Abstract
BACKGROUND
Inflammatory breast cancer (IBC) often affects women at a relatively young age. The rate of BRCA variants among patients with IBC is not known. To determine the association between BRCA status and IBC we evaluated its rate and compared the clinicopathologic characteristics of patients with IBC and those with other breast cancers (non-IBC).
METHODS
Patients who presented at our institution’s cancer genetics program and who underwent BRCA genetic testing were included in this study. We compared clinicopathologic data between patients with IBC and those with non-IBC utilizing propensity score matching to identify predictors.
RESULTS
We included 1789 patients who underwent BRCA genetic testing (1684 with non-IBC and 105 with IBC). BRCA pathogenic variants were found in 27.3% with non-IBC and 18.1% with IBC (p = 0.0384). After propensity score matching, there were no significant differences between patients with IBC and those with non-IBC, including the rate of BRCA pathogenic variants (p = 0.5485). However a subgroup analysis of the patients with BRCA pathogenic variants (n = 479) showed that patients with IBC (n = 19) were diagnosed at significantly younger ages than patients with non-IBC were (p = 0.0244).
CONCLUSIONS
There was not a clear association between BRCA pathogenic variants and IBC, however among patients who tested positive for BRCA pathogenic variants, those with IBC were younger at diagnosis than those with non-IBC breast cancers. These results confirm that genetic testing is important for patients with IBC who meet the current clinical criteria for genetic testing in breast cancer.
Keywords: Inflammatory breast cancer, BRCA, genetic testing, pathogenic variant, Inflammatory Breast Neoplasms
Background
Inflammatory breast cancer (IBC) is an aggressive subset of breast cancer comprising approximately 1%–6% of all breast cancers diagnosed annually in the United States.1 IBC is characterized by young age at diagnosis, aggressive tumor features such as high nuclear grade, HER2/neu receptor (HER2) amplification, triple receptor negativity (estrogen receptor [ER], progesterone receptor [PR], and HER2 negativity), high metastatic potential, and poor overall survival compared with breast cancers other than IBC (non-IBC).1–3
The etiology of this rapidly progressive cancer remains poorly understood. Although the term “inflammatory breast cancer” is derived from its distinctive clinical appearance, current evidence suggests that inflammation plays a central role in IBC tumor formation as well.4 Epidemiologic studies have suggested that several risk factors may be associated with the development of IBC, including younger age of menarche, younger age of first live birth, African-American race/ethnicity, higher body mass index, and lower socioeconomic status.5–7
An unexamined potential contributor to the development of IBC is the presence of pathogenic variants in the tumor suppressor genes BRCA1 and BRCA2, which are generally associated with an up to 87% lifetime risk of developing breast cancer.8,9 The current National Comprehensive Cancer Network® (NCCN®) guidelines recommend that women diagnosed with breast cancer at age 45 years or younger, with triple-negative breast cancer (TNBC) at age 60 years or younger, or with two or more primary breast cancers with the first diagnosis at 50 years or younger be tested for pathogenic gene variants, in the BRCA1 and BRCA2 genes. Similarly, personal and family histories of breast, ovarian, prostate, and pancreatic cancers are associated with hereditary breast and ovarian cancer syndrome (HBOC), which is caused by BRCA1 and BRCA2 pathogenic variants.10
The characteristics shared between IBC and patients with BRCA mutations, including younger age at diagnosis and increased likelihood of TNBC, suggest that IBC could be associated with BRCA mutations. However, whether BRCA pathogenic variants play a role in the development of IBC is currently unknown. There is scant literature examining the association between IBC and BRCA pathogenic variants, including only one case report.11 To determine whether if BRCA pathogenic variants are associated with IBC1,5, we compared the rate of BRCA mutations, and other clinicopathologic characteristics, between patients with IBC and patients with non-IBC who underwent BRCA genetic testing.
Patients and Methods
Female patients who presented to the Clinical Cancer Genetics Program at The University of Texas MD Anderson Cancer Center and underwent genetic testing for BRCA1 and BRCA2 were retrospectively evaluated for this study. All patients were either self-referred or physician-referred to the program on the basis of their age at the time of their breast cancer diagnosis (≤50 years) and/or their family history of breast or ovarian cancer. The institutional referral guidelines were based on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) from 2014.10
Data collection
Data collection began on February 19, 2004, and ended on December 18, 2014, and used the High-Risk Breast database to identify patients with non-IBC and the IBC registry database to identify patients with IBC. Both databases are prospectively maintained at The University of Texas MD Anderson Cancer Center, a research protocol for data collection was approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center and all patients provided written informed consent to one or both of the protocols. Genetic test results from 1996 to 2014 were obtained from the High Risk Breast database, and only patients with known BRCA results were included.
Patients without an uninformative BRCA variant result were excluded (44 patients: 43 with non-IBC and 1 with IBC). One patient with pathogenic variants in both BRCA1 and BRCA2 (non-IBC) was also excluded since she could be not be categorized by a single gene. Lastly, 1 patient whose results we could not confirm was excluded (non-IBC). Therefore 1789 patients remained for analysis (1684 with non-IBC and 105 with IBC).
All patients in this study were cared for by a multidisciplinary team comprised of a breast medical oncologist, a surgeon, and a radiation oncologist. A clinical diagnosis of IBC was defined according to the criteria outlined in the seventh edition of the American Joint Committee on Cancer staging manual and the recommendations of an expert panel on IBC.12,13 All pathologic specimens were reviewed by a dedicated breast pathologist at our institution, and all patients underwent routine staging workup. HER2, ER, and PR status were determined according to the American Society of Clinical Oncology/College of American Pathologists recommendations.12–14 Family history was obtained from patient reports provided during a genetic counseling session and collection of a three-generation pedigree or from the IBC registry questionnaire.
Statistical analysis
Patient demographic and clinical characteristics were summarized and compared between non-IBC and IBC groups that included all patients in the study and between non-IBC and IBC groups among patients with BRCA pathogenic variants. In addition to BRCA variant status, the variables of interest were age at first diagnosis, race/ethnicity, genetic test results, family history of breast cancer and/or ovarian cancer, histopathologic features of tumors such as ER, PR, and HER2 status, and Ashkenazi Jewish status. In a supplemental analysis, IBC patients identified from the High Risk Breast registry and who were referred for genetic testing were compared with an additional sample from the IBC registry of IBC patients who were not referred for genetic testing. The factors potentially associated with genetic test referral of IBC patients were investigated using univariable and multivariable logistic regression analysis. Mean, standard deviation, median, and range were presented for continuous variables, and frequency and percentage were presented for categorical variables. Two-sample t-test or Wilcoxon rank-sum test was used to compare continuous variables, and chi-square test or Fisher exact test was used to compare categorical variables.
Because our sample was limited by lower numbers of patients in the IBC group than in the non-IBC group, we performed a propensity score–matching analysis to allow for a more balanced comparison. IBC propensity score, defined as the probability of being diagnosed with IBC based on observed patient characteristics, was obtained using logistic regression with covariates. The covariates included having a first-degree relative with breast cancer, having any relatives with breast cancer, tumor marker status (ER, PR, and HER2 status), age at the time of first cancer diagnosis, and time from the first cancer diagnosis to genetic testing. For each IBC patient, one non-IBC patient with a similar propensity score was selected as a propensity-matched control. Conditional logistic regression analyses with BRCA pathogenic variants as a response variable were performed for the IBC and non-IBC patients selected by propensity matching to assess the significance of each variable on the odds of having BRCA pathogenic variants.
Univariable and multivariable logistic regression analyses were used to compare the rates of BRCA pathogenic variants between IBC and non-IBC patients. These analyses included scenarios without adjustment for covariates, with adjustment for covariates, with adjustment for covariates and propensity scores, and with stratification by propensity scores.
A p value of less than 0.05 indicated statistical significance. SAS 9.4 (SAS Institute Inc., Cary, NC) was used for data analysis.
Results
The final analysis included a total of 1789 female patients who underwent genetic testing: 1684 patients with non-IBC and 105 patients with IBC. Table 1 summarizes their demographic and clinicopathological characteristics. IBC and non-IBC patients were similar in age at diagnosis and age at the time of genetic testing. However, the time from diagnosis to genetic testing was significantly shorter for patients in the IBC group. The proportion of patients with a first-degree relative with breast cancer was significantly higher in the non-IBC group than in the IBC group (37.8% vs. 17.3%, p < 0.0001). The proportion of patients with Ashkenazi Jewish ancestry was significantly higher in the non-IBC group than in the IBC group (5.1% vs. 0%, p = 0.0133). However, the IBC and non-IBC groups were similar with regard to having relatives with breast cancer or relatives with ovarian cancer. No differences between the IBC and non-IBC groups were observed in race/ethnicity or TNBC status. As expected, patients with IBC presented significantly less frequently with hormone receptor–positive tumors and significantly more frequently with HER2-positive tumors.
Table 1.
Comparison of IBC and non-IBC groups including all patients in the study
| Variable | Non-IBC (N=1684) | IBC (N=105) | p value |
|---|---|---|---|
| Age at first diagnosis (years)* | 42.0 ± 9.3, 41 (20–88) | 42.2 ± 9.7, 41 (22–68) | 0.8633 |
| Age at the time of genetic test (years)* | 46.1 ± 10.8, 45 (21–89.1) | 44.4 ± 10.2, 43.7 (22.7–68.7) | 0.1307 |
| Time from diagnosis to genetic test (years)* | 4.1 ± 6.4,1.2 (−7.9–46.9) | 2.2 ± 3.8,0.9 (−0.4–17.1) | 0.0096 |
| First-degree relative with BC | |||
| No | 1041 (62.2%) | 86 (82.7%) | <0.0001 |
| Yes | 633 (37.8%) | 18 (17.3%) | |
| Relative with BC | |||
| No | 476 (28.3%) | 28 (26.7%) | 0.7237 |
| Yes | 1208 (71.7%) | 77 (73.3%) | |
| First-degree relative with OC | |||
| No | 1551 (92.7%) | 94 (91.3%) | 0.6015 |
| Yes | 123 (7.3%) | 9 (8.7%) | |
| Relative with OC | |||
| No | 1340 (79.6%) | 83 (79.8%) | 0.9539 |
| Yes | 344 (20.4%) | 21 (20.2%) | |
| BRCA pathogenic variants | |||
| No | 1224 (72.7%) | 86 (81.9%) | 0.0384 |
| Yes | 460 (27.3%) | 19 (18.1%) | |
| ER | |||
| No | 549 (36.0%) | 59 (56.7%) | <0.0001 |
| Yes | 978 (64.0%) | 45 (43.3%) | |
| PR | |||
| No | 712 (47.4%) | 69 (67.0%) | 0.0001 |
| Yes | 789 (52.6%) | 34 (33.0%) | |
| HER2 | |||
| No | 1043 (82.0%) | 62 (63.3%) | <0.0001 |
| Yes | 229 (18.0%) | 36 (36.7%) | |
| TNBC | |||
| No | 1176 (77.5%) | 73 (72.3%) | 0.2288 |
| Yes | 342 (22.5%) | 28 (27.7%) | |
| Race/ethnicity | |||
| White | 1222 (72.7%) | 77 (74.0%) | 0.6614 |
| Hispanic | 239 (14.2%) | 13 (12.5%) | |
| Black | 128 (7.6%) | 10 (9.6%) | |
| Asian | 65 (3.9%) | 4 (3.8%) | |
| Other | 27 (1.6%) | 0 (0%) | |
| Ashkenazi Jewish ancestry | |||
| No | 1491 (94.9%) | 102 (100%) | 0.0133 |
| Yes | 80 (5.1%) | 0 (0%) | |
Mean ± standard deviation, median (range); all other values are no. (%)
BC, breast cancer; OC, ovarian cancer
BRCA pathogenic variants were identified in 460 women (27.3%) with non-IBC and 19 women (18.1%) with IBC (p = 0.0384; Table 1). Of the women with non-IBC with BRCA pathogenic variants, 264 had BRCA1 and 196 had BRCA2 pathogenic variants. Similarly, among women with IBC who had BRCA pathogenic variants, 14 had in BRCA1 gene and five had in BRCA2 gene. The odds of having a BRCA pathogenic variant were significantly lower in patients with IBC than in those with non-IBC (odds ratio [OR], 0.588; 95% confidence interval [CI], 0.354–0.977, p = 0.0405) without adjustment for covariates. When we adjusted for age at diagnosis, time from diagnosis to testing, for having a first-degree relative with breast cancer, any relative with breast cancer, first-degree relative with ovarian cancer, any relative with ovarian cancer, and for ER, PR, and HER2 status; the association between IBC status and BRCA pathogenic variant status was no longer significant (OR, 0.608; 95% CI, 0.331–1.119; p = 0.1098). When the same covariates and the propensity scores were adjusted for, the association between IBC status and BRCA pathogenic variant status was still not significant (OR, 0.634; 95% CI, 0.343–1.169; p = 0.1444).
In the propensity score–matched analysis (Table 2), in which IBC and non-IBC groups were matched for significant predictors of IBC, no statistically significant differences were detected between matched patients with IBC and those with non-IBC in any of the variables, including rate of BRCA pathogenic variant positivity (p = 0.5485).
Table 2.
Comparison of IBC and non-IBC groups selected by propensity score matching
| Variable | Non-IBC (N=96) | IBC (N=96) | p value |
|---|---|---|---|
| Age at first diagnosis (years)* | 43.3 ± 9.5, 42 (25–79) | 42.1 ± 10, 41 (22–68) | 0.3571 |
| Age at the time of genetic test (years)* | 44.9 ± 10.1, 44.23 (25.1–82) | 43.6 ± 10, 42.87 (22.7–68.7) | 0.3050 |
| Time from diagnosis to genetic test (years)* | 1.7 ± 2.7, 0.83 (−2.4–13.9) | 1.5 ± 2.3, 0.89 (−0.4–14.8) | 0.5961 |
| First-degree relative with BC | |||
| No | 80 (83.3%) | 80 (83.3%) | 1.0000 |
| Yes | 16 (16.7%) | 16 (16.7%) | |
| Relative with BC | |||
| No | 24 (25.0%) | 24 (25.0%) | 1.0000 |
| Yes | 72 (75.0%) | 72 (75.0%) | |
| First-degree relative with OC | |||
| No | 90 (93.8%) | 87 (91.6%) | 0.5637 |
| Yes | 6 (6.3%) | 8 (8.4%) | |
| Relative with OC | |||
| No | 79 (82.3%) | 75 (78.9%) | 0.5637 |
| Yes | 17 (17.7%) | 20 (21.1%) | |
| BRCA pathogenic variants | |||
| No | 77 (80.2%) | 80 (83.3%) | 0.5485 |
| Yes | 19 (19.8%) | 16 (16.7%) | |
| ER | |||
| No | 56 (58.3%) | 56 (58.3%) | 1.0000 |
| Yes | 40 (41.7%) | 40 (41.7%) | |
| PR | |||
| No | 62 (65.3%) | 66 (68.8%) | 0.4795 |
| Yes | 33 (34.7%) | 30 (31.3%) | |
| HER2 | |||
| No | 61 (63.5%) | 60 (62.5%) | 0.8474 |
| Yes | 35 (36.5%) | 36 (37.5%) | |
| TNBC | |||
| No | 64 (66.7%) | 68 (70.8%) | 0.5371 |
| Yes | 32 (33.3%) | 28 (29.2%) | |
| Race/ethnicity | |||
| Non-black | 85 (88.5%) | 85 (89.5%) | 0.8084 |
| Black | 11 (11.5%) | 10 (10.5%) | |
| Ashkenazi Jewish ancestry | |||
| No | 88 (96.7%) | 94 (100%) | - |
| Yes | 3 (3.3%) | 0 (0%) | |
Mean ± standard deviation, median (range); all other values are no. (%)
-, designates that a p-value could not be calculated
BC, breast cancer; OC, ovarian cancer
Next, we performed conditional logistic regression analysis with the presence of BRCA pathogenic variants as a response variable (Table 3), using the propensity score–matched pairs described above. HER2 negativity (p = 0.0281) and having TNBC diagnosis (p = 0.0155) were the only variables significantly associated with the presence of BRCA pathogenic variants.
Table 3.
Conditional logistic regression analysis with BRCA pathogenic variants as a response variable
| Variable | OR | 95% CI | p value | |
|---|---|---|---|---|
| Age at first diagnosis | 0.975 | 0.921 | 1.033 | 0.3892 |
| Age at the time of genetic test | 0.970 | 0.911 | 1.032 | 0.3347 |
| Time from diagnosis to genetic test | 0.993 | 0.805 | 1.225 | 0.9494 |
| First-degree relative with BC | ||||
| No | 1.000 | 1.0000 | ||
| Yes | 1.000 | 0.323 | 3.101 | |
| Relative with BC | ||||
| No | 1.000 | 0.1785 | ||
| Yes | 3.000 | 0.606 | 14.864 | |
| First-degree relative with OC | ||||
| No | 1.000 | 0.1785 | ||
| Yes | 3.000 | 0.606 | 14.864 | |
| Relative with OC | ||||
| No | 1.000 | 0.0795 | ||
| Yes | 4.000 | 0.849 | 18.836 | |
| IBC | ||||
| No | 1.000 | 0.5495 | ||
| Yes | 0.786 | 0.357 | 1.731 | |
| ER | ||||
| No | 1.000 | 0.0694 | ||
| Yes | 0.385 | 0.137 | 1.079 | |
| PR | ||||
| No | 1.000 | 0.0994 | ||
| Yes | 0.333 | 0.090 | 1.231 | |
| HER2 | ||||
| No | 1.000 | 0.0281 | ||
| Yes | 0.100 | 0.013 | 0.781 | |
| TNBC | ||||
| No | 1.000 | 0.0155 | ||
| Yes | 4.667 | 1.341 | 16.239 | |
| Race/ethnicity | ||||
| Non-black | 1.000 | |||
| Black | 0.500 | 0.045 | 5.514 | 0.5714 |
| Ashkenazi Jewish ancestry | ||||
| No | 1.000 | 0.9961 | ||
| Yes | NR | NR | NR | |
NR: Owing to the small number of patients with Ashkenazi Jewish ancestry (n = 3), therefore OR (95% CI) was not reliably estimated.
BC, breast cancer; OC, ovarian cancer
However in an age distribution analysis, for every 1-year decrease in age at diagnosis those with IBC were associated with an 8% increase in the odds of having a BRCA pathogenic variant (p = 0.0075). Therefore among patients with IBC, BRCA pathogenic variants were most likely to occur in younger age groups (p = 0.0096; Figure 1).
Figure 1.
In the subgroup analysis of the patients with BRCA pathogenic variants (n = 479), we compared clinical characteristics between patients with IBC (n = 19) and non-IBC (n = 460; Table 4). Among these patients, those with IBC were diagnosed at significantly younger ages ((mean ± standard deviation) than those with non-IBC were (36.6 ± 8.2 years vs. 41.5 ± 9.4 years; p = 0.0244). These IBC and non-IBC groups showed a similar difference in age at the time of genetic testing (p = 0.0387). Patients with BRCA pathogenic variants who had IBC were less likely to have first-degree relatives with breast cancer than those with non-IBC were (p = 0.0111).
Table 4.
Comparison of IBC and non-IBC in patients with BRCA pathogenic variants(n = 479)
| Variable | IBC (N=19) | Non-IBC (N=460) | p value |
|---|---|---|---|
| Age at first diagnosis (years)* | 36.6 ± 8.2, 36 (23–54) | 41.5 ± 9.4, 41 (20–84) | 0.0244 |
| Age at the time of genetic test (years)* | 41.1 ± 9.6, 38.8 (24.2–57.1) | 46.2 ± 10.7, 45 (22.3–86.1) | 0.0387 |
| First-degree relative with BC | |||
| No | 15 (78.9%) | 226 (49.2%) | 0.0111 |
| Yes | 4 (21.1%) | 233 (50.8%) | |
| Relative with BC | |||
| No | 5 (26.3%) | 76 (16.5%) | 0.3426 |
| Yes | 14 (73.7%) | 384 (83.5%) | |
| First-degree relative with OC | |||
| No | 17 (89.5%) | 379 (82.6%) | 0.7547 |
| Yes | 2 (10.5%) | 80 (17.4%) | |
| Relative with OC | |||
| No | 13 (68.4%) | 285 (62.0%) | 0.5690 |
| Yes | 6 (31.6%) | 175 (38.0%) | |
| ER | |||
| No | 11 (57.9%) | 212 (53.3%) | 0.6927 |
| Yes | 8 (42.1%) | 186 (46.7%) | |
| PR | |||
| No | 12 (66.7%) | 242 (63.5%) | 0.7860 |
| Yes | 6 (33.3%) | 139 (36.5%) | |
| HER2 | |||
| No | 14 (87.5%) | 288 (91.1%) | 0.6459 |
| Yes | 2 (12.5%) | 28 (8.9%) | |
| TNBC | |||
| No | 12 (66.7%) | 235 (60.4%) | 0.5953 |
| Yes | 6 (33.3%) | 154 (39.6%) | |
| Race/ethnicity | |||
| White | 15 (78.9%) | 334 (72.6%) | 0.8884 |
| Hispanic | 2 (10.5%) | 65 (14.1%) | |
| Black | 1 (5.3%) | 38 (8.3%) | |
| Asian | 1 (5.3%) | 17 (3.7%) | |
| Other | 0 (0%) | 6 (1.3%) | |
| Ashkenazi Jewish ancestry | |||
| No | 16 (100%) | 377 (95%) | 1.0000 |
| Yes | 0 (0%) | 20 (5%) | |
Mean ± standard deviation, median (range); all other values are no. (%)
BC, breast cancer; OC, ovarian cancer
In the supplementary analysis of referral patterns (Supplementary Table 1A) among IBC patients, we compared family history and age at diagnosis between patients who were referred for genetic testing (n = 105) and patients who were not referred for genetic testing (n = 162). As expected, patients who were referred for genetic testing had a significantly higher rates of a family history of breast cancer (p < 0.0002) and of a family history of ovarian cancer (p < 0.0013) than those who were not referred. In addition, younger age was significantly associated with referral for genetic testing (p < 0.0001). Among patients older than 45 years at diagnosis, 77% were not referred for testing; whereas those who were 45 years or younger, 38% were referred for testing (p < 0.0001). These associations remained statistically significant in a multivariable logistic regression analysis (p = 0.0025 for family history of breast cancer and p = 0.0094 for family history of ovarian cancer; Supplementary Table 1B).
Discussion
In the present study, there seems to be no association between BRCA pathogenic variants and IBC. However, those with IBC were younger at the time of diagnosis than those with non-IBC, suggesting that IBC has a younger onset in individuals with BRCA pathogenic variants. Genetic testing should continue to be made available to those who meet current clinical testing criteria genetic testing.
We found that 18.1% of patients with IBC and 27.3% of patients with non-IBC had BRCA pathogenic variants (p = 0.0384). However, after adjustment for covariates in a multivariable logistic regression model, and after matching for predictors of IBC in a propensity score analysis, no significant association between IBC status and BRCA variant status remained. The absence of a statistically significant difference in the proportion of individuals with germline BRCA pathogenic variants–between IBC and non-IBC does not necessarily imply an absence of association between BRCA pathogenic variants and IBC; these BRCA variant rates may instead reflect the distribution of important predictors such as breast cancer subtype, which is known to be strongly associated with BRCA pathogenic variants.
A relationship between BRCA pathogenic variants and IBC is supported by the results of the subgroup analysis of the patients with pathogenic variants in BRCA. Among these patients, those with IBC were significantly younger at diagnosis than those with non-IBC (p = 0.0244). Also, there was a 9% increase in the odds of having a BRCA pathogenic variant for every 1-year decrease in age at diagnosis (p = 0.0075), despite the fact that the IBC and non-IBC groups had similar median ages at diagnosis at both the descriptive level and after propensity score matching. Importantly, this relationship of BRCA pathogenic variants with younger age was also observed in the comparison of BRCA pathogenic variant IBC with BRCA negative IBC (data not shown) and in the distribution of BRCA status rate across age groups (p = 0.0096; Figure 1).
A similar association between IBC and BRCA pathogenic variant status was previously suggested in a case report that described a mother and daughter who were both diagnosed with IBC.11 The proband was diagnosed at the age of 40 years and found to have a pathogenic variant in BRCA2. The patient’s mother had been diagnosed and had died at the age of 35 years. The patient’s tumor was hormone receptor positive and HER2 negative with biopsy-confirmed metastasis in the right paratracheal lymph nodes. Her personal history of early-onset invasive breast cancer and a family history of breast cancer warranted genetic counseling. There are no other reports describing pathogenic variants in BRCA concomitant with an IBC diagnosis.
Previous studies have suggested an association between a family history of breast cancer and a diagnosis of IBC. In a small case-comparison study conducted at MD Anderson Cancer Center, Chang et al. observed that 13% of patients with IBC, but only 8% of patients with non-IBC, reported a positive family history of breast cancer, although the difference was not statistically significant.15 A case-comparison study conducted in Pakistan found that 20% of women with IBC, but only 5% of women with non-IBC, had a family history of breast cancer (p < 0.0002).16 However, the degree of relativity to the IBC patients was not defined, nor was the ovarian cancer rate explored in that study. More recently, a study from the Breast Cancer Surveillance Consortium examining 617 IBC cases found that the presence of a family history of breast cancer was associated with an increased risk of developing IBC similar to that of developing non-IBC 7; however, that study investigated only the presence of female first-degree relatives with breast cancer among patients with IBC compared with those with non-IBC.
In the present study, the proportion of patients with a first-degree relative with breast cancer was significantly higher in the non-IBC group than in the IBC group (37.8% vs. 17.3%; p < 0.0001). However, the IBC and non-IBC groups had similar rates of all relatives with breast cancer and of relatives with other cancers. Similarly, among patients with BRCA pathogenic variants, patients with non-IBC had a higher rate of first-degree relatives with breast cancer compared with patients with IBC (50.8% vs. 21.1%; p = 0.0111). These differences were lost upon propensity score–matched analysis. A supplementary analysis comparing patterns of referral for genetic testing among patients with IBC was found to reflect the expected from NCCN 10 and institutional guidelines for referral in the breast cancer. There were significant associations between referral for genetic testing and a family history of breast cancer (p = 0.0025) and ovarian cancer (p = 0.0094). Similarly, an age of 45 years or younger was significantly associated with referral for genetic testing (p < 0.0001; Supplementary Table 1B). However, it is difficult to draw conclusions from these results due to the highly selective nature of our sample, especially because the presence of a family history is part of our institutional criteria for referral to genetic counseling.
Despite previous reports that showed a higher proportion of TNBC tumors are associated with IBC than with non-IBC, the proportion of patients with TNBC in our sample was similar between IBC and non-IBC groups, probably reflecting the selection criteria for genetic testing. The association between TNBC and BRCA pathogenic variant was confirmed by conditional logistic regression analysis (p = 0.0155; Table 3).
Our study has several limitations, including its retrospective nature, the small number of IBC patients, and the fact that it was conducted at a single institution. Moreover, the cohort examines a highly selected group of patients who were referred for genetic counseling. Furthermore, the referral guidelines (institutional guidelines and NCCN Guidelines®) were based on those from 2014 and earlier; both guidelines have since been updated to include referral/testing recommendations for individuals with family histories of pancreatic and prostate cancers and to address low/moderately penetrant genes commonly included in panel testing (NCCN Guidelines 2017).10 These limitations are partially due to the rarity of IBC and in particular of IBC with the presence of BRCA pathogenic variants. Perhaps the aggressive nature and rapid progression of IBC play a role in the past lack of referrals for genetic consultations; however that cannot be determined within the parameters of this study.
To our knowledge, our study uniquely describes the rate of BRCA pathogenic variants among patients with IBC. These results suggest that the role played by BRCA pathogenic variants in the development of IBC tumors may be similar to the role of these variants in other types of breast cancer. Our study results confirm that patients diagnosed with IBC may undergo testing based on testing guidelines, as we found no significant difference in BRCA positivity rate between IBC and non-IBC. Our results also suggest that carriers of BRCA pathogenic variants with breast cancer may develop IBC at an earlier age than non-IBC patients do. Therefore, given that genetic testing is already warranted for younger patients and those with a family history of breast cancer and/or ovarian cancer, testing should continue to be made available to those who meet current clinical testing criteria from the NCCN.10
Supplementary Material
Acknowledgments
Research support: This study is supported by generous donations to Clinical Cancer Genetics from the Lowe Foundation, Posey Foundation, and International Bank of Commerce (IBC) Foundation. The statistical analysis work was supported in part by the Cancer Center Support Grant (National Cancer Institute Grant P30CA016672). Authors (NTU, AV, TMF) are supported by the Morgan Welch Inflammatory Breast Cancer Research Program Grant and State of Texas Rare and Aggressive Breast Cancer Research Program Grant.
Footnotes
Conflicts of Interest Disclosures: The manuscript has never been published and is not under consideration for publication elsewhere. The authors have no financial disclosures to declare.
Author Contribution Statement:
Angelica M. Gutierrez Barrera: Conceptualization, Data curation; Project administration; Visualization; original draft; review & editing
Tamer M. Fouad: Data curation; Methodology; Project administration; Visualization; original draft; review & editing
Juhee Song: Formal analysis; Methodology; Resources; Visualization; review & editing
Rachel Webster: review & editing
Nisreen Elsayegh: review & editing
Anita Vines: review & editing
Atakan Demir: review & editing
Jennifer K. Litton: review & editing
Naoto T. Ueno: review & editing
Banu K. Arun: Conceptualization; Funding acquisition; Methodology; Project administration; Resources; Supervision; Visualization, original draft; review & editing
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