الفهرس 
Breast Cancer EpidemiologyOnly 14 pages are availabe for public view
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Abstract
Worldwide, breast cancer is the most prevalent cancer in females
with estimated number of 2.261.419 new cases in 2020. It represents
24.5% of all cancers that affect females in the world. In Egypt, breast
cancer is the most common malignancy in women, accounting for 32.4%
of cancers with the estimated number of breast cancer cases nearly 22.038
in 2020.
The aim of this study is to evaluate immunohistochemical
expression ofRCC2, Rac1 and p53 in primary breast invasive duct
carcinoma and corresponding metastatic sites and correlation of the
results with the available clinicopathological parameters.
Using the standard IHC technique, we assessed RCC2, Rac1 and
p53 expressions in 120 breast cancer specimens. Eighty one cases with
corresponding positive lymph nodes and thirty nine cases without lymph
nodes metastasis. This selective cross-sectional retrospective study
included 120 primary breast infiltrating duct carcinoma (IDC), NOS
specimens from Egyptian patients retrieved from archival material in
pathology Department, Faculty of Medicine, Menoufia University
spanning the period between January 2018 and December 2020.
In this study, patient’s age ranges from 27– 75 years with a mean ±
SD of 51.37 ±10.82 and a median of 50.5. More than half of cases
(68/120, 56.7%) were postmenopausal. Left breast was involved in sixty
percent (72/120) of cases. The majority of cases were presented as single
mass (102/120, 85%). Tumor size ranges from 1 – 15 cm with mean ±
SD of 3.68 ±1.95 and a median of 3.5. Most of cases were of grade 2
(105/120, 87.5%). Fifty eight (48.3%) cases showed DCIS component
and 38 of them (38/58, 65.5%) were comedo pattern. Only 35 cases
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showed necrosis (29.2%). Mitotic figures count ranges from 1 – 5
mitoses/10 HpF with mean ±SD of 1.34 ±0.68 and a median of 1.
Apoptotic bodies count ranges from 2 – 9 apoptotic bodies / 10 HpF with
mean ± SD of 3.08 ± 1.47 and a median of 3. Sixty seven cases showed
low TILs (55.8%), 20 cases showed intermediate TILs (16.7%) and 33
cases showed high TILs (27.5%) Thirteen cases showed LVI (10.8%).
Seventy cases were of pT2 (58.3%), while 26 cases (21.7%) and 24 cases
(20%) were of pT1 and pT3, respectively. Thirty nine cases were of N0
(32.5 %), 43 of N1 (35.8%) while 24 cases (20%) and 14 cases (11.7%)
were of N2 and N3, respectively. NPIs ranges from 2.8 – 8 with mean ±
SD of 4.79 ± 0.98 and a median of 4. Eighty cases (66.7%) showed
positive ER. Fifty eight cases (48.3%) showed positive PR. Twenty five
cases (20.8%) showed positive Her2neu. Most of cases (73/120, 60.8%)
showed >14% Ki67 expression. Sixty seven cases (55.8%) were luminal
A, 22 were luminal B (18.3%), 3 were Her2neu enriched (2.5%) and 28
were triple negative (23.4%).
As regards RCC2 expression, the majority of cases showed positive
RCC2 expression (116/120, 96.7%). Sixty three cases showed low
expression (≤ 40%) (52.5%) and 57 cases showed high expression
(>40%) (47.5%). RCC2 percentage of expression ranged between 0 – 90
with mean ± SD of 43.67 ± 22.3 and a median of 40. Regarding intensity
of expression, four cases were negative (3.3%), eight cases were mild
(6.7%), 47 cases were moderate (39.2%) and 61 cases showed strong
intensity of expression (50.8%). In the present study, N +ve IDC showed
positive expression of RCC2 in 78/81 cases (96.3%). Low RCC2
expression (≤ 40%) was observed in more than half of nodal +ve IDC
(56.8%). RCC2 percentage of expression in N +ve IDC ranged between
0– 90 with mean ± SD of 42.96 ± 22.33 and a median of 40. Regarding
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RCC2 intensity in N +ve IDC, three cases were negative (3.7%), 7 cases
were mild (8.6%), 36 cases were moderate (44.4%) and 35 cases showed
strong intensity of expression (43.3%).
Corresponding +ve LNs showed positive expression of RCC2 in
79/81 cases (97.5%). Low RCC2 expression (≤ 40%) was observed in
more than half of corresponding +ve LNs (51.9%). RCC2 percentage in
corresponding +ve LNs ranged between 0 – 90 with mean ± SD of 43.46
± 21.34 and a median of 40. Regarding RCC2 intensity in corresponding
+ve LNs, two cases were negative (2.5%), 7 cases were mild (8.6%), 32
cases were moderate (39.5%) and 40 cases were strong intensity of
expression (49.4%).
As regards RCC2, high expression, percent and intensity showed
significant association with frequent mitoses (p =<0.001 and <0.001
respectively), high apoptotic count (p=<0.001, <0.001 and 0.042
respectively), high Ki67 (p=<0.001 and <0.001 respectively), LVI
(p=0.024 and 0.03 respectively). There was a near significant association
between low RCC2 expression and advanced nodal stage (p=0.057). High
RCC2 percent and strong RCC2 intensity showed a significant
association and positive Her2neu (p=0.012 and 0.017 respectively) and
molecular subtypes (p=0.012 and 0.021 respectively). A statistically
significant correlation in the percent of RCC2 in the primary breast tissue
versus metastatic lymph node specimens (r= 0.29, p= 0.008).
As regards Rac1 expression, all studied cases showed Rac1
positive expression (100%). Sixty four cases showed low expression (≤
30%) (53.3%) and 56 cases showed high expression (>30%) (46.7%).
Rac1 percentage of expression ranged between 10 –70 with mean ± SD of
31.0 ± 16.97 and a median of 30. Regarding intensity of expression, 36
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cases were mild (30%), 40 cases were moderate (33.3%) and 44 cases
showed strong intensity of expression (36.7%).
In the present study, N +ve IDC showed positive Rac1 expression
(100%). High Rac1 percentage of expression (>30%) was observed in 41
cases of nodal +ve IDC (50.6%). Rac1 percentage of expression in N +ve
IDC ranged between 10 -70 with mean ± SD of 31.85 ± 17.40 and a
median of 40.
Regarding N +ve IDC, twenty five cases were mild (30.9%), 27
cases were moderate (33.3%) and 29 cases showed strong intensity of
expression (35.8%).
Corresponding +ve LNs showed positive expression of Rac1 in
72/81 of cases (88.9%). High Rac1 percentage of expression (>30%) was
observed in 45 cases of their corresponding +ve LNs (55.6%). Rac1
percentage of expression in corresponding +ve LNs ranged between 0 –
60 with mean ± SD of 32.22 ± 18.10 and a median of 40. Regarding their
corresponding +ve LNs, nine cases were negative (11.1 %), 14 cases
were mild (17.3%), 26 cases were moderate (32.1%) and 32 cases were
strong intensity of expression (39.5%).
As regards Rac1, high expression, percent and intensity showed
significant association with high Ki67 status (p=<0.001 and <0.001
respectively), molecular subtypes (p=0.009 and 0.010 respectively),
frequent apoptosis (p=0.019 and 0.003 respectively), presence of LVI
(p=0.021 and 0.036 respectively), positive ER (p=0.028 and 0.022
respectively), positive PR (p=0.030) and positive Her2neu (p=0.016,
0.013 and 0.036 respectively). There was a near significant association
between high Rac1 expression and older age (p=0.054) and large tumor
size (p=0.057). There was a significant association between moderate/
strong Rac1 intensity and frequent mitoses (p=0.047).
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A regards p53 expression, the majority of cases showed negative
p53 expression p53 (87/120, 72.5%) and 33 cases (27.5%) were positive.
p53 percentage of expression among positive cases ranged between 5 –
50 with mean ± SD of 22.73 ± 16.35 and a median of 20. Regarding
intensity of expression, eight cases were mild (24.2%), 5 cases were
moderate (15.2%) and 20 cases were strong (60.6%).
Nodal +ve IDC showed negative expression in (58/81, 71.6%) and
positive expression of p53 in (23/81, 28.4%). p53 percentage of
expression in N +ve IDC ranged between 5– 50 with mean ± SD of 22.17
± 15.65 and a median of 20. Regarding N +ve IDC, five cases were mild
(21.7%), 4 cases were moderate (17.4%) and 14 cases showed strong
intensity of expression (60.9%).
Corresponding +ve LNs showed negative expression in (58/81,
71.6%) positive expression of p53 in (23/81, 28.4%). p53 percentage of
expression in corresponding +ve LNs ranged between 5– 50 with mean ±
SD of 23.48 ± 16.41 and a median of 20. Regarding their corresponding
+ve LNs, six cases were mild (26.1%), 6 cases were moderate (26.1%)
and 11 cases showed strong intensity of expression (47.8%).
As regards p53, significant association was found between positive
p53 expression and increased tumor size (p=0.009), high TILs (p=0.008),
high Ki67 status (p=0.001) and Apoptosis (p=0.013). On the other hand,
there was a significant inverse relation between p53 percent and strong
p53 intensity and PR status (p=0.041 and 0.002 respectively). There was
a highly significant association between strong p53 intensity and early
nodal stage (N0+N1) (p=0.009). There was a near significant relation
between strong p53 intensity and high tumor grade (grade 3) (p=0.060)
and absence of in situ component (p= 0.055). A statistically significant
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correlation in the percent of p53 in the N+ve IDC versus corresponding
metastatic lymph node specimens (r= 0.32, p= 0.003).
There was a highly significant direct correlation between each
marker in this study and the other 2 markers (p= <0,001, <0.001 and
0.006).
As regards survival data, Twenty three cases (28 %) have positive
family history. Four cases had cardiac disease (4.9 %), six cases had
Hepatitis C virus +ve (7.3 %), seven cases had Diabetes Mellitus (8.5%),
thirteen cases had Hypertension (15.9%) and four cases had both
Hypertension and Diabetes Mellitus (4.9%). Thirteen cases showed
metastasis to distant organs (15.9%). 25 cases were having gross
disease during received treatment, 13 cases (52%) showed progressive
disease (pD), 9 cases (36%) showed partial response (pR), two cases
(8%) showed stationary disease (SD) and one cases (4%) showed
complete response (CR). Seventy five cases were alive (75/81, 91.5%)
and seven cases were dead (7/81, 8.5%). PFS ranged between 6 – 52
months with a mean ±SD of 31.87 ± 13.37 and a median of 35 months.
OS ranged between 11 and 52 months with a mean ±SD of 34.93 ± 10.60
and a median of 37 months.
As regards response to treatment, significant association between
progressive disease and low TILs (p= 0.009), advanced tumor stage (T3)
(p=0.002), metastatic status (p=<0.001), dead patients (p= 0.005), and
short OS (p<0.001), larger tumor size (p=0.011) and short PFS
(p=0.011).
As regards distant metastatic status, significant association between
positive distant metastatic status and large tumor size (p=0.003), higher
NPIs (p=0.007), progressive disease (p<0.001), death of patients
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(p<0.001), short PFS (p<0.001), positive Her2neu status (p=0.023) and
short OS (p=0.024).
As regards PFS, significant association between shorter
progression free survival and advanced tumor stage (T3) (p=0.001),
presence of metastasis to distant organs (p<0.001) and progressive
disease (p<0.001), positive Her2neu status (p=0.011) and Luminal B
molecular subtypes (p=0.023). Multivariate analysis for the parameters
affecting progression free survival revealed that presence of metastasis to
distant organs was the most independent factor affecting progression free
survival (p=0.001).
As regards OS, significant association between shorter overall
survival in patients presented by multifocal tumors (p=0.017), advanced
tumor stage (T3) (p=0.010) and Luminal B cases (p=0.015), progressive
disease (p=0.003), positive Her2neu status (p=0.008) and presence of
metastasis to distant organs (p<0.001). Results of RCC2, Rac1 and p53
immunostaining showed a non-significant relation to response to
treatment, distant metastatic status, PFS or overall survival.