Mammographic breast density as a predictive factor of local recurrence in female patients with invasive breast cancer
Emad Sadaka1&Walid Almorsy2and Amr Albadry3
Clinical Oncology Department, Faculty of Medicine, Kafer Elsheikh university1, Tanta university2 &Radiology department Tanta University3
Purpose: Mammographic breast density (MBD)is one of the strongest breast cancer risk factors. Dense breast tissue wasdemonstrated toincrease the risk of local recurrence after modified radical mastectomy. The aim of this study was to evaluate MBD as a predictive factor for local recurrence in female patients with invasive breast cancer. Methods: Eighty sevenfemale patients with local recurrence after mastectomy forinvasive breast cancer were included in this study. Patient’s data were recorded concerning mammographic density, age, menopausal status and tumor features (histological type, grade, size, nodal status, LVI, hormonal receptors status, Ki67 and Her-2/neu). Results:Among all patients, 23 (26.44%) patients had low dense breasts (;25%) while 64 (73.66%) patients had high dense breasts (?25%). Analysis of risk factors associated with local recurrence according to the mean time ( in months) showed a significant association between early local relapse (LR) andhigh MBD (p;0.001), age ;50 (p=0.006), LVI (p=0.044), positive axillary nodes (p=0.014) and high Ki67 expression (p=0.007). In multivariate analysis, MBD was an independent risk factor for LR (p;0.001). Age and nodal status was near significant (p=0.07). Conclusion: mammographic breast densityhas a significant impact on local recurrence in female patients with invasive breast cancer. Further studies with large number of patients still needed to confirm the predictive value of MBD in the incidence of local recurrence in female patients with invasive breast cancer..

Keywords: Mammographic Breast density, local recurrence, prediction.

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Introduction
Worldwide, Breast cancer remains the most common cancer and leading cause of cancer related death in women.1 Mammography plays a key role in the diagnosis of breast cancer and is currently considered to be the primary investigative modality.Mammographic breast density (MBD) can change over time and is largely influenced by inherited genetic factors, decreases with age, and is further reduced by multiparity and menopause.2,3
Breast density, one of the strongest breast cancer risk factors, refers to the radiographic appearance of the female breast. 5,6 Fat, which is radiolucent, appears dark on a mammogram. Epithelial and fibrous stromal tissues, on the other hand, appear white or radio dense and are collectively referred to as mammographic density. Relative to a low percentage, a high mammographic density is inversely associated with age and body weight and can be measured with qualitative and quantitative methods 4.
patients with already diagnosed breast cancer tumors originating in breasts with very low density were shown to be associated with a poorer prognosis even after correcting for possible confounders.7- 9Several possible mechanisms by which density could affect prognosis have been investigated. The MBD has consistently been associated with breast stromal composition, which is involved in tumor progression.10-13
Modified radical mastectomy (MRM) has been the primary treatment method for local breast cancer.14,15 According to published data, nearly one tenth of mastectomized patients are at risk of locoregional recurrence (LRR), and a quarter of patients are at risk of developing distant metastases during follow up.16 Huang et al evaluated MBD as a predictive for locoregional relapse in patients with invasive breast cancer and they demonstrated that dense breast tissue increased the risk of locoregional recurrence after modified radical mastectomy.17
Material and methods
The medical records of 87 patients were reviewed among women with invasive breast diagnosed in clinical oncology department, Tanta university hospital presented in the period from December 2012 to December 2017. Patients with invasive breast carcinoma who experienced local relapse (LR) after modified radical mastectomy were included. Patients with unavailable pretreatment mammography were excluded. Information’s were recorded concerning mammographic density, age, menopausal status and tumor features (histological type, grade, size, nodal status, LVI, hormonal receptors status, Ki67 and Her-2/neu).Mammographic characteristics and the percentile mammographic density of all patients was evaluated visually using the craniocaudal projections of the original diagnostic mammograms. In an effort to minimize bias, tow radiologists took part in the analysis. Patients were categorized for mammographic density based on the Wolfe classification10.as either low (<25% density)or high (>25% density).

The percentile mammographic breast density (MBD) of all patients was evaluated visually using the craniocaudal projections of the original diagnostic mammograms. Patients were categorized for mammographic density based on the Wolfe classification 10 as either low (<25% density), or high (>25% density).
Statistical analysis:
Descriptive characteristics were compared using the chi-squared test.The multivariate analysis was assessed using logistic regression model. Mann- Whitney test used to evaluate the potential risk factors forLR. Overall, a p value <0.05 was considered statistically significant.

Results
Table (1): correlation between mammographic breast density and patients characteristics.

Total(n = 87) Low
(n = 23) High
(64) P
Age ?50 39(44.8%) 4(17.4%) 35(54.7%) 0.002*
>50 48(55.2%) 19(82.6%) 29(45.3%) Pathology Ductal 76(87.4%) 19(82.6%) 57(89.1%) 0.42
Lobular 11(12.6%) 4(17.4%) 7(10.9%) Menopause Pre 38(43.7%) 5(21.7%) 33(51.6%) 0.013*
Post 49(56.3%) 18(78.3%) 31(48.4%) N
N0
N1
N2
N3 26(29.9%)
22 ( 25.3% )
26( 29.9% )
13( 14.9% ) 10(43.5%)
6(26.1%)
3(13%)
4(17.4%) 16(25%)
16( 25%)
23(35.9 )
9(14.1) 0.17
Grade G1&2 59(67.8%) 16(69.6%) 43(67.2%) 0.83
G3 28(32.2%) 7(30.4%) 21(32.8%) LVI Non 47(54%) 19(82.6%) 28(43.8%) 0.001*
Yes 40(46%) 4(17.4%) 36(56.2%) radiotherapy Yes 68(78.2%) 12(52.2%) 56(87.5%) <0.001
No 19(21.8%) 11(47.8%) 8(12.5%) Ki67 Low 32(36.8%) 15(65.2%) 17(26.6%) 0.001*
High 55(63.2%) 8(34.8%) 47(73.4%) Her-2
Positive
Negative 14(16.1%)
73(83.9%) 2(8.7) 21(91.3%) 12(18.8%)
52(81.2%) 0.26
Tumor size
<=5
>5 53(60.9)
34(39.1) 20(87)
3(13) 33(51.6)
34(39.1) 0.003*
Hormonal status
+ve
-ve 64(73.6)
23(26.4) 14(60.8)
9(39.1) 50(78.1)
14(21.9) 0.11
Table 1 showed the correlation between patient’s characteristics and MBD. Among all
patients, 23 (26.44%) patients had low dense breasts (;25%) while 64 (73.66%) patients had high dense breasts (;25%). Age ; 50 (p=0.002), premenopausal women (p=0.013), tumor size ;5cm (p=0.003), LVI (p=0.001), high Ki67 expression (p;0.001) and patients who received adjuvant radiotherapy (p;0.001) were significantly associated with more frequent high breast density.
Table (2) Univariate analysis for factors affecting LR
Factor Mean time to local recurrence P
Age?50 years
;50 years 35.74
50.71 0.006
Pathology
Ductal Ca.

Lobular Ca. 42.51
54.32 0.147
N stageNegative
Positive 54.17
39.66 0.014
Mens. statusPre-
Post- 38.79
48.04 0.090
LVI -ve
+ve 49.00
38.13 0.044|
Her-2 +ve
-ve 38.29
45.10 0.355
Tumor size; 5
? 5 47.32
38.82 0.125
Grade1-2
3 45.50
40.84 0.421
HRPositive
negative 43.80
44.57 0.900
MBDLow
High 67.59
35.52 ;0.001
Ki67Low
high 53.53
38.45 0.007
Table 2 showed analysis of risk factors associated with local recurrence according to the mean time (months) to local relapse. There were a significant association between early local relapse (LR) andhigh MBD (p;0.001), age ;50 (p=0.006), LVI (p=0.044), positive axillary nodes (p=0.014) and high Ki67 expression (p=0.007). In multivariate analysis (table3), MBD was an independent risk factor for LR (p;0.001). Age and nodal status was near significant (p=0.07).
Table(3) multivariate analysis for factor affecting LR
factor HR (95% CI) p-value
Age 0.623(0.372-1.042) 0.071
Nodal stage 1.640 (.960 – 2.800) 0.070
LVI 1.064(0.658-1.721) 0.800
MBD 1.687 (1.273 – 2.236) ;0.001
Ki67 1.042(0.630-1.724) 0.872
Discussion
Mammographic density is one of the risk factors for breast cancerandlocoregional recurrence in patients with invasivebreast cancer.20in the present study there was correlation between patient’scharacteristics and MBD. Among 87 patients, 23 (26.44%) patients had low dense breasts (<25%) while 64 (73.66%) patients had high dense breasts (?25%). Age < 50 (p=0.002), premenopausal women (p=0.013), tumor size ?5cm (p=0.003), LVI (p=0.001), high Ki67 expression (p<0.001) and patients who received adjuvant radiotherapy (p<0.001) were significantly associated with more frequent high breast density.
The analysis of risk factors associated with local recurrence according to the mean time (months) to local relapse showed a significant association between early local relapse (LR) andhigh MBD (p<0.001), age <50 (p=0.006), LVI (p=0.044), positive axillary nodes (p=0.014) and high Ki67 expression (p=0.007). In multivariate analysis (table2), MBD was an independent risk factor for LR (p<0,001). Age and nodal status was near significant (p=0.07).
TulinCil et al 200919 evaluated the role of mammographic density as a risk factor for the development of local recurrenceand found that patients in the high mammographic density group experienced a much greater risk of local disease recurrence compared with women with the least dense breasts. The difference in the rates of disease recurrence at 10 years was pronounced for women who did not receive radiotherapy (40% vs 0% for patients with >50% density and <25% density, respectively; P < .0001). They concluded that mammographic breast density is an important risk factor for local breast cancer recurrence especially among women not receiving breast irradiation.

Louise Eriksson et al 201320 found that percentage density (PD) was associated withlocal and locoregional recurrence (HR 1.92, p = 0.039, HR 1.67, p = 0.033 respectively)for women with PD?25% compared to PD<25%. Stratification on surgical procedure showed that the associations were also present in mastectomized women. They concluded that high mammographic density is an independent risk factor of both local and locoregional recurrence. Thus, mammographic density should possibly influence adjuvant therapy decisions in the future.

Yu-Sen Huang et al 17 2016 evaluated patients with heterogeneously dense (50–75% density) and extremely dense (>75% density) breasts and found that those patients had an increased risk of locoregional recurrence. Their results demonstrate that dense breast tissue (>50% density) increased the risk of locoregional recurrence after modified radical mastectomy in patients with invasive breast cancer.
Chengshuai et al 21 evaluated 814 patients with invasive breast cancer and found on univariate and multivariate analysis that tumor size and tumor subtype show statistical significance with LN involvement. Using TNBC as a reference, both Luminal B type (Luminal HER2-, Luminal HER2+) shows significant higher probability of LN involvement. They conclude that LN involvement is an intrinsic characteristic for molecular subtype of breast cancer. Triple positive and triple negative breast cancer accounts the most and least possibility of LN involvement.

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