| کلیدواژههای انگلیسی مقاله |
Breast neoplasms, Neoplasm metastasis, Receptors, Progesterone, What&,rsquo s Known Breast cancer is the most common type of cancer in women. It has metastatic potential and is the principal determinant of patient survival. The expression of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR) has been associated with patient survival and metastatic sites. What&,rsquo s New The bone is a common site for metastasis. Luminal A and B subtypes show higher rates of bone metastasis. The frequency of HER2, ER, and PR expression differs at the first metastatic site, in patients with bone, brain, or lung metastasis, and in relation to the size of liver metastasis. IntroductionBreast cancer (BC) is the most common type of cancer in women worldwide. The lifetime risk of developing BC is about 12%, i.e., approximately one in eight women. 1, In 2019, the United States recorded 1,762,450 new cancer cases and 606,880 cancer deaths, of which BC alone accounted for 30% of all new cases and the second leading cause of death in women. 2, The age-standardized rate of developing BC in Iranian women is estimated at 27.4%, the lowest in the Middle East. 3, Nonetheless, BC is the most common type of cancer in Iranian women, and the majority of cases are diagnosed at advanced stages with an upward trend in mortality rates. 4, , 5, One of the important factors in determining disease stage and mortality rate in patients with BC is distant metastasis, affecting about 6-60% of patients. 6, The prognosis of patients with metastatic breast cancer (MBC) is site-dependent. Patients with bone metastasis have the best prognosis, and those with brain metastasis have the worst. 7, Recently, research studies have focused on the metastatic ability of BC tumors as a prognostic factor. Several MBC risk factors have been suggested, such as patients&,rsquo age, race/ethnicity, cigarette smoking, history of cancer in first-degree relatives, endogenous hormones, menopause, breastfeeding duration, and tumor histopathology, size, and grade. 8, Molecular studies have shown that biological subtypes of BC are important predictors of metastasis. The subtypes include luminal A, luminal B, and triple-negative breast cancer (TNBC)/basal-like, which are classified based on the expression of receptors, i.e., human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR). 9, ER is a nuclear hormone receptor that acts as a transcription factor, and PR plays a role in ER signaling. Both the ER and PR are important drivers of BC development. 10, Patients with ER+ and PR+ respond to endocrine therapy, but not to cytotoxic chemotherapy and are thus, less likely to achieve a complete response. 11, On the other hand, HER2+ is highly proliferative with higher histological grade and aggressive biological and clinical behavior. 12, TNBC subtype is biologically aggressive and has a high mortality rate and earlier recurrence. 13, Consequently, these are important contributors to disease recurrence and overall survival (OS). 14, There is a significant association between the site and pattern of metastasis and disease survival and recurrence rates. There is also emerging evidence on the biological nature of MBC. 15, Hence, in the present study, we examined the frequency of HER2, ER, and PR expression in patients with MBC and their association with the metastatic site, size, and pattern. The outcome of the study demonstrates whether these receptors can be used as effective markers for the prediction of the disease and to monitor and follow-up patients with MBC.Materials and MethodsIn this retrospective study, the medical records of patients diagnosed with MBC during 2017-2019 were examined. The patients were treated at Shahid Motahari Clinic affiliated with Shiraz University of Medical Sciences, Shiraz, Iran. The inclusion criteria were being diagnosed with BC for less than 10 years, with at least one apparent site of metastasis, and a complete medical record. Metastasis was confirmed using computed tomography (CT) scanner (GE BrightSpeed, Milwaukee, WI, USA) with 512&,times 512 matrix size and 10 mm slice thickness. The diagnosis of BC and metastasis was confirmed by three attending radiologists using CT imaging. Based on the convenient sampling method, medical records of 276 patients that fulfilled the inclusion criteria were selected. The study protocol was approved by the Ethics Committee of Shiraz University of Medical Sciences, Shiraz, Iran (code, IR.Sums.Med.Rec.1398.118). Written informed consent was obtained from the patients including permission for anonymized use of the results for research purposes and publications.Based on pathology reports, the data associated with the metastatic site (the brain, liver, lungs, bones, etc.), size (&,lt 2 cm, 2&,ndash 4 cm, &,gt 4 cm), and pattern were extracted from the medical records. In addition, the status of the three receptors (HER2, ER, PR) was noted. Patients with ER+ and/or PR+ and HER2- were classified as luminal A subtype, those with ER+ and/or PR+ and HER2+ as luminal B subtype, ER- and/or PR- and HER2+ as HER2&,ndash enriched subtype, and ER-, PR-, and HER2- as TNBC subtype. 9, Statistical AnalysisThe data were analyzed using SPSS software, version 21.0 (IBM Corp. Armonk, NY, USA). A Chi square test was used to compare the frequency of variables between the study groups. Descriptive data were expressed as frequency and percentage. P&,lt 0.05 was considered statistically significant. ResultsThe frequency of receptor positivity from the 276 selected medical records were of the HER2-enriched (n=48), luminal A (n=43), luminal B (n=146), and TNBC (n=39) subtype. The most common sites of single or multiple metastases were the bones (n=130, 47.1%), lungs (n=94, 34.4%), liver (n=77, 27.9%), brain (n=56, 20.3%), and other organs (n=35, 12.7%) (figure 1,). The first site of metastasis occurred in the bones (n=101, 36.6%), lungs (n=48, 17.4%), liver (n=43, 15.6%), brain (n=29, 10.5%), and other organs (n=21, 7.6%). Note that the medical records of 34 (12.3%) patients did not include complete information about the first metastatic site.Figure 1. The figure shows the frequency of metastases to different sites in patients with breast cancer. The most common sites were the bones, lungs, liver, and brain, respectively. Metastases to other sites were less frequent. The frequency of receptor expression at different metastatic sites and their categorization based on the site of the first metastasis and pattern is shown in figure 2, and table 1,, respectively. As shown in the table, there was a statistically significant difference between the frequency of receptors in relation to the first metastatic sites (P=0.024). Luminal A and B subtypes showed higher rates of bone metastasis as the first metastatic site. There was a statistically significant difference between the frequency of receptors in patients with bone (n=130, P=0.036), brain (n=56, P=0.031), and lung (n=94, P=0.020) metastases. The frequency of receptors was significantly different in relation to the size of liver metastasis (P=0.009), while no difference was observed in relation to the size and pattern of other metastatic sites (P&,gt 0.05).Figure 2. The figure shows the frequency of BC subtypes at different metastatic sites in patients with breast cancer. Luminal B is the most frequent subtype at all metastatic sites. The results of the Chi square test showed significant differences between the frequency of receptor expression in the bones (P=0.036), brain (P=0.031), and lungs (P=0.020).VariableCategoriesTotalHER2&,dagger ,Luminal ALuminal BTriple-negativeP value*,Site of first metastasisBrain29 (100%)5 (17.20%)3 (10.40%)15 (51.70%)6 (20.70%)0.024Liver43 (100%)10 (23.20%)3 (7.0%)22 (51.20%)8 (18.60%)Bone101 (100%)8 (7.90%)22 (21.80%)64 (63.40%)7 (6.90%)Lung48 (100%)10 (20.80%)5 (10.40%)25 (52.10%)8 (16.70%)Other sites21 (100%)6 (28.60%)3 (14.30%)9 (42.80%)3 (14.30%)Not reported34 (100%)9 (26.50%)7 (20.60%)11 (32.30%)7 (20.60%)Liver metastasisPresence of metastasisPositive (27.9%)77 (100%)12 (15.60%)11 (14.30%)42 (54.50%)12 (15.60%)0.912Negative199 (100%)36 (18.10%)32 (16.10%)104 (52.20%)27 (13.60%)Metastatic patternNecrotic18 (100%)2 (11.10%)2 (11.10%)11 (61.10%)3 (16.70%)0.927Hypervascular11 (100%)1 (9.10%)2 (18.20%)7 (63.60%)1 (9.10%)Hypovascular48 (100%)9 (18.70%)7 (14.60%)24 (50%)8 (16.70%)Tumor size&,le 2 cm41 (100%)5 (12.20%)5 (12.20%)27 (65.80%)4 (9.80%)0.0092&,ndash 4 cm17 (100%)2 (11.80%)2 (11.80%)12 (70.50%)1 (5.90%)&,ge 4 cm19 (100%)5 (26.30%)4 (21.10%)3 (15.80%)7 (36.80%)Brain metastasisPresence of metastasisPositive (20.3%)56 (100%)7 (12.50%)5 (8.90%)30 (53.60%)14 (25%)0.031Negative220 (100.0%)41 (18.60%)38 (17.30%)116 (52.70%)25 (11.40%)Metastatic patternNecrotic16 (100%)2 (12.60%)3 (18.70%)8 (50%)3 (18.70%)0.102Hemorrhagic4 (100%)0 (0.0%)2 (50%)0 (0.0%)2 (50%)Hypervascular24 (100%))3 (12.50%)0 (0.00%)14 (58.30%)7 (29.20%)Dural4 (100%)0 (0.0%)0 (0.00%)4 (100%)0 (0.0%)Leptomeningeal7 (100%)2 (28.60%)0 (0.00%)3 (42.80%)2 (28.60%)Hypovascular1 (100%)0 (0.0%)0 (0.00%)1 (100%)0 (0.0%)Tumor size&,le 2 cm19 (100%)3 (15.80%)0 (0.00%)11 (57.90%)5 (26.30%)0.5162&,ndash 4 cm31 (100%)3 (9.70%)4 (12.90%)15 (48.40%)9 (29%)&,ge 4 cm6 (100%)1 (16.70%)1 (16.70%)4 (66.60%)0 (0.0%)Bone metastasisPresence of metastasisPositive 130 (100%)14 (10.80%)23 (17.70%)76 (58.40%)17 (13.10%)0.036Negative146 (100%)34 (23.30%)20 (13.70%)70 (47.90%)22 (15.10%)Metastatic patternsclerotic57 (100%)7 (12.30%)8 (14.00%)34 (59.70%)8 (14.00%)0.937Lytic32 (100%)3 (9.40%)7 (21.90%)17 (53.10%)5 (15.60%)Mixed41 (100%)4 (9.70%)8 (19.60%)25 (61%)4 (9.70%)Tumor size&,le 2 cm78 (100%)11 (14.10%)15 (19.20%)43 (55.10%)9 (11.60%)0.5202&,ndash 4 cm41 (100%)3 (7.30%)6 (14.60%)27 (65.90%)5 (12.20%)&,ge 4 cm11 (100%)0 (0.0%)2 (18.20%)6 (54.50%)3 (27.30%)Lung metastasisPresence of metastasisPositive 94 (100%)9 (9.50%)12 (12.80%)61 (64.90%)12 (12.80%)0.020Negative182 (100%)39 (21.40%)31 (17%)85 (46.70%)27 (14.90%)Metastatic patternCavitary2 (100%)0 (0.0%)1 (50%)1 (50%)0 (0.0%)0.950Lymphangitic19 (100%)1 (5.30%)2 (10.50%)14 (73.70%)2 (10.50%)Single15 (100%)2 (13.30%)2 (13.30%)10 (66.70%)1 (6.70%)Multiple57 (100%)6 (10.50%)7 (12.30%)35 (61.40%)9 (15.80%)Cavitary/Multiple1 (100%)0 (0.0%)0 (0.0%)1 (100%)0 (0.0%)Tumor size&,le 2 cm64 (100%)5 (7.80%)7 (11%)42 (65.60%)10 (15.60%)0.5052&,ndash 4 cm16 (100%)1 (6.20%)3 (18.80%)10 (62.50%)2 (12.50%)&,ge 4 cm14 (100%)3 (21.40%)2 (14.30%)9 (64.30%)0 (0.0%)Other sitesPresence of metastasisPositive 35 (100%)9 (25.70%)7 (20%)15 (42.90%)4 (11.40%)0.381Negative241 (100%)39 (16.20%)36 (14.90%)131 (54.40%)35 (14.50%)Tumor size&,le 2 cm14 (100%)6 (42.90%)2 (14.20%)6 (42.90%)0 (0.0%)0.1032&,ndash 4 cm13 (100%)2 (15.40%)3 (23.10%)7 (53.80%)1 (7.70%)&,ge 4 cm8 (100%)1 (12.50%)2 (25%)2 (25%)3 (37.50%)*Chi square test (significance level, P&,lt 0.05), &,dagger Human epidermal growth factor receptor 2 |