Progesterone Receptor Positive Breast Cancer Research Articles

Single-cell multiplex immunocytochemistry in cell block preparations of metastatic breast cancer confirms sensitivity of GATA-binding protein 3 over gross cystic disease fluid protein 15 and mammaglobin.

Metastatic breast cancers are frequently encountered in cytology and require immunocytochemistry (ICC). In this study, traditional and multiplex ICC (mICC) for GATA-binding protein 3 (GATA3), gross cystic disease fluid protein 15 (GCDFP15), and mammaglobin (MMG) were performed with the aim of validating mICC in cell blocks, with further single-cell expression pattern analysis to identify the single markers and combinations of markers most sensitive in subtypes of breast cancer. GATA3, GCDFP15, and MMG were paired with OptiView 3,3'-diaminobenzidine and Ventana DISCOVERY Purple and Blue, respectively, with cyclical and serial staining. Bright-field imaging was performed with the Mantra 2 system and analyzed with the inForm Tissue Finder (Akoya Biosciences). Cell detection and phenotyping were further confirmed by two pathologists. In the 36 cases studied, traditional ICC and mICC demonstrated good concordance (kappa coefficient, >0.5; p<.01) at three cutoffs (1%, 5%, and 50%), except for GATA3 at the 1% cutoff. Single-marker positivity outnumbered double-marker positivity and the exceedingly rare triple-marker positivity (<3%). GATA3 was the leading single marker-positive phenotype in all breast cancer subtypes, except for MMG in estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-positive (ER+/PR+/HER2+) breast cancers. Limited to two markers, GATA3/MMG included the greatest number of tumor cells for luminal breast cancers (ER+/PR+/HER2+, 60.6%; ER+/PR+/HER2+, 31.4%), whereas HER2-overexpressed breast cancers (27.4%) and triple-negative breast cancers (26.4%) favored the combination of GATA3/GCDFP15. For a single marker, GATA3 displayed the highest sensitivity. The addition of MMG for hormone receptor-positive breast cancers and GCDFP15 for hormone receptor-negative breast cancers further increased sensitivity. The low proportion of multimarker-positive cells suggested that the coexpression observed with traditional ICC is attributable to intratumoral heterogeneity, not genuine coexpression.

Immunoglobulin A-dominant membranoproliferative glomerulonephritis-like pattern of injury as a possible paraneoplastic nephropathy in a breast cancer patient.

A middle-aged woman was found to have proteinuria during a health check-up. About sixteen months later, she was diagnosed with stage IIA invasive ductal carcinoma of the right breast. Her proteinuria progressed to nephrotic syndrome with significant hematuria. Hormone therapy was initiated for her estrogen and progesterone receptor-positive breast cancer. A kidney biopsy performed 47days after starting the therapy revealed an IgA-dominant membranoproliferative glomerulonephritis-like pattern of injury. Electron microscopy showed subendothelial-dominant electron-dense deposits (EDD), with small amounts of mesangial EDD and a single occurrence of subepithelial hump-like EDD, along with occasional mesangial interpositions. Similar pathology can be caused by IgA vasculitis with nephritis, IgA-dominant infection-associated glomerulonephritis, and liver disease-associated glomerulopathy, but all of these were ruled out. The deposited IgA was found to be galactose-deficient IgA1. Thus, IgA nephropathy with glomerular capillary IgA deposition was considered. She underwent a right partial mastectomy and sentinel lymph node biopsy in the right axilla 75days after starting hormone therapy, followed by adjuvant radiation. Proteinuria and hematuria tended to decrease after the treatment, and this trend continued even after corticosteroid therapy for glomerulonephritis, which was administered 156days after starting hormone therapy. Approximately 15months after starting hormone therapy, her proteinuria had reduced to around 1.0g/g of creatinine, and her hematuria was negative. IgA nephropathy with glomerular capillary IgA deposition is known to be resistant to corticosteroid therapy. The favorable clinical course of the rare glomerulopathy following breast cancer treatment suggested a diagnosis of paraneoplastic glomerulopathy secondary to breast cancer in our patient.

Arthralgia and myalgias associated with aromatase inhibitors: Frequency and characterization in real-life patients.

e12504 Background: Adjuvant treatment with aromatase inhibitors (AI) in estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer (BC) has been shown to increase overall survival (OS). However, arthralgias and myalgias are common adverse effects in patients treated with AI. Objective: To evaluate the frequency and characteristics of arthralgias and myalgias in patients with early BC, treated adjuvantly with AI at the Mastology Unit of the Oncology Service of the Hospital de Clínicas and the Soriano Departmental Hospital. Methods: A prospective, cross-sectional, descriptive study was conducted. A questionnaire was administered to the patients to assess the presence and characteristics of arthralgias and myalgias associated with AI. Statistical analysis: "Age" was described using measures of central tendency and dispersion. Qualitative variables were presented in absolute and relative frequencies. Logistic models were used to assess the association between patient, tumor, and treatment characteristics and the presence of pain. Results: Results were presented using Odds Ratio and p-value, using R software (version 4.1.2) with a significance threshold of 5%. 83 patients were included, with a median age of 69 years. 75.9% presented treatment-related arthralgias and/or myalgias, with an average intensity of 5 to 7. 80.9% received NSAIDs, achieving satisfactory analgesia. The presence of arthralgias and myalgias was significantly associated with age and time since last menstruation, being more frequent in patients over 50 years old and those with more than 5 years since the last menstruation. Conclusions: Approximately 70% of the patients presented arthralgias or myalgias. These findings suggest a possible role of estrogen withdrawal in their development mechanism. It is crucial to carry out multidisciplinary and translational research to evaluate the etiology and therapeutic options for patients with AI-related arthralgia.

Arthralgia and myalgia associated with aromatase inhibitors: frequency and characterization in real-life patients.

Adjuvant treatment with aromatase inhibitors (AI) in oestrogen receptor-positive and/or progesterone receptor-positive breast cancer (BC) has been shown to increase overall survival. However, arthralgias and myalgias are common adverse effects in patients treated with AI. To evaluate the frequency and characteristics of arthralgias and myalgias in patients with early BC-treated adjuvantly with AI in the Mastology Unit of the Oncology Service of the Hospital de Clínicas and the Departmental Hospital of Soriano. A prospective, cross-sectional and descriptive study was performed. A questionnaire was administered to patients to assess the presence and characteristics of arthralgias and myalgias associated with AI. 'Age' was described with measures of central tendency and dispersion. Qualitative variables were presented in absolute and relative frequencies. Logistic models were used to evaluate the association between patient characteristics, tumour characteristics, treatment characteristics and the presence of pain. Results were presented by odds ratio and p-value, using R software (version 4.1.2) with a significance threshold of 5%. 83 patients were included, with a median age of 69 years. 75.9% presented arthralgias and/or myalgias related to treatment, with an average intensity of 5-7. 80.9% received non-steroidal anti-inflammatory drugs (NSAIDs), achieving satisfactory analgesia. The presence of arthralgias and myalgias was significantly associated with age and time since the last menstrual period (LMP), being more frequent in patients older than 50 years and those with more than 5 years since the LMP. Approximately 70% of the patients presented arthralgias or myalgias. These findings suggest a possible role of oestrogen withdrawal in its mechanism of development. Multidisciplinary and translational research is crucial to evaluate the ethology and therapeutic options for patients with AI-related arthralgia.

Tumor Lipid Signatures Are Descriptive of Acquisition of Therapy Resistance in an Endocrine-Related Breast Cancer Mouse Model.

The lipid metabolism adaptations of estrogen and progesterone receptor-positive breast cancer tumors from a mouse syngeneic model are investigated in relation to differences across the transition from hormone-dependent (HD) to hormone-independent (HI) tumor growth and the acquisition of endocrine therapy (ET) resistance (HIR tumors). Results are articulated with reported polar metabolome results to complete a metabolic picture of the above transitions and suggest markers of tumor progression and aggressiveness. Untargeted nuclear magnetic resonance metabolomics was used to analyze tumor and mammary tissue lipid extracts. Tumor progression (HD-HI-HIR) was accompanied by increased nonesterified cholesterol forms and phospholipids (phosphatidylcholine, phosphatidylethanolamine, sphingomyelins, and plasmalogens) and decreased relative contents of triglycerides and fatty acids. Predominating fatty acids became shorter and more saturated on average. These results were consistent with gradually more activated cholesterol synthesis, β-oxidation, and phospholipid biosynthesis to sustain tumor growth, as well as an increase in cholesterol (possibly oxysterol) forms. Particular compound levels and ratios were identified as potential endocrine tumor HD-HI-HIR progression markers, supporting new hypotheses to explain acquired ET resistance.

A prospective cohort study of clinical characteristics and outcomes in Chinese patients with estrogen receptor-negative/progesterone receptor-positive early breast cancer

PurposeThis study aimed to examine the clinical characteristics and outcomes of patients with estrogen receptor-negative (ER−)/progesterone receptor-positive (PR+) early breast cancer. We also aimed to investigate the benefits of adjuvant endocrine therapy (ET) in this patient population.MethodsPatients with early breast cancer diagnosed at West China Hospital were divided into the ER−/PR+, ER+, and ER−/PR− groups. The chi-square test was used to analyze differences in clinical and pathological features among the groups. Multivariable Cox and Fine–Gray regression models were used to compare mortality and locoregional recurrence (LRR)/distant recurrence (DR), respectively. We performed a subgroup analysis to determine which ER−/PR+ patients can benefit more from ET.ResultsFrom 2008 to 2020, we enrolled 443, 7104, and 2892 patients into the ER−/PR+, ER+, and ER−/PR− groups, respectively. The ER−/PR+ group showed more unfavorable clinical features and aggressive pathological characteristics than the ER+ group. The mortality, LRR, and DR rates were higher in the ER−/PR+ than in the ER+ group. Most clinical features and pathological characteristics were similar between the ER−/PR+ and ER−/PR− group and their outcomes were comparable. In the ER−/PR+ group, patients who received ET showed significantly lower LRR and mortality rates than those who did not; however, no difference was observed in DR. Subgroup analysis suggested that ER−/PR+ patients age ≥ 55 years, and postmenopausal status can benefit from ET.ConclusionER−/PR+ tumors have more aggressive pathological characteristics and more unfavorable clinical features than ER+ tumors. ET can reduce the LRR and mortality rates in ER−/PR+ patients. Postmenopausal and age ≥ 55 years ER−/PR+ patients can benefit from ET.

Abstract OT2-01-04: ELONA: An open-label, phase 1b-2 study of elacestrant, in combination with onapristone in patients with estrogen receptor-positive, progesterone receptor-positive, HER2-negative advanced or metastatic breast cancer

Abstract Objectives: The addition of a CDK 4/6 inhibitors to endocrine therapy, in the first or second line setting, provides a significant improvement in progression free survival (PFS), and in some cases in overall survival (OS), with a tolerable toxicity profile. Regardless, most patients experience disease progression on these agents and ultimately develop endocrine resistance, thus, emphasizing the critical need for novel treatments. Elacestrant showed a statistically significant improvement in PFS when compared to standard of care endocrine therapy after progression on CDK4/6 inhibitors in combination with endocrine therapy (Bidard et al, 2022). Onapristone is a type I antiprogestin which prevents the progesterone receptor (PgR) from dimerizing and blocks ligand-induced protein kinase-mediated phosphorylation of the PgR. The clinical anticancer activity of onapristone, in immediate release formulation, has been previously documented in patients with hormone therapy-naïve (Robertson et al, 1999) or tamoxifen-resistant (Jonat et al, 2002) breast cancer (BC). More recently, onapristone, in extended release formulation, was evaluated in doses up to 50 mg BID in a phase 1 trial that enrolled 52 heavily pretreated patients with metastatic solid tumors, with no dose limiting toxicity observed. Among the 20 breast cancer patients enrolled, 7 (35%) had stable disease (Cottou et al, 2018). Methods: ELONA is a phase 1b/2, open-label, multicenter study. The phase 1b portion of the study will assess the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of elacestrant plus onapristone to determine the combinations’ recommended phase 2 dose. The primary endpoint of the phase 2 part of the trial is objective response rate and secondary endpoints will include safety, duration of response, clinical benefit rate, PFS, and OS, in addition to pharmacodynamics markers using ctDNA. Eligible patients are pre-, peri- and post-menopausal women and men aged ≥18 years with ER+/PgR+,HER2- tumors and an Eastern Cooperative Oncology Group performance status ≤2 with at least one measurable lesion at baseline, as per RECIST version 1.1. Prior therapy in the metastatic setting includes at least one anti-hormonal therapy in combination with a CDK4/6i. No prior chemotherapy regimen in the metastatic setting is allowed. The phase 1b dose-escalation portion of the study will evaluate dose-limiting toxicities (DLTs) of the combination in up to 4 cohorts of 6 patients each. Citation Format: Erika Hamilton, Lajos Pusztai, Hatem H. Soliman, Sara Hurvitz, Krzysztof Grzegorzewski, Nassir Habboubi, Priya Marreddy, Tarek Sahmoud, Nuhad Ibrahim. ELONA: An open-label, phase 1b-2 study of elacestrant, in combination with onapristone in patients with estrogen receptor-positive, progesterone receptor-positive, HER2-negative advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-04.

Treatment efficacy of ribociclib or palbociclib plus letrozole in hormone receptor-positive/HER2-negative metastatic breast cancer.

Background: Ribociclib, palbociclib and abemaciclib are currently approved CDK4/6 inhibitors along with aromatase inhibitors as the first-line standard-of-care for patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Methods: The authors report retrospective real-life data for 600patients with estrogen receptor- and/or progesterone receptor-positive and HER2-negative metastatic breast cancer who were treated with ribociclib and palbociclibin combination with letrozole. Results & conclusion: The results demonstrated that the combination of palbociclib or ribociclib with letrozole has similar progression-free survival and overall survival benefit in real life for the patient group with similar clinical features. Specifically, endocrine sensitivity may be a factor to be considered in the treatmentpreference.

Abstract P2-23-06: Estrogen receptor-negative progesterone receptor-positive breast cancer is a molecularly distinct group characterized by the down-regulation of genes controlled by ESR1 and SUZ12

Abstract Background: Single hormone receptor-positive breast cancers (BCs) display two distinct phenotypes: ER+/PgR– and ER–/PgR+ further stratified by their HER2 status. Their molecular features are not well defined. Our study aimed to identify differentially expressed genes in ER–/PgR+ BCs compared to other phenotypes. Methods: Our cohort comprised 15 ER+/PgR–/HER2–, 11 ER+/PgR–/HER2+, 17 ER–/PgR+/HER2–, 9 ER–/PgR+/HER2+, 5 ER+/PgR+/HER2–, and 5 ER–/PgR–/HER2– invasive BCs collected from 9 Polish and 2 Hungarian centers. The cases were selected from a larger cohort after being matched according to grade, HER2 status, lymph nodes, and distant metastasis status. ER–/PgR+ group was thoroughly validated via immunohistochemistry [Kunc et al. 2022]. The expression of 776 genes was profiled with nCounter® Breast Cancer 360™ Panel in archival formalin-fixed paraffin-embedded tissue samples. A gene was defined as differentially expressed between groups if it met the following criteria: the log2 fold-change in the expression of &amp;gt;1 or ←1 and the p-value &amp;lt; 0.05 (Mann-Whitney U test). Additionally, weighted correlation network analysis (WGCNA) was performed to identify modules of at least 15 highly correlated genes. Subsequently, the association between gene modules and PgR status in ER– subgroup was performed. Identified mRNAs were subjected to functional annotation analysis to determine the top enriched pathways. Results: ER–/PgR+ BCs were characterized by significantly lower expression of ESR1 compared to double-positive (p&amp;lt; 0.001) and ER+/PgR– tumors (p&amp;lt; 0.001), whereas PGR expression was higher compared to ER+/PgR– (p&amp;lt; 0.001), and no significantly different from ER+/PgR+ BCs (p=0.14). Triple-negative BCs had no detectable PGR mRNA. Four genes (MIA, ID4, FOXC1, CDC20) were consistently up-regulated and six genes (FAM214A, MLPH, NFKBIZ, FOS, SLC44A4, SPDEF) were down-regulated in ER–/PgR+/HER2– tumors compared to other HER2– subgroups. Compared to ER+/HER2– BCs, ER–/PgR+/HER2– cases showed up-regulation of 15 genes associated with response to vitamin D, response to ketone, and regulation of transcription, and downregulation of 33 genes involved in response to estrogen, negative regulation of cell population proliferation, regulation of epithelial-mesenchymal transition, and controlled by ESR1 and SUZ12. In WGCNA analysis of the ER– subgroup, PgR status was negatively correlated with 4 gene modules and positively correlated with 1 gene module. In line with differential gene expression analysis, genes negatively correlated with ER–/PgR+ status are regulated by ESR1 and SUZ12 and are involved in the regulation of cell proliferation, extracellular matrix organization, and NOTCH1 signaling. Genes positively correlated with ER–/PgR+ status are regulated by E2F4, FOXM1, SIN3A, NFYB, E2F1, FOS, IRF1, ZMIZ1, and UBTF and participate in cell cycle, regulation of mitosis, and microtubule cytoskeleton regulation. Conclusions: ER–/PgR+ BCs display a distinct mRNA expression profile characterized by the down-regulation of genes controlled by ESR1 and SUZ12. The latter as a part of Polycomb Repressive Complex 2 contributes to chromatin silencing, and some previous studies suggested its role in the regulation of steroid hormone receptors expression. Additionally, ER–/PgR+ BCs overexpress FOXC1 which is linked to more aggressive, high-grade, and treatment-resistant breast cancers. Our data indicate the need to unravel the mechanism of epigenetic regulation of PGR expression, especially its methylation status, in ER–/PgR+ breast cancer. Citation Format: Michał Kunc, Marta Popęda, Michał Bieńkowski, Marcin Braun, Aleksandra Łacko, Barbara Radecka, Joanna Pikiel, Maria Litwiniuk, Katarzyna Pogoda, Magdalena Niemira, Anna Szałkowska, Ewa Iżycka-Świeszewska, Gabor Cserni, Wojciech Biernat, Elżbieta Senkus. Estrogen receptor-negative progesterone receptor-positive breast cancer is a molecularly distinct group characterized by the down-regulation of genes controlled by ESR1 and SUZ12 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-06.

ABCB1 Amplicon Contains Cyclic AMP Response Element-Driven TRIP6 Gene in Taxane-Resistant MCF-7 Breast Cancer Sublines.

A limited number of studies are devoted to regulating TRIP6 expression in cancer. Hence, we aimed to unveil the regulation of TRIP6 expression in MCF-7 breast cancer cells (with high TRIP6 expression) and taxane-resistant MCF-7 sublines (manifesting even higher TRIP6 expression). We found that TRIP6 transcription is regulated primarily by the cyclic AMP response element (CRE) in hypomethylated proximal promoters in both taxane-sensitive and taxane-resistant MCF-7 cells. Furthermore, in taxane-resistant MCF-7 sublines, TRIP6 co-amplification with the neighboring ABCB1 gene, as witnessed by fluorescence in situ hybridization (FISH), led to TRIP6 overexpression. Ultimately, we found high TRIP6 mRNA levels in progesterone receptor-positive breast cancer and samples resected from premenopausal women.

Lessons learned from long-term side effects after zoledronic acid infusion following denosumab treatment: a case report and review of the literature

BackgroundZoledronic acid is an intravenous, highly potent aminobisphosphonate for use in patients with primary or secondary osteoporosis. Zoledronic acid-induced prolonged side-effects are well known and quite common. However, severe side-effects can be a threat to life. We report a case of severe side-effects induced by zoledronic acid infusion, and its positive effect on long-term back pain.Case presentationIn 2012, a 62-year-old white native Finnish woman was operated on for an estrogen and progesterone receptor-positive breast cancer. After radiotherapy, an aromatase inhibitor (letrozole) was started. Nine months after the operation, the patient suffered a low-energy compression fracture of Th XII. She received denosumab to prevent fragility fractures and to improve bone mineral density. Letrozole was discontinued after 5.5 years, and the last denosumab injection was given after 7 years. Six months later, at the age of 71 years, the patient received a single intravenous zoledronic acid infusion. Suddenly, at 10 hours from the infusion, she complained of severe trismus, muscle twitching, spasms, and tingling, matching hypocalcemia and several other symptoms. Her serum 25-hydroxyvitamin D concentration was high (163 nmol/L), the concentration of serum calcium and calcium-ion was normal (2.32 mmol/L and 1.23 mmol/L, respectively). However, the neutrophil to lymphocyte ratio (NLR) was low (1.6). A complete recovery took 2 months. Zoledronic acid infusion also had a positive effect: for many years, the patient had suffered low back pain and strain, which came to an end after this single infusion.ConclusionIt is important that the potential patients receive sufficient information about the possibility of side-effects following the administration of intravenous zoledronic acid. To ensure that a zoledronic acid infusion is given as safely as possible, the safety information should include that the patient should not be left without monitoring for a minimum 24 hours after the infusion. Being alone and experiencing serious side-effects may lead to acute cardiac problems. Furthermore, the chronic low back pain and strain that our patient suffered for many years has clearly reduced for 16 months after infusion, so far. We conclude that this is a positive effect of zoledronic acid.

Multiple receptor conversions during the course of metastatic breast cancer therapy: a case report and review of the literature

BackgroundAdjuvant systemic therapy decreases recurrence and death from breast cancer, but late relapse still occurs. Therapeutic decisions are based heavily on receptor tissue characterization. Even though the vast majority of metastatic sites do not have receptor conversions, they can occur at the time of metastasis and/or during the course of treatment. However, multiple receptor conversions are uncommon.Case presentationWe present an unusual case of a Caucasian patient originally diagnosed with an estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative primary breast cancer who had a recurrence after 15 years of therapy. Her metastatic tumor had a different receptor status than the original tumor. During the course of therapy, at the time of progression, a new biopsy showed that her tumor had changed once more.Conclusion/DiscussionTracking receptor conversions is important in metastatic breast cancer treatment. Single receptor conversions have been documented to occur, but not much is known of multiple receptor conversions. This case sheds light on the possibility of patients having multiple receptor conversions and the importance of performing multiple biopsies during the course of metastatic treatment.

The association between serum lipid levels and histological type of breast cancer

BackgroundStudies have investigated the association between serum lipids level or apolipoprotein levels and breast cancer (BC) risk. However, the relationship between serum lipids level and apolipoprotein levels and histological type of breast cancer remains unclear. This study was aimed to explore the association between serum lipids level and the histological type of BC, particularly to estrogen receptor (ER) and progesterone receptor (PR) positive BC.Materials and methods220 cases of pathology-confirmed BC were retrospectively collected in this study. Patients’ demographic information, clinical data, and pathological features were obtained from medical records. Serum levels including high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), total cholesterol (TC), triglyceride (TG), apolipoprotein A (ApoA), ApoB, ApoE and lipoprotein a(LP(a)) were collected before treatment. Logistic regression analyses were used to show the association between serum lipids and subtypes of BC. Receiver operating characteristic (ROC) curves were generated to analyze the predictive performance.ResultsThere were 70 ER-negative and 73 PR-negative BC. Patients with ER-negative BC had higher HDL-c, higher LDL-c, and higher LP(a) than those in ER-positive one (p < 0.05). Patients with PR-negative BC were more likely to have high LDL-c and high LP(a) levels than patients with PR-positive one (p < 0.05). Multivariate logistic regression analysis showed that serum HDL-c (odds ratio (OR): 0.27, 95% confidence interval (CI) 0.10–0.76), LDL-c (OR: 0.19, 95%CI 0.04–0.93) and LP(a) (OR: 0.23,95%CI 0.07–0.80) levels were negatively associated with ER-positive BC, and serum HDL-c and LDL-c levels were significantly negatively associated with PR-positive BC (OR: 0.32, 95%CI 0.12–0.82; OR: 0.14, 95%CI 0.03–0.77). In addition, ER and PR positive BC was negatively associated with serum HDL-c and LDL-c levels (OR = 0.39, 95% CI 0.17–0.91; OR = 0.22, 95% CI 0.06–0.85) after adjusting with confounders. Serum HDL-c level (OR = 0.13, 95% CI 0.02–0.87) was still independently associated with ER and PR positive BC in postmenopausal women. The area under the curves (AUCs) of HDL-c to identify ER-positive BC, PR-positive BC, and ER and PR positive BC were 0.65 (95%CI 0.58–0.73, P < 0.01), 0.62 (95%CI 0.54–0.69, P < 0.01) and 0.64 (95%CI 0.56–0.72, P < 0.01), respectively.ConclusionsSerum HDL-c and LDL-c levels were related to ER or PR positive BC. Lipid levels may also have acceptable performance in identifying BC histological type.

Abstract 649: Targeting progesterone receptor (PR) with the antiprogestin onapristone in patient-derived xenograft (PDX) models of estrogen receptor positive (ER+), PR positive (PR+) bone metastasis of breast cancer

Abstract Background: Onapristone (ONA) is a progesterone receptor (PR) antagonist that prevents PR-mediated DNA transcription. ONA is currently being evaluated in metastatic breast cancers (MBC), as well as other hormone-dependent cancers. Recently, therapeutic options for metastatic estrogen receptor (ER) positive breast cancers have been expanded by the introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), administered in combination with endocrine treatments, as first line therapy. Moreover, the selective PI3K inhibitor alpelisib (ALP) has been approved for the treatment of PIK3CA-mutated endocrine resistant MBC. The objective of this study was to evaluate the efficacy of ONA in combination with fulvestrant (FUL) and palbociclib (PAL) or ALP in different PDX models established from ER and PR positive breast cancers. Methods: PDX models were established from primary tumors or biopsies from bone metastases from endocrine therapy patients with progressing tumors. ER and PR expression were analyzed by immunohistochemistry (IHC) and western blot (WB) analysis in 17 PDX models. The anti-tumor activity of onapristone alone or combined with FUL and PAL was tested in 2 ER+/PR+ PDX studies, while the combination with ALP+FUL was tested in one PIK3CA-mutated PDX study. Phosphorylation of both PR and ER-PR interactions were analyzed in treated tumors by WB and by the in situ Proximity Ligation Assay (PLA), respectively. Results: PR expression was found in 1/9 PDX established from primary breast tumors and 4/8 PDX established from bone metastases. ONA in vivo activity was tested in 2 PDX of bone metastases: PDX BC1101 (PR low) and BC1117 (PR high). BC1101 showed amplification of FGFR1 and CCND1 genes, while BC1117 has an activating mutation of PIK3CA gene. In the low PR PDX BC1101, treatment with ONA was ineffective in both the monotherapy and combination setting. Conversely, in the PDX with high expression of PR, BC1117, ONA treatment, given as monotherapy, decreased tumor growth. The anti-tumor activity of ONA+FUL+PAL combination was significantly increased as compared to FUL+PAL, with the majority of xenografts showing tumor regression. Expression of PR and phospho-PR were inhibited in the tumors treated by FUL, ONA+FUL, and ONA+FUL+PAL. Interaction between ER and PR, analyzed by the in situ PLA assay, was inhibited in the ONA+FUL treated xenografts ±PAL. Finally, treatment with the triple combination of ONA+FUL+ALP was also highly effective and significantly greater than the combination of FUL+ALP. RNAseq analysis of treated xenografts is ongoing to identify transcriptomic changes in the different treatment arms. In conclusion, our study demonstrates that ONA improved the response to endocrine treatment using CDK4/6 or PI3K inhibitors in a MBC-derived PDX model with high PR expression. Citation Format: Martin Lehr, Ahmed Dahmani, Léa Huguet, Rania El-Botty, Charlène Thiebaut, Muriel Romancer, Paul Cottu, Elisabetta Marangoni. Targeting progesterone receptor (PR) with the antiprogestin onapristone in patient-derived xenograft (PDX) models of estrogen receptor positive (ER+), PR positive (PR+) bone metastasis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 649.

Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Guideline Update.

To update evidence-based guideline recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. An Expert Panel conducted a targeted systematic literature review (for both systemic treatment and CNS metastases) and identified 545 articles. Outcomes of interest included efficacy and safety. Of the 545 publications identified and reviewed, 14 were identified to form the evidentiary basis for the guideline recommendations. HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and trastuzumab deruxtecan for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations. There is a lack of head-to-head trials; therefore, there is insufficient evidence to recommend one regimen over another. The patient and the clinician should discuss differences in treatment schedule, route, toxicities, etc during the decision-making process. Options include regimens with tucatinib, trastuzumab emtansine, trastuzumab deruxtecan (if either not previously administered), neratinib, lapatinib, chemotherapy, margetuximab, hormonal therapy, and abemaciclib plus trastuzumab plus fulvestrant, and may offer pertuzumab if the patient has not previously received it. Optimal duration of chemotherapy is at least 4-6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive or progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone.Additional information is available at www.asco.org/breast-cancer-guidelines.

Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism.

Simple SummaryBreast cancers are largely controlled by hormones, expressing abundant receptors for estrogen (ER) and progesterone (PR). Reprogramming of energy metabolism is a common feature of tumors, yet how estrogen and progestins (synthetic progesterone drugs) control breast cancer cell metabolism, particularly in combination, is understudied. Here we evaluated the impact of estrogens and progestins, alone or together, on breast cancer cell metabolism. Our results show that hormones significantly impact metabolism, especially in combination. Estrogens tend to target tumor-promoting genes that alter glucose metabolism while progestins target fat storage. Combined hormone treatment increases both glucose metabolism and fat storage, features advantageous for tumor progression. These results may explain, in part, why estrogen-progestin combinations increase breast cancer incidence in post-menopausal women. Targeting hormone-regulated metabolism is a potential novel therapeutic strategy for ER+PR+ breast cancer.Metabolic reprogramming remains largely understudied in relation to hormones in estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer. In this study, we investigated how estrogens, progestins, or the combination, impact metabolism in three ER and PR positive breast cancer cell lines. We measured metabolites in the treated cells using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Top metabolic processes upregulated with each treatment involved glucose metabolism, including Warburg effect/glycolysis, gluconeogenesis, and the pentose phosphate pathway. RNA-sequencing and pathway analysis on two of the cell lines treated with the same hormones, found estrogens target oncogenes, such as MYC and PI3K/AKT/mTOR that control tumor metabolism, while progestins increased genes associated with fatty acid metabolism, and the estrogen/progestin combination additionally increased glycolysis. Phenotypic analysis of cell energy metabolism found that glycolysis was the primary hormonal target, particularly for the progestin and estrogen-progestin combination. Transmission electron microscopy found that, compared to vehicle, estrogens elongated mitochondria, which was reversed by co-treatment with progestins. Progestins promoted lipid storage both alone and in combination with estrogen. These findings highlight the shift in breast cancer cell metabolism to a more glycolytic and lipogenic phenotype in response to combination hormone treatment, which may contribute to a more metabolically adaptive state for cell survival.

Abstract P4-06-01: OncotypeDX testing does not appear to benefit patients with grade 1, progesterone receptor positive breast cancers: A TAILORx validated study

Abstract Background: We previously described a validated (AAMC) risk prediction model, based on pathology, which may eliminate the need for OncotypeDX testing in AAMC low-risk (grade 1, progesterone (PR) positive) tumors. Our previous study used the SEER database and examined breast cancer specific survival (BCSS) and overall survival (OS), but was limited by our inability to assess distant recurrence-free interval (DRFI) and invasive disease-free survival (IDFS) with the available data. The purpose of this study was to validate the AAMC model using the TAILORx database, specifically with regard to DRFI and IDFS. Methods: We retrospectively analyzed TAILORx trial data and categorized patients into groups based on the AAMC model (Table). AAMC low-risk were defined as tumors that were both grade 1 and PR positive, while high-risk tumors were grade 3 or estrogen (ER) negative/PR positive. Intermediate-risk were those not categorized as low- or high-risk. The AAMC model recommends against OncotypeDX testing in low-risk tumors, but recommends testing in intermediate- or high-risk tumors. Kaplan-Meier curves were used to examine DRFI and IDFS. Results: A total of 9143 patients with grade and ER/PR information were categorized into AAMC low-risk (24.6%), intermediate-risk (57.9%), and high-risk (17.5%) groups. In the AAMC low-risk cohort, 22.3% had Recurrence Score (RS) 0-10 and did not receive chemotherapy per the TAILORx protocol, while 75.3% had RS 11-25 and were randomized to chemotherapy versus no-chemotherapy, and 2.4% had RS &amp;gt; 25 and received adjuvant chemotherapy. In these AAMC low-risk patients, DRFI did not differ for patients who received adjuvant chemotherapy versus those that did not (log-rank p=.96). Similarly, IDFS was comparable between the chemotherapy and no-chemotherapy groups (log-rank p=.66). Only 2.4% of AAMC low-risk patients were categorized as high-risk per OncotypeDX testing (RS &amp;gt; 25). To account for the fact that all patients in this small group received chemotherapy per protocol, a sensitivity analysis was performed in which AAMC low-risk patients with RS &amp;gt; 25 were re-classified into the no-chemotherapy group and assumed to have experienced recurrences at rates expected without chemotherapy. Under these assumptions, there still was no difference in DRFI (log-rank p=.16) between chemotherapy and no-chemotherapy groups. Conclusion: This study validates our previous recommendations that OncotypeDX testing may be omitted in early-stage breast cancers with grade 1 and PR positive tumors (AAMC low-risk), as adjuvant chemotherapy does not improve distant recurrence-free interval in this group of patients. Based on our recommendations, 1 in 4 TAILORx participants would not need OncotypeDX testing. This would result in substantial cost savings to the healthcare system. Percent of TAILORx trial participants and treatment recommendations based on OncotypeDX testing versus AAMC model.ModelAAMC ModelLow-risk (n=2246, 24.6%)Intermediate-risk (n=5298, 57.9%)High-risk (n=1599, 17.5%)Treatment recommendation*No chemotherapy/No OncotypeDX testingProceed with OncotypeDX testProceed with OncotypeDX testOncotypeDX testing*RS 0 to 15No chemotherapy1240 (55.2%)2224 (42.0%)306 (19.1%)RS 16 to 20, age ≤50Chemotherapy and/or OFS/AI258 (11.5%)492 (9.3%)108 (6.8%)RS 21 to 25, age ≤50Chemotherapy and/or OFS/AI93 (4.1%)274 (5.2%)101 (6.3%)RS 16 to 25, age &amp;gt;50No chemotherapy600 (26.7%)1719 (32.4%)450 (288.1%)RS &amp;gt;25Chemotherapy55 (2.4%)589 (11.1%)634 (39.6%)Ovarian function suppression (OFS); Aromatase inhibitor (AI)*Based on TAILORx results Citation Format: Young Lee, W. Charles Mylander, Tasha Martin, Martin Rosman, Thomas J Sanders, Udai S Sibia, Lorraine Tafra, Rubie S Jackson. OncotypeDX testing does not appear to benefit patients with grade 1, progesterone receptor positive breast cancers: A TAILORx validated study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-06-01.

Abstract P5-04-05: Loss of REST in breast cancer promotes tumor progression through estrogen sensitization, MMP24 and CEMIP overexpression

Abstract Breast cancer is the most common malignancy in women and is the second leading cause of cancer-related deaths. Breast cancer is both pathologically and genetically heterogeneous, making early detection and treatment difficult. A subset of breast cancers expresses normal levels of REST (Repressor Element 1 Silencing Transcription factor) mRNA but lacks functional REST protein. Loss of REST function is seen in ~20% of breast cancers and is associated with a more aggressive phenotype and poor prognosis. Despite the frequent loss of REST, little is known about the role of REST in the molecular pathogenesis of breast cancer. TCGA data was analyzed for the expression of REST and its target genes in breast cancer patient samples. MCF7, an estrogen and progesterone receptor positive breast cancer cell line, and MDA-MB-231, a triple-negative breast cancer cell line were used for in vitro studies to understand the function of REST. To evaluate the role of REST in the regulation of hormone receptor pathways, RNA sequencing was carried out on total RNA from MCF7 cells after siRNA knockdown of REST followed by treatment of hormones estrogen and progesterone. Chromatin Immunoprecipitation and PCR were performed on REST knockdown cells to evaluate gene regulation by REST and understand its tumor suppressor role in breast cancer. We show that REST directly regulates CEMIP (Cell Migration-Inducing and Hyaluronan-Binding Protein, KIAA1199) and MMP24 (Matrix Metallopeptidase 24), genes known to have roles in invasion and metastasis. REST knockdown in breast cancer cell lines leads to significant upregulation of CEMIP and MMP24. In addition, we found that REST binds to RE-1 sites (Repressor Element-1) within the genes and influences their transcriptional regulation. Aberrant expression of CEMIP and MMP24 results in CD44 dependent cell signaling that promotes cell proliferation and survival. We also found that the estrogen receptor signaling pathway is activated in the absence of REST regardless of hormone treatment. Our studies show that REST plays a significant role in altering the estrogen signaling pathway in hormone-sensitive breast cancers. REST transcriptionally regulates genes known to affect cell invasion and metastasis. Importantly, we demonstrate that loss of REST promotes aggressive breast cancer and see REST as an attractive therapeutic target. Citation Format: Aditya M. Vargheese, Ashley S. Cloud, Sumedha Gunewardena, Raeann M. Shimak, Sornakala Ganeshkumar, Easwari Kumaraswamy, Roy A. Jensen, Vargheese M. Chennathukuzhi. Loss of REST in breast cancer promotes tumor progression through estrogen sensitization, MMP24 and CEMIP overexpression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-04-05.

Immunotherapy for Breast Cancer Treatment: Current Evidence and Therapeutic Options.

Breast Cancer (BC) has the highest incidence among all forms of malignancies detected in women globally. The therapeutic approaches available for BC include chemotherapy, radiation therapy, hormonal therapy, and surgery. Recently, advanced immunology-based therapeutics with potential for BC treatment, including immune checkpoint blockades, vaccines, and combinations with other treatment strategies, have emerged. Although commonly used treatments such as trastuzumab/ pertuzumab for human epidermal growth factor receptor 2-positive BC and hormone therapy for estrogen receptor-positive and/or progesterone receptor-positive BC are specific, triple-negative BC cases remain a great challenge for treatment measures. Immune checkpoint inhibitors (anti- PD-1/anti-CTLA-4) and anti-cancer vaccines (NeuVax, MUC-1, AVX901, INO-1400, and CEA), either alone or in combination with other therapies, represent a new paradigm in cancer therapeutics. In this review, we highlight the current immunotherapeutic aspects and ongoing trials aimed at the development of better treatment regimens for BC.

Risks of Aromatase Inhibitor-Related Cardiotoxicity in Patients with Breast Cancer in Asia.

Simple SummaryIn Asian breast cancer patients, whether the risks of major adverse cardio- and cerebrovascular events (MACCEs) are different between users of aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs) remains uncertain. In this nationwide cohort study, the risks of MACCEs were significantly higher in users of SERMs compared with users of AIs in those who were at an old age (above 50 years old) or with advanced cancer stage (stage 3–4). Although the choice of hormone therapies is primarily based on the effectiveness regarding cancer survival, AI treatment should be considered for patients for whom the benefits outweigh the risks.Background: Despite a preferred endocrine therapy for women with estrogen and progesterone receptor-positive breast cancer, aromatase inhibitors (AIs) have been reported to increase risks of cardiovascular events. Given that breast cancer patients in Asia are younger at diagnosis, it is urgent to investigate this safety concern. Methods: Through the Taiwanese National Cohort, we identified breast cancer patients initiating selective estrogen receptor modulators (SERMs) or AIs from 2010 to 2016. Outcomes includes major adverse cardio- and cerebrovascular events (MACCEs). The average follow-up duration was five years. Results: We identified 16,730 breast cancer patients treated with SERMs and 11,728 receiving AIs. The population was older and had more comorbidities in the AI group than in the SERM group. After adjusting for age, cancer stage, cancer therapies, cardiovascular drugs and comorbidities, despite similar risks of MACCEs between AI and SERM users, the risk of HF was significantly higher in patients treated with SERMs after adjusted mortality as a competing risk. When divided by the age of 50 years, despite a similar MACCEs in the younger population, MACCEs remained significantly higher in the older population who received SERMs. Conclusions: In this Asian cohort, we found that among patients of old age or with advanced cancer stage, the use of SERMs was associated with a higher risk of cardiovascular events than the use of AIs.