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PurposeThis 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.MethodsA 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.ResultsThe 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).ConclusionsDbPET 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.

PurposeFebrile 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.MethodsIn 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.ResultsFN 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.ConclusionFN 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.

Background/Aim: The maximum standardized uptake value (SUVmax) obtained using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is presumed to indicate tumor and active immune cells in the tumor immune microenvironment (TIME) based on their glycolysis activity. Therefore, this study investigated whether the metabolic parameter SUVmax could provide information regarding TIME in triple-negative breast cancer (TNBC) patients. Patients and Methods: Fifty-four patients with TNBC underwent FDG PET/CT before neoadjuvant chemotherapy. Pretreatment biopsy specimens were pathologically evaluated. Expression statuses of CD8, forkhead box P3 (FOXP3), programmed cell death-1 (PD-1), and programmed cell death-ligand 1 (PD-L1) were assessed by immunohistochemistry. The relationships between immunological factors, including the tumor-infiltrating lymphocyte (TIL) grade and SUVmax or pathological complete response (pCR), were investigated. Results: CD8, FOXP3, PD-1, and PD-L1 were high in 15 (27.8%), 39 (72.2%), 18 (33.3%), and 26 (48.2%) patients, respectively. SUVmax was significantly correlated with tumor size, Ki-67 labeling index, and CD8/FOXP3 ratio. Multiple linear regression analysis indicated that tumor size and the CD8/FOXP3 ratio predicted SUVmax. Seventeen patients (31.5%) achieved a pCR; TILs, the CD8/FOXP3 ratio, PD-1, and PD-L1 were significantly correlated with pCR rate. Multivariate analysis indicated that the CD8/FOXP3 ratio was the only independent predictive factor for pCR. Conclusion: SUVmax could provide metabolic information regarding TIME for TNBC patients and might be beneficial for formulating a treatment strategy and predicting pCR after neoadjuvant chemotherapy.

The classification according to uptake patterns and metabolic parameters on ring-type dedicated breast positron emission tomography (dbPET) is useful for detecting breast cancer. This study investigated the performance of dbPET for incidental findings that were not detected by mammography and ultrasonography. In 1,076 patients with breast cancer who underwent dbPET, 276 findings were incidentally diagnosed before treatment. Each finding was categorized as focus (uptake size ≤ 5 mm), mass (> 5 mm), or non-mass (multiple uptake) according to uptake patterns. Non-mass uptakes were additionally classified based on their distributions as—linear, focal, segmental, regional, or diffuse. Thirty-two findings (11.6%) were malignant and 244 (88.4%) were benign. Visually, 227 (82.3%) findings were foci, 7 (2.5%) were masses, and 42 (15.2%) were non-masses. Malignant rates of focus, mass, and non-mass were 9.7%, 28.6%, and 19.0%, respectively. In the non-mass findings, 23 were regional and diffuse distributions, and presented as benign lesions. Focus uptake with low lesion-to-background ratio (LBR) and no hereditary risk were relatively low (2.7%) in breast cancer. In multivariate analysis, LBR and hereditary risk were significantly associated with breast cancer ( p  = 0.006 and p  = 0.013, respectively). Uptake patterns, LBR, and hereditary risk are useful for predicting breast cancer risk in incidental dbPET findings.

Background/Aim: Docetaxel and cyclophosphamide (TC) combination therapy is widely used as adjuvant chemotherapy for early-stage breast cancer and is associated with a high incidence of febrile neutropenia (FN). Granulocyte colony-stimulating factor (G-CSF) is recommended in the primary prevention of febrile neutropenia (FN). This study aimed to evaluate the FN-suppressing effect of G-CSF in patients with breast cancer receiving TC. Patients and Methods: We performed 272 treatment cycles after FN onset in 106 patients with breast cancer receiving TC. We retrospectively evaluated the effect of G-CSF as secondary prophylaxis. The frequency of FN was calculated based on the treatment cycles to adjust for differences in the number of cycles per case and FN occurrence. Results: FN occurred in 58 cycles (21.3%). The incidence of FN with and without secondary prophylactic G-CSF was 10.1% and 25.9%, respectively (p=0.003). Multivariate analysis showed secondary prophylactic G-CSF administration to be an independent predictor of FN incidence [odds ratio (OR)=0.33, 95% confidence interval (CI)=0.14-0.74, p=0.007]. Conclusion: Secondary prophylaxis with G-CSF is recommended for patients with breast cancer undergoing TC chemotherapy to reduce the incidence of FN.

Aim: To investigate whether tumor-infiltrating lymphocyte (TIL) scoring based on 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) can predict the pathological response to neoadjuvant chemotherapy. Patients and Methods: A total of 261 patients with breast cancer underwent complete resection after neoadjuvant chemotherapy. PET-TIL score was calculated using tumor size, Ki-67 labeling index, and maximum standardized uptake value (SUVmax) on FDG PET/CT. The efficacy of the PET-TIL score in predicting the pathological complete response (pCR) was retrospectively evaluated. Results: pCR rates were 11.4%, 58.6%, and 38.8% in luminal, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative breast cancer, respectively. The corresponding median PET-TIL scores were 28, 37, and 45. pCR rates were 20.0% and 44.2% in the low and high PET-TIL score groups, respectively (p<0.001). HER2-positive and triple-negative subtypes and high PET-TIL score were independent predictors for pCR. Conclusion: PET-TIL score can predict pCR after neoadjuvant chemotherapy in breast cancer.

Breast cancer stem cells are a promising therapeutic target in cancer. We explored breast cancer stem cell diversity and establish a methodology for selectively culturing breast cancer stem cells. We collected breast cancer tissues from surgical samples of treatment-naïve patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Following isolation, cells were subjected to spheroid culture on non-adherent plates. Of the 57 cases, successful culture was achieved in 48 cases, among which the average ratio of CD44+/CD24− breast cancer cells increased from 13.8% in primary tumors to 61.6% in spheroids. A modest number of spheroid cells successfully engrafted in mice and subsequently re-differentiated within the murine environment, confirming their stemness. ER expression in spheroid cells exhibited negative conversion in 52.1% of cases. The proportion of Twist-, Snail-, and Vimentin-positive cells increased from 43.8%, 12.9%, and 7.7–75.0%, 58.1%, and 37.7%, respectively. ER-positive, HER2-negative breast cancer stem cells were classified into two groups using DNA microarrays. Gene Ontology analysis unveiled higher expression of immune response-related genes in one group and protein binding-associated genes in the other. We demonstrated stable and selective culture of breast cancer stem cells from patient-derived breast cancer tissue using spheroid cultures.

Purpose18F-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.MethodsA 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).ResultsSUVmax 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).ConclusionsBoth 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.

BackgroundTumor-infiltrating lymphocytes–ultrasonography (TILs–US) score is used to predict lymphocyte-predominant breast cancer (LPBC) in surgical specimens. We aimed to compare diagnostic performance of TILs–US score for predicting pathological complete response (pCR) with that of LPBC in biopsy specimens.MethodsTILs ≥ 50% in biopsy specimens was defined as biopsy–LPBC, and TILs–US score ≥ 4 was categorized as TILs–US score-high. Basic nomogram for pCR was developed using stepwise logistic regression based on the smallest Akaike Information Criterion, and biopsy–LPBC and TILs–US score nomograms were developed by integrating biopsy–LPBC or TILs–US scores into a basic nomogram. The diagnostic performance of the nomograms for pCR was compared using area under the curve (AUC), categorical net reclassification improvement (NRI), and integrated discrimination improvement (IDI).ResultsThis retrospective study evaluated 118 patients with breast cancer, including 33 (28.0%) with biopsy–LPBC, 52 (44.1%) with TILs–US score-high, with 34 (28.8%) achieving pCR. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and AUC for predicting pCR were 0.53, 0.82, 2.96, 0.57, and 0.68, respectively, for biopsy–LPBC, and 0.76, 0.69, 2.47, 0.34, and 0.73, respectively, for TILs–US score. The biopsy–LPBC nomogram showed significant improvements in categorical NRI (p = 0.023) and IDI (p = 0.007) but not in AUC (p = 0.25), compared with the basic nomogram. The TILs–US nomogram exhibited significant improvements in AUC (p = 0.039), categorical NRI (p = 0.010), and IDI (p < 0.001).ConclusionsThe TILs–US score may serve as a novel marker for prediction of pCR in patients with breast cancer. An external validation study is warranted to confirm our findings.

Aim: To investigate the usefulness of classification of ring-type dedicated breast positron-emission tomography (dbPET) findings in detection of breast cancer. Patients and Methods: A total of 709 patients with breast cancer underwent dbPET before treatment. Each finding was morphologically categorized as a focus (uptake size ≤5 mm), mass (>5 mm), or non-mass (multiple uptakes not belonging to a three-dimensional mass or without distinct mass features). Non-mass uptakes were additionally classified as linear, focal, segmental, regional, or diffuse distributions. Lesion-to-background ratios were calculated. Results: Among 910 abnormal findings, 700 (76.9%) were malignant and 210 (23.1%) were benign. Morphologically, 198 (21.8%) lesions were foci, 431 (47.4%) were masses, and 281 (30.9%) were non-masses. In multivariate analysis, mass, focal and segmental distributions of non-mass lesions and high lesion-to-background ratio were significantly related to breast cancer (all p<0.001). Conclusion: Classification of abnormal findings on dbPET using morphology and lesion-to-background ratio were useful to detect breast cancer.