Anti-HER2 therapy response assessment for guiding treatment (de-)escalation in early HER2-positive breast cancer using a novel deep learning radiomics model.

OBJECTIVES: Anti-HER2 targeted therapy significantly reduces risk of relapse in HER2 + breast cancer. New measures are needed for a precise risk stratification to guide (de-)escalation of anti-HER2 strategy. METHODS: A total of 726 HER2 + cases who received no/single/dual anti-HER2 targeted therapies were split into three respective cohorts. A deep learning model (DeepTEPP) based on preoperative breast magnetic resonance (MR) was developed. Patients were scored and categorized into low-, moderate-, and high-risk groups. Recurrence-free survival (RFS) was compared in patients with different risk groups according to the anti-HER2 treatment they received, to validate the value of DeepTEPP in predicting treatment efficacy and guiding anti-HER2 strategy. RESULTS: DeepTEPP was capable of risk stratification and guiding anti-HER2 treatment strategy: DeepTEPP-Low patients (60.5%) did not derive significant RFS benefit from trastuzumab (p = 0.144), proposing an anti-HER2 de-escalation. DeepTEPP-Moderate patients (19.8%) significantly benefited from trastuzumab (p = 0.048), but did not obtain additional improvements from pertuzumab (p = 0.125). DeepTEPP-High patients (19.7%) significantly benefited from dual HER2 blockade (p = 0.045), suggesting an anti-HER2 escalation. CONCLUSIONS: DeepTEPP represents a pioneering MR-based deep learning model that enables the non-invasive prediction of adjuvant anti-HER2 effectiveness, thereby providing valuable guidance for anti-HER2 (de-)escalation strategies. DeepTEPP provides an important reference for choosing the appropriate individualized treatment in HER2 + breast cancer patients, warranting prospective validation. CLINICAL RELEVANCE STATEMENT: We built an MR-based deep learning model DeepTEPP, which enables the non-invasive prediction of adjuvant anti-HER2 effectiveness, thus guiding anti-HER2 (de-)escalation strategies in early HER2-positive breast cancer patients. KEY POINTS: • DeepTEPP is able to predict anti-HER2 effectiveness and to guide treatment (de-)escalation. • DeepTEPP demonstrated an impressive prognostic efficacy for recurrence-free survival and overall survival. • To our knowledge, this is one of the very few, also the largest study to test the efficacy of a deep learning model extracted from breast MR images on HER2-positive breast cancer survival and anti-HER2 therapy effectiveness prediction.

Clinical characteristics, tumor-infiltrating lymphocytes, and prognosis in HER2-low breast cancer: A comparison study with HER2-zero and HER2-positive disease.

INTRODUCTION: HER2-low breast cancer is a gradually recognized and unexplored group of diseases. We aimed to investigate the clinical and prognosis features and to identify the role of stromal tumor-infiltrating lymphocytes (sTILs) in this population. METHODS: Consecutive primary breast cancer patients treated between January 2009 to June 2013 were retrospectively reviewed. HER2-low was defined as immunohistochemistry (IHC) 1+, or 2+ and fluorescence in situ hybridization (FISH) negative. sTILs were scored following the international guidelines. Clinicopathologic features and survival were compared according to HER2 and sTILs category. RESULTS: A total of 973 breast cancer patients were enrolled, including 615 (63.2%) HER2-low patients. HER2-low patients shared more similarity with HER2-0 cases in clinicopathological features. sTILs in HER2-Low patients was comparable to HER2-0 patients (p = 0.064), both significantly lower than HER2-positive ones (p < 0.001). Meanwhile, tumors with sTILs ≥50% accounted for the least proportion of HER2-low cases (p < 0.001). HER2 status had no significant influence on recurrence-free survival (RFS, p = 0.901) in the whole population. However, in the estrogen receptor (ER)-negative subgroup, HER2-low was related to worse RFS (p = 0.009) and OS (p = 0.001) compared with HER2-positive ones. sTILs increment was an independent favorable prognostic factor in the whole (OS, p = 0.003; RFS, p = 0.005) and HER2-low population (OS, p = 0.007; RFS, p = 0.009) after adjusted to clinicopathological parameters. CONCLUSIONS: HER2-low patients shared similar clinicopathological features with HER2-0 rather than HER2-positive cases and had relatively low sTILs. ER-negative/HER2-low patients had significantly inferior survival. sTILs increment was independently associated with favorable survival in the HER2-low group, suggesting a potential benefit from a novel treatment strategy.

Single-cell atlas reveals a distinct immune profile fostered by T cell-B cell crosstalk in triple negative breast cancer.

BACKGROUND: Characterizing the unique immune microenvironment of each tumor is of great importance for better predicting prognosis and guiding cancer immunotherapy. However, the unique features of the immune microenvironment of triple negative breast cancer (TNBC) compared with other subtypes of breast cancer remain elusive. Therefore, we aimed to depict and compare the immune landscape among TNBC, human epidermal growth factor receptor 2-positive (HER2+ ) breast cancer, and luminal-like breast cancer. METHODS: Single-cell RNA sequencing (scRNA-seq) was performed on CD45+ immune cells isolated from human normal breast tissues and primary breast tumors of various subtypes. By analyzing the scRNA-seq data, immune cell clusters were identified and their proportions as well as transcriptome features were compared among TNBC, human HER2+ breast cancer, and luminal-like breast cancer. Pseudotime and cell-cell communication analyses were also conducted to characterize the immune microenvironment. RESULTS: ScRNA-seq data of 117,958 immune cells were obtained and 31 immune clusters were identified. A unique immunosuppressive microenvironment in TNBC was decoded as compared to that in HER2+ or luminal-like breast cancer, which was characterized by higher proportions of regulatory T cells (Tregs) and exhausted CD8+ T cells and accompanied by more abundant plasma cells. Tregs and exhausted CD8+ T cells in TNBC exhibited increased immunosuppression signature and dysfunctional scores. Pseudotime analyses showed that B cells tended to differentiate to plasma cells in TNBC. Cell-cell communication analyses indicated that these unique features are fostered by the diversified T cell-B cell crosstalk in TNBC. Based on the T cell-B cell crosstalk, a prognostic signature was established that could effectively predict the prognosis status for patients with TNBC. Additionally, it was found that TNBC had a higher proportion of cytotoxic natural killer (NK) cells, whereas HER2+ or luminal-like breast cancer lost this feature, suggesting that HER2+ or luminal-like breast cancer, but not TNBC, may benefit from NK-based immunotherapy. CONCLUSIONS: This study identified a distinct immune feature fostered by T cell-B cell crosstalk in TNBC, which provides better prognostic information and effective therapeutic targets for breast cancer.

Ki67 increase after core needle biopsy associated with worse disease outcome in HER2-negative breast cancer patients.

Ki67 would change after core needle biopsy (CNB) in invasive breast cancer. However, whether Ki67 alteration (ΔKi67) influences disease outcomes remains unclear. Here we aim to evaluate the prognostic value of ΔKi67. Patients with paired CNB and open excision biopsy (OEB) samples between January 2009 and June 2016 were retrospectively analyzed. ΔKi67 was calculated as the absolute difference between Ki67 level in CNB and OEB samples, and the median value of 5% was adopted to category patients into high- and low ΔKi67 groups. Disease-free survival (DFS) and overall survival (OS) were compared between different ΔKi67 groups. Overall, 2173 invasive breast cancer patients were included. Median Ki67 was higher in OEB than CNB samples: 25.00% versus 20.00% (P < 0.001). Axillary nodal status, STI, histological grading, and molecular subtype were independently associated with ΔKi67 (P < 0.05). In the whole population, patients with low ΔKi67 showed superior 5-year DFS (89.6% vs 87.0%, P = 0.026), but similar OS (95.8% vs 94.3%, P = 0.118) compared to those with high ΔKi67. HER2 status at surgery was the only significant factor interacting with ΔKi67 on both DFS (P = 0.026) and OS (P = 0.007). For patients with HER2-negative disease, high ΔKi67 was associated with worse 5-year DFS (87.2% vs 91.2%, P = 0.004) as well as impaired 5-year OS (93.9% vs 96.8%, P = 0.010). ΔKi67 had no significant impact on survival of HER2-positive patients. Ki67 increase after CNB was significantly associated with worse disease outcomes in HER2-negative, but not in HER2-positive patients, which warrants further study.

Neoadjuvant docetaxel, epirubicin, and cyclophosphamide with or without metformin in breast cancer patients with metabolic abnormality: results from the randomized Phase II NeoMET trial.

PURPOSE: Breast cancer patients with metabolic syndrome (MetS) and its components show worse treatment responses to chemotherapy. Metformin is a widely used antidiabetic drug which also shows potential anticancer effect. This study aims to evaluate the efficacy, safety, and metabolic parameters change of metformin combined with docetaxel, epirubicin, and cyclophosphamide (TEC) in neoadjuvant treatment (NAT) for breast cancer patients with metabolic abnormality. METHODS: Eligible breast cancer patients were randomized to receive six cycles of TEC (docetaxel 75 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2, d1, q3w) or TEC with metformin (TECM, TEC with oral metformin 850 mg once daily for the first cycle, then 850 mg twice daily for the following cycles). The primary end point was total pathological complete response (tpCR, ypTis/0N0) rate. RESULTS: Ninety-two patients were enrolled and randomized from October 2013 to December 2019: 88 patients were available for response and safety assessment. The tpCR rates were 12.5% (5/40) and 14.6% (7/48) in the TEC and TECM groups, respectively (P = 0.777). There was no difference in Ki67 decrease after NAT between two groups (P = 0.456). Toxicity profile were similar between two groups. No grade 3 or higher diarrhea were recorded. Total cholesterol (TC) and high-density lipoprotein cholesterol worsened after NAT in the TEC arm but remained stable in the TECM arm. The absolute increase of TC and low-density lipoprotein cholesterol (LDL-C) was significantly lower in the TECM group compared with the TEC group. After a median follow-up of 40.8 (4.7-70.8) months, no survival difference was observed between TEC and TECM groups (all P > 0.05). CONCLUSION: Adding metformin to TEC didn't increase pCR rate and disease outcome in breast cancer patients with metabolic abnormality. However, additional metformin treatment with chemotherapy would prevent TC and LDL-C increase after NAT. Trial Registration ClinicalTrials.gov Identifier: NCT01929811.

Association of tumor immune microenvironment profiling and 21-gene recurrence assay in early breast cancer patients.

INTRODUCTION: Tumor immune microenvironment (TIME) plays a vital role in breast cancer development, treatment resistance, and prognosis. This study evaluates the association of TIME profiling and 21-gene recurrence score (RS) in early Luminal breast cancer patients. METHODS: ER+ /HER2-, pN0 breast cancer patients with available RS results who received surgery between January 2009 and December 2013 were enrolled. TIME markers, including stromal tumor infiltrating lymphocytes (TILs), CD3, CD4, CD8, and tumor PD-L1 expression, were comprehensively analyzed. Association of TIME markers with RS, as well as their correlation with breast cancer-specific survival (BCSS) were tested. RESULTS: Overall, 385 patients were included, of whom 341 (88.6%) had TILs ≤10%. TIME markers were positively but moderately correlated with each other (Spearman r 0.28-0.53, all P < 0.05). Continuous RS showed a weak correlation with continuous TILs, CD3, CD8, and PD-L1. Regarding single gene mRNA level in the 21-gene RS panel, higher expression of TIME markers was related to lower ER group genes expression, but higher proliferation and invasion group genes level. After a median follow-up of 91.67 (range 5.03-134.03) months, TILs (P = 0.049) and PD-L1 (P = 0.034) were inversely associated with BCSS. CONCLUSIONS: Breast cancer TIME markers, including TILs, CD3, CD4, CD8, and PD-L1, were correlated with 21-gene RS score. Lower expression of ER group genes, as well as higher expression of proliferation and invasion group genes were associated with a higher level of these TIME markers, warranting further exploration.

HER2-Low Status Is Not Accurate in Breast Cancer Core Needle Biopsy Samples: An Analysis of 5610 Consecutive Patients.

Background: HER2-Low status is found in approximately half of breast cancer patients and shows potential benefits from novel antibody−drug conjugates (ADCs). Data on the accuracy of HER2-Low status between core needle biopsy (CNB) and surgical excision specimen (SES) samples are lacking. We aimed to investigate the accuracy of HER2-Low status diagnosis between CNB and SES samples. Methods: Consecutive early-stage breast cancer patients who underwent surgery from January 2009 to March 2022 with paired CNB and SES samples were retrospectively reviewed. HER2-Low was defined as IHC 1+ or IHC2+ and FISH-negative. Concordance rates were analyzed by the Kappa test. Further clinicopathological characteristics were compared among different HER2 status and their changes. Results: A total of 5610 patients were included, of whom 3209 (57.2%) and 3320 (59.2%) had HER2-Low status in CNB and SES samples, respectively. The concordance rate of HER2 status in the whole population was 82.37% (Kappa = 0.684, p < 0.001), and was 76.87% in the HER2-Negative patients (Kappa = 0.372, p < 0.001). Among 1066 HER2-0 cases by CNB, 530 patients were classified as HER2-Low tumors. On the contrary, in 3209 patients with HER2-Low tumor by CNB, 387 were scored as HER2-0 on the SES samples. ER-negative or Ki67 high expression tumor by CNB had a high concordance rate of HER2-Low status. Conclusions: A relatively low concordance rate was found when evaluating HER2-Low status between CNB and SES samples in HER2-Negative breast cancer patients, indicating the necessity of retesting HER2 low status at surgery, which may guide further therapy in the era of anti-HER2 ADCs.

Can HER2 1+ Breast Cancer Be Considered as HER2-Low Tumor? A Comparison of Clinicopathological Features, Quantitative HER2 mRNA Levels, and Prognosis among HER2-Negative Breast Cancer.

Background: Human epidermal growth factor receptor 2 (HER2)-low tumor is a new entity defined as HER2 immunohistochemistry (IHC) 1+ or 2+/fluorescence in situ hybridization (FISH)-negative. We aimed to evaluate whether HER2 mRNA levels tested by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) could better define HER2-low tumors. Patients and methods: Consecutive breast cancer patients with hormonal receptor-positive, HER2-negative diseases, and HER2 mRNA results were included. Clinicopathologic features, HER2 mRNA expression level, and prognosis were compared among HER2 0, 1+ and 2+/FISH− groups. Concordance of the HER2 category between qRT-PCR and IHC/FISH was analyzed for each group. Results: 2296 patients were included: 368 (16.0%) HER2 0, 911 (39.7%) 1+, and 1017 (44.3%) 2+/FISH− tumors. HER2 1+ cases shared similarities with HER2 0 tumors in terms of clinicopathologic features (all p > 0.05), whereas IHC 2+/FISH− cases were less often non-IDC (p = 0.045), node-negative (p = 0.044), and Ki-67 < 14% (p <0.001). The mRNA expression was similar between HER2 0 and 1+ cases (p = 0.063), and both were lower than 2+/FISH− cases (p < 0.001). A poor concordance rate was found between IHC/FISH and qRT-PCR for HER2 0 and HER2-low cases (Cohen's kappa 0.126, p < 0.001). No survival difference was observed among these groups, whether stratified by HER2 IHC/FISH status or mRNA level (all p > 0.05). Conclusions: HER2 1+ cases had similar clinicopathological features to HER2 0 breast cancers, and both were different from HER2 2+/FISH− cases. HER2 mRNA levels were comparable between HER2 0 and 1+ tumors, and both were significantly lower than IHC 2+/FISH− tumors. Neither IHC nor qRT-PCR may be optimal to quantify HER2-low expression, especially for HER2 1+ patients.

Accuracy of ultrasonographic changes during neoadjuvant chemotherapy to predict axillary lymph node response in clinical node-positive breast cancer patients.

Purpose: To evaluate whether changes in ultrasound features during neoadjuvant chemotherapy (NAC) could predict axillary node response in clinically node-positive breast cancer patients. Methods: Patients with biopsy-proven node-positive disease receiving NAC between February 2009 and March 2021 were included. Ultrasound (US) images were obtained using a 5-12-MHz linear array transducer before NAC, after two cycles, and at the completion of NAC. Long and short diameter, cortical thickness, vascularity, and hilum status of the metastatic node were retrospectively reviewed according to breast imaging-reporting and data system (BI-RADS). The included population was randomly divided into a training set and a validation set at a 2:1 ratio using a simple random sampling method. Factors associated with node response were identified through univariate and multivariate analyses. A nomogram combining clinical and changes in ultrasonographic (US) features was developed and validated. The receiver operating characteristic (ROC) and calibration plots were applied to evaluate nomogram performance and discrimination. Results: A total of 296 breast cancer patients were included, 108 (36.5%) of whom achieved axillary pathologic complete response (pCR) and 188 (63.5%) had residual nodal disease. Multivariate regression indicated that independent predictors of node pCR contain ultrasound features in addition to clinical features, clinical features including neoadjuvant HER2-targeted therapy and clinical response, ultrasound features after NAC including cortical thickness, hilum status, and reduction in short diameter ≥50%. The nomogram combining clinical features and US features showed better diagnostic performance compared to clinical-only model in the training cohort (AUC: 0.799 vs. 0.699, P=0.001) and the validation cohort (AUC: 0.764 vs. 0.638, P=0.027). Conclusions: Ultrasound changes during NAC could improve the accuracy to predict node response after NAC in clinically node-positive breast cancer patients.

Association of Obesity and Luminal Subtypes in Prognosis and Adjuvant Endocrine Treatment Effectiveness Prediction in Chinese Breast Cancer Patients.

Purpose: To evaluate the influence of obesity on clinicopathological characteristics of breast cancer; to explore the effect of obesity on the prognosis and performance of endocrine therapy in breast cancer patients. Methods: Patients with luminal/HER2-negative early breast cancer were included and categorized into the non-obese (BMI<28kg/m2) and obese (BMI≥28kg/m2) groups according to body mass index (BMI). Clinicopathological characteristics and treatment modalities were compared between groups. Interaction of adjuvant endocrine therapy with obesity was analyzed. Results: A total of 2,875 patients were included: 2,598 non-obese and 277 obese. A higher rate of patients with comorbidities (OR: 2.83, 95%CI 2.13-3.74, P<0.001) or PR-positive tumor (OR: 1.63, 95%CI 1.03-2.58, P=0.037) were identified in the obese group. Obesity was not associated with disease recurrence (P=0.839) or overall survival (P=0.140) in the whole population. Subgroup analysis did show an association with worse relapse-free survival (RFS, HR 3.48, 95%CI 1.31-9.22, P=0.012) and overall survival (OS, HR 4.67, 95%CI 1.28-16.95, P=0.019) in luminal A breast cancer. These results could not be reproduced in the luminal B subtype with a RFS (HR 0.78, 95%CI 0.41-1.49, P=0.454) or OS (HR 1.17, 95%CI 0.50-2.74, P=0.727). Furthermore, obesity did not impact endocrine therapy effectiveness in Tamoxifen or the aromatase inhibitor group (RFS: interact P=0.381; OS: interact P=0.888). Conclusions: The impact of obesity on prognosis interacted with luminal subtype status in Chinese breast cancer patients which was not related with endocrine treatment modality.

Association of machine learning ultrasound radiomics and disease outcome in triple negative breast cancer.

Triple negative breast cancer (TNBC) is a breast cancer subtype with unfavorable prognosis. We aimed to establish a machine learning-based ultrasound radiomics model to predict disease-free survival (DFS) in TNBC. Invasive TNBC>T1b between January 2009 and June 2018 with preoperative ultrasound were enrolled and assigned to training and independent test cohort. Radiomics and clinicopathological features related with DFS were selected by univariate and multivariate regression analysis. Training cohort of combined features was resampled with SMOTEENN to balance distribution and put into classifiers. Areas Under Curves (AUCs) of models were compared by DeLong's test. 562 women were included with 68 DFS events observed. Twenty prognostic radiomics features were extracted. Machine learning model by Naïve Bayes combining radiomics, clinicopathological features, and SMOTEENN had an AUC of 0.86 (95% CI 0.84-0.88), with sensitivity of 74.7% and specificity of 80.1% in training cohort. In independent test cohort, this three-combination model delivered an AUC of 0.90 (95% CI 0.83-0.95), higher than models based on radiomics (AUC=0.69, P=0.016) or radiomics + SMOTEENN (AUC=0.73, P=0.019). Integrating machine learning radiomics model based on ultrasound and clinicopathological features can predict DFS events for TNBC patients.

Prognostic Factors and Surgery for Breast Cancer Patients With Locoregional Recurrence: An Analysis of 5,202 Consecutive Patients.

PURPOSE: With the application of "less extensive surgery" in breast cancer treatment, the pattern of locoregional recurrence (LRR) has significantly changed. This study aims to evaluate the risk and prognostic factors of LRR in a recent large breast cancer cohort. METHODS: Consecutive early breast cancer patients who received surgery from January 2009 to March 2018 in Shanghai Ruijin Hospital were retrospectively analyzed. LRR was defined as recurrence at the ipsilateral breast (IBTR), chest wall, or regional lymph nodes and without concurrent distant metastasis (DM). Patients' characteristics and survival were compared among these groups. RESULTS: Among 5,202 patients included, 87 (1.7%) and 265 (5.1%) experienced LRR and DM as first event after a median 47.0 (3.0-122.5) months' follow-up. LRR was significantly associated with large tumor size and positive lymph node status (p < 0.05). Forty (46.0%) patients received further salvage surgery after LRR and had a significantly better 3-year post-recurrence overall survival than those who did not (94.7% vs. 60.7%, p = 0.012). Multivariate analysis showed that salvage surgery for LRR was independently associated with better survival (HR = 0.12, 95% CI 0.02-0.93, p = 0.043) along with estrogen receptor (ER) positivity (HR = 0.33, 95% CI 0.12-0.91, p = 0.033). CONCLUSION: LRR rate was relatively low in recent era of breast cancer treatment. Tumor size and lymph node status were associated with risk of LRR, and salvage surgery for selected LRR patients achieved an excellent outcome.

21-Gene Recurrence Assay Associated With Favorable Metabolic Profiles in HR-Positive, HER2-Negative Early-Stage Breast Cancer Patients.

Background: Comprehensive investigations of the associations between 21-gene recurrence assay and metabolic profiles in Chinese breast cancer patients are limited. Methods: We evaluated the relations of the 21-gene recurrence risk score (RS) and the expression of cancer-related genes with metabolic factors and biomarkers of insulin and the insulin-like growth factor (IGF) axis, and examined the interactions between the 21-gene RS and these metabolic profiles on breast cancer recurrence in Chinese women with HR-positive, HER2-negative early-stage breast cancer. Results: The 21-gene RS was inversely associated with body mass index ([BMI]ß: -0.178 kg/m2; P=0.040), the homeostasis model assessment of insulin resistance index ([HOMA-IR] ß: -0.031; P=0.042), insulin (ß: -0.036 uIU/ml; P=0.009), and C-peptide (ß: -0.021 ug/L; P=0.014) and was positively associated with high-density lipoprotein cholesterol (ß: 0.025 mmol/L; P=0.004), which were driven by the relation patterns between specific cancer-related genes and these metabolic profiles. Each 10-unit increase in the 21-gene RS was associated with 28% (95% CI: 5-47%) higher risk of breast cancer recurrence; this association was also observed in patients with favorable metabolic profiles in relevant to an absence of obesity, insulin resistance, hyperglycemia, hypertension, or dyslipidemia (28-44% higher risk) and among women with a low level of insulin, C-peptide, or the IGF1/IGFBP3 ratio (41-155% higher risk). Conclusions: The 21-gene RS was related to favorable metabolic profiles including lower BMI, HOMA-IR, insulin, and C-peptide, and higher HDL in Chinese breast cancer patients, and its prognostic impact on breast cancer recurrence was more likely to present among patients with relatively favorable metabolic profiles.

Diverse Distribution and Gene Expression on the 21-Gene Recurrence Assay in Breast Cancer Patients with Locoregional Recurrence Versus Distant Metastasis.

BACKGROUND: It remains uncertain whether the 21-gene recurrence score (RS) of a primary tumor has selective prognostic value for locoregional recurrence (LRR) or distant metastasis (DM). The current study aimed to compare the distribution and single-gene expression on the RS panel in breast cancer patients with LRR versus DM. METHODS: Consecutive early breast cancer patients who had been operated on at the Comprehensive Breast Health Center, Ruijin Hospital from January 2009 to December 2016 were retrospectively reviewed. Patients were divided into LRR, DM, and no-recurrence groups according to the first reported recurrent event. Comparison and subgroup analysis of 21-gene RS, RS category, and single-gene expression on the RS panel were conducted among patients with different recurrence status. RESULTS: A total of 1,287 patients were included, with median follow-up of 61.5 months, and 27, 47, and 1,213 patients were classified as LRR, DM, and no recurrence groups, respectively. RS was significantly diversely distributed among the three groups (P<0.001). No-recurrence patients (median 22) presented much lower RS than LRR (median 39, P<0.001) and DM (median 30, P<0.001) patients. LRR patients had lower PR (P<0.001), BCL2 (P=0.010), and CEGP1 (P<0.001) expression, and DM patients had higher STMY3 (P=0.019) expression than no-recurrence patients. Moreover, CEGP1 expression was significantly lower in the LRR group than the DM one (P=0.028). CONCLUSION: RS was differently distributed between recurrent and nonrecurrent patients. PR, BCL2, CEGP1, and STMY3 expression was associated with LRR and DM, while CEGP1 was lower in the LRR group than DM patients, warranting further clinical evaluation.

Association of Biomarker Discrepancy and Treatment Decision, Disease Outcome in Recurrent/Metastatic Breast Cancer Patients.

BACKGROUND: Biomarker discrepancy between primary and recurrent/metastatic breast cancer is well known, however its impact on prognosis and treatment after relapse is still unclear. Current study aims to evaluate biomarkers discrepancy between primary and recurrent/metastatic lesions as well as to investigate its association with following treatment pattern and disease outcome. PATIENTS AND METHODS: We retrospectively included consecutive breast cancer patients undergoing surgery in our center from Jan. 2009 to Dec. 2016 and reported disease recurrence. Patients with re-biopsy and paired biomarkers statuses on primary and recurrent/metastatic lesions were further analyzed. Kappa test was used to analyze the concordance rate of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) status. Post-recurrence survival (PRS) was compared between subgroups by Kaplan-Meier curve. Cox regression model was applied to identify impact factors for PRS. RESULTS: A total of 156 patients were finally included, of whom 70 and 86 had loco-regional and distant recurrence, respectively. Concordance rates of ER, PR and HER2 were 83.3%, 66.7%, and 97.1%, respectively, which was similarly distributed among different recurrent sites (all P > 0.05). Primary ER-positivity (vs ER-negativity, P = 0.014) and loco-regional recurrence (vs distant metastasis, P = 0.001) were independently associated with superior PRS, while patients with visceral metastasis (P < 0.001) had the worst disease outcome. Hormone receptor/HER2 status discrepancy was observed in 28 patients. Fifteen of them changed systemic treatment based on biomarker statuses of recurrent lesion, however, their PRS was not improved compared to those 13 patients who continued the same treatment according to primary biomarkers statuses (P = 0.298). CONCLUSION: Biomarker discrepancy was observed between primary and recurrent/metastatic breast cancer lesions and had certain influence on treatment strategies after relapse. However, its impact on disease outcome wasn't established in the current study, which deserves further evaluation.

Comprehensive Association Analysis of 21-Gene Recurrence Score and Obesity in Chinese Breast Cancer Patients.

PURPOSE: A center-specific 21-gene recurrence score (RS) assay has been validated in Luminal-like, HER2-, pN0-1 Chinese breast cancer patients with both predictive and prognostic value. The association between RS and host factors such as obesity remains unclear. The objectives of the current study are to comprehensively analyze the distribution, single gene expression, and prognostic value of RS among non-overweight, overweight and obese patients. PATIENTS AND METHODS: Luminal-like patients between January 2009 and December 2018 were retrospectively reviewed. Association and subgroup analysis between BMI and RS were conducted. Single-gene expression in RS panel was compared according to BMI status. Disease-free survival (DFS) and overall survival (OS) were calculated according to risk category and BMI status. RESULTS: Among 1876 patients included, 124 (6.6%), 896 (47.8%) and 856 (45.6%) had RS < 11, RS 11-25, and RS ≥ 26, respectively. Risk category was significantly differently distributed by BMI status (P=0.033). Obese patients were more likely to have RS < 11 (OR 2.45, 95% CI 1.38-4.35, P=0.002) compared with non-overweight patients. The effect of BMI on RS significantly varied according to menstruation (P<0.05). Compared to non-overweight patients, obese ones presented significantly higher ER, PR, CEGP1, Ki67, CCNB1 and GSTM1 (all P<0.05) mRNA expression, and such difference was mainly observed in postmenopausal population. After a median follow-up of 39.40 months (range 1.67-119.53), RS could significantly predict DFS in whole population (P=0.001). RS was associated with DFS in non-overweight (P=0.046), but not in overweight (P=0.558) or obese (P=0.114) population. CONCLUSIONS: RS was differently distributed among different BMI status, which interacted with menopausal status. Estrogen receptor and proliferation group genes were more expressed in obese patients, especially in postmenopausal population.

Association between tumor molecular subtype, clinical stage and axillary pathological response in breast cancer patients undergoing complete pathological remission after neoadjuvant chemotherapy: potential implications for de-escalation of axillary surgery.

BACKGROUND: Axillary node status is used in clinical practice to guide the selection of axillary surgery in breast cancer patients. However, to date, the optimal axillary management following neoadjuvant therapy (NAT) for breast cancer remains controversial. Our study aimed to investigate the association of molecular subtype, clinical stage, and ypN status after NAT in breast cancer patients, especially those achieving breast pathological complete remission (pCR). PATIENTS AND METHODS: Patients receiving ⩾4 cycles of NAT were retrospectively included between January 2009 and January 2020. ypN status was compared among patients with different breast pCR statuses, clinical stages, and molecular subtypes in univariate and multivariate analyses. RESULTS: A total of 1999 patients were included: 457 (22.86%), 884 (44.22%), and 658 (32.92%) patients with cT1-2N0, cT1-2N1, and locally advanced breast cancer (LABC), respectively. Altogether, 435 (21.8%) patients achieved breast pCR: 331 with ypN- and 104 with ypN+ status. Patients achieving breast pCR had a significantly lower ypN+ rate than those without pCR [23.9% versus 62.5%, odds ratio (OR) = 0.14, 95% confidence interval (CI) = 0.09-0.21]. For patients with breast pCR, the ypN+ rate was 6.4%, 25.7%, and 33.9% in cT1-2N0, cT1-2N1, and LABC patients, respectively (p < 0.001). Furthermore, the ypN+ rate was 30.8%, 16.8%, 17.5%, 29.6%, and 27.6% in breast pCR patients with the Luminal A, Luminal B (HER2+), HER2-amplified, Luminal B (HER2-), and triple-negative subtype, respectively. Luminal B (HER2+) (OR = 0.20, 95% CI = 0.05-0.82) and HER2-amplified (OR = 0.19, 95% CI = 0.05-0.83) tumors were associated with lower ypN+ rates. Moreover, 100% of breast pCR patients with cT1-2N0 and HER2-positive disease achieved pathological pN0. CONCLUSION: In breast pCR patients after NAT, clinical stage and molecular subtype were significantly associated with ypN status. Patients with cT1-2N0 and HER2-positive disease who achieved breast pCR had a very low ypN+ rate, possibly indicating the possibility for de-escalation of axillary surgery in this patient subgroup.

Predictors of Nodal Pathological Complete Response in Asian Women with Stage II-III Node-Positive Breast Cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is increasingly used to treat node-positive (N+) breast cancer. Predictors of nodal pathological complete response (pCR) in Asian women are poorly described and there is variety in the management of the axilla after NAC. We evaluated predictors of nodal pCR and axillary management in a cohort of Asian N+ patients. METHODS: Consecutive biopsy-proven N+ breast cancer patients treated with NAC were identified from the Shanghai Ruijin Hospital in China. Axillary lymph node dissection was performed on all patients, irrespective of the nodal response to NAC. RESULTS: A total of 323 patients were included. Nodal pCR was achieved in 105 patients (33%), 15% of HR+/HER2- tumors, 38% of HR+/HER2+ tumors, 49% of HR-/HER2+ tumors, and 42% of HR-/HER2-tumors (p < 0.001). Factors associated with nodal pCR were (1) receptor status (HR+/HER2- [referent]: OR 3.42, 95% CI 1.43-8.16, p = 0.006 for HR+/HER2+; OR 4.19, 95% CI 1.85-9.50, p = 0.001 for HR-/HER2+; and OR 2.94, 95% CI 1.11-7.74, p = 0.029 for HR-/HER2-), (2) breast pCR (no pCR [referent]: OR 15.22, 95% CI 6.29-36.79, p < 0.001), and (3) absence of lymphovascular invasion (LVI [referent]: OR 9.04, 95% CI 2.09-39.18, p = 0.003). CONCLUSION: This study confirmed expected predictors of nodal pCR in Asian women and the benefit of NAC in downstaging the axilla independently of ethnicity.

Primary 21-Gene Recurrence Score and Disease Outcome in Loco-Regional and Distant Recurrent Breast Cancer Patients.

Background: The 21-gene recurrence score (RS) assay has been proven prognostic and predictive for hormone receptor-positive/HER2-negative, node-negative early breast cancer patients. However, whether primary 21-gene RS can predict prognosis in recurrent breast cancer patients remained unknown. Patients and Methods: Consecutive breast cancer patients operated in Comprehensive Breast Health Center, Shanghai Ruijin Hospital between January 2009 and December 2018 were retrospectively analyzed. Patients with available 21-gene RS result for the primary tumor and reporting disease recurrence during follow-up were included. Association of 21-gene RS and overall survival (OS), post-recurrence overall survival (PR-OS), post-recurrence progression-free survival (PR-PFS), and first-line systemic treatment after recurrence were compared among different groups. Results: A total of 74 recurrent patients were included, with 10, 27, 37 patients in the RS <18, 18-30, and ≥ 31 groups, respectively. Recurrent patients with RS ≥ 31 were more likely to receive chemotherapy as their first-line treatment compared to those with RS <31 (P = 0.025). Compared to those with RS <31, patients with RS ≥ 31 had significantly worse OS (P = 0.025), worse PR-OS (P = 0.026), and a trend of inferior PR-PFS (P = 0.106). Multivariate analysis demonstrated that primary ER expression level (OS: P = 0.009; PR-OS: P = 0.017) and histological grade (OS: P = 0.003; PR-OS: P = 0.009), but not primary 21-gene RS (OS: P = 0.706; PR-OS: P = 0.120), were independently associated with worse OS and PR-OS. Conclusions: High primary 21-gene RS tended to be associated with worse disease outcome in loco-regional and distant recurrent breast cancer patients, which could influence the first-line systemic treatment after relapse, warranting further clinical evaluation.

IGF-1 Interacted With Obesity in Prognosis Prediction in HER2-Positive Breast Cancer Patients.

Purpose: Dysmetabolism and high circulating insulin-like growth factor 1 (IGF-1) would increase breast cancer risk, but its association with survival in HER2+ breast cancer patients has not been well-studied. Herein, we aim to evaluate the prognostic value of IGF-1 and metabolic abnormalities in HER2+ population. Patients and Methods: HER2+ breast cancer patients treated in Ruijin Hospital between November 2012 and June 2017 were retrospectively analyzed. Median value of circulating IGF-1 was adopted to classify low or high IGF-1 group. Metabolic syndrome (MetS) was defined using AHA/NHLBI criteria. Overweight was defined by body mass index (BMI) ≥ 24.0 kg/m2 in Chinese population. Results: Overall, 679 patients were included and 209 had synchronous MetS. High IGF-1 level was more common in pre/peri-menopausal women (P < 0.001) and high IGFBP-3 patients (P < 0.001). After a median follow-up of 36 months, 52 patients had disease recurrences. IGF-1 level was not associated with recurrence-free survival (RFS, P = 0.620) in the whole population. However, exploratory subgroup analysis found that BMI and IGF-1 interacted in predicting RFS (P = 0.009). For non-overweight patients, high IGF-1 showed a superior 4-years RFS (91.1 vs. 85.0%; HR 0.53, 95% CI 0.27-1.00, P = 0.049) compared with patients with low IGF-1 level. In contrast, for overweight patients, high IGF-1 was associated with an impaired 4-years RFS (88.3 vs. 95.7%, HR 3.20, 95% CI 1.00-10.21, P = 0.038). Furthermore, high IGF-1 level was independently associated with better OS in the whole (HR 0.26, 95% CI 0.08-0.82, P = 0.044) as well as non-overweight population (HR 0.15, 95% CI 0.03-0.68, P = 0.005). Conclusions: IGF-1 level was not associated with RFS in HER2+ breast cancer patients. However, IGF-1 and BMI had significant interaction in disease outcome prediction in HER2+ patients. High IGF-1 was protective in non-overweight patients, but risk factor for those overweight, which deserves further evaluation.