Is postmastectomy radiotherapy necessary for breast cancer patients with clinically node-positive downstaging to ypN0 after neoadjuvant chemotherapy?

PURPOSE: The significance of postmastectomy radiotherapy (PMRT) in breast cancer patients who initially have clinically node-positive (cN +) status but achieve downstaging to ypN0 following neoadjuvant chemotherapy (NAC) remains uncertain. This study aims to assess the impact of PMRT in this patient subset. METHODS: Patients were enrolled from West China Hospital, Sichuan University from 2008 to 2019. Overall survival (OS), Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and breast cancer-specific survival (BCSS) were estimated using the Kaplan-Meier method and assessed with the log-rank test. The impact of PMRT was further analyzed by the Cox proportional hazards model. Propensity score matching (PSM) was performed to reduce the selection bias. RESULTS: Of the 333 eligible patients, 189 (56.8%) received PMRT, and 144 (43.2%) did not. At a median follow-up period of 71 months, the five-year LRFS, DMFS, BCSS, and OS rates were 99.1%, 93.4%, 96.4%, and 94.3% for the entire cohort, respectively. Additionally, the 5-year LRFS, DMFS, BCSS, and OS rates were 98.9%, 93.8%, 96.7%, and 94.5% with PMRT and 99.2%, 91.3%, 94.9%, and 92.0% without PMRT, respectively (all p-values not statistically significant). After multivariate analysis, PMRT was not a significant risk factor for any of the endpoints. When further stratified by stage, PMRT did not show any survival benefit for patients with stage II-III diseases. CONCLUSION: In the context of comprehensive treatments, PMRT might be exempted in ypN0 breast cancer patients. Further large-scale, randomized controlled studies are required to investigate the significance of PMRT in this patient subset.

Differential Diagnosis of DCIS and Fibroadenoma Based on Ultrasound Images: a Difference-Based Self-Supervised Approach.

Differentiation of ductal carcinoma in situ (DCIS, a precancerous lesion of the breast) from fibroadenoma (FA) using ultrasonography is significant for the early prevention of malignant breast tumors. Radiomics-based artificial intelligence (AI) can provide additional diagnostic information but usually requires extensive labeling efforts by clinicians with specialized knowledge. This study aims to investigate the feasibility of differentially diagnosing DCIS and FA using ultrasound radiomics-based AI techniques and further explore a novel approach that can reduce labeling efforts without sacrificing diagnostic performance. We included 461 DCIS and 651 FA patients, of whom 139 DCIS and 181 FA patients constituted a prospective test cohort. First, various feature engineering-based machine learning (FEML) and deep learning (DL) approaches were developed. Then, we designed a difference-based self-supervised (DSS) learning approach that only required FA samples to participate in training. The DSS approach consists of three steps: (1) pretraining a Bootstrap Your Own Latent (BYOL) model using FA images, (2) reconstructing images using the encoder and decoder of the pretrained model, and (3) distinguishing DCIS from FA based on the differences between the original and reconstructed images. The experimental results showed that the trained FEML and DL models achieved the highest AUC of 0.7935 (95% confidence interval, 0.7900-0.7969) on the prospective test cohort, indicating that the developed models are effective for assisting in differentiating DCIS from FA based on ultrasound images. Furthermore, the DSS model achieved an AUC of 0.8172 (95% confidence interval, 0.8124-0.8219), indicating that our model outperforms the conventional radiomics-based AI models and is more competitive.

The Value of the 8th Edition of American Joint Committee on Cancer Pathological Prognostic Staging on the Selection of Postmastectomy Radiotherapy for T1-2N1 Breast Cancer.

Methods and Materials: Patients diagnosed with pT1-2N1M0 breast cancer between 2008 and 2018 in West China Hospital, Sichuan University were included. Locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS) were defined as endpoints. The propensity score matching (PSM), receiver operating characteristic (ROC) curve, the Kaplan-Meier analysis, and the Cox multivariable model were used for data analysis. Results: We identified 1,615 patients with T1-2N1M0 breast cancer, and 44.9% (n = 744) of them were treated with PMRT. With a median follow-up of 76 months, 46 (2.8%) recurrences, 96 (5.9%) deaths, and 80 (5.0%) breast cancer-related deaths occurred. The 5-year LRFS, DMFS, DFS, BCSS, and OS were 98.6%, 95.3%, 93.7%, 96.5%, and 96.0%, respectively. PMRT could not improve 5-year LRFS, DMFS, DFS, BCSS, and OS compared with non-PMRT neither before nor after PSM in the era of contemporary systemic treatment. ROC curve showed that the 8th pathological prognostic staging had better discriminative ability compared with the 7th anatomical staging [the area under the curve (AUC) 0.653 vs. 0.546, P < 0.001]. In the anatomical staging system, PMRT had comparable 5-year BCSS in comparison with non-PMRT both in stages IIA (97.4% vs. 96.8%, P = 0.799) and IIB (95.3% vs. 97.0%, P = 0.071). When stratified according to the pathological staging, PMRT was associated with better 5-year BCSS in stage IIB (97.1% vs. 90.7%, P = 0.039), while not in stages IA, IB, IIA, and IIIA. Multivariate analysis demonstrated that PMRT was a significantly protective factor for BCSS in stage IIB (HR 0.331, 95% CI: 0.100-0.967, P = 0.044). Conclusion: The new staging could better select high-risk patients with T1-2N1 breast cancer for radiotherapy compared with the 7th staging, and PMRT might be exempted except the 8th staging of IIB in the era of contemporary systemic therapy in this disease.

The Effect of Postmastectomy Radiotherapy on Breast Cancer Patients After Neoadjuvant Chemotherapy by Molecular Subtype.

BACKGROUND: The effect of postmastectomy radiotherapy (PMRT) on patient outcomes after neoadjuvant chemotherapy (NAC) remains controversial. We aimed to establish a model to identify the subsets benefiting from PMRT and to examine the effect of PMRT according to molecular subtype. PATIENTS AND METHODS: We retrospectively analyzed 1118 cT1-4cN0-3M0 breast cancer patients treated with NAC and mastectomy. A nomogram predicting locoregional recurrence (LRR) was established based on 418 unirradiated patients, and X-tile analysis was performed to divide the patients into two risk groups. The effect of PMRT on LRR, distant recurrence (DR), and breast cancer mortality (BCM) was estimated for patients with different molecular subtypes in two risk groups. RESULTS: A nomogram predicting LRR was developed using six factors: histologic classification, lymphovascular invasion, ypT stage, ypN stage, estrogen receptor status, and Ki-67 expression. Our study found that PMRT correlated with lower 5-year LRR, DR, and BCM rates for the high-risk group; however, no significant improvement in these endpoints was observed in the low-risk group. Among patients with high risk, subgroup analysis showed that LRR control was improved after PMRT for the human epidermal growth factor receptor 2 (HER2)-negative/hormone receptor (HR)-positive (HER2-/HR+), HER2-positive (HER2+)/HR+, and HER2-/HR-negative (HR-) subtypes, with hazard ratios of 0.113 (95% confidence [CI] 0.034-0.379; p < 0.001), 0.159 (95% CI 0.038-0.671; p = 0.017), and 0.243 (95% CI 0.088-0.676; p = 0.007), respectively, but not for the HER2+/HR- subtype (p = 0.468). CONCLUSIONS: We built a nomogram showing favorable risk quantification and patient stratification. Patients in the high-risk group benefited from PMRT, but patients in the low-risk group did not. PMRT may show different benefits for each molecular subtype.

Changes in Body Mass Index, Leptin, and Leptin Receptor Polymorphisms and Breast Cancer Risk.

Obesity is a strong risk factor for breast cancer. The polymorphisms of leptin (LEP) and leptin receptor (LEPR) may be associated with breast cancer by regulator of adipose tissue mass and tumor cell growth. A total of 794 cases and 805 matched controls were sequentially enrolled. Time-of-flight mass spectrometry was used to determine the LEPrs7799039, LEPRrs1137100, and LEPRrs1137101 genotypes for each participant. Associations between polymorphisms of these genes, change in body mass index (BMI), and breast cancer risk were assessed by unconditional multivariable logistic regression models. The unconditional logistic regression model showed that persistent overweight (BMI ≥24 kg/m2) over the preceding 10 years was associated with increased breast cancer risk in premenopausal women (odds ratio [OR] = 1.67, 95% confidence interval [CI]: 1.19-2.35). No associations between LEPrs7799039, LEPRrs1137100, or LEPRrs1137101 polymorphisms alone and breast cancer risk were found. Persistent overweight over the preceding 10 years and carrying the LEPrs7799039 AA genotype together increased breast cancer risk in premenopausal women (ORadj = 2.00, 95% CI: 1.26-3.16). Persistent overweight over the preceding 10 years and carrying the LEPRrs1137100 GG genotype increased breast cancer risk in premenopausal women (ORadj = 1.68, 95% CI: 1.06-2.68). In premenopausal women, persistent overweight (BMI ≥24 kg/m2) over the preceding 10 years increases breast cancer risk. Persistent overweight along with LEPrs7799039 AA or LEPRrs1137100 GG genotypes synergistically increase risk of breast cancer among premenopausal women.

CD55 and CD59 expression protects HER2-overexpressing breast cancer cells from trastuzumab-induced complement-dependent cytotoxicity.

A large proportion (40-60%) of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer do not benefit from trastuzumab treatment, potentially due to the lack of complement-dependent cytotoxicity (CDC) activation. In the present study, the effect of complement decay-accelerating factor (CD55) and CD59 glycoprotein precursor (CD59) expression on trastuzumab-induced CDC in HER2-positive breast cancer cell lines was investigated. The CD55 and CD59-overexpressing and HER2-positive cell lines SK-BR-3 and BT474 were selected for subsequent experiments. Blocking CD55 and CD59 function using targeting monoclonal antibodies significantly enhanced the cell lysis of SK-BR-3 and BT474 cells following treatment with trastuzumab. In addition, following treatment with 0.1 U/ml phosphatidylinositol-specific phospholipase C (PI-PLC) for 1 h, CD55 and CD59 surface expression was significantly decreased, and the cell lysis rate was further enhanced. Treatment of SK-BR-3 cells with short hairpin RNA (shRNA) targeting CD55 and CD59 downregulated CD55 and CD59 expression at the mRNA and protein levels, and resulted in significantly enhanced trastuzumab-induced CDC-dependent lysis. The data from the present study suggested that CD55 and CD59 serve roles in blocking trastuzumab-induced CDC, therefore strategies targeting CD55 and CD59 may overcome breast cancer cell resistance to trastuzumab. The results from the present study may provide a basis for developing suitable, personalized treatment strategies to improve the clinical efficacy of trastuzumab for patients with HER2-positive breast cancer.

[Survival of Patients with Metastatic Recurrent Triple-negative Breast Cancer].

OBJECTIVES: To determine factors associated with the survival of patients with metastatic recurrent triple-negative breast cancer (mrTNBC). METHODS: Initial metastatic recurrent (during or after therapy) patients with triple-negative breast cancer (TNBC) confirmed by post-operate pathology in the West China Hospital of Sichuan University were followed up. The accumulative survival rates after recurrence were calculated using Kaplan-Meier method and differences were tested using log-rank tests. Cox proportional hazards regression analyses were performed to identify independent predictors of survival rates. RESULTS: A total of 142 patients were included in this study. They were followed up on average 41.9 months (range: 5.1-189.5 months), and had median post-recurrence survival time of 22.0 months.Tumor diameter, lymph node status, TNM stage, disease-free interval (DFI), numbers of recurrent lesions, brain metastasis, liver metastasis and the rapeutic patterns were associated with the survival of patients. The Cox proportional hazards regression model identified multi-lesions recurrence ( P=0.004), DFI≤12 months ( P=0.010), brain metastasis ( P=0.037) and single-modal therapy (SMT) ( P<0.001) as independent risk predictors of post-recurrence survival. In the patients with local recurrence, multi-modal therapy (MMT) had 53.0%post-recurrence 3-year survival rate compared with 11.4% of SMT ( P=0.024). Similar results were also found in the patients with distant metastases (post-recurrence 3-year survival rate 58.1% for MMT versus 29.3% for SMT, P=0.003). CONCLUSIONS: Multi-lesions recurrence, short DFI and brain metastasis are independent risk predictors, while MMT is a protective factor for the survival of patients with mrTNBC.

Correlation between activation of PI3K/AKT/mTOR pathway and prognosis of breast cancer in Chinese women.

BACKGROUND: Abnormal activation of PI3K/AKT/mTOR (PAM) pathway, caused by PIK3CA mutation, KRAS mutation, PTEN loss, or AKT1 mutation, is one of the most frequent signaling abnormalities in breast carcinoma. However, distribution and frequencies of mutations in PAM pathway are unclear in breast cancer patients from the mainland of China and the correlation between these mutations and breast cancer outcome remains to be identified. METHODS: A total of 288 patients with invasive ductal breast cancer were recruited in this study. Mutations in PIK3CA (exons 4, 9 and 20), KRAS (exon 2) and AKT1 (exon 3) were detected using Sanger sequencing. PTEN loss was measured by immunohistochemistry assay. Correlations between these genetic aberrations and clinicopathological features were analyzed. RESULTS: The frequencies of PIK3CA mutation, KRAS mutation, AKT1 mutation and PTEN loss were 15.6%, 1.8%, 4.4% and 35.3%, respectively. However, except for PTEN loss, which was tied to estrogen receptor (ER) status, these alterations were not associated with other clinicopathological features. Survival analysis demonstrated that PIK3CA mutation, PTEN loss and PAM pathway activation were not associated with disease-free survival (DFS). Subgroup analysis of patients with ER positive tumors revealed that PIK3CA mutation more strongly reduced DFS compared to wild-type PIK3CA (76.2% vs. 54.2%; P = 0.011). PIK3CA mutation was also an independent factor for bad prognosis in ER positive patients. CONCLUSIONS: AKT1, KRAS and PIK3CA mutations and PTEN loss all exist in women with breast cancer in the mainland China. PIK3CA mutation may contribute to the poor outcome of ER positive breast carcinomas, providing evidence for the combination of PI3K/AKT/mTOR inhibitors and endocrine therapy.

Membrane-bound complement regulatory proteins are prognostic factors of operable breast cancer treated with adjuvant trastuzumab: a retrospective study.

Complement-dependent cytotoxicity (CDC) is an important antitumor mechanism of monoclonal antibodies (mAbs). However, trastuzumab, an anti-HER2 mAb, exerts only minor CDC. Overexpression of membrane-bound complement regulatory proteins (mCRPs), which suppress CDC, have been implicated in various malignant tumors. Here, we explored the predictive role of the expression levels of three mCRPs (CD55, CD59 and CD46) in the prognosis of breast cancer cases that underwent adjuvant trastuzumab treatment. We also studied the effect of mCRP downregulation on trastuzumab-induced CDC in vitro. Sixty-five HER2-positive breast cancer patients who received adjuvant therapy containing trastuzumab, were retrospectively analyzed. Levels of CD55, CD59 and CD46 expression were detected by immunohistochemistry. Chi-square test, Kaplan­Meier survival analysis and a Cox proportional hazards model were used to analyze the association between CD55, CD59 and CD46 expression and prognosis. HER2-positive SK-Br3 and BT-474 breast cancer cells were pretreated with various drugs to reduce mCRP expression. Afterwards, trastuzumab­mediated cytolytic effects were measured. Among the 65 patients, 46.2% had high expression of CD55, 44.6% had high expression of CD59 and 44.6% had high expression of CD46. The median follow-up duration was 47 months (range from 24 to 75 months). Patients with CD55 or CD59 overexpression had a higher relapse rate than those with low expression of CD55 (33.3 vs. 8.6%; P=0.013) or CD59 (31.0 vs. 11.1%; P=0.046). Similarly, mean disease-free survival of patients with CD55 or CD59 overexpression was significantly shorter than those with a low expression of CD55 (56 vs. 70 months; log-rank test, P=0.008) or CD59 (56 vs. 69 months; log-rank test, P=0.033). Multivariate analysis confirmed that CD55, but not CD59, was an independent risk factor of recurrence (HR=4.757; 95% CI, 0.985-22.974; P=0.05). In vitro, we found that tamoxifen inhibited both the protein and mRNA expression levels of CD55, but not CD59 or CD46 in SK-Br3 and BT-474 cells. After pretreatment of tamoxifen, trastuzumab-induced cytolysis was enhanced through CD55 downregulation. In conclusion, CD55 overexpression is an independent risk factor for recurrence in breast cancer patients receiving postoperative adjuvant therapy containing trastuzumab. Combined use of tamoxifen and trastuzumab for HER2-positive breast cancer treatment may enhance the antitumor effects of trastuzumab by elevated CDC, which warrants further study.

Vascular endothelial growth factor (VEGF) gene polymorphisms and breast cancer risk in a Chinese population.

Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in the development and progression of solid tumours. Associations between three VEGF gene polymorphisms (-634 G/C, +936 C/T, and +1612 G/A) and breast cancer risk have been extensively studied, but the currently available results are inconclusive. Our aim was to investigate associations between three VEGF gene polymorphisms and breast cancer risk in Chinese Han patients. We performed a hospital-based case-control study including 680 female incident breast cancer patients and 680 female age-matched healthy control subjects. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect the three VEGF gene polymorphisms. We observed that women carriers of +936 TT genotypes [odds ratio (OR) =0.46, 95% confidence interval (CI) = 0.28, 0.76; P=0.002] or 936 T-allele (OR=0.81, 95% CI= 0.68, 0.98; P=0.03) had a protective effect concerning the disease. Our study suggested that the +1612G/A polymorphism was unlikely to be associated with breast cancer risk. The -634CC genotype was significantly associated with high tumor aggressiveness [large tumor size (OR=2.63, 95% CI=1.15, 6.02; P=0.02) and high histologic grade (OR=1.47, 95% CI= 1.06, 2.03; P=0.02)]. The genotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status. Our study revealed that the VEGF -634 G/C and +936 C/T gene polymorphisms may be associated with breast cancer in Chinese Han patients.