Utility of human epidermal growth factor 2 heterogeneity as a prognostic factor in triple-negative breast cancer.

In some cases of human epidermal growth factor 2 (HER2)-negative breast cancer, including triple-negative breast cancer, HER2 expression is sporadically and strongly upregulated, a condition known as HER2 heterogeneity. We investigated the clinicopathological features of patients with HER2 heterogeneity in triple-negative breast cancers treated with neoadjuvant chemotherapy. Thirty-nine patients with triple-negative breast cancer who had undergone preoperative chemotherapy participated in this study. To assess for HER2 heterogeneity, we used dual in situ hybridization slides. We evaluated the association between HER2 heterogeneity and clinicopathological factors such as rates of pathologic complete response (pCR) and of recurrence-free survival. Of the 39 patients, 15 (38.5%) had cancers with HER2 heterogeneity. The pCR rates were 13.3% among patients with HER2 heterogeneity and 20.8% among those with HER2 nonheterogeneity, but the difference was not significant. The recurrence-free survival rate was significantly lower in patients with HER2 heterogeneity than in those without (P = 0.025). HER2 heterogeneity is a significant predictor of poor prognosis in patients with triple-negative breast cancer treated with neoadjuvant chemotherapy.

Oncological safety of immediate breast reconstruction with skin- or nipple-sparing mastectomy: the value of tumor-to-dermis distance measured by preoperative ultrasonography.

BACKGROUND: Immediate breast reconstruction with skin-sparing (SSM) or nipple-sparing mastectomy (NSM) has become a common procedure. In this study, we evaluated the distance between breast tumor and skin in a series of patients undergoing IBR as it relates to oncologic safety, namely, the incidence of recurrence. METHODS: The distance of the tumor to the dermis, rather than the outer layer of skin, was the key parameter of our preoperative ultrasound measurements. Our data set comprised the cases of 171 patients and 181 breasts with breast cancer that had undergone two-stage breast reconstruction by expander. The median age of the patients was 47 years (25-75 years). The overall median follow-up period was 47.1 months (8.8-125.3 months). Eighty-five breasts underwent IBR with SSM/NSM; the others underwent conventional mastectomy. RESULTS: Among the total of 181 reconstructed breast mounds, the locoregional recurrence rate was 1.1% (2 breasts) with no cases of skin flap recurrence or skin flap necrosis. The tumor-to-dermis distance of cases with skin preservation (NSM/SSM) was significantly less than that of cases with conventional mastectomy (3.8 ± 2.7 mm vs 5.2 ± 2.4 mm). In cases with invasive carcinoma, all cases whose tumor-to-dermis distance was less than 2 mm underwent resection of the skin immediately overlying the tumor. CONCLUSIONS: Our results suggested that a 2-mm distance between the dermis and tumor on ultrasound evaluation is sufficient for the use of this tissue as a skin flap in SSM/NSM procedures. Our study indicated that immediate breast reconstruction with SSM/NSM can be an oncologically safe surgical option for breast cancer. However, we recommend that resection of the skin overlying the tumor be performed in cases with invasive breast cancer in which the tumor-to-dermis distance is less than 2 mm. TRIAL REGISTRATION: Patients in this study were retrospectively registered. This study design was approved by our Clinical Ethics Committee (No 1297) ( http://ciru.dept.showa.gunma-u.ac.jp/guidance/storage-sample/list.html ).

FDG uptake reflects breast cancer immunological features: the PD-L1 expression and degree of TILs in primary breast cancer.

BACKGROUND: High F18-fluorodeoxyglucose (FDG) uptake has been reported to be a predictor of poor prognosis in patients with breast cancer. We investigated the relationship between FDG uptake and immunological factors, including the data of programmed cell death-ligand 1 (PD-L1), CD8, and tumor-infiltrating lymphocytes (TILs). METHODS: Breast cancer tissues of 97 patients who underwent surgery without preoperative therapy were examined. The grade of stromal TILs was immunohistochemically evaluated using the criteria of the International TILs Working Group in breast cancer. PD-L1 positivity and CD8 positivity were immunohistochemically evaluated. The FDG uptakes were evaluated based on the standardized uptake value max (SUVmax). The relationships between SUVmax and TIL grade and expression of PD-L1 and CD8 were investigated. RESULTS: Among the 97 patients, 41 (42.3%) had a high SUVmax in their primary tumor, based on the SUVmax cut-off value 3 yielded by receiver operating characteristic curves. PD-L1 was positive in 17 patients (17.5%). Our analyses revealed that large tumor size, high nuclear grade, high degree of TILs and positive expression of PD-L1 were significantly associated with high SUVmax in the primary tumor. There were significant associations between SUVmax and the degree of TILs (r = 0.428, p < 0.001) and between SUVmax and the PD-L1 positivity (r = 0.413, p < 0.001). All cases with a high degree of TILs showed high CD8 expression. CONCLUSION: Our results indicate that the FDG uptake may be predictive of immunological features including TILs and PD-L1 expression in breast cancer patients. Additional research is necessary to further evaluate FDG-PET as a biomarker of immune checkpoint therapy in breast cancer.

Phase II study of sequential S-1 and cyclophosphamide therapy in patients with metastatic breast cancer.

BACKGROUND: S-1 and cyclophosphamide (CPA) can be given orally, and their combination may have great potential for treating metastatic breast cancer (MBC). A phase I study of sequential S-1 and CPA therapy was conducted in patients with MBC; the recommended doses that were determined for this regimen were 80 mg/m2/day for S-1 and 100 mg/m2/day for CPA. We then conducted a phase II study of this oral S-1 and CPA regimen. METHODS: This was a single-arm, open-label, single-center prospective phase II study to evaluate the efficacy of a sequential S-1 and CPA regimen for MBC. S-1 was administered orally 2×/day for 14 consecutive days, and then CPA was administered orally 2×/day for 14 consecutive days in a repeating 4-week cycle (S-1 for 2 weeks, CPA for 2 weeks). The primary endpoint was the overall response rate (ORR). Secondary endpoints included the overall survival (OS), progression-free survival (PFS), clinical benefit rate (CBR) and safety. RESULTS: Thirty-six patients were enrolled in this study. The overall response was complete response in 0 (0%), partial response in 12 (33.3%), stable disease in 12 (33.3%), and progressive disease in 11 (30.1%) patients. The ORR was 33.3% (12/36). The CBR was 66.7% (24/36). The median PFS was 9.5 months (95%CI: 7.8-12.6 months). The median OS was 20.2 months (95%CI: 15.0-25.4 months) Grade 3/4 adverse events included leukopenia in seven patients (19.4%). Dose reductions because of adverse events occurred in 12 patients (33.3%). There was no treatment-related mortality. CONCLUSION: The combination of sequential therapy with S-1 and CPA was tolerable and had efficacy with good disease control. Sequential therapy with S-1 and CPA may be a feasible new treatment option for patients with MBC; however, further study is warranted to explore the efficacy of this therapy. TRIAL REGISTRATION: JRCT, JRCTs031180296 . Registered 2 December 2019 - Retrospectively registered.

Efficacy of Mirogabalin for Taxane-associated Chemotherapy-induced Peripheral Neuropathy in Perioperative Chemotherapy for Early Breast Cancer.

BACKGROUND/AIM: Treatment with taxanes can result in chemotherapy-induced peripheral neuropathy (CIPN). We investigated the efficacy and safety of mirogabalin for the treatment of CIPN in patients who had been administered perioperative chemotherapy including taxane-based agents for breast cancer. PATIENTS AND METHODS: We retrospectively analyzed the case of 43 patients with early breast cancer who received a taxane as perioperative chemotherapy and were administered mirogabalin at the diagnosis of CIPN. RESULTS: Thirty-six patients (83.7%) had grade 1 CIPN and the other seven patients (16.3%) had grade 2 CIPN. The median mirogabalin dose was 10 mg (5-30 mg). CIPN improved from grade 1 to 0 in 12 patients (27.9%) and from grade 2 to 1 in one patient (2.3%); 13 (30.2%) patients thus had an objective therapeutic response. There were no cases in which chemotherapy was reduced or discontinued due to CIPN. Adverse events were evaluated by Common Terminology Criteria for Adverse Events and included five cases of dizziness (11.7%), three of somnolence (7.0%), and two of nausea (4.7%), all of which were grade ≤2. There were no cases of serious (grade ≥3) adverse effects. CONCLUSION: Mirogabalin may be effective and safe for treating CIPN of patients who receive a taxane in a perioperative breast cancer setting.

Association Between High Expression of Phosphorylated-STMN1 and Mesenchymal Marker Expression and Cancer Stemness in Breast Cancer.

BACKGROUND/AIM: In patients with breast cancer, the expression of stathmin1 (STMN1) has been significantly related to a poor prognosis, cancer aggressiveness, and expression of cancer stem cell markers. The STMN1 protein is closely regulated by phosphorylation in four sites. However, few studies have investigated the relationship between the expression of phosphorylated STMN1 (pSTMN1) and clinicopathological findings, including tumor-aggressive biomarkers, in patients with breast cancer. MATERIALS AND METHODS: The expression levels of four pSTMN1 (Ser16, Ser25, Ser38, and Ser63) were immunohistochemically analyzed in 213 breast cancer cases. The clinicopathological factors evaluated included epithelial-mesenchymal transition (EMT) markers and cancer stem cell markers. RESULTS: The cytoplasmic expression of pSTMN1 (Ser16, Ser25, Ser38, and Ser63) in normal breast tissues was low. The positive expression ratios of Ser25 (54.5%) and Ser38 (39.0%) were high compared to those of Ser16 (25.8%) and Ser63 (23.9%). The overexpression of pSTMN1 (Ser38) was associated with tumor-aggressive characteristics, such as triple-negative breast cancer (TNBC) phenotypes, high mesenchymal marker, and expression of cancer stem cell markers. CONCLUSION: STMN1 phosphorylation might be associated with clinicopathological factors, breast cancer subtypes, and expression of mesenchymal markers and breast cancer stem cell markers through the regulation of STMN1 function. Ser38 phosphorylation of STMN1 may be a novel biomarker for high-grade TNBC associated with mesenchymal marker expression and cancer stemness.

Characteristics of Patients With Metastatic Breast Cancer Who Survived more than 10 Years.

BACKGROUND/AIM: Despite advances in the treatment of breast cancer, metastatic breast cancer (MBC) remains difficult to cure, and few MBC patients survive 10 years after receiving a breast cancer metastasis diagnosis. We collected the cases of patients with MBC who survived >10 years post-metastasis diagnosis and assessed the patients' characteristics. PATIENTS AND METHODS: We retrospectively analyzed the cases of 245 consecutive patients diagnosed with MBC between January 2005 and December 2012 at our institution. Among them, 167 patients with confirmed survival of >10 years (i.e., long-term survival) or confirmed death at ≤10 years post-metastasis diagnosis were enrolled. RESULTS: There were 22 patients with MBC who survived >10 years. Regarding the cancer subtypes, 11 patients (50%) with long-term survival were HER2-positive. Seven of the 11 patients with HER2-positive MBC have been without recurrence although anti-HER2 therapy was discontinued. Triple-negative breast cancer (TNBC) was most common in the patients who survived ≤5 years but was not present in the >10-year survival group. In the HER2-negative cases, more cases in the long-term survival group were treated with local therapy (34.4% in the <5-year survival group, 43.8% in the 5-10-year group, and 72.7% in the >10-year group). CONCLUSION: MBC patients who survive >10 years after being diagnosed with metastasis are more likely to be HER2-positive and treated with local therapy. This suggests the efficacy of anti-HER2 therapy, and, conversely, clarifies unmet needs in TNBC and luminal-type MBC. The usefulness of local therapy was also supported by our findings.

The Impact of Being Underweight on the Prognosis of Older Patients With Early Breast Cancer.

Background/Aim: The number of older patients with breast cancer has been increasing and a major challenge is to develop optimal treatment strategies for these patients, who often have comorbidities. Obesity is reportedly a poor prognostic factor in breast cancer, however there is limited research on underweight patients. Clarifying the relationship between physique and prognosis may contribute to the establishment of optimal treatment strategies for older patients with breast cancer. Patients and Methods: This retrospective study examined clinicopathological data from a multicenter collaborative database on 1,076 patients aged 70 years or older who had undergone curative surgery. According to the body mass index (BMI), patient physique was defined as underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2) or obese (≥25 kg/m2). In this study, we explored the relationship between the physique of patients with breast cancer and outcomes. Results: Underweight patients had a significantly lower rate of chemotherapy administration (p=0.017) and a higher rate of presence of other cancer (p=0.022). During the observation period (median of 75.2 months), 133 patients (12%) developed recurrent disease and 131 patients (12%) died. Age, BMI, tumor size, progesterone receptor and the presence of other cancer were independent factors relating to overall survival (p<0.001, p=0.027, p=0.002, p=0.008 and p=0.005, respectively). Patients with a low BMI had a significantly shorter overall survival, but there was no association with disease-free survival in this subset of patients. Conclusion: Overall survival was shorter in underweight older patients with breast cancer. Our data indicate that being underweight should be considered both in treatment decisions and in future studies of outcomes for older patients with breast cancer.

Is adjuvant chemotherapy necessary in older patients with breast cancer?

BACKGROUND: Due to the lack of clinical trials on the efficacy of chemotherapy in older patients, an optimal treatment strategy has not been developed. We investigated whether adjuvant chemotherapy could improve the survival of older patients with breast cancer in Japan. METHODS: We retrospectively analyzed data of patients with breast cancer aged ≥ 70 years who underwent breast cancer surgery in eight hospitals between 2008 and 2013. Clinical treatment and follow-up data were obtained from the patients' medical electric records. RESULTS: A total of 1095 patients were enrolled, of which 905 were included in the initial non-matched analysis. The median age and follow-up period were 75 (range 70-93) and 6.3 years, respectively. Of these patients, 127 (14%) received adjuvant chemotherapy (Chemo group) while the remaining 778 (86%) did not (Control group). The Chemo group was younger (mean age in years 73 vs 76; P < 0.0001), had a larger pathological tumor size (mean mm 25.9 vs 19.9; P < 0.0001), and more metastatic axillary lymph nodes (mean numbers 2.7 vs 0.7; P < 0.0001) than the Control group. The disease-free survival (DFS) and overall survival (OS) did not differ significantly between the two groups (P = 0.783 and P = 0.558). After matched analyses, DFS was found to be significantly prolonged with adjuvant chemotherapy (P = 0.037); however, OS difference in the matched cohort was not statistically significant (P = 0.333). CONCLUSION: The results showed that adjuvant chemotherapy was associated with a reduced risk of recurrence, but survival benefits were limited.

Prospective observational study of chemotherapy-induced alopecia after sequential FEC + taxane and the effects of age in breast cancer patients.

BACKGROUND: Chemotherapy-induced alopecia (CIA) is a common and quite distressing adverse effects of chemotherapy. There are few detailed observational studies of CIA or of the impact of age on CIA. We performed a prospective observational study to investigate the prevalence and degree of CIA, including CIA of eyebrows, eyelashes, and body, and we examined patient's recovery from CIA, focusing on age-depending effects. METHODS: We analyzed 68 female Japanese patients with breast cancer (median age 53 years, range 29-76 years) who received perioperative adjuvant chemotherapy with fluorouracil/epirubicin/cyclophosphamide (FEC) and taxane. A questionnaire was administered at the point of chemotherapy completion and 6 and 12 months after chemotherapy completion. RESULTS: CIA occurred in all patients, with severe hair loss irrespective of age. CIA occurred mainly in the scalp but also in the eyebrows, eyelashes, and body for most of the patients. There were significant associations between the patient's age and the onset of hair regrowth in the eyebrows, eyelashes, and body. The onset of eyebrows, eyelash, and body hair growth were significantly shorter in the premenopausal patients. Any hair changes (e.g., thinned diameter, softer texture, curlier structure) were reported by 85.3% of the patients. CONCLUSIONS: Severe CIA occurred in all 68 patients who received FEC and taxane chemotherapy. The present findings provide the first data demonstrating that age was not associated with the degree or incidence of hair loss, but age affected the recovery from CIA. These results contribute more accurate information provision and insights regarding the proper treatment of CIA.

Prognostic value of tumor-infiltrating lymphocytes in estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.

Tumor-infiltrating lymphocytes (TILs) are a significant prognostic factor in triple-negative breast cancer. However, the clinicopathological significance of TILs in estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer remains unclear. The purpose of the present study was to evaluate the role of TILs in the prognosis of ER-positive and HER2-negative breast cancer. A total of 65 consecutive patients with ER-positive and HER2-negative breast cancer were examined. TILs in stromal tissue (str-TILs) were graded using the International TILs Working Group criteria. The association between several clinicopathological factors and TIL grade were investigated, and the prognostic impact of TILs was compared between luminal A-like and luminal B-like breast cancer. A total of 51 patients (78.5%) had low-grade (0-10%), 11 (16.9%) had intermediate (10-40%) and 3 (4.6%) had high-grade (40-90%) str-TIL levels. There was a significant association between high levels of Ki67 expression and a high str-TIL count. Relapse-free survival was significantly worse in patients with luminal B-like cancer compared with that in patients with luminal A-like cancer. Patients with an intermediate or high str-TIL count had a better prognosis compared with those with a low str-TIL count. All patients with luminal B-like cancer and intermediate or high str-TIL levels developed no recurrence during follow-up. In conclusion, there was a significant correlation between high-grade str-TIL levels and high tumor cell proliferation rate, as well as high levels of Ki67 expression.

Relationship Between FDG Uptake and the Platelet/lymphocyte Ratio in Patients With Breast Invasive Ductal Cancer.

BACKGROUND/AIM: We investigated the relationship between F18-fluorodeoxyglucose (FDG) uptake and the platelet/lymphocyte ratio (PLR), as both represent inflammation. PATIENTS AND METHODS: We retrospectively analyzed the cases of 143 consecutive invasive ductal carcinoma patients who had undergone preoperative FDG-PET and surgery. We divided the patients into groups based on their maximum standardized uptake value (SUVmax) values: low (<2.5) and high (≥2.5) and based on their PLRs: low (<130) and high (≥130). We determined the relationships between the SUVmax or PLR and clinicopathological features. RESULTS: Seventy-three patients (51.0%) had a high SUVmax in their primary tumor. There were significant associations between SUVmax and the PLR. A multivariate analysis revealed that high PLR, but not NLR, was independent factor associated with a high SUVmax. Seventy-four patients (51.7%) had a high PLR; The factors significantly associated with high PLR were large tumor size, presence of node metastasis, presence of vascular invasion, high NLR, and high SUVmax. CONCLUSION: In breast cancer patients, the PLR is independently associated with the SUVmax, but not with recurrent disease. In breast cancer patients with a high SUVmax and/or PLR, these values may reflect the tumor microenvironment.

Eribulin Suppresses New Metastases in Patients With Metastatic Breast Cancer.

BACKGROUND/AIM: This study aimed to investigate the progression type of metastatic breast cancer (MBC) in patients undergoing eribulin chemotherapy. MATERIALS AND METHODS: We retrospectively investigated the cases of 66 consecutive patients with MBC who underwent eribulin chemotherapy. RESULTS: A total of 15 patients (22.7%) received eribulin as a 3rd-line or later treatment, and 17 (25.8%) received eribulin as a 1st-line treatment. The overall response was complete response in 0 (0%), partial response in 15 (22.7%), stable disease in 27 (40.9%), and progressive disease in 24 (36.4%) patients. By the time of data cut-off, time to treatment failure (TTF) events had been observed in 60 patients (90.9%), among whom, 15 (25%) had disease progression due to NM, and 45 (75%) had disease progression due to PL. In the regimen before eribulin administration, among 49 patients, 24 (49.0%) had disease progression due to NM. Luminal-type patients and those with triple-negative breast cancer exhibited a similar tendency, i.e., the rate of NM was lower in the patients treated with eribulin. The rate of NM was lower in the patients treated with eribulin in the 1st-line setting than that in patients treated with eribulin as a later treatment. CONCLUSION: Eribulin has a potential antitumor mechanism to prevent new metastasis. Eribulin may be effective against both the epithelial-mesenchymal transition (EMT) process and new metastasis.

Implications of Low Serum Albumin as a Prognostic Factor of Long-term Outcomes in Patients With Breast Cancer.

BACKGROUND/AIM: We examined the relationship between preoperative serum albumin levels and long-term outcomes in patients with breast cancer. PATIENTS AND METHODS: We retrospectively analyzed the records of 157 patients who underwent breast cancer surgery at a single institution. We divided the patients into those with <4.0 g/dl and those with ≥4.0 g/dl preoperative serum albumin. RESULTS: The overall median follow-up period was 86.7 months. Among the 157 patients, 19 (12.1%) had decreased serum albumin levels preoperatively. A significant association with preoperative albumin levels was found only for patient age; however, we were unable to determine an association between preoperative albumin levels and various clinical features. The recurrence-free survival (p=0.030) and the overall survival (p=0.001) were both significantly shorter in patients with low albumin levels. CONCLUSION: Low serum albumin levels were associated with poor prognosis, but not with poor-prognostic factors. Therefore, low albumin levels may reflect the tumor microenvironment in breast cancer.

VEGF-A Is Associated With the Degree of TILs and PD-L1 Expression in Primary Breast Cancer.

BACKGROUND/AIM: Vascular endothelial growth factor-A (VEGF-A), an important angiogenic factor, has been reported to effect cancer growth and development. Recent reports indicated that anti-VEGF therapy has an important effect of enhancing anti-tumor immunity in various cancers. In the current study, we investigated the relationship between VEGF-A expression and immunological factors, including programmed cell death ligand 1 (PD-L1) and the degrees of stromal tumor-infiltrating lymphocytes (TILs) in breast cancer. PATIENTS AND METHODS: This study enrolled 97 cases with invasive breast cancer who had undergone surgery without preoperative therapy. The grades of stromal-TILs were evaluated using the criteria of the International Working Group for TILs in breast cancer: low, intermediate, and high. VEGF-A and PD-L1 positivity were evaluated by immunohistochemistry. The relationship between VEGF-A expression and the expression of PD-L1 and TILs was investigated. RESULTS: Among the 97 cases, 37 (38.1%) had positive VEGF-A expression in the breast tumor. We divided the cases in two groups based on the VEGF-A expression levels. The analysis revealed that PD-L1 positivity was significantly associated with VEGF-A expression in the breast tumor (29.7% vs. 10.0%, p=0.014). Among the cases with positive PD-L1, 36.7% of VEGF-positive cases and none of VEGF-negative cases had low TILs in the breast tumor. CONCLUSION: VEGF-A expression in breast cancer may reflect PD-L1 expression in the tumor. VEGF-A may act as a negative biomarker of TILs in PD-L1-positive breast cancer. Our results suggest that VEGF-A may be predictive of immunological features and may serve as a useful biomarker for immuno-targeting therapy in patients with breast cancer.

Carboxypeptidase A4 accumulation is associated with an aggressive phenotype and poor prognosis in triple-negative breast cancer.

Using whole transcriptome analysis and a lentiviral short hairpin RNA screening library, carboxypeptidase A4 (CPA4) was identified as a novel marker in breast cancer and a therapeutic target in triple­negative breast cancer (TNBC) in the present study. Immunohistochemistry was used to evaluate the presence of CPA4, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki67, epidermal growth factor receptor, cytokeratin 5/6, aldehyde dehydrogenase 1, cluster of differentiation (CD)44, CD24, claudins, E­cadherin, vimentin and androgen receptor in 221 cases of breast cancer, including 68 TNBC cases. The effects of CPA4 on the viability and migration ability of TNBC cells were analyzed using RNA interference methods. Increased CPA4 expression, specifically in the cytoplasm of cancer tissue cells, was detected. Furthermore, high CPA4 expression in TNBC cases was associated with low expression of E­cadherin and with the expression of cancer stem cell markers (high CD44/low CD24). Patients with TNBC and high levels of CPA4 expression had a significantly poorer prognosis compared with those with low CPA4 expression. Notably, viability and migration were reduced, but E­cadherin expression was upregulated in CPA4­suppressed TNBC cells. The present data suggested that CPA4 may be a novel inducer for epithelial­mesenchymal transition, which is characterized by the downregulation of E­cadherin and mesenchymal phenotypes. To conclude, CPA4 may be a marker for poor prognosis and a promising therapeutic target in TNBC with aggressive phenotypes.

Relationship Between FDG Uptake and Neutrophil/Lymphocyte Ratio in Patients with Invasive Ductal Breast Cancer.

BACKGROUND: 18F-Fluorodeoxyglucose-positron-emission tomography (FDG-PET) is used to evaluate the glucose metabolic rates of tumors. Several studies have reported that high FDG uptake is predictive of poor prognosis and aggressive features in patients with breast cancer. FDG uptake is influenced by many factors, including inflammation. In this study, the relationship between FDG uptake and neutrophil/lymphocyte ratio (NLR), which is an indicator of systemic inflammation, was investigated. PATIENTS AND METHODS: A retrospective investigation of the cases of 143 consecutive patients with invasive ductal carcinoma who had undergone surgery and FDG-PET preoperatively. PET was evaluated using standardized uptake value max (SUVmax). The median SUVmax was 2.5 (range=0-10.5). The cases were divided into two groups based on the value of SUVmax: low (<2.5) and high (≥2.5). The relationships between SUVmax and clinicopathological features, including NLR, were investigated. RESULTS: Among the 143 patients, 73 (51.0%) had high SUVmax in the primary tumor. The analysis revealed that large tumor size (p<0.001), high nuclear grade (p<0.001), the presence of lymphovascular invasion (p<0.001), high C-reactive protein (p=0.046) and high NLR (p<0.001) were significantly associated with high SUVmax in the primary tumor. SUVmax and NLR were significantly positively correlated (r=0.323, p<0.001). Among the 70 cases with low SUVmax, there was no recurrent disease, while out of the 73 cases with high SUVmax had disease recurrence. It is interesting to note that the group with high SUVmax and low NLR had no recurrent disease. CONCLUSION: The present study demonstrated that the finding of high preoperative FDG uptake in breast cancer may be reflective of poor prognosis and that a high NLR may be predictive of aggressive features among patients with breast cancer. On the other hand, among patients with breast cancer with high SUVmax in the primary tumor, it will be useful to identify those with a low NLR in order to improve prognostic accuracy.

Clinicopathological Features of Ductal Carcinoma In Situ from 18F-FDG-PET Findings.

AIM: The presence of ductal carcinoma in situ (DCIS) can increase the risk of developing an invasive ductal carcinoma (IDC), but it is difficult to predict what will occur if a DCIS is left untreated. We reported the usefulness of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for DCIS, and that the presence of FDG uptake in the tumor could be considered a predictor of invasive potential in patients with DCIS. In this study, we retrospectively evaluated the clinicopathological features of DCIS by using FDG-PET findings, and we evaluated the possibility of using FDG-PET in DCIS cases as a biomarker of which lesions will go on to become invasive. PATIENTS AND METHODS: We investigated the cases of 185 consecutive patients with primary breast cancer who were diagnosed as having DCIS or IDC and underwent FDG-PET preoperatively. RESULTS: We divided the cases into two groups on the basis of histology; DCIS vs. IDC (n=171). The DCIS cases were divided into two groups on the basis of FDG uptake in the primary tumor. Fourteen of the 185 patients (7.4%) were revealed to have a DCIS. The analysis revealed that the SUVmax and the number of cases not detected by FDG-PET were significantly different between the DICS and IDC groups. The extent of the primary tumor was not significantly different between the two groups. In six cases (42.9%) of the 14 DCIS cases, no FDG uptake was detected by FDG-PET. The extent of tumor did not significantly differ between the two groups. In addition, all six cases without FDG uptake were of the diffuse-spread type, without mass formation. All eight cases with mass formation had FDG uptake. CONCLUSION: Our present findings suggest that the FDG-PET uptake reflects tumor burden or tumor density, which should be considered to be associated with the presence of invasion.

Stathmin1 expression is associated with aggressive phenotypes and cancer stem cell marker expression in breast cancer patients.

Stathmin1 (STMN1) regulates progression in various cancers. The present study aimed to determine the relationship between STMN1 expression and several cancer-related markers in breast cancer. Using immunohistochemistry, we evaluated STMN1, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67, epidermal growth factor receptor (EGFR), CK5/6, CD44, CD24, aldehyde dehydrogenase 1, E-cadherin, epithelial cell adhesion molecule, and vimentin in 237 breast cancer patients and the clinical significance of STMN1. STMN1 expression was evaluated in 51 breast cancer cell lines, and the prognostic value of STMN1 was calculated. Higher STMN1 expression was detected in cancer tissues and was predominantly localized in the cytoplasm. High STMN1 expression was associated with the triple negative subtype, nuclear grade progression, high expression of Ki-67, EGFR, CK5/6, E-cadherin and high CD44/low CD24. According to gene expression-based outcome for breast cancer online and the Kaplan-Meier plotter, STMN1 expression was higher in basal-type cell lines than in luminal-type cell lines, and overall survival and post-progression survival in the high STMN1 expression breast cancer patients were shorter than in low STMN1 expression patients. High STMN1 expression is a possible marker of breast cancer aggressiveness in association with proliferation, phenotype and cancer stem cell type.

Clinicopathological Features of Cases with Primary Breast Cancer not Identified by 18F-FDG-PET.

Several studies have reported that high F18-fluorodeoxyglucose (FDG) uptake is predictive of poor prognosis and aggressive features in patients with breast cancer. While these studies evaluated the prognostic value for cases with high FDG uptake, they did not elucidate the meaning of FDG negativity in primary breast cancer. In this study, we evaluated the clinicopathological features of breast cancer cases without FDG uptake. We retrospectively investigated the cases of 219 consecutive patients with primary breast cancer who underwent FDG-positron emission tomography (PET) preoperatively. Among the 219 patients, 25 (11.4%) did not have FDG uptake in the tumor. The 219 cases with breast cancer were divided into two groups based on the presence of FDG uptake in the primary tumor. The present univariate analysis revealed that histology, small invasive tumor size, high estrogen receptor (ER) or progesterone receptor (PgR) expression, low nuclear grade and absence of lymph node metastasis were significantly associated with negative FDG uptake in the primary tumor. On the other hand, the size of ductal spread was not significantly different between the two groups. Multivariate analysis revealed that small-size tumor invasion and lower nuclear grade were statistically significant. Among the 25 cases without FDG uptake, there was no recurrent disease in spite of there being no case that underwent chemotherapy, while 4 cases among the 194 cases with FDG uptake had disease recurrence. Our findings imply that preoperative FDG negativity in primary breast cancer is effective in predicting better prognosis, but is less effective in predicting ductal spread. Cases without FDG uptake in the primary tumor may have a lower risk of recurrent disease and may be able to safely avoid adjuvant chemotherapy.