• Development and Reproduction
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• v.5 no.2
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• pp.175-180
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• 2001

The ectopic expression of gonadotropin releasing hormone(GnRH and luteinizing hormone(LH) in several tissues is a quite intriguing phenomenon. Recently, the presence of GnRH and its receptor has been clearly demonstrated in rodents and human mammary gland. In this context, one can postulate that the presence of local circuit composed of GnRH and LH in the gland. The present study was undertaken to elucidate whether there is a correlation between the LH expression in rat mammary gland and physiological status during the process of mammary differentiation. LH contents in mammary gland from cycling to weaning rats were measured by radioimmunoassay(RIA). In cycling rats, changes of the LH level in both serum and mammary gland showed similar pattern as the highest level in proestrus and the lowest level in diestrus II stage. While the serum LH levels were fluctuated from pregnant through involution stage, a sharp decline of mammary LH contents was observed in the lactating rats. This decrement was recovered in involuting rats to the level of proestrus stage. Reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analyses demonstrated that the transcriptional activities of the mammary LH and GnRH were increased from diestrus I stage to estrus stage, and the increased levels were maintained in pregnant, lactation and involution stages. To test the hypothesis that the alteration in mammary LH expression might be steroid-dependant, ovariectomy(OVX) and steroid supplement model was employed. As expected, supplement of estradiol(E$_2$) after OVX remarkably decreased serum LH level compared to that in serum from vehicle-only treated rats. Likewise, administration of E$_2$ significantly reduced the mammary LH content. The present study demonstrated that (i) the LH expression in mammary gland could be altered by some physiological parameters such as estrous cycle, pregnancy, lactation and involution, and (ii) ovarian steroid especially estrogen seems to be one of major endocrine factors which are responsible for regulation of mammary LH expression.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.1881-1886
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• 2012

Breast cancer is a heterogeneous disease that is affected by ethnicity of patients. According to hormone receptor status and gene expression profiling, breast cancers are classified into four molecular subtypes, each showing distinct clinical behavior. Lack of sufficient data on molecular subtypes of breast cancer in Iran, prompted us to investigate the prevalence and the clinicopathological features of each subtype among Iranian women. A total of 428 women diagnosed with breast cancer from 2002 to 2011 were included and categorized into four molecular subtypes using immunohistochemistry. Prevalence of each subtype and its association with patients' demographics and tumor characteristics, such as size, grade, lymph-node involvement and vascular invasion, were investigated using Chi-square, analysis of variance and multivariate logistic regression. Luminal A was the most common molecular subtype (63.8%) followed by Luminal B (8.4%), basal-like (15.9%) and HER-2 (11.9%). Basal-like and HER-2 subtypes were mostly of higher grades while luminal A tumors were more of grade 1 (P<0.001). Vascular invasion was more prevalent in HER-2 subtype, and HER-2 positive tumors were significantly associated with vascular invasion (P=0.013). Using muti-variate analysis, tumor size greater than 5 cm and vascular invasion were significant predictors of 3 or more nodal metastases. Breast cancer was most commonly diagnosed in women around 50 years of age and the majority of patients had lymph node metastasis at the time of diagnosis. This points to the necessity for devising an efficient screening program for breast cancer in Iran. Further, prospective surveys are suggested to evaluate prognosis of different subtypes in Iranian patients.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.15
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• pp.6359-6364
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• 2015

Background: Preclinical studies have shown that the combination of an aromatase inhibitor (AI) and capecitabine in estrogen receptor (ER)- positive cell lines enhance antitumor efficacy. This retrospective analysis of a group of patients with metastatic breast cancer (MBC) evaluated the efficacy and safety of combined AI with capecitabine. Materials and Methods: Patients with hormone receptor-positive metastatic breast cancer treated between 1st January 2005 and 31st December 2010 with a combination of capecitabine and AI were evaluated and outcomes were compared with those of women treated with capecitabine in conventional dose or AI as a monotherapy. Results: Of 72 patients evaluated, 31 received the combination treatment, 22 AI and 19 capecitabine. The combination was used in 20 patients as first-line and 11 as second-line treatment. Mean age was 46.2 years with a range of 28-72 years. At the time of progression, 97% had a performance status of <2 and 55% had visceral disease. No significant difference was observed between the three groups according to clinical and pathological features. Mean follow up was 38 months with a range of 16-66 months. The median PFS of first-line treatment was significantly better for the combination (PFS 21 months vs 8.0 months for capecitabine and 15.0 months for AI). For second-line treatment, the PFS was longer in the combination compared with capecitabine and Al groups (18 months vs. 5.0 months vs. 11.0 months, respectively). Median 2 year and 5 year survival did not show any significant differences among combination and monotherapy groups. The most common adverse events for the combination group were grade 1 and 2 hand-for syndrome (69%), grade 1 fatigue (64%) and grade 1 diarrhoea (29%). Three grade 3 hand-foot syndrome events were reported. Conclusions: Combination treatment with capecitabine and AI used as a first line or second line treatment was safe with much lowered toxicity. Prospective randomized clinical trials should evaluate the use of combination therapy in advanced breast cancer to confirm these findings.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.17
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• pp.7975-7979
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• 2015

Purpose: This study aimed to explore the value of IHC4 in predicting pathological response after neoadjuvant chemotherapy in patients with hormonal receptor (HR)-positive breast cancer (BC). Materials and Methods: In this retrospective exploratory study, data for 68 HR-positive BC patients who received neoadjuvant chemotherapy were recorded. IHC4 scores were calculated based on estrogen receptors/progesterone receptors, Ki-67 and HER2 status. Logistic and ordinal regression analyses in addition to likelihood ratio test were used to explore associations of IHC4 scores and other clinico-pathological parameters with pathological complete response (pCR) and pathological stage. Results: Taking the 25th percentile as the cut-off, a lower IHC4 score was associated with an increased probability of pCR (low; 52.9% vs. High; 21.6%, OR=4.1, 95% CI=1.28-13.16, p=0.018) and a lower pathological stage (OR=3.9, 95% CI=1.34-11.33, p=0.012). When the IHC4 score was treated as a continuous variable, a lower score was again associated with an increased probability of pCR (OR=1.010, 95% CI=1.001-1.018, p=0.025) and lower pathological stage (OR=1.009, 95% CI=1.002-1.017, P=0.008). Lower clinical stage was associated with a better pCR rate that was of borderline significance (P=0.056). When clinical stage and IHC4 score were incorporated together in a logistic model, the likelihood ratio test gave a P-value of 0.004 after removal of the IHC4 score and 0.011 after removal of the stage, indicating a more significant predictive value of the IHC4 score for pCR. Conclusions: This study suggests that the IHC4 score can predict pathological response to neoadjuvant chemotherapy in HR-positive BC patients. This finding now needs to be validated in a larger cohort of patients.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.117-122
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• 2014

Background: Breast cancer is the most common malignancy and the second leading cause of cancer-related death among women in the developed countries. Despite advances in screening, improved local therapies and adjuvant systemic treatments, median survival of metastatic breast cancer patients (MBC) is in the range of 2-3 years at most. We aimed to investigate whether the prognostic factors and therapeutic responses of our Turkish patients are similar to those in the literature. Materials and Methods: We reviewed the medical records of MBC patients who had been treated in our institution between 1999-2009 and analyzed their clinicopathological features and survival outcomes retrospectively Results: A hundred and sixty patients were included. Median age was 47 (23-82), median follow up was 24 (2-186) months. At the time of diagnosis 59% of patients were under the age of 50 and 46% were postmenopausal. The majority (37%) had multiple sites of metastases. Forty percent received endocrine therapy and 40% chemotherapy as first line metastatic treatment. Thirty (20%) patients were treated with molecular targeting agents like trastuzumab, lapatinib and sunitinib, frequently combined with a chemotherapy agent. Five-year overall survival (OS) was 32% and median OS was 38 months for the whole group. Five year progression free survival (PFS) was 10% and median PFS was 10 months. Menopausal status, hormone receptor expression and disease free status had a significant impact on overall survival in the multivariate analysis (p 0.018, p 0.018 and p:0.003, respectively). Conclusions: All our patients were treated with the modern oncologic therapies recommended by the international guidelines. From our data, MBC patients live up to 3-4 years, indicating that further improvement beyond that requires development of new treatment modalities. The survival outcomes of our patients were consistent with the data reported in the literature.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.6
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• pp.2501-2504
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• 2014

Background: Capecitabine is an oral fluoropyrimidine derivative which is frequently used alone or in combination regimens for the treatment of metastatic breast cancer. Although overall and progression free survivals have increased in recent years with the use of new generation drugs, predictive factors that would further improve the outcomes are needed. Previous studies have demonstrated the relation between post-treatment increase in mean corpuscular volume (MCV) and predicting therapy response as well as survival. The present study investigated the clinical impact of MCV elevation in metastatic breast cancer patients treated with capecitabine. Materials and Methods: The data of a total of 82 patients from three centers followed between June 2005 and June 2013 were retrospectively analyzed. The demographic data and hormone receptor status of the patients, as well as initial examination before and after treatment and data concerning progression were recorded. MCV ${\geq}100$ fl was considered as macrocytosis. Capecitabine was given at a dose of $2500mg/m^2$ daily for 14 days every three weeks. Pre-treatment and post-treatment MCV and other parameters of complete blood count were recorded. Post-treatment initial evaluation was performed after 2 cycles of therapy. Results: The median age of the patients was 46.5 years (range 26-72 years) and 54% were premenopausal. Performance status was ECOG 0 and 1 in 81 (99%) patients. The median number of cycles for capecitabine therapy was 5 (min-max: 2-18). The median ${\Delta}MCV$ level (post-treatment values at sixth week - baseline) was 6.4. Whilst ${\Delta}MCV$ was ${\geq}6.4$ in 42 patients, it was <6.4 in 40 patients. Clinical benefit (complete response+partial response+stable disease) was observed in 37 (88%) of 42 patients with a median ${\Delta}MCV$ ${\geq}6.4$ and in 30 (75%) of 40 patients with ${\Delta}MCV$ <6.4 with no statistically significant difference (p=0.158). No significant difference was determined between the group with ${\Delta}MCV$ ${\geq}6.4$ and the group with ${\Delta}MCV$ <6.4 in terms of progression-free survival (11 vs 12 months) (p=0.55) and overall survival (20 months vs. 24 months) (p=0.11). Conclusions: The identification of new predictive markers in metastatic breast cancer is very important. In some recent studies, increase in MCV has been suggested as a marker in tumor response. In the present study, however, no significant difference was determined between tumor response and increase in MCV. Further studies including higher numbers of patients are needed to determine whether increase in MCV is a predictive marker or not.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6397-6403
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• 2014

Background: Aberrant promoter hypermethylation has been recognized in human breast carcinogenesis as a frequent molecular alteration associated with the loss of expression of a number of key regulatory genes and may serve as a biomarker. The E-cadherin gene (CDH1), mapping at chromosome 16q22, is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections. The aim of our study was to assess the methylation pattern of CDH1 and to correlate it with the expression of E-cadherin, clinicopathological parameters and hormone receptor status in breast cancer patients of Kashmir. Materials and Methods: Methylation specific PCR (MSP) was used to determine the methylation status of CDH1 in 128 invasive ductal carcinomas (IDCs) paired with the corresponding normal tissue samples. Immunohistochemistry was used to study the expression of E-cadherin, ER and PR. Results: CDH1 hypermethylation was detected in 57.8% of cases and 14.8% of normal adjacent controls. Reduced levels of E-cadherin protein were observed in 71.9% of our samples. Loss of E-cadherin expression was significantly associated with the CDH1 promoter region methylation (p<0.05, OR=3.48, CI: 1.55-7.79). Hypermethylation of CDH1 was significantly associated with age at diagnosis (p=0.030), tumor size (p=0.008), tumor grade (p=0.024) and rate of node positivity or metastasis (p=0.043). Conclusions: Our preliminary findings suggest that abnormal CDH1 methylation occurs in high frequencies in infiltrating breast cancers associated with a decrease in E-cadherin expression. We found significant differences in tumor-related CDH1 gene methylation patterns relevant to tumor grade, tumor size, nodal involvement and age at diagnosis of breast tumors, which could be extended in future to provide diagnostic and prognostic information.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.11
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• pp.4603-4608
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• 2015

Background: To determine the potential value of serum tumor markers in predicting pCR (pathological complete response) during neoadjuvant chemotherapy. Materials and Methods: We retrospectively monitored the pro-, mid-, and post-neoadjuvant treatment serum tumor marker concentrations in patients with locally advanced breast cancer (stage II-III) who accepted pre-surgical chemotherapy or chemotherapy in combination with targeted therapy at Fudan University Shanghai Cancer Center between September 2011 and January 2014 and investigated the association of serum tumor marker levels with therapeutic effect. Core needle biopsy samples were assessed using immunohistochemistry (IHC) prior to neoadjuvant treatment to determine hormone receptor, human epidermal growth factor receptor 2(HER2), and proliferation index Ki67 values. In our study, therapeutic response was evaluated by pCR, defined as the disappearance of all invasive cancer cells from excised tissue (including primary lesion and axillary lymph nodes) after completion of chemotherapy. Analysis of variance of repeated measures and receiver operating characteristic (ROC) curves were employed for statistical analysis of the data. Results: A total of 348 patients were recruited in our study after excluding patients with incomplete clinical information. Of these, 106 patients were observed to have acquired pCR status after treatment completion, accounting for approximately 30.5% of study individuals. In addition, 147patients were determined to be Her-2 positive, among whom the pCR rate was 45.6% (69 patients). General linear model analysis (repeated measures analysis of variance) showed that the concentration of cancer antigen (CA) 15-3 increased after neoadjuvant chemotherapy in both pCR and non-pCR groups, and that there were significant differences between the two groups (P=0.008). The areas under the ROC curves (AUCs) of pre-, mid-, and post-treatment CA15-3 concentrations demonstrated low-level predictive value (AUC=0.594, 0.644, 0.621, respectively). No significant differences in carcinoembryonic antigen (CEA) or CA12-5 serum levels were observed between the pCR and non-pCR groups (P=0.196 and 0.693, respectively). No efficient AUC of CEA or CA12-5 concentrations were observed to predict patient response toward neoadjuvant treatment (both less than 0.7), nor were differences between the two groups observed at different time points. We then analyzed the Her-2 positive subset of our cohort. Significant differences in CEA concentrations were identified between the pCR and non-pCR groups (P=0.039), but not in CA15-3 or CA12-5 levels (p=0.092 and 0.89, respectively). None of the ROC curves showed underlying prognostic value, as the AUCs of these three markers were less than 0.7. The ROC-AUCs for the CA12-5 concentrations of inter-and post-neoadjuvant chemotherapy in the estrogen receptor negative HER2 positive subgroup were 0.735 and 0.767, respectively. However, the specificity and sensitivity values were at odds with each other which meant that improving either the sensitivity or specificity would impair the efficiency of the other. Conclusions: Serum tumor markers CA15-3, CA12-5, and CEA might have little clinical significance in predicting neoadjuvant treatment response in locally advanced breast cancer.

• Radiation Oncology Journal
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• v.37 no.2
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• pp.91-100
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• 2019

Purpose: Internal mammary lymph node (IMN) involvement is associated with poor prognosis in breast cancer. This study investigated the treatment outcomes of initial clinically IMN-positive breast cancer patients who received adjuvant radiotherapy (RT), including IMN irradiation, following primary breast surgery. Materials and Methods: We retrospectively reviewed data of 95 breast cancer patients with clinically detected IMNs at diagnosis treated with surgery and RT between June 2009 and December 2015. Patients received adjuvant RT to the whole breast/chest wall and regional lymph node (axillary, internal mammary, and supraclavicular) areas. Twelve patients received an additional boost to the IMN area. Results: The median follow-up was 43.2 months (range, 4.5 to 100.5 months). Among 77 patients who received neoadjuvant chemotherapy, 52 (67.5%) showed IMN normalization and 19 (24.6%) showed a partial response to IMN. There were 3 and 24 cases of IMN failure and any recurrence, respectively. The 5-year IMN failure-free survival, disease-free survival (DFS), and overall survival (OS) were 96%, 70%, and 84%, respectively. IMN failure-free survival was significantly affected by resection margin status (97.7% if negative, 87.5% for close or positive margins; p = 0.009). All three patients with IMN failure had initial IMN size ≥1 cm and did not receive IMN boost irradiation. The median age of the three patients was 31 years, and all had hormone receptor-negative tumors. Conclusion: RT provides excellent IMN control without the support of IMN surgery. Intensity-modulated radiotherapy, including IMN boost for breast cancer patients, is a safe and effective technique for regional lymph node irradiation.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3595-3600
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• 2016

Background: To investigate the association between preoperative pathological Ki-67 labeling index and serum tumor marker cancer antigen 15-3 (CA 15-3) with clinic-pathological parameters and treatment outcomes in early breast cancer. Materials and Methods: A retrospective study at 4 cancer centers in Saudi Arabia and Egypt was performed. Data were collected for female patients diagnosed with unilateral early breast cancer between March 2010 and October 2013. Cases treated with neoadjuvant chemotherapy (NACT) followed by surgery and radiotherapy were included. NACT included 6-8 cycles of anthracycline and taxane based regimens. Trastuzumab and hormonal treatments were added according to HER2 and hormone receptor status. Baseline serum CA15.3 and pathological Ki67 levels were evaluated and correlated with disease free survival (DFS) and overall survival (OS). Results: A total of 280 pts was included. The median age was 49 years (38-66 y) and median overall survival was 35 (20-38) months (mo). Estrogen receptors (ER), progesterone receptors (PR) and HER 2 receptors were positive in 233 (83.2%), 198 (70%) and 65 cases (23.2%), respectively. High preoperative Ki67 and CA15.3 were noted in 177 (63.2%) and 131 (46.8%). A total of 45 (16%) patients had distal or local recurrence and 24 (8.6%) died of their disease. Most of the relapsed cases had high preoperative Ki-67 (n=41, 91%) and CA15.3 (n=28, 62%) values. All of the patients who died had a high Ki-67 but CA15.3 was high in 9 (37%) only. Mean DFS/OS in patients with high preoperative Ki-67 was 32 months /32 months as compared to 37 months/35 months in those with normal Ki-67 (p<0.001). Correlation of preoperative CA15.3 and survival was statistically not significant. Conclusions:Preoperative Ki-67 can be a predictive and prognostic marker. Higher levels are associated with poor DFS and OS in patients with early BC.