Hypofractionated radiotherapy with simultaneous tumor bed boost (Hi-RISE) in breast cancer patients receiving upfront breast-conserving surgery: study protocol for a phase III randomized controlled trial.

BACKGROUND: The effectiveness and safety of moderately hypofractionated radiotherapy (HFRT) in patients undergoing breast-conserving surgery (BCS) has been demonstrated in several pivotal randomized trials. However, the feasibility of applying simultaneous integrated boost (SIB) to the tumor bed and regional node irradiation (RNI) using modern radiotherapy techniques with HFRT needs further evaluation. METHODS: This prospective, multi-center, randomized controlled, non-inferiority phase III trial aims to determine the non-inferiority of HFRT combined with SIB (HFRTsib) compared with conventional fractionated radiotherapy with sequential boost (CFRTseq) in terms of five-year locoregional control rate in breast cancer patients undergoing upfront BCS. A total of 2904 participants will be recruited and randomized in a 1:1 ratio into the HFRTsib and CFRTseq groups. All patients will receive whole breast irradiation, and those with positive axillary nodes will receive additional RNI, including internal mammary irradiation. The prescribed dose for the HFRTsib group will be 40 Gy in 15 fractions, combined with a SIB of 48 Gy in 15 fractions to the tumor bed. The CFRTseq group will receive 50 Gy in 25 fractions, with a sequential boost of 10 Gy in 5 fractions to the tumor bed. DISCUSSION: This trial intends to assess the effectiveness and safety of SIB combined with HFRT in early breast cancer patients following BCS. The primary endpoint is locoregional control, and the results of this trial are expected to offer crucial evidence for utilizing HFRT in breast cancer patients after BCS. TRIAL REGISTRATION: This trial was registered at ClincalTrials.gov (NCT04025164) on July 18, 2019.

Molecular subtypes predict second breast events of ductal carcinoma in situ after breast-conserving surgery.

PURPOSE: Currently, the prognostic value of molecular subtypes in ductal carcinoma in situ (DCIS) remains unclear. In this study, we explored whether molecular subtypes could predict second breast events (SBEs) in patients after breast-conserving surgery (BCS). METHODS: From January 2008 to December 2016, 291 DCIS patients treated with BCS were retrospectively analyzed. Patients were classified into four molecular subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) overexpression, and triple-negative breast cancer (TNBC). The SBE incidence was calculated by the competing risk model and compared by Gray's test. The disease-free survival rates were estimated by the Kaplan-Meier method and compared by the log-rank test. Prognostic factors were evaluated by univariate and multivariate COX proportional hazards regression model. RESULTS: With a median follow-up of 66 months, 12 SBEs were identified. The 5-year overall SBE incidence of luminal A, luminal B, HER2 overexpression, and TNBC was 2.18%, 4.25%, 15.15%, and 0.00%, respectively. In the univariate analysis, the HER2 overexpression subtype was the predictor of overall (p = 0.005), in situ (p = 0.004), and ipsilateral SBEs (p = 0.008). Patients with endocrine therapy were less likely to develop in situ SBEs (p = 0.039). Additionally, patients with closed (<2 mm) or involved margins were related to a higher risk of contralateral SBEs (p = 0.029). In the multivariate analysis, the HER2 overexpression subtype remained of prognostic values for overall (p = 0.006), in situ (p = 0.029), and ipsilateral SBEs (p = 0.012). CONCLUSIONS: The molecular subtype, especially the HER2 overexpression subtype, was the independent prognostic factor for DCIS patients who underwent BCS.

Radiomics predicts the prognosis of patients with locally advanced breast cancer by reflecting the heterogeneity of tumor cells and the tumor microenvironment.

BACKGROUND: This study investigated the efficacy of radiomics to predict survival outcome for locally advanced breast cancer (LABC) patients and the association of radiomics with tumor heterogeneity and microenvironment. METHODS: Patients with LABC from 2010 to 2015 were retrospectively reviewed. Radiomics features were extracted from enhanced MRI. We constructed the radiomics score using lasso and assessed its prognostic value. An external validation cohort from The Cancer Imaging Archive was used to assess phenotype reproducibility. Sequencing data from TCGA and our center were applied to reveal genomic landscape of different radiomics score groups. Tumor infiltrating lymphocytes map and bioinformatics methods were applied to evaluate the heterogeneity of tumor microenvironment. Computational histopathology was also applied. RESULTS: A total of 278 patients were divided into training cohort and validation cohort. Radiomics score was constructed and significantly associated with disease-free survival (DFS) of the patients in training cohort, validation cohort and external validation cohort (p < 0.001, p = 0.014 and p = 0.041, respectively). The radiomics-based nomogram showed better predictive performance of DFS compared with TNM model. Distinct gene expression patterns were identified. Immunophenotype and immune cell composition was different in each radiomics score group. The link between radiomics and computational histopathology was revealed. CONCLUSIONS: The radiomics score could effectively predict prognosis of LABC after neoadjuvant chemotherapy and radiotherapy. Radiomics revealed heterogeneity of tumor cell and tumor microenvironment and holds great potential to facilitate individualized DFS estimation and guide personalized care.

Symptoms Related to Brachial Plexus Neuropathy After Supraclavicular Irradiation and Boost in Breast Cancer.

PURPOSE: To evaluate the incidence of symptoms related to brachial plexus neuropathy (BPN) and the dose distribution to the brachial plexus (BP) in patients with breast cancertreated with supraclavicular (SCV) irradiation and boost. METHODS AND MATERIALS: In this study, 117 patients with initial ipsilateral supraclavicular lymph node (SLN) metastasis and 39 with recurrent SLN metastasis between 2008 and 2018 in our cancer center were retrospectively analyzed. All patients were treated with 50 Gy of SCV irradiation in 25 fractions and a boost (median dose, 10 Gy; range, 10-16 Gy) to involved nodes in the SCV area. Symptoms related to BPN (including ipsilateral arm numbness, pain, and weakness) were recorded and graded according to the Common Terminology Criteria for Adverse Events, version 5.0. The BP was delineated on simulation computed tomography, and the dose distributions to the BP were evaluated. Meanwhile, 297 patients treated with SCV irradiation without boost during the same period were identified as a control group to compare the incidences of BPN-related symptoms and dosimetric data with patients who received an SCV boost. RESULTS: The 5-year overall survival rate was 80.3% for patients with initial SLN metastasis and 51.0% for patients with recurrent SLN metastasis. For patients who received an SCV boost, incidence rates of ipsilateral arm numbness, pain, and weakness were 23.9%, 18.3%, and 34.3%, respectively. Four patients (5.6%) developed grade 2 numbness and 3 (4.3%) developed grade 2 arm weakness. In the control group, incidence rates of arm numbness, pain, and weakness were 31.6%, 21.9%, and 36.0%, respectively. The incidence of BPN-related symptoms was not significantly different between the 2 groups. Symptoms of grade 3 were not observed in either cohort. The mean doses to the BP in patients who received boost and who did not were 56.8 and 46.8 Gy, respectively (P < .001). The maximum doses to the BP in patients who received boost and who did not were 64.5 and 53.5 Gy, respectively (P < .001). The BP volumes receiving at least 50 Gy, 60 Gy, 61 Gy, and 62 Gy were also significantly higher in the boosted group compared with the control group (P < .001). CONCLUSIONS: This study found that an SCV boost of 10 Gy did not increase the incidence of BPN-related symptoms and that the toxicity to the BP was acceptable. Comprehensive treatment including SCV irradiation and boost led to satisfactory survival outcomes in patients with breast cancer who had SLN metastasis.

Impact of clinical-pathological factors on locoregional recurrence in mastectomy patients with T1-2N1 breast cancer: who can omit adjuvant radiotherapy?

PURPOSE: Postmastectomy radiation therapy (PMRT) in T1-T2 tumors with 1-3 positive axillary lymph nodes (ALNs) is controversial. This study was to identify prognostic factors of locoregional control (LRC) following mastectomy with or without PMRT for patients with T1-2N1 breast cancer and to discuss the selection of patients who might omit PMRT. MATERIALS AND METHODS: Between January 2006 and December 2012, the data of 1474 postmastectomy patients staged pT1-2N1 were analyzed. PMRT was applied in 663 patients. LRC and disease-free survival (DFS) were calculated using the Kaplan-Meier method. Cox regression model was applied in the univariate and multivariate analyses to recognize the recurrence risk factors. RESULTS: With the median follow-up duration of 93 months (range, 5-168 months), 78 patients (5.3%) failed to secure LRC and 220 patients (14.9%) experienced any recurrence. The 7.7-year LRC and DFS was 94.9% and 85.4% respectively in the entire cohort. PMRT significantly improved 7.7-year LRC from 93.4% to 96.6% (p = 0.005), but not the DFS (p = 0.335). Multivariate analysis revealed that PMRT was an independent prognostic factor of LRC (p < 0.001), meanwhile, age ≤ 40 years (p = 0.012), histological grade 3 (p = 0.004), 2-3 positive nodes (p < 0.001) and tumor size of 3-5 cm (p = 0.045) were significantly associated with decreased LRC. The 7.7-year LRC for patients with 0, 1, and 2-4 risk factors was 97.7% / 98.9% (p = 0.233), 95.3% / 98.0% (p = 0.092), and 80.3% / 94.8% (p < 0.001) in the non-PMRT and PMRT group, respectively. CONCLUSIONS: In patients with T1-2N1 breast cancer, clinical-pathological factors including young age, histological grade 3, 2-3 positive nodes, and tumor size of 3-5 cm were identified to be predictors of a poorer LRC following mastectomy. Patients with 0-1 risk factor might consider the omission of PMRT.

Does the protocol-required uniform margin around the CTV adequately account for setup inaccuracies in whole breast irradiation?

PURPOSE: To use cone-beam computed tomography (CBCT) imaging to determine the impacts of patient characteristics on the magnitude of geometric setup errors and obtain patient-specific planning target volume (PTV) margins from the correlated patient characteristics in whole breast irradiation (WBI). METHODS: Between January 2019 and December 2019, a total of 97 patients who underwent breast-conserving surgery, followed by intensity-modulated radiation therapy in WBI, were scanned with pre-treatment CBCT for the first three treatment fractions and weekly for the subsequent fractions. Setup errors in the left-right (LR), superior-inferior (SI) and anterior-posterior (AP) directions were recorded and analyzed with patient characteristics-including age, tumor location, body mass index (BMI), chest circumference (CC) and breast volume (BV)-to examine the predictors for setup errors and obtain specific PTV margins. RESULTS: A total of 679 CBCT images from 97 patients were acquired for analysis. The mean setup errors for the whole group were 2.32 ± 1.21 mm, 3.71 ± 2.21 mm and 2.75 ± 1.56 mm in the LR, SI and AP directions, respectively. Patients' BMI, CC and BV were moderately associated with setup errors, especially in the SI directions (R = 0.40, 0.43 and 0.22, respectively). Setup errors in the SI directions for patients with BMI > 23.8 kg/m2, CC > 89 cm and BV > 657 cm3 were 4.56 ± 2.59 mm, 4.77 ± 2.42 mm and 4.30 ± 2.43 mm, respectively, which were significantly greater than those of patients with BMI ≤ 23.8 kg/m2, CC ≤ 89 cm and BV ≤ 657 cm3 (P < 0.05). Correspondingly, the calculated PTV margins in patients with BMI > 23.8 kg/m2, CC > 89 cm and BV > 657 cm3 were 4.25/7.95/4.93 mm, 4.37/7.66/5.24 mm and 4.22/7.54/5.29 mm in the LR/SI/AP directions, respectively, compared with 3.64/4.64/5.09 mm, 3.31/4.50/4.82 mm and 3.29/5.74/4.73 mm for BMI ≤ 23.8 kg/m2, CC ≤ 89 cm and BV ≤ 657 cm3, respectively. CONCLUSIONS: The magnitude of geometric setup errors was moderately correlated with BMI, CC and BV. It was recommended to set patient-specific PTV margins according to patient characteristics in the absence of daily image-guided treatment setup.

Outcomes in Patients with pT3N0M0 Breast Cancer with and without Postmastectomy Radiotherapy.

PURPOSE: The role of adjuvant postmastectomy radiotherapy (PMRT) remains controversial for patients with pT3N0M0 breast cancer, especially when patients are treated with the updated adjuvant chemotherapy. Our study aimed to compare locoregional recurrence-free survival (LRFS), disease-free survival (DFS), and breast cancer-specific survival (BCSS) in pT3N0M0 patients with and without postmastectomy radiotherapy. PATIENTS AND METHODS: Between October 2000 and 8 September 2016, the database of the Breast Cancer Center of Shanghai yielded 114 patients with node-negative non-metastatic breast cancer larger than 5 cm. Univariate and multivariate analyses were performed to assess the risk factors for survivals. Differences between the two groups were compared using the Log rank test. RESULTS: Fifty-nine (51.8%) of the patients received adjuvant PMRT. The median follow-up was 62.3 months. Five-year LRFS was 100% in the PMRT group vs 98.1% in the non-PMRT group (P=0.17); 5-year DFS was 97.1% for the entire cohort, 98.0% for the PMRT group vs 96.2% for the non-PMRT group (P=0.18). Univariate analysis identified that family history of malignant tumors, lymphovascular invasion (LVI), or triple-negative breast cancer (TNBC) molecular subtype were associated with higher locoregional recurrence (LRR) (P<0.05). No PMRT was the only risk factor independently associated with poorer DFS (P=0.048) on multivariate analysis. No difference in BCSS was observed between the two groups. CONCLUSION: The present study demonstrated a low LRR rate and good survival for node-negative breast cancer >5 cm. Patients with family history of malignant tumors, TNBC subtype, LVI positivity, or grade 3 disease are at high risk for LRR and might benefit from PMRT.

Postoperative radiotherapy improves overall survival in patients with primary squamous cell carcinoma of the breast.

BACKGROUND: Primary squamous cell carcinoma of the breast (PSCCB) is a rare clinical classification of breast tumors. Little is known about its clinicopathological features, prognosis and potential therapeutic strategies. The purpose of this study is to evaluate the effect of postoperative radiotherapy (PORT) on patients with squamous cell carcinoma (SCC) of the breast. METHODS: We retrospectively analyzed patients diagnosed with PSCCB in our center. All pathological slides were reviewed by an experienced pathologist to confirm the diagnosis. Furthermore, we searched the public database for patients with SCC of the breast. Then, we analyzed the clinicopathological features, treatment methods and patient outcomes. RESULTS: We identified 14 patients with primary SCC of the breast in our center. Additionally, 739 patients with SCC of the breast from the Surveillance, Epidemiology and End Results (SEER) database were diagnosed between 1975 and 2016. Only 453 patients who underwent surgery were included in this study. Patients from the SEER database had a more advanced tumor node metastasis (TNM) stage than patients from our center. The median overall survival (OS) of all patients was 104 months (95% confidence interval [CI], 87.2-120.8 months), and the 5-year OS was 60.8% (95% CI, 56.1%-65.5%). Most of the patients (58%) tested negative for hormonal receptor expression. Multivariate analysis showed that PORT was an independent prognostic factor for OS. CONCLUSION: The results of our study demonstrate that SCC of the breast presents aggressive behavior with unique clinical characteristics. PORT improved OS significantly in patients with SCC of the breast. Longer-term studies are needed to confirm our findings.

CDK4/6 inhibitors: a novel strategy for tumor radiosensitization.

Recently, the focus of enhancing tumor radiosensitivity has shifted from chemotherapeutics to targeted therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a novel class of selective cell cycle therapeutics that target the cyclin D-CDK4/6 complex and induce G1 phase arrest. These agents have demonstrated favorable effects when used as monotherapy or combined with endocrine therapy and targeted inhibitors, stimulating further explorations of other combination strategies. Multiple preclinical studies have indicated that CDK4/6 inhibitors exhibit a synergistic effect with radiotherapy both in vitro and in vivo. The principal mechanisms of radiosensitization effects include inhibition of DNA damage repair, enhancement of apoptosis, and blockade of cell cycle progression, which provide the rationale for clinical use. CDK4/6 inhibitors also induce cellular senescence and promote anti-tumor immunity, which might represent potential mechanisms for radiosensitization. Several small sample clinical studies have preliminarily indicated that the combination of CDK4/6 inhibitors and radiotherapy exhibited well-tolerated toxicity and promising efficacy. However, most clinical trials in combined therapy remain in the recruitment stage. Further work is required to seek optimal radiotherapy-drug combinations. In this review, we describe the effects and underlying mechanisms of CDK4/6 inhibitors as a radiosensitizer and discuss previous clinical studies to evaluate the prospects and challenges of this combination.

Biological subtype predicts locoregional recurrence after postmastectomy radiotherapy in Chinese breast cancer patients.

AIM: To investigate the impact of biological subtypes in locoregional recurrence in Chinese breast cancer patients receiving postmastectomy radiotherapy (PMRT). METHODS AND MATERIALS: About 583 patients who received postmastectomy radiation between 2010 and 2012 were retrospectively analyzed. According to immunohistochemical staining profile, patients were classified into: Luminal A-like, Luminal B-like, HER2-positive, and triple-negative breast cancer (TNBC). Local and regional recurrence (LRR) cumulative incidences were calculated by competing risks methodology and the power of prognostic factors was examined by Gray's test and the test of Fine and Gray. RESULTS: The median follow-up was 70.9 months. About 34 LRR events occurred. For Luminal A, Luminal B, HER2-positive, and TNBC patients, the 5-year LRR cumulative incidence rates were 1.57%, 4.09%, 10.74%, and 10.28%. Compared with Luminal A, HER2-positive subtype and TNBC had a significant increased risk of LRR (HR was 5.034 and 5.188, respectively). In univariate analysis, predictive factors for higher LRR were HER2-positive subtype (HR = 4.43, P < .05), TNBC (HR = 4.70, P < .05), and pN3 (HR = 5.83, P < .05). In the multivariate model, HER2-positive subtype (HR = 5.034, P < .05), TNBC (HR = 5.188, P < .05), and pN3 (HR = 9.607, P < .01) were independent predictors of LRR. LRR without trastuzumab was similar to that of TNBC (without vs TNBC, 17.88% vs 10.28%, P > .05) in HER2-positive subtype patients, while LRR with trastuzumab was approximate to Luminal A (with vs Luminal A, P > .05). Additionally, endocrine therapy also significantly reduced LRR incidence in the luminal subtype cohort (without vs with therapy, 6.25% vs 2.89%, HR = 0.365, P < .1). CONCLUSIONS: Biological subtype was a prognostic factor of LRR in the PMRT setting among Chinese breast cancer patients.

Internal mammary node irradiation improves 8-year survival in breast cancer patients: results from a retrospective cohort study in real-world setting.

BACKGROUND: Regional nodal irradiation (RNI) improves disease outcome in breast cancer patients, but the contribution of internal mammary node irradiation (IMNI) in the context of modern systemic treatment is still controversial. The aim of our study is to evaluate the effect of IMNI in patients with modern systemic treatment in real-world setting. METHODS: We retrospectively analyzed patients with primary breast cancer treated with surgery followed by adjuvant chemotherapy and adjuvant chestwall/breast irradiation and RNI from 5/2007-12/2010. RNI was delivered to the ipsilateral supraclavicular region and infraclavicular region + / - IMNs. We separated two groups based on the presence and the absence of IMNI. The primary end point was disease-free survival (DFS). DFS and overall survival (OS) were evaluated with Kaplan-Meier method. Differences between two groups were compared with the log-rank test (p < 0.05 considered significant). We used two methods to account for potential confounders: propensity score matching (PSM) and Cox regression analysis. RESULTS: We analyzed 872 patients who received RNI with IMNI (n = 390) or without IMNI (n = 482). Median radiation dose was 50 Gy. Median follow-up was 98 months. IMNI improved 8-year DFS rates versus no IMNI: 75.9% and 64.9% (p < 0.001). After PSM, baseline characteristics were well balanced between the two groups. IMNI significantly improved DFS (p < 0.001) in patients after PSM. IMNI was an independent prognostic factor for DFS. CONCLUSIONS: In this study, we found that IMNI improved DFS and OS in breast cancer patients in the context of modern systemic treatment. These data continue to support that IMNI is a key component of RNI.

Single institution experience of split course radiotherapy in patients with desmoid tumors.

PURPOSE: This study aimed to assess the feasibility of split course radiotherapy (SCRT) and reports long-term outcomes in patients with desmoid tumors (DT). PATIENTS AND METHODS: Between 2001 and 2004, 31 patients with recurrent (n=19) or primary large desmoid fibromatosis (≥10 cm) (n=12) who were treated with SCRT were retrospectively analyzed. All patients were treated with two phases of radiotherapy with a median interval time of 99 days (range: 81-122 days) and a median total dose of 6,399 cGy (range: 5,013-7,039 cGy). The median dose for the first phase was 3,969 cGy/22 Fx (range: 2,999-4,305 cGy), and 2,495 cGy/14 Fx (range: 1,982-3,039 cGy) for the second phase. Progression-free survival (PFS) in response to radiotherapy was evaluated using the Kaplan-Meier method and compared using the log-rank test. The prognostic factors associated with survival were evaluated by univariate and multivariate analyses. RESULTS: The median age of all patients was 30 years (range, 7-58 years). With a median follow-up of 60.4 months (range, 2-187 months), eight patients experienced disease progression after treatment. The PFS rate at 3 and 5 years for the whole population was 90% and 71.3%, respectively. PFS for patients with split course of <100 days or ≥100 days interval was 100% vs 78.6% at 3 years, and 80.4% vs 62.9% at 5 years, respectively (P=0.189). In multivariate analysis, the radiotherapy (RT) interval time was an independent prognostic factor for PFS (≥100 days vs <100 days, HR 11.544, 95% CI 1.034-128.878, P=0.047). PFS was not significantly influenced by age, gender, surgery, tumor location, RT technology, or RT dose. Radiation-related acute complications occurred in nine (29%) patients after RT, and RT-related long-term complications occurred in three (9.7%) patients. CONCLUSION: SCRT with an appropriate treatment interval (<100 days) is well tolerated by DT patients with favorable long-term outcomes.

The Impact of Radiotherapy on Reoperation Rates in Patients Undergoing Mastectomy and Breast Reconstruction.

OBJECTIVE: The aim of this study was to determine the impact of postmastectomy radiotherapy (PMRT) on reoperation rates in women with breast cancer undergoing mastectomy and breast reconstruction. METHODS: Between June 2001 and December 2015, 832 breast cancer patients treated with mastectomy and breast reconstruction with (n = 159) or without (n = 673) PMRT were analyzed retrospectively. Reoperations following breast reconstruction were categorized into the following three types: anticipated, unanticipated, and others. Multivariable logistic regression models were used to evaluate the impact of PMRT on overall and unanticipated reoperations according to different breast reconstruction types after adjusting for relevant covariates. RESULTS: With a median follow-up of 58.5 months, a total of 1298 operations were performed in 832 breast cancer patients. The rates of overall and unanticipated reoperations were 46.2% and 7.7%, respectively. Multivariable analysis showed that PMRT was not associated with overall reoperations in either implant-based reconstruction patients (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.43-2.37, p = 0.995) or autologous reconstruction patients (OR 0.85, 95% CI 0.52-1.40, p = 0.533); however, the impact of PMRT on unanticipated reoperations differed by reconstruction type. In patients who received implant-based reconstructions, PMRT was associated with a 3.05-fold (95% CI 1.20-7.75, p = 0.019) higher odds of unanticipated reoperations, while there was no difference in patients who underwent autologous reconstruction (OR 1.17, 95% CI 0.51-2.66, p = 0.713). Delayed reconstruction or delayed-immediate reconstructions were associated with an increased risk of both overall and unanticipated reoperations in both reconstruction cohorts. CONCLUSIONS: PMRT appears to be associated with an increased risk of unanticipated reoperations among patients receiving implant-based reconstruction, but not among those receiving autologous reconstruction. The risk of reoperation should be taken into consideration when selecting the appropriate breast reconstruction type when PMRT is planned.

Internal Mammary Node Irradiation (IMNI) Improves Survival Outcome for Patients With Clinical Stage II-III Breast Cancer After Preoperative Systemic Therapy.

PURPOSE: The indication for internal mammary node irradiation (IMNI) after preoperative systemic therapy in breast cancer remains vague. This study was designed to evaluate the effect of IMNI in patients with clinical stage II-III breast cancer after preoperative systemic therapy and surgery. METHODS AND MATERIALS: Between August 2005 and December 2013, 497 patients with clinical stage II-III breast cancer underwent anthracycline- or taxane-based preoperative systemic therapy, surgery, and postoperative radiation therapy. A median dose of 50 Gy (range, 46-60 Gy) in 25 fractions was delivered to the chest wall or breast with IMNI (n = 236) or without IMNI (n = 261). Disease-free survival (DFS) and overall survival (OS) rates with or without IMNI were evaluated using the Kaplan-Meier method and compared with the log-rank test. Propensity score matching was performed to adjust for the unbalanced characteristics between the 2 groups. Prognostic factors associated with survival were evaluated by univariate and multivariate analysis. RESULTS: The median follow-up time was 64 months. Patients with IMNI presented with more advanced clinical T stage, pathologic N stage, positive lymph-vascular invasion, and medically or centrally located disease (P < .05). The 5-year DFS and OS rates were 73.7% and 86.3% in the IMNI group and 71.5% and 86.7% in the non-IMNI group, respectively (P > .05). Multivariate analysis demonstrated that IMNI was an independent prognostic factor for DFS (P = .018) and resulted in a borderline improvement in OS (P = .067). After propensity score matching, characteristics were well balanced. The 5-year DFS rates of IMNI and non-IMNI group were 76.8% and 63.4%, respectively (P = .030), and the 5-year OS rates were 88.9% and 84.1%, respectively (P = .083). IMNI was independently prognostic for DFS (P = .014) and OS (P = .047) in matched patients. CONCLUSIONS: IMNI improves survival outcomes in patients with clinical stage II-III breast cancer after preoperative systemic therapy. Further prospective studies are warranted to identify the role of IMNI in the preoperative systemic therapy setting.

Postmastectomy radiotherapy reduces locoregional and disease recurrence in patients with stage II-III triple-negative breast cancer treated with neoadjuvant chemotherapy and mastectomy.

BACKGROUND: This study investigated the effect of postmastectomy radiotherapy (PMRT) in patients with stage II-III triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC) and modified radical mastectomy (MRM). PATIENTS AND METHODS: A total of 104 women with stage II-III TNBC who received NAC and MRM at our institution between January 2000 and July 2007 were identified. Patients were divided into 2 groups (PMRT and non-PMRT) for statistical analysis. RESULTS: The median follow-up time was 64 months (range 12-123 months). The 5 year cumulative locoregional recurrence (LRR) and disease recurrence (DR) rates were 26.5% and 49.6%, respectively. Despite their more adverse prognostic features, patients with PMRT had lower 5 year cumulative LRR and DR rates than those without PMRT (LRR: 18.3% vs 52.2%, respectively, p=0.0005; DR: 45% vs 69.1%, p=0.0334, respectively). On multivariate analysis of the entire study cohort, forgoing PMRT was significantly associated with developing LRR and DR. Subset analysis revealed that PMRT significantly reduced the 5 year LRR rate in patients with pre-chemotherapy clinical stages IIA (8.3% vs 46.2%, p=0.019) and IIIA (16% vs 66.7%, p=0.003). PMRT also significantly reduced the 5 year DR rate in patients with pre-chemotherapy clinical stage IIA (24.5% vs 69.3%, p=0.0151) and ≥IIIB (70.8% vs 100%, p=0.0481). CONCLUSION: In our cohort of patients with TNBC treated with NAC and MRM, PMRT significantly improved locoregional control and disease-free survival in the entire cohort as well as in patients with stage IIA disease. Our results may help in tailoring adjuvant treatment decisions for these particular patient populations.

Targeting deubiquitinase USP28 for cancer therapy.

As one of the most important post-translational modifications, ubiquitination plays versatile roles in cancer-related pathways, and is involved in protein metabolism, cell-cycle progression, apoptosis, and transcription. Counteracting the activities of the E3 ligases, the deubiquitylating enzymes have been suggested as another important mechanism to modulate the ubiquitination process, and are implicated in cancer as well. In this article, we review the emerging roles of USP28 in cancer pathways as revealed by recent studies. We discuss the major mechanisms by which USP28 is involved in the cancer-related pathways, whereby USP28 regulates physiological homeostasis of ubiquitination process, DNA-damage response, and cell cycle during genotoxic stress. We further review the studies where USP28 was targeted for treating multiples cancers including non-small cell lung cancer, breast cancer, intestinal cancers, gliomas, and bladder cancer. As a result, the clinical significance of targeting USP28 for cancer therapy merits further exploration and demonstration.

Estrogen Receptor Mediates the Radiosensitivity of Triple-Negative Breast Cancer Cells.

BACKGROUND This study aimed to evaluate differences in the radiosensitivities of triple-negative breast cancer (TNBC) and luminal-type breast cancer cells and to investigate the effects of estrogen receptor (ER) expression on the biological behaviors of the cells. MATERIAL AND METHODS Colony-forming assays were performed to detect differences in radiosensitivities in breast cancer cell lines. Gene transfection technology was used to introduce the expression of ERα in TNBC cells to compare the difference in radiosensitivity between the TNBC cells and ERα transfected cells. CCK-8 assays were used to observe changes in the proliferation of TNBC cells after ERα transfection. Immunofluorescence was used to detect the number of γH2AX foci in nuclei. Flow cytometry was used to detect changes in cell cycle distribution and apoptosis. Western blotting was used to detect changes in autophagy-associated proteins. RESULTS The radioresistance of the TNBC cell line MDA-MB-231 (231 cells) was greater than that of ERα-positive luminal-type breast cancer cell line MCF-7. Moreover, 231 cell proliferation and radioresistance decreased after ERα transfection. Interestingly, ERα-transfected 231 cells showed increased double-stranded breaks and delayed repair compared with 231 cells, and ERα-transfected 231 cells showed increased G2/M phase arrest and apoptosis after irradiation compared with those in 231 cells. ERα transfection in 231 cells reduced autophagy-related protein expression, suggesting that autophagy activity decreased in 231 ER-positive cells after irradiation. CONCLUSIONS TNBC cells were more resistant to radiation than luminal-type breast cancer cells. ERα expression may have major roles in modulating breast cancer cell radiosensitivity.

The Chk1 inhibitor MK-8776 increases the radiosensitivity of human triple-negative breast cancer by inhibiting autophagy.

MK-8776 is a recently described inhibitor that is highly selective for checkpoint kinase 1 (Chk1), which can weaken the DNA repair capacity in cancer cells to achieve chemo-sensitization. A number of studies show that MK-8776 enhances the cytotoxicity of hydroxyurea and gemcitabine without increasing normal tissue toxicities. Thus far, there is no evidence that MK-8776 can be used as a radiotherapy sensitization agent. In this study, we investigated the effects of MK-8776 on the radiosensitivity of 3 human triple-negative breast cancer (TNBC) cell lines MDA-MB-231, BT-549 and CAL-51. MK-8776 dose-dependently inhibited the proliferation of MDA-MB-231, BT-549 and CAL-51 cells with IC50 values of 9.4, 17.6 and 2.1 µmol/L, respectively. Compared with irradiation-alone treatment, pretreatment with a low dose of MK-8776 (100-400 nmol/L) significantly increased irradiation-induced γH2A.X foci in the 3 TNBC cell lines, suggesting enhanced DNA damage by MK-8776, inhibited the cell proliferation and increased the radiosensitivity of the 3 TNBC cell lines. Similar results were obtained in MDA-MB-231 xenograft tumors in nude mice that received MK-8776 (15 or 40 mg/kg, ip) 26 d after irradiation. To explore the mechanisms underlying the radio-sensitization by MK-8776, we used TEM and found that irradiation significantly increased the numbers of autophagosomes in the 3 TNBC cell lines. Moreover, irradiation markedly elevated the levels of Atg5, and promoted the transformation of LC3-I to LC3-II in the cells. Pretreatment with the low dose of MK-8776 suppressed these effects. The above results suggest that MK-8776 increases human TNBC radiosensitivity by inhibiting irradiation-induced autophagy and that MK-8776 may be a potential agent in the radiosensitization of human TNBC.

The Value of 18F-FDG PET/CT Imaging Combined With Pretherapeutic Ki67 for Early Prediction of Pathologic Response After Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer.

To evaluate the value of F-fluorodeoxyglucose-positron emission tomography/computed tomography (F-FDG PET/CT) and pretherapeutic Ki67 in predicting pathologic response in locally advanced breast cancer (LABC) after neoadjuvant chemotherapy (NAC).As a training set, total 301 LABC patients treated with NAC were retrospectively analyzed to evaluate the potential predictive value of pretherapeutic Ki67 for pathologic complete response (pCR) after NAC. Another 60 LABC patients were prospectively included as a validation set to evaluate the value of Ki67 combined PET/CT as pCR predictors. Ki67 was assessed in pretherapy core needle biopsy specimens and PET/CT scans were performed at baseline (before initiating NAC), after the 2nd, and 4th cycle of NAC. Maximum standardized uptake value (SUVmax) and its changes relative to baseline (ΔSUVmax%) were used as parameters of PEC/CT.In the training set, Ki67 was a predictor of pCR to NAC, with area under the curve (AUC) of 0.624 (P = 0.003) in receiver-operating characteristic (ROC) analysis. In the validation set, Ki67 alone did not show significant value in predicting pCR in the validation set. ΔSUVmax% after then 2nd or 4th course are predictors of pCR to NAC with the AUC of 0.774 (P = 0.002) and 0.791 (P = 0.002), respectively. When combined with ΔSUVmax% after the 2nd and 4th course NAC, Ki67 increased the value of ΔSUVmax% in predicting pCR with the AUC of 0.824 (P = 0.001). Baseline SUVmax and after 2nd, 4th course NAC had no predictive value for pCR, but SUVmax after the 2nd and 4th course showed remarkable predictive value for nonpathologic response (Grade 1 in Miller-Payne Grading System) with the AUC of 0.898 (P = 0.0001) and 0.801 (P = 0.003).Both PET/CT and Ki67 can predict pCR to NAC in LABC patients in the early phases of treatment. PET/CT combined Ki67 is a better pCR predictor for response to NAC. This helps the physician to predict the probability of pCR, and facilitates the optimization of individual treatment plan in case of ineffective and/or excessive chemotherapy.