Tumor characteristics by patient characteristics, age at breast cancer diagnosis and BBD calendar year at diagnosis
Characteristics of the BBD patients are detailed in Supplemental Tables 1 and 2. The median age of BBD diagnosis was 51.5 years and over 60% of cases were diagnosed between 1980–1999. As mammography screening became more common after 1993 compared to BBD diagnoses prior to 1993, we observed an increased frequency of proliferative disease without atypia (38.5 vs 27.6%) and with atypia (7.3 vs 4.0%, Supplemental Table 1) subsequent to 1993. We also observed increased detection of prevalent breast cancer and a stage shift, with a 12% increase in diagnosed stage I tumors after 1993 (Supplemental Table 1). The median follow-up between BBD and breast cancer diagnosis was 9.0 years (IQR = 4.4, 15.8 years), with a median age at breast cancer diagnosis of 62.7 years. Descriptive characteristics of the BBD patients subsequently diagnosed with breast cancer, overall, and stratified by age < 50 and ≥ 50 at breast cancer diagnosis, are presented in Table 1. Most cases were older than 50 years (87%) at diagnosis. Breast cancers were mostly diagnosed from 1996–2005, and 55% of cases were diagnosed within 10 years of their initial BBD diagnosis.
Table 1
Characteristics of BBD histology among breast cancer cases, overall and by age at breast cancer diagnosis (N = 514)
| | | Age at breast cancer diagnosis | | ER status |
| Cases | ≤ 50 years (N = 69) | > 50 years (N = 445) | | | ER+ (N = 391) | ER- (N = 64) | |
| N | % | N | % | N | % | Pᵃ | | N | % | N | % | Pᵃ |
Age at BBD, years | | | | | | | | | | | | | |
< 40 | 90 | 17.5 | 41 | 59.4 | 49 | 11.0 | < 0.0001 | | 61 | 15.6 | 13 | 20.3 | 0.83 |
40–49 | 141 | 27.4 | 28 | 40.6 | 113 | 25.4 | | | 113 | 28.9 | 17 | 26.6 | |
50–59 | 145 | 28.2 | 0 | 0 | 145 | 32.6 | | | 111 | 28.4 | 19 | 29.7 | |
60–69 | 86 | 16.7 | 0 | 0 | 86 | 9.3 | | | 65 | 16.6 | 8 | 12.5 | |
≥ 70 | 52 | 10.1 | 0 | 0 | 52 | 11.7 | | | 41 | 10.5 | 7 | 10.9 | |
mean (SD) | 52.2 (12.5) | 37.5 (6.9) | 54.4 (11.6) | | | 52.4 (12.5) | 51.7 (12.9) | |
median (IQR) | 51.5 (42.6, 60.8) | 39.0 (34.9, 42.9) | 53.6 (46.1, 62.1) | | | 51.7 (42.8, 61.0) | 50.6 (42.8, 59.8) | |
Year of BBD diagnosis | | | | | | | 0.062 | | | | | | 0.92 |
1971–1979 | 95 | 18.5 | 19 | 27.5 | 76 | 17.1 | | | 50 | 12.8 | 10 | 15.6 | |
1980–1989 | 173 | 33.7 | 16 | 23.2 | 157 | 35.3 | | | 134 | 34.3 | 20 | 31.3 | |
1990–1999 | 161 | 31.3 | 25 | 36.2 | 136 | 30.6 | | | 134 | 34.3 | 22 | 34.4 | |
2000–2006# | 85 | 16.5 | 9 | 13.0 | 76 | 17.1 | | | 73 | 18.7 | 12 | 18.8 | |
BBD histology | | | | | | | 0.22 | | | | | | 0.39 |
Normal/Non-proliferative | 324 | 63.0 | 50 | 72.5 | 274 | 61.6 | | | 243 | 62.2 | 43 | 67.2 | |
Proliferative without atypia | 163 | 31.7 | 16 | 23.2 | 147 | 33.3 | | | 127 | 32.5 | 20 | 31.3 | |
Proliferative with atypia | 27 | 5.3 | 3 | 4.4 | 24 | 5.4 | | | 21 | 5.4 | 1 | 1.6 | |
Year of breast cancer diagnosis | | | | | | < 0.0001 | | | | | | 0.53 |
1973–1990 | 72 | 14.1 | 22 | 31.9 | 51 | 11.4 | | | 21 | 5.4 | 3 | 4.7 | |
1991–1995 | 68 | 13.2 | 10 | 14.5 | 58 | 13.0 | | | 49 | 12.5 | 12 | 18.8 | |
1996–2000 | 101 | 19.7 | 17 | 24.6 | 84 | 18.8 | | | 81 | 20.7 | 17 | 26.6 | |
2001–2005 | 116 | 22.6 | 11 | 15.9 | 106 | 23.7 | | | 104 | 26.6 | 12 | 18.8 | |
2006–2010 | 106 | 20.6 | 5 | 7.3 | 101 | 22.6 | | | 91 | 23.3 | 14 | 21.9 | |
2011–2013 | 51 | 9.9 | 4 | 5.8 | 47 | 10.6 | | | 45 | 11.5 | 6 | 9.4 | |
Years from BBD to breast cancer diagnosis | | | | | | | < 0.0001 | | | | | | 0.55 |
≤ 10 | 284 | 55.3 | 54 | 78.3 | 230 | 51.7 | | | 198 | 50.6 | 35 | 54.7 | |
> 10 | 230 | 44.8 | 15 | 21.7 | 215 | 48.3 | | | 193 | 49.4 | 29 | 45.3 | |
mean (SD) | 10.8 (7.9) | 7.3 (6) | 11.4 (8) | | | 11.6 (8) | 10.5 (8.3) | |
median (IQR) | 9.0 (4.4, 15.8) | 5.6 (2.9, 9.4) | 9.8 (4.7, 16.3) | | | 10.0 (5.3, 16.4) | 8.7 (3.3, 15.7) | |
Tumor size/mm | | | | | | | 0.13 | | | | | | 0.63 |
< 10 | 143 | 28.9 | 26 | 37.7 | 117 | 27.5 | | | 90 | 23.9 | 16 | 26.2 | |
10–20 | 211 | 42.6 | 29 | 42.0 | 182 | 42.7 | | | 173 | 45.9 | 24 | 39.3 | |
> 20 | 141 | 28.5 | 14 | 20.3 | 127 | 29.8 | | | 114 | 30.2 | 21 | 34.4 | |
Missing | 19 | | 0 | | 19 | | | | 14 | | 3 | | |
Tumor gradec | | | | | | | 0.14 | | | | | | < 0.0001 |
Well differentiated | 141 | 34.7 | 14 | 31.8 | 127 | 34.9 | | | 134 | 39.3 | 5 | 8.6 | |
Moderately differentiated | 159 | 38.9 | 13 | 29.6 | 146 | 40.1 | | | 149 | 43.7 | 6 | 10.3 | |
Poorly differentiated | 108 | 26.4 | 17 | 38.6 | 91 | 25.0 | | | 58 | 17.0 | 47 | 81.0 | |
Not determined | 106 | | 25 | | 81 | | | | 50 | | 6 | | |
ER | | | | | | | 0.026 | | | | | | -- |
Negative | 64 | 14.1 | 12 | 24.5 | 52 | 12.8 | | | -- | -- | -- | -- | |
Positive | 391 | 85.9 | 37 | 75.5 | 354 | 87.2 | | | -- | -- | -- | -- | |
Missing/Unknown | 59 | | 20 | | 39 | | | | -- | -- | -- | -- | |
PR | | | | | | | 0.53 | | | | | | < 0.0001 |
Negative | 131 | 28.9 | 16 | 32.7 | 115 | 28.4 | | | 73 | 18.7 | 58 | 90.6 | |
Positive | 323 | 71.2 | 33 | 67.4 | 290 | 71.6 | | | 317 | 81.3 | 6 | 9.4 | |
Missing/Unknown | 60 | | 20 | | 40 | | | | 1 | | 0 | | |
HER2d | | | | | | | 0.99ᵇ | | | | | | 0.0028 |
Negative | 224 | 79.4 | 17 | 73.9 | 207 | 79.9 | | | 203 | 81.5 | 20 | 62.5 | |
Positive | 50 | 17.7 | 4 | 17.4 | 46 | 17.8 | | | 38 | 15.3 | 12 | 37.5 | |
Equivocal | 8 | 2.8 | 2 | 8.7 | 6 | 2.3 | | | 8 | 3.2 | 0 | 0.0 | |
Missing/Unknown | 232 | | 46 | | 186 | | | | 142 | | 32 | | |
Regional lymph nodes | | | | | | | 0.98 | | | | | | 0.11 |
Negative | 337 | 73.6 | 47 | 73.4 | 230 | 73.6 | | | 264 | 74.6 | 36 | 64.3 | |
Positive | 121 | 26.4 | 17 | 26.6 | 104 | 26.4 | | | 90 | 25.4 | 20 | 35.7 | |
Missing | 56 | | 5 | | 51 | | | | 37 | | 8 | | |
Tumor histology | | | | | | | 0.54ᵇ | | | | | | 0.14b |
Ductal | 439 | 83.5 | 59 | 85.5 | 370 | 83.2 | | | 322 | 82.4 | 54 | 84.4 | |
Lobular | 48 | 9.3 | 8 | 11.6 | 40 | 9.0 | | | 39 | 10.0 | 4 | 6.3 | |
Mixed ductal/lobular | 26 | 5.1 | 2 | 2.9 | 24 | 5.4 | | | 23 | 5.9 | 2 | 3.1 | |
Other | 11 | 2.1 | 0 | 0.0 | 11 | 2.5 | | | 7 | 1.8 | 4 | 6.3 | |
Tumor stage | | | | | | | 0.46ᵇ | | | | | | 0.30b |
0 - I | 262 | 58.0 | 32 | 62.8 | 230 | 57.4 | | | 223 | 59.3 | 29 | 47.5 | |
II | 150 | 33.2 | 13 | 25.5 | 137 | 34.2 | | | 120 | 31.9 | 25 | 41.0 | |
III | 29 | 6.4 | 4 | 7.8 | 25 | 6.2 | | | 24 | 6.4 | 5 | 8.2 | |
IV | 11 | 2.4 | 2 | 3.9 | 9 | 2.2 | | | 9 | 2.4 | 2 | 3.3 | |
Missing | 62 | | 18 | | 44 | | | | 15 | | 3 | | |
Note: Among all cases, 13.4% were diagnosed with breast cancer by 50 years old versus 86.6% were diagnosed after age at 50 years. Fifty-nine cases who had missing ER status were excluded from analyses with ER status. ᵃP values from Chi-square test except where noted; cases with missing tumor characteristics were excluded from reported % and tests; p values less than 0.05 are in bold font. ᵇP values from Fisher exact test. cPatients with tumor grade as "Not determined" were excluded from analysis. dPatients with equivocal HER2 were excluded from analysis. Involution and columnar cell lesions associations were adjusted for all factors above line indicated in OR*. #One control had a BBD diagnosis in 2012. BBD, benign breast disease; ER, estrogen receptor status; HER2, human epidermal growth factor; IQR, inter-quartile range; PR, progesterone receptor status; SD, standard deviation |
Tumors diagnosed in this population were predominantly small (71.6% ≤20 mm), well or moderately differentiated (73.6%), ER-positive (85.9%), PR-positive (71.2%), HER2-negative (79.4%), lymph node negative (73.6%), and of ductal histology (83.5%). The invasive cases were overwhelmingly of low stage with < 10% of cases being diagnosed as stage III or IV. As expected, ER status differed significantly by age at breast cancer diagnosis, with a higher proportion (24.5%) of ER-negative breast cancers diagnosed among women ≤ 50 compared to older than 50 (12.8%) for ER –positive BC. We also assessed whether there were differences in tumor characteristics by calendar period before and after 1993 [15]. Of the tumor characteristics evaluated, HER2 status showed a statistically significant difference by BBD diagnosis before and after 1993, with a higher proportion of HER2 negative cases diagnosed after 1993 compared to prior years (84.2 vs 73.9%, Supplemental Table 1). After 1993 there were significantly more tumors noted among women ≥ 50 years of age, tumors of smaller size of 10–20 mm (44.4% after 1993 vs 34.8% before 1993), and a higher proportion with no or mild involution after 1993 (48.93% vs 36.56%, Supplemental Table 1). Histologic grade data were not routinely reported prior to 1993.
Breast cancer risk factors among women with BBD
Association results for all cases combined for established risk factors, including BBD characteristics, are shown in Supplemental Table 2. We found that younger age at first full term birth and history of bilateral oophorectomy were inversely associated with breast cancer risk, whereas positive family history of breast cancer in a 1st degree relative, increasing severity of BBD histology and presence of CCL at BBD diagnosis were associated with increased breast cancer risk (Supplemental Table 2). A representative image of CCL is shown in Fig. 1. CCL with atypia, also known as flat epithelial atypia, is a more severe lesion that has been suggested to be associated with increased risk of breast cancer [3]; however, in our study only 2 controls and 1 case had flat epithelial atypia. Lobular involution, which has been proposed in other BBD patient populations as a key risk factor for subsequent breast cancer [6, 17], was weakly inversely associated with breast cancer risk in our population [complete vs no involution, OR (95%CI) = 0.89 (0.65, 1.24)]. Neither radial scar nor sclerosing adenosis conferred a significant risk among those with proliferative BBD disease (data not shown).
Breast cancer risk by ER status among women with BBD
Risk associations by ER status for patient characteristics and histologic features of BBD are presented in Table 2. Most tumors were ER-positive, which limited power to detect heterogeneity; as a result, patterns of association observed for overall invasive breast cancer were generally consistent with those observed for ER-positive breast cancer risk. Having an age at first birth < 30 years was associated with reduced risk of ER-positive (OR = 0.69, 95%CI = 0.49–0.98), but not ER-negative (OR = 1.08, 95% CI = 0.51–2.30), breast cancer; p-heterogeneity = 0.24. Compared with patients with non-proliferative BBD, those with proliferative BBD with atypia had higher risk for ER-positive (OR = 5.48, 95% CI = 2.14–14.01) than ER-negative disease (OR = 1.52, 95% CI = 0.18–13.05, albeit with only one ER-negative case); p-heterogeneity = 0.45. After accounting for BBD histology, the presence of CCLs at BBD diagnosis was associated with 1.5-fold increased risk for both ER-positive (95% CI = 1.03–2.29) and ER-negative (95% CI = 0.73–3.07) tumors; p-het = 0.94.
Table 2
Multivariable associations between select patient characteristics and histologic features with breast cancer risk by ER status (N = 969)
| Controls (N = 514) | Cases, ER+ (N = 391) | ER + vs. Controls | Cases, ER- (N = 64) | ER- vs. Controls | |
Variable | Nᵃ | %ᵃ | Nᵃ | %ᵃ | OR (95% CI)* | Nᵃ | %ᵃ | OR (95% CI)* | P-het† |
Age at first full-term birth/years | | | | | | | | | |
Nulliparous/≥30 | 108 | 20.9 | 88 | 27.6 | 1.00 (Ref) | 13 | 20.3 | 1.00 (Ref) | 0.24 |
< 30 | 406 | 79.1 | 231 | 72.4 | 0.69 (0.49, 0.98) | 51 | 79.7 | 1.08 (0.51, 2.30) | |
P-value | | | | | 0.038 | | | 0.84 | |
Family history of breast cancer | | | | | | | | | |
No | 434 | 84.4 | 257 | 80.7 | 1.00 (Ref) | 50 | 77.5 | 1.00 (Ref) | 0.56 |
Yes | 80 | 15.6 | 62 | 19.3 | 1.30 (0.89, 1.88) | 14 | 22.5 | 1.60 (0.77, 3.33) | |
P-value | | | | | 0.17 | | | 0.20 | |
History of bilateral oophorectomy | | | | | | | | | |
No | 429 | 83.4 | 346 | 88.6 | 1.00 (Ref) | 55 | 85.9 | 1.00 (Ref) | 0.42 |
Yes | 85 | 16.6 | 45 | 11.4 | 0.59 (0.38, 0.90) | 9 | 14.1 | 0.82 (0.37, 1.80) | |
P-value | | | | | 0.015 | | | 0.62 | |
BBD histology | | | | | | | | | |
Normal/Non-proliferative | 384 | 74.7 | 243 | 62.2 | 1.00 (Ref) | 43 | 67.2 | 1.00 (Ref) | 0.45 |
Proliferative without atypia | 124 | 24.1 | 127 | 32.5 | 1.70 (1.25, 2.30) | 20 | 31.3 | 1.49 (0.84, 2.67) | |
Proliferative with atypia | 6 | 1.2 | 21 | 5.4 | 5.48 (2.14, 14.01) | 1 | 1.6 | 1.52 (0.18, 13.05) | |
P-trend | | | | | < 0.0001 | | | 0.19 | |
Subjective impression of involution | | | | | | | | | |
None/mildly involuted (0–24%) | 235 | 45.7 | 187 | 47.8 | 1.00 (Ref) | 27 | 42.2 | 1.00 (Ref) | 0.85 |
Partially involuted (25–74%) | 75 | 14.6 | 78 | 20.0 | 1.38 (0.93, 2.04) | 12 | 18.8 | 1.48 (0.70, 3.13) | |
Completely involuted (≥ 75%) | 135 | 26.3 | 84 | 21.5 | 0.87 (0.61, 1.24) | 15 | 23.4 | 1.07 (0.53, 2.13) | |
No TDLU observed | 69 | 13.4 | 42 | 10.7 | 0.69 (0.43, 1.10) | 10 | 15.6 | 1.28 (0.57, 2.91) | |
P-trendᵇ | | | | | 0.68 | | | 0.90 | |
Columnar cell lesionsc | | | | | | | | | |
None | 450 | 87.9 | 328 | 84.1 | 1.00 (Ref) | 53 | 82.8 | 1.00 (Ref) | 0.94 |
Present with/without atypia | 62 | 12.1 | 62 | 15.9 | 1.54 (1.03, 2.29) | 11 | 17.2 | 1.50 (0.73, 3.07) | |
P-value | | | | | 0.034 | | | 0.27 | |
59 cases who had missing ER status were excluded from modeling analyses. ᵃAveraged frequencies and percentages. ᵇWomen with zero-TDLU observed were not included in trend tests or heterogeneity tests. cTwo controls and two cases were missing for columnar cell lesions. *OR and 95% CI estimates were calculated using polytomous logistic regression models adjusted for categorized BBD diagnosis calendar year as a trend, continuous age at BBD and follow-up period from BBD diagnosis to breast cancer diagnosis, family history of breast cancer in 1st degree relatives, history of bilateral oophorectomy, BBD histology, and parity. †P-heterogeneity were calculated from case-case analyses. Involution and columnar cell lesions associations were adjusted for all factors above line indicated in OR*.BBD, benign breast disease; CI, confidence interval; ER, estrogen receptor; OR, odds ratio. |
Breast cancer risk by grade and tumor size among women with BBD
While breast cancer risk associations for patient and histologic characteristics were generally consistent by tumor grade, we found suggestive evidence of heterogeneity by grade for impression of involution, with higher levels of involution being inversely associated with risk among well-differentiated tumors (complete vs no involution, OR (95%CI) = 0.51 (0.29, 0.90), Supplemental Table 3); this association was not evident among moderately or poorly differentiated tumors; p-het = 0.054. Associations for patient and histologic characteristics by tumor size (≤ 20 mm indicating small and > 20 mm larger tumors) are presented in Supplemental Table 4. We did not observe any significant heterogeneity by tumor size, although associations of severity of BBD histology (P < 0.0001) and presence of CCLs (P = 0.038) with increased breast cancer risk were somewhat stronger among patients with smaller tumors.
Breast cancer risk by menopausal status at BBD diagnosis
We performed additional analyses stratified by menopausal status using factors that have been significantly associated with breast cancer risk, in our study population (Table 3). The association of CCLs with elevated breast cancer risk was most apparent for postmenopausal women (OR = 2.08, 95% CI = 1.21, 3.58); p-het = 0.09.
Table 3
Associations between key risk factors and breast cancer risk stratified by menopausal status at BBD diagnosisᵃ
| Premenopausal women, N = 449 (43.6%)ᵃ | | Postmenopausal women, N = 579 (56.4%)ᵃ | |
| Control N = 217 (21.1%) | Case N = 233 (22.5%) | Multivariable model* | | Control N = 297 (28.9%) | Case N = 282 (27.5%) | Multivariable model* | |
Variable | Nᵃ | %ᵃ | Nᵃ | %ᵃ | OR (95% CI)* | | Nᵃ | %ᵃ | Nᵃ | %ᵃ | OR (95% CI)* | P-het† |
Age at first full-term birth/years | | | | | | | | | | | | |
Nulliparous/≥30 | 57 | 26.3 | 83 | 35.7 | 1.00 (Ref) | | 50 | 17.0 | 56 | 20.0 | 1.00 (Ref) | 0.35 |
< 30 | 160 | 73.7 | 150 | 64.3 | 0.59 (0.38, 0.90) | | 247 | 83.0 | 226 | 80.0 | 0.81 (0.47, 1.38) | |
P-value | | | | | 0.015 | | | | | | 0.43 | |
Family history of breast cancer | | | | | | | | | | | | |
No | 190 | 87.5 | 186 | 80.0 | 1.00 (Ref) | | 244 | 82.2 | 225 | 79.9 | 1.00 (Ref) | 0.28 |
Yes | 27 | 12.5 | 47 | 20.0 | 1.75 (1.00, 3.07) | | 53 | 17.8 | 57 | 20.1 | 1.18 (0.76, 1.83) | |
P-value | | | | | 0.052 | | | | | | 0.46 | |
History of bilateral oophorectomy | | | | | | | | | | | | |
No | -- | -- | -- | -- | -- | | 212 | 71.3 | 221 | 78.3 | 1.00 (Ref) | -- |
Yes | -- | -- | -- | -- | -- | | 85 | 28.7 | 61 | 21.7 | 0.66 (0.44, 0.99) | |
P-value | | | | | -- | | | | | | 0.044 | |
BBD histology | | | | | | | | | | | | |
Normal/Non-proliferative | 178 | 81.9 | 157 | 67.5 | 1.00 (Ref) | | 206 | 69.5 | 167 | 59.4 | 1.00 (Ref) | 0.47 |
Proliferative without atypia | 37 | 17.2 | 67 | 28.7 | 2.06 (1.27, 3.33) | | 87 | 29.2 | 97 | 34.2 | 1.41 (0.97, 2.03) | |
Proliferative with atypia | 2 | 0.9 | 9 | 3.9 | 5.45 (1.14, 26.15) | | 4 | 1.4 | 18 | 6.4 | 5.65 (1.86, 17.14) | |
P-trend | | | | | 0.015 | | | | | | 0.41 | |
Columnar cell lesionsᵇ | | | | | | | | | | | | |
None | 179 | 83.2 | 188 | 81.1 | 1.00 (Ref) | | 271 | 91.3 | 238 | 84.6 | 1.00 (Ref) | 0.09 |
Present with/without atypia | 36 | 16.9 | 44 | 18.9 | 1.09 (0.65, 1.82) | | 26 | 8.7 | 43 | 15.4 | 2.08 (1.21, 3.58) | |
P-value | | | | | 0.73 | | | | | | 0.008 | |
ᵃAveraged frequencies and percentages. ᵇTwo controls (all premenopausal women) and two cases (1 pre- and 1 postmenopausal women) were missing for columnar cell lesions.*OR and 95% CI estimates were calculated using unconditional logistic regression models adjusted for continuous age at BBD and follow-up period from BBD diagnosis to breast cancer diagnosis, categorized BBD calendar year as a trend, family history of breast cancer in 1st degree relatives, BBD histology, and parity. Postmenopausal women were additionally adjusted for history of bilateral oophorectomy. †P-heterogeneity were calculated from multivariable analyses comparing pre- versus post-menopausal women. BBD, benign breast disease; CI, confidence interval; OR, odds ratio. |