Endocrine Therapy For Breast Cancer Research Articles

The link between aberrant splicing and B cell infiltration in breast cancer hormone therapy

Increasing evidence has suggested alternative splicing (AS) is an essential mechanism for tumor initiation and progression. However, the functions of aberrant splicing have not been well understood in hormone therapy-treated breast cancer (HTBC) patients yet. By mining the SpliceSeq data of TCGA, we characterized 1388 survival-associated AS events (SASEs) that are markedly related to the overall survival (OS) of HTBC patients. Subsequently, a SASE prognostic signature was deduced via the least absolute shrinkage and selection operator (LASSO) and multivariate Cox analysis, and the HTBC patients were stratified into high- and low-risk groups based on the signature. The differentially expressed genes between the high- and low-risk patients were enriched with immune response genes. Furthermore, we revealed that B cell infiltration was significantly low in the high-risk patients with single-sample gene set enrichment analysis (ssGSEA), suggesting a link between AS abnormality and B cell infiltration in tumor immune microenvironment (TIME). Next, a similar prognostic signature based on splicing factor expression was deduced using Molecular Taxonomy of Breast Cancer (METABRIC) HTBC patients. When this prognostic signature was applied to stratify HTBC patients in the METABRIC and TCGA cohorts, the high-risk subgroups both had significantly low B cell infiltration in TIME. CIBERSORT analysis further demonstrated plasma cells infiltrated less in TIME. Also, both the AS (P < 0.0001) and SF (P = 0.009) prognostic signatures performed well in predicting OS of HTBC patients. In summary, our study has demonstrated that AS abnormality is a potential cause of B cell infiltration alteration, which is a critical factor for cancer death risks in HTBC patients and might be exploited therapeutically in the future.

206TiP Randomized, multicenter, international phase III ARTEST study to evaluate enobosarm versus active control for the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who previously received an estrogen-blocking agent and a CDK 4/6 inhibitor

Targeting the androgen receptor (AR) may be the next important endocrine therapy for advanced breast cancer. Enobosarm is an oral selective AR targeting agonist that activates the AR in breast cancer. Enobosarm has an extensive clinical experience in 25 clinical trials including in 2 phase 2 studies conducted in patients (pts) with AR+ ER+ HER2- metastatic breast cancer (MBC). An open-label, parallel design phase 2 study, was conducted in 136 women with heavily pretreated ER+ HER2- MBC that were randomized to oral daily enobosarm at a dose of 9 or 18 mg.

Maintenance endocrine therapy plus bevacizumab for advanced or metastatic breast cancer.

Endocrine therapy is the preferred option for patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar However, first-line chemotherapy is used in approximately half of this patient population, notably in the context of organ failure or resistance to endocrine therapy. 2 Werutsky G Reinert T Rosa ML Barrios CH Real-world data on first-line systemic therapy for hormone receptor-positive HER2-negative metastatic breast cancer: a trend shift in the era of CDK 4/6 inhibitors. Clin Breast Cancer. 2021; 21: e688-e692 Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar , 3 Jacquet E Lardy-Cléaud A Pistilli B et al. Endocrine therapy or chemotherapy as first-line therapy in hormone receptor-positive HER2-negative metastatic breast cancer patients. Eur J Cancer. 2018; 95: 93-101 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar In these patients, chemotherapy is frequently stopped, despite disease stabilisation, because of acute and cumulative toxic effects. 4 Giuliano M Schettini F Rognoni C et al. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019; 20: 1360-1369 Summary Full Text Full Text PDF PubMed Scopus (66) Google Scholar Switching to maintenance endocrine therapy after first-line induction chemotherapy has been proposed to improve disease control and to maintain quality of life (QOL). Switch maintenance therapy is regularly used in clinical practice, 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar , 3 Jacquet E Lardy-Cléaud A Pistilli B et al. Endocrine therapy or chemotherapy as first-line therapy in hormone receptor-positive HER2-negative metastatic breast cancer patients. Eur J Cancer. 2018; 95: 93-101 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar although clinical trials attesting to its relevance are scarce. 5 Ren W Yu Y Hong H et al. Clinical evidence of chemotherapy or endocrine therapy maintenance in patients with metastatic breast cancer: meta-analysis from randomized clinical trials and propensity score matching of multicentre cohort study. Cancer Res Treat. 2022; (published online Feb 4.)https://doi.org/10.4143/crt.2021.698 Crossref PubMed Google Scholar Moreover, the first-line combination of bevacizumab (an anti-angiogenic monoclonal antibody) plus chemotherapy has been shown in clinical trials to improve progression-free survival, although its effect on overall survival remains controversial. 6 Miyashita M Hattori M Takano T Toyama T Iwata H Risks and benefits of bevacizumab combined with chemotherapy for advanced or metastatic breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer. 2020; 27: 347-354 Crossref PubMed Scopus (7) Google Scholar These results have led to the consideration of this combination as an acceptable first-line strategy. 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar Similarly, bevacizumab plus endocrine therapy is efficacious in improving progression-free survival and overall survival while being well tolerated as a first-line treatment for advanced or metastatic breast cancer. 7 Martín M Loibl S Hyslop T et al. Evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for hormone receptor-positive metastatic breast cancer: a pooled analysis from the LEA (GEICAM/2006–11_GBG51) and CALGB 40503 (Alliance) trials. Eur J Cancer. 2019; 117: 91-98 Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar Switch maintenance endocrine therapy plus bevacizumab after bevacizumab plus paclitaxel in advanced or metastatic oestrogen receptor-positive, HER2-negative breast cancer (BOOSTER): a randomised, open-label, phase 2 trialSwitch to maintenance endocrine therapy plus bevacizumab with the possibility of weekly paclitaxel reinduction if needed is an efficacious alternative, with a better safety profile, to continuing weekly paclitaxel plus bevacizumab in patients with ER-positive, HER2-negative advanced or metastatic breast cancer who have responded to induction therapy. Full-Text PDF

The MDM2 and CDKN2A Copy-number-variation Influence the TP53-signature-score in Wild-type TP53 Luminal Type Breast Cancer.

The TP53-signature is a multi-gene signature that can predict TP53 structural mutations. It has presented remarkable ability to predict the prognosis of early-stage breast cancer. However, some samples presented discordance with the signature status and structure status. We aimed to investigate whether the mRNA expression levels or copy number variation (CNV) of MDM2 and CDKN2A influence the TP53-signature-score, subtype classification, and prognosis prediction in TP53 wild-type, luminal type early-stage breast cancer samples. We selected TP53 wild-type, luminal type early-stage breast cancer samples from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. Then, we analyzed the correlation between the TP53-signature-score and mRNA expression levels or CNV of MDM2 and CDKN2A. The samples with MDM2 copy number (CN) amplification or those with CDKN2A CN deep deletion presented higher TP53-signature-score. Moreover, samples with MDM2 CN amplification or those with CDKN2A CN deep deletion had more characteristics of the luminal B type. In addition, they showed lower estrogen response early score, which correlated with response to endocrine therapy in breast cancer. However, MDM2 and CDKN2A mRNA expression did not present the same tendency. Furthermore, samples with MDM2 CN amplification or those with CDKN2A CN deep deletion had a worse prognosis in METABRIC cohort. The MDM2 or CDKN2A CNV may be useful for classifying subtypes and predicting prognosis more accurately in TP53 wild-type, luminal type early-stage breast cancer patients.

Prognostic Relevance of Estrogen Receptor Status in Circulating Tumor Cells in Breast Cancer Patients Treated With Endocrine Therapy.

Recently, female breast cancer (BC) has surpassed lung cancer to occupy the first place of the most commonly diagnosed cancer. The unsatisfactory prognosis of endocrine therapy for breast cancer might be attributed to the discordance in estrogen receptor (ER) status between primary tumors and corresponding metastases, as well as temporal and spatial receptor status heterogeneity at point-in-time between biopsy and treatment. The purpose of this study was to evaluate the prognostic and predictive value of ER status in circulating tumor cells (CTCs) in BC patients. We analyzed ER expression on CTCs isolated using the Pep@MNPs method in 2.0 ml of blood samples from 70 patients with BC and 67 female controls. The predictive and prognostic value of ER expression in CTCs and immunohistochemistry results of biopsies for progression-free survival (PFS) and overall survival (OS) of patients in response to therapies were assessed. The detection rate for CTCs was 95.71% (67/70 patients), with a median of 8 CTCs within 2 ml of peripheral venous blood (PVB). A concordance of 76.56% in ER status between CTCs and corresponding primary tumor and 69.23% between CTCs and corresponding metastases was observed. We also found that patients with ER-positive CTCs (CTC ER+) had longer PFS and OS than those without ER-positive CTCs (CTC ER-). Our findings suggested that ER status in CTCs of BC patients may provide valuable predictive and prognostic insights into endocrine therapies, although further evaluation in larger prospective trials is required.

The relationship among psychosocial adaptation, medication adherence and quality of life in breast cancer women with adjuvant endocrine therapy

BackgroundPatients undergoing endocrine therapy for breast cancer often suffer from poor psychosocial adaptation, low compliance with endocrine therapy and poor quality of life. However, the relationship among the three is not completely clear. The aims of this study were to investigate the status of psychosocial adaptation (PSA), medication adherence and quality of life (QOL) in breast cancer women with adjuvant endocrine therapy (AET), and to analyze the influencing factors of QOL and explore the relationship among them.Methods346 breast cancer women were selected who underwent endocrine therapy after surgery, and data collected by the general information questionnaire, the PSA questionnaire among breast cancer women with AET, Morisky Medication Adherence Scale and The Functional Assessment of Cancer Therapy-Breast (FACT-B). The relationship among the variables was investigated by univariate analysis, multiple stepwise regression analysis and mediating effect analysis.ResultsThe scores of PSA, medication adherence and QOL were slightly above the medium level. Univariate analysis showed that there were significant differences in QOL among breast cancer women of AET with different types of exercise, medical payment methods, discomfort symptoms (headache, hypomnesis, arthralgia, perturbation), type of discomfort symptoms, medication adherence and PSA; Multi-factor analysis showed that PSA and medication adherence were the influential factors of QOL; mediating effect showed that medication adherence played a partial mediating role in PSA and QOL.ConclusionThe QOL of breast cancer women with AET will be directly affected by PSA. Medication compliance has a weak mediating effect in the indirect impact of PSA on the QOL. In the future, clinical nursing work should take targeted measures to improve the PSA level of patients, and effectively improve the compliance of patients with medication, so as to better improve the QOL of breast cancer women.

Association of treatment-emergent symptoms identified by patient-reported outcomes with adjuvant endocrine therapy discontinuation

Many patients discontinue endocrine therapy for breast cancer due to intolerance. Identification of patients at risk for discontinuation is challenging. The minimal important difference (MID) is the smallest change in a score on a patient-reported outcome (PRO) that is clinically significant. We evaluated the association between treatment-emergent symptoms detected by worsening PRO scores in units equal to the MID with discontinuation. We enrolled females with stage 0-III breast cancer initiating endocrine therapy in a prospective cohort. Participants completed PROs at baseline, 3, 6, 12, 24, 36, 48, and 60 months. Measures included PROMIS pain interference, fatigue, depression, anxiety, physical function, and sleep disturbance; Endocrine Subscale of the FACT-ES; and MOS-Sexual Problems (MOS-SP). We evaluated associations between continuous PRO scores in units corresponding to MIDs (PROMIS: 4-points; FACT-ES: 5-points; MOS-SP: 8-points) with time to endocrine therapy discontinuation using Cox proportional hazards models. Among 321 participants, 140 (43.6%) initiated tamoxifen and 181 (56.4%) initiated aromatase inhibitor (AI). The cumulative probability of discontinuation was 23% (95% CI 18–27%) at 48 months. For every 5- and 4-point worsening in endocrine symptoms and sleep disturbance respectively, participants were 13 and 14% more likely to discontinue endocrine therapy respectively (endocrine symptoms HR 1.13, 95% CI 1.02–1.25, p = 0.02; sleep disturbance HR 1.14, 95% CI 1.01–1.29, p = 0.03). AI treatment was associated with greater likelihood of discontinuation than tamoxifen. Treatment-emergent endocrine symptoms and sleep disturbance are associated with endocrine therapy discontinuation. Monitoring for worsening scores meeting or exceeding the MID on PROs may identify patients at risk for discontinuation.

SETDB1 interactions with PELP1 contributes to breast cancer endocrine therapy resistance

BackgroundMethyltransferase SETDB1 is highly expressed in breast cancer (BC), however, the mechanisms by which SETDB1 promotes BC progression to endocrine therapy resistance remains elusive. In this study, we examined the mechanisms by which SETDB1 contribute to BC endocrine therapy resistance.MethodsWe utilized therapy sensitive (MCF7 and ZR75), therapy resistant (MCF7-TamR, MCF7-FR, MCF7-PELP1cyto, MCF7-SETDB1) estrogen receptor alpha positive (ER+)BC models and conducted in vitro cell viability, colony formation, 3-dimensional cell growth assays to investigate the role of SETDB1 in endocrine resistance. RNA-seq of parental and SETDB1 knock down ER+ BC cells was used to identify unique pathways. SETDB1 interaction with PELP1 was identified by yeast-two hybrid screen and confirmed by immunoprecipitation and GST-pull down assays. Mechanistic studies were conducted using Western blotting, reporter gene assays, RT-qPCR, and in vitro methylation assays. Xenograft assays were used to establish the role of PELP1 in SETDB1 mediated BC progression.ResultsRNA-seq analyses showed that SETDB1 regulates expression of a subset of estrogen receptor (ER) and Akt target genes that contribute to endocrine therapy resistance. Importantly, using yeast-two hybrid screen, we identified ER coregulator PELP1 as a novel interacting protein of SETDB1. Biochemical analyses confirmed SETDB1 and PELP1 interactions in multiple BC cells. Mechanistic studies confirmed that PELP1 is necessary for SETDB1 mediated Akt methylation and phosphorylation. Further, SETDB1 overexpression promotes tamoxifen resistance in BC cells, and PELP1 knockdown abolished these effects. Using xenograft model, we provided genetic evidence that PELP1 is essential for SETDB1 mediated BC progression in vivo. Analyses of TCGA datasets revealed SETDB1 expression is positively correlated with PELP1 expression in ER+ BC patients.ConclusionsThis study suggests that the PELP1/SETDB1 axis play an important role in aberrant Akt activation and serves as a novel target for treating endocrine therapy resistance in breast cancer.

Cognitive complaints during breast cancer endocrine therapy: aromatase inhibitors versus tamoxifen

ObjectivePrevious data hypothesise that women receiving aromatase inhibitors (AIs) exhibit worse cognitive functioning than patients on tamoxifen (TAM) since their oestrogen levels are lower. We aimed to compare cognitive complaints...

Older patients' experience of living with cognitive impairment related to hormone therapy for breast cancer: A qualitative study.

Patients with breast cancer may develop cognitive impairment as a result of hormone therapy and aging. This study aimed to describe older patients' experience of cognitive impairment related to hormone therapy for breast cancer. A qualitative and descriptive design was used. Semi-structured interviews were conducted with 11 patients asking about their experience in daily life related to their cognitive impairment. Study participants were evaluated by cancer-specific geriatric assessment. Inductive content analysis was conducted using the interview records. Three themes emerged from the patients' narrative data: recognizing of cognitive impairments, impacts on mental health, and coping with cognitive impairments. Recognizing of cognitive function consisted of two categories: perception of cognitive changes and acknowledging their cognitive function status through interacting with others. Impacts on mental health consisted of six categories: decreased motivation for social activities, upset by perception of cognitive decline, concerns about impacts of cognitive impairment on treatment of breast cancer, concerns about the care burden of their family, concerns about progression of cognitive impairments, and feeling secure that their cognitive impairment is not unusual. Coping with cognitive impairments consisted of two categories: coping with problems related to cognitive impairment and trying to maintain and improve cognitive function. Oncology nurses should assess cognitive function and complete a comprehensive evaluation of older patients receiving hormone therapy for breast cancer. An evaluation of cognitive function would enable a tailored approach to education and support to enhance coping ability in the longer term.

Cardiac Toxicity From Adjuvant Targeting Treatment for Breast Cancer Post-Surgery.

Breast cancer is one of the most prevalent types of cancers worldwide, especially for females. Surgery is the preferred treatment for breast cancer, and various postoperative adjuvant therapies can be reasonably used according to different pathological characteristics, especially traditional radiotherapy, chemotherapy, and endocrine therapy. In recent years, targeting agent therapy has also become one of the selective breast cancer treatment strategies, including anti-HER-2 drugs, CDK4/6 inhibitor, poly ADP-ribose polymerase inhibitor, PI3K/AKT/mTOR pathway inhibitor, ER targeting drugs, and aromatase inhibitor. Because of the different pathologic mechanisms of these adjuvant therapies, each of the strategies may cause cardiotoxicity in clinic. The cardiac adverse events of traditional endocrine therapy, radiotherapy, and chemotherapy for breast cancer have been widely detected in clinic; however, the targeting therapy agents have been paid more attention with the extension of application. This review will summarize the cardiac toxicity of various adjuvant therapies for breast cancer, especially for targeting drug therapy.

Cyclin-dependent kinase 4 and 6 inhibitors in combination with neoadjuvant endocrine therapy in estrogen receptor-positive early breast cancer: a systematic review and meta-analysis.

The combination of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine treatment has benefited patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER + /HER2-) metastatic breast cancer; however, its effects in the neoadjuvant setting for ER + /HER2- early breast cancer (EBC) are unclear. Systematic searches were performed in PubMed, Embase, Cochrane Library, and major oncological meetings for trials of CDK4/6 inhibitors plus neoadjuvant endocrine treatment (NET) vs. NET/neoadjuvant chemotherapy (NACT) alone up to January 30, 2021. We assessed the efficacy of CDK4/6 inhibitors plus NET vs. NET/NACT alone in ER + /HER2- EBC. Six studies that included 803 patients treated with CDK4/6 inhibitors plus NET vs. NET/NACT alone were used. Compared with NET/NACT alone, CDK4/6 inhibitors plus NET increased the complete cell cycle arrest (CCCA) rate (OR, 9.00; 95% CI, 5.42-14.96; P < 0.001). Nonsignificant differences between CDK4/6 inhibitors and NET/NACT alone occurred in the preoperative endocrine prognostic index (PEPI)-0 rate (OR, 1.13; 95% CI, 0.59-2.18; P = 0.71), pathological complete response (pCR) rate (OR, 0.75; 95% CI, 0.13-4.29; P = 0.74), objective response rate (ORR) (OR, 0.70; 95% CI, 0.21-2.29; P = 0.55), and disease control rate (DCR) (OR, 1.16; 95% CI, 0.47-2.89; P = 0.74). CDK4/6 inhibitors plus NET indicated a high risk of neutropenia (OR, 56.43; 95% CI, 15.76-202.11; P < 0.001) as an adverse effect (AE) and elevated alanine aminotransferase (ALT) level (OR, 15.30; 95% CI, 2.02-115.98; P = 0.008) as grade 3/4 AEs. Compared with NET/NACT alone, CDK4/6 inhibitors plus NET increased CCCA rate in ER + /HER2- EBC patients. CDK4/6 inhibitors plus NET did not substantially improve the PEPI-0 rate, pCR rate, ORR, or DCR. The combination increased the risk of neutropenia and elevated ALT levels. In the neoadjuvant setting, addition of CDK4/6 inhibitors to NET may be an option for treating ER + /HER2- EBC.

Feasibility of a pharmacist-led symptom monitoring and management intervention to improve breast cancer endocrine therapy adherence

BackgroundAdjuvant endocrine therapy (AET) for breast cancer reduces mortality, but one-third to one-half of patients discontinue it early or are nonadherent. ObjectiveWe developed a pilot single-site study of patients with evidence of early nonadherence to AET to assess the feasibility of a novel, clinical pharmacist-led intervention targeting symptom and medication management. MethodsPatients with prescription fill records showing nonadherence were enrolled in a single-arm feasibility study. Automated reminders were sent by e-mail or text with a link to symptom monitoring assessments weekly for 1 month and monthly until 6 months. Clinical oncology pharmacists used guideline-based symptom management and other medication management tools to support adherence and ameliorate symptoms reported on the assessments. Patient-reported outcome assessments included physical, mental, and social health domains and self-efficacy to manage symptoms and medications. Feasibility outcomes included completion of symptom reports and pharmacist recommendations. ResultsOf 19 participants who were nonadherent who enrolled and completed initial assessments, 18 completed all final study procedures, with 14 completing all assessments and no patient missing more than 3 assessments. All 18 participants reported at least one of 3 symptom types, and the majority reported attempting pharmacist recommendations. Patient-reported measures of physical, mental, and social health and self-efficacy improved, and 44% of the patients became adherent. ConclusionAn intervention using pharmacists in an oncology practice to systematically monitor and manage symptoms shows promise to reduce symptoms, enhance support and self-efficacy, and improve adherence to AET.

Characterizing Beliefs About Breast Cancer and Comorbid Diabetes After Cancer Treatment.

To investigate how breast cancer survivors with comorbid diabetes mellitus (diabetes) conceptualize their illnesses. 19 community-dwelling, English- or Spanish-speaking women with diabetes in New York, New York, who received chemotherapy or hormone therapy for stage I-IIIA breast cancer in the past five years. Semistructured interviews were administered by trained research staff, and were audio recorded and transcribed. Three coders reviewed transcripts through an iterative coding process. An interpretive descriptive approach was used to identify themes. Major themes included an inverse relationship between illness control and concern, variation in perceived illness permanence, and differences in illness consequences. Women with a greater perceived control over breast cancer viewed their diabetes as a larger concern; others felt that their breast cancer could not be controlled but diabetes could. Understanding how breast cancer survivors view diabetes and cancer may explain the variation in survivors' self-management behaviors, and how it may influence their attitudes and behaviors in the context of cancer treatment.

Interstitial lung disorders following postoperative radiotherapy with concurrent or sequential hormonal therapy for breast cancer: a nationwide database study in Japan.

Hormonal therapy and radiotherapy are conducted concurrently or sequentially after breast cancer surgery. It remains unclear whether concurrent or sequential treatment is safer in terms of lung complications. Using a Japanese nationwide database, this study aimed to compare the occurrence of severe lung complications between concurrent and sequential treatments. We identified patients who underwent partial mastectomy for stage 0-III breast cancer from July 2010 to March 2020 and received adjuvant hormonal therapy and radiotherapy concurrently (n = 1851) or sequentially (n = 18,429). Two propensity score analyses (1:4 matching and overlap weighting) were conducted to compare hospitalization for radiation pneumonitis and pneumonia within 1year after surgery, and intensive care unit admission and mortality during the hospitalization. We conducted additional analyses stratified by hormonal drugs (aromatase inhibitors and tamoxifen). The propensity score-matched analysis showed no significant differences in occurrence of hospitalization for radiation pneumonitis (0.27 vs. 0.58%, p = 0.10) and pneumonia (0.16 vs. 0.58%, p = 0.05) between the concurrent and sequential treatments. The overlap propensity score-weighted analysis also showed no significant differences (0.25 vs. 0.56%, p = 0.08 and 0.15 vs. 0.44%, p = 0.06, respectively). Intensive care unit admission and in-hospital mortality did not differ significantly between the two treatments. The stratified analysis showed similar results. Our propensity score analyses revealed no significant differences in severe lung complications between concurrent and sequential hormonal therapy with radiotherapy following breast cancer surgery, regardless of the type of hormonal drugs. Clinicians can provide concurrent or sequential treatment with equivalent attention to early lung complications.

Abstract P4-12-14: Assessing patients perceptions on hormone therapy for breast cancer: Insights from a Brazilian patient group

Abstract Introduction Breast cancer has a high incidence in the population, and it still is a major cause of mortality among women. About 2/3 of these tumors express hormone receptor which are important therapeutical targets for both adjuvant and metastatic settings. Hormone therapy (HT) is an important strategy for adjuvant treatment in breast cancer, enhancing disease-free and overall survival. But the side effects of this strategy are multiple, especially by mimicking or intensifying menopausal symptoms, which can substantially compromise quality of life of patients. Moreover, treatment of women with breast cancer is rising both in intensity and extension, maximizing hormone deprivation effects. Another major factor is patient adherence as it is known that about 50% of women don’t complete the whole treatment. Bad adherence occurs mainly because side effects are poorly controlled, either being neglected or less valued during medical check-ups. Outside clinical trials, there is not enough data of patients’ perceptions about HT. Objective To evaluate adherence, side effects and medical care perceptions of breast cancer patients in use of HT. Method A questionnaire was developed and applied online to users of Oncoguia, an NGO for cancer patient’s advocacy. The adhesion was volunteer and individual data were not identified. Primarily qualitative analysis was performed to identify patterns in no meeting needs of patients using HT for breast cancer. Results 310 answers were submitted from February to July of 2020. 84.1% of patients (261) referred having used HT. Tamoxifen was used in 47.5% of these, aromatase inhibitor in 29% and double blockage in 8.1%. Related to orientation about side effects, 43.2% consider they were properly orientated, 25% superficially and 11.2% weren’t oriented. 50% of women who previously didn’t exercise started physical activities after HT. Of those who were previously active, 73,4% kept regular exercises during HT. Considering weight gain, 63% of women who didn’t have prior problems experienced trouble with weight gain; and in those who already had issues with weight there were persistence in 71.7%. For patients with normal libido before HT, 42,9% noticed reduction and 36,4% of them considered the libido absent after onset of treatment. When vaginal dryness was addressed, 75% of women had it as a new symptom. Hot flashes onset on 86.5% of women who previously didn’t present it.Humor distress wise 67.9% of patients considered they developed irritability, prior inexistent, in use of HT. Depression or depressive episodes were related by 45.5% of patients without personal history of these disturbers and by 65.2% of patients with depressive personal history.When asked about how much the symptoms interfered in their daily lives, 45.2% consider a huge/considerable interference, 32% a little interference and only 5.8% of women considered symptoms didn’t interfere on their daily lives. Discussion Bringing patients to the center of treatment, more than aiming better therapeutic results, also includes listening to their needs and perceptions about it. Outside clinical trials, there is few information about adherence to HT and factors that leads to HT drop. Surveys applied to oncologic communities may reveal concerns and perceptions that can be differently influenced by local characteristics. This kind of survey can open a window of opportunity for actions directly focused on patients demands. Conclusion Real life data has the potential to direct educational actions for patients and health professionals, according to the specifics perceptions of patient community, aiming for adherence and consequent better treatment results. Citation Format: Marina S Montemor, Lycia TV Neumann, Anna CA Siqueira, Luciana HC Barros, Solange M Sanches. Assessing patients perceptions on hormone therapy for breast cancer: Insights from a Brazilian patient group [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 P4-12-14.

Abstract P4-10-01: Quality of life and symptom severity in the PALLAS randomized trial of palbociclib with adjuvant endocrine therapy in early breast cancer (AFT-05)

Abstract P4-10-01: Quality of life and symptom severity in the PALLAS randomized trial of palbociclib with adjuvant endocrine therapy in early breast cancer (AFT-05)

Abstract P2-01-04: Esr1 hotspot mutations in circulating tumor DNA mutation are associated with endocrine therapy resistance in metastatic breast cancer

Abstract Introduction: Metastatic breast cancer (MBC) is a challenging clinical condition because most tumors will develop resistance to endocrine treatment as the cancer progresses. We previously reported the correlation of ESR1 mutations in circulating tumor DNA (ctDNA) and CTCs resulted in worse prognosis in MBC (ASCO-2020). In this study, we report a new finding that specific hotspots of ESR1 ctDNA mutations are associated with endocrine therapy resistance status in MBC and their allele frequency (AF) can be used to monitor response. . Methods: Plasma cfDNA were collected from a total of 299 MBC patients (2016-2019) after informed consent under an IRB-approved trial at the Lurie Cancer Center at Northwestern University. ER+ patients are 180 out of 297 (61%). Patients with HR+ MBC were evaluated before endocrine therapy (Anastrozole, Exemestane and Letrozole ) +/- CDK4/6 inhibitors (Palbociclib, Ribociclib, Abemaciclib), and every six months after initiation of therapy. Response to therapy was recorded according to the different time points. Endocrine resistance is defined as relapse during the first 2 years of adjuvant endocrine therapy or progressive disease within the first 6 months of first-line endocrine therapy for metastatic breast cancer. Plasma ctDNA was isolated using a Qiagen circulating nucleic acid kit, and then was analyzed using the Guardant360 Health next-generation sequencing (NGS)-based assay (Guardant Health). In this study, only patients with ESR1 mutations were included for statistical analyses of correlation between the hotspots mutation with the endocrine therapy resistance by using Causal Inference approach. All statistical analyses were conducted Mann-Whitney U test by IBM SPSS version 23.0. Results: There were total of 239 ESR1 ctDNA mutations detected in 18 hotspots from 42 patients at different time points, among which there were 131 endocrine therapy resistance status in all time points. The numbers of ESR1 hotspots mutations and the corresponding endocrine therapy resistance cases were found in the following hotspots respectively as Q314 (3 cases with mutation, 0 cases with resistance), T347T (4, 0), N359I (4, 0), K362N (4, 0), E380Q(32, 16), V392I (1, 1), G442R(3, 0), F461I(3, 0), S463P (3, 2), S464 (1, 0), I487M(14, 0), K520K (2, 0), M528V (5, 0), L536H (31, 19), Y537N/C/S (46, 34), D538G (77, 59), D545D(2, 0) and Q565 (4, 0). There were 50%, 61.2%, 73.9% and 76.6% patients developed endocrine therapy resistance when they had E380Q, L536H, Y537N/C/S and D538G mutations respectively at any time points. Furthermore, among these 4 hotspot mutations, the MBC patients with lack of response to endocrine therapy have significantly higher percentage of mutated DNA than the patients with sensitive response. For the patients with E380Q mutation, the mean percentage of mutation DNA was 8.44% for those with lack of response and lower than 0.01% for those with sensitive response (P&amp;lt;0.001). For the patients with L536H mutation, the mean percentage of mutation DNA was 3.48% for those with lack of response and lower than 0.01% for those with sensitive response (P&amp;lt;0.001). For the patients with Y537N/C/S mutation, the mean percentage of mutation DNA was 5.23% for those with lack of response and 0.02% for those with sensitive response (P&amp;lt;0.001). For the patients with D538G mutation, the median percentage of mutation DNA was 5.13% for those with lack of response and 0.01% for those with sensitive response (P&amp;lt;0.001). Conclusions: The outcome of this study demonstrated that patients with mutations on known ESR1 hotspots (E380Q, L536H, Y537N/C/S and D538G) develop clinical resistance to endocrine therapy. Evaluation of these ESR1 hotspots mutations by ctDNA could be reliably used to monitor the response to endocrine therapy and predict the prognosis for MBC patients. Citation Format: Qiang Zhang, Paolo D'Amico, Weijun Qin, Jianhua Jiao, Andrew A. Davis, Lorenzo Gerratana, Saya L. Jacob, Youbin Zhang, Jeannine Donahue, Wenan Qiang, Ami N. Shah, Amir Behdad, Lisa Flaum, William Gradishar, Leonidas C Platanias, Massimo Cristofanilli. Esr1 hotspot mutations in circulating tumor DNA mutation are associated with endocrine therapy resistance in metastatic breast cancer [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 P2-01-04.

Abstract P2-15-01: Conversion from luminal to normal intrinsic subtype by PAM50 after neoadjuvant endocrine therapy is associate with biomarkers of good prognosis in luminal breast cancer

Abstract Background. Neoadjuvant endocrine therapy (NET) in luminal breast cancer (LBC) is the perfect scenario for real-time evaluation of the biological and molecular changes that occur after estrogenic deprivation. This evaluation is mainly performed in surgical specimens after NET and has been used as a research tool to obtain prognostic and predictive information using tumor response to decide adjuvant treatment. Nevertheless, there are not many validated biomarkers in this setting to predict response beyond Ki67 levels and modified Preoperative Prognostic Index (mPEPI score) after treatment. Hence, the aim of this study is to determine if changes in mRNA-based PAM50 analysis (intrinsic subtype) after NET in LBC correlate with such biomarkers. Methods. We collected a series of postmenopausal ER+/HER2- breast cancer patients (n=58) treated for at least 4 months with NET before surgery. Next, we performed gene expression analysis by PAM50 accompanied by pathological characterization of surgical tumor specimens and immunohistochemistry characterization of ER and Ki67 levels, both at diagnosis and in surgery specimen. Finally, we studied the association of our results with clinical and histopathological features and with validated biomarkers for endocrine response, such as mPEPI score and changes in Ki67 levels. Results. The distribution of changes in intrinsic subtype determined by PAM50 after NET is presented in Table 1. We observed that tumors that changed from luminal to a normal intrinsic subtype showed larger changes in Ki67 levels after NET and reduced percentage of Ki67 positive cells at surgery, compared to those that presented a luminal persistent status: both analysis P&amp;lt;0.0001 (Mann-Whitney test). Similarly, we found a statistical association between lower mPEPI score in those tumors that change from luminal to a normal intrinsic subtype compared to those that presented a luminal persistent status: P=0.0034 (Mann-Whitney test). Moreover, in agreement with these results, we also studied ROR-P (PAM50 risk of recurrence (ROR) of subtype plus proliferation) in tumors that change from luminal to a normal intrinsic subtype and in those that presented a luminal persistent status. Results showed the same trends as the ones observed for Ki67-related parameters and mPEPI. Conclusions. PAM50 analysis revealed that changes from luminal A and luminal B to normal intrinsic subtype are associated with response to NET, measured by different well-established parameters. This result gives us clues to further explore which genes are orchestrating these changes and their impact on clinical outcomes. However, more analyses should be performed to determine the relationship between ROR and parameters used to measure response in NET in order to validate the results presented. In conclusion, our data support that the determination of the changes in gene expression profile using PAM50, before and after NET, can be used as a tool to predict response, conjointly with other clinical parameters. Table 1.- Intrinsic subtypes determined by PAM50 in samples pre and post NETPAM50 PREPAM50 POSTNO.%PERSISTANT LUMINAL STATUSCHANGE FROM LUMINAL TO A NOLMAL INTRINSIC SUBTYPELumALumA2136YESLumANormal1526YESLumALumB35YESLumBLumA610YESLumBNormal35YESLumBLumB59YESHER2HER223NANAHER2LumA12NANALumAHER212NANANormalNormal12NANATOTAL58100Lum=LuminalNA= Not applicable Citation Format: Joanna Ines Lopez Velazco, María Otaño, Inazio Lacambra, Kepa Elorriaga, Ainhara Lahuerta, Ana Martínez, Virginia Segur, Sara Manzano, Aleix Prat, María Caffarel, Ander Urruticoechea. Conversion from luminal to normal intrinsic subtype by PAM50 after neoadjuvant endocrine therapy is associate with biomarkers of good prognosis in luminal breast cancer [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 P2-15-01.

Abstract PD9-08: Prognostic value of EndoPredict test in patients screened for UNIRAD, a UCBG randomized, double blind, phase III international trial evaluating the addition of everolimus (EVE) to adjuvant hormone therapy (HT) in women with high risk HR+, HER2- early breast cancer (eBC)

Abstract Background: The double blind randomized UNIRAD trial (NCT01805271) showed no evidence that adding Everolimus (EVE) to adjuvant endocrine therapy (EHT) for high-risk early breast cancer (BC) improved 3-year disease-free survival (iDFS) compared with EHT alone. In this trial, high risk was defined by any T and either ≥4N+, or ≥1N+ after neoadjuvant treatment, or ≥1N+ and EPclin high risk (EPCH) score ≥3.3. This sub analysis is aimed to verify prognostic added value of EndoPredict test results on outcomes in patients screened for the UNIRAD study.. Material and methods: From May 2015 to March 2020, 777 patients were screened with the EndoPredict test. Complete results were obtained for 767 of them. 662 pts were classified as EPCH and 429 were randomized in UNIRAD. 233 pts with EPCH and 105 pts with EPclin low risk (EPCL) were not randomized but followed up for iDFS. Statistical analysis: Kaplan-Meier estimates the association of the integrated molecular-clinico-pathologic EPclin score, and the 12-gene molecular EP score, with iDFS (primary endpoint) and dMFS (secondary endpoint). Independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics (Grade and T, N). A two-sided p-value less than 0.05 considered as statistically significant, 95% confidence intervals reported with HR. Results: Median follow-up of the cohort was 36.6 mo (0-69) since EndoPredict test. As for the whole population, there was no significant difference in iDFS between treatment arms in the randomized EPCH group. On the other hand, EPclin was an independent prognostic factor for iDFS. 36 mo relapse rate from testing for patients in the EPCL group and the EPCH group was 0% and 7%, respectively (HR supposing continuous EPclin score: 2.36, 95%CI: 1.7-3.3, p &amp;lt; .0001). This difference remained significant when assessed in a cox model with tumor size, number of positive nodes and tumor grade (HR: 1.96, 95%CI: 1.32-2.9, p=0.0008). Furthermore, EPclin results was independently correlated to distant metastatic free survival: 36 mo dMFS for patient in the EPCL and EPCH group was 100% and 94%, respectively (adjusted HR: 2.13, 95%CI:11.3-3.4, p = .0014). Of interest when assessing prognostic of patients within quartiles of EPclin Score (&amp;lt;3.6; 3.6-4.1; ≥4.1-4.8; ≥ 4.8), 36 mo iDFS was 99%; 95%; 94% and 86%, respectively. Conclusion: These prospective results confirm the significance of EPclin score as an independent prognostic parameter in node positive ER+/HER2- eBC patients receiving standard adjuvant treatment. This information can be of importance for selection of specific adjuvant intervention, particularly chemotherapy and new targeted therapy. Further analysis on the EP score will be presented at the meeting. Citation Format: Frederique Penault-Llorca, Florence Dalenc, Sylvie Chabaud, Paul Cottu, Djelila Allouache, David Cameron, Jean-Philippe Jacquin, Julien Grenier, Laurence Venat Bouvet, Apurna Jegannathen, Mario Campone, Francesco Del Piano, Marc Debled, Anne-Claire Hardy-Bessard, Sylvie Giacchetti, Philippe Barthelemy, Laure Kaluzinski, Audrey Mailliez, Marie-Ange Mouret-Reynier, Eric Legouffe, Anne Cayre, Mathilde Martinez, Catherine Delbaldo, Delphine Mollon-Grange, E. Jane Macaskill, Matthew Sephton, Laëtitia Stefani, Blaha Belgadi, Matthew Winter, Hubert Orfeuvre, Magali Lacroix-Triki, Herve Bonnefoi, Judith Bliss, Jean-Luc Canon, Jerome Lemonnier, Fabrice Andre, Thomas Bachelot. Prognostic value of EndoPredict test in patients screened for UNIRAD, a UCBG randomized, double blind, phase III international trial evaluating the addition of everolimus (EVE) to adjuvant hormone therapy (HT) in women with high risk HR+, HER2- early breast cancer (eBC) [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 PD9-08.