Abstract
Background:
Although several prognostic variables and risk factors for breast cancer are age-related, the association between age and risk of cancer with breast atypia is controversial. This study aimed to compare the type of breast atypia and risk of underlying or subsequent breast cancer by age.
Methods:
Adult women with breast atypia [atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS)] at a single institution from 2008–2017 were stratified by age at initial diagnosis: <50y, 50–70y, and >70y. Regression modeling was used to estimate the association of age with risk of underlying carcinoma or subsequent cancer diagnosis.
Results:
530 atypia patients were identified: 31.1% <50y (N=165), 58.1% 50–70y (N=308), and 10.8% >70y (N=57). The proportion of women with ADH steadily increased with age, compared to atypical lobular proliferations (p=0.04). Of those with atypia on needle biopsy, the overall rate of underlying carcinoma was 17.5%. After adjustment, older age was associated with a greater risk of underlying carcinoma (OR 1.028, 95% CI 1.003–1.053; p=0.03). Of those confirmed to have atypia on surgical excision, the overall rate of a subsequent cancer diagnosis was 15.7%. Age was not associated with a long-term risk for (p=0.48) or the time to a subsequent diagnosis of carcinoma (log-rank p=0.41).
Conclusion:
Although atypia diagnosed on needle biopsy may be sufficient to warrant surgical excision, older women may be at a greater risk for an underlying carcinoma, albeit the long-term risk for malignancy associated with atypia does not appear to be affected by age.
Keywords: age, atypical breast lesions, breast atypia, breast cancer risk
INTRODUCTION
Breast cancer is the most common non-cutaneous malignancy in adult women across all age groups.1 Age is a well-studied risk factor for invasive and in situ breast cancer, with both breast cancer incidence and death rates increasing with age.2 This variation has been attributed, in part, to differences in treatment patterns among older women,3–5 as well as additive cumulative risks from lifetime estrogen exposure and differences in intrinsic tumor biology.6–8
Breast atypia is a common diagnosis found in 10% of benign breast biopsies, and it carries an increased risk for the development of a subsequent breast malignancy.9 Breast atypia represents a histopathologic spectrum, including atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). While ADH and ALH have an estimated lifetime risk of breast cancer of 20–30%,10,11 a diagnosis of LCIS carries a lifetime risk of breast cancer that approaches 40%.10,12,13 Current management of these lesions is controversial. While surgical excision may be recommended for many patients,14 active surveillance may be preferred in certain populations and/or in the context of certain radiopathologic findings.15,16 Thus, estimating the individual risk of underlying carcinoma among various cohorts is important to guide decision-making regarding active surveillance versus surgical excision.13 Patient characteristics such as pre-menopausal status and use of hormone replacement therapy have been shown to increase a woman’s risk of cancer after an atypia diagnosis15,17 and may influence management decisions. However, despite extensive research into how breast cancer biology, prognosis, and treatment strategies vary across age groups,4,5,7,8,18–20 the effect of age on clinical outcomes following a diagnosis of atypia are not clearly defined. The aim of this study was to stratify types of breast atypia and risk of breast cancer by age.
METHODS
After obtaining Institutional Review Board approval, the medical records of adult women diagnosed with breast atypia (LCIS, ADH, or ALH) at a major academic institution from 2008–2017 were identified. Given the methods and scope of the research (retrospective chart review with minimal risk to participants), a waiver of informed consent was granted. Exclusion criteria were [1] patients with unknown age, [2] patients with prior histories or concurrent diagnoses of breast malignancy, and [3] males. Age groups were defined as <50, 50–70, and >70 years old at first atypia diagnosis. Patients with multiple types of atypia were coded according to their most advanced atypia as follows: (1) LCIS; (2) ADH; (3) ALH. Demographic characteristics captured at the time of atypia diagnosis included age, body mass index (BMI), and breast cancer risk factors including family history (in a first- or second-degree relative), menopausal status, use of hormone replacement therapy (HRT) or oral contraceptives, gravidity and parity, and alcohol and tobacco use. Diagnostic and therapeutic information, as related to their atypia and/or breast cancer diagnosis, were also captured. Of note, the management strategy for each patient was driven by surgeon-patient discussions, not institution-specific guidelines, although national guidelines at the time of the discussion were presumably considered.
Patient characteristics were summarized with N (%) for categorical variables and median (interquartile range, IQR) for continuous variables. Differences between age groups were tested using the Chi-square test or Fisher’s exact test for categorical variables, and the analysis of variance (ANOVA) or Kruskal-Wallis test for continuous variables, as appropriate. Logistic regression was used to estimate the effect of age (as a continuous variable) on the odds of identifying an underlying carcinoma (ductal carcinoma in situ [DCIS] or invasive breast cancer) on excision after atypia on needle biopsy, after adjusting for select covariates; odds ratios (OR) and 95% confidence intervals (CI) reported. Poisson regression was used to estimate the effect of age on the risk of a subsequent breast cancer diagnosis, after adjusting for select covariates; risk ratios (RR) and 95% CI reported. This model accounts for differences in patient observation time by including an offset value of the log-transformed follow-up time in months.
Time to a subsequent diagnosis of DCIS or invasive carcinoma was calculated as the time in months from date of first atypia diagnosis to date of subsequent carcinoma diagnosis (in situ or invasive) or date of last follow-up for patients who did not develop a subsequent carcinoma. Patients who were found to have an underlying malignancy (DCIS or invasive carcinoma) on excision after their initial atypia biopsy were excluded from the time to subsequent diagnosis model. Median time to a subsequent carcinoma diagnosis and 5-year no-subsequent-carcinoma rates were estimated using the Kaplan-Meier method; differences between age groups were tested using the log-rank test. A Cox Proportional Hazards model was used to estimate the association of age (as a continuous variable) with time to subsequent diagnosis of DCIS or invasive carcinoma, after adjustment for covariates. Given the small number of deaths in the cohort during the follow-up period (N=14), these were not accounted for as a competing risk in the multivariate modeling.
Only patients with available data for all covariates for a given analysis were included in each model, and effective sample sizes are reported for each table/figure. A p-value <0.05 was considered significant, and no adjustments were made for multiple comparisons. All statistical analyses were conducted using SAS, version 9.4 (SAS Institute, Cary NC).
RESULTS
Application of the defined inclusion and exclusion criteria resulted in the final study population of 530 women diagnosed with breast atypia from 2008–2017. The cohort included 165 women <50y (31.1%), 308 women 50–70y (58.1%), and 57 women >70y (10.8%). Notably, there were 26 women under the age of 40y (4.9%). For the overall cohort, the median age at diagnosis was 54y (IQR 48–64y). Median follow-up time from the first atypia diagnosis was 49 months (95% CI 44–53.9 months), and there were 14 deaths during this time period (2.6%); 1 patient after identification of an underlying breast cancer on excision (following needle biopsy with atypia), 3 after a subsequent diagnosis of breast cancer, and 10 without a breast cancer diagnosis at any time. The majority of women were post-menopausal at diagnosis (67.9%), and a family history of breast cancer in either a first- or second-degree relative was present in 80% of women (Table 1). Only 24 patients underwent a breast MRI within 18 months of diagnosis, including 11 in women <50y (6.7%), 12 in those 50–70y (3.9%), and only 1 in a woman >70y (1.8%). ADH was the most common initial histopathologic diagnosis in 75.1% of patients (N=398), followed by LCIS in 13.2% (N=70) and ALH in 11.7% (N=62). Of note, 10 patients were diagnosed with pleomorphic LCIS specifically, which was equally distributed across all age groups (<50y: 1.8%; 50–70y: 1.9%; >70y: 1.8%). The proportion of women with ADH steadily increased with age, compared to atypical lobular proliferations (overall p=0.04) (Table 1).
Table 1. Select patient and breast disease characteristics by age group.
Data presented as N (%) unless otherwise specified. Percentages may not add up to 100 due to rounding or missing values. IQR: interquartile range. ADH: atypical ductal hyperplasia. ALH: atypical lobular hyperplasia. LCIS: lobular cancer in situ.
| All Patients (N=530) | Age Group (Years) | P-Value | |||
|---|---|---|---|---|---|
| <50 (N=165) | 50–70 (N=308) | >70 (N=57) | |||
| First Atypia Diagnosis | 0.04 | ||||
| Atypical ductal hyperplasia | 398 (75.1%) | 115 (69.7%) | 232 (75.3%) | 51 (89.5%) | |
| Atypical tabular hyperplasia | 62 (11.7%) | 24 (14.5%) | 34 (11%) | 4 (7%) | |
| Lobular carcinoma in situ | 70 (13.2%) | 26 (15.8%) | 42 (13.6%) | 2 (3.5%) | |
| Most Advanced Atypia Diagnosis* | 0.21 | ||||
| Atypical ductal hyperplasia | 396 (74.7%) | 116 (70.3%) | 231 (75%) | 49 (86%) | |
| Atypical lobular hyperplasia | 25 (4.7%) | 9 (5.5%) | 14 (4.5%) | 2 (3.5%) | |
| Lobular carcinoma in situ | 109 (20.6%) | 40 (24.2%) | 63 (20.5%) | 6 (10.5%) | |
| Age (years) – Median (IQR) | 54 (48–64) | 45 (42–47) | 58 (53–64) | 75 (73–78) | <0.001 |
| Age at First Live Birth – Median (IQR) | 25 (20–30) | 28 (23–32) | 24 (20–30) | 21 (19–24) | <0.001 |
| Menopausal Status | <0.001 | ||||
| Pre | 91 (17.2%) | 84 (50.9%) | 7 (2.3%) | 0 (0%) | |
| Peri | 31 (5.8%) | 14 (8.5%) | 17 (5.5%) | 0 (0%) | |
| Post | 360 (67.9%) | 43 (26.1%) | 262 (85.1%) | 55 (96.5%) | |
| Use of Hormone Replacement Therapy | <0.001 | ||||
| Yes, currently | 19 (3.6%) | 2 (1.2%) | 12 (3.9%) | 5 (8.8%) | |
| Yes, in the past | 102 (19.2%) | 8 (4.8%) | 79 (25.6%) | 15 (26.3%) | |
| No, never | 297 (56%) | 134 (81.2%) | 144 (46.8%) | 19 (33.3%) | |
| Not sure | 105 (19.8%) | 19 (11.5%) | 69 (22.4%) | 17 (29.8%) | |
| Parity – Median (IQR) | 2 (1–3) | 2 (1–2) | 2 (1–2) | 3 (2–4) | <0.001 |
| Family History of Cancer | 0.05 | ||||
| No | 82 (15.5%) | 17 (10.3%) | 52 (16.9%) | 13 (22.8%) | |
| Yes | 424 (80%) | 139 (84.2%) | 243 (78.9%) | 42 (73.7%) | |
| Germline Genetic Testing | <0.001 | ||||
| No or unknown | 467 (88.1%) | 130 (78.8%) | 281 (91.2%) | 56 (98.3%) | |
| Yes, negative | 60 (11.3%) | 33 (20%) | 26 (8.4%) | 1 (1.8%) | |
| Yes, mutation identified | 3 (0.6%) | 2 (1.2%) | 1 (0.3%) | 0 (0%) | |
| Diagnosis Method of Initial Atypia | 0.98 | ||||
| Surgical excision | 59 (11.1%) | 19 (11.5%) | 34 (11%) | 6 (10.5%) | |
| Needle biopsy | 471 (88.9%) | 146 (88.5%) | 274 (89%) | 51 (89.5%) | |
| Atypia on Needle Biopsy +/− Underlying Malignancy on Excision† | 0.29 | ||||
| No | 329 (82.5%) | 107 (84.9%) | 190 (82.6%) | 32 (74.4%) | |
| Yes | 70 (17.5%) | 19 (15.1) | 40 (17.4%) | 11 (25.6%) | |
| Type of Atypia on Needle Biopsy +/− Underlying Malignancy on Excision† | 0.37 | ||||
| No underlying malignancy | 329 (82.5%) | 107 (84.9%) | 190 (82.6%) | 32 (74.4%) | |
| Underlying malignancy + first atypia ADH | 53 (13.3%) | 12 (9.5%) | 32 (13.9%) | 9 (20.9%) | |
| Underlying malignancy + first atypia ALH | 6 (1.5%) | 3 (2.4%) | 2 (0.9%) | 1 (2.3%) | |
| Underlying malignancy + first atypia LCIS | 11 (2.8%) | 4 (3.2%) | 6 (2.6%) | 1 (2.3%) | |
| Type of Malignant Diagnosis on Excision‡ | 0.40 | ||||
| Ductal carcinoma in situ | 43 (61.4%) | 10 (52.6%) | 27 (67.5%) | 6 (54.5%) | |
| Invasive carcinoma | 26 (37.1%) | 9 (47.4%) | 12 (30%) | 5 (45.5%) | |
| Subsequent Diagnosis of Malignancy** | 0.66 | ||||
| No | 386 (84.3%) | 124 (86.1%) | 222 (82.8%) | 40 (87%) | |
| Yes | 72 (15.7%) | 20 (13.9%) | 46 (17.2%) | 6 (13%) | |
| Type of Atypia on Initial Biopsy +/− Subsequent Diagnosis of Malignancy** | 0.58 | ||||
| No subsequent malignancy | 386 (84.3%) | 124 (86.1%) | 222 (82.8%) | 40 (87%) | |
| Subsequent malignancy + first atypia ADH | 49 (10.7%) | 11 (7.6%) | 32 (11.9%) | 6 (13%) | |
| Subsequent malignancy + first atypia ALH | 10 (2.2%) | 3 (2.1%) | 7 (2.6%) | 0 (0%) | |
| Subsequent malignancy + first atypia LCIS | 13 (2.8%) | 6 (4.2%) | 7 (2.6%) | 0 (0%) | |
| Type of Subsequent Malignancy Diagnosis†† | 0.93 | ||||
| Ductal Carcinoma in situ | 33 (45.8%) | 10 (50%) | 20 (43.5%) | 3 (50%) | |
| Invasive Carcinoma | 39 (54.2%) | 10 (50%) | 26 (56.5%) | 3 (50%) | |
Patients with multiple types of atypia were coded according to their most advanced atypia as follows: (1) LCIS; (2) ADH; (3) ALH.
Among women who were diagnosed with atypia by needle biopsy and underwent surgical excision (N=399).
Among women who were found to have an underlying malignancy on surgical excision after needle biopsy with atypia (N=70).
Among women who were NOT found to have an underlying malignancy on surgical excision after needle biopsy with atypia (N=458).
Among women who were diagnosed with a subsequent malignancy.
Breast cancer risk factors by age
BMI varied by age, with a higher median BMI among women aged 50–70y (<50y: 26.9; 50–70y: 29.4; >70y: 26.4; p=0.004). Women >70y were less likely to drink alcohol currently (<50y: 50.3%; 50–70y: 46.8%; >70y: 24.6%; p=0.03) or use tobacco currently (<50y: 6.7%; 50–70y: 6.5%; >70y: 0%; p=0.02). Age at first live birth was highest among younger women <50y (p<0.001). Given that women >70y were more often post-menopausal at diagnosis (p<0.001), they were also more likely to report a history of HRT (p<0.001). Older women >70y also had a higher median parity (p<0.001). Younger women <50y reported higher rates of oral contraceptive use (<50y: 46.1%; 50–70y: 42.2%; >70y: 19.3%; p=0.003) and were more likely to have a family history of breast cancer in either a first- or second-degree relative (p=0.05). Germline genetic testing was uncommon overall (11.9% had testing), but was more common among women <50y (p<0.001) (Table 1). It was also more common among patients with LCIS (22.9% vs. 9.6% of ADH and 12% of ALH; p=0.002). Notably, only 3 patients had a germline genetic mutation (all BRCA½, all women <70y).
Risk of underlying carcinoma by age
Fifty-nine (11.1%) patients were diagnosed with breast atypia by surgical excision, and 471 (88.9%) were diagnosed by needle biopsy. Of the women diagnosed with breast atypia by needle biopsy (N=471), 399 underwent surgical excision, and 17.5% (N=70 of 399) were found to have an underlying carcinoma (DCIS or invasive disease) at the time of excision (Table 1). Of the 70 women diagnosed with an underlying carcinoma, 61.4% had DCIS and 37.1% had invasive disease, which was similar between age groups (p=0.40). For those with an underlying carcinoma, tumor stage, grade, and biomarkers were similar across all age groups (Table 2). After adjustment, increasing age was associated with an increased risk of underlying carcinoma at surgical excision (OR 1.028; 95% CI 1.003–1.053; p=0.03). However, the type of atypia diagnosis (p=0.12) and family history of breast cancer (p=0.52) were not associated with underlying carcinoma at the time of surgical excision (Table 3). Of note, 72 patients diagnosed with atypia on needle biopsy did not undergo surgical excision at that time. Of the 59 women diagnosed with breast atypia by surgical excision, 3.4% (N=2) were found to have an underlying breast cancer after additional surgery.
Table 2. Summary of those with atypia on needle biopsy and found to have an underlying malignancy at surgical excision (N=70) by age group, including DCIS (N=43) or invasive disease (N=26).
DCIS: ductal carcinoma in situ. ER: estrogen receptor. PR: progesterone receptor. HER2: human epidermal growth factor receptor 2.
| All Patients (N=70) | Age Group (Years) | P-Value | |||
|---|---|---|---|---|---|
| <50 (N=19) | 50–70 (N=40) | >70 (N=11) | |||
| DCIS, Estrogen Receptor† | 0.33 | ||||
| Positive | 38 (88.4%) | 9 (90%) | 24 (88.9%) | 5 (83.3%) | |
| Negative | 3 (7%) | 1 (10%) | 1 (3.7%) | 1 (16.7%) | |
| DCIS, Progesterone Receptor† | 1.00 | ||||
| Positive | 36 (83.7%) | 9 (90%) | 22 (81.5%) | 5 (83.3%) | |
| Negative | 5 (11.6%) | 1 (10%) | 3 (11.1%) | 1 (16.7%) | |
| DCIS, Grade† | 0.25 | ||||
| 1 | 7 (16.3%) | 0 (0%) | 5 (18.5%) | 2 (33.3%) | |
| 2 | 23 (53.5%) | 7 (70%) | 13 (48.1%) | 3 (50%) | |
| 3 | 2 (4.7%) | 0 (0%) | 1 (3.7%) | 1 (16.7%) | |
| Invasive Cancer, T stage† | 0.75 | ||||
| T0 | 1 (3.8%) | 0 (0%) | 1 (8.3%) | 0 (0%) | |
| T1 | 20 (76.9%) | 7 (77.8%) | 8 (66.7%) | 5 (100%) | |
| T2 | 2 (7.7%) | 0 (0%) | 2 (16.7%) | 0 (0%) | |
| Invasive Cancer, N stage† | 0.14 | ||||
| N0 | 20 (76.9%) | 7 (77.8%) | 11 (91.7%) | 2 (40%) | |
| N1 | 1 (3.8%) | 0 (0%) | 0 (0%) | 1 (20%) | |
| Invasive Cancer, ER Status† | - | ||||
| Positive | 21 (80.8%) | 6 (66.7%) | 11 (91.7%) | 4 (80%) | |
| Negative | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | |
| Invasive Cancer, PR Status† | 1.00 | ||||
| Positive | 20 (76.9%) | 6 (66.7%) | 10 (83.3%) | 4 (80%) | |
| Negative | 1 (3.8%) | 0 (0%) | 1 (8.3%) | 0 (0%) | |
| Invasive Cancer, HER2 Status | 0.19 | ||||
| Positive | 4 (15.4%) | 0 (0%) | 4 (33.3%) | 0 (0%) | |
| Negative | 17 (65.4%) | 6 (66.7%) | 7 (58.3%) | 4 (80%) | |
| Unknown | 5 (19.2%) | 3 (33.3%) | 1 (8.3%) | 1 (20%) | |
| Invasive Cancer, Grade† | 1.00 | ||||
| 1 | 11 (42.3%) | 3 (33.3%) | 5 (41.7%) | 3 (60%) | |
| 2 | 8 (30.8%) | 2 (22.2%) | 4 (33.3%) | 2 (40%) | |
| 3 | 2 (7.7%) | 0 (0%) | 2 (16.7%) | 0 (0%) | |
| Treatment with Radiation Therapy* | 0.01 | ||||
| No | 28 (40%) | 12 (63.2%) | 10 (25%) | 6 (54.5%) | |
| Yes | 39 (55.7%) | 6 (31.6%) | 28 (70%) | 5 (45.5%) | |
| Treatment with Chemotherapy** | 0.68 | ||||
| No | 22 (84.6%) | 8 (88.9%) | 9 (75%) | 5(100%) | |
| Yes | 2 (7.7%) | 0 (0%) | 2 (16.7%) | 0 (0%) | |
| Treatment with Endocrine Therapy* | 0.16 | ||||
| No | 46 (65.7%) | 12 (63.2%) | 29 (72.5%) | 5 (45.5%) | |
| Yes | 21 (30%) | 6 (31.6%) | 9 (22.5%) | 6 (54.5%) | |
| Treatment with Endocrine Therapy, if ER+and/or PR+ * | 0.20 | ||||
| No | 17 (24.3%) | 4 (21.1%) | 8 (20%) | 5 (45.5%) | |
| Yes | 39 (55.7%) | 10 (52.6%) | 25 (62.5%) | 4 (36.4%) | |
Among women with known results/status.
Among women who have either DCIS and/or invasive disease.
Among women who have invasive disease only.
Table 3. Adjusted logistic regression for underlying malignancy at surgical excision after needle biopsy with atypia (N=367).
63/367 patients included in this model were found to have an underlying malignancy at surgical excision after atypia on needle biopsy. Hispanic patients were excluded due to lack of events. DCIS: ductal carcinoma in situ.
| Odds Ratio (95% Cl) | P-Value | Overall P-Value | |
|---|---|---|---|
| Age (Years) | 1.028 (1.003–1.053) | 0.03 | 0.03 |
| Race/Ethnicity | 0.42 | ||
| Non-Hispanic white | REF | ||
| Non-Hispanic black | 1.279 (0.699–2.339) | 0.42 | |
| First Atypia Diagnosis | 0.12 | ||
| Atypical ductal hyperplasia | REF | ||
| Atypical lobular hyperplasia | 0.724 (0.269–1.953) | 0.52 | |
| Lobular carcinoma in situ | 2.095 (0.965–4.552) | 0.06 | |
| Family History of Cancer | 0.52 | ||
| No | REF | ||
| Yes | 1.336 (0.556–3.209) | 0.52 |
Risk of subsequent breast cancer and time to carcinoma by age
During the follow-up (median 49 months) of the 458 women with atypia who did not have an underlying carcinoma at the time of initial surgical excision, 15.7% (N=72) developed a subsequent diagnosis of breast cancer (in situ or invasive), which was similar for all age groups (p=0.66) (Table 1). Of those who subsequently developed breast cancer, 45.8% were diagnosed with DCIS and 54.2% with invasive disease, which did not differ by age group (p=0.93) (Table 1). For those who subsequently developed breast cancer, tumor stage, grade, and biomarkers did not significantly differ by age (Table 4). After adjustment, age was not associated with a risk of subsequent breast cancer (p=0.48). In addition, a family history of breast cancer (p=0.30) and type of atypia (p=0.14) were not associated with the risk of subsequent malignancy (Table 5). The 5-year no-subsequent-carcinoma rate was similar across all age groups (<50y: 0.881, 50–70y: 0.811, >70y: 0.885; p=0.41), and the time to a subsequent breast cancer diagnosis did not vary significantly by age group (log-rank p=0.41; Figure 1, Table 6).
Table 4. Summary of those with a subsequent malignant diagnosis after atypia (N=72) by age group, including DCIS (N=33) or invasive disease (N=39).
DCIS: ductal carcinoma in situ. HER2: human epidermal growth factor receptor 2. ER: estrogen receptor. PR: progesterone receptor.
| AllPatients (N=72) | Age Group (Years) | P-Value | |||
|---|---|---|---|---|---|
| <50 (N=20) | 50–70 (N=46) | >70 (N=6) | |||
| DCIS, Estrogen Receptor† | 0.29 | ||||
| Positive | 29 (87.9%) | 9 (90%) | 18 (90%) | 2 (66.7%) | |
| Negative | 3 (9.1%) | 1 (10%) | 1 (5%) | 1 (33.3%) | |
| DCIS, Progesterone Receptor† | 0.19 | ||||
| Positive | 28 (84.8%) | 8 (80%) | 18 (90%) | 2 (66.7%) | |
| Negative | 4 (12.1%) | 2 (20%) | 1 (5%) | 1 (33.3%) | |
| DCIS, Grade† | 0.25 | ||||
| 1 | 5 (1 5.2%) | 0 (0%) | 5 (25%) | 0 (0%) | |
| 2 | 15 (45.5%) | 6 (60%) | 8 (40%) | 1 (33.3%) | |
| 3 | 10 (30.3%) | 4 (40%) | 4 (20%) | 2 (66.7%) | |
| Invasive Cancer, T stage† | 0.17 | ||||
| T0 | 1 (2.6%) | 0 (0%) | 1 (3.8%) | 0 (0%) | |
| T1 | 26 (66.7%) | 8 (80%) | 16 (61.5%) | 2 (66.7%) | |
| T2 | 8 (20.5%) | 0 (0%) | 8 (30.8%) | 0 (0%) | |
| T3 | 1 (2.6%) | 1 (10%) | 0 (0%) | 0 (0%) | |
| Invasive Cancer, N stage† | 0.16 | ||||
| N0 | 29 (74.4%) | 6 (60%) | 21 (80.8%) | 2 (66.7%) | |
| N1 | 4 (10.3%) | 3 (30%) | 1 (3.8%) | 0 (0%) | |
| N2 | 2 (5.1%) | 0 (0%) | 3 (11.5%) | 0 (0%) | |
| Invasive Cancer, ER Status† | 0.65 | ||||
| Positive | 35 (89.7%) | 9 (90%) | 23 (88.5%) | 3 (100%) | |
| Negative | 3 (7.7%) | 0 (0%) | 3 (11.5%) | 0 (0%) | |
| Invasive Cancer, PR Status† | 0.81 | ||||
| Positive | 31 (79.5%) | 8 (80%) | 20 (76.9%) | 3 (100%) | |
| Negative | 7 (17.9%) | 1 (10%) | 6 (23.1%) | 0 (0%) | |
| Invasive Cancer, HER2 Status | 0.39 | ||||
| Positive | 7 (17.9%) | 3 (30%) | 4 (15.4%) | 0 (0%) | |
| Negative | 30 (76.9%) | 6 (60%) | 21 (80.8%) | 3 (100%) | |
| Unknown | 2 (5.1%) | 1 (10%) | 1 (3.9%) | 0 (0%) | |
| Invasive Cancer, Grade† | 0.72 | ||||
| 1 | 11 (28.2%) | 2 (20%) | 9 (34.6%) | 0 (0%) | |
| 2 | 19 (48.7%) | 5 (50%) | 12 (46.2%) | 2 (66.7%) | |
| 3 | 5 (12.8%) | 2 (20%) | 3 (11.5%) | 0 (0%) | |
| Laterality of Subsequent Malignancy Compared to Initial Atypia | 0.23 | ||||
| Ipsilateral | 55 (76.4%) | 18 (90%) | 34 (73.9%) | 3 (50%) | |
| Contralateral | 15 (20.8%) | 2 (10%) | 10(21.7%) | 3 (50%) | |
| Unknown | 2 (2.8%) | 0 (0% | 2 (4.4%) | 0 (0%) | |
| Treatment with Radiation Therapy* | 0.09 | ||||
| No | 40 (55.6%) | 12 (60%) | 22 (47.8%) | 6 (100%) | |
| Yes | 25 (34.7%) | 6 (30%) | 19 (41.3%) | 0 (0%) | |
| Treatment with Chemotherapy** | 0.31 | ||||
| No | 27 (69.2%) | 5 (50%) | 19 (73.1%) | 3 (100%) | |
| Yes | 9 (23.1%) | 4 (40%) | 5(19.2%) | 0 (0%) | |
| Treatment with Endocrine Therapy* | 0.80 | ||||
| No | 27 (37.5%) | 8 (40%) | 16(34.8%) | 3 (50%) | |
| Yes | 40 (55.6%) | 10 (50%) | 27 (58.7%) | 3 (50%) | |
| Treatment with Endocrine Therapy, if ER+and/or PR+ * | 0.41 | ||||
| No | 23 (31.9%) | 7 (35%) | 13 (28.3%) | 3 (50%) | |
| Yes | 37 (51.4%) | 9 (45%) | 26 (56.5%) | 2 (33.3%) | |
Among women with known results/status.
Among women who have either DCIS and/or invasive disease.
Among women who have invasive disease only.
Table 5. Adjusted Poisson regression for a subsequent diagnosis of DCIS or invasive breast cancer (N=400), adjusting for log-transformed follow up time.
66/400 patients included in this model had a subsequent diagnosis of DCIS or invasive breast cancer. Hispanic patients were excluded due to lack of events. DCIS: ductal carcinoma in situ.
| Risk Ratio (95% Cl) | P-Value | Overall P-Value | |
|---|---|---|---|
| Age (Years) | 1.008 (0.986–1.031) | 0.48 | 0.48 |
| Race/Ethnicity | 0.56 | ||
| Non-Hispanic white | REF | ||
| Non-Hispanic black | 1.176 (0.685–2.019) | 0.56 | |
| Most Advanced Atypia Diagnosis * | 0.14 | ||
| Atypical ductal hyperplasia | REF | ||
| Atypical tabular hyperplasia | 0.482 (0.066–3.539) | 0.47 | |
| Lobular carcinoma in situ | 1.612 (0.946–2.746) | 0.08 | |
| Chemoprevention | 0.67 (0.298–1.509) | 0.33 | 0.33 |
| Family History of Cancer | 0.30 | ||
| No | REF | ||
| Yes | 1.522 (0.689–3.362) | 0.30 |
Patients with multiple types of atypia were coded according to their most advanced atypia as follows: (1) LCIS; (2) ADH; (3) ALH.
Figure 1. Unadjusted time to subsequent diagnosis of DCIS or invasive breast cancer by age group (N=447).
DCIS: ductal carcinoma in situ.
Table 6. (to be shown with Figure 1). Unadjusted time to subsequent diagnosis of DCIS or invasive breast cancer by age group (N=447).
DCIS: ductal carcinoma in situ.
| Age Group | Total | Experienced Subsequent Carcinoma (%) | Median Time to Subsequent Carcinoma (95% Cl) | 5-Year No-Subsequent-Carcinoma Rate |
Log-Rank P-Value |
|---|---|---|---|---|---|
| <50 Years | 140 | 20 (14.3%) | 226.6 Months (226.6-NE) | 0.881 (0.806–0.929) | 0.41 |
| 50–70 Years | 261 | 46 (17.6%) | 195.6 Months (118.8–222.3) | 0.811 (0.745–0.862) | |
| >70 Years | 46 | 6 (13%) | NE (NE-NE) | 0.885(0.745–0.951) | |
| Total | 447 | 72 (16.1%) |
NE=Non-Estimable.
Breast cancer prevention (chemoprevention) after atypia by age
Of the 458 women not initially diagnosed with breast cancer after their atypia diagnosis, 92.4% (N=423) had chemoprevention data available (Supplemental Table 1). Of note, 1 patient may have taken chemoprevention as a part of a clinical trial. Utilization of chemoprevention was uncommon across all age groups (10.6% received chemoprevention, N=45), and none of the women >70y received chemoprevention after their atypia diagnosis (p=0.02). Further stratification by the type of atypia yielded similar findings (low utilization rates across all age groups and all atypia subtypes; p=0.08; Supplemental Table 1). Notably, the reasons for receiving or not receiving chemoprevention were not available in this data set. Within this cohort of 458 women, 63 subsequently developed breast cancer (13.8%), including 55 in the no-chemoprevention group (55 of 378 = 14.6%) and 8 in the chemoprevention group (8 of 45 = 17.8%). The risk of a subsequent malignant diagnosis was not significantly different between age groups after stratifying by receipt of chemoprevention (p=0.18).
DISCUSSION
In this retrospective series of women with high-risk atypical breast lesions, we found that the age at diagnosis of atypia does not influence the long-term risk of a subsequent breast cancer. However, our data suggests that age at diagnosis may be associated with the type of atypia diagnosed at presentation and with the risk of identifying underlying carcinoma at surgical excision. These findings that may inform patient counseling and tailor risk estimates for the subsequent development of cancer in this population.
With the standardization and acceptance of breast cancer screening, diagnoses of breast atypia have increased significantly in the past two decades.9 Many women with atypia, in accordance with the National Comprehensive Cancer Network (NCCN) guidelines14, undergo surgical excision to rule out an underlying malignancy missed by a sampling error.21 However, atypia has been shown to carry a spectrum of risk related to malignancy, and some low-risk populations may benefit from active surveillance when identified on needle biopsy.10,11,13,15,17,21–26 To inform this decision-making, numerous retrospective studies have aimed to identify clinical and histopathologic risk factors that predict underlying carcinoma after a diagnosis of atypia on needle biopsy. For example, factors such as multiplicity of atypical lesions26–28 and overall extent of atypia13,15,26,27 have been linked with an increased risk of underlying carcinoma. However, whether demographic characteristics, such as age, influence a woman’s risk of underlying malignancy remains controversial.29
For invasive carcinoma, the influence of age on cancer biology and prognosis has been well-studied. While older women have been shown to have tumors with less aggressive behavior compared to younger women,30 older age has been consistently linked to a higher incidence of breast cancer,2 as well as a poorer prognosis.31,32 These differences likely stem from multiple factors, including access to and uptake of both screening and standard treatment strategies,3–5 as well as reported biological and genetic differences in tumors with age.6–8 The genomic and biologic landscapes of atypia, DCIS, and invasive cancer have been shown to share similar cellular expression33 and gene expression profiles,34 suggesting that these diagnoses represent a histopathologic spectrum.35 However, to date, few studies have assessed whether age similarly impacts atypia biology and outcomes in this high-risk population, and the ones that have been published yield conflicting results. While some studies show that an older age at diagnosis increases the risk of carcinoma at excision15,21,25 and that younger age at diagnosis may be associated with an increased long-term risk for breast cancer,26 other studies have found no significant association between age at diagnosis and cancer risk associated with atypia.29,36,37
Our study represents one of the largest single institution, retrospective series to assess patterns of atypia diagnoses and cancer outcomes by age. We demonstrated that the histology of the initial atypia diagnosis varied with age, with increasing prevalence of ADH in older women. However, this finding may be due to a disproportionate decrease in ALH/LCIS due to the progressive, age-related loss of lobules, where atypical lobular proliferations commonly reside. In addition, it could be that older women are more likely to have mammographic calcifications, which may lead to more needle biopsies, and ADH is often associated with mammographic calcifications. In contrast, ALH and LCIS typically lack specific imaging and/or clinical characteristics and are often considered incidental findings.
Furthermore, we demonstrated that older age may increase the risk of underlying carcinoma on excision following a diagnosis of atypia on needle biopsy, a finding which may inform the ongoing debate regarding active surveillance versus surgical excision as the optimal management strategy in this population. Our findings, in conjunction with previous reports identifying older age as a risk factor for carcinoma,15,21,25 suggest that age may be key when stratifying risk to inform management decision-making. While active surveillance may be considered in younger women in certain clinical settings, surgical excision may be more appropriate in women diagnosed at an older age due to a higher risk of underlying malignancy.
Similar to previous studies identifying no association between age and cancer risk after a diagnosis of atypia,29,36,37 we found that the long-term risk for developing DCIS or invasive cancer may be similar across all ages in women with preceding atypia, given a similar time period. In contrast, the baseline risk of breast cancer in general has been shown to increase with increasing age.38 Based on these observations, one might predict that older women with atypia would be more likely to develop breast cancer within 5 years after their atypia diagnosis. However, our findings indicate these risk factors do not have an additive effect. Therefore, a woman’s risk of breast cancer after atypia may be more closely related to an underlying predisposition rather than her chronologic age and suggests that similar ongoing surveillance strategies may be beneficial across all age groups (given a reasonable life expectancy). For ongoing surveillance of patients with atypia, the NCCN guidelines recommend a clinical encounter every 6–12 months, annual screening mammogram, and consideration of annual breast MRI. Based on our findings, these recommendations should be considered for all women with atypia and not dismissed based on age alone.
Our study additionally supports the notion that age may influence the recommendation or uptake of preventative treatment strategies for atypia. The significant risk reduction associated with chemoprevention in atypia patients has been demonstrated retrospectively39 and in multiple clinical trials (e.g. NSABP P-1,40 MAP.3,41 IBIS-I,42 and IBIS-II trials43), all of which reported substantial relative-risk reductions of 41–79%9. However, only a minority of high-risk patients have been reported to utilize prophylactic endocrine therapy nationally despite the demonstrated benefits.44,45 Similarly, we found a 10.6% overall chemoprevention uptake rate. Although no significant difference in the risk of a subsequent breast cancer diagnosis was noted with or without chemoprevention in our study, this may be related to the relatively short follow-up (median 49 months) and/or the small number of patients who received chemoprevention (N=45). For patients with invasive breast cancer, utilization of endocrine therapy has been shown to be influenced by age, with reduced uptake of adjuvant endocrine therapy among older patients.5,46 Similarly, in our study we found that patients >70y were less likely to receive chemoprevention, although the reasons for the difference in utilization are unclear (e.g. do patients decline treatment; are they poor candidates due to contraindications; or are providers not discussing/recommending treatment?). Understanding the association between age-related treatment patterns and use of endocrine therapy, and that this association may extend to atypia patients, may inform tailored counseling in high-risk populations.
There are some limitations to our study, many of which are inherent to its retrospective design and manual data entry. For example, data regarding clinical trial participation was limited, and although there was only documentation for 1 patient participating in a prevention trial, there could have been other patients that participated but did not have adequate documentation. While younger women <40y represented a minority of our patient population (N=26), we were unable to account for the reasons this young population underwent imaging, as screening in this age group is generally outside of current guidelines. However, we did find that roughly one third of patients underwent a breast MRI within 18 months of diagnosis, which was more common among younger women, but we were unable to determine the indications for this imaging. Similarly, we were unable to determine if the atypical biopsies were thought to be concordant or discordant with the imaging findings, which may have affected the surgeon’s decision to excise and/or breast cancer risk assessment. It is important to note that although recent national guidelines suggest surveillance may be indicated in select clinical settings, these guidelines notably changed during the study period, and excision was likely recommended to nearly all atypia patients in the earlier years. In addition, geographic differences in patient populations (as related to differences in the proportions of certain races/ethnicities, and/or environmental exposures) may limit generalizability. Regardless, this study represents a foundation for further research into how patient characteristics, such as age, may differentially impact prognosis following a diagnosis of an atypical breast lesion. Future directions should include multicenter studies representing larger and more diverse populations with high-risk breast lesions and further explore some of the biologic differences in atypia that likely exist among various cohorts.
CONCLUSIONS
Among women with atypical breast lesions, age did not influence the long-term risk of a subsequent breast cancer. However, older women presented more commonly with ductal atypia and have a higher risk of underlying carcinoma at the time of initial surgical excision. Moreover, older women with atypia are less likely to utilize chemoprevention strategies. Additional research into the inter-relationship of age, histologic subtype, and use of chemoprevention are necessary.
Supplementary Material
Supplemental Table 1. Uptake of endocrine therapy (chemoprevention) after atypia diagnosis (before cancer diagnosis, if any) for prevention of breast cancer by age group (N=423). Patients without chemoprevention data were excluded. Patients found to have an underlying breast cancer at the time of their initial surgical excision were also excluded.
ACKNOWLEDGEMENTS:
The database used for this study was created by Mary Beth Aschenbrenner, Chandra Almond, and Matthew Small. Data verification was performed by Madeline Thornton.
FUNDING SOURCES:
Dr. R. Greenup is supported by the National Institutes of Health Office of Women’s Research Building Interdisciplinary Research Careers in Women’s Health K12HD043446 (PI: Andrews).
Dr. O. Fayanju is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under Award Number 1KL2TR002554 (PI: Svetkey).
This project and its authors (SMT, OMF, CSM, LHR, RAG, TH, ESH, JKP) are all supported by the Duke Cancer Institute through NIH grant P30CA014236 (PI: Kastan).
Footnotes
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Presentation: Quickshot presentation at the Academic Surgical Congress in February 2019.
- The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
- Dr. J. Plichta has a research project supported by the Color Foundation (PI: Plichta).
- The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Table 1. Uptake of endocrine therapy (chemoprevention) after atypia diagnosis (before cancer diagnosis, if any) for prevention of breast cancer by age group (N=423). Patients without chemoprevention data were excluded. Patients found to have an underlying breast cancer at the time of their initial surgical excision were also excluded.