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1.
Cancer Sci ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31724785

RESUMO

Analysis of anti-cancer immunity aids in assessing the prognosis of patients with breast cancer. From 250 operated breast cancers, we focused on serum levels of C-C motif chemokine ligand 5 (CCL5), which is involved in cancer immune reactions. Serum levels of CCL5 were measured using a cytometric bead-based immunoassay kit and CCL5 expression in cancer cells was determined using immunohistochemical staining. In addition, mRNA in cancer and stromal cells was analyzed by microdissection and comparison with the public dataset. Disease-free survival (DFS) of patients with high CCL5 levels (cut-off, 13.87 ng/mL; n = 192) was significantly better than those with low CCL5 levels (n = 58; hazard ratio, 0.20; 95% confidence interval, 0.10-0.39; p < 0.0001). An improved overall survival was observed in patients with high CCL5 levels compared to those with low CCL5 levels (p = 0.024). On the contrary, high immunohistochemical expression of CCL5 in cancer cells was significantly associated with decreased DFS. Since serum CCL5 levels did not correlate with CCL5 expression in cancer cells and the relative expression of mRNA CCL5 was elevated in stromal cells in relation to cancer cells, serum CCL5 may be derived not from cancer cells, but from stromal cells. CCL5 expression in serum but not in cancer cells may contribute to improved patient prognosis mediating through not only immune reaction, but through other mechanisms. Determination of circulating CCL5 levels may be useful for predicting patient prognosis.

2.
Anticancer Res ; 39(10): 5653-5662, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570463

RESUMO

BACKGROUND/AIM: Factors influencing fulvestrant efficacy may be useful in selecting the optimal treatment regimen for postmenopausal Japanese women with metastatic/recurrent HR-positive, HER2-negative breast cancer. PATIENTS AND METHODS: We retrospectively evaluated progression-free and overall survival (PFS and OS) in 100 fulvestrant-treated patients according to metastatic site. RESULTS: Median PFS was significantly better in patients with non-visceral (bone and regional metastases; 22.8 months) vs. visceral metastasis (lung, liver, and other organs; 8.2 months; p=0.024), although median OS did not differ (p=0.922). Median PFS in patients with lung metastasis (20.8 months) and non-visceral metastasis (22.8 months) were comparable; patients with liver metastasis (6.1 months) and other organ metastases (3.7 months) had worse prognoses. CONCLUSION: Patients with non-visceral metastases had a better prognosis than those with visceral metastases. Fulvestrant induced a longer PFS in patients with non-visceral metastasis, and also in those with lung metastasis without liver or other organ involvement.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fulvestranto/uso terapêutico , Metástase Neoplásica/prevenção & controle , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Intervalo Livre de Progressão , Receptor ErbB-2/genética , Receptores de Superfície Celular/genética , Estudos Retrospectivos
3.
Anticancer Res ; 39(9): 5009-5018, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519608

RESUMO

BACKGROUND/AIM: Interleukin (IL)-18, which belongs to the IL-1 superfamily of cytokines, is a known interferon-gamma (IFN-γ)-inducing factor. Since IFN-γ plays an essential role in anticancer immunity mediated through cytotoxic T cells, IL-18 may also contribute to the function of immunosurveillance. The aim of the study was to examine the association of IL-18 with the outcomes of patients with breast cancer. PATIENTS AND METHODS: Serum IL-18 levels were determined at baseline in 270 patients operated for breast cancer, and the relapse-free survival (RFS) was compared between IL-18-high and -low groups. The relationships between IL-18 and tumor-infiltrating lymphocytes (TILs) or the neutrophil-to-lymphocyte ratio (NLR) were also investigated. RESULTS: The RFS of patients was significantly better in the IL-18-low group than in the IL-18-high group (p=0.032). According to the multivariate analysis, IL-18 was a significant and independent predictive factor for RFS (hazard ratio(HR)=0.336; 95% confidence interval(CI)=0.147-0.727; p=0.0053). No association was observed between the IL-18 levels and TILs or NLRs. CONCLUSION: IL-18 levels may be useful for predicting the prognosis of patients who have received surgical treatment for breast cancer.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Interleucina-18/sangue , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Citocinas/sangue , Citocinas/metabolismo , Feminino , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Neutrófilos/imunologia , Neutrófilos/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Valores de Referência , Estudos Retrospectivos , Carga Tumoral
4.
Breast Cancer ; 26(6): 738-747, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31098866

RESUMO

BACKGROUND: The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been established in breast cancers with estrogen receptor (ER)-negative and human epithelial growth factor receptor 2 (HER2)-negative or HER2-positive subtypes; however, its utility concerning the ER + /HER2 - subtype remains unclear. METHODS: We evaluated the prognostic value of TILs by analyzing 717 invasive breast cancer operation cases. TILs were classified into three groups based on the proportion of area within the tumor: low ( < 10%), intermediate (10-50%), and high ( > 50%). Disease-free survival (DFS) and overall survival (OS) were calculated according to TIL levels. RESULTS: Although there was no significant association between TIL levels and DFS or OS in all patients, high TILs were significantly associated with favorable DFS in Ki67-high (n = 238, p = 0.035) but not in Ki67-low (n = 470, p = 0.46) breast cancers. Multivariable analysis showed that high TILs were a significant and independent factor for DFS (HR 0.34; 95% CI 0.10-0.87; p = 0.023) among the Ki67-high group. In the ER + /HER2 - subtype, high-TILs showed favorable DFS in the Ki67-high group, although this was not statistically significant (p = 0.48); in contrast, unfavorable DFS was observed in the Ki67-low group (p = 0.027). CONCLUSIONS: In Ki67-high breast cancers, high TILs were associated with favorable DFS, irrespective of subtype, but increasing TIL levels correlated with worse DFS in the Ki67-low group with the ER + /HER2 - subtype. These results highlight variation in TIL prognostic significance between Ki67-high and -low breast cancers, particularly for the ER + /HER2 - subtype.

5.
Ann Surg Oncol ; 26(7): 2175-2183, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30941655

RESUMO

BACKGROUND: The usefulness of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography for evaluating the treatment efficacy of breast cancers is well-established; however, the predictive values of parameters such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) remain unknown. METHODS: This study examined 199 breast cancers treated with primary systemic chemotherapy (PSC) followed by operation, and determined the values of maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), mean SUV (SUVmean), MTV, and TLG at baseline. Among these cases, data on early changes in these metabolic parameters in 70 breast cancers were also assessed. RESULTS: A pathological complete response (pCR) was achieved in 64 breast cancers. Breast cancers with low MTV at baseline had a significantly higher pCR rate than breast cancers with high MTV (47.9% vs. 23.4%; p = 0.0005). High reduction rates (∆) of SUVmax (p = 0.0001), SUVpeak (p = 0.0001), and SUVmean (p < 0.0001) resulted in an increased pCR compared with those for low ∆. The pCR rate was highest for the combination of low MTV and high ∆SUVmean (86.7%), and lowest for high MTV and low ∆SUVmean (15.4%); the remaining combinations were intermediate (58.6%; p < 0.0001). The combination of low MTV at baseline and high ∆SUVmean was a significant and independent predictor for pCR (odds ratio 28.63; 95% confidence interval 1.94-422.42; p = 0.0146) in multivariable analysis. CONCLUSIONS: Low levels of MTV at baseline and a high reduction of SUVmean after PSC was significantly associated with pCR. These findings suggest the usefulness of these metabolic parameters for predicting the treatment efficacy of breast cancers.

6.
Sci Rep ; 9(1): 1811, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755651

RESUMO

The efficacy of trastuzumab emtansine (T-DM1) is prolonged for some patients; however, the predictive factors remain unknown. We focused on a peripheral blood biomarker, the neutrophil-to-lymphocyte ratio (NLR), regarding T-DM1 treatment efficacy. Fifty-three advanced or metastatic breast cancers treated with T-DM1 were retrospectively recruited from three institutes. The NLR in the peripheral blood was measured at baseline and after one cycle. The cutoff value of the NLR was set at median value 2.56. The progression-free survival (PFS) of patients with NLR-low at baseline (n = 26; median, not reached) was significantly better than that of patients with NLR-high (n = 27; median, 4.13 months; hazard ratio [HR], 0.226; 95% confidence interval [CI], 0.112-0.493; p = 0.0001). Longer overall survival was significantly associated with a low NLR (HR, 0.384; 95% CI, 0.170-0.910; p = 0.0296). In the subgroup analysis, patients with NLR-low consistently had longer PFS compared to those with NLR-high irrespective of the number of prior chemotherapy regimens, prior trastuzumab, visceral metastasis, estrogen receptor status, and human epidermal growth factor receptor 2 (HER2) score. Although detailed mechanisms remain unknown, treatment efficacy of T-DM1 may be partly mediated by activation of the immune system. Low baseline NLR appears to be beneficial for treatment with T-DM1 in HER2-positive breast cancers.

7.
J Surg Oncol ; 118(1): 228-237, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29936704

RESUMO

BACKGROUND AND OBJECTIVES: To identify surrogate markers for prognosis of breast cancer patients with non-pathological complete response (non-pCR) to neoadjuvant chemotherapy (NAC), our investigation focused on the serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA15-3) as well as clinicopathological factors both before and after NAC. METHODS: A total of 185 breast cancer patients treated with NAC were recruited. Serum carcinoembryonic antigen and CA15-3 were measured at baseline and at completion of NAC. RESULTS: Among the non-pCR cancers (n = 142), the disease-free survival (DFS) of patients with CA15-3-low at baseline (3-year DFS: 0.908, n = 73) was significantly better than of those with CA15-3-high (3-year DFS: 0.681, n = 69, P = .0134). Multivariable analysis demonstrated that baseline CA15-3 levels (hazard ratio: 3.31, 95% confidence interval: 1.28-10.23; P = .0122) and residual invasive size (hazard ratio: 4.47, 1.26-28.39; P = .0171) were significant independent factors for DFS. The combination of these factors proved to be an accurate predictor for DFS regardless of breast cancer subtypes. CONCLUSIONS: The combination of residual invasive size and serum CA15-3 levels at baseline seems to be a significant and independent surrogate marker of poor outcome for patients with non-pCR. These findings suggest that these markers may be useful for identifying patients with inferior prognosis and candidates for additional adjuvant treatments.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Antígeno Carcinoembrionário/sangue , Mucina-1/sangue , Antraciclinas/administração & dosagem , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Antígeno Ki-67/biossíntese , Terapia Neoadjuvante , Cuidados Pré-Operatórios/métodos , Prognóstico , Taxoides/administração & dosagem , Trastuzumab/administração & dosagem
8.
Clin Breast Cancer ; 18(5): 400-409, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29605174

RESUMO

INTRODUCTION: Although eribulin and nab-paclitaxel are chemotherapy agents widely used for locally advanced or metastatic breast cancer (MBC), their predictive factors remain unknown. Because the absolute neutrophil-to-lymphocyte ratio (NLR) is a significant prognostic factor for early-stage breast cancer, we investigated its usefulness in terms of the eribulin or nab-paclitaxel treatment efficacy for MBC. PATIENTS AND METHODS: A total of 85 patients with MBC treated with eribulin (n = 59) or nab-paclitaxel (n = 26) were recruited. NLR values were collected at baseline, after 1 cycle, after 2 cycles, and at the end of treatment. The NLR cutoff value was set at 3. RESULTS: The progression-free survival (PFS) of patients with an NLR < 3 at baseline (median, 242 days; n = 24) was significantly better than that of patients with an NLR of ≥ 3 (median, 98 days; n = 35; hazard ratio, 0.37, 95% confidence interval, 0.18-0.71; P = .0032). Similarly, the overall survival was marginally significantly better in patients with an NLR < 3 who were treated with eribulin (P = .058). However, the NLR was not significantly associated with PFS or overall survival for patients treated with nab-paclitaxel. No significant association was found between the NLR during treatment and PFS in the eribulin group. The significance of the NLR for the efficacy of eribulin was consistent, irrespective of estrogen receptor status, previous anthracycline or endocrine use, and the number of previous chemotherapy regimens. CONCLUSION: A low NLR at baseline was significantly associated with improved PFS in patients treated with eribulin but not in those treated with nab-paclitaxel. Therefore, the baseline NLR might be clinically useful for selecting patients who would benefit from eribulin.

9.
World J Surg Oncol ; 16(1): 26, 2018 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-29433529

RESUMO

BACKGROUND: Although the prognosis for operable breast cancers is reportedly worse if serum carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels are above normal, the usefulness of this prognosis is limited due to the low sensitivity and specificity; in addition, the optimal cutoff levels remain unknown. METHODS: A total of 1076 patients who were operated for breast cancers (test set = 608, validation set = 468) without evidence of metastasis were recruited, and their baseline and postoperative serum CEA and CA15-3 levels were analyzed. The optimal cutoff values of CEA and CA15-3 for disease-free survival (DFS) were 3.2 ng/mL and 13.3 U/mL, respectively, based on receiver operating characteristic curve and area under the curve analyses. RESULTS: The DFS of patients with high CEA levels (CEA-high: n = 191, 5-year DFS 70.6%) was significantly worse (p < 0.0001) than that of CEA-low patients (n = 885, 5-year DFS 87.2%). There was a significant difference in DFS (p < 0.0001) between CA15-3-high and CA15-3-low patients (n = 314 and n = 762, respectively; 5-year DFS 71.8 vs. 89.3%). Significant associations between DFS and CA15-3 levels were observed irrespective of the subtypes. Multivariable analysis indicated that tumor size, lymph node metastasis, tumor grade, and CEA (p = 0.0474) and CA15-3 (p < 0.0001) levels were independent prognostic factors (hazard ratio [HR] 1.520, 95% confidence interval [CI] 1.005-2.245 for CEA; HR 2.088, 95% CI 1.457-2.901 for CA15-3). CONCLUSIONS: These findings suggest that CEA and CA15-3 levels might be useful for predicting the prognosis of patients with operable early breast cancer irrespective of the subtype. Serum levels at baseline may reflect tumor characteristics for metastatic potential even when these levels are within the normal ranges.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Antígeno Carcinoembrionário/sangue , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/secundário , Mucina-1/sangue , Cuidados Pré-Operatórios , Neoplasias da Mama/sangue , Neoplasias da Mama/classificação , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/classificação , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/sangue , Carcinoma Lobular/classificação , Carcinoma Lobular/cirurgia , Feminino , Seguimentos , Humanos , Metástase Linfática , Prognóstico , Curva ROC , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida
10.
Breast Cancer Res Treat ; 168(1): 135-145, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29168063

RESUMO

PURPOSE: The therapeutic effect of systemic treatment for breast cancer (BC) generally depends on its intrinsic subtypes. In addition, tumor infiltrating lymphocytes (TILs) are considered to be an independent factor for tumor shrinkage and disease prognosis. High TILs at baseline or after primary systemic chemotherapy are reported to be associated with better survival in triple-negative or human epithelial growth factor receptor 2 (HER2)-positive BCs. However, the prognostic value of TILs in estrogen receptor (ER)-positive and HER2-negative (ER+/HER2-) BC is still controversial. METHODS: We assessed TIL score (low, intermediate, and high) before and after primary systemic chemotherapy in every subtype of BC, and compared the clinical outcomes. Biopsy specimens of 47 triple-negative, 58 HER2+ and 91 ER+/HER2- BCs were used to assess TILs before treatment. To assess TILs after treatment, we examined residual invasive carcinoma in surgically resected samples of 28 triple-negative, 30 HER2+ and 80 ER+/HER2- BCs. RESULTS: A high TIL score in triple-negative BC before treatment resulted in a significantly higher proportion of pathological complete response (pCR). In contrast, ER+/HER2- BC exhibited fewer instances of pCR than other subtypes. Although not statistically significant, ER+/HER2- cases with a high TIL score also tended to achieve pCR (p = 0.088). Moreover, we revealed that low TIL BCs after chemotherapy, but not at baseline, had significantly better relapse-free survival in ER+/HER2- BC (p = 0.034). CONCLUSION: Pathological examination of TILs after treatment may be a surrogate marker for prognosis in ER+/HER2- BC.

11.
Breast ; 30: 5-12, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27569020

RESUMO

Adjuvant treatments for operable breast cancers are determined according to subtypes defined based on estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status. The ER+/HER2- subtype can be divided into luminal A and luminal B usually by Ki67 expression levels. Although tumor size, lymph node metastasis and tumor grade have been widely accepted in daily clinical practice, the identification of further prognostic indicators especially in the ER+/HER2- subtype is warranted. A total of 387 operated breast cancers for which maximum standardized uptake value (SUVmax) on the 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) were available at baseline were retrospectively analyzed. The optimal cutoff value of SUVmax for relapse-free survival (RFS) was determined to be 3.585 by means of the receiver operating characteristics curve with an area under the curve of 0.6795 (95% CI: 0.5972 to 0.7618, p = 0.0006, sensitivity: 78.8%, specificity: 57.1%). The RFS of patients with SUVmax-high (n = 178) was significantly (p = 0.0003) worse compared with those with SUVmax-low (n = 209). This significant association was prominently recognized in the ER+/HER2- subtype. By multivariable analysis, SUVmax (hazard ratio: 3.83, 95% confidence interval: 1.28-11.51, p = 0.017), tumor size (4.22, 1.39-12.82, p = 0.011) and lymph node metastasis (4.44, 1.81-10.87, p = 0.0012) were significant and independent prognostic factors for RFS. The ER+/HER2- subtype demonstrated consistently worse RFS in the SUVmax-high patients both in the luminal A (p = 0.037) and luminal B (p = 0.047) subtypes. Combination of Ki67 and SUVmax appears to be useful for selecting patients who have inferior prognosis and need further adjuvant treatment of the ER+/HER2- subtype.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Lobular/diagnóstico por imagem , Recidiva Local de Neoplasia/epidemiologia , Idoso , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Lobular/terapia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Fluordesoxiglucose F18 , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Antígeno Ki-67/metabolismo , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Período Pré-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Compostos Radiofarmacêuticos , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Tamoxifeno/uso terapêutico , Carga Tumoral
12.
Nihon Geka Gakkai Zasshi ; 117(6): 516-22, 2016 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-30173476

RESUMO

The estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor type 2 (HER2), and Ki67 are biomarkers for early breast cancer. These markers are usually examined by immunohistochemistry (IHC), and positive is defined as more than 1% for ER or PgR, and a score of 3+ or 2+ with in situ hybridization positivity for HER2. Indications for endocrine therapy and anti-HER2 therapy are determined according to these cutoff values. These markers are also clinically useful for classifying IHC-based subtypes. Although a cutoff value for Ki67 has yet to be determined, ER-positive/HER2-negative breast cancer is further divided into luminal A or B using Ki67 and PgR expression levels. In addition, multigene assays are clinically available to assess the indications for chemotherapy. Since a discordance in biomarkers between primary and metastatic cancer occurs in some cases, rebiopsy is recommended. It is also important to take measures to ensure the accuracy of IHC procedures because the results can easily be affected by a number of factors. The appropriate treatment should be selected by taking the clinical significance of these biomarkers into consideration.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/terapia , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica , Recidiva , Resultado do Tratamento
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