCIS was calculated as 2.4 (95% CI 1.1, 4.9) compared to 1.7 (95% CI 0.9, 3.4) for invasive cancer . Similarly, in women aged 50 years, the risks were slightly reduced, but the OR was 2.2 for DCIS (95% CI 1.0, 4.2) and 1.5 for invasive disease (95% CI 1.0, 2.2) [43].
However, these findings were not confirmed in the Million Women Study , in which the association with family history was similar for DCIS and IDC [44].
2.3.2 Age
As reported previously, age is an important risk factor to develop a DCIS (see Table 2.1).
2.3.3 Genetic Risk Assessment
Petridis et al. [45] have tried to identify genetic polymorphisms that predispose to DCIS. They pooled data from 38 studies including 5067 cases of DCIS, 24,584 cases of invasive ductal carcinoma, and 37,467 controls, all genotyped using a selected array.
They found that 67% of 76 known breast cancer predisposition loci also showed an association with DCIS and concluded that there is a shared genetic susceptibility for invasive ductal carcinoma and DCIS [45].
Furthermore, two independent single nucleotide polymorphisms (SNPs) were specific to low-/intermediate-grade DCIS, while no association with high-grade DCIS was found, and this was independent of ER status [45].
An additional study from the National Cancer Institute’s Breast and Prostate Cancer Cohort Consortium (BPC3) found that five SNPs were significantly associated with DCIS risk and that several of the known BC susceptibility loci are risk factors for both DCIS and invasive breast cancer [46].
van der Groep et al. [47] compared DCIS lesions of 34 proven BRCA1 and BRCA2 germline mutation carriers with their accompanying invasive lesions. Both were stained by immunohistochemistry for ER, progesterone receptor (PR), human epidermal growth factor receptor (HER)2/neu, cytokeratin (CK) 5/CK6 and CK14, epidermal growth factor receptor (EGFR), and Ki67. They concluded that although the number of cases studied was low, DCIS lesions, in BRCA1 and BRCA2 mutations carriers, and their accompanying invasive cancers are usually of a similar molecular subtype, thereby providing evidence that DCIS is a direct precursor lesion in these hereditary predisposed patients.
Authors also hypothesized that crucial carcinogenetic events leading to these phenotypes are antecedents to the invasive stage.
Although it is generally recognized that a multitude of factors are involved in the risk of developing in situ cancer or an invasive recurrence, it was shown that the microenvironment has a major role in the transition from preinvasive to invasive growth [48, 49] and that the myoepithelium is considered a regulatory mechanism in this process [6].
2.3.4 Ethnicity
DCIS is more common in Caucasian and Black women compared with Asian and Pacific Islander and is less common in Hispanics [2]. Lower incidence may be, however, accounted for a lower access and utilization of mammography.
No data about the incidence of DCIS in both the urban and rural populations was available before 1973, when a study reported that the incidence of DCIS, although increasing in both populations, was higher in the former [50].
Women with poor schooling (particularly those with no high school degree) are reported to have a higher incidence of DCIS, as well [51].
‡DCIS rates vary consistently with county-level poverty within each racial and ethnic group, according to a study of the American Cancer Society [2] (Fig. 2.3).
Fig. 2.3
Ductal carcinoma in situ incidence rates (per 100,000 females and age adjusted to the 2000 US standard population) by race, ethnicity, and county-level poverty (low poverty: county poverty rate <10%; medium poverty: county poverty rate 10.0–19.9%; high poverty: country poverty rate ≥20.0%), US, 2007–2011. Hispanic origin is not mutually exclusive from Asian/Pacific Islander or American Indian/Alaska Native. ‡Data based on Indian Health Service Contract Health Service Delivery Areas. Rates exclude data from Kansas. Source: NAACCR, 2014 (With permission from American Cancer Society, Inc., Surveillance Research, 2015)
Finally, the risk of death from breast cancer and invasive recurrence after DCIS are higher in Black women than in White women (RR of 1.35 and 1.4, respectively). However, studies adjusted for a more detailed set of tumor factors found no differences between racial groups and risk of DCIS or invasive recurrence (RR 1.12) [5].
2.3.5 Reproductive Factors
Women with older age at menopause have an increased incidence of DCIS based on data from the Connecticut Tumor Registry [52].This was conformed from a study of 2019 women with DCIS in a population-based research from Australia [53].
Several studies found that nulliparity or women who had a pregnancy after 30 years of age also experience a higher incidence of DCIS [43].
A study of 1.2 million women living in the UK showed no association of DCIS with early menarche [44].
2.3.6 Hormone Replacement Therapy
The Women’s Health Initiative (WHI) study reported that estrogen plus progestin use might increase risk of DCIS in postmenopausal women, while estrogen alone seem to be associated with a decreased risk [56].
A large prospective study in the UK reported a 56% increased risk for DCIS in women taking HRT, and the risk increased proportionally with the duration of HRT assumption [57].
However, while women with a HRT use for more than 5 years had greater risk of DCIS compared with never users (pooled RR = 1.41) [58, 59], women with HRT use for less than 5 years had a significantly lower risk of DCIS compared to those who never received HRT (pooled relative risk [RR] = 0.78).
2.3.7 Dietary and Metabolic Factors
The association between body mass index (BMI) and DCIS is mixed and not widely studied.
While BMI [65–72], high alcohol consumption [73–75], tobacco use [76], and a diet rich of animal fat with a low consumption of fibers would appear to be associated with an increased risk of breast cancer [77], there is insufficient evidence that this holds true for DCIS.
In fact, multiple studies found no association between BMI, or alcohol consumption, and DCIS [43, 52, 60]. In contrast, a study on 287,115 women found an increased risk for DCIS in heavily obese (BMI ≥ 35.0 kg/m2) postmenopausal women not taking HRT (OR 1.46) [78].
A population-based case-control study conducted in Los Angeles County analyzed the relationship between DCIS and physical activity on 567 women compared with 1026 control. The authors reported approximately 35% lower risk of DCIS among women with any exercise activity compared with inactive women, although no significant trend was observed [79].
Observational studies have suggested that beta-carotene, vegetables, fruits, and antioxidants may have protective effects against breast cancer. However, a recent randomized controlled trial which compared 624 women to a placebo group for a period of 9.4 years found no such protective effects of a diet supplemented with beta-carotene, vitamins C and E, fruits, and other antioxidants [80].
2.3.8 Drugs
Data from clinical trials on chemoprevention for women with high risk of breast cancer reported a decreased incidence of DCIS using tamoxifen or raloxifene [64].
2.3.9 Density of Breast Tissue
Mammographic detection of increased density of breast tissue is also a risk factor for breast cancer. A recent study reported that women with 75% or higher density had an increased risk of breast cancer compared with women with mammograms with less than 10% density [81].
For this reason, high-risk patients who have dense breast tissue detected by mammogram have been recommended to obtain a follow-up MRI of the breast so that lesions are not missed [82].
Breast density is also an associated risk factor for the development of contralateral breast cancer after treatment for DCIS. In one study, there was a threefold increased risk of invasive contralateral cancer as compared to women with an average breast density [83].
Data on six studies including more than 10,000 women found a strong association between DCIS and breast density in the group of more than 55 years of age. In general, higher mammographic density is associated with a twofold increase risk for DCIS, and this is particularly evident in women younger than age 55 [84].
2.3.10 Subsequent Breast Cancer
At last, risk of a subsequent breast cancer event following DCIS was significantly correlated with age at diagnosis, grade of tumor, primary treatment, and the use of adjuvant radiotherapy [41].
The Eastern Cooperative Oncology Group (ECOG) study reported in a large, prospective, nonrandomized protocol including 670 patients that the low-intermediate grade group had a 10.5% risk of local recurrence while the high-grade group had an 18% risk, at a median follow-up of 6.7 years. Interestingly, 35% of such recurrences were invasive [85].
However, many studies have reported that, strikingly, grade may not be significantly associated with risk of local recurrence after diagnosis of DCIS [5, 86, 87].
Conclusions
In conclusion, DCIS is a heterogeneous disease which is frequently diagnosed in women undergoing screening mammography programs.
Although the natural history of different subtypes of DCIS is yet to be fully clarified, current protocols are centered on early diagnosis and treatment to prevent progression and invasive disease.
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