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Purpose This study investigated pathological complete response (pCR) according to androgen receptor (AR) in breast cancer patients undergoing neoadjuvant chemotherapy and estimated the relationship between AR expression and clinicopathological factors.Materials and Methods We identified 624 breast cancer patients who underwent surgery after neoadjuvant chemotherapy at the National Cancer Center in Goyang, Korea from April 2016 to October 2019. We retrospectively collected the clinicopathologic information and AR expression results and analyzed the data according to cancer stage, hormonal receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status, tumor subtype, and pCR.Results Among the 624 breast cancer patients, 529 (84.8%) were AR-positive (AR+) patients and 95 (15.2%) were AR-negative (AR–) patients. AR+ patients showed more estrogen receptor (ER) positivity, progesterone receptor (PR) positivity, HER2-positivity, and HR-positive and HER2-negative (HR+/HER2–) subtype. The rate of pCR was 31.4% (196/624). AR– patients had a significantly higher rate of pCR than AR+ patients (AR– 43.2% vs. AR+ 29.3%, p=0.007). The tumor factors associated with pCR were early stage, histologic grade 3, ER-negative, PR-negative, AR-negative, HER2-positive, and high Ki-67 values. In univariable analysis, AR+ significantly decreased the state of pCR (odds ratio, 0.546; 95% confidence interval, 0.349 to 0.853; p=0.008). According to tumor subtype, AR– tumor showed higher pCR rate in HR+/HER2– subtype (AR– 28.6% vs. AR+ 7.3%, p=0.022).Conclusion AR expression is predominant in the HR+/HER2– subtype. AR– is significantly associated with the pCR rate in breast cancer patients, especially within HR+/HER2– subtype. When determining neoadjuvant chemotherapy for the HR+/HER2– subtype, AR expression can be considered as a pCR predictive marker.

Dong-Hoe Koo,1,* Keun Seok Lee,2,* Sung Hoon Sim,2 Heejung Chae,2 Eun-Gyeong Lee,2 Jai Hong Han,2 So-Youn Jung,2 Seeyoun Lee,2 Han-Sung Kang,2 Eun Sook Lee,2 Cheol-Young Park,1,* Sang Woo Oh3,* 1Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 2Center for Breast Cancer, Research Institute and Hospital, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea; 3Department of Family Medicine, Center for Obesity, Metabolism, and Nutrition, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi-do, Republic of Korea*These authors contributed equally to this workCorrespondence: Cheol-Young Park, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul, 03181, Republic of Korea, Tel +82-2-2001-1869, Fax +82-2-2001-1588, Email cydoctor@chol.com Sang Woo Oh, Center for Obesity, Nutrition, and Metabolism, Department of Family Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, 27 Donggung-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10326, Republic of Korea, Tel +82-31-961-7000, Email osw6021@gmail.comBackground: We have reported that serum progranulin (PGRN) levels are clinically significant in predicting recurrence in patients with HR-positive breast cancer. The aim of the present study was to examine whether PGRN levels might be associated with breast cancer mortality.Methods: This was a cohort study of 695 newly diagnosed breast cancer patients who underwent curative surgery between 2001 and 2004. The relationship between breast cancer mortality and pre-operative serum PGRN levels in these patients with a median follow-up of 12.7 years was evaluated until May 2020.Results: A total of 118 (17%) deaths were identified in the cohort. According to the HR status, (10, 15, and 20)-year overall survival (OS) rates were (91.4, 81.1, and 75.9) % for HR-positive patients, and (76.5, 74.2, and 69.8) % for HR-negative patients, respectively (p = 0.003). Higher levels of PGRN were significantly associated with poor OS in the HR-positive group (p for trend = 0.001). In particular, hazard ratios for PGRN quartiles suggested a dose–response relationship, with the highest quartile having the worst OS in the HR-positive group (highest vs lowest: 15-year OS, (68.3 vs 90.0) %; 20-year OS, (62.3 vs 84.8) %, even after adjusting for age, tumor stage, and metabolic confounders.Conclusion: Pre-operative serum PGRN levels had clinical significance for predicting cancer mortality in breast cancer patients independent of tumor stage and metabolic parameters, especially in HR-positive tumors.Keywords: breast cancer, progranulin, mortality, long-term follow-up

Background: Early biologic response to endocrine therapy, such as changes in Ki67 labeling index (LI), has been suggested to predict long-term outcomes in hormone sensitive breast cancer. The addition of a CDK4/6 inhibitor to endocrine therapy has been shown to augment biological response in breast cancer. Pre-operative Endocrine Prognostic Index (PEPI) scores, generated based on post-treatment Ki67 LI, have been shown to predict patient outcomes. EndoPredict® is a multigene assay that predicts the risk of distant recurrence in patients with operable estrogen receptor (ER)-positive HER2-negative breast cancer. This study was conducted to evaluate the efficacy of the neoadjuvant endocrine therapy plus palbociclib versus neoadjuvant endocrine therapy plus placebo. Patients and Methods: This is a phase III randomized, double-blind study of neoadjuvant hormonal therapy plus palbociclib versus neoadjuvant hormonal therapy plus placebo in untreated pre/peri- and post-menopausal women with operable, hormone receptor-positive (ER and/or progesterone receptor), HER2-negative breast cancer. The other major inclusion criteria included tumor size ≥ 15mm, T1c-3N0-1, Ki67 LI ≥14% by central assessment, and no previous history of radiotherapy or systemic therapy for breast cancer. Patients were randomly assigned 1:1 to receive 16 weeks of hormonal therapy plus palbociclib or hormonal therapy plus placebo. Hormonal therapy consisted of letrozole for post-menopausal patients and tamoxifen plus LH-RH agonist for pre/peri-menopausal patients. The co-primary endpoints included PEPI score and EPclin Risk Score, a score combining EndoPredict® molecular score with clinical factors. These scores were sequentially analyzed on a modified intent-to-treat basis according to the gatekeeping procedure: if statistical significance was detected on the PEPI score, the statistical significance of EPclin Risk Score would be assessed. The sample size was 100 patients in each arm, which was calculated with < 5% type I error rate (two sided) and 80% power. Results: Between 16 July 2019 – 7 July 2021, 141 eligible patients were randomized from 25 participating institutes in Japan, Korea, Taiwan, Hong Kong and Australia. One hundred twenty-six patients completed the treatment duration and surgical samples were collected to evaluate endpoints. All randomized patients were evaluable for safety assessment. Randomization was well-balanced in terms of age, menopausal status and cancer stage. The proportion of patients who had a low, moderate, or high PEPI score was 15.2%, 50.0% and 34.8% in the hormonal therapy plus palbociclib arm and 13.3%, 55.0% and 31.7% in the hormonal therapy plus placebo arm, respectively. There was no statistically significant difference in PEPI score between two arms (one-sided p-value=0.563). The proportion of patients who had a high risk EPclin Risk Score seemed lower in the palbociclib arm than in the placebo arm (62.1% vs 68.3%) although hypothesis testing was not performed on EPclin Risk Score because statistical significance was not detected on the PEPI score. No new safety signals were found in the study. Permanent discontinuation from the study in association with adverse events was reported for 7 (9.7%) patients in the hormonal therapy plus palbociclib arm and for 0 patients in the hormonal therapy plus placebo arm. Conclusions: The addition of palbociclib to neoadjuvant hormonal therapy did not improve efficacy measured by PEPI score. In palbociclib arm, the rate of patients who had a high risk EPclin Risk Score after treatment was lower than in placebo arm. Translational researches are ongoing to analyze molecular changes by treatments. The role of chemotherapy after neoadjuvant therapy is under investigation. Clinical trial identification: NCT03969121 Funding: Pfizer Inc. Citation Format: Takayuki Ueno, Louis W.C. Chow, Wonshik Han, Chiun Sheng Huang, G Bruce Mann, Satoshi Morita, Hironori Haga, Elham Fakhrejahani, Takayuki Kobayashi, Kenichi Inoue, Mariko Tokiwa, Hirofumi Suwa, Tomoyuki Aruga, Sachiko Minamiguchi, Yosuke Yamada, Yuko Tanabe, Masahiro Takada, Toshinari Yamashita, Hiroji Iwata, Chi-Feng Chung, Sachiko Takahara, Eriko Tokunaga, Shigeru Imoto, Eun Sook Lee, Yasuaki Sagara, Jee Hyun Kim, Richard H DeBoer, Hyun-Ah Kim, Hung Wen Lai, Ming-Feng Hou, Michelle White, Yoshiko Umeyama. Neoadjuvant hormonal therapy plus palbociclib versus hormonal therapy plus placebo in women with operable, hormone sensitive and HER2-negative primary breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-09-01.

Background: Triple-negative breast cancer (TNBC) is highly heterogeneous cancer and the most challenging subtype of breast cancer. And its prognosis is poor compared to the other subtypes. Unlike luminal type cancers, there is no valid biomarker to predict the prognosis of patients with early TNBC. To establish an elaborate therapeutic strategy for TNBC, biomarkers that accurately predict the prognosis and response to treatment are needed. Method: 184 patients with early stage TNBC (training cohort, n = 76; validation cohort, n = 108) were enrolled. Median Follow-up period was 51.5 months (range: 4.6-230.8) for training cohort and 58.3 months (range: 6.6-99.8) for validation cohort. Of the patients in training cohort, 13 patients had recurrence or metastasis. Of the patients in validation cohort, 23 patients had recurrence or metastasis. Using a HiSeq sequencer, RNA sequencing was conducted to analyze the gene expression profiles of tumor samples from TNBC patients. Gene signature was analyzed by combination of DEGs which found in gene expression profiles. Cross validation and meta-analysis were conducted as pre-validation. Meta-analysis was conducted using CBS probePINGS. To compare gene signature and other methods, PAM 50 call and TCR diversity analysis were investigated. Statistical analyses were conducted using R language (v.3.4.3). Result: To predict prognosis of recurrence or metastasis for TNBC patients, we identified the 10-gene signature (DGKH, GADD45B, KLF7, LYST, NR6A1, PYCARD, ROBO1, SLC22A20P, SLC24A3 and SLC45A4) that stratified patients with TNBC by risk score (sensitivity = 92.31%; specificity = 92.06%; accuracy = 92.11%) and validated in a cohort of separate institutions. Meta-analysis supported the biological relevance of the 10-gene signature to well-known driving pathways in TNBC. When compared with other potential biomarkers like PAM 50 call and T-cell receptor β diversity, the 10-gene signature was the only independent factor that can predict prognosis for invasive disease-free survival in multivariate analysis. Conclusion: Our novel findings can contribute to solving the diagnostic challenges in TNBC and the 10-gene signature may serve as a novel biomarker for risk-based patient care. Citation Format: Chang Min Kim, Kyong Hwa Park, Yun Suk Yu, Ju Won Kim, Jin Young Park, Jeong Eon Lee, Sung Hoon Sim, Bo Kyoung Seo, Jin Kyeoung Kim, Eun Sook Lee, Yeon Hee Park, Sun-Young Kong. A 10-gene signature to predict the prognosis of early-stage triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-25.

Potential toxic effects of CWP232228 in nude mice.

Sphere-forming 4T1 cell culture leads to the expression of stem cell markers.

The comparison of CWP232228 activities with another well-known small molecule inhibitor.

Supplementary figure legends

Pharmacokinetic/pharmacodynamic (PK/PD) analysis.

Characterization of primary human breast cancer cells.

Sphere-forming MDA-MD-435 cell culture leads to the expression of stem cell markers.

Gene expression profiles of breast cancer cells grown as monolayer or sphere-forming cells.

The expression levels of stem cell markers.

The extreme limiting dilution(ELDA)assay.

Chemical structure and pharmacokinetic properties of the small-molecular weight inhibitor CWP232228.

The list of the PCR primer sequences.

Expression profiles of the genes associated with Wnt/β-catenin signaling in premalignant mammary and breast cancer tissues.

Effect of CWP232228 on the growth of BCSCs obtained from human primary breast cancers.

Background: We previouslyreported that invasive disease-free survival (IDFS), the primary outcome, and distantdisease-free survival (DDFS), a secondary outcome, differed by menopausalstatus in a pre-specified analysis. Here,we report updates on IDFS and DDFS with additional follow-up, as well as distantrecurrence-free interval (DRFI) and post hoc analyses in premenopausal women.Methods: Eligibilitycriteria included women > 18 years of age with HR+, HER2-BC and 1-3 +LN and no contraindications to taxane and/or anthracycline basedCT. DRFI was defined as time to distant recurrence or death from breast cancer.Analyses were intent-to-treat among eligible pts. We performed a post hocanalysis evaluating IDFS between treatment arms in premenopausal pts with pN1mi.In addition, we conducted a two-year landmarked IDFS analysis by ovarianfunction suppression (OFS) or not in the ET arm, as well as by regularmenstrual periods or not in both treatment arms.Results: Among the 4,984eligible pts, there were 553 IDFS events and median follow-up of 6.1 years.Postmenopausal women do not have any IDFS or DDFS benefit with CT; however, 5-yearabsolute benefits for IDFS and DDFS with CT for premenopausal pts were 5.9% and3.3%, respectively. In pre-menopausal pts, CT was associated with improved DRFIfor all RS values < 25, with an absolute improvement of 2.3% for RS0-13 and of 2.8% for RS 14-25. Among premenopausal pts, 12.4% (n=206) had pNmi)disease. In a post hoc analysis, there was a trend for CT benefit for thosewith pNmi [hazard ratio (HR)=0.44, confidence interval (CI)=0.18-1.08]. Therewere only 22 IDFS events. Only 17.2% of premenopausal pts assigned to ETunderwent OFS in the first 24 months and in two-year landmarked analysis, therewas no IDFS difference in those who underwent OFS or not (HR=0.88,CI=0.47-1.63). In premenopausal women assigned to ET, 58.9% stopped havingperiods within the first 24 months, and have anumerically improved IDFS compared to those who continued regular periods (HR=1.48,CI: 0.92-2.40). Among premenopausal assigned to CT followed by ET, 80.8%stopped having periods within the first 24 months and have a numericallyimproved IDFS compared to those who continue to have regular periods (HR=1.56, CI:0.85-2.86).Discussion: In accordancewith the differential IDFS and DDFS benefit based upon menopausal status inS1007, premenopausal pts with 1-3+LN and RS < 25 had a statisticallysignificant improvement in DRFI with the addition of CT. A small proportion of S1007premenopausal participants underwent OFS. The role of OFS as it relates to CTbenefit cannot be determined from this study. A future randomized trial should address the clinical question if OFScan replace CT in premenopausal pts with HR+/HER2-, node-positive breast cancer.Funding: Supported by National Cancer Institute grants U10CA180888, U10CA180819,U10CA180820, U10CA180821, U10CA180868, U10CA180863, and in part by Susan G.Komen for the Cure® Research Program, The Hope Foundation for Cancer Research,Breast Cancer Research Foundation, and Genomic Health, Inc. Citation Format: Kevin M Kalinsky, William E Barlow, Julie R Gralow, Funda Meric-Bernstam, Kathy S Albain, Daniel F Hayes, Nancy U Lin, Edith A Perez, Lori A Goldstein, Stephen KL Chia, Sukhbinder Dhesy-Thind, Priya Rastogi, Emilio Alba, Suzette Delaloge, Miguel Martin, Catherine M Kelly, Manuel Ruiz-Borrego, Miguel Gil-Gil, Claudia H Arce-Salinas, Etienne GC Brain, Eun Sook Lee, Jean-Yves Pierga, Begoña Bermejo, Manuel Ramos-Vasquez, Kyung Hae Jung, Jean-Marc Ferrero, Anne Schott, Steven Shak, Priyanka Sharma, Danika Lew, Jieling Miao, Debasish Tripathy, Lajos Pusztai, Gabriel Hortobagyi. Updated results from a phase 3 randomized clinical trial in participants (pts) with 1-3 positive lymph nodes (LN), hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) ≤ 25 randomized to endocrine therapy (ET) +/- chemotherapy (CT): SWOG S1007 (RxPONDER) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-07.

Background The rate of Nipple Areolar Complex (NAC) sparing mastectomy with implant reconstruction is rapidly increasing as the Korean National Health Insurance reimbursed reconstructive surgery for breast cancer patients from 2015. However, only a few reports about oncologic safety have been reported in the absence of large-scale data. We have analyzed the oncologic outcomes of all consecutive breast cancer patients who had NAC sparing mastectomy with immediate implant reconstruction. Methods We used the data from prospectively collected clinical data of patients who underwent immediate implant reconstruction after NAC sparing mastectomy at the National Cancer Center between January 2012 and December 2017. Demographics, clinicopathological characteristics and the follow-up results were analyzed. The statistical analysis was done to infer relations between risk factors and oncologic outcomes such as death, distant metastasis or locoregional recurrence. Results: A total of 538 breasts was analyzed in 486 patients. The mean age of the patients was 44.6 years. The mean BMI was 22.48 kg/m2. The number of bilateral cases was 52 (10.7%) and 135 patients (27.8%) had multiple tumors. Median follow-up was 4.5 years. Molecular subtypes were 373 HR(+)/HER2(-) (69.3%), 31 HR(+)/HER2(+) (5.8%), 76 HR(-)/HER2(+) (14.1%) and 35 HR(-)/HER2(-) (6.5%). Chemotherapy was performed in a total of 212 (43.6%) patients, of which 68 (32.1%) were neoadjuvant and 144 (67.9%) were adjuvant purposes. Trastuzumab was administered to 53 (10.9%) of patients whose tumor size are larger than 1cm under guideline of reimbursement. Postoperative radiotherapy was performed in 131 patients (26.9%). Distant metastasis occurred in 20 patients (3.7%), and seven (1.4%) died. Locoregional recurrence occurred in 43 cases (8.0%) of 538 breasts, including 14 nipples (2.6%) and 12 subareolar lesions (2.2%). Analyzing risk factors related to locoregional recurrence, HR(-)/HER2(+) type showed the highest incidence of 11/76 (14.7%) among four subtypes. The incidence was statistically significantly lower in the group that received postmastectomy radiotherapy than in the group that did not. (6/131 (4.6%) vs 37/355 (10.4%), p=0.001). The node negative group who did not have postmastectomy radiotherapy (31/377 (8.2%)) showed a numerically higher incidence than the node positive group (8/121 (6.6%)). Conclusion Our results showed that NAC sparing mastectomy with immediate implant reconstruction had similar oncologic outcome in terms of overall survival or distant metastasis, however the locoregional recurrence was rather high. Even this is remediable problems we would admit that NAC sparing mastectomy is a bit different from traditional mastectomy. In case that we inevitably apply this operation to relatively young women with multifocal breast cancer, careful consideration would be needed. In addition, identifying risk factors of locoregional recurrence and tailored post-operative radiation therapy are expected to improve the disease-free survival of breast cancer. Citation Format: Ji Young You, Eun-Gyeong Lee, Soo Jin Park, Byeong Nam Kim, Seeyoun Lee, Eun Sook Lee, So-Youn Jung, Youngmi Kwon, Yun Ju Kim, Chan Wha Lee, Tae Hyun Kim. A higher locoregional recurrence rate of nipple areolar complex sparing mastectomy with immediate implant reconstruction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-21-01.

Background: Androgen receptors (AR) has emerged as a prognostic factor predicting survival and recurrence in breast cancer. However, the role of AR as a predictor of pathological complete response (pCR) rate after neoadjuvant chemotherapy by subtypes is unclear. This study aimed to investigate according to AR in breast cancer patients undergoing neoadjuvant chemotherapy as a predictor. Furthermore, we estimated the relationship between AR expression and clinicopathological factors. Method: We identified 624 breast cancer patients who underwent surgery after neoadjuvant chemotherapy at the National Cancer Center from April 2016 to October 2019. We retrospectively collected the medial records that the clinicopathologic information and AR expression analyzed according to cancer stage, hormonal receptor status, HER2 status, tumor subtype, pCR. Results: Among the 624 breast cancer patients, 529 (84.8%) were AR positive patients and 95 (15.2%) were AR negative patients. The mean age of the patients was 50.0 years. The rate of pCR was 31.4% (196/624). AR negative patients had significantly high rate of pCR than AR positive patients. (AR (-) 43.2% vs. AR (+) 29.3%, p = 0.0074). AR positive patients showed more ER positivity, PR positivity, HER2 positivity and luminal A subtype. A higher proportion of AR positive patients compared to AR negative patients received target therapy and hormonal therapy (target therapy, AR (-) 15.8% vs. AR (+) 43.9%, hormonal therapy, 14.7% vs. 71.0%, p Citation Format: Eun-Gyeong Lee, Dong-Eun Lee, Jai Hong Han, Seeyoun Lee, Han-Sung Kang, Eun Sook Lee, Youngmee Kwon, Hyun Hee Kim, Hee Jung Chae, Sung Hoon Sim, Keun Seok Lee, So-Youn Jung. Androgen receptor as predictive marker for pathologic complete response in breast cancer with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-23.

Impairment of the astrocytic glutamate transporter excitatory amino acid transporter 2 (EAAT2) is associated with neurological disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and manganism, a neurological disorder caused by overexposure to manganese (Mn) which shares the features of sporadic PD. Mechanisms of Mn-induced neurotoxicity include dysregulation of EAAT2 following activation of the transcription factor Yin Yang 1 (YY1) by transcriptional upregulation, but the posttranslational mechanisms by which YY1 is activated to repress EAAT2 remain to be elucidated. In the present study, we tested if Mn activates YY1 through posttranslational phosphorylation in cultured H4 human astrocytes, leading to EAAT2 repression. The results demonstrate that Mn exposure induced phosphorylation of YY1 at serine residues via kinases Aurora B kinase (AurkB) and Casein kinase II (CK2), leading to YY1 nuclear translocation, YY1/HDAC interactions, binding to the EAAT2 promoter, and consequent decreases in EAAT2 promoter activity and mRNA/protein levels. Although further studies are warranted to fully elucidate the mechanisms of Mn-induced YY1 phosphorylation and resultant EAAT2 impairment, our findings indicate that serine phosphorylation of YY1 via AurkB and CK2 is critical, at least in part, to its activation and transcriptional repression of EAAT2.

BACKGROUND: The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary lymph-node–negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear. METHODS: In a prospective trial, we randomly assigned women with hormone-receptor–positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease–free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse–free survival. RESULTS: A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease–free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease–free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease–free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse–free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased. CONCLUSIONS: Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.)

Purpose Sentinel lymph node biopsy (SLNB) alone following neoadjuvant chemotherapy (NAC) remains controversial in patients with breast cancer who are initially lymph node-positive. The present study aimed to evaluate the impact of SLNB and axillary lymph node dissection (ALND) on breast cancer recurrence and survival in patients who converted from lymph node-positive to pathological node-negative (ypN0) after NAC. Methods This single-center retrospective study included 223 patients who converted to axillary lymph node-negative status after NAC and underwent breast and axillary surgery between January 2006 and December 2015. This study compared the overall survival (OS), disease-free survival (DFS), ipsilateral axillary lymph node recurrence rates and incidence of postoperative complications, especially, arm lymphedema and shoulder stiffness between SLNB and ALND. Results This study included 223 patients with axillary pathological complete response (pCR) after NAC and surgery. The SLNB and ALND groups included 94 and 129 patients, respectively. The median follow-up time was 57 (range, 6–155) in the SLNB group and 99 (range 2–159) months in the ALND group. The corresponding 5-year OS and DFS rates were 96.3% and 94.2% (p = 0.392), and 89.2% and 86.4% (p = 0.671), respectively. Four patients (4.3%) in the SLNB group and nine (7.0%) in the ALND group developed locoregional recurrences. Ipsilateral axillary lymph node recurrence and distant metastasis were observed in one (1.1%) and three (2.3%) patients, and in 10 (10.6%) and 11 (8.5%) patients, respectively. Patients in the ALND group were more likely than their SLNB counterparts to experience complications, such as shoulder stiffness (9 [7.0%] vs. 4 [4.3%] patients, p = 0.57). The rate of lymphedema in the ALND group was three times that in the SLNB group (35 [27.1%] vs. 8 [8.5%] patients, p < 0.001). Conclusion As an alternative to ALND, SLNB has oncological safety in patients with axillary pathological complete response after NAC.

The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the farreaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.

In recent years, postponing childbearing has increased the prevalence of pregnancy-associated breast cancer (PABC). PABC has a poorer prognosis than breast cancer not associated with pregnancy (non-PABC) due to delayed diagnosis and aggressive subtype. Additionally, pregnancy itself predicts a poor prognosis; but, this is a subject of debate. Thus, we analyzed the effects of known prognostic factors and pregnancy on the prognosis of PABC. We retrospectively analyzed women aged 20 to 49 years who were diagnosed with breast cancer (BC) between 1989 and 2014. Patients were distributed into PABC and non-PABC groups, and 1:4 propensity score matching was performed to adjust for baseline characteristics. Primary endpoints were overall survival (OS) and BC-specific survival (BCSS). Secondary endpoint was the difference in prognosis according to BC subtype. Of the 34,970 recruited patients with BC, 410 (1.2%) had PABC. Patients with PABC were younger and tended to have triple-negative BC (TNBC) subtype than non-PABC patients. The 1640 matched non-PABC patients showed a significantly worse mean survival rate than the unmatched non-PABC patients. Patients with PABC had a significantly worse OS and BCSS than those with non-PABC. In multivariate analyses, patients with PABC of luminal B (Ki-67 ≥14.0%) and TNBC subtypes had worse OS and BCSS than patients with non-PABC. Patients with PABC had poorer prognosis than non-PABC patients after adjusting for several prognostic factors. This difference was particularly significant in patients with the luminal B and TNBC subtypes.

Dysregulation of the astrocytic glutamate transporter excitatory amino acid transporter 2 (EAAT2) is associated with several neurological disorders, including Parkinson’s disease, Alzheimer’s disease, and manganism, the latter induced by chronic exposure to high levels of manganese (Mn). Mechanisms of Mn-induced neurotoxicity include impairment in EAAT2 function secondary to the activation of the transcription factor Yin Yang 1 (YY1) by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). However, the upstream mechanisms by which Mn-induced NF-κB activates YY1 remain has yet to be elucidated. In the present study, we used the H4 human astrocyte cell line to test if Mn activates YY1 through the canonical NF-κB signaling pathway, leading to EAAT2 repression. The results demonstrate that Mn exposure induced phosphorylation of the upstream kinase IκB kinase IKK-β, leading to NF-κB p65 translocation, increased YY1 promoter activity, mRNA/protein levels, and consequently repressed EAAT2. Results also demonstrated that Mn-induced oxidative stress and subsequent TNF-α production was upstream of IKK-β activation, as antioxidants attenuated Mn-induced TNF-α production and IKK-β activation. Moreover, the TNF-α inhibition attenuated Mn-induced activation of IKK-β and YY1. Taken together, Mn-induced oxidative stress and TNF-α mediates activation of NF-κB signaling and YY1 upregulation, leading to the repression of EAAT2. Thus, targeting reactive oxygen species (ROS), TNF-α and IKK-β may attenuate Mn-induced YY1 activation and consequent EAAT2 repression.