Recurrence Of ER-positive Breast Cancer Research Articles

Abstract PO3-17-09: Outcome after the introduction of personalized treatment for axilla in patients with clinically node-negative early breast cancer

Abstract Background : After the results of ACOSOG Z0011 and AMAROS trials were reported, axillary treatment has been promoted to de-escalation. For clinically negative cases of axillary lymph node metastasis (cN0), axillary dissection (Ax) has been the standard treatment when sentinel lymph node (SN) metastasis is positive. In our hospital, for patients with cN0, if SN macro metastasis is positive, Ax or irradiation (RT) is selected after sufficient explanation to the patients. Five years have passed since the introduction of treatment selection for the axilla, we examined treatment outcomes retrospectively. Methods : The subjects were 1376 patients who underwent SN biopsy for primary breast cancer with cN0 at our hospital from October 2004 to December 2018 (median observation period 79 months). Cases who underwent preoperative chemotherapy were excluded. We have introduced the treatment choice system since December 2015, and compared prognosis (local recurrence, distant recurrence and breast cancer specific death) before and after introduction using the log-rank test. Results : There were 947 cases before introduction of treatment choice system (pre group) and 429 cases after introduction (post group). The median observation period for each group was 91 months and 41 months. The maximum observation period post group was 67 months, then we compared the number of events in patients with observation period less than 67 months in pre group. There was no significant difference between two groups (Pre/Post) in terms of age (p=0.52), menopausal status (p=0.90), invasion of primary lesion (p=0.19), biology and SN metastasis status (p=0.41). There were 54 patients (12.6%) in pre group and 135 (14.3%) patients in post group had positive sentinel lymph nodes. In post group, 33 patient (61.1%) were macrometastasis of SN, 28 of whom underwent Ax and 5 underwent RT. Local recurrence was 4 cases (1.7%) in pre group, 9 cases (2.1%) in post group (p=0.84), distant recurrence was 13 cases (5.6%) and 5 cases (1.2%) (p=0.0002), and breast cancer specific death was 8 cases (0.8%) and 1 case (0.2%) (p=0.0003), respectively. Discussion : There was no significant difference in local recurrence rate within 67 months, but were poor prognosis in pre introduction group for distant metastasis and breast cancer specific survival. In the results of this study, there was no significant difference in local recurrence, but the prognosis for distant recurrence and breast cancer-specific death was poor in the before introduction group. The median observation period in the post introduction group was 47 months, and late recurrence of ER-positive breast cancer occurs later. It is necessary to continue the study by extending period and accumulation cases. Conclusion : For cN0 cases, if the case is suitable, we introduced the treatment choice system that allows omitting Ax by performing radiotherapy in SN macrometastasis positive patients. After introduction, there was no increase in the relapse rate after introduction in the short term. Appropriate case selection allowed the safety introduction of individualizes treatment for axilla. Citation Format: Mai Tomiguchi, Kaori Hidaka, Lisa Goto-Yamaguchi, Ayako Kajiwara, Kanako Nishikido, Toko Inao, Yutaka Yamamoto. Outcome after the introduction of personalized treatment for axilla in patients with clinically node-negative early breast cancer [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 PO3-17-09.

Abstract 464: Chromatin associated long non-coding RNAs involved in dormancy for late recurrence of ER-positive breast cancer

Abstract Late recurrence is one of the major problems for hormone receptor-positive breast cancer patients. It is suggested that the risk of recurrence may be maintained by cancer cells that have been already disseminated in the body at surgery. They enter long-term dormancy, thus evade immune surveillance and become resistant to therapies. The detailed molecular mechanism for this process is largely unknown.Nuclear long noncoding RNAs, which are not translated to proteins, often function as epigenetic regulators and determine the phenotype of cells and individuals. We found that a cluster of long noncoding RNAs, ELEANORS, is specifically expressed in ER (estrogen receptor)-positive recurrent breast cancer cells, forms a molecular condensate (RNA cloud) in the nucleus, and activates the ESR1 gene that encodes ER. ELEANORS define a large chromatin domain, the 0.7 Mb topologically associated domain (TAD), which contains the ESR1 and three other breast-cancer-associated genes. ELEANORS also regulates the three-dimensional genome architecture. They mediate a long-range chromatin interaction of ESR1 and FOXO3 genes, which are 42.9 Mb apart, and contribute to their cooperatively activate transcription, equilibrating cell proliferation (ESR1) and apoptosis (FOXO3). Upon ELEANOR knockdown, the ELEANOR clouds are disappeared, and ESR1 gene transcription is repressed. Further, the two genes are dissociated and only the FOXO3 gene remains transcriptionally active, resulting in the induction of apoptosis.Further analysis of clinical specimens revealed that ELEANOR expression in primary tumors correlates with recurrences over 5 years after surgeries, suggesting that ELEANORs are involved in late recurrence. We also found that ELEANOR activates transcription of CD44, a breast cancer stem cell marker gene. Cancer stem cell maintenance and equilibration of proliferation and apoptosis by ELEANOR may be involved in long-term tumor dormancy in late recurrence. This study suggests the possibility of ELEANORS as a biomarker to predict late recurrence, as well as a therapeutic target for ER-positive breast cancer. (References)Abdalla, MOA. et al., Nat. Commun, 10, 3778 (2019) Tomita, S. et al., Nat. Commun, 6, 6966 (2015) Citation Format: Noriko Saitoh, Maierdan Palihati, Hiroaki Tachiwana. Chromatin associated long non-coding RNAs involved in dormancy for late recurrence of ER-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 464.

High PD-L2 Predicts Early Recurrence of ER-Positive Breast Cancer.

T-cell-mediated cytotoxicity is suppressed when programmed cell death-1 (PD-1) is bound by PD-1 ligand-1 (PD-L1) or PD-L2. Although PD-1 inhibitors have been approved for triple-negative breast cancer, the lower response rates of 25%-30% in estrogen receptor-positive (ER+) breast cancer will require markers to identify likely responders. The focus of this study was to evaluate whether PD-L2, which has higher affinity than PD-L1 for PD-1, is a predictor of early recurrence in ER+ breast cancer. PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, localized or locoregional ER+ breast cancers were measured retrospectively by quantitative immunofluorescence histocytometry and correlated with progression-free survival (PFS) in the main study cohort (n = 684) and in an independent validation cohort (n = 273). All patients subsequently received standard-of-care adjuvant therapy without immune checkpoint inhibitors. Univariate analysis of the main cohort revealed that high PD-L2 expression in cancer cells was associated with shorter PFS (hazard ratio [HR], 1.8; 95% CI, 1.3 to 2.6; P = .001), which was validated in an independent cohort (HR, 2.3; 95% CI, 1.1 to 4.8; P = .026) and remained independently predictive after multivariable adjustment for common clinicopathological variables (HR, 2.0; 95% CI, 1.4 to 2.9; P < .001). Subanalysis of the ER+ breast cancer patients treated with adjuvant chemotherapy (n = 197) revealed that high PD-L2 levels in cancer cells associated with short PFS in univariate (HR, 2.5; 95% CI, 1.4 to 4.4; P = .003) and multivariable analyses (HR, 3.4; 95% CI, 1.9 to 6.2; P < .001). Up to one third of treatment-naive ER+ breast tumors expressed high PD-L2 levels, which independently predicted poor clinical outcome, with evidence of further elevated risk of progression in patients who received adjuvant chemotherapy. Collectively, these data warrant studies to gain a deeper understanding of PD-L2 in the progression of ER+ breast cancer and may provide rationale for immune checkpoint blockade for this patient group.

High expression of SLC20A1 is less effective for endocrine therapy and predicts late recurrence in ER-positive breast cancer.

Estrogen receptor-positive (ER+) breast cancer intrinsically confers satisfactory clinical outcomes in response to endocrine therapy. However, a significant proportion of patients with ER+ breast cancer do not respond well to this treatment. Therefore, to evaluate the effects of endocrine therapy, there is a need for identification of novel markers that can be used at the time of diagnosis for predicting clinical outcomes, especially for early-stage and late recurrence. Solute carrier family 20 member 1 (SLC20A1) is a sodium/inorganic phosphate symporter that has been proposed to be a viable prognostic marker for the luminal A and luminal B types of ER+ breast cancer. In the present study, we examined the possible association of SLC20A1 expression with tumor staging, endocrine therapy and chemotherapy in the luminal A and luminal B subtypes of breast cancer. In addition, we analyzed the relationship between SLC20A1 expression and late recurrence in patients with luminal A and luminal B breast cancer following endocrine therapy. We showed that patients with higher levels of SLC20A1 expression (SLC20A1high) exhibited poorer clinical outcomes in those with tumor stage I luminal A breast cancer. In addition, this SLC20A1high subgroup of patients exhibited less responses to endocrine therapy, specifically in those with the luminal A and luminal B subtypes of breast cancer. However, patients with SLC20A1high showed good clinical outcomes following chemotherapy. Patients tested to be in the SLC20A1high group at the time of diagnosis also showed a higher incidence of recurrence compared with those with lower expression levels of SLC20A1, at >15 years for luminal A breast cancer and at 10–15 years for luminal B breast cancer. Therefore, we conclude that SLC20A1high can be used as a prognostic biomarker for predicting the efficacy of endocrine therapy and late recurrence for ER+ breast cancer.

A prognostic eight-lncRNA expression signature in predicting recurrence of ER-positive breast cancer receiving endocrine therapy.

Long noncoding RNAs (lncRNAs) have the main role in the tumorigenesis of breast cancer. In the present study, lncRNA expression profiling was collected to identify a lncRNA expression signature from the Gene Expression Omnibus database. An eight-lncRNA signature was established to predict the survival of patients with estrogen receptor (ER)-positive breast cancer receiving endocrine therapy. Patients were separated into a low-risk group and a high-risk group based on this signature. Patients in high-risk group have worse survival compared to those in low-risk group using Kaplan-Meier curve analysis with log-rank test. Receiver operating characteristic analysis suggested good diagnostic efficiency of the eight-lncRNA signature. When adjusting the clinical features, including age, grade, lymph node status, and tumor size, this signature was independently associated with the relapse-free survival. The prognostic value of the lncRNA prognostic model was then validated in validation sets. When validated in a cohort of patients treated with neoadjuvant chemotherapy and endocrine therapy, this signature demonstrated good performance as well. Besides, we have built a nomogram that integrated the conventional clinicopathological features and the eight-lncRNA-based signature. To sum up, our results indicated that the eight-lncRNA prognostic model was a reliable tool to group patients at high and low risk of disease relapse. This signature may have possible implication in prognostic evaluations of patients with ER-positive breast cancer receiving endocrine therapy.

Abstract 2121: Overcoming tamoxifen resistance and inhibiting metastatic recurrence in estrogen receptor-positive breast cancer

Abstract Estrogen receptor (ER)-positive breast cancer accounts for almost 75% of all breast cancers. Tamoxifen has been used for over 40 years to treat early, locally advanced and metastatic ER-positive breast cancer; however, patients develop resistance over time. Furthermore, metastatic recurrence, the major cause of death, is common in ER-positive breast cancer patients whose cancer progressed on tamoxifen and other hormone therapies. In this line, we and others reported epithelial-mesenchymal (EMT)-like changes upon acquisition of tamoxifen resistance hinting towards the co-occurrence of resistance and metastatic abilities of the cells. However, little is known about common molecular mediators of drug resistance and metastatic recurrence. Therefore, we addresses the question of how we concurrently overcome tamoxifen resistance and prevent lethal metastatic recurrence whereby eliminating the mortality associated with metastatic breast cancer. Combining whole-transcriptome sequencing and downstream pathway analysis, we identified cyclic AMP (cAMP) signaling to be the most significantly altered pathway in acquired tamoxifen resistant breast cancer cells. We found that PDE4D (Phosphodiesterase 4D), which hydrolyzes cAMP, was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. We demonstrated that PDE4D inhibition overcomes tamoxifen resistance in cell lines and tumor xenografts via cAMP induced endoplasmic reticulum stress and cell death. Importantly, our TamR cells have partial EMT and enrichment of TGF-beta signaling, and PDE4D inhibition in combination with tamoxifen inhibited cell migration in vitro and blocked TGF-beta induced EMT. RNA-Seq experiment also identified one of the highly oncogenic long non-coding RNAs (lncRNA) to be upregulated in TamR cells, and its targeting inhibits PDE4D and leads to tamoxifen sensitization. We showed that higher expressions of both PDE4D and the candidate lncRNA predict worse survival in tamoxifen-treated breast cancer patients. Currently, we are testing the tamoxifen sensitizer and metastasis blocker functions of PDE4D and our candidate lncRNA using patient-derived xenograft (PDX) models of metastatic ER-positive breast cancer. Overall, our results suggest that targeting PDE4D, or its upstream regulatory lncRNA, can simultaneously overcome tamoxifen resistance and prevent metastatic recurrence in ER-positive breast cancer. This is then expected to dramatically reduce mortality rates among ER-positive breast cancer patients in future. Citation Format: Pelin Gulizar Ersan, Ozge Saatci, Oguzhan Tarman, Rasmi Mishra, Nevin Belder, Unal Metin Tokat, Yasser Riazalhosseini, Ozgur Sahin. Overcoming tamoxifen resistance and inhibiting metastatic recurrence in estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2121.

Predicting late recurrence in ER-positive breast cancer.

Identification of factors predicting recurrence of breast cancer is a long-standing goal, ranging from classical clinicopathological factors through to immunohistochemical assays of receptor levels and, more recently, the expression levels of several genes. A new paper now explores novel expression markers, especially for late recurrence of oestrogen receptor-positive breast cancer.

Abstract ES5-3: Late recurrence in ER-positive breast cancer

Abstract The risk of recurrence in early stage, ER-positive breast cancer patients persists for 15-20+ years after diagnosis, and never declines to zero. Rates of late recurrence can be reduced by extending tamoxifen therapy beyond 5 years, with additional tamoxifen or a switch to an aromatase inhibitor. The benefits of extending aromatase inhibitors beyond 5 years remains unclear. The benefit of extended adjuvant endocrine therapy for the average early stage breast cancer patient is small. Extended therapy can be associated with serious increased risks, including thromboembolic events and endometrial cancer with tamoxifen, and fractures and possibly cardiovascular events with aromatase inhibitors. Quality of life can also be impacted, including vasomotor symptoms, sexual dysfunction, and arthralgias. Determining which patients have high residual risk of recurrence beyond 5 years, and importantly whether additional therapy is likely to mitigate that risk, has been the subject of considerable recent research. Tumor size, nodal status and grade of the primary tumor at the time of diagnosis have been shown to be associated with risk of late recurrence in ER-positive breast cancer. Several multi-parameter molecular biomarker assays performed on the primary tumor are able to separate patients into groups at low and high risk for recurrence beyond 5 years when using retrospective data sets. To date, no specific assay has been felt to have high enough level evidence to recommend inclusion in treatment guidelines or use in decision-making regarding continuing, stopping or switching endocrine therapy. Recent studies have evaluated whether there are better determinants of late risk of recurrence, beyond the biology of the primary tumor, that can be performed years after the original diagnosis. Assays that may predict the presence of dormant tumor cells and late relapse include Circulating Tumor Calls (CTCs), Disseminated Tumor Cells (DTCs) in the bone marrow, and circulating tumor DNA, proteins or metabolites. While early data is promising, further research is needed before incorporating into clinical decision-making. Identifying a biomarker to determine patients most likely to benefit from longer duration endocrine therapy, or additional therapeutic approaches, could help in reducing late relapse as well as minimizing the risk of side effects and overtreatment. Citation Format: Gralow J. Late recurrence in ER-positive 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 ES5-3.

Are Circulating Tumor Cells Predictive of Late Recurrence of ER-Positive Breast Cancer?

To determine if the presence of circulating tumor cells (CTCs) in the blood can predict late recurrence of ER-positive breast cancer, investigators

Breast density change as a predictive surrogate for response to adjuvant endocrine therapy in estrogen receptor-positive breast cancer.

e21160 Background: Previous studies showed that anti-estrogen therapy lowers mammographic breast density (MD). We hypothesized that the short-term change of breast density can be a surrogate marker predicting response to adjuvant endocrine therapy (ET) for breast cancer. Methods: We analyzed data of 1,065 estrogen receptor (ER)-positive breast cancer patients who underwent surgery between 2003 and 2006 and received at least 2 years of ET including tamoxifen and aromatase inhibitor. MD was measured using Cumulus software 4.0 and expressed as a percentage. MD reduction was defined as an absolute difference between the MD of two mammography images: taken preoperatively and 8-20months after the start of adjuvant ET.. Results: After median follow up of 68.8 months, overall recurrence rate was 7.5% (80/1065). Mean MD reduction was 5.9% (-17.2 to 36.9). In a logistic regression analysis, age&lt;50, high preoperative MD, and longer interval between start of ET to the 2nd mammogram were significantly associated with higher MD reduction (p value&lt;0.05). In a survival analysis using Cox model, tumor size (&gt;2cm), lymph node positive, high Ki-67 (≥10%), and lower MD reduction were independent factors significantly associated with recurrence-free survival (p&lt;0.05). The hazard of recurrence increased proportionally according to the less degree of MD reduction. Conclusions: MD change during short-term use of adjuvant ET was a significant predictive factor for long-term recurrence in ER-positive breast cancer. It is urgent to develop effective treatment strategy in patients who have less MD reduction in spite of about 1 year of ET.

Deep Time: The Long and the Short of Adjuvant Endocrine Therapy for Breast Cancer

Deep Time: The Long and the Short of Adjuvant Endocrine Therapy for Breast Cancer

Gene profile identifies early recurrence in ER-positive breast cancer

Gene profile identifies early recurrence in ER-positive breast cancer

Score predicts late recurrence in ER-positive breast cancer

Score predicts late recurrence in ER-positive breast cancer

Is obesity associated with increased recurrence risk in estrogen receptor (ER)-positive breast cancer?

171 Background: Oncotype DX Score is a 21-gene expression analysis that has been validated clinically as a reliable predictor of breast cancer recurrence for ER-positive, node-negative breast cancers. Obesity is recognized as a risk factor for many cancers, including breast cancer. Additionally obesity has been shown to be an independent prognostic factor in breast cancer. The primary objective of this study is to determine the correlation between obesity and Oncotype DX score, hence the relationship between obesity and breast cancer recurrence in ER-positive breast cancer. The secondary objective is to investigate the association between weight gain after diagnosis and breast cancer recurrence. Methods: An IRB-exempted retrospective chart review of female patients at Wellspan Group with ER-positive breast cancer who had Oncotype DX analysis in 2008 and 2009. Data collected included Oncotype DX score and BMI (at diagnosis, 6 months and 12 months). Data were analyzed to determine the correlation between Oncotype DX score and BMI at diagnosis, at 6 months and at 12 months. The correlation between Oncotype DX score and BMI changes at 12 months also was determined. Results: A total of 125 patients were identified; 103 had BMI recorded at diagnosis, 88 had BMI recorded at 6 months and 87 had BMI recorded at 12 months. Of these, we were able to determine the BMI changes at 12 months for 82 patients. The Pearson correlation scores were 0.091 (p = 0.361), 0.074 (p = 0.492), and 0.047 (p = 0.669) for BMI at diagnosis, at 6 months and at 12 months respectively. The Pearson correlation score was 0.007 (p = 0.948) for BMI changes at 12 months. Conclusions: Obesity and weight gain are not independent predictors of recurrence in patients with ER-positive breast cancer. The reported adverse prognostic associations may be more prominent in ER-negative breast cancers. This is consistent with the reports suggesting a higher rate of ER-negative, high-grade cancers in obese women as well as a greater magnitude of benefit from dietary and weight reduction interventions seen in women with ER-negative cancers.

5194 UK national survey on the use of Adjuvantonline as a decision-making tool in early breast cancer (www.adjuvantonline.com)

The non-receptor tyrosine kinases c-Src and focal adhesion kinase (Fak) mediate signal transduction pathways that regulate cell proliferation, survival, invasion, and metastasis. Here, we investigated whether c-Src and Fak are activated during progression of hormone-dependent breast cancer. Maximally active c-Src was overexpressed in a subset of tamoxifen-resistant variants and in metastases of recurrent hormone-treated breast cancer. Active Fak was also frequently observed in these tumors. We also show that estrogen receptor (ER) can bind to Fak and that estrogen can modulate Fak autophosphorylation supporting a cross-talk between these two pathways. Inhibition of c-Src activity blocked proliferation of all tamoxifen-resistant variants, suggesting that inhibitors of c-Src–Fak activity may delay or prevent progression and metastasis of ER-positive tumors. These studies also raise the possibility that fully active forms of c-Src and Fak in breast tumors may be biomarkers to predict tamoxifen resistance and/or risk of recurrence in ER-positive breast cancer.

Role of c-Src and focal adhesion kinase in progression and metastasis of estrogen receptor-positive breast cancer

The non-receptor tyrosine kinases c-Src and focal adhesion kinase (Fak) mediate signal transduction pathways that regulate cell proliferation, survival, invasion, and metastasis. Here, we investigated whether c-Src and Fak are activated during progression of hormone-dependent breast cancer. Maximally active c-Src was overexpressed in a subset of tamoxifen-resistant variants and in metastases of recurrent hormone-treated breast cancer. Active Fak was also frequently observed in these tumors. We also show that estrogen receptor (ER) can bind to Fak and that estrogen can modulate Fak autophosphorylation supporting a cross-talk between these two pathways. Inhibition of c-Src activity blocked proliferation of all tamoxifen-resistant variants, suggesting that inhibitors of c-Src–Fak activity may delay or prevent progression and metastasis of ER-positive tumors. These studies also raise the possibility that fully active forms of c-Src and Fak in breast tumors may be biomarkers to predict tamoxifen resistance and/or risk of recurrence in ER-positive breast cancer.