Breast-Conserving Surgery is Oncologically Safe for Well-Selected, Centrally Located Breast Cancer.

OBJECTIVE: The aim of this study was to evaluate the long-term survival outcomes of breast-conserving surgery (BCS) in centrally located breast cancer (CLBC) compared with mastectomy in CLBC and BCS in non-CLBC, based on the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Female patients aged < 80 years with unilateral T1-T2 invasive ductal or lobular breast cancer undergoing BCS or mastectomy were enrolled. The differences in clinical-pathological characteristics were evaluated using Chi square tests. Multivariate logistic regression was used to measure the relationship between predictive variables and performing BCS in CLBC. Survival outcomes were estimated using the Kaplan-Meier method and compared using Cox proportional hazards models. To overcome the effects of baseline differences on survival outcome in patients treated with BCS in the central and upper-outer locations, a 1:1 ratio propensity score matching method was performed. RESULTS: Overall, among 16,522 CLBC patients, 7982 cases (48.3%) underwent BCS between 1998 and 2015. Factors such as older age, Black race, invasive ductal carcinoma (IDC), grade I, small tumor size, none or limited lymph node metastasis, positive progesterone receptor status, and receiving chemotherapy were independently correlated with BCS. BCS was an independent favorable prognostic factor among CLBC patients, based on multivariate Cox analysis. It was also shown that CLBC had similar survival outcomes compared with tumors in the upper-outer quadrant, and had a better breast cancer-specific survival compared with tumors in the lower quadrants, based on multivariate Cox analysis. CONCLUSIONS: BCS should be an acceptable and preferable alternative to mastectomy for well-selected, early-stage T1 or T2 CLBC.

Human drug efflux transporter ABCC5 confers acquired resistance to pemetrexed in breast cancer.

AIM: Pemetrexed, a new generation antifolate drug, has been approved for the treatment of locally advanced or metastatic breast cancer. However, factors affecting its efficacy and resistance have not been fully elucidated yet. ATP-binding cassette (ABC) transporters are predictors of prognosis as well as of adverse effects of several xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and can contribute to the optimization of breast cancer treatment regimen. METHODS: First, we measured the expression levels of ABC transporter family members in cell lines. Subsequently, we assessed the potential role of ABC transporters in conferring resistance to pemetrexed in primary breast cancer cells isolated from 34 breast cancer patients and the role of ABCC5 in mediating pemetrexed transport and apoptotic pathways in MCF-7 cells. Finally, the influence of ABCC5 expression on the therapeutic effect of pemetrexed was evaluated in an in vivo xenograft mouse model of breast cancer. RESULTS: The expression levels of ABCC2, ABCC4, ABCC5, and ABCG2 significantly increased in the pan-resistant cell line, and the ABCC5 level in the MCF-7-ADR cell line was 5.21 times higher than that in the control group. ABCC5 expression was inversely correlated with pemetrexed sensitivity (IC50, r = 0.741; p < 0.001) in breast cancer cells derived from 34 patients. Furthermore, we found that the expression level of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cells, with IC50 values of 0.06 and 0.20 µg/mL in ABCC5 knockout and over-expression cells, respectively. In the in vivo study, we observed that ABCC5 affected the sensitivity of pemetrexed in breast tumor-bearing mice, and the tumor volume was much larger in the ABCC5-overexpressing group than in the control group when compared with their own initial volumes (2.7-fold vs. 1.3-fold). CONCLUSIONS: Our results indicated that ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and it may serve as a target or biomarker for the optimization of pemetrexed regimen in breast cancer treatment.

Concurrent neoadjuvant chemotherapy and estrogen deprivation in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (CBCSG-036): A randomized, controlled, multicenter trial.

BACKGROUND: The current randomized, controlled, multicenter clinical trial was conducted to investigate the efficacy of concurrent neoadjuvant chemotherapy (NCT) and estrogen deprivation in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: Eligible patients with AJCC stage IIB to stage IIIC, ER-positive, HER2-negative breast cancer were enrolled and randomly assigned to receive NCT with or without estrogen deprivation. The primary endpoint was the objective response rate (ORR). RESULTS: A total of 249 patients were assigned to either neoadjuvant chemoendocrine therapy (NCET) (125 patients) or the NCT group (124 patients). In the intention-to-treat analysis, the ORR was found to be significantly higher in the NCET group compared with the NCT group (84.8% vs 72.6%; odds ratio, 2.11 [95% CI, 1.13-3.95; P = .02). The efficacy of NCET was more prominent in tumors with a higher Ki-67 index (>20%), with an ORR of 91.2% reported in the NCET group versus 68.7% in the NCT group (P = .001). The pathologic complete response and pathological response rates did not differ significantly between the 2 groups. Although there was no significant difference with regard to progression-free survival (PFS) between the 2 groups (P = .188), patients with a higher baseline Ki-67 index appeared to derive a greater PFS benefit from NCET (2-year PFS rate of 91.5% in the NCET group vs 76.5% in the NCT group; P = .058). Adding endocrine agents to NCT did not result in significant differences in adverse events (grade 3 or 4; graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) between the 2 groups. CONCLUSIONS: The addition of estrogen deprivation to NCT appears to improve the clinical response in patients with ER-positive, HER2-negative breast cancer, especially for those individuals with a higher Ki-67 index. Patients with a higher Ki-67 index might derive more PFS benefit from concurrent neoadjuvant treatment.

Post-mastectomy immediate breast reconstruction is oncologically safe in well-selected T4 locally advanced breast cancer: a large population-based study and matched case-control analysis.

PURPOSE: Although it is well accepted that the survival outcome is most probably unaffected by immediate breast reconstruction (IBR) for T1-T3 tumors, the safety of IBR in T4 locally advanced breast cancer (LABC) remains unclear. METHODS: By using data from the Surveillance, Epidemiology, and End Results (SEER) database, the trend of IBR for female T4 LABC patients undergoing mastectomy, chemotherapy and radiotherapy was explored. The predictors of IBR in T4 LABC were evaluated by multivariate logistic regression. The survival outcomes were compared by means of Cox hazards models adjusting for known clinicopathological variables and stratifying on the T stage and contralateral prophylactic mastectomy (CPM). RESULTS: Altogether 714 cases underwent IBR between 1998 and 2015. The IBR cohort had a lower percentage of cases with T4d disease whereas higher percentage with CPM. The IBR rate was 10.1% and increased from 4.1% in 1998 to 17.7% in 2015. Since 2009, the rate of implant-based IBR exceeded that of the autologous tissue method. An age less than 45 years (OR 2.930, 95% CI 2.299-3.735) and CPM (OR 2.758, 95% CI 2.306-3.299) were the strongest predictors of IBR. In the 1:2 matched case-control analysis, IBR was not an independent prognostic factor for breast cancer specific-survival (BCSS) (HR 0.893, p = 0.236, 95% CI 0.741-1.077) and overall survival (OS) (HR 0.886, p = 0.183, 95% CI 0.741-1.059). BCSS and OS were similar among patients undergoing IBR whether they underwent CPM or not and whether they were inflammatory breast cancer (IBC) or not. CONCLUSIONS: IBR is oncologically safe in well-selected T4 LABC.

The Prognostic Significance of the Oncotype DX Recurrence Score in T1-2N1M0 Estrogen Receptor-Positive HER2-Negative Breast Cancer Based on the Prognostic Stage in the Updated AJCC 8th Edition.

BACKGROUND: This study aimed to evaluate the prognostic significance of the Oncotype DX recurrence score (RS) in T1-2N1M0 estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer based on the prognostic stage in the updated American Joint Commission on Cancer, 8th edition. METHODS: The Surveillance, Epidemiology, and End Results database was searched to identify ER-positive invasive ductal breast cancer in T1-2N1M0 with RS results diagnosed between 2004 and 2012. Patients with RS were categorized into low-risk (RS < 11), intermediate-risk (RS 11-25), and high-risk (RS > 25) groups. The distributions of clinical-pathological characteristics were compared among the RS risk groups using Pearson's Chi square. Breast cancer-specific survival (BCSS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared across RS groups using the log-rank statistic. Cox models were fitted to assess the factors independently associated with survival. RESULTS: The study enrolled 4059 cases categorized into prognostic stages IA to IIB. The RS risk groups were positively correlated with pathological prognostic stages (P < 0.001). The RS risk groups differed significantly in terms of BCSS and OS (P < 0.001). According to the multivariate analysis, RS risk group was an independent prognostic factor for BCSS and OS together with the pathological prognostic stage. The subgroup analysis showed similar survival rates across pathological prognostic stages in the RS low-risk group but significant differences in survival rates among pathological prognostic stages in the RS intermediate-risk group. The survival rates among the RS risk groups also differed significantly in pathological prognostic stage IA. CONCLUSIONS: Oncotype DX RS provided independent prognostic significance to complement the prognostic staging system.

Growing Trends of Contralateral Prophylactic Mastectomy and Reconstruction in Young Breast Cancer.

BACKGROUND: The aim of this study was to evaluate the trends of surgical treatments among young patients in T1N0-1M0 stage based on the Surveillance, Epidemiology, and End Results database. MATERIALS AND METHODS: Patients aged less than 40 y diagnosed between 1998 and 2015 were enrolled, with tumors in T1N0-1M0 stage and not located in the central area. Differences in clinical-pathological characteristics were evaluated using chi-square tests. Multivariate logistic regression was used to measure the various factors associated with contralateral prophylactic mastectomy (CPM). Independent prognostic factors were evaluated by Cox model. RESULTS: The total rate of breast-conserving surgery (BCS) was 51.6%, which declined from 64.5% in 1998 to 39.6% in 2015. The total rate of CPM was 22.7%, which increased from 3.7% in 1998 to 38.7% in 2014 despite a decline to 32.7% in 2015. Meanwhile, the rate of reconstruction increased in line with that of CPM, from 9.4% in 1998 to 35.0% in 2015. There was a trend of increasing use of implant-based reconstruction. Significant higher odds of CPM were found in recent year of diagnosis between 2010 and 2015 and in implant-based reconstruction. Patients undergoing CPM had similar survival outcomes compared with those undergoing BCS and unilateral mastectomy, whereas those undergoing BCS had better survival outcomes compared with those undergoing unilateral mastectomy. CONCLUSIONS: A trend of growing preference for CPM and reconstruction was observed among young patients in early stage in recent years without survival benefits. Efforts should be made to promote efficient communication and evidence-based decision-making.

Upregulation of PAG1/Cbp contributes to adipose-derived mesenchymal stem cells promoted tumor progression and chemoresistance in breast cancer.

C-terminal Src kinase (Csk)-binding protein (Cbp) is a ubiquitously expressed transmembrane adaptor protein which regulating Src family kinase (SFK) activities. Although SFKs are well known for their involvement in breast cancer, the function of Cbp in breast carcinogenesis upon the adipose-tumor microenvironment has not been investigated. Here, we reported that adipose-derived mesenchymal stem cells (ASCs) induced increased expression of Cbp accompanied by enhanced cell proliferation and chemotherapy resistance in breast cancer cell MCF-7/ADR. Depletion of Cbp in breast cancer cell by RNA interference led to remarkable inhibition of cell proliferation, invasion as well as synergy with adriamycin hydrochloride to suppress the tumor growth. Furthermore, silencing of Cbp concomitantly inhibited the expression of phosphoryl of Src, AKT and mTOR signals. Our study highlights the underlying mechanism of cross interaction between ASCs and breast cancer cells, and indicates that PAG1/Cbp in breast cancer cell may modulate tumor progression and acquired chemoresistance in the ASCs-associated breast cancer microenvironment through Src and AKT/mTOR pathways.

[The fertility-associated treatment of young breast cancer patients].

There is no treatment norm on the fertility issue of breast cancer patients. The clinical studies show that the effects of chemotherapy and endocrine treatment on menstrual cycle and ovarian function have connection with patients' age, therapeutic regimen and drug dose. The time to be pregnant should be decided according to the stage of tumor and the therapeutic regimen. The trimester of pregnancy and tumor stage should be considered when making the therapeutic regimen for the breast cancer patients during pregnancy. And it is not recommended to choose the induced abortion for the therapeutic aim. Theoretically, ovarian function inhibition drugs have great application prospects, while, of which the long-term affect on human body and the relation with tumor development need more researches to study. The available evidence-based practices consider that the pregnancy after breast cancer treatment has no adverse affects on the prognosis of early and middle stage breast cancer patients. More study results are needed to normalize and detail the therapeutic regimen and fertility guidance.

[Research progress on the clinical value of Ki-67 in breast cancer and its cut-off definition].

Ki-67 has an important application value in clinical practice. However, it is still a little tough in clinical application because of the debate on the cut-off definition of Ki-67 index. This review summarizes most studies on the prognostic and predictive value of Ki-67, analyzes the reasons for the discrepancies among the studies cited, and presents the necessity and clinical significance of scientifically defining the cut-off of Ki-67 index, providing a theoretical basis for Ki-67 in clinical application.

Neoadjuvant radiochemotherapy is safe and feasible for breast conserving surgery or immediate reconstruction.

This study aimed to evaluate the survival outcomes of neoadjuvant radiochemotherapy (NARCT) for early breast cancer. Female patients ≤ 80 years old with unilateral T1-T4 invasive ductal breast cancer treated with neoadjuvant chemotherapy (NAC) and radiation therapy (RT) between 2006 and 2015 were enrolled from SEER database. Baseline differences in clinical and pathological characteristics were evaluated using chi-square test. The survival outcomes were estimated by Kaplan-Meier analysis and compared using Cox hazards models. The effects of baseline differences on survival outcome in patients treated with neoadjuvant radiation therapy (NART) and post-operation radiation therapy (PORT) were circumvented by propensity score matching (PSM). Altogether 14,151 patients receiving NAC and RT were enrolled, among whom 386 underwent NART. Based on a 1:4 PSM cohort, NART was an independent unfavorable prognostic factor for breast cancer-specific survival (BCSS) and overall survival (OS) for the whole cohort. However, among patients receiving breast conserving surgery (BCS) (HR 1.029, P = 0.915 for BCSS; HR 1.003, P = 0.990 for OS) or implant-based immediate breast reconstruction (IBR) (HR 1.039, P = 0.921 for BCSS; HR 1.153, P = 0.697 for OS), those treated with NART had similar survival outcomes compared with patients treated with PORT. In conclusion, NARCT was a safe and feasible approach for patients undergoing BCS and IBR.

LILRB2 promotes immune escape in breast cancer cells via enhanced HLA-A degradation.

PURPOSE: Increased expression of leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) is associated with immune evasion in breast cancer (BC). The aim of this study to elucidate the role of LILRB2 in BC progression. METHODS: LILRB2 expression in tumor tissues was detected by immunohistochemical staining. Human leukocyte antigen A (HLA-A) expression in BC cells was detected by Western blotting, and HLA-A ubiquitination was detected by immunoprecipitation and histidine pulldown assay. An in-situ tumor model was established in nude BALB/c mice to verify the role of LILRB2 in immune escape. Finally, the functions and potential mechanisms of LILRB2 in BC progression were explored using in silico data. RESULTS: LILRB2 was upregulated in BC tissues and cells, and correlated positively with poor prognosis. LILRB2 promoted BC progression by downregulating HLA-A expression. Mechanistically, LILRB2 facilitates the ubiquitination and subsequent degradation of HLA-A by promoting the interaction between the ubiquitin ligase membrane-associated ring finger protein 9 (MARCH9) and HLA-A. In syngeneic graft mouse models, LILRB2-expressing BC cells evaded CD8 + T cells and inhibited the secretion of cytokines by the cytotoxic CD8 + T cells. CONCLUSION: LILRB2 downregulates HLA-A to promote immune evasion in BC cells and is a promising new target for BC treatment.

Axillary lymph node dissection in triple-negative or HER2-positive breast cancer patients with clinical N2 achieving pathological complete response after neoadjuvant therapy: Is it necessary?

AIM: This study aims to identify suitable candidates for axillary sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) among clinical N2 (cN2) triple-negative (TN) or HER2 positive (HER2+）breast cancer patients following neoadjuvant therapy（NAT）. BACKGROUND: Despite the substantial axillary burden in cN2 breast cancer patients, high pathological response rates can be achieved with NAT in TN or HER2+ subtypes, thus enabling potential downstaging of axillary surgery. METHODS: A retrospective analysis was conducted on data from the CSBrS-012 study, screening 709 patients with initial cN2, either HER2+ or TN subtype, from January 1, 2010 to December 31, 2020. The correlation between axillary pathologic complete response (pCR) (yPN0) and breast pCR was examined. RESULTS: Among the 177 cN2 patients who achieved breast pCR through NAT, 138 (78.0 %) also achieved axillary pCR. However, in the 532 initial clinical N2 patients who did not achieve breast pCR, residual axillary lymph node metastasis persisted in 77.4 % (412/532) of cases. The relative risk of residual axillary lymph node metastasis in patients who did not achieve breast pCR was 12.4 (8.1-19.1), compared to those who did achieve breast pCR, P < 0.001. CONCLUSION: For cN2 TN or HER2+ breast cancer patients who achieve breast pCR following NAT, consideration could be given to downstaging and performing an axillary SLNB or TAD.

A nomogram for predicting pathologic node negativity after neoadjuvant chemotherapy in breast cancer patients: a nationwide, multicenter retrospective cohort study (CSBrS-012).

Purpose: This study aimed to investigate the factors associated with pathologic node-negativity (ypN0) in patients who received neoadjuvant chemotherapy (NAC) to develop and validate an accurate prediction nomogram. Methods: The CSBrS-012 study (2010-2020) included female patients with primary breast cancer treated with NAC followed by breast and axillary surgery in 20 hospitals across China. In the present study, 7,711 eligible patients were included, comprising 6,428 patients in the primary cohort from 15 hospitals and 1,283 patients in the external validation cohort from five hospitals. The hospitals were randomly assigned. The primary cohort was randomized at a 3:1 ratio and divided into a training set and an internal validation set. Univariate and multivariate logistic regression analyses were performed on the training set, after which a nomogram was constructed and validated both internally and externally. Results: In total, 3,560 patients (46.2%) achieved ypN0, and 1,558 patients (20.3%) achieved pathologic complete response in the breast (bpCR). A nomogram was constructed based on the clinical nodal stage before NAC (cN), ER, PR, HER2, Ki67, NAC treatment cycle, and bpCR, which were independently associated with ypN0. The area under the receiver operating characteristic curve (AUC) for the training set was 0.80. The internal and external validation demonstrated good discrimination, with AUCs of 0.79 and 0.76, respectively. Conclusion: We present a real-world study based on nationwide large-sample data that can be used to effectively screen for ypN0 to provide better advice for the management of residual axillary disease in breast cancer patients undergoing NAC.

Superior outcome after neoadjuvant chemotherapy with docetaxel, anthracycline, and cyclophosphamide versus docetaxel plus cyclophosphamide: results from the NATT trial in triple negative or HER2 positive breast cancer.

The purpose of this study is to evaluate the efficacy and safety of docetaxel plus cyclophosphamide(TC) compared with docetaxel, anthracycline, and cyclophosphamide(TEC) in neoadjuvant treatment of triple negative or HER2 positive breast cancer. Eligible breast cancer patients were randomized to receive six cycles of TC or TEC. The primary end point was pathological complete remission (pCR). Secondary end points included safety, clinical response rate, and survival outcome. One hundred and two patients were initially randomized and 96 patients were available for efficacy analysis. 96.9 % patients were treated with epirubicin as an anthracycline agent. pCR rates were 6.8 % (3/45) and 17.6 % (9/51) in TC and TEC group, respectively, P = 0.113. After a mean follow up of 20 (3­36) months, non-anthracycline-containing TC regimen treatment resulted in a worse event free survival (adjusted hazard ratio [HR] 2.42; 95 % CI1.11­5.30) and disease-free survival (HR 2.85; 95 % CI1.21­6.74) compared with TEC regimen, which was more apparent in triple negative subtype. Severe adverse event rates were similar, except that patients treated with TEC had a higher rate of neutropenia and leucopenia. TEC treatment had a superior survival outcome and trend of higher pCR rate compared with TC in this trial setting, especially in triple negative subtype, which deserves further validation.

Curcumin induces apoptosis in gallbladder carcinoma cell line GBC-SD cells.

BACKGROUND: Gallbladder carcinoma is a malignant tumor with a very low 5-year survival rate because of the difficulty with its early diagnosis and the very poor prognosis of the advanced cancer state. The aims of this study were to determine whether curcumin could induce the apoptosis of a gallbladder carcinoma cell line, GBC-SD, and to clarify its related mechanism. METHODS: First, the anti-proliferative activities of curcumin-treated and untreated GBC-SD cells were determined using the MTT and colony formation assays. Then, the early apoptosis of cells was detected by the annexin V/propidium iodide double-staining assay and Hoechst 33342 staining assay. Detection of mitochondrial membrane potential was used to validate the ability of curcumin on inducing apoptosis in GBC-SD cells. Cell cycle changes were detected by flow cytometric analysis. Finally, the expressions of the apoptosis-related proteins or genes caspase-3, PARP, Bcl-2, and Bax were analyzed by western blot and quantitative real time PCR assay. Statistical analyses were performed using the Student's t-test for comparison of the results obtained from cells with or without curcumin treatment. RESULTS: The MTT assay revealed that curcumin had induced a dose- and a time-dependent decrease in cell viability. Colony counting indicated that curcumin had induced a dose-dependent decrease in the colony formation ability in GBC-SD cells. Cells treated with curcumin were arrested at the S phase, according to the flow cytometric analysis. A significant induction of both the early and late phases of apoptosis was shown by the annexin V-FITC and PI staining. Morphological changes in apoptotic cells were also found by the Hoechst 33342 staining. After treatment with curcumin fluorescence shifted from red to green as ΔΨm decreased. Furthermore, western blot and quantitative real time PCR assays demonstrated that the curcumin induced apoptosis in GBC-SD cells by regulating the ratio of Bcl-2/Bax and activating the expression of cleaved caspase-3. CONCLUSIONS: Taken together, the results indicate that curcumin may be a potential agent for the treatment of gallbladder cancer.

[The correlation of synuclein-γ and matrix metalloproteinase 9 in breast cancer].

OBJECTIVES: To evaluate the expression of synuclein-γ (SNCG) and metalloproteinase 9 (MMP-9) both in the invasive ductal breast cancer samples and T47D and T47D(SNCG)- cell lines, to investigate the correlation between SNCG and MMP-9. METHODS: Totally 96 invasive ductal breast cancer samples (female, mean age of (56 ± 8) years) were collected between June 2009 and June 2012. The expressions of SNCG and MMP-9 were investigated by immunohistochemistry. T47D and SNCG knock down T47D(SNCG)- cell lines were established and SNCG and MMP-9 protein expression were investigated by Western blot and gene expression by real-time PCR. RESULTS: Among 96 samples, 26 (27.1%) of them co-expressed SNCG and MMP-9, 30(31.2%) of them expressed neither SNCG nor MMP-9. The expression of SNCG was correlated with the expression of MMP-9 (r = 0.655, P = 0.000).SNCG mRNA level of T47D cell line was 13.5 fold of T47D(SNCG)- cell line and SNCG protein expression was 2.1 fold. While MMP-9 mRNA level of T47D cell line was 7.3 fold of T47D(SNCG)- cell line and MMP-9 protien expression was 1.6 fold.When SNCG was knocked down, the expression of MMP-9 decreased. CONCLUSIONS: SNCG and MMP-9 are significantly correlated with each other in breast cancer. SNCG may promote the invasion and metastasis of breast cancer mediated by up-regulating the expression of MMP-9.

A model-free approach to do long-term volatility forecasting and its variants.

Volatility forecasting is important in financial econometrics and is mainly based on the application of various GARCH-type models. However, it is difficult to choose a specific GARCH model that works uniformly well across datasets, and the traditional methods are unstable when dealing with highly volatile or short-sized datasets. The newly proposed normalizing and variance stabilizing (NoVaS) method is a more robust and accurate prediction technique that can help with such datasets. This model-free method was originally developed by taking advantage of an inverse transformation based on the frame of the ARCH model. In this study, we conduct extensive empirical and simulation analyses to investigate whether it provides higher-quality long-term volatility forecasting than standard GARCH models. Specifically, we found this advantage to be more prominent with short and volatile data. Next, we propose a variant of the NoVaS method that possesses a more complete form and generally outperforms the current state-of-the-art NoVaS method. The uniformly superior performance of NoVaS-type methods encourages their wide application in volatility forecasting. Our analyses also highlight the flexibility of the NoVaS idea that allows the exploration of other model structures to improve existing models or solve specific prediction problems.