Factor In Early Breast Cancer Research Articles

Abstract PO1-27-07: Is HER2-low a biologically distinct breast cancer (BC) subtype? Prognosis and pathological complete response rate after neoadjuvant treatment (NAT) in early breast cancer (BC) HER2 negative

Abstract Background: Overexpression of HER2 is a significant prognostic and predictive factor in early breast cancer. HER2 positive tumors are those scored by immunohistochemistry (IHC) 3+ or 2+ with amplification by in situ hybridization (ISH). These tumors may benefit from HER2-targeted treatment and additionally, in early HER2-positive BC, achieving a complete pathological response after neoadjuvant treatment improves patient survival. In recent years, new anti-HER2 antibody-drug conjugates have proven effective for HER2 low BC (defined as IHC score 1+ or 2+ not amplified) in the metastatic disease setting; however, in HER2-low early BC, studies testing novel anti-HER2 antibody-drug conjugates as neoadjuvant therapy (NAT) are ongoing. Currently, we don´t know exactly whether HER2 expression can influence the pathological response rate after NAT or disease-free survival (DFS) in these patients compared to HER2-zero (IHC 0). The aim of our study is to determine the impact on response rate to NAT and survival outcomes in early HER2-negative BC. Methods: We conducted a retrospective study in two hospitals in Andalucia, Spain. Patients with early HER2 negative BC treated with NAT from January 2015 to June 2022 were included. Patients were divided into HER2 low patients (IHC 1+ or 2+ not amplified) and HER2 0 (IHC 0). We collected clinical and pathological characteristics, pathological response rate using the Residual Cancer Burden (RCB) system where a complete pathological response (pCR) was defined as ypT0/ypTis and ypN0, and survival outcomes. The primary objective of the study was to analyze the pCR rate after NAT according to HER2 score, and secondary objectives were to assess disease-free survival and overall survival (DFS and OS rates). Results: 574 patients were included (100% women). 397 patients had hormone receptors (luminal BC) on these tumors, and 177 did not have them, i.e., triple-negative BC (TNBC). 225 patients were HER2-zero, and 312 patients were HER2-low (253/312 patients had luminal BC and 59/312 patients were TNBC). The pCR in HER2-low patients was 17.3% and 23.1% in HER2-zero patients (p=0.047). For luminal BC patients, the pCR was 16.7% in HER2-low tumors and 13.7% in HER2-zero tumors (p=0.29). Similarly, there was no difference in pCR rates in TNBC patients (45.8% in HER2-low and 53.8% in HER2-zero tumors, respectively, (p=0.958). The overall survival (OS) at 96 months was 88.7% (95% CI 85.6%-92%). Regarding survival outcomes, neither HER2 expression level was associated with higher 8-year DFS: 81.1% in HER2-low patients (95% CI 75.7%-86.8%) and 74.9% in HER2-zero patients (95% CI 62.3%-90.1%) p=0.64. There was no difference between histological subtypes at 8-years regarding DFS rate: 80.5% (95% CI 74.3%-87.2%) in luminal HER2-low patients and 76.3% (95% CI 60.8%-95.7%) in luminal HER2-zero patients, p=0.22; 83.8% in TNBC HER2-low (95% CI 74.5%-94.2%) and 77.5% in TNBC HER2-zero patients (95% CI 69.4%-86.6%) p=0.26. We also didn´t find significant differences in terms of OS. For HER2-low patients, the 8-year OS was 90.9% (95% CI 87%-94.9%) and for HER2-zero patients, it was 86.4% (95% CI 80.8%- 92.5%) p=0.46. There were also no differences in OS for different histological subgroups with an 8-year OS in luminal HER2-low breast cancer patients of 92.5% (95% CI 88%-96.7%) and 87% in HER2-zero (95% CI 78.9%-96.1%) p=0.91. In patients with triple-negative breast cancer phenotype, the OS was 84.2% for HER2-low (95% CI 74.5%-95.2%) and 85.3% for HER2-zero (95% CI 77.9%-93.4%) p=1. Conclusions: We found no difference in survival outcomes and response rate to conventional NAT between HER2-low and HER2-zero expression levels. Therefore, our data do not support the hypothesis of HER2-low as a biologically specific breast cancer subtype. Further research on this approach with HER2 antibody-drug conjugate schemes as an alternative to traditional NAT schemes is warranted. Citation Format: Ana Gil-Torralvo, Yeray Rodriguez, Alejandro Falcon, David Morales, Mónica Cejuela, Isabel Miras, Marta Amérigo, Manuel Ruíz - Borrego, Juan Bayo, Francisco Javier Salvador Bofill. Is HER2-low a biologically distinct breast cancer (BC) subtype? Prognosis and pathological complete response rate after neoadjuvant treatment (NAT) in early breast cancer (BC) HER2 negative [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-27-07.

Effect of a telephone-based weight loss intervention (WLI) on weight at 12-months in women with early breast cancer: Results from the Breast Cancer Weight Loss (BWEL) trial.

12001 Background: Obesity is a poor prognostic factor in early breast cancer. The Breast Cancer Weight Loss (BWEL) trial (Alliance for Clinical Trials in Oncology A011401; NCT02750826) evaluates the impact of a WLI on invasive disease-free survival in breast cancer patients (pts) with a body mass index (BMI) ³27 kg/m2. Here we report the impact of the WLI on weight change. Methods: Eligible pts were within 14 months of diagnosis of stage 2-3 HER2-negative breast cancer, had completed chemotherapy and radiation (if administered), and were randomized 1:1 to a telephone-based WLI plus health education (HE) or an HE alone control group. The WLI was delivered by telephone-based health coaching and focused on caloric restriction and increased exercise. Height and weight were measured at baseline and 12 months. Changes in weight were compared between groups. Analysis was performed with univariable and multivariable (including arm, baseline weight, menopausal status, race/ethnicity, and hormone receptor [HR] status) regression models. A 0.05 level of significance was used. Results: 3181 women were randomized between 8/2016 and 2/2021. At baseline, mean BMI was 34.5 (±5.74) kg/m2, mean age was 53.4 (±10.58) years, and 57% of pts were postmenopausal at the time of diagnosis. 80.3% of participants were White, 12.8% were Black, and 7.3% were Hispanic. Follow-up weight was available from 2293 pts alive and disease-free at 12 months. The WLI led to a significant decrease in weight relative to controls; pts randomized to WLI lost an average of 4.8% (±7.9) of baseline body weight at 12 months vs. 0.8% (± 6.4) weight gain in controls (p<0.0001). Pts randomized to WLI experienced significant weight loss (vs controls) across demographic and tumor factors (Table). WLI effect differed significantly by menopausal status (interaction p value = 0.0057) and race/ethnicity (interaction p-value = 0.019), but not HR status (interaction p-value = 0.17). Conclusions: A telephone-based WLI induced significant, clinically meaningful weight loss in breast cancer pts with overweight and obesity across demographic and tumor factors. Additional tailoring of the WLI could be useful to enhance weight loss in Black and younger pts. Further follow-up of the BWEL trial will evaluate whether the WLI improves disease outcomes. Support: U10CA180821, U10CA180882, UG1CA189823; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02750826 . [Table: see text]

56P Association between HER2 expression level and prognosis using RT-PCR in HER2-low breast cancer

The variation and heterogeneity of conventional immunohistochemistry (IHC) or in situ hybridization (ISH) techniques for measuring HER2 has long been pointed out, and the method of testing for HER2 has been discussed for the selection of appropriate treatment. Therefore, we compared HER2 expression in RT-PCR using OncotypeDX have correlation with conventional IHC, and evaluated HER2 expression in RT-PCR as a prognostic factor in HER2-negative early breast cancer. ER+/HER2- patients who underwent breast cancer surgery between 2004 and 2016 and underwent OncotypeDX testing were included. Data from 632 patients were collected and analyzed by retrospective chart review at 9 centers to determine if there was a correlation between HER2 expression by IHC and RT-PCR. HER2 expression was classified as negative, HER2-low, and positive when HER2 mRNA levels were ≤ 9.1, 9.2-11.4, and11.5≤, respectively, based on the median mRNA level in HER2 negative in IHC. Survival curves were estimated using the Kaplan-Meier method with a log-rank test between the three groups. The median age of the 632 patients was 51 years. Of the 632 patients, 311(49.2%) were pStage I, the 309 (48.9%) were pStage II, and 11(1.7%) were pStage III. 127 (20%) patients received postoperative chemotherapy, and 54 (8.5%) patients had relapse. HER2 IHC rates were HER2 0: 166 (26.3%), 1+: 304 (48.1%), and 2+: 162 (25.6%). There was a weak correlation between the IHC and RT-PCR methods for HER2 expression (Spearman rank correlation P<0.001, r=0.33). The recurrence rates of IHC 0, 1+, and 2+ were 1.8%, 3.9%, 2.6%, respectively. There was no statistically significant difference in DFS between the three groups of HER2 expression by the IHC method (P=0.59). In addition, in the study of HER2 expression and prognosis by RT-PCR, the patients were divided into HER2 negative: 269, HER2-low: 357, and HER2 positive: 1. There was no statistically significant difference between the three groups (P=0.832). The recurrence rates were 3.9%, 4.4%, and 0%, respectively. In the analysis of HER2 expression, there was a weak correlation between IHC and RT-PCR mRNA expression levels; in the HER2-negative population, RT-PCR mRNA expression of HER2 was not a prognostic factor in early breast cancer.

31P C-reactive protein as a prognostic factor in early breast cancer

31P C-reactive protein as a prognostic factor in early breast cancer

Association between CD8+ Tumor Infiltrating Lymphocytes and the Clinical Outcome of Patients with Operable Breast Cancer Treated with Adjuvant Dose-Dense Chemotherapy-A 10 Year Follow-Up Report of a Hellenic Cooperative Oncology Group Observational Study.

Tumor-infiltrating lymphocytes (TILs) contribute to breast cancer (BC) prognosis. We investigated the prognostic impact of CD8+ TILs in patients with early breast cancer treated with adjuvant chemotherapy in a large observational clinical trial. Along with a 10 year follow-up, considering the efficacy and safety, we report the results of the translational part of our study. We examined the patients' tumors for total (t), stromal (s), and intratumoral (i) CD8 lymphocyte density (counts/mm2) on tissue-microarray cores. The impact of CD8+ TILs counts on DFS and OS, and its correlation with breast cancer subtypes and standard clinicopathological parameters, were investigated, along with efficacy and safety data. Among the 928 eligible patients, 627 had available CD8+ data. Of which, 24.9% had a high expression of sCD8, iCD8, and total CD8, which were correlated with higher Ki67, TILs density, ER/PgR negativity, and higher histological grade. The 5year DFS and OS rates were 86.1% and 91.4%, respectively. Patients with high iCD8 and tCD8 had longer DFS and OS compared to those with low counts/mm2 (DFS: HR = 0.58, p = 0.011 and HR = 0.65, p = 0.034 and OS: HR = 0.63, p = 0.043 and HR = 0.58, p = 0.020, respectively). Upon adjustment for clinicopathological parameters, iCD8 and tCD8 retained their favorable prognostic significance for DFS and OS, whereas high sCD8 was only prognostic for DFS. Menopausal status, tumor size, and nodal status retained their prognostic significance in all examined multivariate models. CD8+ TILs, and especially their intratumoral subset, represent a potential favorable prognostic factor in early BC.

Long-Term Survival Outcomes of Patients with Small (≤1 cm) Node-Negative HER2-Positive Breast Cancer Not Treated with Adjuvant Anti-HER2-Targeted Therapy: A 10-Year Follow-Up Study

Introduction: Human epidermal growth factor receptor 2 (HER2) expression is considered an unfavourable prognostic factor in early breast cancer when the patients are not treated with HER2-targeted therapy. However, the long-term prognostic importance of HER2 expression in small (≤1 cm, stage pT1a-b), node-negative HER2+ breast cancer is still incompletely known. Methods: A retrospective analysis was performed based on a prospectively collected database including patients with pT1 breast cancer operated at the Helsinki University Hospital, Finland, between March 2000 and April 2006. In this database, 44 patients with pT1a-bN0M0, HER2+ cancer, not treated with adjuvant anti-HER2-targeted therapy (the HER2+ group) and 291 pT1a-bN0M0, hormone receptor-positive, HER2-negative cancers (the ER+/HER2– group) were identified and included in the study. Survival outcomes were analysed using the Kaplan-Meier method. Results: The median follow-up time was 9.7 years after primary breast surgery. Ten-year distant disease-free survival (DDFS) was 84.0% in the HER2+ group and 98.2% in the ER+/HER2– group (p < 0.001). Ten-year overall survival was only 78.5% in the HER2+ group, but 91.7% in the ER+/HER2– group (p = 0.09). Conclusions: Cancer HER2 status is strongly associated with unfavourable DDFS during the first decade of follow-up in patients with small (pT1a-bN0M0) breast cancer when adjuvant anti-HER2-targeted treatment is not administered.

Correlation between Grading Histopathology and Sentinel Lymph Node Metastasis in Early Breast Cancer in University of Sumatera Utara Hospital

BACKGROUND: Breast cancer is a malignancy in breast tissue from the duct or lobar epithelium. American Joint Committee on Cancer has specified important prognostic factors such as primary tumor size, regional lymph node status, and distant metastasis. Axillary lymph node status has been one of the most reliable prognostic factors in early breast cancer in women. Axillary lymph node dissection is an old method to identify metastasis in axillary lymph nodes and started being replaced by sentinel lymph node biopsy (SLNB). SLNB has been introduced as a minimal invasive procedure, but in Indonesia, this procedure cannot be done due to technology limitation. Grading tumor is one of the predictor factors that can predict lymph node metastasis. This predictor factor has been associated with sentinel lymph node metastasis significantly. AIM: According to this, we conduct this study to analyze the correlation between grading histopathology in breast cancer with sentinel lymph node metastasis to lower false-negative rate in SLNB using methylene blue dye. MATERIALS AND METHODS: In this study, we included 51 patients that qualified using inclusion and exclusion criteria. Then, sentinel lymph node metastasis and grading histopathology data were retrieved from the patient’s medical record. This data are analyzed using SPSS with Chi-square test. RESULTS: The most type of breast cancer in this study is invasive ductal carcinoma was found in 40 patients (78.4%). There are 22 of 51 patients (51.6%) with metastasis to sentinel lymph node, have Grade 3 in histopathologic findings. CONCLUSIONS: The statistical evaluation showed that there is significant correlation between grading histopathology and SLNB with p = 0.001.

Intraoperative radiotherapy versus whole-breast external beam radiotherapy, and other factors associated with the prognosis of early breast cancer treated with breast-conserving surgery and radiotherapy: a retrospective study from SEER database.

BackgroundThis study was aimed to investigate the prognostic factors of early breast cancer treated with breast-conserving surgery (BCS) and radiotherapy. Besides, we focused our attention exclusively on the comparison of the impact on prognosis between intraoperative radiotherapy (IORT) and whole-breast external beam radiotherapy (EBRT).MethodsAn observational cohort study was performed on patients with Tis-2 N0–1 M0 breast cancer from the Surveillance, Epidemiology, and End Results (SEER) database who treated with BCS and radiotherapy. Cox regression analysis, Kaplan-Meier analysis, and propensity score matching (PSM) were used to estimate risk factors for overall survival (OS) and breast cancer-specific survival (BCSS).ResultsOf the 98,614 early breast cancer patients treated with BCS and radiotherapy, 97,164 (98.5%) patients underwent EBRT and 1,450 (1.5%) underwent IORT. Multivariable Cox regression analysis showed that early breast cancer patients with age ≥65, poor marital status, lack of medical insurance, histological grade III/IV (SEER 4 grades), high T stage, high N stage, and TNBC were associated with a decreased OS/BCSS, whereas ER-positive and PR-positive were associated with an improved OS/BCSS. No significant difference was observed in survival between IORT and EBRT groups (P=0.213 for OS, P=0.180 for BCSS), or between intraoperative beam radiation and intraoperative radioactive implants groups (P=0.319 for OS, P=0.972 for BCSS).ConclusionsOur study can help clinicians identify patients with poor prognosis after breast-conserving therapy. IORT may be an alternative to EBRT for early breast cancer patients who are unable to complete the long-term postoperative radiation treatment. Beam radiation and radioactive implants are both ideal alternatives for patients who choose IORT.

Preclinical and Clinical Evaluation of Magnetic-Activated Cell Separation Technology for CTC Isolation in Breast Cancer.

Circulating tumor cell (CTC) count is an independent prognostic factor in early breast cancer. CTCs can be found in the blood of 20% of patients prior to neoadjuvant therapy. We aimed to assess the suitability of magnetic-activated cell separation (MACS) technology for isolation and cytological characterization of CTCs. In the preclinical part of the study, cell lines were spiked into buffy coat samples derived from healthy donors, and isolated using MACS. Breast cancer cells with preserved cell morphology were successfully isolated. In the clinical part, blood for CTC isolation was drawn from 44 patients with early and locally advanced breast cancer prior to neoadjuvant chemotherapy. Standard Giemsa, Papanicolaou and pancytokeratin staining was applied. 2.3% of samples contained cells that meet both the morphological and immunocytochemical criteria for CTC. In 32.6% of samples, partially degenerated pancytokeratin negative cells with morphological features of tumor cells were observed. In 65.1% of samples, CTCs were not found. In conclusion, our results demonstrate that morphologically intact tumor cells can be isolated using MACS technology. However, morphologically intact tumor cells were not detected in the clinical part of the study. At present, MACS technology does not appear suitable for use in a clinical cytopathology laboratory.

Influences of preoperative metformin on immunological factors in early breast cancer

PurposeMetformin has been suggested to possibly reduce cancer risk. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. We conducted a prospective study to evaluate the effects of preoperative metformin in patients with early breast cancer.MethodWe evaluated the effects on immunological factors (TILs, CD4 + , CD8 + , PD-L1, IFNγ and IL-2) by comparing core needle biopsies (CNB) obtained before metformin treatment with surgical specimens. Seventeen patients were enrolled in this prospective study from January to December 2016. We also analyzed 59 patients undergoing surgery during the same period to reveal the correlation of immune factors between CNB and surgical specimen.ResultThere was a moderate correlation between CNB and surgical specimens on TILs and CD8 + lymphocyte. (TILs Rs = 0.63, CD4 + Rs = 0.224, CD8 + Rs = 0.42) In the metformin group, TILs increases were confirmed in five (29%) patients, while a decrease was confirmed in two (12%). The expressions of CD4 + and CD8 + by TILs were increased in 41% and 18% of surgical specimens, respectively. However, TILs number (p = 0.0554), CD4+ (p = 0.0613) and CD8 + (p = 0.0646) expressions did not significantly increased. Furthermore, IFNγ expression appeared to be increased in response to metformin (p = 0.08).ConclusionPreoperative metformin tends to increase TILs, as well as the numbers of CD4 and CD8 positive lymphocytes, and IFNγ levels. Metformin might improve immune function and have a possibility of chemo-sensitivity and thereby increase the effectiveness of immunotherapy, based on the results of this preliminary study.

Establishment of Simple Nomograms for Predicting Axillary Lymph Node Involvement in Early Breast Cancer.

PurposeAxillary lymph node (ALN) involvement is an important prognostic factor of early invasive breast cancer. The objective of this study was to establish simple nomograms for predicting ALN involvement based on ultrasound (US) characteristics and evaluate the predictive value of US in the detection of ALN involvement.Patients and MethodsA total of 1328 patients with cT1-2N0 breast cancer by physical exam were retrospectively analyzed. Univariate analysis was used for the comparison of variables, and multivariate analysis was performed by binary logistic regression analysis. The R software was used to establish simple nomograms based on the US characteristics alone. The receiver operating characteristic (ROC) curves of the prediction model and the verification group were drawn, and the area under the curve (AUC) was calculated to evaluate the discrimination of the prediction model. A calibration curve was plotted to assess the nomogram predictions vs the actual observations of the ALN metastasis rate and axillary tumor burden rate.ResultsThe ALN metastasis rates of the training group and the validation group were 35.1% and 34.1%, respectively. Multivariate analysis showed that molecular subtype, lymphovascular invasion, mass descriptors (size, margin, microcalcification and blood flow signal) and LN descriptors (shape, cortical thickness and long-to-short ratio) were independent impact factors in early breast cancer. The AUC of ALN metastasis rate of prediction model based on US features was 0.802, the AUC of high tumor burden rate was 0.873, and the AUC of external validation group was 0.731 and 0.802, respectively. The calibration curve of the nomogram showed that the nomogram predictions are consistent with the actual metastasis rate and the high tumor burden rate. The results showed that preoperative US had a sensitivity of 59.4% and a specificity of 88.9% for predicting the ALN metastasis rate.ConclusionThe successfully established nomograms based on US characteristics to predict ALN metastasis rate and high axillary tumor burden rate in early breast cancer can achieve individual prediction. Compared with other nomogram predictions, it is more intuitive, and can help clinical decision-making; thus, it should be promoted. However, at this time US features alone are insufficient to replace sentinel lymph node biopsy.

Effect of Obesity on Neoadjuvant Systemic Therapy Outcomes in Patients with Early Breast Cancer: A Retrospective Institutional Study.

Background:Obesity and overweight are usually considered as poor prognostic factors in early breast cancer. Body mass index (BMI) is a significant predictive factor for lower pathologic complete response (pCR) rates after neo-adjuvant systemic therapy (NST). The relationship between obesity and breast cancer prognosis varies according to patient and tumor characteristics such as menopausal status and tumor subtype, respectively. Patients and Methods:Between March 2010 and October 2013, 80 patients with early breast cancer who had received standard NST from KFSH Saudi Arabia were included in this study. For statistical analysis, the study participants were categorized into two groups based on their BMI, as normal (BMI < 25 kg/m2) and obese groups (BMI ≥ 25 kg/m2). pCR was defined as non-invasive cancer in the breast/axillary tissue. Results:The median age of our patients was 48 (range, 38-68) years. Invasive ductal carcinoma (IDC) subtype was identified in 93.8% of the cases. Additionally, 26 (32.5%) and 33 (41.25%) patients were diagnosed with stage II and stage IIIA breast cancer, respectively. Lymphovascular invasion was detected in 32.5%, whereas intermediate and high-grade malignancy were found in 61.25% and 32.5% of the patients, respectively. Forty-four patients (55%) were obese. pCR was achieved in 56 patients (70%), and the comparison between patients with and without pCR revealed that those in the former group had significantly lower tumor grades. Significantly, lower relapse and mortality rates were distinguished in patients who achieved pCR than in those who did not. Additionally, comparison between normal and obese patients revealed that a high number of patients in both groups were post-menopausal (p = 0.001). However, survival analysis indicated the absence of significant differences in disease-free survival between the two groups based on BMI (p = 0.19). Conversely, patients with normal BMI had significantly better overall survival than obese patients (p = 0.029), with a higher mortality rate noted in the obese group (16.7% vs 2.3%, p = 0.037). Conclusions:In the present study, 58.3% of patients that failed to achieve pCR had BMI above the normal level; they moreover had higher relapse rates and lower survival compared with normal BMI patients. This finding needs to be verified through further prospective studies to determine if BMI is a risk factor for breast cancer.

Predictive factors of 5-year relapse-free survival in HR+/HER2- breast cancer patients treated with neoadjuvant endocrine therapy: pooled analysis of two phase 2 trials

BackgroundFew data are available on survival and predictive factors in early breast cancer (BC) patients treated with neoadjuvant endocrine therapy (NET).MethodsThis is a pooled analysis of two multicentre, randomised non-comparative phase 2 clinical trials evaluating neoadjuvant anastrozole and fulvestrant efficacy for postmenopausal HR+/HER2- breast cancer patients: HORGEN (NCT00871858) and CARMINA02 (NCT00629616) studies.ResultsIn total, 236 patients were included in CARMINA02 and HORGEN trials. Modified intention-to-treat analysis was available for 217 patients. Median follow-up was 65.2 months. Relapse-free survival (RFS) and overall survival (OS) at 5 years were 83.7% (95% CI: 77.9–88) and 92.7% (95% CI: 88.2–95.6), respectively, with no difference between treatment arms. On univariate analysis, tumour staging (T2 vs T3–4; p = 0.0001), Ki-67 at surgery (≤10% vs >10%; p = 0.0093), pathological tumour size (pT1–2 vs pT3–4; p = 0.0012) and node status (pN negative vs positive; p = 0.007), adjuvant chemotherapy (p = 0.0167) and PEPI score (PEPI group I + II vs III; p = 0.0004) were associated with RFS. No events were observed in patients with pathological response according to the Sataloff classification. Multivariate analysis showed that preoperative endocrine prognostic index (PEPI) group III was associated with significantly worse RFS (p = 0.0069, hazard ratio = 3.33 (95% CI: 1.39–7.98)).ConclusionsPostmenopausal HR+/HER2- breast cancer patients receiving NET generally have a favourable outcome. The PEPI score identifies a subset of patients of poorer prognosis who are candidates for further additional treatment.

PD-1 protein and gene expression as prognostic factors in early breast cancer

BackgroundThere is a paucity of data on the prognostic value of programmed cell death protein 1 (PD-1) protein and gene expression in early breast cancer (BC) and the present study’s aim was to comprehensively investigate it.MethodsThe study consisted of three parts: a correlative analysis of PD-1 protein and gene expression from an original patient cohort of 564 patients with early BC; a systematic review and trial-level meta-analysis on the association between PD-1 protein expression and disease-free survival/overall survival (OS) in early BC; and a pooled gene expression analysis from publicly available transcriptomic datasets regarding PDCD1 expression.ResultsIn the study cohort, PD-1 protein, but not gene expression, was associated with improved OS (HRadj=0.73, 95% CI 0.55 to 0.97, p=0.027 and HRadj=0.88, 95% CI 0.68 to 1.13, p=0.312, respectively). In the trial-level meta-analysis, PD-1 protein expression was not found to be statistically significantly associated with outcomes in the overall population. Finally, in the pooled gene expression analysis, higher PDCD1 expression was associated with better OS in multivariable analysis in the entire population (HRadj=0.89, 95% CI 0.80 to 0.99, p=0.025) and in basal-like tumours.ConclusionsPD-1 protein and gene expression seem to be promising prognostic factors in early BC. Standardisation of detection and assessment methods is of utmost importance.

Young age at diagnosis is associated with better prognosis in stage IV breast cancer.

Numerous studies have shown that young age is a risk factor in early breast cancer. But for stage IV breast cancer, it is unclear whether age has a similar effect on patient survival. We collected and analyzed data from patients with stage IV breast cancer between January 2010 and December 2015 in SEER database. Multivariate Cox proportional hazard model was used in this study. 13,069 patients with stage IV breast cancer were included in the analysis, of which 1,135 were young breast cancer patients (≤40 years old). In a multivariate analysis that adjusted for sociodemographic factors, clinical-pathological characteristics and therapeutic methods, the risk of death in patients with stage IV ≤40 years was significantly reduced (hazard ratio [HR], 0.72; 95% CI, 0.65-0.79). Subgroup analyses showed that, with the same adjustment of all factors, young age only significantly reduced the risk of death in patients with luminal A (HR, 0.78; 95% CI, 0.68-0.89) and luminal B (HR 0.46; 95% CI, 0.35-0.60) subtypes. Young age at diagnosis is associated with better survival in patients with stage IV breast cancer. The effect of young age at diagnosis on the survival outcome of stage IV breast cancer varies by subtypes.

266P - Pathologic response and survival efficacy in patients with initial nodal involvement after neoadjuvant chemotherapy in early breast cancer

BackgroundNodal involvement is a common prognostic factor in early breast cancer (EBC) but their response and assessment after neoadjuvant chemotherapy (NAC) is controversial, hence its impact in survival is not clear. MethodsWe analyze a cohort of 308 EBC patients with initial nodal involvement and their response to neoadjuvant chemotherapy and their impact in disease free survival (DFS). ResultsMedian age was 52 (range 29-87), median tumor size was 38mm (10-100) and 178 patients (57,8%) had initial palpable node involvement. According to the immunohistochemical expression of hormonal receptors, Ki 67 and HER2; 110 patients (35,7%) was HER2 positive, 119 (38,6%) luminal and 79 (25,6%) triple negative breast cancer. After NAC we found a total of pathological complete response in breast (pCRb) of 30% and pathological complete response in axilla (pCRa) of 45%. Response by different subtypes was: in HER2 a pCRb 41,8% and pCRa 56,3%; luminal a pCRb 13% pCRa 30,3% and triple negative a pCRb 41,8% pCRa 50,6%. Luminal patients achieved the worst axillary response (p:0,004) and without other variables with significant association like tumor initial size or palpable axillary nodes. The global coincidence between pCRb and pCRa was 83% and very similar in the different subtypes. Axillary pCR was associated with a better DFS in the global series (HR: 0,377 p:0,000) but not in the luminal patients (HR:0,455 p:0,072) and the median survival in patients with pCRa was 157 months in contrast to 121 in patients that not achieve a pCRa (153 vs 99 in HER2, 160 vs 141 in luminal and 167 vs 93 in triple negative). ConclusionsThe complete pathological response in axila after neoadjuvant chemotherapy is 45% in our serie but lower in luminal patients with only a 30%. There was a high level of concordance between pCR in breast and axilla in all subtypes with an 83%. Achieving pCR in axilla is associated with better disease free survival but this benefit is lower in luminal phenotype. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

The influences of preoperative metformin on immunological factors in early breast cancer.

e14182 Background: Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and some reports have suggested that metformin may reduce cancer risk. Diabetics treated with metformin have a 23% reduction in the risk of cancer, including breast cancer. In addition, it is reported that the breast cancer patients with metformin treatment for diabetes showed favorable prognosis compared with those without metformin treatment. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. Methods: We conducted a prospective study to evaluate the effect of preoperative metformin on early breast cancer patients. The patients took a daily dose of metformin orally for 7 to 21 days before surgery. We evaluated the effects on immunological factors (TILs, CD4+, CD8+, PD-L1 and ALDH1) by comparing core needle biopsies (CNB) obtained before surgery with surgical specimens. Results: Seventeen breast cancer patients were enrolled in this prospective study and administered metformin before surgery, during the period from January to December 2016. We analyzed 59 patients who received surgery during the same period as a control group. In the control group, there was no significant difference in TILs between CNB and surgical specimens (Rs = 0.63). In the metformin group, TILs were negative in CNB and surgical specimens of 15 (88%) and 8 (48%) cases, low in 2 (12%) and 8 (48%), and intermediate in 0 and 1 (6%), respectively. These TILs increases were confirmed in 5 (29%) patients (p = 0.09), while a decrease was confirmed in 2 (12%). The expressions of CD4+ and CD8+ by TILs were increased in 41% and 18% of surgical specimens, respectively. (p = 0.02, p = 0.09) However, there was no statistically significant difference in these immunological factors and PD-L1 or ALDH1 expression between before and after metformin. Conclusions: In our small cohort, preoperative metformin administration shows positive impact on CD4 positive lymphocytes significantly and has tendency of increasing both TILs and CD8 positive lymphocytes. However, we should keep in mind that our sample size is small. Further study is necessary to uncover the mechanisms of favorable effects of metformin on breast cancer patients.

Abstract P2-08-25: PD-L1 expression at the protein and RNA levels as prognostic factor in early breast cancer

Abstract Introduction:PD-L1 expression as assessed by immunohistochemistry (IHC) is a clinically relevant biomarker in certain malignancies such as lung cancer, since it selects appropriate candidates for PD-1 blockade. Since these agents are under evaluation for breast cancer, discovering and validating predictive biomarkers is of outmost importance. However, the clinical utility of PD-L1 expression in breast cancer is questionable, in light of prior inconclusive reports which have used various IHC antibodies, scoring methods and cut-offs. Moreover, there are only few previous studies on comparing IHC and RNA data at the same cohort, not limited to a single subtype.Methods: Our cohort is derived from a nested case-control study consisting of 619 patients diagnosed with primary breast cancer between 1997-2005 in Stockholm health care region.Tissue microarrays from epithelial tumor areas have been constructed using duplicate cores from primary tumors and tissue sections were used for IHC with PD-L1 (Ventana; clone SP263) antibody. Positivity was defined as the presence of any single cell with membranous expression of PD-L1. Gene expression profiling was performed using DNA microarrays (GSE48091). Data on clinical and pathological tumor characteristics, survival, loco-regional and systemic treatments, and follow-up have been collected. Correlations between transcript and protein expression levels were estimated using Mann-Whitney test, while survival analyses were conducted using the Kaplan-Meier method. Furthermore, we associated an immune gene module score (IMS) –whose predictive power in neoadjuvant and metastatic settings has been previously demonstrated- with PD-L1 transcript levels by using Spearman's rank correlation coefficient.Results: IHC data were available for 87.4% (541/619) of the patients. PD-L1 was expressed on tumor cells in 9.6% (52/541) of the patients while it was also expressed by immune cells in 23.1% (125/541) of the patients. Any PD-L1 expression (tumor and/or immune cells) was noted in 24.2% (131/541) of the patients. PD-L1 transcript levels and protein expression on tumor, immune and/or both cell types were statistically significantly associated (p&amp;lt; 2.2e-16). In the whole cohort, patients with higher PD-L1 transcript levels were associated with better breast cancer-specific survival(BCSS) (p=0.0061). In addition, within intrinsic subtypes, high PD-L1 transcript expression was significantly associated with better BCSS only in basal-like (p=0.019) disease. There was no significant correlation between improved BCCS and PD-L1 protein expression by tumor (p=0.13), immune (p=0.12) or both types of cells (p=0.2). PD-L1 transcript levels were also positively associated with the IMS (Spearman's rho = 0.85). Conclusions:The prognostic value of PD-L IHC expression in breast cancer remains inconclusive. However, RNA expression of PD-L1 may be more informative as a prognostic factor, especially in basal-like disease and merits further validation. Citation Format: Zerdes I, Sifakis E, Matikas A, Tobin NP, Charlotte R, Rassidakis GZ, Bergh J, Foukakis T. PD-L1 expression at the protein and RNA levels as prognostic factor in early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-25.

NR2F1 stratifies dormant disseminated tumor cells in breast cancer patients

BackgroundThe presence of disseminated tumor cells (DTCs) in bone marrow (BM) is an independent prognostic factor in early breast cancer but does not uniformly predict outcome. Tumor cells can persist in a quiescent state over time, but clinical studies of markers predicting the awakening potential of DTCs are lacking. Recently, experiments have shown that NR2F1 (COUP-TF1) plays a key role in dormancy signaling.MethodsWe analyzed the NR2F1 expression in DTCs by double immunofluorescence (DIF) staining of extra cytospins prepared from 114 BM samples from 86 selected DTC-positive breast cancer patients. Samples collected at two or more time points were available for 24 patients. Fifteen samples were also analyzed for the proliferation marker Ki67.ResultsOf the patients with detectable DTCs by DIF, 27% had ≥ 50% NR2F1high DTCs, chosen a priori as the cut-off for “dormant profile” classification. All patients with systemic relapse within 12 months after BM aspiration carried ≤ 1% NR2F1high DTCs, including patients who transitioned from having NR2F1high-expressing DTCs in previous BM samples. Of the patients with serial samples, half of those with no relapse at follow-up had ≥ 50% NR2F1high DTCs in the last BM aspiration analyzed. Among the 18 relapse-free patients at the time of the last DTC-positive BM aspiration with no subsequent BM analysis performed, distant disease-free intervals were favorable for patients carrying ≥ 50% NR2F1high DTCs compared with those with predominantly NR2F1low DTCs (p = 0.007, log-rank). No survival difference was observed by classification according to Ki67-expressing DTCs (p = 0.520).ConclusionsOur study translates findings from basic biological analysis of DTC dormancy to the clinical situation and supports further clinical studies of NR2F1 as a marker of dormancy.

The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer.

Purpose: The most significant prognostic factor in early breast cancer is lymph node involvement. This stage between localized and systemic disease is key to understanding breast cancer progression; however, our knowledge of the evolution of lymph node malignant invasion remains limited, as most currently available data are derived from primary tumors.Experimental Design: In 11 patients with treatment-naïve node-positive early breast cancer without clinical evidence of distant metastasis, we investigated lymph node evolution using spatial multiregion sequencing (n = 78 samples) of primary and lymph node deposits and genomic profiling of matched longitudinal circulating tumor DNA (ctDNA).Results: Linear evolution from primary to lymph node was rare (1/11), whereas the majority of cases displayed either early divergence between primary and nodes (4/11) or no detectable divergence (6/11), where both primary and nodal cells belonged to a single recent expansion of a metastatic clone. Divergence of metastatic subclones was driven in part by APOBEC. Longitudinal ctDNA samples from 2 of 7 subjects with evaluable plasma taken perioperatively reflected the two major evolutionary patterns and demonstrate that private mutations can be detected even from early metastatic nodal deposits. Moreover, node removal resulted in disappearance of private lymph node mutations in ctDNA.Conclusions: This study sheds new light on a crucial evolutionary step in the natural history of breast cancer, demonstrating early establishment of axillary lymph node metastasis in a substantial proportion of patients. Clin Cancer Res; 24(19); 4763-70. ©2018 AACR.