Time-series blood cytokine profiles correlate with treatment responses in triple-negative breast cancer patients.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype. Partly due to its heterogeneity, it is currently challenging to stratify TNBC patients and predict treatment outcomes. METHODS: In this study, we examined blood cytokine profiles of TNBC patients throughout treatments (pre-treatment, during chemotherapy, pre-surgery, and 1 year after the surgery in a total of 294 samples). We analyzed the obtained cytokine datasets using weighted correlation network analyses, protein-protein interaction analyses, and logistic regression analyses. RESULTS: We identified five cytokines that correlate with good clinical outcomes: interleukin (IL)-1α, TNF-related apoptosis-inducing ligand (TRAIL), Stem Cell Factor (SCF), Chemokine ligand 5 (CCL5 also known as RANTES), and IL-16. The expression of these cytokines was decreased during chemotherapy and then restored after the treatment. Importantly, patients with good clinical outcomes had constitutively high expression of these cytokines during treatments. Protein-protein interaction analyses implicated that these five cytokines promote an immune response. Logistic regression analyses revealed that IL-1α and TRAIL expression levels at pre-treatment could predict treatment outcomes in our cohort. CONCLUSION: We concluded that time-series cytokine profiles in breast cancer patients may be useful for understanding immune cell activity during treatment and for predicting treatment outcomes, supporting precision medicine. TRIAL REGISTRATION: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with the unique trial number UMIN000023162. The association Japan Breast Cancer Research Group trial number is JBCRG-22. The clinical outcome of the JBCRG-22 study was published in Breast Cancer Research and Treatment on 25 March 2021. https://doi.org/10.1007/s10549-021-06184-w .

Prognosis and effectiveness of chemotherapy for medullary breast carcinoma.

PURPOSE: We aimed to determine the prognosis and potential benefit of postoperative chemotherapy according to subtype of medullary breast carcinoma (MedBC), a very rare invasive breast cancer. METHODS: A cohort of 1518 female patients with unilateral MedBC and 284,544 invasive ductal carcinoma (IDC) cases were enrolled from the Japanese Breast Cancer Registry. Prognosis of MedBC was compared to IDC among patients with estrogen receptor (ER)-negative and HER2-negative subtype (553 exact-matched patients) and ER-positive and HER2-negative subtype (163 MedBC and 489 IDC patients via Cox regression). Disease free-survival (DFS) and overall survival (OS) were compared between propensity score-matched adjuvant chemotherapy users and non-users with ER-negative and HER2-negative MedBC. RESULTS: Among ER-negative and HER2-negative subtype patients, DFS (hazard ratio (HR) 0.45; 95% confidence interval (95% CI), 0.30-0.68; log-rank P < 0.001) and OS (HR 0.51; 95% CI 0.32-0.83; log-rank P = 0.004) were significantly better in MedBC than IDC. Patients treated with postoperative chemotherapy showed better DFS (HR 0.27; 95% CI 0.09-0.80; log-rank P = 0.02) and OS (HR 0.27; 95% CI 0.09-0.80; log-rank P = 0.02) compared to those without. For the ER-positive and HER2-negative subtype, the point estimate for HR for DFS was 0.60 (95% CI 0.24-1.22) while that for OS was 0.98 (95% CI 0.46-1.84) for MedBC. CONCLUSION: In ER-negative and HER2-negative MedBC, the risk of recurrence and death was significantly lower than that of IDC, about half. Postoperative chemotherapy reduced recurrence and mortality. ER-positive and HER2-negative MedBC may have a lower risk of recurrence compared to IDC.

Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR.

BACKGROUND: Triple-negative breast cancer (TNBC) is a biologically diverse disease, with characteristics such as homologous recombination deficiency (HRD), gene mutation, and immune reactions. Japan Breast Cancer Research Group 22 is a multicenter trial examining TNBC's response to neoadjuvant chemotherapy (NAC) according to the HRD status. This translational research investigated the clinical significance of the immune microenvironment of TNBC in association with HRD, tumor BRCA1/2 (tBRCA1/2) mutation, and response to NAC. METHODS: Patients aged below 65 years with high HRD or germline BRCA1/2 (gBRCA1/2) mutation randomly received paclitaxel + carboplatin (group A1) or eribulin + carboplatin (A2), followed by anthracycline. Patients aged below 65 years with low HRD or those aged 65 years or older without gBRCA1/2 mutation randomly received eribulin + cyclophosphamide (B1) or eribulin + capecitabine (B2); nonresponders to the first four cycles of the therapy received anthracycline. A pathological complete response (pCR) was defined as the absence of residual cancer cells in the tissues. Pretreatment biopsy specimens were stained by multiplexed fluorescent immunohistochemistry using antibodies against CD3, CD4, CD8, Foxp3, CD204, and pan-cytokeratin. Immune cells with specific phenotypes were counted per mm2 in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response. RESULTS: This study analyzed 66 samples. T1 tumors had a significantly higher density of intratumoral CD8+ T cells than T2 or larger tumors. The tBRCA1/2 mutation or HRD status was not associated with the density of any immune cell. The density of intratumoral and stromal CD4+ T cells was higher in patients showing pCR than in those without pCR. In a multivariate analysis, intratumoral and stromal CD4+ T cell density significantly predicted pCR independent of age, chemotherapy dose, HRD status, and treatment groups (P = 0.009 and 0.0057, respectively). In a subgroup analysis, the predictive value of intratumoral and stromal CD4+ T cell density persisted in the platinum-containing chemotherapy group (A1+A2) but not in the non-platinum-containing group (B1+B2). CONCLUSIONS: Intratumoral and stromal CD4+ T cell density was an independent predictor of pCR in patients with TNBC. A larger study is warranted to confirm the results. TRIAL REGISTRATION: UMIN000023162.

[A Case of Breast Metastasis from Renal Cell Carcinoma].

The patient was a woman in her 90s. Right radical nephrectomy for right renal cell carcinoma had been performed 2 years and 6 months ago. Since then, there had been no recurrence. However, computed tomography during postoperative follow- up period showed a 3 cm mass in the right breast, and the patient was referred to our department. Breast ultrasonography indicated a well-circumscribed, oval, and almost smooth-surfaced tumor, 27 mm in size, located in the D region of the right breast. Results of a core needle biopsy showed metastatic renal cell carcinoma and clear cell carcinoma. Preoperative examination confirmed intramammary metastases of renal cell carcinoma. Given that the patient did not experience systemic metastases, partial mastectomy of the right breast was performed. Metastatic renal cell carcinoma is associated with poor prognosis. Generally, standard treatment in this disease is chemotherapy. However, surgical resection is selected with the aim of improving the prognosis and achieving radical cure of patients with this complication if these patients are in an oligometastatic state and complete resection of metastatic lesions is feasible, as in the present case. To achieve radical cure, the patient underwent partial mastectomy under local anesthesia, which is a relatively minimally invasive surgery.

Performance of dedicated breast positron emission tomography in the detection of small and low-grade breast cancer.

PURPOSE: This study compares the sensitivity of dedicated breast positron emission tomography (DbPET) and whole body positron emission tomography (WBPET) in detecting invasive breast cancer based on tumor size and biology. Further, we explored the relationship between maximum standardized uptake value (SUVmax) of DbPET and biological features of the tumor. METHODS: A total of 639 invasive breast cancer lesions subjected to both DbPET and WBPET before surgery, between January 2016 and May 2019, were included in the study. The sensitivity of DbPET and WBPET in detection and the biology of the tumor according to the clinicopathological features were retrospectively evaluated. RESULTS: The overall sensitivity of DbPET was higher than that of WBPET (91.4% vs. 80.3%, p < 0.001). Subcentimetric tumors were significant (80.9% vs. 54.3%, p < 0.001). Regardless of the nuclear grade, DbPET could detect more lesions than WBPET. The SUVmax was positively correlated with tumor size (R = 0.395, p < 0.001) and the nuclear grade (p < 0.001). Luminal A-like breast cancer had significantly lower SUVmax values than the other subtypes (p < 0.001). CONCLUSIONS: DbPET is superior to WBPET in the detection of subcentimetric, low-grade breast cancers. Further, by using SUVmax, DbPET can distinguish luminal A-like breast cancer from the other subtypes.

Eribulin-based neoadjuvant chemotherapy for triple-negative breast cancer patients stratified by homologous recombination deficiency status: a multicenter randomized phase II clinical trial.

PURPOSE: To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients. METHODS: Patients in group A (aged < 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline BRCA mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety. RESULTS: The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%-81%) and 45% (27%-65%) in groups A1 and A2, respectively, and 19% (8%-35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively. CONCLUSIONS: In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen. TRIAL REGISTRATION: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.

Febrile neutropenia and role of prophylactic granulocyte colony-stimulating factor in docetaxel and cyclophosphamide chemotherapy for breast cancer.

PURPOSE: Febrile neutropenia (FN) incidence during docetaxel and cyclophosphamide (TC) chemotherapy, known as a high-risk regimen, differs among countries. The role of prophylactic granulocyte colony-stimulating factor (G-CSF) in FN is unclear. This study aimed to investigate FN frequency and relative dose intensity (RDI) of TC chemotherapy in patients with breast cancer and identify the correct population requiring prophylactic G-CSF. METHODS: In total, 205 patients with breast cancer were scheduled for TC chemotherapy (docetaxel/cyclophosphamide 75/600 mg/m2, every 3 weeks, 4 cycles) as adjuvant chemotherapy. Trastuzumab (8 mg/kg; continued with 6 mg/kg) was administrated intravenously for human epidermal growth factor receptor 2 (HER2)-positive cancer. Fifty-five patients received primary prophylactic measures (G-CSF: 20 and antibiotics: 35). We investigated the frequency of FN and hospitalization, RDI, and the factors related to FN, adverse events, hospitalization, and RDI. RESULTS: FN occurred in 70 patients (35.7%). FN incidence was noted in 41.1% without any prophylactic measures and in 5.0% with prophylactic G-CSF. In multivariate analysis, the independent risk factors of FN were older age (≥ 60 years, P = 0.017) and without primary prophylactic G-CSF (P = 0.011). Eleven patients (5.6%) were hospitalized of which 8 (72.7%) were elderly. The median RDIs of docetaxel and cyclophosphamide were 96.7% and 99.7%, respectively. CONCLUSION: FN frequency during TC chemotherapy was high, and primary prophylactic G-CSF reduced FN incidence. Primary prophylactic G-CSF is an effective therapy for preventing FN during TC chemotherapy. However, prophylactic G-CSF should be considered for elderly patients based on the low hospitalization rate and the high RDI.

Predicting the presence of breast cancer using circulating small RNAs, including those in the extracellular vesicles.

Emerging evidence indicates that small RNAs, including microRNAs (miRNAs) and their isoforms (isomiRs), and transfer RNA fragments (tRFs), are differently expressed in breast cancer (BC) and can be detected in blood circulation. Circulating small RNAs and small RNAs in extracellular vesicles (EVs) have emerged as ideal markers in small RNA-based applications for cancer detection. In this study, we first undertook small RNA sequencing to assess the expression of circulating small RNAs in the serum of BC patients and cancer-free individuals (controls). Expression of 3 small RNAs, namely isomiR of miR-21-5p (3' addition C), miR-23a-3p and tRF-Lys (TTT), was significantly higher in BC samples and was validated by small RNA sequencing in an independent cohort. Our constructed model using 3 small RNAs showed high diagnostic accuracy with an area under the receiver operating characteristic curve of 0.92 and discriminated early-stage BCs at stage 0 from control. To test the possibility that these small RNAs are released from cancer cells, we next examined EVs from the serum of BC patients and controls. Two of the 3 candidate small RNAs were identified, and shown to be abundant in EVs of BC patients. Interestingly, these 2 small RNAs are also more abundantly detected in culture media of breast cancer cell lines (MCF-7 and MDA-MB-231). The same tendency in selective elevation seen in total serum, serum EV, and EV derived from cell culture media could indicate the efficiency of this model using total serum of patients. These findings indicate that small RNAs serve as significant biomarkers for BC detection.

Diagnostic performance of peripheral leukocyte telomere G-tail length for detecting breast cancer.

The telomere G-tail (G-tail) plays an essential role in maintaining chromosome stability. In this study, we assessed the leukocyte G-tail length of breast cancer (BC) patients and cancer-free individuals and evaluated the association between the G-tail length and the presence of BC. A significant shortening of the median G-tail length was observed in BC patients compared with cancer-free individuals and was found in the early phase of BC. Our study indicated that the leukocyte G-tail length might be a potential biomarker for BC detection.

A randomized study comparing docetaxel/cyclophosphamide (TC), 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by TC, and TC followed by FEC for patients with hormone receptor-positive HER2-negative primary breast cancer.

PURPOSE: Our primary objective was to determine the benefit/risk of anthracycline-free regimens by comparing docetaxel + cyclophosphamide (TC) alone, fluorouracil + epirubicin + cyclophosphamide (FEC) followed by TC, or TC followed by FEC as a primary treatment for patients with HR-positive, HER2-negative BC. METHODS: We randomized patients with stage I-III HR-positive HER2-negative, operable BC to receive either six cycles of TC (TC6), three cycles of FEC followed by three cycles of TC (FEC-TC), or three cycles of TC followed by three cycles of FEC (TC-FEC). The primary endpoint was the pathological response. Secondary endpoints included clinical response, type of surgical procedure, recurrence, death, and adverse events (by NCI-Common Terminology Criteria for Adverse Events v.3.0). We conducted all statistical analyses using SAS Version 9.2. RESULTS: We enrolled 195 patients and analyzed data from 193 as the intention-to-treat population. Pathological complete response rates were numerically higher in the TC6 group than in the other groups (p = 0.321). The breast conservation rate was significantly higher in the TC6 group (73%) than in the other groups (FEC-TC 51%, TC-FEC 45%, p = 0.007). Adverse events with grade > 3 were not common in the treatment groups (p = 0.569). The overall and distant disease-free survivals were similar among the groups with median follow-up of 5.80 years. CONCLUSIONS: Despite similar long-term efficacy and safety profile, the higher breast conservation rate in the TC6 group suggests that preoperative chemotherapy without an anthracycline may benefit patients with HR-positive HER2-negative BC. TRIAL REGISTRATION: UMIN000003283 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003873.

The relationship between ring-type dedicated breast PET and immune microenvironment in early breast cancer.

PURPOSE: 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) is related to the biological parameters and prognosis of breast cancer. However, whether whole-body PET (WBPET) and dedicated breast PET (DbPET) can reflect the tumor microenvironment is unclear. This study investigated the relationship between stromal tumor-infiltrating lymphocytes (TILs) and maximum standardized uptake value (SUVmax) in WBPET and DbPET. METHODS: A total of 125 invasive breast cancers underwent WBPET and ring-type DbPET and resected specimens were pathologically assessed. The impact of SUVmax on the tumor biological parameters and TILs was retrospectively evaluated. SUVmax was classified as high and low relative to the median values (WBPET-SUVmax: 2.2 and DbPET-SUVmax: 6.0). RESULTS: SUVmax correlated with tumor size, nuclear grade, Ki-67 labeling index, and TILs in both WBPET and DbPET (all p < 0.001). In multiple linear regression analysis, tumor size, Ki-67 labeling index, and TILs predicted SUVmax in WBPET and DbPET. The cutoff values of tumor size, Ki-67 labeling index, and TILs predicting high SUVmax were 20 mm, 20%, and 20%, respectively. In multivariate analysis, the predictive factors for high SUVmax were tumor size and Ki-67 labeling index for WBPET and tumor size and TILs for DbPET. High SUVmax in DbPET was related to high numbers of TILs after propensity score matching analysis; however, WBPET was not (p = 0.007 and p = 0.624, respectively). CONCLUSIONS: Both SUVmax values in WBPET and DbPET predicted TIL concentration of the primary breast cancer. In DbPET, SUVmax represented the immune microenvironment after adjusting for tumor biological factors.

A population-based recurrence risk management study of patients with pT1 node-negative HER2+ breast cancer: a National Clinical Database study.

PURPOSE: Recurrence risk management of patients with small (≤ 2 cm), node-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains challenging. We studied the effects of adjuvant chemotherapy and/or trastuzumab and survival outcomes among these patients, using data from the population-based Japanese National Clinical Database (NCD). METHODS: We identified a cohort of 2736 breast cancer patients with HER2+ pT1N0 disease: 489 pT1a, 642 pT1b, and 1623 pT1c. The median observation period was 76 months, and the 5-year follow-up rate was 48.2%. The number of events was 212 for disease-free survival (DFS), 40 for breast cancer-specific survival, and 84 for overall survival (OS). RESULTS: There were 24.5% of pT1a, 51.9% of pT1b, and 63.3% of pT1c patients who were treated systemically after surgery. OS in pT1b (logrank test; p = 0.03) and DFS in pT1c (logrank test; p < 0.001) were significantly improved in treated compared with untreated patients. In the Cox proportional hazards model, treated patients had significantly longer OS than untreated patients in pT1b (hazard ratio (HR) 0.20) and pT1c (HR 0.54) groups. Estrogen receptor-negative tumors was also a significant predictor of survival in pT1c (HR 2.01) but not pT1ab patients. Furthermore, HR was greater in patients aged ≤ 35 years (3.18) compared to that in patients aged 50-69 years in the pT1b group. CONCLUSIONS: NCD data revealed that systemic treatment improved OS in pT1bc but not in pT1a node-negative HER2+ breast cancer patients. Future observational research using big-sized data is expected to play an important role in optimizing treatment for patients with early-stage breast cancer.

Prediction of biological characteristics of breast cancer using dual-phase FDG PET/CT.

PURPOSE: The aim of this study was to assess whether the retention index (RI) determined using dual-phase 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) reflects the malignant features of breast cancer. METHODS: A total of 1,523 patients with breast cancer were retrospectively evaluated. PET/CT scans were performed at 1 h and 2 h after FDG administration before treatment. The maximum standardized uptake value (SUVmax) at both time points (SUVmax1 and SUVmax2) in the primary tumour and RI were calculated. Primary tumour tissues were evaluated in terms of biological features, such as histology, nuclear grade, lymphovascular invasion and molecular subtype. RESULTS: Of the 1,523 patients, 463 (30.4%) had luminal A-like, 661 (43.4%) had luminal B-like, 229 (15.0%) had human epidermal growth factor receptor 2-positive (HER2-positive), and 157 (10.3%) triple-negative breast cancer. The median SUVmax1, SUVmax2 and RI values were 2.2, 2.3 and 2.6%, respectively. These metabolic parameters were correlated with tumour size, nodal metastasis, histology, nuclear grade, lymphovascular invasion, and molecular subtype (all P < 0.001). The median RI values were 0% in luminal A-like, 5.3% in luminal B-like, 6.9% in HER2-positive, and 11.4% in triple-negative breast cancer. RI was associated with malignant features when the tumour accumulated a significant amount of FDG. In a subanalysis of patients with tumours of stages T2 to T4, RI was correlated with nodal metastasis, histology, nuclear grade, and molecular subtype (luminal A-like 4.8%, luminal B-like 12.3%, HER2-positive 15.8%, and triple-negative 16.3%). CONCLUSION: RI determined using delayed-phase FDG PET/CT is associated with malignant features in breast cancers with significant FDG uptake. Dual-phase imaging was helpful in distinguishing luminal A-like breast cancer from luminal B-like, HER2-positive, and triple-negative breast cancers.

Identification of Axillary Lymph Node Metastasis in Patients With Breast Cancer Using Dual-Phase FDG PET/CT.

OBJECTIVE. The aim of this study was to assess the diagnostic performance of dual-phase 18F-FDG PET/CT in detecting axillary lymph node metastasis in patients with breast cancer. MATERIALS AND METHODS. A total of 826 patients with breast cancer were retrospectively evaluated. PET/CT scans were performed 1 hour and 2 hours after FDG administration before treatment. The maximum standardized uptake value (SUVmax) in the axillary lymph node at both time points (hereafter referred to as SUVmax1 and SUVmax2, respectively) and the retention index (RI) were calculated. RESULTS. Axillary lymph node metastasis was detected in 285 of 826 patients (34.5%). The median axillary SUVmax1, SUVmax2, and RI in patients with nodal metastasis were higher than those in patients without metastasis (1.5 vs 0.6, 1.6 vs 0.5, and 7.7 vs -3.7, respectively; all p < 0.001). The diagnostic accuracy of axillary SUVmax1 and SUVmax2 was equivalent, and the sensitivity and specificity of SUVmax1 were 74.7% and 83.4%, respectively. Although the performance of the axillary RI was inferior to that of SUVmax1 and SUVmax2, both the SUVmax and the RI were independent predictors of nodal metastasis, and a positive RI suggested axillary lymph node involvement when the SUVmax1 was significantly high. Of 533 patients with category T1-2 breast cancer without lymph node swelling, 101 (19.0%) had pathologic lymph node involvement; the negative predictive value of axillary SUVmax1 was 86.8%. CONCLUSION. Delayed phase imaging identified axillary lymph node metastasis as accurately as standard PET/CT. A high negative predictive value of PET/CT for the detection of nodal metastasis is helpful to avoid surgical axillary assessment in patients with category T1-2 breast cancer without lymph node swelling.

Intratumoral heterogeneity on dedicated breast positron emission tomography predicts malignancy grade of breast cancer.

PURPOSE: Dedicated breast positron emission tomography (DbPET) provides detailed high-resolution images and can detect intratumoral heterogeneity using 18F-fluorodeoxyglucose (FDG). We aimed to evaluate the correlation between FDG uptake on DbPET and the clinicopathological features of breast cancer, particularly those with an intratumoral heterogeneous distribution of FDG on DbPET. METHODS: We evaluated 195 consecutive patients with invasive breast cancer who underwent preoperative whole-body PET (WBPET) and DbPET concurrently between January 2016 and March 2017. The relationships between clinicopathological factors and the maximum standard uptake values (SUVmax) of DbPET and WBPET, including clinical stage, nuclear grade, Ki67 proliferation index, estrogen receptor (ER) and human epidermal growth factor receptor type 2 (HER2) statuses, and the intratumoral heterogeneous distribution of FDG on DbPET, were evaluated. RESULTS: The SUVmax of DbPET was significantly correlated with clinical T stage, N stage, nuclear grade, and Ki67 proliferation index (all p < 0.001) as well as the ER (p = 0.006) and HER2 (p = 0.040) statuses. Intratumoral heterogeneous distribution of FDG on DbPET was significantly related with high nuclear grade (p = 0.016) and high Ki67 proliferation index (p = 0.015) but not with clinical T stage, N stage, and ER and HER2 statuses. CONCLUSIONS: The SUVmax of DbPET correlates with clinicopathological factors and also WBPET does. In addition, intratumoral heterogeneity on DbPET provides predictive value for malignancy grade and could inform therapeutic decisions.

Ability of contrast-enhanced ultrasonography to determine clinical responses of breast cancer to neoadjuvant chemotherapy.

OBJECTIVE: We aimed to determine whether contrast-enhanced ultrasonography can predict the effects of neoadjuvant chemotherapy on breast cancer. METHODS: The clinical responses of 63 consecutive patients with breast cancer (T1-4, N0-1, M0) to neoadjuvant chemotherapy between October 2012 and May 2015 were assessed using contrast-enhanced magnetic resonance imaging, positron emission tomography/computed tomography and contrast-enhanced ultrasonography. Perfusion parameters for contrast-enhanced ultrasonography were created from time-intensity curves based on enhancement intensity and temporal changes to objectively evaluate contrast-enhanced ultrasonography findings. The sensitivity, specificity and accuracy of contrast-enhanced ultrasonography, magnetic resonance imaging and positron emission tomography/computed tomography to predict a pathological complete response were compared after confirming the pathological findings of surgical specimens. RESULTS: Twenty-three (36.5%) of the 63 patients achieved pathological complete response. The sensitivity, specificity and accuracy of contrast-enhanced ultrasonography for predicting pathological complete response were 95.7% (82.5-99.2%), 77.5% (69.9-79.5%) and 84.1% (74.5-86.7%). The sensitivity of contrast-enhanced ultrasonography was significantly greater than that of magnetic resonance imaging (95.7 vs. 69.6%, P = 0.047). The specificity and accuracy were significantly greater and tended to be greater, respectively, for contrast-enhanced ultrasonography than positron emission tomography/computed tomography (specificity, 77.5 vs. 52.5%, P = 0.02; accuracy, 84.1 vs. 69.8%, P = 0.057). CONCLUSIONS: Contrast-enhanced ultrasonography might serve as a new diagnostic modality when planning therapeutic strategies for patients with breast cancer after neoadjuvant chemotherapy.

Comparison of visual assessment and image analysis in the evaluation of Ki-67 expression and their prognostic significance in immunohistochemically defined luminal breast carcinoma.

OBJECTIVES: To compare the Ki-67 labeling index value obtained through immunohistochemistry analysis by human examiners to that obtained from computer-assisted image analysis, and to establish a cut-off value for Ki-67 labeling index for each method in luminal B breast carcinoma. METHODS: Immunohistochemistry analysis for Ki-67 was performed on the formalin-fixed, paraffin-embedded tissue samples from 403 patients with primary luminal breast cancers. Whole slide images were obtained using the NanoZoomer (Hamamatsu Photonics, Hamamatsu, Japan) and thoroughly analyzed using the Definiens Tissue Studio version 1.1 (Definiens AG, Munich, Germany) to detect the percentage of positively-stained nuclei of carcinoma cells. RESULTS: Although a significant correlation was found between the Ki-67 labeling index obtained by manual assessment and computer-assisted image analysis (Spearman rank correlation coefficient, P < 0.01), the Ki-67 labeling index value obtained by manual assessment was significantly higher than that obtained by computer-assisted image analysis (Wilcoxon signed rank test, P < 0.0001). Disease-free survival was significantly lower in 403 patients with tumors having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P < 0.00001) and visual counting (cut-off value: 28.5%; P < 0.00001). Disease-free survival was also significantly lower in 288 patients who received adjuvant endocrine therapy alone having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P < 0.0001) and visual counting (cut-off value: 19.7%, P < 0. 0001). CONCLUSIONS: The Ki-67 labeling index values determined by automated analysis and visual counting could equally predict disease-free survival in patients with luminal B breast carcinoma, including those who received endocrine therapy.

Utility of (18)F FDG-PET/CT for predicting prognosis of luminal-type breast cancer.

Postoperative prognosis is better for hormonal receptor-positive breast cancer than for other phenotypes; however, there are no definitive predictive factors for relapse or survival. This study aimed to evaluate the maximum standardized uptake value (SUVmax) on (18)F-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) and clinicopathological characteristics as possible predictors of postoperative relapse-free survival (RFS) and overall survival (OS) in hormonal receptor-positive breast cancer patients. We evaluated 262 patients with Stage I-III breast cancer diagnosed as luminal type (luminal A, 166; luminal B, 96 patients) who underwent preoperative FDG-PET/CT between January 2006 and December 2011 at two institutions. The relationships among SUVmax and clinicopathological factors (age, clinical T/N stage, nuclear grade, lymph node metastasis and vascular invasion) were evaluated. A phantom study was performed to correct differences in PET/CT analysis between two institutions. The patients were divided according to the SUVmax cutoff on receiver operating characteristic (ROC) analysis for OS (≤6.0 group vs. >6.0 group, AUC = 0.742). Clinical T-factor and nuclear grade were significantly correlated with SUVmax (p < 0.0001 and p = 0.0092, respectively). In the uni- and multivariate analyses using the Cox model for relapse, SUVmax was significant (p = 0.013 and p = 0.055, respectively) among characteristics. RFS curves showed that prognosis was significantly better for the SUVmax ≤ 6.0 group than for the SUVmax > 6.0 group (p = 0.004). Similarly, SUVmax was significant for OS (p = 0.007 and p = 0.008). OS was significantly different between the SUVmax ≤ 6.0 and >6.0 groups (p < 0.001). SUVmax was useful for predicting outcomes in patients with luminal-type breast cancer.

Cross-Correlation of Confocal Images for Excised Breast Tissues of Total Mastectomy.

OBJECT: The purpose of this study is to develop an image artifact removal method for radar-based microwave breast imaging and demonstrates the detectability on excised breast tissues of total mastectomy. METHODS: A cross-correlation method was proposed and measurements were conducted. A hand-held radar-based breast cancer detector was utilized to measure a breast at different orientations. Images were generated by multiplying the confocal image data from two scans after cross-correlation. The optimum reconstruction permittivity values were extracted by the local maxima of the confocal image intensity as a function of reconstruction permittivity. RESULTS: With the proposed cross-correlation method, the contrast of the imaging result was enhanced and the clutters were removed. The proposed method was applied to 50 cases of excised breast tissues and the detection sensitivity of 72% was achieved. With the limited number of samples, the dependency of detection sensitivity on the breast size, breast density, and tumor size were examined. CONCLUSION AND SIGNIFICANCE: The detection sensitivity was strongly influenced by the breast density. The sensitivity was high for fatty breasts, whereas the sensitivity was low for heterogeneously dense breasts. In addition, it was observed that the sensitivity was high for extremely dense breast. This is the first detailed report on the excised breast tissues.

Role of maximum standardized uptake value in fluorodeoxyglucose positron emission tomography/computed tomography predicts malignancy grade and prognosis of operable breast cancer: a multi-institute study.

The malignant biological behavior of breast cancer remains obscure on diagnostic images, although understanding the grade of such malignancy is important for selecting appropriate treatment. Therefore, malignancy grades in operable breast cancer were evaluated using positron emission tomography/computed tomography (PET/CT) in a multicenter setting. We prospectively examined the features and prognosis of 344 patients (mean age ± SD: 58.0 ± 12.5 years) with clinical stages I-III breast cancer, who underwent surgical intervention without induction therapy between January 2006 and December 2011. Maximum standardized uptake values (maxSUV) obtained from whole-body fluorodeoxyglucose-PET/CT immediately before surgery were assessed to predict the malignant aggressiveness of tumors including the recurrence-free survival of the patients. Variations in maxSUV among institutions, which are limitations of PET assessments in multicenter studies, were adjusted using a phantom study. The median follow up period was 52 months. The patients were divided into groups according to cut-off maxSUV (≤3.0 vs. >3.0) values established from receiver operating characteristic analysis of recurrence (area under the curve = 0.713). A higher maxSUV was significantly associated with a higher T-factor (p < 0.0001), N-factor (p = 0.0049), nuclear grade (p < 0.0001), negative for estrogen (p = 0.0309), and progesterone receptors (p = 0.0063), positive for human epidermal growth factor receptor 2 (p = 0.0012), lymph node metastasis (p = 0.0128), and vascular invasion (p = 0.0110). Multivariate analysis using Cox proportional hazard regression model revealed high maxSUV and negative estrogen receptor status as significantly prognostic factors (p = 0.033 and p = 0.004, respectively). This study demonstrated that maxSUV on PET/CT as well as estrogen receptor status is useful to predict malignancy grades and the prognosis of patients with breast cancer.