Background
Inflammatory breast cancer (IBC) is a rare form of breast cancer characterized by an early average age of diagnosis (52 years versus 57 years for non-inflammatory breast cancer), aggressive histopathologic features (at least stage IIB at diagnosis), and poor survival [
1]. Clinically, IBC is defined by the American Joint Committee on Cancer (AJCC) as a disease characterized by redness, warmth and edema (peau d’orange) involving at least one-third of the breast [
2]. IBC accounts for an estimated 1.0 %-5.0 % of all incident breast carcinomas and 8.0–10.0 % of breast cancer mortality [
3‐
5]. Variable incidence trends of IBC have been reported in various geographic areas and among different ethnic/racial groups, with increasing trends reported in the United States [
4‐
6] and decreasing trends in Tunisia [
7].
The etiologic components of IBC are generally unknown and the contributions of hereditary versus environmental/life style factors remain subject of controversy in the literature. Case reports and case-case studies of IBC have reported associations with factors such as early age at first birth [
8,
9], high body mass index (BMI) [
10,
11], trauma [
12], and longer duration of breast feeding (hypothesized to increase risk through an estrogen surge) [
9]. Reports of IBC clusters [
8,
13], seasonal variations in the risk of IBC [
14], higher occurrence in rural versus urban settings [
15], and declining incidence with improving socioeconomic status [
7] further highlight the role of environmental factors in the etiology of IBC. On the other hand, reports of familial IBC, including in association with
BRCA mutations [
16] suggest a role for heredity. Furthermore, genetic influences play a role in susceptibility to other malignancies with a major environmental component, such as lung and colorectal cancers [
17‐
20].
In order to investigate the importance of hereditary factors in the etiology of IBC, we compared patients with IBC to several carefully chosen comparison groups with known prevalence of first-degree breast cancer family history. These comparison groups consisted of population-based and hospital-based non-inflammatory breast cancer and ovarian cancer cases as well as healthy controls (with no personal history of breast or ovarian cancer). As a secondary objective, comparisons were also made with respect to selected environmental/lifestyle risk factors for breast cancer.
Results
Average age of diagnosis for IBC cases (48.3 years) was lower than that of non-inflammatory breast cancer cases from GWU (51.8 years) and WHI (73.6 years) as well as ovarian cancer cases (56.1 years) (Table
1). Average age of diagnosis for CGEMS breast cancer cases was not available but the investigators reported all cases to be post-menopausal at diagnosis [
22]. Average age at study entry for CGEMS subjects was estimated from ranges provided as part of the secondary data (Table
1). Older average ages of diagnosis for WHI breast cancer cases reflect the postmenopausal inclusion criteria and the prospective study design of the WHI trials.
Table 1
Hereditary and Selected Environmental Risk Factors among Inflammatory Breast Cancer Cases and Comparison Groups
Average Age at Study Entry | 50.3 | 53.8 | 59.2 | 57.9 | 60.1 | 52.2 | 67.0 | 67.0 | 65.4h
| 65.6h
|
Average Age at Diagnosis | 48.3 | 51.8 | 56.1 | 54.6 | 57.1 | NA | 73.6 | NA | Unavailablei
| NA |
Average Body Mass Index (Kg/m2) | 28.9 | 26.5 | 24.5 | 24.3 | 24.5 | 24.9 | 30.2 | 28.8 | | |
First-Degree Breast Cancer Family History | | | | | | | | | | |
Yes | 24 (17.0) | 43 (24.4) | 63 (24.2) | 33 (34.4) | 30 (18.3) | 37 (11.2) | 74 (16.9) | 1105 (12.6) | 274 (23.9) | 204 (17.9) |
Parity (≥1 Pregnancy) | | | | | | | | | | |
Yes | 114 (80.9) | 130 (73.9) | 233 (89.6) | 89 (92.7) | 144 (87.8) | 286 (86.4) | 418 (90.1) | 8661 (93.1) | | |
Oral Contraceptive Use | | | | | | | | | | |
Yes | 113 (80.1) | 125 (71.0) | 101 (38.8) | 43 (44.8) | 58 (35.4) | 216 (65.3) | 159 (34.2) | 3089 (33.1) | | |
Regular Alcohol Use (≥1 drink per day) | | | | | | | | | | |
Yes | 30 (21.3) | 32 (18.2) | 35 (13.5) | 16 (16.7) | 19 (11.6) | 42 (12.7) | 69 (15.2) | 1184 (12.8) | | |
First-degree breast cancer family history was defined as the presence of at least one case of breast cancer among the mothers and/or sisters of the index cases. The prevalence of first-degree breast cancer family history among the IBC cases (17.0 %) was lower in comparison to the prevalence among the non-inflammatory breast cancer cases from GWU (24.4 %), breast cancer cases from CGEMS (23.9 %), and ovarian cancer cases irrespective of the
BRCA mutation status (24.2 %) (Table
1). Comparisons revealed nearly similar frequency of first-degree family history of breast cancer among IBC cases compared to WHI breast cancer cases (16.9 %),
BRCA-negative ovarian cancer cases (18.3 %), and CGEMS controls (17.9 %), and higher prevalence compared to UT-controls (11.2 %) and WHI controls (12.6 %) (Table
1). None of the comparisons involving family history reached statistical significance; adjusted analyses of GWU data produced similar odds ratios to unadjusted analyses. These results suggest a lower or similar prevalence of first-degree breast cancer family history among IBC cases compared to hospital-based and population-based breast and ovarian cancer cases but higher prevalence compared to unaffected individuals.
We identified several multiplex IBC families. The IBC index case in one family had a mother, a paternal aunt, and a paternal uncle with breast cancer. The disease was pre-menopausal in one relative and a paternal cousin was reported to have died from ovarian cancer at age 30. The index case in another family reported a sister and two aunts with breast cancer, including one with premenopausal disease. Another family was notable for reported pre- and peri-menopausal breast cancer in two sisters of the index case and a maternal relative diagnosed in her late 30’s. To our knowledge, these are among the first reported families with multiple cases of non-inflammatory breast cancer among first- and second-degree relatives of the IBC index case.
Body mass index (BMI) is considered a risk factor for both IBC [
10] and for non-inflammatory breast cancer (post-menopausal only) [
29]. BMI for IBC cases in our study (28.9 kg/m
2) was slightly higher than the BMI of breast cancer cases from GWU (26.5 kg/m
2) and of ovarian cancer cases and controls (24.5 kg/m
2 and 24.9 kg/m
2, respectively) (Table
1) but the comparisons did not reach statistical significance. WHI breast cancer cases had higher BMI (30.2 kg/m
2) compared to all other groups including the IBC cases, but comparisons did not reach statistical significance.
Nulliparity is a risk factor for both non-inflammatory breast cancer [
30] and ovarian cancer [
26] but has not been reported in association with the risk of IBC. IBC cases in our study had a higher prevalence of parous women (80.9 %) compared to non-inflammatory breast cancer cases from GWU (73.9 %) but the comparison did not reach statistical significance. The prevalence of parous women among IBC cases was significantly lower than the prevalence among WHI breast cancer cases (OR = 0.46, 95 % CI: 0.27–0.81) and WHI controls (OR = 0.31, 95 % CI: 0.20–0.49) as well as the prevalence among ovarian cancer cases (OR = 0.49, 95 % CI: 0.26–0.91).
Long-term use (>10 years) of oral contraceptives has been associated with an increased risk for non-inflammatory breast cancer [
31] and its short-term use is believed to reduce the risk of ovarian cancer [
32,
33]. Oral contraceptive use has not been previously reported in association with the risk of IBC. Data on duration of oral contraceptive use was not available on some of the comparison groups in our study and hence we limited our comparisons to ever use of oral contraceptives. The prevalence of ever use of oral contraceptives among IBC cases (80.1 %) was significantly higher compared to WHI breast cancer cases (OR = 7.77, 95 % CI: 4.82–12.59) and controls (OR = 8.14, 95 % CI: 5.28–12.61). IBC cases also reported a significantly higher ever use of oral contraceptives compared to ovarian cancer cases (OR = 6.35, 95 % CI: 3.83–10.62) and controls (OR = 2.15, 95 % CI: 1.31–3.54) from UT. The higher prevalence of oral contraceptive use among IBC cases in comparison to non-inflammatory breast cancer cases from GWU was of borderline statistical significance (OR = 1.71, 95 % CI: 0.98–2.99).
Excess alcohol consumption (>35 g per day) is an established risk factor for non-inflammatory breast cancer [
34‐
37] but has not been previously reported in association with the risk of IBC. In our study, IBC cases had significantly higher prevalence of regular alcohol use (≥1 drink per day) compared to WHI controls (OR = 1.84, 95 % CI: 1.20–2.82) and UT controls (OR = 1.86, 95 % CI: 1.07–3.22). Of note, the prevalence of regular alcohol use was higher among IBC cases (21.3 %) compared to non-inflammatory breast cancer cases from GWU (18.2 %) and from WHI (15.2 %) (Table
1) but the difference did not reach statistical significance. The association between alcohol intake and increased risk of IBC needs further investigation in future studies.
Discussion
We undertook this study to assess the importance of heredity in the etiology of IBC because of the many reports emphasizing the strong impact of the environment on IBC [
7‐
9,
11‐
15]. We compared the prevalence of breast cancer among first-degree relatives (i.e., mothers and sisters) between IBC cases and several comparison groups chosen to represent case and control groups with a range of high and low prevalence of first-degree breast cancer family history. Breast cancer and ovarian cancer patients are expected to have a high prevalence of first-degree breast cancer family history [
38,
39] while healthy individuals with no personal history of breast or ovarian cancer are expected to have a lower prevalence [
40]. Our comparisons revealed that IBC cases in our study had a slightly lower or similar prevalence of first-degree breast cancer family history compared to breast and ovarian cancer patients but a higher prevalence compared to unaffected controls.
Up to twenty percent of breast cancer cases are believed to be hereditary (characterized by multiple cases of breast and/or other cancers among relatives) and due to segregation of high-penetrance [i.e., relative risk (RR) = 20)] susceptibility genes in the affected families [
41]. Ovarian cancer has the highest rate of hereditary incidence world-wide; current estimates put the percentage of hereditary cases at 20 % of all cases of this disease [
42]. Besides age, a family history of breast and ovarian cancer is the most significant risk factor for ovarian cancer [
42]. Mutations in the breast and ovarian cancer susceptibility genes,
BRCA1 and
BRCA2, are responsible for the majority of hereditary cases of breast cancer [
41] and ovarian cancer [
42]. In addition to the genetic link between breast and ovarian cancers, there are several shared environmental risk factors which predispose to both conditions [
26]. Therefore, ovarian cancer was considered a suitable case group for comparison with IBC.
The prevalence of breast cancer among first-degree relatives of both breast and ovarian cancer cases in our study was between 16.9 % and 24.4 %, which is within the range reported in the literature (i.e., 6.2 %-27.1 % for general breast and ovarian cancer cases irrespective of
BRCA mutation status [
27,
28,
43‐
45]). Thus, IBC cases had slightly lower prevalence of first-degree breast cancer family history than the breast and ovarian cancer cases (irrespective of
BRCA carrier status) in our study but a slightly higher prevalence than general breast and ovarian cancer cases in some studies reported in the literature. A recent nested case–control study in the Breast Cancer Surveillance Consortium (BCSC) investigated the association between IBC risk and number of factors, including family history of breast cancer. This study also found a higher risk of IBC in association with first-degree family history of breast cancer [
46]. An earlier study had reported a 20 % frequency of breast cancer family history among IBC cases [
47].
The prevalence of first-degree breast cancer family history among UT controls (11.2 %) and WHI controls (12.6 %) was slightly higher than the range (4.8–7.3 %) of estimates reported in the literature for healthy women with no personal history of breast or ovarian cancer [
43,
45]. The even higher estimates for CGEMS controls (17.9 %) may reflect a particular aspect of the study design or subject characteristics of the CGEMS genome-wide association study [
22]. Nonetheless, the prevalence of first-degree breast cancer family history among the IBC cases was higher than the prevalence among healthy individuals from the UT and WHI studies as well as the prevalence estimates reported in the literature.
We identified several IBC cases with non-inflammatory breast cancer and other cancers among first- and second-degree relatives, as discussed in the previous section. Three families with multiple cases of IBC were also identified in our study; one index case had a daughter with IBC, one had a sister with IBC and the third had a cousin with IBC. A case report of hereditary IBC in a mother and a daughter had identified a deleterious
BRCA2 mutation responsible for the disease in that family [
16]. Accurate estimates of
BRCA mutation frequency among IBC cases from systematic studies remain to be reported. Our results indicate that a proportion of IBC cases occur in the context of familial breast cancer which may be explained by aggregation of common hereditary factors and/or shared environmental risk factors predisposing to both inflammatory and non-inflammatory breast cancer in these families. Our findings and the previous case report of hereditary IBC highlight the importance of obtaining pedigrees on IBC cases and noting all diagnoses of cancer and benign disease among the relatives.
As part of this study, we also conducted comparisons between IBC and other groups with respect to the prevalence of selected environmental/life style risk factors for breast cancer, such as parity, BMI, oral contraceptive use, and consumption of alcoholic beverages. These comparisons were secondary to the main study objective and the secondary nature of some of the comparison groups was a limitation with respect to the ability to conduct a comprehensive analysis of all relevant environmental/lifestyle factors. Therefore, our findings with respect to the selected environmental/life style factors need to be interpreted with caution. Our comparisons revealed a higher prevalence of nulliparity, oral contraceptive use and regular alcohol consumption (≥1 drink on daily basis) among IBC cases.
The prevalence of ever use of oral contraceptives was significantly higher among IBC cases (80.1 %) compared to all other comparison groups including breast cancer and ovarian cancer cases in our study. The differences between groups with respect to oral contraceptive use may be due to differences in age or other confounding factors between groups. Therefore, the association between oral contraceptive use and IBC risk needs further investigation in future studies accounting for all potential confounding variables. We had previously reported associations between aggressive (high-grade) breast cancer with long-term oral contraceptive use [
11].
Our findings with respect to the association between alcohol consumption and IBC are also novel. The prevalence of regular alcohol use (≥1 drink per day) was higher among IBC cases compared to all other comparison groups in our study. These findings are particularly noteworthy given that excess alcohol consumption (>35 g per day) is an established risk factor for non-inflammatory breast cancer [
34‐
37]. Ethanol and acetaldehyde have been classified as group I carcinogens (i.e., carcinogenic to humans) by International Agency for Research on Cancer (IARC) and are believed to be the carcinogenic components of alcohol [
37]. IARC classification is based on sufficient evidence in humans for carcinogenicity of alcohol consumption as demonstrated from case–control, cohort and mechanistic studies [
48]. Carcinogenic components of alcohol may exert their effects directly through inducing genetic or epigenetic mutations or indirectly through inducing inflammatory processes [
48]. The role of inflammatory processes in IBC development is not known. A number of markers of inflammation such as NF-kB, Cox, and JAK/STAT signaling have been suggested to play a role in the tumorigenesis of IBC [
49]. Inflammation may contribute to IBC development through promoting proliferation, creating a pro-inflammatory tumor microenvironment, and/or promoting metastasis of malignant cells [
49].
As mentioned earlier, the secondary nature of some of the comparison groups is a limitation of our study, particularly with respect to analysis of environmental/life style factors. Strengths of our study include systematic data collection through the use of epidemiologic questionnaires on all case and control groups; the exact same questionnaire was used on the IBC and non-inflammatory breast cancer cases from GWU. Other strengths include validation of the family history-related questions through collection of detailed pedigrees on a subset of IBC cases and access to raw (secondary) data from several case–control studies, which could be used as additional comparison groups. The case–control comparison groups in our study were sufficiently large to allow statistically meaningful comparisons and the unaffected individuals used as controls in these studies were appropriately matched to the breast and ovarian cancer cases on important criteria such as age and ethnicity.
Abbreviations
AJCC, American Joint Committee on Cancer; BC, Breast Cancer; BMI, Body Mass Index; CGEMS, Cancer Genetic Markers of Susceptibility; GWU, George Washington University; IBC, Inflammatory Breast Cancer; NHS, Nurses’ Health Study; OC, Ovarian Cancer; UT, University of Toronto; WHI: Women’s Health Initiative.
Acknowledgements
We thank the Principal Investigators of the UT [
27], CGEMS [
22,
23] and WHI [
24,
25] studies and the NIH dbGaP administrators for access to data from those studies. We thank Dr. J.M. Friedman at the University of British Columbia for guidance provided to RM. We are grateful to all women who participated as cases and controls in the studies analyzed in this report.